Name: 155899-66-4|(3aR,4S,6R,6aS)-6-Amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol|97%
Brand: Ambeed
SKU: A199601
Price: 19.0 USD
Availability: InStock
Rating: 96 (22 reviews)

1
[ 155855-53-1 ]
[ 155899-66-4 ]

Yield	Reaction Conditions	Operation in experiment
88%	With palladium 10% on activated carbon; hydrogen In methanol at 30℃; for 5h;	21 Example 21 : Preparation of (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclo- penta[d][1 ,3]dioxol-4-ol (H) A mixture of (1 .0 g), 10 % Pd/C (0.10 g) and methanol (10 mL) was stirred under hydrogen (3 bar) at 30 °C for 5 hours. The palladium on charcoal was removed by filtration ant the solvent was removed to give H (0.59 g, 88 %).
88%	With palladium 10% on activated carbon; hydrogen In methanol at 30℃; for 5h;	15 Preparation of (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclo-penta[d][1,3]dioxol-4-ol (IX) A mixture of VIII' (1.0 g), 10 % Pd/C (0.10 g) and methanol (10 mL) was stirred under hydrogen (3 bar) at 30 °C for 5 hours. The palladium on charcoal was removed by filtration ant the solvent was removed to give IX (0.59 g, 88 %).
75%	With ammonium formate In methanol for 1h; Heating;

Reference： [1]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - WO2013/92900, 2013, A1 Location in patent: Page/Page column 52
[2]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - EP2666771, 2013, A1 Location in patent: Paragraph 0079; 0080
[3]Gallos, John K.; Goga, Efthymia G.; Koumbis, Alexandros E. [Journal of the Chemical Society. Perkin transactions I, 1994, # 6, p. 613 - 614]

2
[ 194220-59-2 ]
[ 155899-66-4 ]

Yield	Reaction Conditions	Operation in experiment
58%	With lithium aluminium tetrahydride In tetrahydrofuran for 72h; Heating;

Reference： [1]Marco-Contelles, Jose; Rodriguez-Fernandez, Ma. Mercedes [Tetrahedron Asymmetry, 1997, vol. 8, # 13, p. 2249 - 2256]

3
[ 24424-99-5 ]
[ 155899-66-4 ]
[ 324535-98-0 ]

Yield	Reaction Conditions	Operation in experiment
94%	In water at 20℃; for 6h; Cooling with ice; Industrial scale;	1-3 Preparation of compound III 865 g of compound II and 2000 mL of water were added to the 5L four-necked flask, and 1200 g of di-t-butyl dicarbonate was added dropwise under an ice bath. After stirring at room temperature for 6 hours, the ice bath was held for 2 hours. The resulting solid was filtered with suction, washed with water, and dried under vacuum to obtain 1284 g of compound III in a yield of 94%.
0.136 g	With sodium carbonate In tetrahydrofuran; water for 2h;
	With sodium carbonate In tetrahydrofuran; water at 20℃;	1 Compound 2 (100 g,) was dissolved in THF (2-15V). A solution of water (2-15V) and sodium carbonate (67.4 g) was added to the solution. The resulting mixture was stirred at room temperature, followed by dropwise addition of Boc-anhydride (138.77g) The reaction mixture was agitated for 1-3 hrs. Then the aqueous and organic layers were separated. The organic layer was concentrated to produce a residue, which was crystallized to produce compound 3 (149.1 g).1H NMR (400 MHz, CDC13 ): δ 5.44 (d, J = 8 Hz, 1H), 4.57-4.49 (m, 2H), 4.27 (t, J = 4Hz, 1H), 4.09 (brs, 1H), 2.55 (brs, 1H), 2.22 (brs, 1H), 1.68 (d, J = 16Hz, 1H), 1.45 (s, 9H), 1.41 (s, 3H), 1.26 (s, 3H). 13C NMR (100 MHz, CDC13) δ 155.20, 110.17, 86.23, 35.47, 28.44, 26.23, 23.85.

Reference： [1]Current Patent Assignee: ZHEJIANG LEPU PHARMACEUTICAL CO LTD - CN110627765, 2019, A Location in patent: Paragraph 0041-0052
[2]Shireman; Miller [Tetrahedron Letters, 2000, vol. 41, # 49, p. 9537 - 9540]
[3]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2 Location in patent: Page/Page column 37

4
[ 190517-38-5 ]
[ 155899-66-4 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen In methanol for 0.5h;

Reference： [1]Shireman; Miller [Tetrahedron Letters, 2000, vol. 41, # 49, p. 9537 - 9540]

5
[ 380307-23-3 ]
[ 155899-66-4 ]

Yield	Reaction Conditions	Operation in experiment
92%	With methylamine In ethanol for 2h; Heating;
	With ammonia In methanol for 6h;
	With hydrazine hydrate In ethanol at 60 - 65℃; for 10h;	6 Preparation of (3aR,4S,6R,6aS)-6-Amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d] [1,3]- dioxol-4-ol A solution of (lS,2R,3S,4R)-(N-phthalimidyl)-2,3-0-isopropylidenecyclopentane-l,2,3-triol (15 g) in ethanol (75 ml) and hydrazine hydrate (10 ml) was stirred for 10 hours at 60-65°C. After completion of the reaction, the reaction mass was cooled to 0-5°C, the precipitated solid was filtered and washed with ethanol (15 ml). The filtrate was concentrated under reduced pressure to give a residue and the residue was dissolved in ethanol (30 ml). The resulting mass was cooled to 0-5°C, the separated solid was filtered and washed with chilled ethanol (7 ml). The filtrate obtained was concentrated and the residue was stirred with diisopropyl ether (20 ml), followed by filtration and drying to produce 7 g of (3aR,4S,6R,6aS)-6-amino-2,2- dimethyltetrahydro-3aH-cyclopenta[d][l,3]-dioxol-4-ol (Chemical purity by GC: 97.1%; and Optical purity by GC: 98.2%).

170 mg	With hydrazine hydrate In ethanol at 70℃; for 2h;	1366.4 Step 4 Compound 1366d (300 mg, 0.98 mmol) was dissolved in ethanol (5 mE) and treated with hydrazine monohydrate (0.5 mE). The reaction was stirred at 70 C for 2 hours. Aftercooling to rt, the solids were filtered and the filtrate wasconcentrated to provide 170 mg of compound 1366e. [M+H]174.17
	With hydrazine In ethanol at 70℃; for 2h;	1366.4 Compound 1366d (300 mg, 0.98 mmol) was dissolved in ethanol (5 mL) and treated with hydrazine monohydrate (0.5 mL). The reaction was stirred at 70 C for 2 hours. After cooling to rt, the solids were filtered and the filtrate was concentrated to provide 170 mg of compound 1366e. [M+H] = 174.17.

Reference： [1]Rajappan; Hegde; Schneller [Synthetic Communications, 2001, vol. 31, # 18, p. 2849 - 2854]
[2]Yin, Xueqiang; Schneller, Stewart W [Nucleosides, nucleotides and nucleic acids, 2004, vol. 23, # 1-2, p. 67 - 76]
[3]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/63126, 2012, A2 Location in patent: Page/Page column 22-23
[4]Current Patent Assignee: SOUTHERN RESEARCH INSTITUTE; MERCK & CO INC - US9433621, 2016, B2 Location in patent: Page/Page column 186; 187; 188
[5]Current Patent Assignee: MERCK & CO INC; SOUTHERN RESEARCH INSTITUTE - WO2010/22121, 2010, A1 Location in patent: Page/Page column 209

6
[ 155899-66-4 ]
[ 53449-14-2 ]
[ 395066-45-2 ]

Reference： [1]Tetrahedron,2001,vol. 57,p. 9049 - 9053

7
[ 155855-51-9 ]
[ 155899-66-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With palladium 10% on activated carbon; hydrogen In methanol at 30℃; for 18h;	19 Example 19: Preparation of (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclo- penta[d][1 ,3]dioxol-4-ol (H) A mixture of G' (60.0 g), 10 % Pd/C (6.0 g) and methanol (0.60 L) was stirred under hydrogen (3 bar) at 30 °C for 18 hours. The palladium on charcoal was removed by filtration ant the solvent was removed to give H (40 g, 100 %). 1 H NMR (CDCI3): δ 1 .29 (s, 3H), 1 .40 (s, 3H), 1 .58 (m, 1 H), 1 .65 (m, 1 H), 2.09 (m, 1 H), 3.60 (m, 1 H), 4.09 (m, 1 H), 4.41 (m, 1 H), 4.69 (m, 1 H) ppm.
100%	With palladium 10% on activated carbon; hydrogen In methanol at 30℃; for 18h;	13 Preparation of (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclo-penta[d][1,3]dioxol-4-ol (IX) A mixture of VII' (60.0 g), 10 % Pd/C (6.0 g) and methanol (0.60 L) was stirred under hydrogen (3 bar) at 30 °C for 18 hours. The palladium on charcoal was removed by filtration ant the solvent was removed to give IX (40 g, 100 %). 1H NMR (CDCl3): δ 1.29 (s, 3H), 1.40 (s, 3H), 1.58 (m, 1H), 1.65 (m, 1H), 2.09 (m, 1H), 3.60 (m, 1H), 4.09 (m, 1H), 4.41 (m, 1H), 4.69 (m, 1H) ppm.
98%	With hydrogen; ammonium formate In methanol at 20℃; for 2h;

92.3%	With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 14h;	(3aR-(3aα,4α,6α,6aα)]-6-Amino-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxo14-ol (18) A solution of 17 (100 mg, 0.38 mmol, 1 eq) in methanol (2 mL) was hydrogenated for 14 h at r.t. over 10% palladium on carbon (15 mg). The reaction mixture was then filtered, and the collected solids were washed with methanol (1 mL). The combined filtrate was concentrated under reduced pressure to give the title product as a colorless oil, which could be recrystallized by PE to give a white solid (60 mg, 92.3% yield). 1H NMR (500 MHz, CDCl3) δ 1.29 (3 H, s), 1.40 (3 H, s), 1.61~1.66 (1 H, d), 2.06~2.13 (1 H, m), 2.63 (2 H, s), 3.60~3.61 (1 H, d), 4.09~4.10 (1 H, d), 4.40~4.42 (1 H, d), 4.68~4.70 (1 H, d). EI-MS m/z 174.1 (M+H)+.
	Multi-step reaction with 2 steps 1: 78 percent / Zn, AcOH / diethyl ether / 48 h / Ambient temperature 2: 75 percent / ammonium formate / Pd/C / methanol / 1 h / Heating
	Multi-step reaction with 2 steps 1.1: zinc; acetic acid / diethyl ether / 72 h / 0 - 25 °C 1.2: pH 7.2 2.1: hydrogen; palladium 10% on activated carbon / methanol / 5 h / 30 °C / 2250.23 Torr
	Multi-step reaction with 2 steps 1: zinc; acetic acid / diethyl ether / 72.48 h / 0 - 25 °C 2: palladium 10% on activated carbon; hydrogen / methanol / 5 h / 30 °C / 2250.23 Torr

Reference： [1]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - WO2013/92900, 2013, A1 Location in patent: Page/Page column 51
[2]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - EP2666771, 2013, A1 Location in patent: Paragraph 0074; 0075
[3]Gallos, John K.; Stathakis, Christos I.; Kotoulas, Stefanos S.; Koumbis, Alexandros E. [Journal of Organic Chemistry, 2005, vol. 70, # 17, p. 6884 - 6890]
[4]Zhang, Hao; Liu, Jun; Zhang, Luyong; Kong, Lingyi; Yao, Hequan; Sun, Hongbin [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 11, p. 3598 - 3602]
[5]Gallos, John K.; Goga, Efthymia G.; Koumbis, Alexandros E. [Journal of the Chemical Society. Perkin transactions I, 1994, # 6, p. 613 - 614]
[6]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - WO2013/92900, 2013, A1
[7]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - EP2666771, 2013, A1

8
[ 2789-25-5 ]
[ 155899-66-4 ]
[ 701917-14-8 ]

Reference： [1]Nucleosides, nucleotides and nucleic acids,2004,vol. 23,p. 67 - 76

9
[ 501-53-1 ]
[ 155899-66-4 ]
[ 274693-53-7 ]

Yield	Reaction Conditions	Operation in experiment
68%	With sodium carbonate; In tetrahydrofuran; water; at 0℃;	Step 7[00113] benzyl (3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyl-tetrahydro-3aH-cyclopentar[d][1,3]dioxo-4-ylcarbamate: At about 0 0C, benzyl carbonochloridate (18.4 g, 107.86 mmol, 1.05 equiv.) was added to the solution of (3aR,4S,6R,6aS)-6-amino-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (17.0 g, 98.15 mmol, 1.00 equiv.) and sodium carbonate (20.8 g, 196.24 mmol, 2.00 equiv) in tetrahydrofuran : water (5:1) (600 mL). Standard extractive workup with ethyl acetate (3 x 200 mL) gave the title product as a white solid (20.5 g; yield = 68 %). 1H NMR (300 MHz, CDCl3) delta: 7.30-7.39 (m, 5 H), 5.20 (s, 2 H), 4.60 (d, / = 5.4 Hz, 1 H), 4.50 (d, / = 5.4 Hz, 1 H), 4.27 (s, 1 H), 4.19 (d, / = 5.7 Hz 1 H), 2.26 (m, 1 H), 1.71 (d, / = 14.4 Hz, 1 H), 1.47 (s, 3 H), 1.28 (s, 3 H).
	With N-ethyl-N,N-diisopropylamine; In 4-methyl-2-pentanone; at 20℃; for 2h;	Cbz-Cl (0.08 mL, 0.58 mmol, 1.0 eq) were added dropewise to a solution of 18 (100 mg, 0.58 mmol, 1.0 eq) in MIBK (2 mL), then DIPEA (0.20 mL, 1.16 mmol, 2.0 eq) was added dropewise. The resulting mixture was stirred at r.t. for 2 h. The solvent was removed by evaporation and the resulting oil was purified by column chromatography on silica gel (PE: EtOAc =2:1) to give the title product as a colorless oil. 1H NMR (300 MHz, CDCl3) delta 1.26 (3 H, s), 1.40 (3 H, s), 1.69 (1 H, d), 2.22 (1 H, s), 4.17~4.19 (1 H, m), 4.24~4.25 (1 H, m), 4.46 (1 H, d), 4.57 (1 H, d) 5.10 (2 H, s), 5.64 (1 H, s), 7.29~7.35 (5 H, m).
	With sodium carbonate; In water; 4-methyl-2-pentanone; at 20℃;Product distribution / selectivity;	Compound 2 (50 g) was dissolved in methylisobutylketone (MIBK) (900 mL). Water (1-5V mL) and potassium carbonate (47.80 g) were added, followed by dropwise addition of benzyl chloroformate (54.16 g). The reaction mixture was stirred at room temperature for 4-6 hours. The aqueous and organic layers were separated and the aqueous layer was extracted with MIBK. The combined organic layers were concentrated and the resulting residue was purified by crystallization in n-hexane give compound 2 (83.36g). ¾ NMR (400 MHz, CDCI3 ): delta 7.37-7.30 (m, 5H), 5.68 (brs, 1H), 5.11 (s, 2H), 4.60 (d, J = 4Hz, 1H), 4.49 (dd, J = 8Hz, J = 4Hz, lH), 4.28 (brs, 1H), 4.20 (t, J = 8Hz, 1H), 2.28- 2.06 (m, 2H), 1.73-1.69 (m, 2H), 1.42 (s, 3H), 1.29 (s, 3H). I3C NMR (100 MHz, CDC13) delta 155.58, 136.51, 128.53, 128.15, 110.30, 86.16, 86.05, 77.59, 66.74, 57.03, 35.33, 26.18, 23.80.

316.7 g	With potassium carbonate; In water; at 20℃; for 5.5h;	To a 5000 ml three-necked flask were added 196 lg of compound VI, 188 g of K2C03, 3000 ml of methyl isobutyl ketone, 974 mlWater, stirring at room temperature, dropping 213. 6g benzyl chloroformate, about 30min drop finished. The organic layer was washed with water and dried over anhydrous sodium sulfate (10 ml x 2). The mixture was suction filtered and evaporated to dryness under reduced pressure. The mixture was stirred with 800 ml of n-hexane, and the mixture was stirred at room temperature for 5 hours. Crystallization and suction filtration gave 316. 7 g of pale yellow solid compound VII.
2.68 g	With potassium carbonate; In water; ethyl acetate; at 0 - 20℃; for 3h;	Add in 250ml reaction flask(3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]-dioxol-4-ol(3.0g),60ml of ethyl acetate,Potassium carbonate (4.84 g).Cool to 0C,Add 20ml water,Dissolved and clarified.Benzyl chloroformate (3.6 g) was added dropwise at 0C.The end of the drip,Insulation 20min,Raise to room temperature and stir 3hour,Ethyl acetate extraction,The organic layer was washed once with 20 ml of water.The organic layer was concentrated under reduced pressure to give Compound a: 2.68 g.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 6013 - 6018
[2]Patent: WO2011/17108,2011,A2 .Location in patent: Page/Page column 38
[3]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3598 - 3602
[4]Patent: WO2012/138981,2012,A2 .Location in patent: Page/Page column 38
[5]Patent: CN106279095,2017,A .Location in patent: Paragraph 0023; 0046
[6]Patent: CN103626743,2018,B .Location in patent: Paragraph 0035-0038

10
C₅H₁₁NO₃*HCl [ No CAS ]
[ 77-76-9 ]
[ 155899-66-4 ]

Yield	Reaction Conditions	Operation in experiment
86%	With toluene-4-sulfonic acid In acetone

Reference： [1]Springthorpe, Brian; Bailey, Andrew; Barton, Patrick; Birkinshaw, Timothy N.; Bonnert, Roger V.; Brown, Roger C.; Chapman, David; Dixon, John; Guile, Simon D.; Humphries, Robert G.; Hunt, Simon F.; Ince, Francis; Ingall, Anthony H.; Kirk, Ian P.; Leeson, Paul D.; Leff, Paul; Lewis, Richard J.; Martin, Barrie P.; McGinnity, Dermot F.; Mortimore, Michael P.; Paine, Stuart W.; Pairaudeau, Garry; Patel, Anil; Rigby, Aaron J.; Riley, Robert J.; Teobald, Barry J.; Tomlinson, Wendy; Webborn, Peter J.H.; Willis, Paul A. [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 21, p. 6013 - 6018]

11
[ 155899-66-4 ]
(1'R,2'S,3'R,4'S)-7-amino-3-(2',3',4'-trihydroxycyclopent-1'-yl)-3H-imidazo[4,5-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 81 percent / triethylamine / butan-1-ol / 36 h / Heating 2: H₂ / Pd/C / ethanol / 20 °C / 2068.59 Torr 3: 320 mg / 2-methoxy-ethanol / 3 h / Heating 4: 75 percent / aq. HCl / methanol / 0.5 h / 20 °C

Reference： [1]Yin, Xueqiang; Schneller, Stewart W [Nucleosides, nucleotides and nucleic acids, 2004, vol. 23, # 1-2, p. 67 - 76]

12
[ 155899-66-4 ]
[ 701917-15-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 81 percent / triethylamine / butan-1-ol / 36 h / Heating 2: H₂ / Pd/C / ethanol / 20 °C / 2068.59 Torr 3: 320 mg / 2-methoxy-ethanol / 3 h / Heating

Reference： [1]Yin, Xueqiang; Schneller, Stewart W [Nucleosides, nucleotides and nucleic acids, 2004, vol. 23, # 1-2, p. 67 - 76]

13
[ 155899-66-4 ]
(3aR,4S,6R,6aS)-6-(3H-Imidazo[4,5-c]pyridin-4-ylamino)-2,2-dimethyl-tetrahydro-cyclopenta[1,3]dioxol-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 81 percent / triethylamine / butan-1-ol / 36 h / Heating 2: H₂ / Pd/C / ethanol / 20 °C / 2068.59 Torr 3: 180 mg / 2-methoxy-ethanol / 3 h / Heating

Reference： [1]Yin, Xueqiang; Schneller, Stewart W [Nucleosides, nucleotides and nucleic acids, 2004, vol. 23, # 1-2, p. 67 - 76]

14
[ 155899-66-4 ]
(3aR,4S,6R,6aS)-6-(3,4-Diamino-pyridin-2-ylamino)-2,2-dimethyl-tetrahydro-cyclopenta[1,3]dioxol-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 81 percent / triethylamine / butan-1-ol / 36 h / Heating 2: H₂ / Pd/C / ethanol / 20 °C / 2068.59 Torr

Reference： [1]Yin, Xueqiang; Schneller, Stewart W [Nucleosides, nucleotides and nucleic acids, 2004, vol. 23, # 1-2, p. 67 - 76]

15
[ 380307-22-2 ]
[ 155899-66-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: p-toluenesulfonic acid / acetone / 15 h 2: NH₃ / methanol / 6 h
	Multi-step reaction with 2 steps 1: 84 percent / p-TsOH / acetone / 20 °C 2: 92 percent / MeNH₂ / ethanol / 2 h / Heating
	Multi-step reaction with 2 steps 1: toluene-4-sulfonic acid / acetone / 4 h / 25 - 30 °C 2: hydrazine hydrate / ethanol / 10 h / 60 - 65 °C

	Multi-step reaction with 2 steps 1: methanesulfonic acid / acetone / 3 h 2: hydrazine hydrate / ethanol / 2 h / 70 °C
	Multi-step reaction with 2 steps 1: methanesulfonic acid / acetone / 3 h 2: hydrazine / ethanol / 2 h / 70 °C

Reference： [1]Yin, Xueqiang; Schneller, Stewart W [Nucleosides, nucleotides and nucleic acids, 2004, vol. 23, # 1-2, p. 67 - 76]
[2]Rajappan; Hegde; Schneller [Synthetic Communications, 2001, vol. 31, # 18, p. 2849 - 2854]
[3]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/63126, 2012, A2
[4]Current Patent Assignee: SOUTHERN RESEARCH INSTITUTE; MERCK & CO INC - US9433621, 2016, B2
[5]Current Patent Assignee: MERCK & CO INC; SOUTHERN RESEARCH INSTITUTE - WO2010/22121, 2010, A1

16
[ 345898-95-5 ]
[ 155899-66-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 730 mg / chlorobenzene / 135 °C 2: 98 percent / hydrogen; HCO₂NH₄ / Pd/C / methanol / 2 h / 20 °C
	Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide; toluene / 5 h / 110 °C 2: palladium 10% on activated carbon; hydrogen / methanol / 14 h / 20 °C
	Multi-step reaction with 2 steps 1: toluene / 5 h / Reflux 2: hydrogen; palladium 10% on activated carbon / methanol / 18 h / 30 °C / 2250.23 Torr

	Multi-step reaction with 3 steps 1.1: toluene / 5 h / Reflux 2.1: zinc; acetic acid / diethyl ether / 72 h / 0 - 25 °C 2.2: pH 7.2 3.1: hydrogen; palladium 10% on activated carbon / methanol / 5 h / 30 °C / 2250.23 Torr
	Multi-step reaction with 2 steps 1: toluene / 5 h / Reflux 2: palladium 10% on activated carbon; hydrogen / methanol / 18 h / 30 °C / 2250.23 Torr
	Multi-step reaction with 3 steps 1: toluene / 5 h / Reflux 2: zinc; acetic acid / diethyl ether / 72.48 h / 0 - 25 °C 3: palladium 10% on activated carbon; hydrogen / methanol / 5 h / 30 °C / 2250.23 Torr
	Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / 2 h / Reflux 2: ammonium formate; palladium 10% on activated carbon / methanol / 1.5 h / Reflux

Reference： [1]Gallos, John K.; Stathakis, Christos I.; Kotoulas, Stefanos S.; Koumbis, Alexandros E. [Journal of Organic Chemistry, 2005, vol. 70, # 17, p. 6884 - 6890]
[2]Zhang, Hao; Liu, Jun; Zhang, Luyong; Kong, Lingyi; Yao, Hequan; Sun, Hongbin [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 11, p. 3598 - 3602]
[3]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - WO2013/92900, 2013, A1
[4]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - WO2013/92900, 2013, A1
[5]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - EP2666771, 2013, A1
[6]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - EP2666771, 2013, A1
[7]Current Patent Assignee: CHONGQING SHENGHUAXI PHARMACEUTICALS CO LTD; CHONGQING HUIZHI PHARMACEUTICAL RES INST - CN106279095, 2017, A

17
[ 38838-06-1 ]
[ 155899-66-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: Zn / aq. ethanol / 1 h / Heating 2: Na₂CO₃ / aq. ethanol / 20 °C 3: 730 mg / chlorobenzene / 135 °C 4: 98 percent / hydrogen; HCO₂NH₄ / Pd/C / methanol / 2 h / 20 °C
	Multi-step reaction with 5 steps 1: Zn / aq. ethanol / 1 h / Heating 2: aq. ethanol / 0.25 h / Ambient temperature 3: chlorobenzene / 0.5 h / Heating 4: 78 percent / Zn, AcOH / diethyl ether / 48 h / Ambient temperature 5: 75 percent / ammonium formate / Pd/C / methanol / 1 h / Heating
	Multi-step reaction with 3 steps 1.1: zinc / ethanol / 1.5 h / Reflux 1.2: 0.83 h / 15 °C 2.1: N,N-dimethyl-formamide / 2 h / Reflux 3.1: ammonium formate; palladium 10% on activated carbon / methanol / 1.5 h / Reflux

Reference： [1]Gallos, John K.; Stathakis, Christos I.; Kotoulas, Stefanos S.; Koumbis, Alexandros E. [Journal of Organic Chemistry, 2005, vol. 70, # 17, p. 6884 - 6890]
[2]Gallos, John K.; Goga, Efthymia G.; Koumbis, Alexandros E. [Journal of the Chemical Society. Perkin transactions I, 1994, # 6, p. 613 - 614]
[3]Current Patent Assignee: CHONGQING SHENGHUAXI PHARMACEUTICALS CO LTD; CHONGQING HUIZHI PHARMACEUTICAL RES INST - CN106279095, 2017, A

18
[ 155934-55-7 ]
[ 155899-66-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: Na₂CO₃ / aq. ethanol / 20 °C 2: 730 mg / chlorobenzene / 135 °C 3: 98 percent / hydrogen; HCO₂NH₄ / Pd/C / methanol / 2 h / 20 °C
	Multi-step reaction with 4 steps 1: aq. ethanol / 0.25 h / Ambient temperature 2: chlorobenzene / 0.5 h / Heating 3: 78 percent / Zn, AcOH / diethyl ether / 48 h / Ambient temperature 4: 75 percent / ammonium formate / Pd/C / methanol / 1 h / Heating
	Multi-step reaction with 3 steps 1: sodium carbonate / ethanol / 1 h / 50 °C 2: N,N-dimethyl-formamide; toluene / 5 h / 110 °C 3: palladium 10% on activated carbon; hydrogen / methanol / 14 h / 20 °C

	Multi-step reaction with 3 steps 1: sodium carbonate; magnesium sulfate / ethanol; water / 23 h / 25 °C 2: toluene / 5 h / Reflux 3: hydrogen; palladium 10% on activated carbon / methanol / 18 h / 30 °C / 2250.23 Torr
	Multi-step reaction with 4 steps 1.1: sodium carbonate; magnesium sulfate / ethanol; water / 23 h / 25 °C 2.1: toluene / 5 h / Reflux 3.1: zinc; acetic acid / diethyl ether / 72 h / 0 - 25 °C 3.2: pH 7.2 4.1: hydrogen; palladium 10% on activated carbon / methanol / 5 h / 30 °C / 2250.23 Torr
	Multi-step reaction with 3 steps 1: sodium carbonate / methanol / 0.5 h / 25 °C 2: toluene / 5 h / Reflux 3: palladium 10% on activated carbon; hydrogen / methanol / 18 h / 30 °C / 2250.23 Torr
	Multi-step reaction with 4 steps 1: sodium carbonate / methanol / 0.5 h / 25 °C 2: toluene / 5 h / Reflux 3: zinc; acetic acid / diethyl ether / 72.48 h / 0 - 25 °C 4: palladium 10% on activated carbon; hydrogen / methanol / 5 h / 30 °C / 2250.23 Torr

Reference： [1]Gallos, John K.; Stathakis, Christos I.; Kotoulas, Stefanos S.; Koumbis, Alexandros E. [Journal of Organic Chemistry, 2005, vol. 70, # 17, p. 6884 - 6890]
[2]Gallos, John K.; Goga, Efthymia G.; Koumbis, Alexandros E. [Journal of the Chemical Society. Perkin transactions I, 1994, # 6, p. 613 - 614]
[3]Zhang, Hao; Liu, Jun; Zhang, Luyong; Kong, Lingyi; Yao, Hequan; Sun, Hongbin [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 11, p. 3598 - 3602]
[4]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - WO2013/92900, 2013, A1
[5]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - WO2013/92900, 2013, A1
[6]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - EP2666771, 2013, A1
[7]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - EP2666771, 2013, A1

19
[ 155899-66-4 ]
3-[(1R,2S,3R,4S)-2,3,4-trihydroxycyclopent-1-yl]imidazo[4,5-g]quinazolin-8-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: 58 percent / triethylamine / butan-1-ol / 48 h / Heating 2.1: 79 percent / hydrogen / Pd/C / methanol / 1 h / 2327.17 Torr 3.1: hydrochloric acid / 48 h / 20 °C 3.2: 44 percent / water / 2 h / 80 °C

Reference： [1]Rajappan, Vasanthakumar P; Schneller, Stewart W [Tetrahedron, 2001, vol. 57, # 44, p. 9049 - 9053]

20
[ 155899-66-4 ]
[ 395066-46-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 58 percent / triethylamine / butan-1-ol / 48 h / Heating 2: 79 percent / hydrogen / Pd/C / methanol / 1 h / 2327.17 Torr

Reference： [1]Rajappan, Vasanthakumar P; Schneller, Stewart W [Tetrahedron, 2001, vol. 57, # 44, p. 9049 - 9053]

21
[ 60410-16-4 ]
[ 155899-66-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 70 percent / Ph₃P; tetrakis(triphenylphosphine)palladium / dimethylsulfoxide; tetrahydrofuran / 16 h / 50 °C 2: 88 percent / aq. N-methylmorpholine N-oxide; OsO₄ / acetone / 2.5 h / 20 °C 3: 84 percent / p-TsOH / acetone / 20 °C 4: 92 percent / MeNH₂ / ethanol / 2 h / Heating
	Multi-step reaction with 4 steps 1.1: sodium hydride / tetrahydrofuran; mineral oil / 2 h / 25 - 45 °C / Inert atmosphere 1.2: 22 h / 25 - 30 °C / Inert atmosphere 2.1: osmium(VIII) oxide; 4-methylmorpholine N-oxide / <i>tert</i>-butyl alcohol; acetone / 8 h / 20 - 25 °C 3.1: toluene-4-sulfonic acid / acetone / 4 h / 25 - 30 °C 4.1: hydrazine hydrate / ethanol / 10 h / 60 - 65 °C
	Multi-step reaction with 4 steps 1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / tetrahydrofuran / 2 h / 25 - 30 °C / Inert atmosphere 2: osmium(VIII) oxide; 4-methylmorpholine N-oxide / <i>tert</i>-butyl alcohol; acetone / 8 h / 20 - 25 °C 3: toluene-4-sulfonic acid / acetone / 4 h / 25 - 30 °C 4: hydrazine hydrate / ethanol / 10 h / 60 - 65 °C

	Multi-step reaction with 4 steps 1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / N,N-dimethyl-formamide / 5 h / 90 °C 2: water; 4-methylmorpholine N-oxide; osmium(VIII) oxide / tetrahydrofuran / 12 h 3: methanesulfonic acid / acetone / 3 h 4: hydrazine hydrate / ethanol / 2 h / 70 °C
	Multi-step reaction with 4 steps 1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / N,N-dimethyl-formamide / 20 - 90 °C 2: osmium(VIII) oxide; 4-methylmorpholine N-oxide / tetrahydrofuran; water / 12 h 3: methanesulfonic acid / acetone / 3 h 4: hydrazine / ethanol / 2 h / 70 °C

Reference： [1]Rajappan; Hegde; Schneller [Synthetic Communications, 2001, vol. 31, # 18, p. 2849 - 2854]
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/63126, 2012, A2
[3]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/63126, 2012, A2
[4]Current Patent Assignee: SOUTHERN RESEARCH INSTITUTE; MERCK & CO INC - US9433621, 2016, B2
[5]Current Patent Assignee: MERCK & CO INC; SOUTHERN RESEARCH INSTITUTE - WO2010/22121, 2010, A1

22
[ 119971-18-5 ]
[ 155899-66-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 88 percent / aq. N-methylmorpholine N-oxide; OsO₄ / acetone / 2.5 h / 20 °C 2: 84 percent / p-TsOH / acetone / 20 °C 3: 92 percent / MeNH₂ / ethanol / 2 h / Heating
	Multi-step reaction with 3 steps 1: osmium(VIII) oxide; 4-methylmorpholine N-oxide / <i>tert</i>-butyl alcohol; acetone / 8 h / 20 - 25 °C 2: toluene-4-sulfonic acid / acetone / 4 h / 25 - 30 °C 3: hydrazine hydrate / ethanol / 10 h / 60 - 65 °C
	Multi-step reaction with 3 steps 1: water; 4-methylmorpholine N-oxide; osmium(VIII) oxide / tetrahydrofuran / 12 h 2: methanesulfonic acid / acetone / 3 h 3: hydrazine hydrate / ethanol / 2 h / 70 °C

Multi-step reaction with 3 steps 1: osmium(VIII) oxide; 4-methylmorpholine N-oxide / tetrahydrofuran; water / 12 h 2: methanesulfonic acid / acetone / 3 h 3: hydrazine / ethanol / 2 h / 70 °C

Reference： [1]Rajappan; Hegde; Schneller [Synthetic Communications, 2001, vol. 31, # 18, p. 2849 - 2854]
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/63126, 2012, A2
[3]Current Patent Assignee: SOUTHERN RESEARCH INSTITUTE; MERCK & CO INC - US9433621, 2016, B2
[4]Current Patent Assignee: MERCK & CO INC; SOUTHERN RESEARCH INSTITUTE - WO2010/22121, 2010, A1

23
[ 542-92-7 ]
[ 155899-66-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: 50 percent / (COCl)2; DMSO; pyridine / CH₂Cl₂ / -78 - 20 °C 2: OsO₄; NMO / tetrahydrofuran; H₂O / 0.5 h 3: 0.783 g / p-TsOH*H₂O / 0.33 h 4: 0.232 g / NaBH₄ / methanol / 0.5 h 5: H₂ / 10 percent Pd/C / methanol / 0.5 h

Reference： [1]Shireman; Miller [Tetrahedron Letters, 2000, vol. 41, # 49, p. 9537 - 9540]

24
[ 171754-71-5 ]
[ 155899-66-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: OsO₄; NMO / tetrahydrofuran; H₂O / 0.5 h 2: 0.783 g / p-TsOH*H₂O / 0.33 h 3: 0.232 g / NaBH₄ / methanol / 0.5 h 4: H₂ / 10 percent Pd/C / methanol / 0.5 h

Reference： [1]Shireman; Miller [Tetrahedron Letters, 2000, vol. 41, # 49, p. 9537 - 9540]

25
[(R)-2-((1S,4R,5S,6S)-5,6-Dihydroxy-2-oxa-3-aza-bicyclo[2.2.1]hept-3-yl)-1-methyl-2-oxo-ethyl]-carbamic acid tert-butyl ester [ No CAS ]
[ 155899-66-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 0.783 g / p-TsOH*H₂O / 0.33 h 2: 0.232 g / NaBH₄ / methanol / 0.5 h 3: H₂ / 10 percent Pd/C / methanol / 0.5 h

Reference： [1]Shireman; Miller [Tetrahedron Letters, 2000, vol. 41, # 49, p. 9537 - 9540]

26
[(R)-2-((1R,2S,6S,7S)-4,4-Dimethyl-3,5,8-trioxa-9-aza-tricyclo[5.2.1.0^2,6]dec-9-yl)-1-methyl-2-oxo-ethyl]-carbamic acid tert-butyl ester [ No CAS ]
[ 155899-66-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 0.232 g / NaBH₄ / methanol / 0.5 h 2: H₂ / 10 percent Pd/C / methanol / 0.5 h

Reference： [1]Shireman; Miller [Tetrahedron Letters, 2000, vol. 41, # 49, p. 9537 - 9540]

27
[ 345898-95-5 ]
[ 155899-66-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: chlorobenzene / 0.5 h / Heating 2: 78 percent / Zn, AcOH / diethyl ether / 48 h / Ambient temperature 3: 75 percent / ammonium formate / Pd/C / methanol / 1 h / Heating

Reference： [1]Gallos, John K.; Goga, Efthymia G.; Koumbis, Alexandros E. [Journal of the Chemical Society. Perkin transactions I, 1994, # 6, p. 613 - 614]

28
[ 155899-66-4 ]
ethyl 2-(6-(benzyloxycarbonylamino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy) acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium carbonate / water; tetrahydrofuran / 0 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / -30 °C 2.2: 5.5 h / 20 °C
	Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / 4-methyl-2-pentanone / 2 h / 20 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / -30 °C 2.2: 3 h / 20 °C
	Multi-step reaction with 2 steps 1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C

Multi-step reaction with 2 steps 1.1: potassium carbonate / water / 5.5 h / 20 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 1 h / -20 °C 2.2: 6.33 h / -20 - 20 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2011/17108, 2011, A2
[2]Zhang, Hao; Liu, Jun; Zhang, Luyong; Kong, Lingyi; Yao, Hequan; Sun, Hongbin [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 11, p. 3598 - 3602]
[3]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[4]Current Patent Assignee: CHONGQING SHENGHUAXI PHARMACEUTICALS CO LTD; CHONGQING HUIZHI PHARMACEUTICAL RES INST - CN106279095, 2017, A

29
[ 155899-66-4 ]
[ 1265919-24-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium carbonate / water; tetrahydrofuran / 0 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / -30 °C 2.2: 5.5 h / 20 °C 3.1: hydrogen / palladium 10% on activated carbon / methanol / 1.33 h / 20 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2011/17108, 2011, A2

30
[ 155899-66-4 ]
[ 1265919-27-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium carbonate / water; tetrahydrofuran / 0 °C 2.1: ethyl bromoacetate / N,N-dimethyl-formamide / 0.5 h / -10 °C 2.2: 24 h / 20 °C 3.1: hydrogen / palladium 10% on activated carbon / methanol / 10 h / 20 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2011/17108, 2011, A2

31
4,4-dimethyl-3,5,8-trioxa-9-aza-tricyclo[5.2.1.02,6]decane [ No CAS ]
[ 155899-66-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	With hydrogen In methanol at 20℃; for 1h;	1.6 Step 6[00112] (3aR,4S,6R,6aS)-6-amino-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol: Under a presurrized hydrogen atmosphere (3 atm), a suspension of 4,4-dimethyl-3,5,8-trioxa-9-aza-tricyclo[5.2.1.02,6]decane (16.7 g, 97.55 mmol, 1.00 equiv.), 10% palladium on carbon (1.67 g), and methanol (250 mL) was stirred at about 20 0C for about 60 minutes. After filtering the solution, the resulting filtrate was concentrated in vacuo to give the title product as a white solid (16.8 g; yield = 99 %). MS: m /z = 174 (MH)+.

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2011/17108, 2011, A2 Location in patent: Page/Page column 37

32
[ 54664-61-8 ]
[ 155899-66-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: disodium hydrogenphosphate / water / 14 h / 25 - 30 °C / pH 7 / Enzymatic reaction 2.1: sodium hydride / tetrahydrofuran; mineral oil / 2 h / 25 - 45 °C / Inert atmosphere 2.2: 22 h / 25 - 30 °C / Inert atmosphere 3.1: osmium(VIII) oxide; 4-methylmorpholine N-oxide / <i>tert</i>-butyl alcohol; acetone / 8 h / 20 - 25 °C 4.1: toluene-4-sulfonic acid / acetone / 4 h / 25 - 30 °C 5.1: hydrazine hydrate / ethanol / 10 h / 60 - 65 °C
	Multi-step reaction with 5 steps 1: disodium hydrogenphosphate / water / 14 h / 25 - 30 °C / pH 7 / Enzymatic reaction 2: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / tetrahydrofuran / 2 h / 25 - 30 °C / Inert atmosphere 3: osmium(VIII) oxide; 4-methylmorpholine N-oxide / <i>tert</i>-butyl alcohol; acetone / 8 h / 20 - 25 °C 4: toluene-4-sulfonic acid / acetone / 4 h / 25 - 30 °C 5: hydrazine hydrate / ethanol / 10 h / 60 - 65 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/63126, 2012, A2
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/63126, 2012, A2

33
[ 98-00-0 ]
[ 155899-66-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1.1: potassium dihydrogenphosphate; phosphoric acid / water / 22 h / 25 - 99 °C / pH 4.1 2.1: sodium tetrahydroborate; cerium(III) chloride heptahydrate / methanol / 2 h / -70 - -60 °C 3.1: dmap; triethylamine / N,N-dimethyl-formamide / 16 h / 10 - 30 °C / Inert atmosphere 4.1: disodium hydrogenphosphate / water / 14 h / 25 - 30 °C / pH 7 / Enzymatic reaction 5.1: sodium hydride / tetrahydrofuran; mineral oil / 2 h / 25 - 45 °C / Inert atmosphere 5.2: 22 h / 25 - 30 °C / Inert atmosphere 6.1: osmium(VIII) oxide; 4-methylmorpholine N-oxide / <i>tert</i>-butyl alcohol; acetone / 8 h / 20 - 25 °C 7.1: toluene-4-sulfonic acid / acetone / 4 h / 25 - 30 °C 8.1: hydrazine hydrate / ethanol / 10 h / 60 - 65 °C
	Multi-step reaction with 8 steps 1: potassium dihydrogenphosphate; phosphoric acid / water / 22 h / 25 - 99 °C / pH 4.1 2: sodium tetrahydroborate; cerium(III) chloride heptahydrate / methanol / 2 h / -70 - -60 °C 3: dmap; triethylamine / N,N-dimethyl-formamide / 16 h / 10 - 30 °C / Inert atmosphere 4: disodium hydrogenphosphate / water / 14 h / 25 - 30 °C / pH 7 / Enzymatic reaction 5: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / tetrahydrofuran / 2 h / 25 - 30 °C / Inert atmosphere 6: osmium(VIII) oxide; 4-methylmorpholine N-oxide / <i>tert</i>-butyl alcohol; acetone / 8 h / 20 - 25 °C 7: toluene-4-sulfonic acid / acetone / 4 h / 25 - 30 °C 8: hydrazine hydrate / ethanol / 10 h / 60 - 65 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/63126, 2012, A2
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/63126, 2012, A2

34
[ 29783-26-4 ]
[ 155899-66-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: dmap; triethylamine / N,N-dimethyl-formamide / 16 h / 10 - 30 °C / Inert atmosphere 2.1: disodium hydrogenphosphate / water / 14 h / 25 - 30 °C / pH 7 / Enzymatic reaction 3.1: sodium hydride / tetrahydrofuran; mineral oil / 2 h / 25 - 45 °C / Inert atmosphere 3.2: 22 h / 25 - 30 °C / Inert atmosphere 4.1: osmium(VIII) oxide; 4-methylmorpholine N-oxide / <i>tert</i>-butyl alcohol; acetone / 8 h / 20 - 25 °C 5.1: toluene-4-sulfonic acid / acetone / 4 h / 25 - 30 °C 6.1: hydrazine hydrate / ethanol / 10 h / 60 - 65 °C
	Multi-step reaction with 6 steps 1: dmap; triethylamine / N,N-dimethyl-formamide / 16 h / 10 - 30 °C / Inert atmosphere 2: disodium hydrogenphosphate / water / 14 h / 25 - 30 °C / pH 7 / Enzymatic reaction 3: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / tetrahydrofuran / 2 h / 25 - 30 °C / Inert atmosphere 4: osmium(VIII) oxide; 4-methylmorpholine N-oxide / <i>tert</i>-butyl alcohol; acetone / 8 h / 20 - 25 °C 5: toluene-4-sulfonic acid / acetone / 4 h / 25 - 30 °C 6: hydrazine hydrate / ethanol / 10 h / 60 - 65 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/63126, 2012, A2
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/63126, 2012, A2

35
4-Hydroxycyclopent-2-enone [ No CAS ]
[ 155899-66-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: sodium tetrahydroborate; cerium(III) chloride heptahydrate / methanol / 2 h / -70 - -60 °C 2.1: dmap; triethylamine / N,N-dimethyl-formamide / 16 h / 10 - 30 °C / Inert atmosphere 3.1: disodium hydrogenphosphate / water / 14 h / 25 - 30 °C / pH 7 / Enzymatic reaction 4.1: sodium hydride / tetrahydrofuran; mineral oil / 2 h / 25 - 45 °C / Inert atmosphere 4.2: 22 h / 25 - 30 °C / Inert atmosphere 5.1: osmium(VIII) oxide; 4-methylmorpholine N-oxide / <i>tert</i>-butyl alcohol; acetone / 8 h / 20 - 25 °C 6.1: toluene-4-sulfonic acid / acetone / 4 h / 25 - 30 °C 7.1: hydrazine hydrate / ethanol / 10 h / 60 - 65 °C
	Multi-step reaction with 7 steps 1: sodium tetrahydroborate; cerium(III) chloride heptahydrate / methanol / 2 h / -70 - -60 °C 2: dmap; triethylamine / N,N-dimethyl-formamide / 16 h / 10 - 30 °C / Inert atmosphere 3: disodium hydrogenphosphate / water / 14 h / 25 - 30 °C / pH 7 / Enzymatic reaction 4: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / tetrahydrofuran / 2 h / 25 - 30 °C / Inert atmosphere 5: osmium(VIII) oxide; 4-methylmorpholine N-oxide / <i>tert</i>-butyl alcohol; acetone / 8 h / 20 - 25 °C 6: toluene-4-sulfonic acid / acetone / 4 h / 25 - 30 °C 7: hydrazine hydrate / ethanol / 10 h / 60 - 65 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/63126, 2012, A2
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/63126, 2012, A2

36
[ 145783-15-9 ]
[ 155899-66-4 ]
[ 220241-60-1 ]

Yield	Reaction Conditions	Operation in experiment
91%	With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 100℃; for 16h;	(3aR,4S,6R,6aS)-6-(5-amino-6-chloro-2-(propylthio)pyrimidin-4-ylamino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (4) To a stirred solution of pyrimido dichloride 3 (16.10 g, 67.67 mmol) in 1,4-dioxane (300 mL), amino alcohol mandelic acid salts 2 (20.03 g, 61.47 mmol) and N,N-diisopropyl-N-ethylamine (23.83 g, 184.40 mmol) were added in one portion, respectively, while the colour of the reaction mixture changed to brown. The reaction mixture was stirred at 100°C for 16 h, and then water (300 mL) was added to the reaction mixture, then the aqueous phase was separated and extracted twice with ethyl acetate. The combined organic phases were washed with brine and dried over MgSO4. The organic solvent was removed under reduced pressure and residue was purified by silica gel column chromatography (ethyl acetate/hexane 1:5) to give brown oil 4 ( 20.97 g, yield 91%).
90%	In methanol at 100℃; for 12h; Sealed tube;	19 (3a/?,45,6/?,6a5)-6-((5-Amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2- dimethyltetrahydro-3a/-/-cyclopenta[ /][l,3]dioxol-4-ol (19a) 4,6-Dichloro-2-(propylthio)pyrimidin-5-amine (0.5 g, 2.1 mmol) was dissolved in methanol (2 mL) and supplemented with (3a/?,45,6/?,6a5)-6-amino-2,2-dimethyltetrahydro-3a/-/- cyclopenta[ /][l,3]dioxol-4-ol (1.1 g, 6.3 mmol). The reaction mixture was introduced in a sealed vessel and heated at 100°C for 12 h. After concentration of the reaction mixture to dryness under vacuum, the residue was purified by silica gel column chromatography.Yield: 90%.Melting point: ND.H NMR (DMSO -d6) d 0.96 (t, J=7.4 Hz, 3H, SCH2CH2CH3), 1.21 (s, 3H, C(CH3)2), 1.36 (s, 3H,C(CH3)2), 1.64 (h, J=7.4 Hz, 2H, SCH2CH2CH3), 1.71 (m, 1H, S'-H), 2.22 (m, 1H, S'-H), 2.98 (t, J=7.2 Hz, 2H, SCH2CH2CH3), 4.06 (bs, 1H, 4’-H), 4.26 (bs, 1H, S'-H), 4.41 (d, J=5.9 Hz, 1H, 3a’-H), 4.51 (d, J=6.0 Hz, 1H, Sa'-H), 4.70 (s, 2H, NH2), 5.27 (d, J=3.1 Hz, 1H, OH), 6.63 (d, J=7.1 Hz, 1H, NH). 13C NMR (DMSO -d6) d 13.3 (SCH2CH2CH3), 22.9 (SCH2CH2CH3), 24.1 (C(CH3)2), 26.5 (C(CH3)2), 32.1 (SCH2CH2CH3), 35.9 (C-5'), 57.2 (C-6'), 75.3 (C-4'), 84.5 (C-6a'), 85.7 (3a'), 109.7 (C(CH3)2), 119.7 (C-5), 136.6 (C-6), 152.4 (C-4), 155.9 (C-2).
90%	In methanol at 100℃; for 12h; Sealed tube;	19 (3a/?,4S,6/?,6aS)-6-((5-Amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2- dimethyltetrahydro-3a/-/-cyclopenta [c/] [l,3]dioxol-4-ol (19a) 4,6-Dichloro-2-(propylthio)pyrimidin-5-amine (0.5 g, 2.1 mmol) was dissolved in methanol (2 mL) and supplemented with (3a/?,4S,6/?,6aS)-6-amino-2,2-dimethyltetrahydro-3a/-/- cyclopenta [c/] [l,3]dioxol-4-ol (1.1 g, 6.3 mmol). The reaction mixture was introduced in a sealed vessel and heated at 100°C for 12 h. After concentration of the reaction mixture to dryness under vacuum, the residue was purified by silica gel column chromatography. (0708) Yield: 90%. (0709) Melting point: ND. (0710) XH NMR (DMSO -d6) d 0.96 (t, J=7.4 Hz, 3H, SCH2CH2CH3), 1.21 (s, 3H, C(CH3)2), 1.36 (s, 3H, C(CH3)2), 1.64 (h, J=7.4 Hz, 2H, SCH2CH2CH3), 1.71 (m, 1H, S’-H), 2.22 (m, 1H, S’-H), 2.98 (t, J=7.2 Hz, 2H, SCH2CH2CH3), 4.06 (bs, 1H, A’-H), 4.26 (bs, 1H, 6’-H), 4.41 (d, J=5.9 Hz, 1H, 3a'-H), 4.51 (d, J=6.0 Hz, 1H, 6a’-H), 4.70 (s, 2H, NH2), 5.27 (d, J=3.1 Hz, 1H, OH), 6.63 (d, J=7.1 Hz, 1H, NH). 13C N MR (DMSO -d6) d 13.3 (SCH2CH2CH3), 22.9 (SCH2CH2CH3), 24.1 (C(CH3)2), 26.5 (C(CH3)2), 32.1 (0711) (SCH2CH2CH3), 35.9 (C-5'), 57.2 (C-6'), 75.3 (C-4'), 84.5 (C-6a'), 85.7 (3a'), 109.7 (C(CH3)2), 119.7 (C-5), 136.6 (C-6), 152.4 (C-4), 155.9 (C-2).

89%	With triethylamine at 110℃; Sealed tube;	4.22 (3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (13b.8) The mixture of 4,6-dichloro-2-(propylthio)pyrimidin-5-amine 12b.3 (1.0g, 4.2mmol), (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydrocyclopenta[d][1,3]dioxol-4-ol (0.93g, 5.4mmol) and triethylamine (0.6mL, 4.2mmol) in acetonitrile (10mL) was introduced in a sealed vessel and heated overnight at 110°C. After evaporation of the solvent, the residue was purified by column chromatography on silica gel using 100% ethyl acetate to give 13b.8 as a brown oil (1.40g, 89% yield, oil). 1H NMR (CDCl3): δ 1.03 (t, J=7.4Hz, 3H, SCH2CH2CH3), 1.26 (s, 3H, CH3), 1.43 (s, 3H, CH3), 1.76 (m, 2H, SCH2CH2CH3), 1.83 (d, J=14.5Hz, 1H, 5′-Ha), 2.14 (s, 1H, OH), 2.36 (m, 1H, 5′-Hb), 3.01 (ddd, J=13.4Hz/8.3Hz/6.4Hz, 1H, SCHa), 3.09 (s, 2H, NH2), 3.13 (ddd, J=13.5Hz/8.3Hz/6.4Hz, 1H, SCHb), 4.38 (s, 1H, 4′-H), 4.51 (dd, J=5.4Hz/1.7Hz, 1H, 3a′-H), 4.57 (dd, J=5.4Hz/1.2Hz, 1H, 6a′-H), 4.62 (t, J=7.4Hz, 1H, 6′-H), 5.93 (d, J=8.4Hz, 1H, NH). 13C NMR (CDCl3): δ 13.5, 23.2, 23.8, 26.2, 33.2, 35.0, 57.2, 78.1, 85.2, 86.2, 110.3, 117.2, 144.4, 154.5, 162.0.
87%	With triethylamine In tetrahydrofuran for 24h; Reflux;	3 AMALCINA was also prepared from AMAL and CLINA. To a solution of AMAL (7.64 g, 44.1 mmol) and CLINA (10.5 g, 44.1 mmol) in dry THF (40 mL) Et3N (6.76 mL, 48.5 mmol) was added at room temperature. Resulting reaction mixture was stirred at reflux for 24 h, then salts were filtered off, and solvent evaporated to afford crude product, which was then purified by chromatography (SiO2, hexane:EtOAc). Brown syrup (14.4 g, 87% yield).
87%	With triethylamine In tetrahydrofuran at 20℃; for 24h; Reflux;	3 Example 3: Preparation of (3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)- 2,2-dimethyltetrahydro-3a/-/-cyclopenta[d][1 ,3]dioxol-4-ol (AMALCINA) To a solution of AMAL (7.64 g, 44.1 mmol) and CLINA (10.5 g, 44.1 mmol) in dry THF (40 mL) Et3N (6.76 mL, 48.5 mmol) was added at room temperature. Resulting reaction mixture was stirred at reflux for 24 h, then salts were filtered off, and solvent evaporated to afford crude product, which was then purified by chromatography (Si02, hexane:EtOAc). Brown syrup (14.4 g, 87% yield).; Or: To a solution of AMAL (1 .45 g, 8.40 mmol) and CLINA (2.0 g, 8.40 mmol) in toluene (20 mL) Na2C03 (1.07 g, 10.1 mmol) and Aliquat 336 (0.34 g, 0.84 mmol) were added at room temperature. Resulting reaction mixture was stirred at 100°C for 48 h, then salts were filtered off, and solvent evaporated to afford crude product, which was then purified by chromatography (Si02. hexane:EtOAc). Brown syrup (2.52 g, 80% yield).
87%	With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 100℃; for 26h;	1.1 (1S,2R,3S,4R)-6-[[5-amino-6-chloro-2-(propylthiouracil)-4-yl]amino]-2,2-dimethyltetrahydro-4H-cyclopentyl[d][1,3]dioxy-4-ol A solution of 4,6-dichloro-5-amino-2-propylthiopyrimidine (16.10 g, 0.068 mol) was added to 300 ml of 1,4-dioxane and2 - [[(3R, 4S , 6R, 6S) -6-aminotetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxolan-4-yl] oxy] -anol mandelate (22.03 g, (43.94 g, 0.34 mol) was added andheated to 100 ° C. The color of the reaction system gradually changed from yellow to brown. The reaction was monitored by thin layer chromatography.After26 hours, After the reaction system basic, cooling to room temperature, 500ml of water was added, extraction, liquid separation, the aqueous phase was extracted with ethyl acetate and thenextracted twice, the combined organic phases were washed with brine once, the organic phase was dried over anhydrous magnesium sulfate And then theorganic solventwas removed by distillation under reduced pressureand purified by column chromatography (ethyl acetate / petroleum ether = 1: 5) to give 20.01 g of a brown oil in 87% yield.
87%	With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 100℃; for 20h;
	With triethylamine; sodium iodide In 1,4-dioxane at 120℃;
	With triethylamine In ethanol Reflux;

Reference： [1]Wang, Yeming; Yan, Hong; Ma, Chao; Lu, Dan [Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 20, p. 4461 - 4463]
[2]Current Patent Assignee: UNIVERSITY OF LIEGE - WO2019/158655, 2019, A1 Location in patent: Page/Page column 66; 67
[3]Current Patent Assignee: UNIVERSITY OF LIEGE - WO2020/212553, 2020, A1 Location in patent: Page/Page column 78
[4]Goffin, Eric; Jacques, Nicolas; Lancellotti, Patrizio; Musumeci, Lucia; Nchimi, Alain; Pirotte, Bernard; Oury, Cécile [European Journal of Medicinal Chemistry, 2020, vol. 208]
[5]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - EP2586773, 2013, A1 Location in patent: Paragraph 0067-0068
[6]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/60837, 2013, A1 Location in patent: Page/Page column 27-28
[7]Current Patent Assignee: BEIJING UNIVERSITY OF TECHNOLOGY - CN107033146, 2017, A Location in patent: Paragraph 0021-0023
[8]Tian, Nana; Wang, Juan; Wang, Yeming; Yan, Hong; Zhao, Zhichang [2021, vol. 12, # 8, p. 1414 - 1427]
[9]Location in patent: scheme or table Zhang, Hao; Liu, Jun; Zhang, Luyong; Kong, Lingyi; Yao, Hequan; Sun, Hongbin [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 11, p. 3598 - 3602]
[10]Tu, Wangyang; Fan, Jiang; Zhang, Haitang; Xu, Guoji; Liu, Zhiwei; Qu, Jian; Yang, Fanglong; Zhang, Lei; Luan, Tianyu; Yuan, Jijun; Gong, Aishen; Feng, Jun; Sun, Piaoyang; Dong, Qing [Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 1, p. 141 - 146]

37
methyl 2,3-O-isopropylidene-D-ribofuranoside [ No CAS ]
[ 155899-66-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: pyridine / 24 h / 20 °C 2: sodium iodide / butanone / 24 h / 120 °C 3: zinc / ethanol / 1 h / 70 °C 4: sodium carbonate / ethanol / 1 h / 50 °C 5: N,N-dimethyl-formamide; toluene / 5 h / 110 °C 6: palladium 10% on activated carbon; hydrogen / methanol / 14 h / 20 °C
	Multi-step reaction with 5 steps 1: 1H-imidazole; triphenylphosphine; iodine / toluene / 2 h / 70 °C 2: zinc; water; hydrogenchloride / ethanol / 19 h / 10 - 24 °C 3: sodium carbonate; magnesium sulfate / ethanol; water / 23 h / 25 °C 4: toluene / 5 h / Reflux 5: hydrogen; palladium 10% on activated carbon / methanol / 18 h / 30 °C / 2250.23 Torr
	Multi-step reaction with 6 steps 1.1: 1H-imidazole; triphenylphosphine; iodine / toluene / 2 h / 70 °C 2.1: zinc; water; hydrogenchloride / ethanol / 19 h / 10 - 24 °C 3.1: sodium carbonate; magnesium sulfate / ethanol; water / 23 h / 25 °C 4.1: toluene / 5 h / Reflux 5.1: zinc; acetic acid / diethyl ether / 72 h / 0 - 25 °C 5.2: pH 7.2 6.1: hydrogen; palladium 10% on activated carbon / methanol / 5 h / 30 °C / 2250.23 Torr

	Multi-step reaction with 6 steps 1: pyridine / 19 h / 0 - 25 °C 2: sodium iodide / butanone / 22 h / 80 °C 3: zinc; water; hydrogenchloride / ethanol / 19 h / 10 - 24 °C 4: sodium carbonate; magnesium sulfate / ethanol; water / 23 h / 25 °C 5: toluene / 5 h / Reflux 6: hydrogen; palladium 10% on activated carbon / methanol / 18 h / 30 °C / 2250.23 Torr
	Multi-step reaction with 6 steps 1: pyridine / 4 h / -10 - -5 °C 2: sodium iodide / butanone / 17 h / 80 °C 3: zinc; water; hydrogenchloride / ethanol / 19 h / 10 - 24 °C 4: sodium carbonate; magnesium sulfate / ethanol; water / 23 h / 25 °C 5: toluene / 5 h / Reflux 6: hydrogen; palladium 10% on activated carbon / methanol / 18 h / 30 °C / 2250.23 Torr
	Multi-step reaction with 6 steps 1: pyridine / 4 h / -10 - -5 °C 2: lithium bromide / butanone / 22 h / 80 °C 3: water; zinc-copper couple; hydrogenchloride / methanol / 18 h / 25 °C 4: sodium carbonate; magnesium sulfate / ethanol; water / 23 h / 25 °C 5: toluene / 5 h / Reflux 6: hydrogen; palladium 10% on activated carbon / methanol / 18 h / 30 °C / 2250.23 Torr
	Multi-step reaction with 7 steps 1.1: pyridine / 19 h / 0 - 25 °C 2.1: sodium iodide / butanone / 22 h / 80 °C 3.1: zinc; water; hydrogenchloride / ethanol / 19 h / 10 - 24 °C 4.1: sodium carbonate; magnesium sulfate / ethanol; water / 23 h / 25 °C 5.1: toluene / 5 h / Reflux 6.1: zinc; acetic acid / diethyl ether / 72 h / 0 - 25 °C 6.2: pH 7.2 7.1: hydrogen; palladium 10% on activated carbon / methanol / 5 h / 30 °C / 2250.23 Torr
	Multi-step reaction with 7 steps 1.1: pyridine / 4 h / -10 - -5 °C 2.1: sodium iodide / butanone / 17 h / 80 °C 3.1: zinc; water; hydrogenchloride / ethanol / 19 h / 10 - 24 °C 4.1: sodium carbonate; magnesium sulfate / ethanol; water / 23 h / 25 °C 5.1: toluene / 5 h / Reflux 6.1: zinc; acetic acid / diethyl ether / 72 h / 0 - 25 °C 6.2: pH 7.2 7.1: hydrogen; palladium 10% on activated carbon / methanol / 5 h / 30 °C / 2250.23 Torr
	Multi-step reaction with 7 steps 1.1: pyridine / 4 h / -10 - -5 °C 2.1: lithium bromide / butanone / 22 h / 80 °C 3.1: water; zinc-copper couple; hydrogenchloride / methanol / 18 h / 25 °C 4.1: sodium carbonate; magnesium sulfate / ethanol; water / 23 h / 25 °C 5.1: toluene / 5 h / Reflux 6.1: zinc; acetic acid / diethyl ether / 72 h / 0 - 25 °C 6.2: pH 7.2 7.1: hydrogen; palladium 10% on activated carbon / methanol / 5 h / 30 °C / 2250.23 Torr
	Multi-step reaction with 6 steps 1: pyridine / 4 h / -10 - -5 °C 2: lithium bromide / butanone / 22 h / 80 °C 3: hydrogenchloride; zinc/copper couple / water; methanol / 18 h / 25 °C 4: sodium carbonate / methanol / 0.5 h / 25 °C 5: toluene / 5 h / Reflux 6: palladium 10% on activated carbon; hydrogen / methanol / 18 h / 30 °C / 2250.23 Torr
	Multi-step reaction with 7 steps 1: pyridine / 4 h / -10 - -5 °C 2: lithium bromide / butanone / 22 h / 80 °C 3: hydrogenchloride; zinc/copper couple / water; methanol / 18 h / 25 °C 4: sodium carbonate / methanol / 0.5 h / 25 °C 5: toluene / 5 h / Reflux 6: zinc; acetic acid / diethyl ether / 72.48 h / 0 - 25 °C 7: palladium 10% on activated carbon; hydrogen / methanol / 5 h / 30 °C / 2250.23 Torr

Reference： [1]Zhang, Hao; Liu, Jun; Zhang, Luyong; Kong, Lingyi; Yao, Hequan; Sun, Hongbin [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 11, p. 3598 - 3602]
[2]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - WO2013/92900, 2013, A1
[3]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - WO2013/92900, 2013, A1
[4]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - WO2013/92900, 2013, A1
[5]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - WO2013/92900, 2013, A1
[6]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - WO2013/92900, 2013, A1
[7]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - WO2013/92900, 2013, A1
[8]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - WO2013/92900, 2013, A1
[9]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - WO2013/92900, 2013, A1
[10]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - EP2666771, 2013, A1
[11]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - EP2666771, 2013, A1

38
((3aR,4R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 4-methylbenzenesulfonate [ No CAS ]
[ 155899-66-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: sodium iodide / butanone / 24 h / 120 °C 2: zinc / ethanol / 1 h / 70 °C 3: sodium carbonate / ethanol / 1 h / 50 °C 4: N,N-dimethyl-formamide; toluene / 5 h / 110 °C 5: palladium 10% on activated carbon; hydrogen / methanol / 14 h / 20 °C
	Multi-step reaction with 5 steps 1: sodium iodide / butanone / 17 h / 80 °C 2: zinc; water; hydrogenchloride / ethanol / 19 h / 10 - 24 °C 3: sodium carbonate; magnesium sulfate / ethanol; water / 23 h / 25 °C 4: toluene / 5 h / Reflux 5: hydrogen; palladium 10% on activated carbon / methanol / 18 h / 30 °C / 2250.23 Torr
	Multi-step reaction with 5 steps 1: lithium bromide / butanone / 22 h / 80 °C 2: water; zinc-copper couple; hydrogenchloride / methanol / 18 h / 25 °C 3: sodium carbonate; magnesium sulfate / ethanol; water / 23 h / 25 °C 4: toluene / 5 h / Reflux 5: hydrogen; palladium 10% on activated carbon / methanol / 18 h / 30 °C / 2250.23 Torr

	Multi-step reaction with 6 steps 1.1: sodium iodide / butanone / 17 h / 80 °C 2.1: zinc; water; hydrogenchloride / ethanol / 19 h / 10 - 24 °C 3.1: sodium carbonate; magnesium sulfate / ethanol; water / 23 h / 25 °C 4.1: toluene / 5 h / Reflux 5.1: zinc; acetic acid / diethyl ether / 72 h / 0 - 25 °C 5.2: pH 7.2 6.1: hydrogen; palladium 10% on activated carbon / methanol / 5 h / 30 °C / 2250.23 Torr
	Multi-step reaction with 6 steps 1.1: lithium bromide / butanone / 22 h / 80 °C 2.1: water; zinc-copper couple; hydrogenchloride / methanol / 18 h / 25 °C 3.1: sodium carbonate; magnesium sulfate / ethanol; water / 23 h / 25 °C 4.1: toluene / 5 h / Reflux 5.1: zinc; acetic acid / diethyl ether / 72 h / 0 - 25 °C 5.2: pH 7.2 6.1: hydrogen; palladium 10% on activated carbon / methanol / 5 h / 30 °C / 2250.23 Torr
	Multi-step reaction with 5 steps 1: lithium bromide / butanone / 22 h / 80 °C 2: hydrogenchloride; zinc/copper couple / water; methanol / 18 h / 25 °C 3: sodium carbonate / methanol / 0.5 h / 25 °C 4: toluene / 5 h / Reflux 5: palladium 10% on activated carbon; hydrogen / methanol / 18 h / 30 °C / 2250.23 Torr
	Multi-step reaction with 6 steps 1: lithium bromide / butanone / 22 h / 80 °C 2: hydrogenchloride; zinc/copper couple / water; methanol / 18 h / 25 °C 3: sodium carbonate / methanol / 0.5 h / 25 °C 4: toluene / 5 h / Reflux 5: zinc; acetic acid / diethyl ether / 72.48 h / 0 - 25 °C 6: palladium 10% on activated carbon; hydrogen / methanol / 5 h / 30 °C / 2250.23 Torr

Reference： [1]Zhang, Hao; Liu, Jun; Zhang, Luyong; Kong, Lingyi; Yao, Hequan; Sun, Hongbin [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 11, p. 3598 - 3602]
[2]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - WO2013/92900, 2013, A1
[3]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - WO2013/92900, 2013, A1
[4]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - WO2013/92900, 2013, A1
[5]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - WO2013/92900, 2013, A1
[6]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - EP2666771, 2013, A1
[7]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - EP2666771, 2013, A1

39
[ 155899-66-4 ]
[ 274693-55-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3598 - 3602
[2]Patent: WO2012/85665,2012,A2
[3]Patent: WO2012/138981,2012,A2
[4]Patent: WO2012/172426,2012,A1
[5]Patent: US2014/206867,2014,A1
[6]Patent: CN106279095,2017,A

40
[ 155899-66-4 ]
[ 274693-54-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3598 - 3602
[2]Patent: WO2012/138981,2012,A2
[3]Patent: CN106279095,2017,A

41
[ 155899-66-4 ]
[ 274693-27-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1.1: N-ethyl-N,N-diisopropylamine / 4-methyl-2-pentanone / 2 h / 20 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / -30 °C 2.2: 3 h / 20 °C 3.1: lithium borohydride / tetrahydrofuran / 5 h / 0 °C 4.1: 5%-palladium/activated carbon / methanol / 1 h / 20 °C 5.1: triethylamine; sodium iodide / 1,4-dioxane / 7 h / 120 °C 6.1: sodium nitrite / water; acetic acid; ethyl acetate / 30 °C 7.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h 8.1: hydrogenchloride; water / methanol / 1 h
	Multi-step reaction with 11 steps 1.1: potassium carbonate / ethanol; water / 3 h / 60 - 65 °C 1.2: 0.25 h 2.1: sodium t-butanolate / N,N-dimethyl-formamide; tetrahydrofuran / 2 h / -10 - 5 °C 3.1: diisobutylaluminium hydride / toluene / 2.5 h / -25 - -20 °C 3.2: 0.25 h 4.1: hydrogen / 20% palladium hydroxide-activated charcoal / methanol / 10 h / 20 - 25 °C / 2327.23 Torr / Autoclave; Inert atmosphere 5.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 6.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 7.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 8.1: iodine / acetone / 2 h / 25 - 60 °C 9.1: potassium carbonate / acetone / 20 h / 55 - 60 °C 10.1: hydrogenchloride; water / methanol / 5 h / 20 - 25 °C 10.2: 25 - 30 °C / pH 10 11.1: formic acid / palladium 10% on activated carbon / 50 °C
	Multi-step reaction with 8 steps 1.1: potassium carbonate / ethanol; water / 3 h / 60 - 65 °C 1.2: 0.25 h 2.1: sodium t-butanolate / N,N-dimethyl-formamide; tetrahydrofuran / 2 h / -10 - 5 °C 3.1: diisobutylaluminium hydride / toluene / 2.5 h / -25 - -20 °C 3.2: 0.25 h 4.1: hydrogen / 20% palladium hydroxide-activated charcoal / methanol / 10 h / 20 - 25 °C / 2327.23 Torr / Autoclave; Inert atmosphere 5.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 6.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 7.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 8.1: hydrogenchloride; water / toluene; methanol / 2 h / 25 - 30 °C 8.2: pH > 8

	Multi-step reaction with 9 steps 1.1: potassium carbonate / ethanol; water / 3 h / 60 - 65 °C 1.2: 0.25 h 2.1: sodium t-butanolate / N,N-dimethyl-formamide; tetrahydrofuran / 2 h / -10 - 5 °C 3.1: diisobutylaluminium hydride / toluene / 2.5 h / -25 - -20 °C 3.2: 0.25 h 4.1: hydrogen / 20% palladium hydroxide-activated charcoal / methanol / 10 h / 20 - 25 °C / 2327.23 Torr / Autoclave; Inert atmosphere 5.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 6.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 7.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 8.1: potassium carbonate / acetone / 24 h / 25 - 60 °C 9.1: hydrogenchloride; water / methanol / 5.5 h / 20 - 55 °C 9.2: 25 - 30 °C / pH 10
	Multi-step reaction with 10 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: acetic acid; iron / methanol / 20 - 35 °C 6.1: sodium hydroxide; water / methanol / 0 - 30 °C 7.1: isopentyl nitrite / acetonitrile / 10 - 70 °C 8.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 30 °C 9.1: lithium aluminium tetrahydride / tetrahydrofuran / -10 - 0 °C 10.1: hydrogenchloride; water / methanol / 25 - 30 °C
	Multi-step reaction with 10 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: acetic acid; iron / methanol / 20 - 35 °C 6.1: sodium hydroxide; water / methanol / 0 - 30 °C 7.1: isopentyl nitrite / acetonitrile / 10 - 70 °C 8.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 30 °C 9.1: hydrogenchloride; water / 16 h / 20 °C 10.1: lithium borohydride / tetrahydrofuran / -10 - 20 °C
	Multi-step reaction with 10 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: acetic acid; iron / methanol / 20 - 35 °C 6.1: sodium hydroxide; water / methanol / 0 - 30 °C 7.1: isopentyl nitrite / acetonitrile / 10 - 70 °C 8.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 30 °C 9.1: lithium aluminium tetrahydride / tetrahydrofuran / -10 - 0 °C 10.1: hydrogenchloride; water / methanol / 25 - 30 °C
	Multi-step reaction with 10 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: acetic acid; iron / methanol / 20 - 35 °C 6.1: sodium hydroxide; water / methanol / 0 - 30 °C 7.1: isopentyl nitrite / acetonitrile / 10 - 70 °C 8.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 30 °C 9.1: hydrogenchloride; water / 16 h / 20 °C 10.1: lithium borohydride / tetrahydrofuran / -10 - 20 °C
	Multi-step reaction with 10 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: lithium borohydride / tetrahydrofuran / 0 - 20 °C 3.2: 20 °C 3.3: pH 6 - 7 4.1: hydrogenchloride; water / methanol / 25 - 30 °C 5.1: toluene-4-sulfonic acid 6.1: ammonium formate / palladium 10% on activated carbon / ethanol / 30 - 70 °C 6.2: 20 - 70 °C 7.1: triethylamine / 1-methyl-pyrrolidin-2-one / 30 - 90 °C / Inert atmosphere 8.1: sodium nitrite; acetic acid / toluene; water / 25 - 30 °C 9.1: potassium carbonate / toluene; water / 25 - 30 °C 10.1: hydrogenchloride; water / toluene; methanol / 0 - 20 °C
	Multi-step reaction with 8 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: triethylamine / ethanol / 36 h / 125 °C / 3677.86 Torr / Autoclave; Inert atmosphere 5.1: isopentyl nitrite / acetonitrile / 50 - 70 °C 6.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 35 °C 7.1: lithium borohydride / tetrahydrofuran / 0 - 30 °C 8.1: hydrogenchloride; water / methanol / 25 - 30 °C
	Multi-step reaction with 8 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: triethylamine / ethanol / 36 h / 125 °C / 3677.86 Torr / Autoclave; Inert atmosphere 5.1: isopentyl nitrite / acetonitrile / 50 - 70 °C 6.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 35 °C 7.1: lithium borohydride / tetrahydrofuran / 0 - 30 °C 8.1: hydrogenchloride; water / methanol / 25 - 30 °C
	Multi-step reaction with 8 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: lithium borohydride / tetrahydrofuran / 0 - 20 °C 3.2: 20 °C 3.3: pH 6 - 7 4.1: ammonium formate / palladium 10% on activated carbon / ethanol / 30 - 70 °C 4.2: 20 - 70 °C 5.1: triethylamine / ethanol / 40 - 80 °C / Inert atmosphere 6.1: hydrogenchloride; water / methanol / 35 °C 7.1: sodium nitrite / water; methanol / 0 - 5 °C 8.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 25 - 35 °C
	Multi-step reaction with 8 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: lithium borohydride / tetrahydrofuran / 0 - 20 °C 3.2: 20 °C 3.3: pH 6 - 7 4.1: ammonium formate / palladium 10% on activated carbon / ethanol / 30 - 70 °C 5.1: triethylamine / ethanol / 40 - 80 °C / Inert atmosphere 6.1: hydrogenchloride; water / methanol / 35 °C 7.1: sodium nitrite / water; methanol / 0 - 5 °C 8.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 25 - 35 °C
	Multi-step reaction with 9 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: acetic acid; iron / methanol / 20 - 35 °C 6.1: isopentyl nitrite / acetonitrile / 50 - 70 °C 7.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 35 °C 8.1: lithium borohydride / tetrahydrofuran / 0 - 30 °C 9.1: hydrogenchloride; water / methanol / 25 - 30 °C
	Multi-step reaction with 9 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: acetic acid; iron / methanol / 20 - 35 °C 6.1: isopentyl nitrite / acetonitrile / 50 - 70 °C 7.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 35 °C 8.1: lithium borohydride / tetrahydrofuran / 0 - 30 °C 9.1: hydrogenchloride; water / methanol / 25 - 30 °C
	Multi-step reaction with 9 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: triethylamine / ethanol / 36 h / 125 °C / 3677.86 Torr / Autoclave; Inert atmosphere 5.1: sodium hydroxide; water / methanol / 0 - 30 °C 6.1: isopentyl nitrite / acetonitrile / 10 - 70 °C 7.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 30 °C 8.1: lithium aluminium tetrahydride / tetrahydrofuran / -10 - 0 °C 9.1: hydrogenchloride; water / methanol / 25 - 30 °C
	Multi-step reaction with 9 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: triethylamine / ethanol / 36 h / 125 °C / 3677.86 Torr / Autoclave; Inert atmosphere 5.1: sodium hydroxide; water / methanol / 0 - 30 °C 6.1: isopentyl nitrite / acetonitrile / 10 - 70 °C 7.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 30 °C 8.1: hydrogenchloride; water / 16 h / 20 °C 9.1: lithium borohydride / tetrahydrofuran / -10 - 20 °C
	Multi-step reaction with 9 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: triethylamine / ethanol / 36 h / 125 °C / 3677.86 Torr / Autoclave; Inert atmosphere 5.1: sodium hydroxide; water / methanol / 0 - 30 °C 6.1: isopentyl nitrite / acetonitrile / 10 - 70 °C 7.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 30 °C 8.1: lithium aluminium tetrahydride / tetrahydrofuran / -10 - 0 °C 9.1: hydrogenchloride; water / methanol / 25 - 30 °C
	Multi-step reaction with 9 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: triethylamine / ethanol / 36 h / 125 °C / 3677.86 Torr / Autoclave; Inert atmosphere 5.1: sodium hydroxide; water / methanol / 0 - 30 °C 6.1: isopentyl nitrite / acetonitrile / 10 - 70 °C 7.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 30 °C 8.1: hydrogenchloride; water / 16 h / 20 °C 9.1: lithium borohydride / tetrahydrofuran / -10 - 20 °C
	Multi-step reaction with 9 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: hydrogenchloride; water / 20 - 70 °C 6.1: acetic acid / methanol / 0 - 30 °C 7.1: isopentyl nitrite / acetonitrile / 30 - 60 °C 8.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 25 - 35 °C 9.1: lithium borohydride / tetrahydrofuran / -10 - 20 °C
	Multi-step reaction with 9 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: hydrogenchloride; water / 20 - 70 °C 6.1: acetic acid / methanol / 0 - 30 °C 7.1: isopentyl nitrite / acetonitrile / 30 - 60 °C 8.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 25 - 35 °C 9.1: lithium borohydride / tetrahydrofuran / -10 - 20 °C
	Multi-step reaction with 9 steps 1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3: sodium hydroxide; water / tetrahydrofuran / 10 - 20 °C 4: ammonium formate / palladium 10% on activated carbon / ethanol / 30 - 70 °C 5: triethylamine / ethanol / 50 - 60 °C / Inert atmosphere 6: hydrogenchloride; water / methanol / 35 °C 7: isopentyl nitrite / acetonitrile / 30 - 60 °C 8: N-ethyl-N,N-diisopropylamine / acetonitrile / 25 - 35 °C 9: lithium borohydride / tetrahydrofuran / -10 - 20 °C
	Multi-step reaction with 8 steps 1.1: triethylamine / tetrahydrofuran / 1 h / 20 °C 2.1: iron; acetic acid / 2 h / 20 °C 3.1: acetic acid; sodium nitrite / 1 h / 20 °C 4.1: potassium carbonate / 2 h 5.1: sodium hydride / tetrahydrofuran; mineral oil / 0.25 h / -10 °C 5.2: 16 h / -10 °C 6.1: lithium borohydride / tetrahydrofuran / 16 h / 20 °C 7.1: dimethyl sulfoxide / 16 h / 60 °C 8.1: phosphoric acid / methanol / 24 h / 20 °C
	Multi-step reaction with 8 steps 1.1: triethylamine / tetrahydrofuran / 1 h / 20 °C 2.1: methanol / 1 h / 20 °C 3.1: sodium carbonate; Aminoiminomethanesulfinic acid / methanol; water / 1 h / 60 °C 4.1: acetic acid; sodium nitrite / 1 h / 20 °C 5.1: sodium hydride / tetrahydrofuran; mineral oil / 0.25 h / -10 °C 5.2: 16 h / -10 °C 6.1: lithium borohydride / tetrahydrofuran / 16 h / 20 °C 7.1: dimethyl sulfoxide / 16 h / 60 °C 8.1: phosphoric acid / methanol / 24 h / 20 °C
	Multi-step reaction with 4 steps 1.1: methanol / 1 h / 20 °C 1.2: 2 h / 20 - 60 °C 1.3: 1 h / 20 °C 2.1: sodium hydride / tetrahydrofuran / 0.25 h / -10 °C 2.2: 2 h / -10 °C 2.3: 2 h / 20 °C 3.1: dimethyl sulfoxide / 16 h / 20 - 60 °C 4.1: phosphoric acid; water / methanol / 24 h / 20 °C
	Multi-step reaction with 5 steps 1.1: methanol / 1 h / 20 °C 1.2: 2 h / 20 - 60 °C 1.3: 1 h / 20 °C 2.1: sodium hydride / tetrahydrofuran / 0.25 h / -10 °C 2.2: 2 h / -10 °C 3.1: lithium borohydride / tetrahydrofuran / 16 h / 0 - 20 °C 4.1: dimethyl sulfoxide / 16 h / 20 - 60 °C 5.1: phosphoric acid; water / methanol / 24 h / 20 °C
	Multi-step reaction with 7 steps 1.1: triethylamine / tetrahydrofuran / 1 h / 20 °C 2.1: methanol / 1 h / 20 °C 3.1: sodium carbonate; Aminoiminomethanesulfinic acid / methanol; water / 1 h / 60 °C 4.1: sodium nitrite; acetic acid / 1 h / 20 °C 5.1: sodium hydride / tetrahydrofuran / 0.25 h / -10 °C 5.2: 2 h / -10 °C 5.3: 2 h / 20 °C 6.1: dimethyl sulfoxide / 16 h / 20 - 60 °C 7.1: phosphoric acid; water / methanol / 24 h / 20 °C
	Multi-step reaction with 7 steps 1.1: triethylamine / tetrahydrofuran / 1 h / 20 °C 2.1: iron; acetic acid / 2 h / 20 °C 3.1: isopentyl nitrite / acetonitrile / 1 h / 70 °C 4.1: potassium carbonate / 2 h / 20 °C 5.1: sodium hydride / tetrahydrofuran / 0.25 h / -10 °C 5.2: 2 h / -10 °C 5.3: 2 h / 20 °C 6.1: dimethyl sulfoxide / 16 h / 20 - 60 °C 7.1: phosphoric acid; water / methanol / 24 h / 20 °C
	Multi-step reaction with 7 steps 1.1: triethylamine / tetrahydrofuran / 1 h / 20 °C 2.1: iron; acetic acid / 2 h / 20 °C 3.1: isopentyl nitrite / acetonitrile / 1 h / 70 °C 4.1: methanol / 0.25 h / 20 °C 5.1: sodium hydride / tetrahydrofuran / 0.25 h / -10 °C 5.2: 2 h / -10 °C 5.3: 2 h / 20 °C 6.1: dimethyl sulfoxide / 16 h / 20 - 60 °C 7.1: phosphoric acid; water / methanol / 24 h / 20 °C
	Multi-step reaction with 8 steps 1.1: triethylamine / tetrahydrofuran / 1 h / 20 °C 2.1: iron; acetic acid / 2 h / 20 °C 3.1: isopentyl nitrite / acetonitrile / 1 h / 70 °C 4.1: methanol / 0.25 h / 20 °C 5.1: sodium hydride / tetrahydrofuran / 0.25 h / -10 °C 5.2: 2 h / -10 °C 6.1: lithium borohydride / tetrahydrofuran / 16 h / 0 - 20 °C 7.1: dimethyl sulfoxide / 16 h / 20 - 60 °C 8.1: phosphoric acid; water / methanol / 24 h / 20 °C
	Multi-step reaction with 8 steps 1.1: triethylamine / tetrahydrofuran / 1 h / 20 °C 2.1: methanol / 1 h / 20 °C 3.1: sodium carbonate; Aminoiminomethanesulfinic acid / methanol; water / 1 h / 60 °C 4.1: sodium nitrite; acetic acid / 1 h / 20 °C 5.1: sodium hydride / tetrahydrofuran / 0.25 h / -10 °C 5.2: 2 h / -10 °C 6.1: lithium borohydride / tetrahydrofuran / 16 h / 0 - 20 °C 7.1: dimethyl sulfoxide / 16 h / 20 - 60 °C 8.1: phosphoric acid; water / methanol / 24 h / 20 °C
	Multi-step reaction with 8 steps 1.1: triethylamine / tetrahydrofuran / 1 h / 20 °C 2.1: iron; acetic acid / 2 h / 20 °C 3.1: isopentyl nitrite / acetonitrile / 1 h / 70 °C 4.1: potassium carbonate / 2 h / 20 °C 5.1: sodium hydride / tetrahydrofuran / 0.25 h / -10 °C 5.2: 2 h / -10 °C 6.1: lithium borohydride / tetrahydrofuran / 16 h / 0 - 20 °C 7.1: dimethyl sulfoxide / 16 h / 20 - 60 °C 8.1: phosphoric acid; water / methanol / 24 h / 20 °C
	Multi-step reaction with 8 steps 1.1: triethylamine / tetrahydrofuran / 1 h / 20 °C 2.1: iron; acetic acid / 2 h / 20 °C 3.1: isopentyl nitrite / acetonitrile / 1 h / 70 °C 4.1: potassium phosphate / 88 h / 70 °C 5.1: sodium hydride / tetrahydrofuran / 0.25 h / -10 °C 5.2: 2 h / -10 °C 6.1: lithium borohydride / tetrahydrofuran / 1 h / 20 °C 7.1: dimethyl sulfoxide / 72 h / 20 - 70 °C 8.1: phosphoric acid; water / methanol / 24 h / 20 °C
	Multi-step reaction with 7 steps 1: potassium carbonate / ethyl acetate; water / 3 h / 0 - 20 °C 2: potassium <i>tert</i>-butylate / tetrahydrofuran / 2 h / -10 °C 3: palladium on activated charcoal; hydrogen / methanol / 20 °C 4: N-ethyl-N,N-diisopropylamine / ethanol / 20 - 100 °C 5: acetic acid; sodium nitrite / water; toluene / 4 h / 15 - 20 °C 6: potassium carbonate / water / 15 °C 7: trifluoroacetic acid / methanol; toluene / 8 h / 15 °C
	Multi-step reaction with 8 steps 1: potassium carbonate / ethyl acetate; water / 3 h / 0 - 20 °C 2: potassium <i>tert</i>-butylate / tetrahydrofuran / 2 h / -10 °C 3: palladium on activated charcoal; hydrogen / methanol / 20 °C 4: N-ethyl-N,N-diisopropylamine / ethanol / 20 - 100 °C 5: acetic acid; sodium nitrite / water; toluene / 4 h / 15 - 20 °C 6: potassium carbonate / water / 15 °C 7: sodium methylate; methanol / 20 °C 8: hydrogenchloride / water; methanol / 8 h / 15 °C

Reference： [1]Zhang, Hao; Liu, Jun; Zhang, Luyong; Kong, Lingyi; Yao, Hequan; Sun, Hongbin [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 11, p. 3598 - 3602]
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/85665, 2012, A2
[3]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/85665, 2012, A2
[4]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/85665, 2012, A2
[5]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[6]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[7]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[8]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[9]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[10]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[11]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[12]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[13]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[14]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[15]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[16]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[17]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[18]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[19]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[20]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[21]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[22]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[23]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - EP2586773, 2013, A1
[24]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - EP2586773, 2013, A1
[25]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/60837, 2013, A1
[26]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/60837, 2013, A1
[27]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/60837, 2013, A1
[28]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/60837, 2013, A1
[29]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/60837, 2013, A1
[30]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/60837, 2013, A1
[31]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/60837, 2013, A1
[32]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/60837, 2013, A1
[33]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/60837, 2013, A1
[34]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - CN103626743, 2018, B
[35]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - CN103626743, 2018, B

42
[ 155899-66-4 ]
[ 220347-05-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: triethylamine; sodium iodide / 1,4-dioxane / 120 °C 2: sodium nitrite / water; acetic acid; ethyl acetate 3: N-ethyl-N,N-diisopropylamine / dichloromethane 4: hydrogenchloride; water / methanol; water
	Multi-step reaction with 4 steps 1: triethylamine / 110 °C / Sealed tube 2: acetic acid; sodium nitrite / 0 - 20 °C 3: triethylamine / acetonitrile / 2 h / 80 °C 4: hydrogenchloride / methanol; water / 0.5 h / 20 °C

Reference： [1]Zhang, Hao; Liu, Jun; Zhang, Luyong; Kong, Lingyi; Yao, Hequan; Sun, Hongbin [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 11, p. 3598 - 3602]
[2]Goffin, Eric; Jacques, Nicolas; Lancellotti, Patrizio; Musumeci, Lucia; Nchimi, Alain; Pirotte, Bernard; Oury, Cécile [European Journal of Medicinal Chemistry, 2020, vol. 208]

43
[ 155899-66-4 ]
[ 220241-61-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: triethylamine; sodium iodide / 1,4-dioxane / 120 °C 2: sodium nitrite / water; acetic acid; ethyl acetate
	Multi-step reaction with 3 steps 1: triethylamine / tetrahydrofuran / 1 h / 20 °C 2: iron; acetic acid / 2 h / 20 °C 3: acetic acid; sodium nitrite / 1 h / 20 °C
	Multi-step reaction with 3 steps 1: triethylamine / tetrahydrofuran / 1 h / 20 °C 2: iron; acetic acid / 2 h / 20 °C 3: isopentyl nitrite / acetonitrile / 1 h / 70 °C

	Multi-step reaction with 2 steps 1: triethylamine / ethanol / Reflux 2: sodium nitrite / water; acetic acid
	Multi-step reaction with 2 steps 1: triethylamine / 110 °C / Sealed tube 2: acetic acid; sodium nitrite / 0 - 20 °C

Reference： [1]Zhang, Hao; Liu, Jun; Zhang, Luyong; Kong, Lingyi; Yao, Hequan; Sun, Hongbin [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 11, p. 3598 - 3602]
[2]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - EP2586773, 2013, A1
[3]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/60837, 2013, A1
[4]Tu, Wangyang; Fan, Jiang; Zhang, Haitang; Xu, Guoji; Liu, Zhiwei; Qu, Jian; Yang, Fanglong; Zhang, Lei; Luan, Tianyu; Yuan, Jijun; Gong, Aishen; Feng, Jun; Sun, Piaoyang; Dong, Qing [Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 1, p. 141 - 146]
[5]Goffin, Eric; Jacques, Nicolas; Lancellotti, Patrizio; Musumeci, Lucia; Nchimi, Alain; Pirotte, Bernard; Oury, Cécile [European Journal of Medicinal Chemistry, 2020, vol. 208]

44
[ 155899-66-4 ]
[ 274693-49-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: triethylamine; sodium iodide / 1,4-dioxane / 120 °C 2: sodium nitrite / water; acetic acid; ethyl acetate 3: N-ethyl-N,N-diisopropylamine / dichloromethane
	Multi-step reaction with 3 steps 1: triethylamine / ethanol / Reflux 2: sodium nitrite / water; acetic acid 3: triethylamine / acetonitrile
	Multi-step reaction with 3 steps 1: triethylamine / 110 °C / Sealed tube 2: acetic acid; sodium nitrite / 0 - 20 °C 3: triethylamine / acetonitrile / 2 h / 80 °C

Reference： [1]Zhang, Hao; Liu, Jun; Zhang, Luyong; Kong, Lingyi; Yao, Hequan; Sun, Hongbin [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 11, p. 3598 - 3602]
[2]Tu, Wangyang; Fan, Jiang; Zhang, Haitang; Xu, Guoji; Liu, Zhiwei; Qu, Jian; Yang, Fanglong; Zhang, Lei; Luan, Tianyu; Yuan, Jijun; Gong, Aishen; Feng, Jun; Sun, Piaoyang; Dong, Qing [Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 1, p. 141 - 146]
[3]Goffin, Eric; Jacques, Nicolas; Lancellotti, Patrizio; Musumeci, Lucia; Nchimi, Alain; Pirotte, Bernard; Oury, Cécile [European Journal of Medicinal Chemistry, 2020, vol. 208]

45
[ 155899-66-4 ]
[ 274693-26-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3598 - 3602
[2]Patent: WO2012/85665,2012,A2
[3]Patent: WO2012/138981,2012,A2
[4]Patent: WO2012/138981,2012,A2
[5]Patent: WO2012/138981,2012,A2
[6]Patent: WO2012/138981,2012,A2
[7]Patent: WO2012/138981,2012,A2
[8]Patent: WO2012/138981,2012,A2
[9]Patent: WO2012/138981,2012,A2
[10]Patent: WO2012/138981,2012,A2
[11]Patent: EP2586773,2013,A1
[12]Patent: EP2586773,2013,A1
[13]Patent: WO2013/60837,2013,A1
[14]Patent: WO2013/60837,2013,A1
[15]Patent: WO2013/60837,2013,A1
[16]Patent: WO2013/60837,2013,A1
[17]Patent: WO2013/60837,2013,A1
[18]Patent: WO2013/60837,2013,A1
[19]Patent: WO2013/60837,2013,A1
[20]Patent: WO2013/60837,2013,A1
[21]Patent: WO2013/60837,2013,A1
[22]Patent: CN103626743,2018,B

46
[ 50600-40-3 ]
[ 155899-66-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3598 - 3602
[2]Patent: WO2013/92900,2013,A1
[3]Patent: WO2013/92900,2013,A1

47
[ 100-39-0 ]
[ 155899-66-4 ]
[ 1383715-55-6 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: benzyl bromide; (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol With potassium carbonate In ethanol; water at 60 - 65℃; for 3h; Stage #2: With ammonia In ethanol; water for 0.25h;	3 Example 3Preparation of (3ai?,4S,6R,6aS)-6-(N,N-Dibenzylamino)-2,2-dimethyltetrahydro-3aH- cyclopenta[ ethyl acetate in hexane) to produce 27.5 g of (3ai?,4S,6R,6aS)-6- N,N-dibenzylamino)-2,2-dimethyltetrahydro-3aH-cyclopenta[(i] [ 1 ,3] dioxol-4-ol.1H-NMR(CDC13, δ): 1.31 (3Η, s), 1.44 (1Η, m), 1.45 (3Η, s), 2.14 (2Η, dd), 3.23 (1Η, m), 3.69 (2Η, s), 3.82 (2Η, s), 4.09 (1Η, m), 4.35 (1Η, d), 4.84 (1Η, d), 7.23-7.36 (10Η, m).Mass [Μ+Η] : 354.6.
	With sodium carbonate In ethanol; water at 25 - 42℃; for 8h;	1 (3aR,45,6R,6a5)-6-Amino-2,2-dimethyltetrahydro-3aH-cyclopenta[(i][l,3]dioxol-4-ol (115 g) was added to a solution of sodium carbonate (246.29 g) in water (450 ml). A solution of benzyl bromide (227.19 g) in denatured ethanol (230 ml) was added to the resulting suspension while maintaining the temperature at about 25-30°C. The resulting mixture was heated at 38-42°C, followed by stirring for 8 hours at 38-42°C. After completion of the reaction, 25% aqueous ammonia solution (75 ml) and water (1150 ml) were added to the reaction mass, followed by stirring for 15 minutes at 25-30°C. The resulting basic solution was extracted with dichloromethane (2 x 575 ml), followed by washing the combined dichloromethane layer with water (2 x 288 ml). The dichloromethane layer was concentrated under reduced pressure while maintaining the temperature at below 40°C. n-Heptane (1380 ml) was added to the concentrated mass, followed by heating at 60-65°C. The resulting solution was cooled to 30-35°C, followed by the addition of seeding (1.15 g). The resulting thick slurry was stirred for 3 hours at 25-30°C, followed by cooling to 0-5°C. The cooled slurry was stirred for 2 hours, followed by isolation of product by filtration. The wet cake was washed with chilled n-heptane (58 ml and 115 ml). The wet cake was further suction dried, followed by drying at 30-35°C under reduced pressure to obtain 197 g of (3aR,45,,6R,6a5,)-6- (N,N-dibenzylamino)-2,2-dimethyltetrahydro-3aH-cyclopenta[(i][l,3]dioxol-4-ol as off white solid (Yield: 171.30% w/w; Purity by HPLC: 98.65% by area).
197 g	With sodium carbonate In ethanol; water at 25 - 42℃; for 8h;	1 Preparation of (3aR,4S,6R,6aS)-6-(N,N-Dibenzylamino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol Example 1 Preparation of (3aR,4S,6R,6aS)-6-(N,N-Dibenzylamino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (3aR,4S,6R,6aS)-6-Amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (115 g) was added to a solution of sodium carbonate (246.29 g) in water (450 ml). A solution of benzyl bromide (227.19 g) in denatured ethanol (230 ml) was added to the resulting suspension while maintaining the temperature at about 25-30° C. The resulting mixture was heated at 38-42° C., followed by stiffing for 8 hours at 38-42° C. After completion of the reaction, 25% aqueous ammonia solution (75 ml) and water (1150 ml) were added to the reaction mass, followed by stirring for 15 minutes at 25-30° C. The resulting basic solution was extracted with dichloromethane (2575 ml), followed by washing the combined dichloromethane layer with water (2288 ml). The dichloromethane layer was concentrated under reduced pressure while maintaining the temperature at below 40° C. n-Heptane (1380 ml) was added to the concentrated mass, followed by heating at 60-65° C. The resulting solution was cooled to 30-35° C., followed by the addition of seeding (1.15 g). The resulting thick slurry was stirred for 3 hours at 25-30° C., followed by cooling to 0-5° C. The cooled slurry was stirred for 2 hours, followed by isolation of product by filtration. The wet cake was washed with chilled n-heptane (58 ml and 115 ml). The wet cake was further suction dried, followed by drying at 30-35° C. under reduced pressure to obtain 197 g of (3aR,4S,6R,6aS)-6-(N,N-dibenzylamino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol as off white solid (Yield: 171.30% w/w; Purity by HPLC: 98.65% by area).

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/85665, 2012, A2 Location in patent: Page/Page column 50
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/172426, 2012, A1 Location in patent: Page/Page column 16-17
[3]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - US2014/206867, 2014, A1 Location in patent: Paragraph 0085

48
[ 155899-66-4 ]
[ 1402149-98-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C
	Multi-step reaction with 3 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2

49
[ 155899-66-4 ]
[ 1402149-99-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C
	Multi-step reaction with 4 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2

50
[ 155899-66-4 ]
[ 1402150-00-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: triethylamine / ethanol / 36 h / 125 °C / 3677.86 Torr / Autoclave; Inert atmosphere
	Multi-step reaction with 4 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: triethylamine / ethanol / 36 h / 125 °C / 3677.86 Torr / Autoclave; Inert atmosphere
	Multi-step reaction with 5 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: acetic acid; iron / methanol / 20 - 35 °C

Multi-step reaction with 5 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium tert-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: acetic acid; iron / methanol / 20 - 35 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[3]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[4]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2

51
[ 155899-66-4 ]
[ 1402150-01-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: triethylamine / ethanol / 36 h / 125 °C / 3677.86 Torr / Autoclave; Inert atmosphere 5.1: isopentyl nitrite / acetonitrile / 50 - 70 °C
	Multi-step reaction with 5 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: triethylamine / ethanol / 36 h / 125 °C / 3677.86 Torr / Autoclave; Inert atmosphere 5.1: isopentyl nitrite / acetonitrile / 50 - 70 °C
	Multi-step reaction with 6 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: acetic acid; iron / methanol / 20 - 35 °C 6.1: isopentyl nitrite / acetonitrile / 50 - 70 °C

Multi-step reaction with 6 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium tert-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: acetic acid; iron / methanol / 20 - 35 °C 6.1: isopentyl nitrite / acetonitrile / 50 - 70 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[3]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[4]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2

52
[ 155899-66-4 ]
[ 1402150-02-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: triethylamine / ethanol / 36 h / 125 °C / 3677.86 Torr / Autoclave; Inert atmosphere 5.1: isopentyl nitrite / acetonitrile / 50 - 70 °C 6.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 35 °C
	Multi-step reaction with 6 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: triethylamine / ethanol / 36 h / 125 °C / 3677.86 Torr / Autoclave; Inert atmosphere 5.1: isopentyl nitrite / acetonitrile / 50 - 70 °C 6.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 35 °C
	Multi-step reaction with 7 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: acetic acid; iron / methanol / 20 - 35 °C 6.1: isopentyl nitrite / acetonitrile / 50 - 70 °C 7.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 35 °C

Multi-step reaction with 7 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium tert-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: acetic acid; iron / methanol / 20 - 35 °C 6.1: isopentyl nitrite / acetonitrile / 50 - 70 °C 7.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 35 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[3]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[4]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2

53
[ 155899-66-4 ]
[ 1402150-03-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: triethylamine / ethanol / 36 h / 125 °C / 3677.86 Torr / Autoclave; Inert atmosphere 5.1: sodium hydroxide; water / methanol / 0 - 30 °C
	Multi-step reaction with 5 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: triethylamine / ethanol / 36 h / 125 °C / 3677.86 Torr / Autoclave; Inert atmosphere 5.1: sodium hydroxide; water / methanol / 0 - 30 °C
	Multi-step reaction with 6 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: acetic acid; iron / methanol / 20 - 35 °C 6.1: sodium hydroxide; water / methanol / 0 - 30 °C

Multi-step reaction with 6 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium tert-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: acetic acid; iron / methanol / 20 - 35 °C 6.1: sodium hydroxide; water / methanol / 0 - 30 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[3]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[4]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2

54
[ 155899-66-4 ]
[ 1402150-04-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: triethylamine / ethanol / 36 h / 125 °C / 3677.86 Torr / Autoclave; Inert atmosphere 5.1: sodium hydroxide; water / methanol / 0 - 30 °C 6.1: isopentyl nitrite / acetonitrile / 10 - 70 °C
	Multi-step reaction with 6 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: triethylamine / ethanol / 36 h / 125 °C / 3677.86 Torr / Autoclave; Inert atmosphere 5.1: sodium hydroxide; water / methanol / 0 - 30 °C 6.1: isopentyl nitrite / acetonitrile / 10 - 70 °C
	Multi-step reaction with 7 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: acetic acid; iron / methanol / 20 - 35 °C 6.1: sodium hydroxide; water / methanol / 0 - 30 °C 7.1: isopentyl nitrite / acetonitrile / 10 - 70 °C

Multi-step reaction with 7 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium tert-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: acetic acid; iron / methanol / 20 - 35 °C 6.1: sodium hydroxide; water / methanol / 0 - 30 °C 7.1: isopentyl nitrite / acetonitrile / 10 - 70 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[3]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[4]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2

55
[ 155899-66-4 ]
[ 1402150-05-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: triethylamine / ethanol / 36 h / 125 °C / 3677.86 Torr / Autoclave; Inert atmosphere 5.1: sodium hydroxide; water / methanol / 0 - 30 °C 6.1: isopentyl nitrite / acetonitrile / 10 - 70 °C 7.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 30 °C
	Multi-step reaction with 7 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: triethylamine / ethanol / 36 h / 125 °C / 3677.86 Torr / Autoclave; Inert atmosphere 5.1: sodium hydroxide; water / methanol / 0 - 30 °C 6.1: isopentyl nitrite / acetonitrile / 10 - 70 °C 7.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 30 °C
	Multi-step reaction with 8 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: acetic acid; iron / methanol / 20 - 35 °C 6.1: sodium hydroxide; water / methanol / 0 - 30 °C 7.1: isopentyl nitrite / acetonitrile / 10 - 70 °C 8.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 30 °C

Multi-step reaction with 8 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium tert-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: acetic acid; iron / methanol / 20 - 35 °C 6.1: sodium hydroxide; water / methanol / 0 - 30 °C 7.1: isopentyl nitrite / acetonitrile / 10 - 70 °C 8.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 30 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[3]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[4]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2

56
[ 155899-66-4 ]
[ 1402150-06-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: hydrogenchloride; water / 20 - 70 °C
	Multi-step reaction with 5 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: hydrogenchloride; water / 20 - 70 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2

57
[ 155899-66-4 ]
[ 1402150-07-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: hydrogenchloride; water / 20 - 70 °C 6.1: acetic acid / methanol / 0 - 30 °C
	Multi-step reaction with 6 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: hydrogenchloride; water / 20 - 70 °C 6.1: acetic acid / methanol / 0 - 30 °C
	Multi-step reaction with 6 steps 1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3: sodium hydroxide; water / tetrahydrofuran / 10 - 20 °C 4: ammonium formate / palladium 10% on activated carbon / ethanol / 30 - 70 °C 5: triethylamine / ethanol / 50 - 60 °C / Inert atmosphere 6: hydrogenchloride; water / methanol / 35 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[3]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2

58
[ 155899-66-4 ]
[ 1402150-08-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: hydrogenchloride; water / 20 - 70 °C 6.1: acetic acid / methanol / 0 - 30 °C 7.1: isopentyl nitrite / acetonitrile / 30 - 60 °C
	Multi-step reaction with 7 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: hydrogenchloride; water / 20 - 70 °C 6.1: acetic acid / methanol / 0 - 30 °C 7.1: isopentyl nitrite / acetonitrile / 30 - 60 °C
	Multi-step reaction with 7 steps 1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3: sodium hydroxide; water / tetrahydrofuran / 10 - 20 °C 4: ammonium formate / palladium 10% on activated carbon / ethanol / 30 - 70 °C 5: triethylamine / ethanol / 50 - 60 °C / Inert atmosphere 6: hydrogenchloride; water / methanol / 35 °C 7: isopentyl nitrite / acetonitrile / 30 - 60 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[3]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2

59
[ 155899-66-4 ]
[ 1402150-11-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: triethylamine / ethanol / 36 h / 125 °C / 3677.86 Torr / Autoclave; Inert atmosphere 5.1: sodium hydroxide; water / methanol / 0 - 30 °C 6.1: isopentyl nitrite / acetonitrile / 10 - 70 °C 7.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 30 °C 8.1: hydrogenchloride; water / 16 h / 20 °C
	Multi-step reaction with 8 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: triethylamine / ethanol / 36 h / 125 °C / 3677.86 Torr / Autoclave; Inert atmosphere 5.1: sodium hydroxide; water / methanol / 0 - 30 °C 6.1: isopentyl nitrite / acetonitrile / 10 - 70 °C 7.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 30 °C 8.1: hydrogenchloride; water / 16 h / 20 °C
	Multi-step reaction with 8 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: hydrogenchloride; water / 20 - 70 °C 6.1: acetic acid / methanol / 0 - 30 °C 7.1: isopentyl nitrite / acetonitrile / 30 - 60 °C 8.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 25 - 35 °C

	Multi-step reaction with 8 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: hydrogenchloride; water / 20 - 70 °C 6.1: acetic acid / methanol / 0 - 30 °C 7.1: isopentyl nitrite / acetonitrile / 30 - 60 °C 8.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 25 - 35 °C
	Multi-step reaction with 8 steps 1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3: sodium hydroxide; water / tetrahydrofuran / 10 - 20 °C 4: ammonium formate / palladium 10% on activated carbon / ethanol / 30 - 70 °C 5: triethylamine / ethanol / 50 - 60 °C / Inert atmosphere 6: hydrogenchloride; water / methanol / 35 °C 7: isopentyl nitrite / acetonitrile / 30 - 60 °C 8: N-ethyl-N,N-diisopropylamine / acetonitrile / 25 - 35 °C
	Multi-step reaction with 9 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: acetic acid; iron / methanol / 20 - 35 °C 6.1: sodium hydroxide; water / methanol / 0 - 30 °C 7.1: isopentyl nitrite / acetonitrile / 10 - 70 °C 8.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 30 °C 9.1: hydrogenchloride; water / 16 h / 20 °C
	Multi-step reaction with 9 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: acetic acid; iron / methanol / 20 - 35 °C 6.1: sodium hydroxide; water / methanol / 0 - 30 °C 7.1: isopentyl nitrite / acetonitrile / 10 - 70 °C 8.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 30 °C 9.1: hydrogenchloride; water / 16 h / 20 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[3]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[4]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[5]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[6]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[7]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2

60
[ 155899-66-4 ]
[ 1402150-31-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: lithium borohydride / tetrahydrofuran / 0 - 20 °C 3.2: 20 °C 3.3: pH 6 - 7 4.1: ammonium formate / palladium 10% on activated carbon / ethanol / 30 - 70 °C 4.2: 20 - 70 °C 5.1: triethylamine / ethanol / 40 - 80 °C / Inert atmosphere
	Multi-step reaction with 5 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: lithium borohydride / tetrahydrofuran / 0 - 20 °C 3.2: 20 °C 3.3: pH 6 - 7 4.1: ammonium formate / palladium 10% on activated carbon / ethanol / 30 - 70 °C 5.1: triethylamine / ethanol / 40 - 80 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2

61
[ 155899-66-4 ]
[ 1402150-32-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: lithium borohydride / tetrahydrofuran / 0 - 20 °C 3.2: 20 °C 3.3: pH 6 - 7 4.1: ammonium formate / palladium 10% on activated carbon / ethanol / 30 - 70 °C 4.2: 20 - 70 °C 5.1: triethylamine / ethanol / 40 - 80 °C / Inert atmosphere 6.1: hydrogenchloride; water / methanol / 35 °C
	Multi-step reaction with 6 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: lithium borohydride / tetrahydrofuran / 0 - 20 °C 3.2: 20 °C 3.3: pH 6 - 7 4.1: ammonium formate / palladium 10% on activated carbon / ethanol / 30 - 70 °C 5.1: triethylamine / ethanol / 40 - 80 °C / Inert atmosphere 6.1: hydrogenchloride; water / methanol / 35 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2

62
[ 155899-66-4 ]
[ 1354945-69-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: lithium borohydride / tetrahydrofuran / 0 - 20 °C 3.2: 20 °C 3.3: pH 6 - 7 4.1: ammonium formate / palladium 10% on activated carbon / ethanol / 30 - 70 °C 4.2: 20 - 70 °C 5.1: triethylamine / ethanol / 40 - 80 °C / Inert atmosphere 6.1: hydrogenchloride; water / methanol / 35 °C 7.1: sodium nitrite / water; methanol / 0 - 5 °C
	Multi-step reaction with 7 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: lithium borohydride / tetrahydrofuran / 0 - 20 °C 3.2: 20 °C 3.3: pH 6 - 7 4.1: ammonium formate / palladium 10% on activated carbon / ethanol / 30 - 70 °C 5.1: triethylamine / ethanol / 40 - 80 °C / Inert atmosphere 6.1: hydrogenchloride; water / methanol / 35 °C 7.1: sodium nitrite / water; methanol / 0 - 5 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2

63
[ 13734-34-4 ]
[ 155899-66-4 ]
[ 1413395-24-0 ]

Yield	Reaction Conditions	Operation in experiment
44.6%	In isopropyl alcohol; toluene at 70℃;	7 (3aR,4S, 6R,6a,S)-6-Amino-2,2-dimethyltetrahydro-3aH-cyclopenta[

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2012/158099, 2012, A1 Location in patent: Page/Page column 4; 10

64
[ 13139-15-6 ]
[ 155899-66-4 ]
[ 1413395-26-2 ]

Yield	Reaction Conditions	Operation in experiment
46.7%	In isopropyl alcohol; toluene at 79℃;	12 (3aR,4S, 6R,6a,S)-6-Amino-2,2-dimethyltetrahydro-3aH-cyclopenta['so-propanol (2x10 mL) and dried in vacuum at 40 °C to give an amount of 5.24 g (46.7%, 99.4% ee).

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2012/158099, 2012, A1 Location in patent: Page/Page column 4; 12-13

65
[ 155899-66-4 ]
[ 1416158-39-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: sodium carbonate / ethanol; water / 8 h / 25 - 42 °C 2: potassium <i>tert</i>-butylate / dichloromethane; tetrahydrofuran / 5.5 h / 0 - 5 °C 3: hydrogen / palladium-on-charcoal / ethanol / 14 h / 43 - 48 °C / 3620.13 Torr / Autoclave
	Multi-step reaction with 4 steps 1.1: sodium carbonate / water; ethanol / 8 h / 25 - 42 °C 2.1: potassium <i>tert</i>-butylate / dichloromethane; tetrahydrofuran / 5.5 h / 0 - 5 °C 3.1: palladium 10% on activated carbon; hydrogen / ethanol-d6 / 14 h / 43 - 48 °C / 3620.13 Torr / Inert atmosphere 3.2: -5 - 55 °C 4.1: potassium carbonate / water; dichloromethane / 20 - 25 °C / pH 10 - 10.5

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/172426, 2012, A1
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - US2014/206867, 2014, A1

66
[ 1427523-85-0 ]
[ 155899-66-4 ]
[ 1427523-87-2 ]

Yield	Reaction Conditions	Operation in experiment
2.14 g	With potassium phosphate In acetonitrile for 2h;	13 Example 13: Preparation of N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-N-(6-(((3aS,4R,6S, 6aR)-6-hydroxy-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)amino)-5-nitro-2-(propylthio)pyrimidin-4-yl)-4-methylbenzenesulfonamide (CTsAMCIN) [0089] To a solution of CPATs (1.29 g, 4 mmol) and CLIN (1.07 g, 4 mmol) in acetonitrile (15 mL) was added anhydrous K3PO4 (1.27 g, 6 mmol) and the mixture stirred for 24 h at 25 °C. AMAL (0.66 g, 3.8 mmol) was then added and stirring continued for additional 2 h. The reaction mixture was then diluted with water (50 mL), extracted with diisopropyl ether (50 mL), the extract washed with water (2 × 50 mL) and evaporated under reduced pressure. The crude product was purified with flash chromatography to give an amorphous solid (2.14 g, 77%): 95 area% HPLC; MS (ESI) m/z: 692 [MH]+; 19F NMR (CDCl3, 470.5 MHz) δ -138.93 (m, 1 F), -141.97 (m, 1 F).
2.14 g	With potassium phosphate In acetonitrile for 2h;	13 Preparation of Λ/-((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-N-(6-(((3aS,4R,6S, 6aF?)-6- hydroxy-2,2-dimethyltetrahydro-3a/-/-cyclopenta[ ][1 ,3]dioxol-4-yl)amino)-5-nitro-2- (propylthio)pyrimidin-4-yl)-4-methylbenzenesulfonamide (CTsAMCIN) To a solution of CPATs (1 .29 g, 4 mmol) and CLIN (1 .07 g, 4 mmol) in acetonitrile (1 5 mL) was added anhydrous K3P04 (1 .27 g, 6 mmol) and the mixture stirred for 24 h at 25Ό. AMAL (0.66 g, 3.8 mmol) was then added and stirring continued for additional 2 h. The reaction mixture was then diluted with water (50 mL), extracted with diisopropyl ether (50 mL), the extract washed with water (2 χ 50 mL) and evaporated under reduced pressure. The crude product was purified with flash chromatography to give an amorphous solid (2.14 g, 77% yield) : 95 area% H PLC; MS (ESI) mlz: 692 [MH]+; 19F NMR (CDCI3, 470.5 MHz) δ - 138.93 (m, 1 F), -141 .97 (m , 1 F).

Reference： [1]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2570405, 2013, A1 Location in patent: Paragraph 0088; 0089
[2]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - WO2013/37942, 2013, A1 Location in patent: Page/Page column 33

67
[ 1427523-86-1 ]
[ 155899-66-4 ]
[ 1427524-09-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate In acetonitrile for 2h;	16 Example 16: Preparation of N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-N-(3-((3aS,4R,6S, 6aR)-6-hydroxy-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)naphthalene-2-sulfonamide (NATAM) [0097] A mixture of CLIN (1.27 g, 4.75 mmol), CPAN (1.80 g, 5 mmol) and K3PO4 (3.03 g, 14.25 mmol) in acetonitrile (20 mL) was stirred for 150 min at 25 °C. AMAL (0.78 g, 4.5 mmol) was added and the mixture stirred for additional 2 hours. At this point formamidinesulfinic acid (2.05 g, 19 mmol) was added and the reaction temperature increased to 60 °C. After 18 hours, the mixture was diluted with water (100 mL), extracted with ethyl acetate (60 mL), the extract washed with 0.1 M HCl(aq) (60 mL) and evaporated under reduced pressure to give a brown resin (3.18 g). This was dissolved in ethyl acetate (30 mL), isopentyl nitrite (0.76 mL, 5.63 mmol) was added and the solution stirred for 1 h at 60 °C. The brown solution was concentrated and the product isolated using flash chromatography with hexane / ethyl acetate eluent (gradient from 5 : 1 to 2 : 1). NATAM was thus obtained as a beige powder (1.86 g, 58%).

Reference： [1]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2570405, 2013, A1 Location in patent: Paragraph 0096; 0097

68
[ 1383715-58-9 ]
[ 155899-66-4 ]
[ 1427523-79-2 ]

Yield	Reaction Conditions	Operation in experiment
93%	With triethylamine In tetrahydrofuran at 20℃; for 1h;	3 Example 3: Preparation of tert-butyl ((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)(6-(((3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydro-3aH-cyclopenta[d]-[1,3]dioxol-4-yl)amino)-5-nitro-2-(propylthio)pyrimidin-4-yl)carbamate (BAAL) To a solution of CPABOCCIN (0.20 g, 0.40 mmol) and triethylamine (0.061 mL, 0.44 mmol) in dry THF (2 mL) was added AMAL (76 mg, 0.44 mmol). The resulting reaction mixture was stirred at room temperature for 1 h, then water was added (10 mL), and the product was extracted to THF (3 x 5 mL). Combined organic layers were dried over MgSO4, and then concentrated. Purification by chromatography (SiO2, hexane:EtOAc) afforded the title compound as a yellow oil (0.24 g, 93% yield). 1H NMR (CDCl3, 500 MHz) δ 0.96 (t, J = 7.3 Hz, 3H), 1.19 (s, 3H), 1.27 (m, 2H), 1.31 (s, 9H), 1.36 (s, 3H), 1.69 (m, 2H), 1.77 (m, 1 H), 2.19 (br s, 1H), 2.26 (m, 1H), 2.67 (m, 1H), 2.91-3.08 (m, 3H), 4.29 (m, 1H), 4.46 (m, 1H), 4.52 (m, 1H), 4.68 (m, 1H), 6.88 (m, 1H), 6.94-7.01 (m, 2H), 8.64 (d, J = 8.0 Hz, 1H); 19F NMR (CDCl3, 470.5 MHz) δ - 139.4 (m, 1 F), -142.6 (m, 1 F); MS (ESI) m/z: 638 [MH]+.
93%	With triethylamine In tetrahydrofuran at 20℃; for 1h;	3 Preparation of ferf-butyl ((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)(6(((3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydro-3a/-/-cyclopenta[G\|-[1,3]dioxol-4- yl)amino)-5-nitro-2-(propylthio)pyrimidin-4-yl)carbamate (BAAL) To a solution of CPABOCCIN (0.20 g, 0.40 mmol) and triethylamine (0.061 mL, 0.44 mmol) in dry THF (2 mL) was added AMAL (76 mg, 0.44 mmol). The resulting reaction mixture was stirred at room temperature for 1 h, then water was added (10 m L), and the product was extracted to THF (3 x 5 m L). Combined organic layers were dried over MgS04, and then concentrated. Purification by chromatography (Si02, hexane:EtOAc) afforded the title compound as a yellow oil (0.24 g, 93% yield). 1 H NMR (CDCI3, 500 MHz) δ 0.96 (t, J = 7.3 Hz, 3H), 1 .1 9 (s, 3H), 1 .27 (m, 2H), 1 .31 (s, 9H), 1 .36 (s, 3H), 1 .69 (m, 2H), 1 .77 (m , 1 H), 2.19 (br s, 1 H), 2.26 (m , 1 H), 2.67 (m , 1 H), 2.91 -3.08 (m, 3H), 4.29 (m , 1 H), 4.46 (m , 1 H), 4.52 (m , 1 H), 4.68 (m , 1 H), 6.88 (m , 1 H), 6.94-7.01 (m , 2H), 8.64 (d, J = 8.0 Hz, 1 H) ; 19F NMR (CDCI3, 470.5 MHz) (5 -139.4 (m , 1 F), -142.6 (m , 1 F) ; MS (ESI) m/z: 638 [MH]+.

Reference： [1]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2570405, 2013, A1 Location in patent: Paragraph 0056; 0057
[2]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - WO2013/37942, 2013, A1 Location in patent: Page/Page column 25; 26

69
[ 145783-14-8 ]
[ 1427523-84-9 ]
[ 155899-66-4 ]
[ 1427524-21-7 ]

Yield	Reaction Conditions	Operation in experiment
3.18 g		A mixture of CLIN (1 .27 g, 4.75 mmol), CPAN (1 .80 g, 5 mmol) and K3P04 (3.03 g, 14.25 mmol) in acetonitrile (20 ml_) was stirred for 150 min at 25 C. AMAL (0.78 g, 4.5 mmol) was added and the mixture stirred for additional 2 hours. At this point formamidinesulfinic acid (2.05 g, 19 mmol) was added and the reaction temperature increased to 60C. After 18 hours, the mixture was diluted with water (100 m l_), extracted with ethyl acetate (60 m l_), the extract washed with 0.1 M HCI(aq) (60 ml_) and evaporated under reduced pressure to give a brown resin (3.18 g). This was dissolved in ethyl acetate (30 m l_), isopentyl nitrite (0.76 m l_, 5.63 mmol) was added and the solution stirred for 1 h at 60C. The brown solution was concentrated and the product isolated using flash chromatography with hexane / ethyl acetate eluent (gradient from 5 : 1 to 2 : 1 ). NAT AM was thus obtained as a beige powder (1 .86 g, 58% yield).

Reference： [1]Patent: WO2013/37942,2013,A1 .Location in patent: Page/Page column 34; 35

70
[ 1431867-39-8 ]
[ 155899-66-4 ]
[ 1431867-41-2 ]

Yield	Reaction Conditions	Operation in experiment
96%	With triethylamine In tetrahydrofuran at 20℃; for 1h;	7 Example 7 Preparation of (3aR,4S,6R,6aS)-6-((6-methoxy-5-nitro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (AMALMIN) To a solution of CMLIN (0.15 g, 0.57 mmol) and Et3N (87 μL, 0.63 mmol) in dry THF (2 mL) AMAL (0.10 g, 0.57 mmol) was slowly added, and reaction mixture was then stirred at room temperature for 1 h. Salts were filtered off and filtrate was concentrated to afford yellow oil (0.22 g, 96% yield). MS (ESI) m/z: 401 [MH]+.
96%	With triethylamine In tetrahydrofuran at 20℃; for 1h;	7 Example 7: Preparation of (3aR,4S,6R,6aS)-6-((6-methoxy-5-nitro-2-(propylthio)pyrimidin-4-yl)amino)- 2.2-dimethyltetrahydro-3aH-cyclopenta[c/][1.3]dioxol-4-ol (AMALMIN) To a solution of CMLIN (0.15 g, 0.57 mmol) and Et3N (87 L, 0.63 mmol) in dry THF (2 mL) AMAL (0.10 g, 0.57 mmol) was slowly added, and reaction mixture was then stirred at room temperature for 1 h. Salts were filtered off and filtrate was concentrated to afford yellow oil (0.22 g. 96% yield). MS (ESI) m/z: 401 [MH]

Reference： [1]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - EP2586773, 2013, A1 Location in patent: Paragraph 0081-0082
[2]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/60837, 2013, A1 Location in patent: Page/Page column 30

71
[ 145783-14-8 ]
[ 155899-66-4 ]
[ 220241-59-8 ]

Yield	Reaction Conditions	Operation in experiment
84%	With triethylamine; In tetrahydrofuran; at 20℃; for 1h;	The title compound was prepared using the method described in . To a solution of CLIN (11.6 g, 43.3 mmol) and Et3N (4.0 mL, 28.9 mmol) in dry THF (100 mL) solution of AMAL (5.0 g, 28.9 mmol) in dry THF (100 mL) was slowly added at room temperature, and resulting reaction mixture was stirred for 1 h. Salts were filtered off, washed with dry THF (50 mL), filtrate was concentrated, and crude product was purified by crystallization from hexane/EtOAc mixture to afford yellowish powder (m = 9.88 g, 84% yield). MP 63C; 1H NMR (DMSO-d6, 500 MHz) delta 0.98 (t, J = 7.3 Hz, 3H), 1.19 (s, 3H), 1.34 (s, 3H), 1.64-1.78 (m, 3H), 2.17 (m, 1H), 3.04 (m, 1H), 3.12 (m, 1H), 4.11 (m, 1H), 4.44 (m, 1H), 4.53-4.58 (m, 2H), 8.76 (br d, J = 7.9 Hz, 1H); MS (ESI) m/z: 405 [MH]+.
84%	With triethylamine; In tetrahydrofuran; at 20℃; for 1h;	To a solution of CLIN (1 1.6 g, 43.3 mmol) and Et3N (4.0 mL, 28.9 mmol) in dry THF (100 mL) solution of AMAL (5.0 g, 28.9 mmol) in dry THF (100 mL) was slowly added at room temperature, and resulting reaction mixture was stirred for 1 h. Salts were filtered off, washed with dry THF (50 mL), filtrate was concentrated, and crude product was purified by crystallization from hexane/EtOAc mixture to afford yellowish powder (m = 9.88 g, 84% yield). MP 63C; H NMR (DMSO-de, 500 MHz) delta 0.98 (t, J = 7.3 Hz, 3H), 1.19 (s, 3H), 1.34 (s, 3H), 1.64-1.78 (m, 3H), 2.17 (m, 1 H), 3.04 (m, 1 H), 3.12 (m, 1 H), 4.1 1 (m, 1 H), 4.44 (m, 1 H), 4.53-4.58 (m, 2H), 8.76 (br d, J = 7.9 Hz, 1 H); MS (ESI) m/z: 405 [MH] ' .

Reference： [1]Patent: EP2586773,2013,A1 .Location in patent: Paragraph 0061-0063
[2]Patent: WO2013/60837,2013,A1 .Location in patent: Page/Page column 27

72
[ 145783-14-8 ]
[ 124-41-4 ]
[ 155899-66-4 ]
[ 1431867-43-4 ]

Yield	Reaction Conditions	Operation in experiment
52%		To a solution of CLIN (0.27 g, 1.0 mmol) in dry MeOH (5 mL) NaOMe (54 mg, 1.0 mmol) was added, and reaction mixture was then stirred at room temperature for 1 h. Then Et3N (0.15 mL, 1.1 mmol) and AMAL (0.18 g, 1 .05 mmol) were added, and reaction mixture was stirred at room temperature for 1 h. Then Na2C03 (0.35 g, 3.3 mmol), formamidinesulfinic acid (0.36 g, 3.3 mmol) and water (0.5 mL) were added. Resulting reaction mixture was stirred at 60C for 1 h, then AcOH (10 mL) was slowly added, followed by NaN02 (76 mg, 1.1 mmol). Resulting reaction mixture was stirred at room temperature for 1 h, then volatile components were evaporated, water (40 mL) was added, and product was extracted to MeTHF (3 x 10 mL). Combined organic phases were washed with saturated NaHC03 (3 x 10 mL), dried over MgS04, and concentrated to afford crude product, which was purified by chromatography (Si02. hexane:EtOAc) to give MOTAM as colorless oil (0.20 g, 52% yield).

Reference： [1]Patent: WO2013/60837,2013,A1 .Location in patent: Page/Page column 31-32

73
[ 145783-15-9 ]
[ 155899-66-4 ]
[ 220241-61-2 ]

Yield	Reaction Conditions	Operation in experiment
72%	Stage #1: 4,6-dichloro-2-(propylsulfanyl)-5-pyrimidinamine; (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol With potassium phosphate In tetrahydrofuran at 20℃; for 24h; Reflux; Stage #2: With acetic acid; sodium nitrite In tetrahydrofuran at 20℃; for 1h;	4 Example 4: Preparation of (3af?,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3/-/-[1 .2.3]triazolo[4,5- d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3a/-/-cyclopenta[c/][1 ,3]dioxol-4-ol (CLTAM) To a solution of AMAL (7.64 g, 44.1 mmol) and CLINA (10.5 g, 44.1 mmol) in dry THF (40 mL) K3P04 (10.3 g, 48.5 mmol) was added at room temperature. Resulting reaction mixture was stirred at reflux for 24 h, then AcOH was slowly added (100 mL) followed by NaN02 (3.65 g, 52.9 mmol). Reaction mixture was stirred at room temperature por 1 h, then solvents were evaporated, water (100 mL) was added, and product was extracted to MeTHF (3 x 50 mL). Combined organic phases were washed with saturated NaHC03 (3 x 50 mL), dried over MgS04, and concentrated to afford crude product, which was then purified by chromatography (Si02. hexane:EtOAc) to afford colorless crystals (12.2 g, 72% yield).

Reference： [1]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/60837, 2013, A1 Location in patent: Page/Page column 28-29

74
[ 4359-87-9 ]
[ 155899-66-4 ]
(3aR,4S,6R,6aS)-6-((2,6-dichloro-5-nitropyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; for 4h;	Dissolve 0.G2 mole (4.53 gm) 2,4,6-Trichloro-5-Nitropyrimidine 31 in 40 ml THF keep at 10C under stirring. Dissolve 0.02 mole (3aR,4S,6R,6aS)-6-amino-2,2- dimethyltetrahydro-3aH-cyclopenta[d][l ,3]dioxol-4-ol 10 (3.46 gm) in 25 ml THF. Charge (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta [d][l ,3]dioxol-4-ol solution dropwise in reaction mass. Stir for 3-4 hours. Check TLC and upon completion of reaction remove THF under vacuum, add water and extract with ethyl acetate. Concentrate ethyl acetate under vacuum to obtain oily liquid, 45, which can be taken directly to next step.

Reference： [1]Patent: WO2015/162630,2015,A1 .Location in patent: Page/Page column 40

75
[ 155899-66-4 ]
[3aR-(3α,4α,6α,6aα)]-6-azido-2,2-dimethyl-tetrahydro-4H-cyclopenta-1,3-dioxol-4-alcohol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90.4%	With imidazole-1-sulfonyl azide hydrochloride; potassium carbonate; copper(II) sulfate In methanol; acetonitrile at 0 - 20℃; for 5h; Inert atmosphere;	IX 1.73 g of [3aR-(3aα,4α,6α,6aα)]-6-amino-2,2-dimethyl-1,3-tetrahydro-cyclopenta-4H-dioxa cyclopentyl-4-ol (XI) (10 mmol), 2.76 g of potassium carbonate (20 mmol), 32 mg of copper sulfate (2% eq) and 25 mL of anhydrous methanol were added to a reaction flask, and added the solution of imidazole azide sulfonyl(XII) (2.1 g, 12 mmol) in methanol under 0° C. and nitrogen atmosphere, stirred at room temperature to react 5 hours, and the reaction ended with the TLC detection. The solution was concentrated under reduced pressure and the residue was recrystallized from n-hexane and ethyl acetate to get 1.8 g of [3aR-(3aα,4α,6α, 6aα)]-6-azido-2,2-dimethyl-tetrahydro-4H-cyclopenta-1,3-dioxol-4-ol (IX), with a yield of 90.4%.

Reference： [1]Current Patent Assignee: SUZHOU MIRACPHARMA TECHNOLOGY CO LTD - US2016/102101, 2016, A1 Location in patent: Paragraph 0056

76
[ 145783-14-8 ]
N’-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]-N,N-dimethylsulfuric diamide [ No CAS ]
[ 155899-66-4 ]
N-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]-N-[6-[(3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]amino}-5-nitro-2-(propylsulfanyl)pyrimidin-4-yl]-N',N’-dimethylsulfuric diamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		In a glass reactor, under a nitrogen atmosphere, 4,6-dichloro-5-nitro-2- (propylthio) pyrimidine (3.00 g, 0.01 ImoL) and K3P04 (3.37 g, 0.016 mmol) weresuspended in acetonitrile (42 mL). N?-[( 1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl] -N,N-dimethylsul furic diamide achieved according to the procedure of example 1 (2.94 g, 0.0 11 mol), was added portion wise and the mixture was stirred at 25 C for 9 hours. (3aR,4S,6R,6aS)-6-amino-2,2-dimethyl- tetrahydro-3aH-cyclopenta[d][ 1 ,3Jdioxol-4-ol (2.28 g, 0.01 3mol), K3P04 (2.70 g, 0.Ol3mol) and acetonitrile (3 mL) were added and the mixture was stirred for further 8 hours. The reaction mixture was diluted with water (50 mL) and extracted with methyL tert-butyl ether (50 mL). The organic phase was separated and concentrated under reduced pressure. The crude was dissolved in N,Ndimethylformamide (5 mL), low boiling solvent were evaporated and the obtained solution is added drop wise to water (50 mL) under vigorous stirring. After stirring 24 hours at 25C the solid was recovered by filtration and washed with water. After dying at 40 C for 24 hours, title compound was obtained as a yellow solid (5.78 g, 84% yield).LC-MS (ESI) mlz 645.197 (MH)A sample of the crude was purified by silica gel chromatography (cluent hexane/ethyl acetate from 9/1 to 8/2) for anaLytical purpose.111 NMR oe ppm (300 MHz, d6-DMSO): 8.62 (IH, d, J 7.8 Hz); 7.7 1-7.13 (2H, m); 7.05 (111, m); 5.74 (1H); 4.57-4.47 (311); 4.12 (IH, bs), 3.11 (IH, m); 2.88 (8H, bs,); 2.17 (dt, 211); 1.64(511, m); 1.35 (3H, s); 1.21 (311, s); 0.91 (311, bs). LC-MS (ESI) m/z 645.197 (MH)

Reference： [1]Patent: WO2015/193165,2015,A1 .Location in patent: Page/Page column 28

77
[ 155899-66-4 ]
[ 540-51-2 ]
2-[(3aR,4S,6R,6aS)-6-amino-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-yloxy]ethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90.4%	With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃;	6 Example 6 synthesis of compound 7 At room temperature, compound 6 (11.8g) dissolved in 100 ml of tetrahydrofuran, joins uncle butanol potassium (13.4g), then added dropwise 2-bromo ethanol (11.2g), after the feeding, the reaction at room temperature overnight. After the reaction, add 100 ml saturated sodium bicarbonate quenching reaction, in order to water-ethanol extraction of acetic acid (100 ml × 3), collection of the organic layer, saturated salt water washing (100 ml × 1), anhydrous magnesium sulfate drying. Filtering, removing the solvent under reduced pressure, to obtain decadent oil objects. Column chromatography purification (200-300 mesh silica gel, dichloromethane: methanol = 5:2 as eluents), to obtain yellow oily 11.8g, yield 90.4%.

Reference： [1]Current Patent Assignee: UNIV JINING MEDICAL - CN105481823, 2016, A Location in patent: Paragraph 0010; 0029; 0030

78
(3aS,4R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-amine [ No CAS ]
[ 155899-66-4 ]

Yield	Reaction Conditions	Operation in experiment
95.8%	With 5%-palladium/activated carbon; hydrogen In ethanol at 20℃;	5 Example 5 synthesis of compound 6 Compound 5 (11.6g) dissolved in 200 ml anhydrous ethanol, then adding 5% Pd/C (1.2g), at room temperature the reaction is H2pressurized (20-60psi) reaction sleepovers. Reaction after the stop, diatomite is filtered to remove 5% Pd/C, collecting the filtrate, the solvent is removed under reduced pressure to obtain a yellow oily 11.6g, yield 95.8%.

Reference： [1]Current Patent Assignee: UNIV JINING MEDICAL - CN105481823, 2016, A Location in patent: Paragraph 0010; 0027; 0028

79
C₁₅H₁₉NO₃ [ No CAS ]
[ 155899-66-4 ]

Yield	Reaction Conditions	Operation in experiment
123.7g	With palladium 10% on activated carbon; ammonium formate In methanol for 1.5h; Reflux;	5 Example 5 Preparation of Compound VI 200.7 g of compound V, 144.5 g of ammonium formate, 60.8 g of 10% Pd / C, 2509 ml of methanol were added to a 3000 ml three-necked flask and heated to reflux with stirring. Maintain reflux reaction 1.5h, suction filtration, the filtrate vacuum distillation to dry, you can get 123.7g white solid compound compounds VI,

Reference： [1]Current Patent Assignee: CHONGQING SHENGHUAXI PHARMACEUTICALS CO LTD; CHONGQING HUIZHI PHARMACEUTICAL RES INST - CN106279095, 2017, A Location in patent: Paragraph 0022; 0045

80
[ 155899-66-4 ]
[ 376608-65-0 ]

Reference： [1]Patent: CN106279095,2017,A

81
[ 85-44-9 ]
[ 155899-66-4 ]
[ 380307-23-3 ]

Yield	Reaction Conditions	Operation in experiment
83%	With N-ethyl-N,N-diisopropylamine In toluene at 100℃; for 9h;	21.1 mixture of (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H- cyclopenta[d] [l,3]dioxol-4-ol (0.43 g, 2.46 mmol, 1.00 eq), Phthalic anhydride (0.36 g, 2.46 mmol, 1 eq) and DIEA (0.65 mL, 3.7 mmol, 1.5 eq) in Toluene (6.2 mL) was stirred at 100 °C for 9 hrs. LCMS showed the reaction was complete. EtOAc was added to the reaction mixture and then washed with aqueous saturated sodium bicarbonate solution (15 mL). The combined organic layers were washed with saturated brine solution, dried over Na2S04 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Hexanes/EtOAc) to get the product 2-((3a.S,4R,6S,6aR)-6-hydroxy-2,2-dimethyltetTahydro-4H-cyclopenta[d] [l,3]dioxol-4- yl)isoindoline- l,3-dione (0.62 g, 83%) as a white solid.

Reference： [1]Current Patent Assignee: BLUEPRINT MEDICINES CORP - WO2017/35354, 2017, A1 Location in patent: Page/Page column 83

82
[ 115983-78-3 ]
[ 155899-66-4 ]
1-[(1′R,2′S,3′R,4′S)-4′-hydroxy-2′,3′-O-isopropylidene-cyclopentan-1′-yl]uracil [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.2 g	Stage #1: (E)-3-ethoxypropenoyl isocyanate; (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol In N,N-dimethyl-formamide; toluene at -15℃; Stage #2: With ammonium hydroxide at 90℃; Sealed tube;	5.1.18 1-[(1′R,2′S,3′R,4′S)-4′-hydroxy-2′,3′-O-isopropylidene-cyclopentan-1′-yl]uracil (33) To a solution of 120 3-ethoxyacrylic acid (2.0g, 17.22mmol) in 86 DCM (70mL) was added 121 thionyl chloride (1.89mL, 25.8mmol) at 0°C. The mixture was refluxed for 3h and then concentrated to get the residue (E)-3-ethoxyacryloyl chloride for next step. To a solution of the residue in 122 toluene (10mL) was added 123 silver cynate (3.89g, 25.98mmol). The mixture was refluxed for 30min and cooled to room temperature. The supernatant liquor was added to a solution of compound 4 (1.5g, 8.66mmol) in 124 DMF (15mL) at -15°C. The reaction was stirred at -15°C for 2h and then stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was used for cyclization without further purification. 102 Aq. ammonia (20mL) was added to the residue in a sealed bomb at 90°C overnight. The solvent was removed under reduced pressure and the residue was purified by column chromatography (20:1, DCM/MeOH) to afford 125 compound 33 (2.2g, 80%) as a white amorphous solid. m.p. 185-187°C. 1H NMR (600MHz, DMSO-d6): δ 11.26 (brs, 1H, NH), 7.81 (d, J=8.0Hz, 1H, H-6), 5.58 (d, J=8.0Hz, 1H, H-5), 5.46 (d, J=3.1Hz, 1H, OH), 4.73-4.72 (m, 1H, H-2), 4.68-4.65 (m, 1H, H-1), 4.43 (dd, J=2.1, 6.5Hz, 1H, H-3), 4.04 (s, 1H, H-4), 2.36-2.32 (m, 1H, H-5), 1.87-1.83 (m, 1H, H-5), 1.39 (s, 3H, CH3), 1.21 (s, 3H, CH3) ppm. 13C NMR (150MHz, DMSO-d6): δ 163.3 (C-4), 151.1 (C-2), 143.6 (C-6), 111.1 [C(CH3)2], 101.1 (C-5), 86.2 (C-3), 83.4 (C-2), 74.5 (C-4), 61.2 (C-1), 36.9 (C-5), 26.8 (CH3), 24.6 (CH3) ppm. HRMS: [M+H]+ calcd for C12H17N2O5, 269.1131; found, 269.1125.

Reference： [1]Wang, Mengmeng; Srivastava, Puneet; Liu, Chao; Snoeck, Robert; Andrei, Graciela; De Jonghe, Steven; Herdewijn, Piet [European Journal of Medicinal Chemistry, 2018, vol. 150, p. 616 - 625]

83
[ 123240-66-4 ]
[ 155899-66-4 ]
[ 204379-33-9 ]

Yield	Reaction Conditions	Operation in experiment
64%	With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 120℃;	To a solution of compound 4 (0.35g, 2,02mmol) and 51 <strong>[123240-66-4]4,6-dichloro-5-formamidopyrimidine</strong> (0.422mg, 2.22mmol) in 52 n-butanol (20mL) was added 53 DIPEA (1.41mL, 8.08mmol). The mixture was refluxed at 120C overnight. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (1:1, hexane/EtOAc) to afford 54 compound 7 (0.40g, 64% yield) as a yellowish amorphous solid. m.p. 134-136C. 1H NMR (500MHz, CDCl3): delta 8.77 (s, 1H, H-2), 8.58 (s, 1H, H-8), 5.13 (d, J=9.0Hz, 1H, H-1), 4.93 (d, J=5.5Hz, 1H, H-2), 4.75 (d, J=5.4Hz, 1H, H-3), 4.58 (d, J=4.8Hz, 1H, H-4), 2.93-2.85 (m, 1H, H-5a), 2.29 (d, J=15.5Hz, 1H, H-5b), 1.54 (s, 3H, CH3), 1.32 (s, 3H, CH3) ppm. 13C NMR (125MHz, CDCl3): delta 151.7 (C-2), 151.4 (C-4), 151.0 (C-6), 145.7 (C-8), 131.6 (C-5), 111.8 [C(CH3)2], 87.0 (C-3), 86.2 (C-2), 76.1 (C-4), 62.5 (C-1), 36.9 (C-5), 26.7 (CH3), 24.2 (CH3) ppm. HRMS: [M+H]+ calcd for C13H16N4O3Cl, 311.0905; found, 311.0903.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 150,p. 616 - 625

84
[ 155899-66-4 ]
[ 171887-03-9 ]
9-[(1′R,2′S,3′R,4′S)-4′-hydroxy-2′,3′-O-isopropylidene-cyclopentan-1′-yl]-2-amino-6-chloro-9H-purine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 120℃;	General procedure: To a solution of compound 4 (0.35g, 2,02mmol) and 51 4,6-dichloro-5-formamidopyrimidine (0.422mg, 2.22mmol) in 52 n-butanol (20mL) was added 53 DIPEA (1.41mL, 8.08mmol). The mixture was refluxed at 120C overnight. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (1:1, hexane/EtOAc) to afford 54 compound 7 (0.40g, 64% yield) as a yellowish amorphous solid.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 150,p. 616 - 625

85
[ 869498-30-6 ]
[ 155899-66-4 ]
1-[(1′R,2′S,3′R,4′S)-4′-hydroxy-2′,3′-O-isopropylidene-cyclopentan-1′-yl]thymine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: ethyl N-[(2E)-3-ethoxy-2-methylprop-2-enoyl]carbamate; (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol In 1,4-dioxane at 100℃; for 3h; Stage #2: With ammonium hydroxide at 90℃; Sealed tube;	13 5.1.13 1-[(1′R,2′S,3′R,4′S)-4′-hydroxy-2′,3′-O-isopropylidene-cyclopentan-1′-yl]thymine (25) To a solution of compound 4 (0.40g, 2.31mmol) in 101 dioxane (30mL) was added 22 ethyl [(2E)-3-ethoxy-2-methylprop-2-enoyl] carbamate 24 (0.46g, 2.31mmol). The mixture was heated at 100°C for 3h. The solvent was removed under reduced pressure, and the residue was used for cyclization without further purification. 102 Aq. ammonia (20mL) was added to the residue in a sealed bomb at 90°C overnight. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (30:1, DCM/MeOH) to afford 103 compound 25 (0.56g, 85%) as a white amorphous solid. m.p. 88-90°C. 1H NMR (300MHz, CDCl3): δ 10.0 (brs, 1H, NH), 7.31 (d, J=1.1Hz, 1H, H-6), 4.90 (dd, J=2.1, 5.9Hz, 1H, H-2), 4.65 (d, J=5.9Hz, 1H, H-1), 4.56 (m, 1H, H-3), 4.33 (s, 1H, H-4), 2.76-2.66 (m, 1H, H-5), 2.05-2.00 (m, 1H, H-5), 1.89 (s, 3H, T CH3), 1.48 (s, 3H, CH3), 1.30 (s, 3H, CH3) ppm. 13C NMR (75MHz, CDCl3): δ 164.3 (C-4), 151.2 (C-2), 140.3 (C-6), 111.6 [C(CH3)2], 110.8 (C-5), 87.2 (C-3), 84.3 (C-2), 76.1 (C-4), 66.1 (C-1), 37.8 (C-5), 26.7 (CH3), 24.3 (CH3), 12.2 (T CH3) ppm. HRMS: [M+H]+ calcd for C13H19N2O5, 283.1288; found, 283.1288.

Reference： [1]Wang, Mengmeng; Srivastava, Puneet; Liu, Chao; Snoeck, Robert; Andrei, Graciela; De Jonghe, Steven; Herdewijn, Piet [European Journal of Medicinal Chemistry, 2018, vol. 150, p. 616 - 625]

86
[ 3438-55-9 ]
[ 155899-66-4 ]
(+/-)-(3aR,4S,6R,6aS)-6-((5-bromo-6-methylpyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	In ethanol; at 80.0℃; for 20.0h;	The (+/-)-(3aR,4S,6R,6aS)-6-amino- in ethanol (9.0 ml, 0.5 M)2,2-Dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-ol (T-1)(786 mg, 4.54 mmol), <strong>[3438-55-9]5-bromo-4-chloro-6-methylpyrimidine</strong>(1.04 g, 4.99 mmol) and trimethylamine (0.822 ml, 5.9 mmol)The mixture was heated to 80 C for 20 hours.The crude reaction mixture was concentrated to a solid and then purified by chromatography on a gradient of 0% to 100% EtOAc in heptane to give T-2 as a white solid, 1.35 g (87% yield).

Reference： [1]Patent: TW2018/2074,2018,A .Location in patent: Page/Page column 150

87
[ 501-53-1 ]
[ 155899-66-4 ]
N-[(3aS,4R,6S,6aR)-tetrahydro-6-hydroxy-2,2-dimethyl-4H-cyclopenta-1,3-dioxolan-4-yl]carbamic acid benzyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92.75%	With potassium hydroxide In water; N,N-dimethyl-formamide at 0℃; for 0.00777778h;	1-6 Example 5: Method for synthesizing ticagrelor intermediate in a microchannel reactor. 1). Weigh the raw material (3aR, 4S, 6R, 6aS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopenteno-1,3-dioxolane-4-ol 400g dissolved in 3.6L of DMF to form material I, the material I is transported to the pre-mixing module of the microchannel reactor for preheating and mixing. 2). Weigh 260 g of potassium hydroxide dissolved in 4L of water as material II, and transport material II to the pre-mixing module of the microchannel reactor for preheating and mixing. 3). Weigh 475g of benzyl chloroformate and dissolve it in 4L of DMF to form material III, and deliver material III to the preheating module of the microchannel reactor. 4). The three materials of step 1), step 2) and step 3) are transported into the reaction module, preheated and mixed, and then enter the reaction module group for reaction, wherein: Adjust the flow rate of the flow pump so that the flow rate of material I is 27ml/min, the flow rate of material II is 30ml/min, the flow rate of material III is 30ml/min, and the flow rate of water entering the quenching module is 25ml/min.Among them, the raw materials (3aR, 4S, 6R, 6aS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopenteno-1,3-dioxolane-4-ol and hydroxide The molar ratio of potassium is 1:2.0, (3aR,4S,6R,6aS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopenteno-1,3-dioxolane The molar ratio of -4-ol and benzyl chloroformate is 1:1.2, and the reaction temperature is 0°C,The temperature of the quenching module is 25°C, and the residence time of the reaction is 28 seconds. The reaction liquid flowing from the outlet of the quenching module is collected and separated. The aqueous phase is extracted twice with 3.0L ethyl acetate.The organic phases were combined, washed once with 2.5L of water, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent to obtain a crude product.The crude product was then dissolved in 2.0L of absolute ethanol,Drop 6.0L of water into it. After the addition, a white flocculent solid is precipitated. After the addition is completed, keep the temperature at 010 and stir for 1 hour, filter, and wash the filter cake with a lot of water.Vacuum drying at 50 to obtain the target product N-[(3aS,4R,6S,6aR)-tetrahydro-6-hydroxy-2,2-dimethyl-4H-cyclopenteno-1,3-dioxide Pentan-4-yl]benzyl carbamate 656.16g,The yield is 92.45%, and the purity is 99.76%.

Reference： [1]Current Patent Assignee: HEILONGJIANG XINCHUANG BIOTECHNOLOGY DEV - CN111574494, 2020, A Location in patent: Paragraph 0033-0068

88
[ 91322-00-8 ]
[ 155899-66-4 ]
(3aR,4S,6R,6aS)-6-((5-amino-2,6-dichloropyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With triethylamine at 110℃; Sealed tube;	4.13 (3aR,4S,6R,6aS)-6-((5-amino-2,6-dichloropyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (13a.1) The mixture of 2,4,6-trichloropyrimidin-5-amine 12a (1.0g, 5.0mmol), (3aR,4S,6R,6aS)-6- amino-2,2-dimethyltetrahydrocyclopenta[d][1,3]dioxol-4-ol (1.1g, 6.4mmol) and triethylamine (0.7mL, 5.0mmol) in acetonitrile (10mL) was placed in a sealed vessel and heated overnight at 110°C. After evaporation of the solvent, the residue was purified by column chromatography on silica gel using 100% ethyl acetate to give 13a.1 as a white solid (1.48g, 88% yield, m.p.: 105°C (dec.)). 1H NMR (CDCl3): δ 1.29 (s, 3H, CH3), 1.45 (s, 3H, CH3), 1.82 (d, J=14.5Hz, 1H, 5′-Ha), 2.17 (d, J=2.0Hz, 1H, OH), 2.36 (dt, J=14.5Hz/5.2Hz, 1H, 5′-Hb), 3.28 (s, 2H, NH2), 4.40 (d, J=2.0Hz, 1H, 4′-H), 4.54 (d, J=5.3Hz, 1H, 3a′-H), 4.57 (d, J=5.3Hz, 1H, 6a′-H), 4.71 (dd, J=8.4Hz/6.6Hz, 1H, 6′-H), 6.11 (d, J=8.7Hz, 1H, NH). 13C NMR (CDCl3): δ 23.8, 26.2, 35.0, 57.0, 78.1, 85.2, 86.1, 110.6, 120.3, 142.8, 150.2, 155.1.

Reference： [1]Goffin, Eric; Jacques, Nicolas; Lancellotti, Patrizio; Musumeci, Lucia; Nchimi, Alain; Pirotte, Bernard; Oury, Cécile [European Journal of Medicinal Chemistry, 2020, vol. 208]

89
[ 5413-85-4 ]
[ 155899-66-4 ]
(3aR,4S,6R,6aS)-6-[(5-amino-6-chloropyrimidin-4-yl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With triethylamine at 110℃; Sealed tube;	4.12 (3aR,4S,6R,6aS)-6-[(5-amino-6-chloropyrimidin-4-yl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (13c.1) The mixture of 4,6-dichloropyrimidin-5-amine (1.0g, 6.1mmol), (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydrocyclopenta[d][1,3]dioxol-4-ol (1.34g, 7.8mmol) and triethylamine (0.85mL, 6.1mmol) in acetonitrile (10mL) was placed in a sealed vessel and heated overnight at 110°C. After evaporation of the solvent, the residue was purified by column chromatography on silica gel using 100% ethyl acetate to give 13c.1 as a white solid (1.43g, 78% yield). 1H NMR (DMSO-d6): δ 1.21 (s, 3H, CH3), 1.36 (s, 3H, CH3), 1.70 (d, J=13.7Hz, 1H, 5′-Ha), 2.22 (m, 1H, 5′-Hb), 4.07 (m, 1H, 4′-H), 4.29 (t, J=5.9Hz, 1H, 6′-H), 4.41 (d, J=6.0Hz, 1H, 3a′-H), 4.51 (d, J=6.0Hz, 1H, 6a′-H), 4.97 (s, 2H, NH2), 5.25 (d, J=3.1Hz, 1H, OH), 6.49 (d, J=7.2Hz, 1H, NH), 7.79 (s, 1H, 2-H). 13C NMR (DMSO-d6): δ 24.1, 26.5, 36.0, 57.0, 75.3, 84.4, 85.7, 109.7, 123.5, 137.6, 146.1, 151.7.

Reference： [1]Goffin, Eric; Jacques, Nicolas; Lancellotti, Patrizio; Musumeci, Lucia; Nchimi, Alain; Pirotte, Bernard; Oury, Cécile [European Journal of Medicinal Chemistry, 2020, vol. 208]

90
methyl 2‐[4,6‐dichloro‐2‐(propylthio)pyrimidin‐5‐yl]acetate [ No CAS ]
[ 155899-66-4 ]
methyl 2‐[4‐chloro‐6‐[[(3aS,4R,6S,6aR)‐6‐hydroxy‐2,2‐dimethyltetrahydro‐4H‐cyclopenta[d][1,3]dioxol‐4‐yl]amino]‐2‐(propylthio)pyrimidin‐5‐yl]acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88.4%	With N-ethyl-N,N-diisopropylamine; trichlorophosphate In 1,4-dioxane for 8h; Reflux;

Reference： [1]Zhao, Zhichang; Wang, Hongjun; Tian, Nana; Yan, Hong; Wang, Juan [Archiv der Pharmazie, 2021, vol. 354, # 11]

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CAS No. :	155899-66-4	MDL No. :	MFCD20527303
Formula :	C₈H₁₅NO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	AXPYGRDXRLICKY-JRTVQGFMSA-N
M.W :	173.21	Pubchem ID :	10352168
Synonyms :

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

[ CAS No. 155899-66-4 ] {[proInfo.proName]}

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[ CAS No. 155899-66-4 ] {[proInfo.proName]}

Quality Control of [ 155899-66-4 ]

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[ 155899-66-4 ] Synthesis Path-Upstream 1~3

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[ 155899-66-4 ]

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