Name: 17159-80-7|Ethyl 4-hydroxycyclohexanecarboxylate|97%
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1
[ 120-47-8 ]
4-hydroxycyclohexyl carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogen In ethanol at 20℃; for 20h;
88%	With hydrogen In ethanol at 100℃; for 48h;
61%	With hydrogen In ethanol at 145 - 150℃; for 18h;

	With hydrogen at 160℃;
	With hydrogen
	With hydrogen In ethanol at 120℃;
	With hydrogen for 120h; Yield given;
	In methanol	1.1 Step 1 Step 1 Ethyl 4-hydroxycyclohexanecarboxylate (32.0) STR43 To a 1-L Pyrex pressure bottle were added sequentially 50 g of ethyl 4-hydroxybenzoate, 300 mL of methanol, and 5 g of 5% Rh on Al2 O3. The sealed bottle was flashed with nitrogen and hydrogenated at 50 psi until 1 H NMR indicated complete reaction (about 8 to about 16 hrs). Filtration of the reaction mixture followed by concentration gave 50 g of the compound of Formula 32.0 as a mixture of trans and cis-isomers with a ratio of 78:22 as determined by GLC. The crude pale-yellow liquid was used directly in the oxidation step (Step 2 below) without further purification. HRMS: 173.1178 (MH+); calculated: 173.1171; 1 H NMR (CDCl3) trans: 4.12 (q, J=7.2 Hz, 2H), 3.89 (m, 1H), 2.36 (m, 1H), 2.04-1.90 (m, 3H), 1.70-1.60 (m, 5H), 1.24 (t, J=7.2 Hz, 3H). IR: 1730 cm--1.

Reference： [1]Kimura; Diwan; Yanagi; Kon-No; Nojima; Kimura [Biological and Pharmaceutical Bulletin, 1995, vol. 18, # 3, p. 407 - 410]
[2]Della, Ernest W.; Knill, Andrew M.; Pigou, Paul E. [Journal of Organic Chemistry, 1993, vol. 58, # 8, p. 2110 - 2114]
[3]Krieg, R.; Schierhorn, M.; Altmann, H.; Deutscher, H.-J. [Journal fur praktische Chemie (Leipzig 1954), 1987, vol. 329, # 6, p. 1123 - 1130]
[4]Musso,H. et al. [Chemische Berichte, 1967, vol. 100, p. 3614 - 3624]
[5]Reed,J.O.; Lwowski,W. [Journal of Organic Chemistry, 1971, vol. 36, # 19, p. 2864 - 2869]
[6]Maillard; Delaunay; Langlois; et al. [European Journal of Medicinal Chemistry, 1984, vol. 19, # 5, p. 457 - 460]
[7]Pettit, George R.; Harvey, Thomas B. [Synthetic Communications, 1981, vol. 11, # 3, p. 167 - 178]
[8]Current Patent Assignee: MERCK & CO INC - US5648484, 1997, A

2
4-hydroxycyclohexyl carboxylic acid ethyl ester [ No CAS ]
[ 17159-79-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With jones reagent In acetone
100%	With pyridinium chlorochromate In dichloromethane at 4℃; for 6h; Heating / reflux;	48 Example 48: preparation of Ethyl 4-ketocyclohexanecarboxylate (16). To a srirred solution of pyridinium chlorochromate (9.48 g, 44.0 mmol) in DCM (50 mL) at [4oC] was added a solution of ethyl 4-hydroxycyclohexanecarboxylate (5.00 g, 29.0 mmol). The mixture was stirred at [4oC] for 2 hours than heated at reflux and stirred for another 4 hours. The reaction was cooled at room temperature, filtered on CeliteTM and the filtrate was evaporated to a residue which was purified by column chromatography using a gradient of 25 to 45 % of EtOAc in hexane as eluant to give 4.93 g (100 %) of the ketone 16 as a clear oil: HRMS calcd for CgH1403 [(M+)] : 170.0943, found : 170.0938 [; 1H] NMR [(CDCLG)] [6] 1.26 (t, 3H, J= 7. [15),] 2.02 (m, 2H), 2.19 (m, 2H), 2.34 (m, 2H), 2.44 (m, [2H),] 2.73 (m, 1H), 4.16 (q, 2H, J= 7.13).
98%	With 4-Benzoylpyridine In acetone at 20℃; for 16h; UV-irradiation; Inert atmosphere;

92%	With sodium dichromate; sulfuric acid In diethyl ether; water for 3h;
90%	Stage #1: 4-hydroxycyclohexyl carboxylic acid ethyl ester With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 3.25h; Stage #2: With triethylamine In dichloromethane at -78 - 20℃;	7.7.i Example 7: c/s-4-hydroxy-4- [2-(6-methoxy- [1,5] naphthyridin-4-yl)-ethyl] - cyclohexanecarboxylic acid (2,3-dihydro-benzo[l,4]dioxin-6-yl)-amide:7.i. 4-oxo-cyclohexanecarboxylic acid ethyl ester.To a solution of oxalyl chloride (6 mL, 68.8 mmol) in DCM (100 mL) at -78°C was added dropwise a solution of DMSO (6.4 mL, 90 mmol) in DCM (2O mL). The mixture was stirred at this temperature for 15 min before the dropwise addition of a solution of ethyl4-hydroxycyclohexane carboxylate (4.8 mL, 30 mmol) in DCM (20 mL). The mixture was stirred at -78°C for 3 h before addition of TEA (29.3 mL, 210 mmol) in DCM (20 mL).The mixture was then gradually warmed to rt, washed with a sat. aq. NH4Cl solution and brine, dried over MgSO4 and concentrated. The residue was purified by chromatography over SiO2 (Hex/EA 1 :1) to give the title ketone (4.6 g, 90% yield) as a colourless oil.1H NMR (CDCl3) δ: 4.19 (q, J = 7.1 Hz, 2H); 2.80-2.70 (m, IH); 2.55-2.45 (m, 2H);2.40-2.30 (m, 2H); 2.25-2.10 (m, 2H); 2.05-2.00 (m, 2H); 1.29 (t, J = 7.1 Hz, 3H).
90%	With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -78℃; for 3.25h;	7.i 7.i. To a solution of oxalyl chloride (6 mL, 68.8 mmol) in DCM (100 mL) at -78° C. was added dropwise a solution of DMSO (6.4 mL, 90 mmol) in DCM (20 mL). The mixture was stirred at this temperature for 15 min before the dropwise addition of a solution of ethyl 4-hydroxycyclohexane carboxylate (4.8 mL, 30 mmol) in DCM (20 mL). The mixture was stirred at -78° C. for 3 h before addition of TEA (29.3 mL, 210 mmol) in DCM (20 mL). The mixture was then gradually warmed to rt, washed with a sat. aq. NH4Cl solution and brine, dried over MgSO4 and concentrated. The residue was purified by chromatography over SiO2 (Hex/EA 1:1) to give the title ketone (4.6 g, 90% yield) as a colourless oil. 1H NMR (CDCl3) δ: 4.19 (q, J=7.1 Hz, 2H); 2.80-2.70 (m, 1H); 2.55-2.45 (m, 2H); 2.40-2.30 (m, 2H); 2.25-2.10 (m, 2H); 2.05-2.00 (m, 2H); 1.29 (t, J=7.1 Hz, 3H).
88%	With pyridinium chlorochromate In dichloromethane at 0 - 23℃; for 16h; Molecular sieve;	13 Ethyl 4-oxocyclohexanecarboxylate (13) Powdered 3 A molecular sieves (5 g) and pyridinium chlorochromate (2.23 g, 10.36mmol) were suspended in a solution of ethyl 4-hydroxycyclohexanecarboxylate (1.19 g,6.91 mmol; mixture of cis and trans isomers) in CH2CI2 (20 mL) at 0 C The resulting reaction mixture was stirred at 23 C for 16 h before it was filtered through a pad ofCelite. The filtration cake was washed with CH2CI2 (4 x 10 mL) and the filtrate wasconcentrated in vacuo. The residue was purified by flash column chromatography (silicagel, hexanes:EtOAc 5:1 -* 1:1) to afford compound 13(1.034 g, 88%) as a colourless oil.1H NMR (400 MHz, ODd3) O = 4.13 (q, J= 7.1 Hz, 2 H), 2.70 (tt, J= 9.7, 4.0 Hz, 1 H),2.43(dt, J= 14.7, 5.4 Hz, 2 H), 2.36-2.25(m, 2 H), 2.23-2.11 (m, 2 H), 2.05-1.91 (m,2 H), 1.23 (t, J= 7.1 Hz, 3 H).
88%	With pyridinium chlorochromate In dichloromethane at 0 - 23℃; for 16h; Inert atmosphere;
83%	With aluminum oxide; pyridinium chlorochromate In chloroform for 3h;
	With sodium dichromate; sulfuric acid
	With chromium(VI) oxide; sulfuric acid In water; acetone
	With chromic acid Yield given;
	With chromium(VI) oxide
	With acetic acid	1.2 Step 2 Step 2 Ethyl 4-oxocyclohexanecarboxylate (33.0) STR44 To a 3-L 3-neck flask equipped with a mechanical stirrer, a thermometer, and an addition funnel were added 50 g (292 mmol) of the compound of Formula 32.0 from Step 1, 33 mL (584 mmol) of acetic acid and 145 mL of commercial bleach (5.25% NaOCl). To the cooled reaction mixture, at 5° C., was added dropwise 479 mL of more bleach. The reaction was allowed to warm to room temperature for 1 hour and then was extracted with 3*400 mL ethyl acetate. The combined extract was washed with water, dried over MgSO4, and concentrated to give 49 g of crude 33.0 as an oil which was used without purification. The spectrum data are identical to that of literature (see Sanchez, I. H.; Ortega, A.; Garcia, G.; Larraza, M. I.; Flores, H. J. Synthetic comm. 1985, 15, 141).
	With sulfuric acid; chromic acid In diethyl ether; isopropyl alcohol; acetone	B Ethyl 4-oxocyclohexanecarboxylate EXAMPLE B Ethyl 4-oxocyclohexanecarboxylate Ethyl 4-hydroxybenzoate is reduced to ethyl 4-hydroxycyclohexanecarboxylate according to the procedure described in R. A. Finnegan and P. L. Bachman, Journal of Organic Chemistry, Volume 30, pages 4145-4150 (1965). The crude material obtained in this reduction (190 g) is dissolved in 1200 ml of reagent grade acetone. The solution is cooled to 0° C. and 152 ml of a 8 N chromic acid solution (prepared from concentrated sulfuric acid and chromium trioxide) is added dropwise to the mechanically stirred reaction mixture. Enough isopropanol is added to the mixture to discharge its red color and it is then filtered through Celite. The salts are washed with several portions of acetone. The filtrate is evaporated in vacuo. The residue is dissolved in 750 ml of diethyl ether and washed with sodium bicarbonate and brine solutions. After drying, the solvent is evaporated and the residue is distilled to yield the title compound; bp12 125 ° C. In a process analogous to Example B using appropriate starting materials the following compound is prepared:
	With pyridinium chlorochromate In dichloromethane at 0 - 20℃; for 1.83333h;	1 Preparation 1 : Ethyl 4-oxocvclohexanecarboxylate; EPO In a 5 L 3-neck flask, fitted with a mechanical stirrer and gas outlet was added ethyl A- hydroxycyclohexanecarboxylate (167.3 g, 0.971 mol) and methylene chloride (2 L) followed by Celite (275 g). The resulting mixture was cooled in an ice bath and pyridium chlorochromate (272.3 g, 1.26 mol) was added in portions over 20 min. The mixture was stirred at room temperature for 1.5 hours, filtered through a plug of Celite, and rinsed with methylene chloride (2 L). The filtrate was concentrated in vacuo and the residue was chromatographed over a Biotage 75L column (eluted with 20% ethyl acetate in hexanes) to afford the title compound as a colorless liquid (165.5 g).1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.3 (t, J=7.3 Hz, 3 H) 2.0 (m, 2 H) 2.2 (m, 2 H) 2.3 (m, 2 H) 2.5 (m, 2 H) 2.7 (m, 1 H) 4.2 (q, J=7.1 Hz, 2 H)

Reference： [1]Kimura; Diwan; Yanagi; Kon-No; Nojima; Kimura [Biological and Pharmaceutical Bulletin, 1995, vol. 18, # 3, p. 407 - 410]
[2]Current Patent Assignee: UNIVERSITY OF MONTREAL - WO2004/22541, 2004, A1 Location in patent: Page 109; 110
[3]Kamijo, Shin; Tao, Keisuke; Takao, Go; Tonoda, Hiroshi; Murafuji, Toshihiro [Organic Letters, 2015, vol. 17, # 13, p. 3326 - 3329]
[4]Della, Ernest W.; Knill, Andrew M.; Pigou, Paul E. [Journal of Organic Chemistry, 1993, vol. 58, # 8, p. 2110 - 2114]
[5]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2007/107965, 2007, A1 Location in patent: Page/Page column 83
[6]Current Patent Assignee: JOHNSON & JOHNSON INC - US2009/105232, 2009, A1 Location in patent: Page/Page column 32-33
[7]Current Patent Assignee: UNIVERSITY OF ABERDEEN - WO2014/184561, 2014, A1 Location in patent: Page/Page column 71
[8]Tseng, Chih-Chung; Noordali, Hannah; Sani, Monica; Madhani, Melanie; Grant, Denis M.; Frenneaux, Michael P.; Zanda, Matteo; Greig, Iain R. [Journal of Medicinal Chemistry, 2017, vol. 60, # 7, p. 2780 - 2789]
[9]Niimi; Orita; Okazawa-Igarashi; Sakashita; Kikuchi; Ball; Ichikawa; Yamagiwa; Sakamoto; Tanaka; Tsukamoto; Fujita [Journal of Medicinal Chemistry, 2001, vol. 44, # 26, p. 4737 - 4740]
[10]Musso,H. et al. [Chemische Berichte, 1967, vol. 100, p. 3614 - 3624]
[11]Maillard; Delaunay; Langlois; et al. [European Journal of Medicinal Chemistry, 1984, vol. 19, # 5, p. 457 - 460]
[12]Pettit, George R.; Harvey, Thomas B. [Synthetic Communications, 1981, vol. 11, # 3, p. 167 - 178]
[13]Khaselev; Mandelbaum [Journal of Mass Spectrometry, 1998, vol. 33, # 9, p. 819 - 835]
[14]Current Patent Assignee: MERCK & CO INC - US5648484, 1997, A
[15]Current Patent Assignee: PFIZER INC - US4988699, 1991, A
[16]Current Patent Assignee: PFIZER INC - WO2006/32987, 2006, A1 Location in patent: Page/Page column 59-60

3
[ 17159-80-7 ]
[ 18162-48-6 ]
[ 676560-15-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With 1H-imidazole In DMF (N,N-dimethyl-formamide) at 35℃; for 12h;	5.a.A; 5.b.A A. 4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexanecarboxylic acid ethyl ester. To a solution of tert-butyldimethylsilyl chloride (10.6 g, 70 mmol) and imidazole (9.9 g, 145 mmol) in DMF (20 mL) was added 4-hydroxy-cyclohexanecarboxylic acid ethyl ester (9.4 mL, 58 mmol). The mixture was stirred at 35° C. for 12 h, diluted with EtOAc (100 mL), washed with H2O (3×), dried (Na2SO4), and concentrated. The resulting white solid was isolated in quantitative yield (16.6 g) and was used in the next step without purification.
100%	With 1H-imidazole; dmap In N,N-dimethyl-formamide at 0 - 20℃; for 16h;
96%	With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 3h;	3.1 Example 3 : 8-(3-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-lH-pyrazol-l-yl)-2- oxaspiro [4.5] decan-1-one; Step 1: ethyl 4-(tert-butyldimethyIsilyloxy)cyclohexanecarboxylate.; [124] tert-Butyldimethylsilyl chloride (3.61 g, 0.0240 mol) was added to a solution of 4- hydroxy-cyclohexanecarboxylic acid ethyl ester (3.44 g, 0.0200 mol; ), and lH-imidazole (3.40 g, 0.0499 mol; ) in N,N-Dimethylformamide (5.0 mL, 0.064 mol). The mixture was stirred at the room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water. The ethyl acetate phase was washed with brine, dried over sodium sulfate, filtered, and then concentrated to give oily crude product. Column chromatography eluting with 0-20% ethyl acetate/hexanes gave 5.5 g (96%) of the title compound as colorless oil. 1H-NMR (300 MHz, CD3Cl) δ 4.12 (m, 2H), 3.72 (m, IH), 2.29 (m, IH), 1.93 (m, 2H), 1.65 (m, 2H), 1.56 (m, 2H), 1.48 (m, 2H), .125 (m, 3H), 0.88 (d, 6H), 0.03 (d, 6H).

74%	With 1H-imidazole In N,N-dimethyl-formamide at 23℃; for 4h;
69.8%	With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 48h;	Intermediate 3-h: 4- ((4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) methoxy) -3-nitrobenzenesulfonamide Step 1: ethyl 4- ((tert-butyldimethylsilyl) oxy) cyclohexane-1-carboxylate To a solution of ethyl 4-hydroxycyclohexane-1-carboxylate (2 g, 11.61mmol) in DMF (50 ml) were added tert-butylchlorodimethylsilane (1.575 g, 10.4 mmol) and imidazole (1.58 g, 23.22 mmol). The mixture was stirred at r.t. for 2 days. The mixture was concentrated. The residue was dissolved with DCM (200 ml), washed with brine, dried over Na 2SO 4 and concentrated. The residue was purified by chromatography column on silica (eluent: EA/PE = 1/40) to give the product (2.32 g, 69.8%).
45%	Stage #1: 4-hydroxycyclohexyl carboxylic acid ethyl ester With triethylamine In dichloromethane at 20℃; for 0.333333h; Stage #2: tert-butyldimethylsilyl chloride In dichloromethane at 20℃; for 40h;	Ethyl 4-[(tert-butyldimethylsilyl)oxy]cyclohexane-1-carboxylate To a solution of ethyl 4-hydroxycyclohexane-1-carboxylate (10 g, 58.06 mmol) in dichloromethane (25 mL) was added triethylamine (13 g, 128.47 mmol) slowly at room temperature. After stirring for additional 20 min, TBDMSC1 (24.9 g, 87.09 mmol) was slowly added. The resulting reaction mixture was then stirred at room temperature for 40 h. The reaction mixture was quenched by the addition of water (100 mL) and extracted with dichloromethane (100 mL×2). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (1% to 10% gradient) to yield ethyl 4-[(tert-butyldimethylsilyl)oxy]cyclohexane-1-carboxylate as yellow oil (7.5 g, 45%).
2.25 g (79%)	With dmap; triethylamine In N,N-dimethyl-formamide at 20℃; for 18h;	5 5-Butyl-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-4-methyl-piperidin-4-yl]-3-(trans-4-hydroxy-cyclohexylmethyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one (I-4) EXAMPLE 5 5-Butyl-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-4-methyl-piperidin-4-yl]-3-(trans-4-hydroxy-cyclohexylmethyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one (I-4) 4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexanecarboxylic acid ethyl ester (38)-To a solution of 4-oxy-cyclohexanecarboxylic acid ethyl ester (CASRN 17159-80-7, 1.7 g, 0.01 mol) in DMF (14 mL) was added DMAP (58 mg, 0.47 mmol), TEA (1.54 mL) and tert-butyl-dimethylsilyl chloride (1.65 g, 0.011 mol). The reaction mixture was stirred at RT for 18 h, poured into ice (10 g), extracted with EtOAc (3*50 mL). The organic extracts were dried (MgSO4) filtered and concentrated. The residue was purified by SiO2 chromatography eluding with EtOAc/hexane (1:20) to afford 2.25 g (79%) of 4-(tert-butyl-dimethyl-silanyloxy)-cyclohexanecarboxylic acid ethyl ester (38) as colorless oil.
	With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 18h;	15 tert-Butyldimethylchlorosilane (9.71 g, 64.45 mmol) was added portion wise to ethyl 4- hydroxycyclohexanecarboxylate (CAS no. 17159-80-7) (10 g, 58 mmol) and imidazole (7.9 g, 116 mmol) in DMF (58 mL) under nitrogen. The resulting solution was stirred at room temperature for 18 hours. The reaction mixture was diluted with diethyl ether (250 mL), and washed with saturated brine (500 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford the product (16.3 g). This was used without any further purification.IH NMR (300 MHz, CDCl3) δ 0.02 - 0.07 (5H, m), 0.87 - 0.90 (9H, m), 0.92 (IH, s), 1.22 - 1.29 (3H, m), 1.30 - 1.54 (3H, m), 1.59 - 1.70 (2H, m), 1.87 - 2.04 (3H, m), 2.21 - 2.32 (IH, m), 3.70 - 3.89 (IH, m), 4.07 - 4.16 (2H, m).
	With 1H-imidazole In N,N-dimethyl-formamide at 20 - 40℃;	1 Chloro(1 ,1-dimethylethyl)dimethylsilane (1 15 g; 0.76 mol) was added in portions over 1 hour to a solution of commercially available ethyl 4-hydroxycyclohexanecarboxylate (118 g; 0.68 mol), imidazole (103 g; 1.52 mol) and dimethylformamide (400 ml.) stirred under an atmosphere of argon. A small exotherm was observed resulting in the reaction mixture temperature increasing to -40 0C. The mixture was stirred at room temperature overnight then poured into 10% citric acid solution (2 L) and extracted with diethyl ether (2 x 800 ml_). The ether extracts were washed with water, brine and then dried (Na2SC>4) and the solvent was removed to give the title compound as an oil (198.4 g) 1H NMR δ (CDCI3, 400 MHz): 0.01 (6H, m), 0.85 (9H, s), 1.2 (3H, m), 1.3-1.5 (2H, m), 1.6 (2H, m), 1.85-2 (3H, m), 2.15-2.3 (1 H, m) 3.5 (0.4H, m) 3.86 (1 H, m) 4.1 (1 H, m).
	With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 20h;	2.a PREPARATION 2: l-(2-(Benzyloxy)ethyl)-4-(/- butyldimethylsilyloxy)cyclohexanecarbaldehyde; Step a: Ethyl 4-(tert-butyldimethylsilyloxy)cyclohexanecarboxylate; [00164] A mixture of ethyl 4-hydroxycyclohexane-carboxylate (50 mL, 0.31mol), imidazole (50.1 g, 0.74 mol), and t-butyldimethylsilyl chloride (56 g, 0.37mol) in DMF (580 mL) was stirred at room temperature for 20 hrs under atmosphere of nitrogen. Water (100 mL) was added to the mixture, and the mixture was extracted with ether (600 mL). The extract was washed with water (400 mL) and brine (500 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give compound 2 as a colorless oil (102 g), which was used for the next step without further purification.
	With 1H-imidazole In DMF (N,N-dimethyl-formamide) at 20℃; for 16h;	45A Example 45 (2S, [5R)-5-ETHYNYL-L- (N- (4-HYDROXY-L-METHYLCYCLOHEXYL)] glycyl) [PYRROLIDINE-2-CARBONITRILE] Example 45A [4- (TERT-BUTYL-DIMETHYL-SILANYLOXY)-CYCLOHEXANECARBOXYLIC] acid ethyl ester To a solution of 4-hydroxy-cyclohexanecarboxylic acid ethyl ester (10.32 g, 59.92 mmol) in dimethylformamide (50 mL) was added imidazole (8.16 g, 119.8 mmol), followed by tert-butyldimethylsilyl chloride (9.94 g, 65.9 mmol). The resulting mixture was stirred at room temperature for 16 hours. Diethyl ether was added (150 mL), and the mixture was washed with 1M [HC1] (150 mL). The aqueous layer was extracted with diethyl ether (150 mL). The combined organic layers were washed with 1M [HC1] (100 mL) and saturated sodium chloride solution (100 mL), dried over magnesium sulfate, filtered and concentrated to afford a clear oil. MS (CI) m/z 287 (M+1) [+]
34.94 g	With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 15h; Cooling with ice;	53.3 Compound 5 (20.04 g) and imidazole (15.84 g) were dissolved in N,N-dimethylformamide (116 mL), tert-butyldimethylsilylchloride (19.47 g) was added under ice cooling, and the mixture was stirred at room temperature for 15hours. The reaction solution was added to ice water, and the mixture was extracted with diethyl ether. The extract waswashed with water and saturated brine. The solution was dried over anhydrous magnesium sulfate, and concentratedunder reduced pressure to obtain Compound 6 (34.94 g) as a colorless oil.MS (m/z): 287 [M+H]+
	With 1H-imidazole In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	2 4.1.2. 4-(tert-Butyldimethylsilanoxy)cyclohexane carboxylic acid (3) To a solution of ethyl 4-hydroxycyclohexanecarboxylate 2 (mixture of cis and trans) (2.5 g, 14.5 mmol) and imidazole (1.97 g, 29 mmol) in anhydrous DMF (20 mL), tert-butyldimethylsilyl chloride (2.63 g, 17.5 mmol) was added. After stirring overnight, Et2O (60 mL) and 1M aqueous HCl (60 mL) were added. After extraction with Et2O, the combined organic phases were washed with 1M aqueous HCl and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a TBS-protected alcohol as a colorless oil (4.14 g), which was used in the next step without further purification. To a solution of the former alcohol (4.14 g, 14.5 mmol) in THF (20 mL) and methanol (12 mL), lithium hydroxide (0.7 g, 29 mmol) was added. The mixture was then stirred at 60 °C for 3 h. After removal of the solvents, water and Et2O were added and the aqueous layer was extracted with diethyl ether, cooled in an ice bath then acidified to pH=1 with 1M aqueous HCl. After extraction with ethyl acetate, the organic phases were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 50:50) to give the title compound 3 as a mixture of cis/trans isomers (3.48 g, 100% yield) as a colorless oil; δH (400 MHz, CDCl3) 10.84 (2H, m, 2COOH), 3.89 and 3.56 (21H, 2bs, 2H-4), 2.41-2.18 (2H, m, 2H-1), 2.10-1.83 (6H, m), 1.74-1.59 (4H, m), 1.58-1.23 (6H, m), 0.88 and 0.87 (29H, 2s, 2(CH3)3CSi), 0.05 and 0.03 (26H, 2s, 2(CH3)2Si); δC (100 MHz; CDCl3) 181.8 (2COOH), 70.5 and 66.7 (2C-4), 42.0 and 41.9 (2C-1), 34.8 (2CH2), 32.9 (2CH2), 27.1 (2CH2), 23.4 (2CH2), 26.1 and 26.0 (2(CH3)3CSi), 18.3 and 18.2 (2(CH3)3CSi), -4.5 and -4.7 (2*(CH3)2Si).
43.1 g	With 1H-imidazole In N,N-dimethyl-formamide at 20℃;	I56 ethyl 4-[tert-butyl(dimethyl)silyl]oxy}cyclohexanecarboxylate(mixture of cis-/trans isomers) tert-Butyldimethylsilyl chloride (26.3 g, hydroxycyclohexanecarboxylate (25.0 g, 171 59-80-7) and imidazole (24.7 g, 363174 mmol) was added to a solution of ethyl 4-145 mmol, mixture of cis-/trans-isomers, Gas Nommol) in N,N-dimethylformamide (36 ml) and the mixture was stirred over night at room temperature. For work-up, water was added and the mixture was extracted with tert-butyl methyl ether (3x). The combined organic phases were washed with brine, filtrated through a silicone filter and concentrated under reduced pressure to yield ethyl 4-[tert-butyl(dimethyl)silyl]oxy}cyclohexanecarboxylate (43.1 g, 104% yield) which was used in the next step without further purification. 1HNMR (400 MHz, DMSO-d6, mixture of isomers): 6 [ppm] = 4.10-3.99 (m, 2H), 3.93-3.86 (m, 0.7H), 3.63-3.51 (m, 0.3H), 2.39-2.28 (m, 0.8H), 2.27-2.14 (m, 0.3H), 1.91-1.21 (m, 8H), 1.20-1.13 (m, 3H), 0.89-0.79 (m, 9H), 0.08-0.00 (m, 6H).
	With 1H-imidazole In N,N-dimethyl-formamide at 20℃;	3 ethyl 4-[tert-butyl(dimethyl)silyl]oxy}cyclohexanecarboxylate (mixture of cis-/trans-isomers) tert-Butyldimethylsilyl chloride (26.3 g, 174 mmol) was added to a solution of ethyl 4-hydroxycyclohexanecarboxylate (25.0 g, 145 mmol, mixture of cis-/trans-isomers, Cas No 17159-80-7) and imidazole (24.7 g, 363 mmol) in N,N-dimethylformamide (36 ml) and the mixture was stirred over night at room temperature. For work-up, water was added and the mixture was extracted with tert-butyl methyl ether (3x). The combined organic phases were washed with brine, filtrated through a silicone filter and concentrated under reduced pressure to yield ethyl 4-[ferf-butyl(dimethyl)silyl]oxy}cyclohexanecarboxylate (43.1 g, 104% yield) which was used in the next step without further purification.1H-NMR (400 MHz, DMSO-cfe, mixture of isomers): δ [ppm] = 4.10-3.99 (m, 2H), 3.93-3.86 (m, 0.7H), 3.63-3.51 (m, 0.3H), 2.39-2.28 (m, 0.8H), 2.27-2.14 (m, 0.3H), 1.91-1 .21 (m, 8H), 1.20-1 .13 (m, 3H), 0.89-0.79 (m, 9H), 0.08-0.00 (m, 6H).
	With 1H-imidazole In N,N-dimethyl-formamide at 20℃;	Intermediate 1 ethyl 4-[tert-butyl(dimethyl)silyl]oxy}cyclohexanecarboxylate (mixture of cis-/trans-isomers) tert-Butyldimethylsilyl chloride (26.3 g, 174 mmol) was added to a solution of ethyl 4- hydroxycyclohexanecarboxylate (25.0 g, 145 mmol, mixture of cis-/trans-isomers, Gas No 17159-80-7) and imidazole (24.7 g, 363 mmol) in DMF (36 ml) and the mixture was stirred overnight at room temperature. For work-up, water was added and the mixture was extracted with tert-butyl methyl ether (3x). The combined organic phases were washed with brine, filtered through a silicone filter and concentrated under reduced pressure to yield ethyl 4-[tert- butyl(dimethyl)silyl]oxy}cyclohexanecarboxylate (43.1 g, 104% yield) which was used in the next step without further purification.1HNMR (400 MHz, DMSO-d6, mixture of isomers): 6 [ppm] = 4.10-3.99 (m, 2H), 3.93-3.86 (m,0.7H), 3.63-3.51 (m, 0.3H), 2.39-2.28 (m, 0.8H), 2.27-2.14 (m, 0.3H), 1.91-1.21 (m, 8H), 1.20-1.13 (m, 3H), 0.89-0.79 (m, 9H), 0.08-0.00 (m, 6H).
	With 1H-imidazole In N,N-dimethyl-formamide at 20 - 40℃;	50 Chloro(1 ,1-dimethylethyl)dimethylsilane (115g; 0.76mol) was added in portions over 1 hour to a solution of ethyl 4-hydroxycyclohexanecarboxylate (118g; 0.68mol), imidazole(103g; 1.52mol) and dimethylformamide (400ml) stirred under an atmosphere of argon. A small exotherm was observed resulting in the reaction mixture temperature increasing to~40°C. The mixture was stirred at room temperature overnight then poured into 10% citric acid solution (2L) and extracted with diethyl ether (2 x 800ml). The ether extracts were washed with water, brine and then dried (Na2SO4) and the solvent was removed to give the title compound as a oil (198.4g) 1H NMR δ (CDCI3, 400 MHz): 0.01 (6H, m), 0.85 (9H, s), 1.2 (3H, m), 1.3-1.5 (2H, m), 1.6 (2H, m), 1.85-2 (3H, m), 2.15-2.3 (1 H, m) 3.5 (0.4H, m) 3.86 (1 H, m) 4.1 (1 H, m).
	With 1H-imidazole In N,N-dimethyl-formamide at 20 - 40℃;	18 Description 18.; cis/trans-Ethy 4-[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}cyclohexanecarboxylate (D18); Chloro(1 ,1-dimethylethyl)dimethylsilane (1 15g) was added in portions over 1 hour to a solution of ethyl 4-hydroxycyclohexanecarboxylate (118g), imidazole (103g) and dimethylformamide (400ml) stirred under an atmosphere of argon. A small exotherm was observed resulting in the reaction mixture temperature increasing to -4O0C. The mixture was stirred at room temperature overnight then poured into 10% citric acid solution (2000ml) and extracted with diethyl ether (2 x 800ml). The ether extracts were washed with water, brine and then dried (Na2SO4) and the solvent was removed to give the title compound as a oil (198.4g)1H NMR δ(CDCI3, 400 MHz): 0.01 (6H, m), 0.85 (9H, s), 1.2 (3H, m), 1.3-1.5 (2H, m), 1.6 (2H, m), 1.85-2 (3H, m), 2.15-2.3 (1 H, m) 3.5 (0.4H, m) 3.86 (1 H, m) 4.1 (1 H, m).
	With 1H-imidazole In dichloromethane at 20℃;	2 tert-Butyldimethylsilyl chloride (8.8 g, 58 mmol) was added to a solution of ethyl 4- hydroxycyclohexanecarboxylate (10 g, 58 mmol) and imidazole (4.3 g, 64 mmol) in DCM (300 ml), and the mixture was stirred overnight at 20 0C. After washing with water (2 X 100 ml), the organic phase was dried (MgSO4) and evaporated to dryness. The residue was dissolved in dry THF (300 ml) and cooled to -10 0C. Dibal-H (1.0 M in toluene, 174 ml, 174 mmol) was added dropwise over a period of 60 min, while the temperature was kept at - 100C. After stirring for 2 hrs the reaction was quenched by slow addition of a saturated ammonium chloride solution (30 ml). The resulting suspension was filtered, and the filtrate was concentrated in vacuo to give 13 g of the title compound as a mixture of two isomers. LC-MS {m/z) : 245 (M + l).
	With 1H-imidazole In N,N-dimethyl-formamide at 20 - 40℃;	60 Description 60. c/s/frans-Ethyl 4-[(1,1 - dimethylethyl)(dimethyl)silyl]oxy}cyclohexanecarboxylate (D60); Chloro(1 ,1-dimethylethyl)dimethylsilane ( 115g ) was added in portions over 1 hour to a solution of ethyl 4-hydroxycyclohexanecarboxylate (118g), imidazole (103g) and dimethylformamide (400ml) stirred under an atmosphere of argon. A small exotherm was observed resulting in the reaction mixture temperature increasing to -4O0C. The mixture was stirred at room temperature overnight then poured into 10% citric acid solution (2000ml) and extracted with diethyl ether (2 x 800ml). The ether extracts were washed with water, brine and then dried (Na2SU4) and the solvent was removed to give the title compound as a oil (198.4g)1H NMR D(CDCI3, 400 MHz): 0.01 (6H, m), 0.85 (9H, s), 1.2 (3H, m), 1.3-1.5 (2H, m), 1.6 (2H, m), 1.85-2 (3H, m), 2.15-2.3 (1 H, m) 3.5 (0.4H, m) 3.86 (1 H, m) 4.1 (1 H1 m).
	With 1H-imidazole In N,N-dimethyl-formamide at 20 - 40℃;	27; 38 Description 27. Ethyl 4-[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}cyclohexanecarboxylate (D27); Chloro(1 ,1-dimethylethyl)dimethylsilane ( 115g ) was added in portions over 1 hour to a solution of ethyl 4-hydroxycyclohexanecarboxylate (118g), imidazole (103g) and dimethylformamide (400ml) stirred under an atmosphere of argon. A small exotherm was observed resulting in the reaction mixture temperature increasing to -4O0C. The mixture was stirred at room temperature overnight then poured into 10% citric acid solution(2000ml) and extracted with diethyl ether (2 x 800ml). The ether extracts were washed with water, brine and then dried (Na2SO4) and the solvent was removed to give the title compound as a oil (198.4g)1H NMR D(CDCI3, 400 MHz): 0.01 (6H, m), 0.85 (9H, s), 1.2 (3H, m), 1.3-1.5 (2H, m), 1.6 (2H, m), 1.85-2 (3H, m), 2.15-2.3 (1 H, m) 3.5 (0.4H, m) 3.86 (1 H, m) 4.1 (1 H, m). Description 38. c/s/frans-Ethyl 4-[(1,1 - dimethylethyl)(dimethyl)silyl]oxy}cyclohexanecarboxylate (D38)Chloro(1 ,1-dimethylethyl)dimethylsilane ( 115g ) was added in portions over 1 hour to a solution of ethyl 4-hydroxycyclohexanecarboxylate (118g), imidazole (103g) and dimethylformamide (400ml) stirred under an atmosphere of argon. A small exotherm was observed resulting in the reaction mixture temperature increasing to ~40°C. The mixture was stirred at room temperature overnight then poured into 10% citric acid solution(2000ml) and extracted with diethyl ether (2 x 800ml). The ether extracts were washed with water, brine and then dried (Na2SO4) and the solvent was removed to give the title compound as a oil (198.4g).1H NMR δ (CDCI3, 400 MHz): 0.01 (6H, m), 0.85 (9H, s), 1.2 (3H, m), 1.3-1.5 (2H, m), 1.6 (2H, m), 1.85-2 (3H, m), 2.15-2.3 (1 H, m) 3.5 (0.4H, m) 3.86 (1 H, m) 4.1 (1 H, m).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US2006/4039, 2006, A1 Location in patent: Page/Page column 13
[2]Liu, Jing; Yang, Chao; Simpson, Catherine; Deryckere, Deborah; Van Deusen, Amy; Miley, Michael J.; Kireev, Dmitri; Norris-Drouin, Jacqueline; Sather, Susan; Hunter, Debra; Korboukh, Victoria K.; Patel, Hari S.; Janzen, William P.; MacHius, Mischa; Johnson, Gary L.; Earp, H. Shelton; Graham, Douglas K.; Frye, Stephen V.; Wang, Xiaodong [ACS Medicinal Chemistry Letters, 2012, vol. 3, # 2, p. 129 - 134]
[3]Current Patent Assignee: BIOGEN IDEC INC. - WO2009/9059, 2009, A1 Location in patent: Page/Page column 30
[4]Wild [Journal of Organic Chemistry, 1994, vol. 59, # 10, p. 2748 - 2761]
[5]Current Patent Assignee: BEIGENE LTD. - WO2019/210828, 2019, A1 Location in patent: Paragraph 0577; 0578; 0579
[6]Current Patent Assignee: MERCK KGAA - US2016/75711, 2016, A1 Location in patent: Paragraph 0219-0220
[7]Current Patent Assignee: ROCHE HOLDING AG - US2008/249087, 2008, A1 Location in patent: Page/Page column 24-25
[8]Current Patent Assignee: ASTRAZENECA PLC - WO2009/24821, 2009, A2 Location in patent: Page/Page column 81
[9]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/37294, 2009, A1 Location in patent: Page/Page column 64-65
[10]Current Patent Assignee: BIOGEN IDEC INC. - WO2007/76086, 2007, A2 Location in patent: Page/Page column 54-55
[11]Current Patent Assignee: ABBVIE INC - WO2004/26822, 2004, A2 Location in patent: Page 68
[12]Current Patent Assignee: MITSUBISHI CHEMICAL HOLDINGS CORPORATION - EP2862856, 2015, A1 Location in patent: Paragraph 0693; 0694
[13]Zeinyeh, Waël; Radix, Sylvie; Terreux, Raphaël; Chemelle, Julie-Anne; Walchshofer, Nadia [Tetrahedron, 2016, vol. 72, # 27-28, p. 4032 - 4038]
[14]Current Patent Assignee: BAYER AG - WO2016/177658, 2016, A1 Location in patent: Page/Page column 223; 224
[15]Current Patent Assignee: BAYER AG - WO2018/78005, 2018, A1 Location in patent: Page/Page column 115
[16]Current Patent Assignee: BAYER AG - WO2018/78009, 2018, A1 Location in patent: Page/Page column 118; 119
[17]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2007/107565, 2007, A1 Location in patent: Page/Page column 72-73
[18]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2008/119713, 2008, A1 Location in patent: Page/Page column 58
[19]Current Patent Assignee: VTV THERAPEUTICS INC. - WO2008/101914, 2008, A2 Location in patent: Page/Page column 65
[20]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2007/107566, 2007, A1 Location in patent: Page/Page column 73-74
[21]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2007/107567, 2007, A1 Location in patent: Page/Page column 54; 59

4
[ 17159-79-4 ]
4-hydroxycyclohexyl carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With methanol; sodium tetrahydroborate at 0 - 20℃; for 1h;
95%	With sodium tetrahydroborate In ethanol
88%	Stage #1: ethyl 4-oxocyclohexane-1-carboxylate With sodium tetrahydroborate In methanol at 0 - 20℃; for 3h; Stage #2: With water In methanol	64 To a solution of ethyl 4-oxocyclohexanecarboxylate (13.5 g, 79 mmol) in MeOH (150 mL) at 0 °C was added NaBH4 (5.3 g, 140 mmol) and the mixture was stirred at rt for 3 h. Then the reaction was quenched by addition of H2O (50 mL) and extracted with AcOEt (150 mL x 1, 50 mL x 2). The combined organic layer was washed with H20 (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane-AcOEt 1.5 : 1-1 : 1) to give the titled compound (12 g, 88%, cisltrans = 3: 7) as clear oil. IH NMR (300MHz, CDC13, cisltrans mixture) 8 : 4.17-4. 08 (m, 2H), 3.90 (bs, 0.3H), 3. 68- 3.57 (m, 0.7H), 2.42-1. 28 (m, 9H), 1.27-1. 22 (m, 3H) ppm. (OH was not observed.)

60%	With tricyclohexylphosphineindium trihydride In toluene at -78 - 20℃; for 15h;
	In sodium borohydrid; ethanol; water	2 Cis- and trans-8-(4-hydroxycyclohexyl)-1,3-dipropylxanthine, EXAMPLE 2 Cis- and trans-8-(4-hydroxycyclohexyl)-1,3-dipropylxanthine, To a stirred solution of ethyl 4-oxocyclohexanecarboxylate (2.0 g, 12 mmol) in 10 mL of ethanol at 5° C. was added, in portions, 0.5 g (13 mmol) of sodium borohydride. After the mixture was stirred for 30 minutes at 5° C. and 18 hours at room temperature it was diluted with 10 mL of water and acidified to pH 3 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate. After being washed with water and brine the extracts were dried over anhydrous sodium sulfate and concentrated to give ethyl 4-hydroxycyclohexanecarboxylate as a colorless liquid.
	With sodium tetrahydroborate In methanol at 0 - 20℃; for 1h;	Prerjaration of reagent R-i0d: ethyl 4-hydroxycyclohexanecarboxylate To a solution of commercially available ethyl 4-oxocyclohexanecarboxylate(5.0 g, 0.029 mol) in MeOH (50 mL) was added NaBH4 (2.24g, 0.058 mol) at0 00 in portions, then the mixture was stirred at room temperature for 1 hr untilTLC showed the starting material was consumed completely, quenched withwater and the mixture was extracted with EtOAc, the organic layer waswashed with brine, dried over anhydrous Na2SO4, concentrated to give thecrude reagent R-i Od (4.95 g, 97.83%) as a pale yellow oil which was used for the next step directly. ESI-MS (Mi-i): 173 calc. for C9H1 603:172.1.
	With methanol; sodium tetrahydroborate In tetrahydrofuran at 0℃; for 1h;	Intermediate 11 a: Ethyl 4-hydroxycyclohexanecarboxylate To a solution of ethyl 4-oxocyclohexanecarboxylate (30.0 g, 176 mmol) in tetrahydrofuran (200 mL) and methanol (70 mL) was added sodium borohydride (3.40 g, 88.0 mmol) at 0 °C. Then the mixture was stirred at 0 °C for 1 hour. After that, it was quenched with water (150 mL) and extracted with ethyl acetate (250 mL) twice. The combined organic layers were washed with brine (100 mL), dried over Na2SO4() andfiltered. The filtrate was concentrated under reduced pressure to give the title compound(29.5 g, 98 % yield) as colorless oil. ‘H NIVIR (300 1VIHz, CDC13) 4.14 - 4.05 (m, 2H),3.89 -3.81 (m, 0.3H), 3.65 -3.52 (m, 0.7H), 2.39-2.31 (m, 0.3H), 2.25 -2.15 (m,0.7H), 2.02- 1.90 (m, 4H), 1.69- 1.60 (m, 1.7H), 1.54 - 1.40 (m, 1.3H), 1.31 - 1.19 (m,4H).

Reference： [1]Rabal, Obdulia; Sánchez-Arias, Juan A.; Cuadrado-Tejedor, Mar; De Miguel, Irene; Pérez-González, Marta; García-Barroso, Carolina; Ugarte, Ana; Estella-Hermoso De Mendoza, Ander; Sáez, Elena; Espelosin, Maria; Ursua, Susana; Haizhong, Tan; Wei, Wu; Musheng, Xu; Garcia-Osta, Ana; Oyarzabal, Julen [Journal of Medicinal Chemistry, 2016, vol. 59, # 19, p. 8967 - 9004]
[2]Location in patent: scheme or table Jiang, Xinglong; Lee, George T.; Villhauer, Edwin B.; Prasad, Kapa; Prashad, Mahavir [Organic Process Research and Development, 2010, vol. 14, # 4, p. 883 - 889]
[3]Current Patent Assignee: PFIZER INC - WO2005/80317, 2005, A2 Location in patent: Page/Page column 150
[4]Abernethy; Cole; Davies; Jones [Tetrahedron Letters, 2000, vol. 41, # 39, p. 7567 - 7570]
[5]Current Patent Assignee: SANOFI - US5175290, 1992, A
[6]Current Patent Assignee: FUNDACION PARA LA INVESTIGACION MEDICA APLICADA - WO2014/131855, 2014, A1 Location in patent: Page/Page column 71
[7]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2019/1420, 2019, A1 Location in patent: Page/Page column 106

5
4-hydroxycyclohexyl carboxylic acid ethyl ester [ No CAS ]
[ 94-18-8 ]
[ 952588-97-5 ]

Yield	Reaction Conditions	Operation in experiment
22%	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃; for 16h;	A 4-(4-Ethoxycarbonyl-cyclohexyloxy)-benzoic acid benzyl ester; To a solution of benzyl 4-hydroxybenzoate (50 g, 0.22 mol) and triphenylphosphine (63.2 g, 0.241 mol) dissolved in THF (800 mL) was added 4-hydroxy-cyclohexanecarboxylic acid ethyl ester (35.3 mL, 0.22 mol). The reaction mixture was cooled on an ice bath and DEAD (38 ml, 0.241 mol) was added dropwise maintaining the temperature at 0 0C. The resulting mixture was allowed slowly to reach room temperature and stirred for 16 hrs. at this temperature. The volume was reduced to app. 250 ml. by evaporation and to the resulting mixture was added water (500 ml.) followed by extraction with DCM (3x400 ml_). The combined organic phases were washed with brine (400 ml_), dried (Na2SO4), filtered and the volatiles evaporated in vacuo. Crude product ~80 g was purified on column chromatography (Flash 75) using first heptane (7.5 L) followed by a mixture of EtOAc-heptane (1 :10) (5 L) and finally a mixture of EtOAc-heptane (1 :6) (8 L). Combined fractions were evaporated in vacuo affording 18.1 g (22 %) of 4-(4-ethoxycarbonyl-cyclohexyloxy)-benzoic acid benzyl ester as an oil.1H-NMR (300 MHz, CDCI3) δ 1.26 (t, 3H), 1.42 - 1.83 (m, 4H), 1.85 - 2.26 (m, 4H), 2.27 - 2.48 (m, 1 H), 4.14 (q, 2H), 4.22 - 4.38 (m, 0.5H), 4.55 (br.s., 0.5H), 5.33 (s, 2H), 6.89 (dd, 2H), 7.27 - 7.49 (m, 5H), 8.01 (d, 2H).

Reference： [1]Current Patent Assignee: VTV THERAPEUTICS INC. - WO2007/115935, 2007, A1 Location in patent: Page/Page column 53-54

6
[ CAS Unavailable ]
[ 17159-80-7 ]
[ 952589-08-1 ]

Yield	Reaction Conditions	Operation in experiment
32%	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃; for 48.5h;	E 4-[4-(Adamantan-2-ylcarbamoyl)-phenoxy]-cyclohexanecarboxylic acid ethyl ester; To a stirred solution of N-adamantan-2-yl-4-hydroxy-benzamide (6 g, 22.1 1 mmol) in dry THF (100 ml.) was added triphenyl phosphine (8.7 g, 33.17 mmol) and 4-hydroxy cyclo- hexane carboxylic acid ethyl ester (4.57 g, 26.53 mmol). The reaction mixture was cooled to 0 0C and DEAD (5.22 ml_, 33.17 mmol) was added dropwise from an addition funnel over a period of 30 min. The reaction was gradually brought to room temperature and stirring con- tinued for 48 hrs. The solvent was removed under vacuum and ether (100 ml.) was added and cooled to 0 0C. The solid formed was filtered off and the clear filtrate concentrated and purified by column chromatography (Gyan-flash). Desired fractions were collected and the solvent evaporated. The residue was crystallised from diethyl ether and filtered off affording 3 g (32 %) of 4-[4-(adamantan-2-ylcarbamoyl)-phenoxy]-cyclohexane carboxylic acid ethyl ester as a solid.1H-NMR (400 MHz, CDCI3) δ 1.27 (t, 3H), 1.41 - 2.25 (m, 22H), 2.30 - 2.47 (m, 1 H), 4.10 - 4.20 (m, 2H), 4.21 - 4.30 (m, 1 H), 4.55 (br.s., 1 H), 6.34 (d, 1 H), 6.92 (t, 2H), 7.73 (d, 2H). m/z: 427 (M+1 )+

Reference： [1]Current Patent Assignee: VTV THERAPEUTICS INC. - WO2007/115935, 2007, A1 Location in patent: Page/Page column 67-68

7
[ 17159-80-7 ]
[ 58479-61-1 ]
[ 956122-83-1 ]

Yield	Reaction Conditions	Operation in experiment
89%	With 1H-imidazole In 1,2-dichloro-ethane at 20℃;	8.1 Intermediate (8)4-(tert-Butyl-diphenyl-silanyloxy)-1-(2-oxo-ethyl)-cyclohexanecarboxylic acid methyl ester Step 1 : 4-(tert-Butyl-diphen l-silanyloxy)-cyclohexanecarboxylic acid ethyl esterTo a solution of ethyl 4-hydroxycyclohexane carboxylate (5 g, 29.03 mmol) in dichloromethane (200 mL) was added imidazole (4.97 g, 73 mmol) and tert- butylchlorodiphenylsilane (15.96 g, 15.2 mL, 58 mmol). The reaction mixture was allowed to stir at room temperature over night. The reaction mixture was poured into water (125 mL) in a separatory funnel and the phases were separated. The aqueous phase was extracted with dichloromethane (2x200 mL). The combined organic solutions were washed with brine, dried over Na2SO4, and concentrated under vacuum. Purification by column chromatography on silica gel eluting with ethyl acetate in heptanes (0-10%) afforded 10.55 g (89%) of the title compound.
89%	With 1H-imidazole In dichloromethane at 20℃;	viii.1 Step 1 : 4-(tert-Butyl-diphen l-silanyloxy)-cyclohexanecarboxylic acid ethyl esterTo a solution of ethyl 4-hydroxycyclohexane carboxylate (5.0 g, 29.03 mmol) in dichloromethane (200 mL) was added imidazole (4.97 g, 73 mmols) and tert- butylchlorodiphenylsilane (15.96 g, 15.2 mL, 58.0 mmol). The reaction mixture was allowed to stir at room temperature over night. The reaction mixture was poured into water (125 mL) in a separatory funnel and the phases were separated. The aqueous phase was extracted with dichloromethane (2x200 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. Purification by column chromatography on silica gel eluting with ethyl acetate in heptanes (0-10%) afforded 10.55 g (89%) of the title compound.
89%	With 1H-imidazole In dichloromethane at 20℃;	iv.1 Step 1 : 4-(tert-Butyl-diphen l-silanyloxy)-cyclohexanecarboxylic acid ethyl esterTo a solution of ethyl 4-hydroxycyclohexane carboxylate (5 g, 29.03 mmol) in dichloromethane (200 ml_) was added imidazole (4.97 g, 73 mmol) and tert- butylchlorodiphenylsilane (15.96 g, 15.2 ml_, 58 mmol). The reaction mixture was allowed to stir at room temperature over night. The reaction mixture was poured into water (125 ml_) in a separatory funnel and the phases were separated. The aqueous phase was extracted with dichloromethane (2x200 ml_). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. Purification by column chromatography on silica gel eluted with ethyl acetate in heptanes (0-10%) afforded 10.55 g (89%) of the title compound.

80%	With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 72h;	15 Preparation 15; 4-(tert-Butyl-diphenyl-silanyloxy)-cyclohexanecarboxylic acid ethyl ester; Treat a solution of cis/trans ethyl 4-hydroxycyclohexanecarboxylate (21.3 g, 0.124 mol) and imidazole (10.10 g, 0.148 mol) in DMF (150 mL) with t-butyl-diphenylsilyl chloride (37.39 g, 0.136 mol) and stir for 72 hours at room temperature. Dilute the reaction with diethyl ether and wash with IN HCl and water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product. Purify with a 0 to 20% ethyl acetate in hexanes gradient on silica gel to afford 40.4 g (80%) of the titled product. Rf = 0.49 and 0.29 (5/1 hexanes/ethyl acetate).
	With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; for 3h;	1.1 (1) (1) Synthesis of ethyl 4-((tert-butyl(diphenyl)silyl)oxy)cyclohexanecarboxylate To a solution of 25 g of 4-hydroxycyclohexanecarboxylic acid in 125 ml of N,N-dimethylformamide were sequentially added 21.7 g of imidazole and 39.6 ml of tert-butyl (diphenyl)silyl chloride under cooling with ice, followed by stirring the reaction mixture at room temperature for 3 hours. To the reaction mixture was added water and extracted with hexane. The resulting hexane solution was washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound.
	With 1H-imidazole In N,N-dimethyl-formamide at 10 - 35℃;	38.A A solution of ethyl 4-hydroxycyclohexanecarboxylate (5 g), tert-butyl(chloro)diphenylsilane (8.30 mL) and imidazole (2.17 g) in DMF (50 mL) was stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate and water. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (12.2 g).1H NMR (300 MHz, DMSO-d6) δ 0.98-1.06 (9H, m), 1.17-1.23 (5H, m), 1.23-1.63 (4H, m), 1.68-1.94 (2H, m), 2.15-2.38 (1H, m), 3.51-3.95 (1H, m), 4.03-4.09 (2H, m), 7.37-7.46 (6H, m), 7.55-7.65 (4H, m).MS (ESI+): [M+H]+ 411.1
21 g	With 1H-imidazole; dmap In N,N-dimethyl-formamide at 20℃; for 24h;	I147 ethyl 4-[tert-butyl(diphenyl)silyl]oxy}cyclohexanecarboxylate Tert-butyl(chloro)diphenylsilane (18 ml, 68 mmol, GAS No 58479-61-1) was added drop wise to a mixture of ethyl 4-hydroxycyclohexanecarboxylate (9.4 ml, 57 mmol, GAS No 171 59-80- 7), 1H-imidazole (9.68 g, 142 mmol, GAS No 16681 -56-4) and N,N-dimethylpyridin-4-amine(348 mg, 2.85 mmol, GAS No 1122-58-3) in dimethylformamid (81 ml), and the mixture wasstirred at room temperature for 24 h. For work-up, the mixture was poured into water,extracted with ethyl acetate (3x) and the combined organic phases were washed until pH=7as reached. The organic phase was dried over sodium sulfate and was concentrated underreduced pressure. The residue was purified by flash chromatography (340 g Snap cartridge,hexane/ethyl acetate gradient, 5%-> 30% ethyl acetate) to give the title compound (21 g).
	With 1H-imidazole; dmap In N,N-dimethyl-formamide at 20℃; for 24h;	3 ethyl 4-[tert-butyl(diphenyl)silyl]oxy}cyclohexanecarboxylate Tert-butyl(chloro)diphenylsilane (18 ml, 68 mmol, CAS No 58479-61-1 ) was added drop wise to a mixture of ethyl 4-hydroxycyclohexanecarboxylate (9.4 ml, 57 mmol, CAS No 17159-80-7), 1H-imidazole (9.68 g, 142 mmol, CAS No 16681-56-4) and N,N-dimethylpyridin-4-amine (348 mg, 2.85 mmol, CAS No 1 122-58-3) in dimethylformamid (81 ml), and the mixture was stirred at room temperature for 24 h. For work-up, the mixture was poured into water, extracted with ethyl acetate (3x) and the combined organic phases were washed until pH=7 as reached. The organic phase was dried over sodium sulfate and was concentrated under reduced pressure. The residue was purified by flash chromatography (340 g Snap cartridge, hexane/ethyl acetate gradient, 5% -> 30% ethyl acetate) to give the title compound (21 g)
21 g	With 1H-imidazole; dmap In N,N-dimethyl-formamide at 20℃; for 24h;	Intermediate 2 ethyl 4-[tert-butyl(diphenyl)silyl]oxy}cyclohexanecarboxylate (mixture of cis-/trans-isomers) Tert-butyl(chloro)diphenylsilane (18 ml, 68 mmol, GAS No 58479-61 -1) was added drop wise to a mixture of ethyl 4-hydroxycyclohexanecarboxylate (9.4 ml, 57 mmol, GAS No 17159-80-7), 1H-imidazole (9.68 g, 142 mmol, GAS No 16681 -56-4) and N,N-dimethylpyridin-4-amine (348 mg, 2.85 mmol, GAS No 1122-58-3) in DMF (81 ml), and the mixture was stirred at roomtemperature for 24 h. For work-up, the mixture was poured into water, extracted with ethyl acetate (3x) and the combined organic phases were washed until pH=7 as reached. The organic phase was dried over sodium sulfate and was concentrated under reduced pressure. The residue was purified by flash chromatography (340 g SNAP cartridge, hexane/ethyl acetate gradient, 5% -> 30% ethyl acetate) to give the title compound (21 g).

Reference： [1]Current Patent Assignee: SANOFI - WO2011/143150, 2011, A1 Location in patent: Page/Page column 39-40
[2]Current Patent Assignee: SANOFI - WO2011/143148, 2011, A1 Location in patent: Page/Page column 31
[3]Current Patent Assignee: SANOFI - WO2011/143163, 2011, A1 Location in patent: Page/Page column 25
[4]Current Patent Assignee: ELI LILLY & CO - WO2007/127763, 2007, A2 Location in patent: Page/Page column 42
[5]Current Patent Assignee: MERCK & CO INC - US2008/58347, 2008, A1 Location in patent: Page/Page column 62
[6]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2011/263562, 2011, A1 Location in patent: Page/Page column 74
[7]Current Patent Assignee: BAYER AG - WO2016/177658, 2016, A1 Location in patent: Page/Page column 285; 286
[8]Current Patent Assignee: BAYER AG - WO2018/78005, 2018, A1 Location in patent: Page/Page column 131
[9]Current Patent Assignee: BAYER AG - WO2018/78009, 2018, A1 Location in patent: Page/Page column 119; 120

8
[ 17159-80-7 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
91%	With hydrazine hydrate for 24h; Reflux;	1.a a) cis/trans-4-Hydroxy-cyclohexanecarboxylic acid hydrazide (2:1)A mixture of cis/trans-4-hydroxycyclohexane carboxylic acid ethyl ester (5.0 g, 29 mmol) and hydrazine hydrate (1.4 g, 29 mmol) was heated at reflux for 24 h. Residual water was removed by azeotropic distillation with toluene. The residue was triturated from tert-butyl methyl ether. The precipitate was collected by filtration and dried in vacuo to give the title compound as white solid in 91% yield.
	With hydrazine In methanol at 55℃; for 4h;	1.1 Example 1; 4-{5-[1-(4-chlorophenyl)cyclopropyl]-4-methyl-4H-1,2,4-triazol-3-yl}cyclohexanol; Step 1. 4-hydroxycyclohexanecarbohydrazide; A mixture of ethyl 4-hydroxycyclohexanecarboxylate (2.0 g, 12 mmol) and hydrazine (1.5 g, 46 mmol) in methanol (20 mL) was stirred at 55° C. for 4 h and then cooled to room temperature (about 25° C.). After cooling, the solvent and excess hydrazine were removed by distillation under reduced pressure to provide a residue. The residue was co-evaporated with methanol (2×), and was then dried under high vacuum to provide the crude product 4-hydroxycyclohexanecarbohydrazide, which was used in the next synthesis step without further purification. LCMS: (M+H)+=155.2.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2011/251183, 2011, A1 Location in patent: Page/Page column 25
[2]Current Patent Assignee: INCYTE CORP - US2007/270424, 2007, A1 Location in patent: Page/Page column 19-20

9
[ 17159-80-7 ]
[ 446-35-5 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
11%	With sodium hydride In ISOPROPYLAMIDE at 4 - 20℃; for 25h;	i Intermediate 1 : c/5-4-(3-FIuoro-4-[5-(2,4,5-trifluoro-phenyIamino)-[l,3,41- oxadiazole-2-carbonyll-amino)-phenoxy)-cvclohexanecarboxylic acid ethyl ester; i) c/s-4-(3-Fluoro-4-nitro-phenoxy)-cyclohexanecarboxylic acid ethyl ester; Sodium hydride (60% dispersion in mineral oil, 5.05 g, 126 mmol) was added in one portion to a stirred solution of ethyl 4-hydroxycyclohexanecarboxylate (20.7 g, 120 mmol) and 2,4-difluoronitrobenzene (19.1g, 120.2 mmol) in DMA (100 mL) at 4°C and the mixture was stirred at 40C for 1 h and then the reaction mixture was warmed to ambient temperature and stirred for 24 h. The reaction mixture was cooled to 0°C and then water and ethyl acetate were added. The layers were separated and the organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo to leave a yellow oil. The oil was purified by column chromatography, using a gradient of 20-50% ethyl acetate in isohexane as eluent, to give the title compound as a pale yellow solid (4.1 g, 11%). 1H NMR δ 1.19 (3H3 1), 1.63-1.9 (9H, m), 4.07 (2H, q), 4.72-4.8 (IH, m), 6.99 (IH, dd), 7.22 (IH, dd), 8.13 (IH5 dd); MS m/e MH+ 312.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2007/138304, 2007, A1 Location in patent: Page/Page column 26-27

10
[ 17159-80-7 ]
[ 446-35-5 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
12%	With sodium hydride In ISOPROPYLAMIDE at 5 - 20℃; for 25h;	i Intermediate 4: Ethyl /*rαn5-4-[3-fluoro-4-[[5-[(2,4,5-trifluorophenyl)aminoll.,3<4- oxadiazole-2-carbonyll amino] phenoxyl cyelohexane-l-carboxylate; i) Ethyl ^m«5-4-(3-fluoro-4-nitro-phenoxy)cyclohexane-l-carboxyIate; To a stirred solution of ethyl 4-hydroxycyclohexanecarboxylate (20.7 g, 120.19 mmol) and 2,4-difluoronitrobenzene (19.125 g, 120.19 mmol) in DMF at ~5 0C was added NaH (5.05 g, 126.2 mmol) in one portion, resulting in a slow exotherm to ~10 0C. The reaction was stirred at 5 0C for 1 hour then allowed to warm to ambient temperature and stirred for 24 hr. The reaction was cooled to 0 0C and quenched with water (-400 mL). The mixture was extracted with EtOAc (3 x -150 mL), the organic layers combined, washed with brine (2 x -100 mL), dried (MgSO4), filtered and evaporated to an orange oil (36g). The crude residue was purified by preparative HPLC (silica, 4:1 ethyl acetate dsohexane) to give the title compound (4.5 g, 12 %) as a pale orange oil.1H NMR: δ 1.19 (3H, t), 1.39-1.53 (4H, m), 1.9-2.0 (2H, m), 2.04-2.13 (2H, m), 2.31-2.41 (IH, m), 4.08 (2H, q), 4.51-4.61 (IH, m), 6.99 (IH, dd), 7.25 (IH, dd), 8.12 (IH, dd); MS m/e MH+ 312.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2007/138304, 2007, A1 Location in patent: Page/Page column 26-27

11
[ 17159-80-7 ]
[ 350-46-9 ]
[ CAS Unavailable ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
1: 23% 2: 18%	With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 2.1h;	i Intermediate 1; Ethyl c/y-4-(4-[hvdrazino(oxo)acetvnamino}phenoxy)cycIohexane- carboxylate; i) Ethyl c/5-4-(4-nitrophenoxy)cyclohexanecarboxylateSodium hydride (60% dispersion in mineral oil, 4.39 g, 109.7 mmol) was added in portions over 1 min to a stirred solution of ethyl 4-hydroxycyclohexanecarboxylate (18 g, 104.5 mmol) and l-fluoro-4-nitrobenzene (11.1 niL, 109.7 mmol) in DMF (200 mL) at O0C under a nitrogen atmosphere. The reaction mixture was stirred at O0C for 5 mins and then warmed to ambient temperature and stirred for 2 h. Water (750 mL) and EtOAc (300 mL) were then added and the layers were separated. The aqueous layer was extracted with EtOAc (2x300 mL) and the combined organic layers were washed with brine (100 mL), dried (MgSO4) and concentrated in vacuo to leave a residue. The crude residue was purified by column chromatography, using a gradient of 10-40% EtOAc in isohexane as eluent, to give the title compound as a yellow oil (6.95 g, 23.7 mmol, 23%). 1H NMR δ 1.15 - 1.23 (m, 3H), 1.65 - 1.90 (m, 8H), 2.45 - 2.54 (m, IH), 4.08 (q, 2H), 4.72 - 4.79 (m, IH), 7.16 (d, 2H), 8.18 (d, 2H). The corresponding tnms-cyclohexyl isomer, ethyl fm/ts-4-(4-nitrophenoxy)cyclohexane- carboxylate (Intermediate 2) was also isolated from this reaction as a white solid (5.5O g,%h 1H NMR (CDCl3) δl.19 (t, 3H), 1.40 - 1.64 (m, 4H), 2.00 - 2.16 (m, 4H), 2.24 - 2.36 (m, IH), 4.07 (q, 2H), 4.23 - 4.32 (m, IH), 6.84 (d, 2H), 8.11 (d, 2H).

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2007/138311, 2007, A1 Location in patent: Page/Page column 33-34

12
[ 3618-04-0 ]
[ 610-81-1 ]
[ 959939-14-1 ]

Yield	Reaction Conditions	Operation in experiment
64%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 16h;	Intermediate 30: m-Ethyl 4-[[2-[5-[(2,4<5-trifluorophenvDa?-ino]-1.3,4-oxadiazol-2- yll -3H-benzoimidazol-5-yll oxyl cyclohexane-l-carboxylate; i) Ethyl 4-(4-amino-3-nitro-phenoxy)cvclohexane-l-earboxylate; Diisopropyl azodicarboxylate (1.72 mL, 8.71 mmol) was added in one portion to a stirred solution of ethyl 4-hydroxycyclohexanecarboxylate (1.0 g, 5.8 mmol), 4-amino-3- nitrophenol (2.69 g, 17.4 mmol) and triphenylphoshine (2.29 g, 8.71 mmol) in THF (40 mL) under an argon atmosphere. The reaction mixture was stirred at ambient temperature <n="63"/>for 16 h and then EtOAc (150 mL) and water (150 niL) were added. The layers were separated and the organic layer was washed with a IM aqueous solution of HCl (150 mL), then a IM aqueous solution of sodium hydroxide (150 mL) and then brine (150 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to leave a dark brown solid. This solid was purified by column chromatography, eluting with a gradient of 30 to 40% EtOAc in isohexane, to give the title compound as an impure orange oil (1.15 g, 64%), that was used with no further purification; MS m/e MH+ 474.

Reference： [1]Patent: WO2007/141517,2007,A1 .Location in patent: Page/Page column 61-62

13
[ 959939-24-3 ]
[ 17159-80-7 ]
[ 959939-25-4 ]
[ 959939-26-5 ]

Yield	Reaction Conditions	Operation in experiment
1: 27% 2: 47%	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 10 - 20℃; for 72h;	33.ii ii) Ethyl /rfl/i5-4-(3-amino-2-fluoro-4-nitrophenoxy)cvclohexane-l-carboxylate and ethyl cιy-4-(3-amino-2-fluoro-4-nitrophenoxy)cvclohexane-l-carboxylate.; To a mixture of 3-amino-2-fluoro-4-nitrophenol (14.1 g, 81.93mmol), ethyl-4- hydroxycyclohexanecarboxylate (14.11 g, 81.93mmol) and triphenylphosphine (26.87 g, 102.41 mmol) in anhydrous THF (200 mL) cooled to 100C was added a solution of diethylazodicarboxylate (17.83 g, 102.41 mmol) in anhydrous THF (50 mL) and the reaction stirred at ambient temperature for 72 hr. The mixture was concentrated in vacuo and the residue purified by silica flash chromatography with 20-50% EtOAc in iso-hexane as eluent to give: ethyl trαrø-4-(3-amino-2-fluoro-4-nitro-phenoxy)cyclohexane-l-carboxylate (3.6g, 27%) as a yellow powder. 1H NMR: δ 1.18 (3H, t), 1.4-1.64 (4H, m), 1.9-2.12 (4H, m), 2.31-2.44 (IH, m), 4.08 (2H, q), 4.43-4.59 (IH, m), 6.65 (IH, m), 7.14 (2H, s), 7.82 (IH, m) and ethyl cw-4-(3-amino-2-fluoro-4-nitro-phenoxy)cyclohexane-l-carboxylate (6.25g, 47%) as a yellow powder. 1H NMR: δ 1.19 (3H, t), 1.62-1.92 (8H, m), 2.4-2.55 (IH, m), 4.08 (2H, q), 4.68-4.8 (IH, m), 6.62 (IH, m), 7.17 (2H, s), 7.84 (IH, m).

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2007/141517, 2007, A1 Location in patent: Page/Page column 69-70

14
[ 64-17-5 ]
[ 3685-22-1 ]
[ 3618-04-0 ]

Yield	Reaction Conditions	Operation in experiment
100%		Example 1625-[4-(2,6-Difluorophenoxy)cyclohexylmethoxy]-quinazoline-2,4-diamine Step 1: 4-Hydroxycyclohexanecarboxylic acid ethyl ester4-Hydroxycyclohexane carboxylic acid (5g, 34.5 mmol) was heated to reflux for 16 hours in the presence of 50 mL of ethyl alcohol and 2 mL of sulfuric acid. Reaction volume was reduce by half at reduced pressure and mixture was poured into sat. Na2CO3. Mixture was extracted 3 X 50 mL of ethyl acetate and combined organics were washed with brine and dried over MgSO4. Title compound was obtained as a colorless crude oil. (5.9 g; 100percent yield).

Reference： [1]Patent: WO2008/16973,2008,A1 .Location in patent: Page/Page column 75

15
[ 17159-80-7 ]
[ CAS Unavailable ]
[ 1005502-85-1 ]

Yield	Reaction Conditions	Operation in experiment
34%	With triphenylphosphine; diethylazodicarboxylate In toluene at 0 - 20℃; for 16.0167h;	162.2 Step 2: 4-(2,6-Difluorophenoxy)cyclohexanecarboxylic acid ethyl ester4-Hydroxycyclohexanecarboxylic acid ethyl ester (300 mg; 1.7 mmol), triphenylphosphine (Ig; 4.2 mmol) and 2,6-difluorophenol (340 mg; 2.6 mmol) were stirred in anhydrous toluene and chilled to O0C under nitrogen flow. Diethyl azodicarboxylate (2 mL; 4.3 mmol) was added to the mixture over 1 minute and warmed to room temperature. Reaction continued for 16 hours. Reaction was quenched with water, and mixture was extracted with 4 X 5 mL with ethyl acetate. Combined organics were washed with brine and dried over MgSO4. Oily residue was triturated with diethyl ether and solids filtered off. Filtrate was concentrated at reduced pressure and purified via flash chromatography using 5-20% ethyl acetate in hexanes to give 162 mg of title compound. (34%yield).

Reference： [1]Current Patent Assignee: FAMILIES OF SPINAL MUSCULAR ATROPHY - WO2008/16973, 2008, A1 Location in patent: Page/Page column 75

16
[ 17159-80-7 ]
[ 15579-15-4 ]
[ 478831-40-2 ]

Yield	Reaction Conditions	Operation in experiment
43%	With dibenzyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃;	367 Example 367; Synthesis of ethyl 4-(1H-indazol-5-yloxy)cyclohexanecarboxylate Ethyl 4-hydroxycyclohexylcarboxylate (1.44 ml, 8.95 mmol), triphenylphosphine (2.15 g, 8.20 mmol) and dibenzyl azodicarboxylate (3.34 g, 11.18 mmol) were added at 0°C to a solution of the 1H-indazol-5-ol (1.0 g, 7.45 mmol) obtained in Reference Example 4 in tetrahydrofuran (40 ml). After 1 hour, the mixture thus obtained was warmed up to room temperature. After stirring overnight, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/ethyl acetate, hexane/ethyl acetate) to obtain ethyl 4-(1H-indazol-5-yloxy)cyclohexanecarboxylate (928 mg, 43%). MS : m/z = 289 (M + 1)

Reference： [1]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED; Sumitomo Pharma (in: Sumitomo Chemical) - EP1403255, 2004, A1 Location in patent: Page 102

17
[ 651735-10-3 ]
[ 17159-80-7 ]
[ 651735-13-6 ]

Yield	Reaction Conditions	Operation in experiment
55%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃;	22.c To a 250-mL dry, round-bottomed flask was added 3-(2,6-Difluoro-3,5-dimethoxy- phenyl)-7-methylsulfanyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine (1.5 g, 4.08 mmol), ethyl-4-hydroxycyclohexanecarboxylate (2.11 g, 12.23 mmol), triphenylphosphine (3.21 g, 12.23 mmol), and tetrahydrofuran (50 mL), and the solution was blanketed with a nitrogen atmosphere. The solution was then cooled to O0C, and diisopropylazodicarboxylate (2.41 mL, 12.23 mmol) was added dropwise. The solution was then warmed to room temperature and stirred overnight. The crude mixture was then concentrated in vacuo and taken up in dichloromethane, washed with water, dried over sodium sulfate, and concentrated. The crude was purified by flash silica chromatography eluting with 3:2 hexane/ethyl acetate to yield the title compound (1.17 g, 55% yield): LRMS: 523.2 (M + H).
55%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃;	22.c c) ethyl-4-[3-(2,6-difluoro-3,5-dimethoxy-phenyl)-7-methylsulfanyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-cyclohexanecarboxylate To a 250-mL dry, round-bottomed flask was added 3-(2,6-Difluoro-3,5-dimethoxy-phenyl)-7-methylsulfanyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine (1.5 g, 4.08 mmol), ethyl-4-hydroxycyclohexanecarboxylate (2.11 g, 12.23 mmol), triphenylphosphine (3.21 g, 12.23 mmol), and tetrahydrofuran (50 mL), and the solution was blanketed with a nitrogen atmosphere. The solution was then cooled to 0° C., and diisopropylazodicarboxylate (2.41 mL, 12.23 mmol) was added dropwise. The solution was then warmed to room temperature and stirred overnight. The crude mixture was then concentrated in vacuo and taken up in dichloromethane, washed with water, dried over sodium sulfate, and concentrated. The crude was purified by flash silica chromatography eluting with 3:2 hexane/ethyl acetate to yield the title compound (1.17 g, 55% yield): LRMS: 523.2 (M+H).

Reference： [1]Current Patent Assignee: PFIZER INC - WO2006/38112, 2006, A1 Location in patent: Page/Page column 52
[2]Current Patent Assignee: PFIZER INC - US2004/19210, 2004, A1 Location in patent: Page 22

18
[ 17159-80-7 ]
[ 106-48-9 ]
[ 863565-70-2 ]

Yield	Reaction Conditions	Operation in experiment
68%	With triphenylphosphine; diethylazodicarboxylate In toluene at 0 - 20℃; for 7h;	65 To a solution of ethyl 4-hydroxycyclohexanecarboxylate (3.1 g, 18 mmol) in toluene (50 mL) were added PPh3 (5.2 g, 20 mmol) and p-chlorophenol (2.6 g, 20 mmol). To the mixture was added DEAD (40% in toluene, 9.4 g, 21 mmol) at 0 °C and the mixture was stirred at rt for 7 h. The reaction was quenched by addition H20 (100 mL) and diluted with AcOEt (100 mL). The aqueous layer was extracted with AcOEt (50 mL) and the combined organic layer was washed with brine (50 mL), dried over MgS04, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane: AcOEt = 12: 1) to give the titled compound (3.5 g, 68%). IH NMR (300MHz, CDC13, cisltrans mixture) 6 : 7.24-7. 19 (m, 2H), 6.86-6. 79 (m, 2H), 4.47-4. 40 (m, 1H), 4.18-4. 09 (m, 2H), 2.44-1. 41 (m, 9H), 1.28-1. 24 (m, 3H) ppm.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2005/80317, 2005, A2 Location in patent: Page/Page column 150

19
[ 851265-83-3 ]
[ 17159-80-7 ]
[ 913573-70-3 ]

Yield	Reaction Conditions	Operation in experiment
68%	With diphenyl phosphoryl azide; triethylamine In toluene at 20 - 80℃; for 18h;	A solution of i-dδ-chloro^-^-methylpropyOoxylphenylJmethyO-S-methyl-IH-pyrazole-S- carboxylic acid (1.00 g, 3.11 mmol) in dry PhCH3 (6.0 ml) was stirred at room temperature under an atmosphere of argon. Et3N (0.649 ml, 4.67 mmol), DPPA (0.803ml, 3.73mmol) and ethyl-4-hydroxy-cyclohexane carboxylate (mixture of cis and trans 98%) (5.349 g, 31.10 mmol) were added to the stirred solution. The solution was heated to 800C for 18 hours. After this time, the solution was allowed to cool to room temperature and then it was diluted with EtOAc (~ 50 ml). Organics were washed with water (3 x 100 ml). The combined organics were dried over MgSO4, filtered and concentrated under reduced pressure to give a yellow oil. The residue was chromatographed [SiO2, Hexane: EtOAc, 20-50%] to give a yellow oil (1.04 g, 68 % yield), t = 3.80 mins, [MH]+ 492, 494.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2006/114313, 2006, A1 Location in patent: Page/Page column 174

20
[ 17159-80-7 ]
[ 18162-48-6 ]
[ 676560-15-9 ]
[ 676560-15-9 ]

Yield	Reaction Conditions	Operation in experiment
	With 1H-imidazole In tetrahydrofuran at 0 - 20℃;	202; 203 To a solution of 4-hydroxycyclohexanecarboxylic acid ethyl ester as a mixture of cis and trans isomers (8.7 g, 50.51 mmol) in THF (300 mL) at 0° C. was added imidazole (4.8 g, 70.72 mmol), DMAP (20 mol %, 1.23 g, 10.10 mmol,) and tert-butyl dimethylchlorosilane (9.1 g, 60.61 mmol). The reaction mixture was warmed to room temperature, stirred overnight, and diluted with ethyl acetate and saturated aqueous ammonium chloride. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulfate. Solvent was removed and the crude oil was filtered through silica gel and solvent removed to give 4-(tert-butyldimethylsilanyloxy)cyclohexanecarboxylic acid ethyl ester (11.1 g, 77%) as a mixture of diastereomers.To a solution of the product of the previous step (11.1 g, 38.7 mmol) in MTBE (150 mL) and methanol (2.35 mL, 58.11 mmol) was added lithium borohydride (1.27 g, 58.11 mmol). The reaction mixture was heated to 50° C. for 2 h, cooled to room temperature and quenched with methanol. The solution was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine, and dried over magnesium sulfate. Solvent was removed in vacuo to give crude [4-(tert-butyldimethylsilanyloxy)cyclohexyl]methanol as a mixture of diastereomers. Crude material was purified via silica gel chromatography (10-40% ethyl acetate/hexanes) to separate cis and trans diastereomers. Top spot (cis isomer) 1H NMR (300 mHz, CD3OD): 3.91-3.95 (m, 1H), 3.31-3.32 (d, 2H), 1.61-1.63 (m, 2H), 1.36-1.46 (m, 7H), 0.85-0.86 (s, 9H), 0.00 (s, 6H). Bottom spot (trans isomer) 1H NMR data (300 mHz, CD3OD): 3.49-3.53 (m, 1H), 3.27-3.28 (d, 2H), 1.81-1.84 (m, 2H), 1.71-1.74 (m, 2H), 1.28-1.36 (m, 1H), 1.18-1.26 (m, 2H), 0.93-0.97 (m, 2H), 0.82-0.84 (s, 9H), 0.00 (s, 6H).
	With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 78h;	1.a PREPARATION 1: 1 - Allyl-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexanecarbaldehyde; Step a: 4-(/ert-Butyl-dimethyl-silanyloxy)-cyclohexanecarboxylic acid ethyl ester:; [00160] To a 50 mL flask was added 4-hydroxy-cyclohexanecarboxylic acid ethyl ester (5.0 g; 29.0 mmol), imidazole (2.37 g; 34.8 mmol), DMF (30 mL) and ter/-buryldimethylsilyl chloride (4.81 g; 32.0 mmol). The solution was stirred for 78h at 20 0C. The reaction was diluted with EtOAc (100 mL), washed with water 2 x 100 mL), brine (100 mL), dried (MgSO4) filtered and concentrated in vacuo. The crude oil was purified by flash chromatography (silica gel, hexanes/EtOAc 1:0 to 1:1) to give pure product (7.79 g, 94% yield) as a 2:1 mixture of diastereomers.1H-NMR (400 MHz, CDCl3) (J = Hz) δ mixture 4.12 (m; 2H), 3.90 (m; 0.65H), 3.58 (m; 0.35H), 2.23 (m; IH), 1.98 (m; 3H), 1.82 (m; 3H), 1.49 (m; 2H), 1.21 (m; 3H), 0.88 (s; 9H), 0.05 (s; 3H), 0.03 (s; 3H). 13C-NMR (400 MHz, CDCl3) δ mixture 175.7, 175.6, 70.5, 66.6, 60.1, 60.0, 42.2, 42.1, 34.8, 32.8, 27.2, 25.8, 25.6, 23.4, 18.2, 18.0, 14.2, -4.7, -4.9. MS (ES+) m/z 287.22 [MH+].
	With 1H-imidazole In N,N-dimethyl-formamide at 18℃; for 20h;	VII VII) Synthesis of CP30450-3; Ethyl 4-[(/erf-butyldimethylsilyl)oxy]cyclohexanecarboxylate (55); Following protocols reported by Wild,10 a solution of Ethyl 4- hydroxycylohexanecarboxylate (54) (1.0 mL, 6.20 mmol) in DMF (3.0 mL) was treated with imidazole (929 mg, 13.6 mmol) and tert-butyldimethylsilyl chloride (1.22 g, 8.09 mmol) and the resulting mixture stirred magnetically at 18 °C under a nitrogen atmosphere for 20 h. The reaction mixture was then treated with Et2O (50 mL), washed with HCl (1 x 5 mL of a 1 M aqueous solution), then dried (MgSO4), filtered and concentrated under reduced pressure. The ensuing residue was subjected to flash chromatography (hexane- »1:49 v/v ethyl acetate/hexane gradient elution) to afford a ca. 1:1 mixture of the cis- and trøns-isomeric forms of the title compound 55 (1.78 g, quant.) as a colourless oil, Rf 0.7 in 3:7 v/v ethyl acetate/hexane.1H NMR (300 MHz) δ 4.12 and 4.11 (2 x q, J 7.1 and 7.1 Hz, 2 x 2H), 3.89 and 3.56 (2 x m, 2 x IH), 2.33-2.16 (complex m, 2 x IH), 1.98-1.87 (complex m, 2 x 2H), 1.68-1.22 (complex m, 2 x 6H), 1.25 and 1.24 (2 x t, J 7.1 and 7.1 Hz, 2 x 3H), 0.88 and 0.87(8) (2 x s, 2 x 9H), 0.05 and 0.03 (2 x s, 2 x 6H).13C NMR (75 MHz) δ 175.8 and 175.7 (2 x C), 70.5 and 66.6 (2 x CH), 60.1 and 60.0 (2 x CH2), 42.2 and 42.0 (2 x CH), 34.8 and 32.8 (4 x CH2), 27.2 and 23.4 (4 x CH2), 25.8 and 25.7(7) (6 x CH3), 18.2 and 18.1 (2 x C), 14.2 (2 x CH3), -4.7 and -4.9 (4 x CH3). IR vmax/cm"1 2934, 2858, 1734, 1463, 1252, 1096, 1049, 835, 774.Mass Spectrum (EI) m/z 229 [(M-C4Hg)+', 92], 57 (100).HRMS found: (M-C4H9)+ 229.1256. C15H30O3Si requires (M-C4Hg)+', 229.1260.

Reference： [1]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - US2007/219278, 2007, A1 Location in patent: Page/Page column 49
[2]Current Patent Assignee: BIOGEN IDEC INC. - WO2007/76086, 2007, A2 Location in patent: Page/Page column 53
[3]Current Patent Assignee: UNIVERSITY OF MELBOURNE - WO2008/124878, 2008, A1 Location in patent: Page/Page column 100

21
[ 17159-80-7 ]
[ 106-41-2 ]
[ 948555-94-0 ]

Yield	Reaction Conditions	Operation in experiment
42.11%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at -20 - 20℃; for 48h;	54.1 A solution of diisopropyl azodicarboxylate (3.4 mL, 0.017 mol) in THF (5 mL) was added dropwise to a solution of ethyl 4-hydroxycyclohexanecarboxylate (1.50 g, 0.00871 mol), 4-bromophenol (3.0 g, 0.017 mol), and triphenylphosphine (4.6 g, 0.017 mol) in THF (10 mL) at -20° C. After addition, the mixture was stirred at RT for 2 days. The mixture was concentrated. The crude residue was purified by flash column chromatography to yield the desired product (1.20 g, 42.11%). LCMS: (M+H)+=327.0; (M-4-BrPh)+=155.2.

Reference： [1]Current Patent Assignee: INCYTE CORP - US2007/208001, 2007, A1 Location in patent: Page/Page column 48-49

22
[ 456-24-6 ]
[ 3618-04-0 ]
[ 1124173-92-7 ]

Yield	Reaction Conditions	Operation in experiment
18%	With potassium tert-butylate; In tetrahydrofuran; at 5 - 20℃; for 1h;	Potassium tert-butoxide (3.95g, 35.2mmol) was added to a stirred solution of ethyl 4- hydroxycyclohexanecarboxylate (3.03g, 17.6mmol) and <strong>[456-24-6]2-fluoro-5-nitropyridine</strong> (2.5g, 17.6mmol) in THF (4OmL) under nitrogen at 5°C. The reaction mixture was allowed to warm to ambient temperature and stirred for Ih. The mixture was then quenched with water (10OmL) and extracted with ethyl acetate (2 x 100 mL) and the organics washed with water (10OmL). The organic phase was dried (MgSO4) and solvent removed in vacuo. The crude product was purified by flash silica chromatography, eluting with 0 to 30percent ethyl acetate in isohexane to afford the title compound as a yellow oil (907mg, 18percent). 1R NMR (400 MHz, CDCl3) deltal.28 (3H, m), 1.51 -2.5 (1OH, m), 4.15 (2H, m), 5.10 - 5.4 (IH, m), 6.78 (IH, m), 8.32 (IH, m), 9.05 (IH, d). m/z 294.9 (M+H)+

Reference： [1]Patent: WO2009/24821,2009,A2 .Location in patent: Page/Page column 106

23
[ 17159-80-7 ]
[ 124-63-0 ]
[ 52814-98-9 ]

Yield	Reaction Conditions	Operation in experiment
99%	With triethylamine In dichloromethane at 10℃; for 0.5h; Inert atmosphere;	1 Step 1 - Ethyl 4-methylsulfonyloxycyclohexanecarboxylate To a solution of ethyl 4-hydroxycyclohexanecarboxylate (3.00 g, 17.4 mmolCAS 17159-80-7) and TEA (3.53 g, 34.8 mmol) in DCM (30 mL) was added MsCl (2.39 g, 20.9 mmol). The reaction mixture was stirred at 10 °C for 30 minutes. On completion, the reaction mixture was washed with 0.1N HCl solution until the pH = 7. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (4.35 g, 99% yield, a mixture of trans and cis) as colorless oil.1H NMR (400 MHz, CDCl3) d 4.97 - 4.60 (m, 1H), 4.19 - 4.10 (m, 2H), 3.05 - 3.00 (m, 3H), 2.48 - 2.27 (m, 1H), 2.25 - 2.01 (m, 3H), 2.00 - 1.58 (m, 5H), 1.50 - 1.22 (m, 3H).
96%	With triethylamine In dichloromethane at 0 - 20℃; for 2h;	14.1 Step 1: Synthesis of ethyl 4-((methylsulfonyl)oxy)cyclohexane-1 -carboxylate A 40-mL round-bottom flask was charged with ethyl 4-hydroxycyclohexane-1- carboxylate (200 mg, 1.16 mmol, 1.00 equiv), TEA (351 mg, 3.47 mmol, 3.00 equiv), and DCM (10 mL). Methanesulfonyl chloride (158 mg, 1.38 mmol, 1.20 equiv) was added dropwise at 0 °C. The resulting solution was stirred for 2 h at room temperature and quenched with water (10 mL). The mixture was extracted with DCM (3 x 10 mL) and theorganic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 280 mg (96% yield) of ethyl 4-(methanesulfonyloxy)cyclohexane-1-carboxylate as a light yellow oil.
55%	With triethylamine In dichloromethane at 0 - 25℃; for 2h;	69.1 Step 1. Ethyl4-(methanesulfonyloxy)cyclohexane- 1 -carboxylate A 250-mE 3-necked round-bottom flask fitted with a magnetic stir bar and thermometer was charged with ethyl 4-hydroxycyclohexane-i -carboxylate (1.5 g, 8.71 mmol), tnethylamine (2.64 g, 26.09 mmol) and dichloromethane (50 mE). To the reaction was added methanesulfonyl chloride (1.49 g, 13.01 mmol) added dropwise with stirring at 00 C. The resulting solution was stirred for 2 h at 25° C. The resulting solution was diluted with water (20 mE) and the product was extracted with dichloromethane (3x20 mE). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:5, v/v) to afford ethyl 4-(methane- sulfonyloxy) cyclohexane- 1 -carboxylate as a light yellow oil (1.2 g, 55%). ECMS: (ESI) mlz 251 [M+H], 155 [M-OMs].

With triethylamine In dichloromethane at 0℃; for 0.5h;

38.A Step A: Ethyl 4-[(methylsulfonyl)oxy]cyclohexanecarboxylate. Methanesulfonyl chloride (2.4 mL, 31 mmol) was slowly added to a dichloromethane solution (75 mL) of ethyl 4-hydroxycyclohexanecarboxylate (4.63 mL, 28.7 mmol) and triethylamine (8.2 mL, 59 mmol) at 0 0C. The reaction mixture was stirred for 30 minutes, concentrated in vacuo and diluted in diethyl ether (100 mL). The solution was washed with 10% hydrochloric acid (25 mL), water (25 mL), and saturated sodium bicarbonate (15 mL). The organics were dried (magnesium sulfate) and concentrated in vacuo to afford the title compound. 1H NMR (500 MHz, CDCl3) δ 1.23 (t, 7= 7.1 Hz, 3H), 1.54-1.82 (m, 4H), 1.87-1.97 (m, 2H), 2.00-2.08 (m, 2H), 2.34-2.41 (m, IH), 3.00 (s, 3H), 4.13 (q, J = 7,1 Hz, 2H), 4.88-4.92 (m, IH).

Reference： [1]Current Patent Assignee: KYMERA THERAPEUTICS INC - WO2020/113233, 2020, A1 Location in patent: Paragraph 00962; 003487-003489
[2]Current Patent Assignee: H. LUNDBECK A/S - WO2018/93949, 2018, A1 Location in patent: Paragraph 00308
[3]Current Patent Assignee: VALO HEALTH INC - US2016/185785, 2016, A1 Location in patent: Paragraph 2242; 2243
[4]Current Patent Assignee: MERCK & CO INC - WO2009/94242, 2009, A1 Location in patent: Page/Page column 36

24
[ 75-15-0 ]
[ 17159-80-7 ]
[ 74-88-4 ]
[ 1227188-04-6 ]

Yield	Reaction Conditions	Operation in experiment
38%	Stage #1: 4-hydroxycyclohexyl carboxylic acid ethyl ester With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.916667h; Stage #2: carbon disulfide In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; Stage #3: methyl iodide In N,N-dimethyl-formamide; mineral oil at 0 - 20℃;	4-Alkoxy-cyclohexanecarboxylic acid ester 23cis/trans-4-Methylsulfanylthiocarboxyoxy-cyclohexanecarboxylic acid ethyl esterTo a solution of ethyl 4-hydroxycyclohexane carboxylate (2:1) (3.0 g, 17 mmol) in N,N-dimethylformamide (35 ml) was added sodium hydride (1.0 g, 21 mmol, 50% in mineral oil) at 0-5° C. The reaction mixture was stirred for 10 minutes at 0° C. and for 45 minutes at room temperature. Carbon disulfide (2.1 ml, 35 mmol) was added dropwise at 0-5° C. over a period of 10 minutes. The reaction mixture was stirred for 7 h at room temperature. Iodomethane (1.3 ml, 21 mmol) was added dropwise at 0-5° C. Stirring for 16 h at room temperature was followed by quenching with saturated aqueous ammonium chloride solution (6 ml). The reaction mixture was partitioned between saturated aqueous ammonium chloride solution (150 ml) and tert-butyl methyl ether (150 ml). The layers were separated. The aqueous layer was extracted with two 150-ml portions of tert-butyl methyl ether. The combined organic layers were washed with two 50-ml portions of water and one 50-ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.46 g, 38%) as colorless oil. MS m/e: 263 (M+H+)

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2010/125066, 2010, A1 Location in patent: Page/Page column 27-28

25
[ 14508-49-7 ]
[ 17159-80-7 ]
[ 1428523-58-3 ]
[ 2758505-99-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methansulfinate; potassium carbonate In N,N-dimethyl-formamide at 120℃;	II To a solution of a 4-hydroxy-cyclohexanecarboxylic acid ester of formula (IV) (1 eq) and a heteroaryl chloride derivative (1 eq) in dry N,N-dimethylformamide (1 M) are added consecutively sodium methanesulfinate (85%, 0.25-1 eq) and potassium carbonate (1.5 eq). After completed addition the reaction mixture is stirred at 120° C. for 3-18 h. After cooling to room temperature the reaction mixture is partitioned between tert-butyl methyl ether and water. The layers are separated and the aqueous layer is extracted with one to two portions of tert-butyl methyl ether. The combined organic layers are washed with one to two portions of water, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash-chromatography gives a 4-heteroaryloxy-cyclohexanecarboxylic acid ester of formula (VI-a).; The title compound was obtained as white solid in 15% yield according to general procedure II.Heteroaryl chloride: 2-Chloropyrazine4-Hydroxy-cyclohexanecarboxylic acid ester: cis/trans-4-Hydroxy-cyclohexanecarboxylic acid ethyl ester ester (2:1)MS m/e: 251 (M+H+)
	With sodium methansulfinate; potassium carbonate In N,N-dimethyl-formamide at 120℃; Overall yield = 15 %;	General procedure IIIB: General procedure: Sodium methanesulfinate mediated arylationTo a solution of a 4-hydroxy-cyclohexanecarboxylic acid ester of formula (IV) (1 eq) and a heteroaryl chloride derivative of formula (XII) (1 eq) in dry Ν,Ν-dimethylformamide (1 M) are added consecutively sodium methanesulfinate (85%>, 0.25 - 1 eq) and potassium carbonate (1.5 eq). After completed addition the reaction mixture is stirred at 120 °C for 3-18 h. After cooling to room temperature the reaction mixture is partitioned between tert-butyl methyl ether and water. The layers are separated and the aqueous layer is extracted with one to two portions of tert-butyl methyl ether. The combined organic layers are washed with one to two portions of water, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by fiash-chromatography gives a 4-heteroaryloxy-cyclohexanecarboxylic acid ester of formula (VII-3).
	With sodium methansulfinate; potassium carbonate In N,N-dimethyl-formamide at 120℃; for 18h;	General Procedure IIIB: Sodium Methanesulfinate Mediated Arylation General procedure: To a solution of a 4-hydroxy-cyclohexanecarboxylic acid ester of formula (IV) (1 eq) and a heteroaryl chloride derivative of formula (XII) (1 eq) in dry N,N-dimethylformamide (1 M) are added consecutively sodium methanesulfinate (85%, 0.25-1 eq) and potassium carbonate (1.5 eq). After completed addition the reaction mixture is stirred at 120° C. for 3-18 h. After cooling to room temperature the reaction mixture is partitioned between tert-butyl methyl ether and water. The layers are separated and the aqueous layer is extracted with one to two portions of tert-butyl methyl ether. The combined organic layers are washed with one to two portions of water, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash-chromatography gives a 4-heteroaryloxy-cyclohexanecarboxylic acid ester of formula (VII-3).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2010/137286, 2010, A1 Location in patent: Page/Page column 30; 32
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2013/45373, 2013, A1 Location in patent: Page/Page column 26; 27
[3]Current Patent Assignee: ROCHE HOLDING AG - US2013/79333, 2013, A1 Location in patent: Paragraph 0124; 0128

26
[ 17159-80-7 ]
[ 103-16-2 ]
[ 1240307-09-8 ]

Yield	Reaction Conditions	Operation in experiment
28.3%	With di-isopropyl azodicarboxylate In tetrahydrofuran at 0 - 20℃;	14 Example No.14: Synthesis of ethyl 4-(4-(benzyloxy)phenoxy)cyclohexanecarboxylate; Triphenylphosphine (polymer bound, 3 mmol/g, 4.99 g, 14.98 mmol) was treated with DIAD (0.971 ml, 4.99 mmol) at about 0° C in dry THF (30 mL). The mixture was stirred for about 1 h then 4-(benzyloxy)phenol (1.0 g, 4.99 mmol) and ethyl 4- hydroxycyclohexanecarboxylate (0.804 ml, 4.99 mmol) wrere added. The mixture was warmed to room temperature and then stirred overnight. The residue was evaporated to dryness and subjected to purification by reversed phase HPLC. The combined fractions were evaporated to dryness, dried in vacuo at about 60° C for about 24 h to afford ethyl 4-(4- (benzyloxy)phenoxy)cyclohexanecarboxylate (501 mg, 1.413 mmol, 28.3% yield) as a pale green oil. 1H NMR (400 MHz, CDCl3): δ 7.51 - 7.31 (5H, m), 6.98 - 6.85 (4H, m), 5.04 (2H, d, J= 4.8 Hz), 4.19 (2H, tt, J= 13.3 Hz, 6.6 Hz), 4.14 - 4.06 (IH, m), 2.49 - 2.31 (IH, m), 2.26 - 1.96 (4H, m), 1.83 - 1.42 (4H, m), 1.34 - 1.25 (3H, m). LC/MS (Table 2, Method b) R»: 3.17 min; m/z 353 (M+H)".

Reference： [1]Current Patent Assignee: ABBOTT LABORATORIES INC - WO2010/93704, 2010, A1 Location in patent: Page/Page column 147

27
[ 110-87-2 ]
[ 17159-80-7 ]
[ 1312478-77-5 ]

Yield	Reaction Conditions	Operation in experiment
85%	With pyridinium p-toluenesulfonate In dichloromethane for 16h;	8.A Pyridinium-4-toluenesulfonate (2.57 g, 10.2 mmol) was added to a solution of ethyl 4- hydroxycyclohexanecarboxylate (8.8 g, 51 .10 mmol) and 3,4-dihydro-2H-pyran (8.60 g, 102 mmol) in DCM (200 mL). After 16 hours the reaction was quenched with saturated aqueous sodium bicarbonate. The layers were separated and the organic layer was washed with water. The organic layer was dried (Na2S04), filtered and concentrated. Purification by flash column chromatography on an Analogix SF65-200g column (hexanes / ethyl acetate 95:05 - 9:1 ) afforded the title compound (clear oil) as a mixture of isomers (1 1.1 g, 85 %).
85%	With pyridinium p-toluenesulfonate In dichloromethane at 20℃; for 16h;	18.A Step A) Ethyl 4-(tetrahydro-2H-pyran-2-yloxy)cyclohexanecarboxylatePyridinium-4-toluenesulfonate (2.57 g, 10.2 mmol) was added to a solution of ethyl 4-hydroxycyclohexanecarboxylate (8.8 g, 51.10 mmol) and 3,4-dihydro-2H-pyran (8.60 g, 102 mmol) in DCM (200 mL) and the reaction was stirred at rt for 16 h. The reaction was quenched with saturated aq NaHCO3. The layers were separated and the organic layer was washed with water. The organic layer was dried (Na2SO4), filtered, and concentrated. Purification via flash chromatography on a 200 g silica column using an eluent of EtOAc in hexanes (5-10%) afforded the title compound as a clear oil (11.1 g, 85%).
9 g	With Amberlyst 15 In dichloromethane at 20℃; for 77h;	13.1 Step 1 : Ethyl 4-(tetrahydro-2H-pyran-2-yloxy)cyclohexanecarboxylate To a solution of ethyl 4-hydroxycyclohexanecarboxylate (5.00 g, 29.0 mmol) in dichloromethane (30 mL) was added 3,4-dihydro-2H-pyran (2.52 g, 29.0 mmol) and Amberlyst 15 (0.5 g). The reaction mixture was stirred at room temperature for 72 h, then another prtion 3,4-dihydro-2H-pyran (1.89 g, 21.8 mmol) and Amberlyst 15 (0.5 g) was added, then after 5 h the reaction mixture was washed with sat. aq. sodium hydrogencarbonate solution. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to afford the title compound as a yellow oil (9 g), which was used directly in the next step.

9 g

With Amberlyst In dichloromethane at 20℃; for 77h;

13.1 Step 1: Ethyl 4-(tetrahydro-2H-pyran-2-yloxy)cyclohexanecarboxylate To a solution of ethyl 4-hydroxycyclohexanecarboxylate (5.00 g, 29.0 mmol) in dichloromethane (30 mL) was added 3,4-dihydro-2H-pyran (2.52 g, 29.0 mmol) and Amberlyst 15 (0.5 g). The reaction mixture was stirred at room temperature for 72 h, then another portion 3,4-dihydro-2H-pyran (1.89 g, 21.8 mmol) and Amberlyst 15 (0.5 g) was added, then after 5 h the reaction mixture was washed with sat. aq. sodium hydrogencarbonate solution. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to afford the title compound as a yellow oil (9 g), which was used directly in the next step.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2011/73845, 2011, A1 Location in patent: Page/Page column 49
[2]Current Patent Assignee: PFIZER INC; KIMBERLY-CLARK CORP - US2012/232083, 2012, A1 Location in patent: Page/Page column 21
[3]Current Patent Assignee: ROCHE HOLDING AG - WO2013/60653, 2013, A1 Location in patent: Page/Page column 63
[4]Current Patent Assignee: ROCHE HOLDING AG - US2013/109718, 2013, A1 Location in patent: Paragraph 0280-0281

28
[ 13466-38-1 ]
[ 3618-04-0 ]
[ 1275993-30-0 ]

Yield	Reaction Conditions	Operation in experiment
62%	With di-isopropyl azodicarboxylate;triphenylphosphine; In tetrahydrofuran; at 20℃; for 17h;	INTERMEDIATE B-33Step 1 : ethyl 4-(5-bromopyridin-2-yloxy)cycIohexanecarboxylate (B-31)To a solution of <strong>[13466-38-1]5-bromo-2-hydroxypyridine</strong> B-30 (1.0 g, 5.75 mmol) and ethyl 4- hydroxycyclohexanecarboxylate (990 mg, 5.75 mmol) in THF (50 mL) was added PPh3 (2.4 g, 9.150 mmol) and DIAD (1.8 mL, 9.14 mmol). The reaction mixture was stirred at RT for 17 h. The solution was then concentrated and purified by ISCO to yield ethyl 4-(5- bromopyridin-2-yloxy)cyclohexanecarboxylate as a colorless oil (1.16 g, 62% yield, 3:2 trans:cis ratio).
	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 17h;	Step A: ethyl 4-(5 -bromopyridin-2-yloxy)cycl ohexanecarboxylateTo a solution of <strong>[13466-38-1]5-bromo-2-hydroxypyridine</strong> (1.0 g, 5.747 mmol) and ethyl 4- hydroxycyclohexanecarboxylate (0.99 g, 5.75 mmol) in THF (50 mL) was added PPh3 (2.4 g,9.15 mmol) and DIAD (1.8 mL, 9.14 mmol). The reaction mixture was stirred at RT for 17 h.The solution was then concentrated and purified by silica gel column chromatography with anISCO system to yield ethyl 4-(5-bromopyridin-2-yloxy)cyclohexanecarboxylate as a colorless oil.

Reference： [1]Patent: WO2011/31628,2011,A1 .Location in patent: Page/Page column 75
[2]Patent: WO2012/24179,2012,A1 .Location in patent: Page/Page column 69

29
[ 3618-04-0 ]
[ 51498-33-0 ]

Yield	Reaction Conditions	Operation in experiment
	With (carbonyl)chloro(hydrido)tris(triphenylphosphine)ruthenium(II); ammonia; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In tert-Amyl alcohol; at 130℃; for 20h;Inert atmosphere; Cooling;	Example 6Direct Single-Stage Amination of Alcohols andHydroxy Acids by Means of Ammonia Over aHomogeneous Ruthenium Catalyst and Xantphos ata high V7J Vgas (according to the invention)Under an argon atmosphere, m g of starting material, mRU g of [carbonylchlorohydridotris(triphenylphosphane)ruthenium(II)] and mp g of 9,9-dimethyl-4,5-bis (diphenylphosphino)xanthene as catalyst and V07 ml of 2-methyl-2-butanol as solvent were introduced into a 50 mlsteel tube. The vessel was closed, pressurized three times with 20 bar of argon and depressurized each time. The vessel was then cooled by means of dry ice and m g of ammonia were condensed in. The reactor is heated to T C. and maintained at this temperature for 20 hours. Afier cooling to room temperature, the reactor was depressurized and opened, the solvent was removed on a rotary evaporator and the residue was dissolved in methanol and then analysed by gas chromatography. Reaction parameters and conversions and selectivities to the desired reaction product are shown in Tab. 5. The results show that many different hydroxy-thnctionalized substrates can be aminated by the method described.

Reference： [1]Angewandte Chemie - International Edition,2011,vol. 50,p. 7599 - 7603
[2]Patent: US2013/331580,2013,A1 .Location in patent: Paragraph 0063

30
[ 17159-80-7 ]
[ 1219741-26-0 ]
[ 1332707-27-3 ]

Yield	Reaction Conditions	Operation in experiment
	With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 80℃;	15.A To a solution of l-(biphenyl-4-ylmethyl)-4,6-difluoro-5-iodo-2- (methylsulfonyl)-lH-benzimidazole (Intermediate 5, 20 g, 38.1 mmol) and ethyl 4- hydroxycyclohexanecarboxylate (21 ml, 130 mmol, Aldrich, a mixture of cis and trans isomers) in DMF (70 ml) was added DBU (23 ml, 130 mmol) dropwise at room temperature. The reaction mixture was heated at 80 °C overnight. Then the volatiles were removed in vacuo and the resulting residue partitioned between EtOAc and H20. The organic phase was separated, washed with water and brine, dried over MgS04 and concentrated in vacuo. Chromatography of the resulting residue over silica eluting with 15% EtOAc/hexane afforded the title compound as a mixture of trans and cis isomers. LC-MS: calculated for C29H27F2IN2O3 61 .1, observed m e: 617.20 (M+H) • (Rt 2.82/4 min).
	With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 80℃;

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2011/106273, 2011, A1 Location in patent: Page/Page column 82
[2]Feng, Danqing; Biftu, Tesfaye; Romero, F. Anthony; Kekec, Ahmet; Dropinski, James; Kassick, Andrew; Xu, Shiyao; Kurtz, Marc M.; Gollapudi, Anantha; Shao, Qing; Yang, Xiaodong; Lu, Ku; Zhou, Gaochao; Kemp, Daniel; Myers, Robert W.; Guan, Hong-Ping; Trujillo, Maria E.; Li, Cai; Weber, Ann; Sebhat, Iyassu K. [ACS Medicinal Chemistry Letters, 2018, vol. 9, # 1, p. 39 - 44]

31
[ 17159-80-7 ]
[ 524734-42-7 ]

Yield	Reaction Conditions	Operation in experiment
68%	With 1-methyl-1H-imidazole; iodine; triphenylphosphine In dichloromethane at 0℃; for 4h; Inert atmosphere;
49%	With 1H-imidazole; iodine; triphenylphosphine In tetrachloromethane; dichloromethane at 0 - 20℃;
35%	With 1H-imidazole; iodine; triphenylphosphine In dichloromethane

	With 1H-imidazole; iodine; triphenylphosphine In dichloromethane at 0 - 20℃;	4.A Step A: ethyl 4-iodocyclohexanecarboxylateTo a solution of ethyl 4-hydroxycyclohexane carboxylate (10.0 g, 58.1 mmol) inCH2C12 (200 mL) at 0 °C was added imidazole (1 1.86 g, 174.0 mmol), triphenylphosphine (25.9 g, 99.0 mmol), and followed by iodine (25.05 g, 99.0 mmol) several portions over a period of 45 min. The resulting suspension was gradually allowed to warm up to rt. After stirring at rt over night, the mixture was partitioned between Et20 (200 mL) and water (200 mL). The organic layer was washed with saturated Na2S203 ( 100 mL) and brine (3x1 OOmL), dried over MgS04, and concentrated. The residue was purified by flash chromatography (Biotage 40+M) using 10- 20% EtOAc hexane gradient, affording the title compound: .H NMR (500 MHz, CDC13) δ 5.70 (m, IH), 4.20-4.10 (m, 2H), 2.58 (m, IH), 2.48-1.60 (m, 8H), 1.28 (mf 3H).
	With 1H-imidazole; iodine; triphenylphosphine In dichloromethane at 0 - 20℃;	ethyl 4-iodocyclohexanecarboxylate Iodine (25 g, 98 mmol) in portions at 0 °C was added to a solution of triphenylphosphine (25.9 g, 99 mmol), imidazole (11.86g, 174 mmol), ethyl 4- hydroxycyclohexanecarboxylate (lOg, 58.1 mmol) in anhydrous DCM (200 mL). The mixture was gradully warm to room temperature and stirred overnight. The mixture wastreated with Et20 (300 mL) and aqueous Na2SO3 solution. The organic layer was washed with aqueous Na2SO3 solution and brine, Na2SO4, filtered and evaporated. The residue was dissolved in DCM and treated with ether. White precipiate formed. The mixture was filtered and the filtrate was evaporated. The residue was purified by silica chromatography (0-50% ethyl acetate in hexanes) to afford the title compound. MS: 283 (M + 1)
	Multi-step reaction with 2 steps 1: dmap; triethylamine / dichloromethane / 18 h / 0 °C 2: sodium iodide / acetonitrile / 80 °C / Inert atmosphere

Reference： [1]Grokenberger, Lucie; Hammann, Jeffrey M.; Karaghiosoff, Konstantin; Knochel, Paul; Lutter, Ferdinand H.; Spieß, Philipp [Angewandte Chemie - International Edition, 2020, vol. 59, # 14, p. 5546 - 5550][Angew. Chem., 2020, vol. 132, p. 5591 - 5595,5]
[2]Press, Neil J.; Taylor, Roger J.; Fullerton, Joseph D.; Tranter, Pamela; McCarthy, Clive; Keller, Thomas H.; Arnold, Nicola; Beer, David; Brown, Lyndon; Cheung, Robert; Christie, Julie; Denholm, Alastair; Haberthuer, Sandra; Hatto, Julia D. I.; Keenan, Mark; Mercer, Mark K.; Oakman, Helen; Sahri, Helene; Tuffnell, Andrew R.; Tweed, Morris; Tyler, John W.; Wagner, Trixie; Fozard, John R.; Trifilieff, Alexandre [Journal of Medicinal Chemistry, 2012, vol. 55, # 17, p. 7472 - 7479]
[3]Thomas, Lucie; Lutter, Ferdinand H.; Hofmayer, Maximilian S.; Karaghiosoff, Konstantin; Knochel, Paul [Organic Letters, 2018, vol. 20, # 8, p. 2441 - 2444]
[4]Current Patent Assignee: MERCK & CO INC - WO2011/53519, 2011, A1 Location in patent: Page/Page column 16
[5]Current Patent Assignee: MERCK & CO INC - WO2018/34918, 2018, A1 Location in patent: Page/Page column 76; 77
[6]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2021/203010, 2021, A1

32
[ 17159-80-7 ]
[ 76-83-5 ]
[ 1402838-25-8 ]

Yield	Reaction Conditions	Operation in experiment
59%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In dichloromethane for 24h; Reflux;	10 Example 10 Eth l 4-(trityloxy)cyclohexanecarboxylate[0145] To a solution of triphenylmethyl chloride (0.97 g, 3.48 mmol) in dichloromethane (10 mL) was added DBU (0.61 mL, 4.06 mmol) and ethyl 4-hydroxycyclohexanecarboxylate (500 mg, 2.90 mmol) and the mixture was refluxed for 24 h. The reaction mixture cooled and cold water (40 mL) was added. The organic layer was collected and the aqueous layer was extracted with dichloromethane (2 x 30 ml). The combined organic layers were dried (Na2S04) and concentrated under reduced pressure. The crude was purified by flash column chromatography to afford 23 as colorless oil (714 mg, 59%). HNMR: (mixture of cis and trans isomers (1 : 1.4)) 1.06 (t, 2H, J = 12.4 Hz), 1.16-1.26 (m, 14H), 1.32-1.35 (m, 2H), 1.54- 1.58 (m, 2H), 1.76-1.79 (m, 3H),1.95-2.04 (m, 2H), 2.1 1-2.22 (m, 2H), 3.35-3.41 (m, 1.4H), 3.72-3.76 (m, 1H), 4.04 (q, 2.8H, J = 7.2 Hz), 4.14 (q, 2H, J = 6.8 Hz), 7.22-7.27 (m, 24H, merged with CHC13), 7.49-7.51 (m, 13H).

Reference： [1]Current Patent Assignee: LUMOS PHARMA INC - WO2012/142237, 2012, A1 Location in patent: Page/Page column 96

33
[ 17159-80-7 ]
[ 1311312-15-8 ]

Yield	Reaction Conditions	Operation in experiment
58%	With sulfuric acid; nitric acid In dichloromethane at 0 - 20℃; for 3h;	19 Example 19Synthesis of 4-Nitrooxy-cyclohexylcarboxylic acid ethyl ester; Concentrated sulphuric acid 96% (1.24 mL, 2.0 eq) was added dropwise to fuming nitric acid 100% (0.97 mL, 2.0 eq) at 0° C. After 10 minutes of stirring at 0° C., a solution of 1 (2.00 g, 1.0 eq) in dichloromethane (20.0 mL) was added dropwise. The reaction mixture was stirred from 0° C. to RT for 3 hours and quenched with water (30.0 mL). The organic layer was washed with water (20.0 mL) and brine (20.0 mL), dried over magnesium sulphate, filtered off and concentrated under vacuum. The residue was adsorbed on silica gel and purified by flash chromatography [Biotage, dichloromethane/methanol 100/0→97/3 (10CV*), 97/3 (5CV)] affording compound 2 as a colourless liquid (1.47 g, yield=58%).

Reference： [1]Current Patent Assignee: KONINKLIJKE DSM N.V. - US2012/315339, 2012, A1 Location in patent: Page/Page column 15

34
[ 17159-80-7 ]
[ 100-52-7 ]
[ 1558003-74-9 ]
[ 1558003-75-0 ]

Yield	Reaction Conditions	Operation in experiment
1: 64% 2: 26%	With triethylsilane; iron(III) chloride In nitromethane at 20℃; for 1h; Inert atmosphere;	Ethyl cis-4-(benzyloxy)cyclohexanecarboxylate 6a and ethyl trans-4-(benzyloxy)cyclohexanecarboxylate 6b This compound was obtained by the procedure described by Oriyama et al. 14 To a suspension of anhydrous iron(III) chloride (21.0mg, 0.13mmol) and benzaldehyde (264μL, 2.60mmol) in nitromethane (13mL) were added successively ethyl 4-hydroxycyclohexanecarboxylate, a mixture of cis and trans (dr value 69:31, determined by NMR) (500μL, 3.10mmol) and triethylsilane (495μL, 3.10mmol) at room temperature under a nitrogen atmosphere. After stirring for 1h, water (100mL) was added, and the aqueous layer was extracted with dichloromethane (3×30mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, hexane-ethyl acetate from 100:0, v/v to 95:5, v/v) to give 6a (faster eluting diastereoisomer, 438.5mg, 64%), and 6b (slower eluting diastereoisomer, 180.1mg, 26%). Overall yield: 90%. Compound 6a: 1H NMR (400MHz, CDCl3) δ 7.39-7.30 (m, 4H, HC7,8), 7.30-7.23 (m, 1H, HC9), 4.51 (s, 2H, HC5), 4.13 (q, J=7.1Hz, 2H, HC11), 3.58 (tt, J=5.1, 2.8Hz, 1H, HC4), 2.36 (tt, J=9.6, 4.0Hz, 1H, HC1), 1.97 (ddd, J=10.7, 8.7, 3.4Hz, 2H, HC2), 1.93-1.84 (m, 2H, HC3), 1.68 (ddd, J=12.9, 8.8, 4.2Hz, 2H, HC2), 1.61-1.50 (m, 2H, HC3), 1.25 (t, J=7.1Hz, 3H, HC12)ppm. 13C {1H} NMR (101MHz, CDCl3) δ 175.6 (C10), 139.2 (C6), 128.4 (C8), 127.5 (C7), 127.4 (C9), 73.2 (C4), 69.8 (C5), 60.3 (C11), 42.0 (C1), 29.2 (C3), 24.0 (C2), 14.4 (C12)ppm. IR νmax 2937, 2866, 1727, 1453cm-1. MS (FAB) m/z (relative intensity, %) 263 (M++H+, 100), 217 (8), 181 (9), 155 (43), 91 (75). HRMS (FAB) Calcd for C16H23O3 [M+H]+: m/z 263.1642, Found: 263.1629. Anal. Calcd for C16H22O3: C, 73.25; H, 8.45. Found: C, 72.71; H, 8.33. Compound 6b: 1H NMR (400MHz, CDCl3) δ 7.37-7.34 (m, 4H, HC7,8), 7.33-7.26 (m, 1H, HC9), 4.58 (s, 2H, HC5), 4.14 (q, J=7.1Hz, 2H, HC11), 3.37 (tt, J=10.3, 4.1Hz, 1H, HC4), 2.30 (tt, J=11.6, 3.6Hz, 1H, HC1), 2.16 (dd, J=12.4, 2.5Hz, 2H, HC3), 2.05 (d, J=12.0Hz, 2H, HC2), 1.57-1.44 (m, 2H, HC2), 1.43-1.30 (m, 2H, HC3), 1.27 (t, J=7.1Hz, 3H, HC12)ppm. 13C {1H} NMR (101MHz, CDCl3) δ 175.7 (C10), 139.0 (C6), 128.5 (C8), 127.7 (C7), 127.6 (C9), 76.6 (C4), 70.1 (C5), 60.4 (C11), 42.6 (C1), 31.4 (C3), 27.3 (C2), 14.3 (C12)ppm. IR νmax 2937, 2863, 1728, 1454cm-1. MS (FAB) m/z (relative intensity, %) 263 (M++H+, 17), 217 (3), 181 (4), 155 (29), 91 (100). HRMS (FAB) Calcd for C16H23O3 [M+H]+: m/z 263.1642, Found: 263.1632. Anal. Calcd for C16H22O3: C, 73.25; H, 8.45. Found: C, 73.30; H, 8.42.

Reference： [1]Cedillo-Cruz, Alberto; Aguilar, Maria Isabel; Flores-Alamo, Marcos; Palomares-Alonso, Francisca; Jung-Cook, Helgi [Tetrahedron Asymmetry, 2014, vol. 25, # 2, p. 133 - 140]

35
[ 17159-80-7 ]
[ 69739-34-0 ]
[ 676560-15-9 ]

Yield	Reaction Conditions	Operation in experiment
96.6%	With 2,6-dimethylpyridine In dichloromethane at 0℃; for 2h;	115A ethyl 4-[tert-butyldimethylsilyl]oxy-cyclohexanecarboxylate 2,6-Dimethylpyridine (6.97 g, 65.03 mmol) and TBSOTf (12.89 g, 48.77 mmol) were added to a solution of ethyl 4-hydroxycyclohexanecarboxylate (5.60 g, 32.52 mmol) in DCM (50.00 mL) at 0°C. The mixture was stirred at 0°C for 2 h. The reaction solution was diluted with DCM (200 mL), washed with water (30 mL * 3) and brine (200 mL), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by column chromatography to give the title compound (colorless oil, 9.00 g, yield of 96.60%). 1H NMR (400MHz, CHLOROFORM-d) δ = 4.06 (dq, J=5.1, 7.2 Hz, 2H), 3.84 (br s, 0.5H), 3.56 - 3.45 (m, 0.5H), 2.28 - 2.11 (m, 1H), 1.98 - 1.79 (m, 3H), 1.64 - 1.54 (m, 2H), 1.48 - 1.36 (m, 2H), 1.31 - 1.24 (m, 1H), 1.20 (dt, J=3.0, 7.2 Hz, 3H), 0.83 (d, J=1.5 Hz, 9H), -0.01 (d, J=8.5 Hz, 6H).
95%	With triethylamine In dichloromethane at 0 - 20℃; for 12h; Molecular sieve; Inert atmosphere;

Reference： [1]Current Patent Assignee: WUXI APPTEC CO., LTD.; SINO BIOPHARMACEUTICAL LIMITED - EP3418282, 2018, A1 Location in patent: Paragraph 0809-0810
[2]Robertson, Keith; Murphy, Cormac D.; Paradisi, Francesca [Amino Acids, 2013, vol. 45, # 5, p. 1157 - 1168]

36
4-hydroxycyclohexyl carboxylic acid ethyl ester [ No CAS ]
[ 33893-85-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 3h; Inert atmosphere;	10.1 Example 10: General procedure for the preparation of modified alkyl chain acyclic purine nucleoside analogues Step 1 : To a stirred solution ethyl 4-hydroxycyclohexanecarboxylate (2.78 g, 16.0 mmol, 1 equiv.) in dry THF (80 mL), was added dropwise lithium aluminum hydride (1 M in THF, 24 mL, 24.0 mmol, 1 .5 equiv.) at 0°C under azote atmosphere. The reaction mixture was warmed to room temperature and stirred for 3h30. The mixture was then cooled to 0°C and water (1 ml_), 15% aqueous sodium hydroxide (1 mL) and water (3 mL) were successively added. The mixture was allowed to warm to room temperature and stirred overnight. The salts were filtered through a pad of celite and the filtrate was dried over Na2S04 and concentrated under vacuum to yield 4- (hydroxymethyl)cyclohexanol (2.10 g, quant.) as a colorless oil.
97%	With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 0.5h;	77.1 4-(Hydroxymethyl)cyclohexanol To a suspension of lithium tetrahydroaluminate (3.11 g, 81.9 mmol) in THF (158 mL) was added a solution of ethyl 4-hydroxycyclohexanecarboxylate (9.40 g, 54.6 mmol) in THF (20 mL) at 0° C. After stirring for 30 min at same temperature, the reaction was quenched with water (10 mL) dropwise, then 15% NaOH solution (10 mL) and water (30 mL). After stirring for 10 min, the reaction mixture was filtered through a pad of Celite, the organic layer was wash with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (0-100% ethyl acetate/hex) to give the desired product as white solid (6.9 g, 97%
96%	With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 4h; Inert atmosphere;

96%

With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 4h; Inert atmosphere;

Reference： [1]Current Patent Assignee: BCI PHARMA - WO2017/191297, 2017, A1 Location in patent: Page/Page column 116; 124; 125
[2]Current Patent Assignee: INCYTE CORP - US2014/121198, 2014, A1 Location in patent: Paragraph 0897; 0898
[3]Wauters, Iris; De Blieck, Ann; Muylaert, Koen; Heugebaert, Thomas S. A.; Stevens, Christian V. [European Journal of Organic Chemistry, 2014, vol. 2014, # 6, p. 1296 - 1304]
[4]Wauters, Iris; De Blieck, Ann; Muylaert, Koen; Heugebaert, Thomas S. A.; Stevens, Christian V. [European Journal of Organic Chemistry, 2014, vol. 2014, # 6, p. 1296 - 1304]

37
[ 17159-80-7 ]
[ 98-59-9 ]
[ 93164-43-3 ]

Yield	Reaction Conditions	Operation in experiment
96%	With N,N-dimethyl-4-aminopyridine; triethylamine In dichloromethane at 20℃; Inert atmosphere;	Intermediate 11 b: Ethyl 4-(tosyloxy)cyclohexanecarboxylate To a solution of ethyl 4-hydroxycyclohexanecarboxylate Intermediate ha (30.0 g, 174 mmol) in dichloromethane (500 mL) was added N,N-dimethylpyridin-4-amine (2.12 g, 17.4 mmol), triethylamine (20.0 g, 192 mmol) and 4-methylbenzene-1-sulfonyl chloride(36.0 g, 192 mmol) at room temperature. After stirred at room temperature under nitrogen atmosphere overnight, the mixture was washed with 0.5 M hydrochloride aqueous solution (300 mL) twice and brine (500 mL), dried over Na2 SO4() and filtered. The filtrate was concentrated under reduced pressure to give the title compound (55.0 g, 96 % yield) as brown oil. ‘H NIVIR (300 1VIFIz, CDC13) 7.79 (d, J 8.1 Hz, 2H), 7.33(d, J= 8.4 Hz, 2H), 4.74-4.68 (m, 0.3H), 4.46 -4.37 (m, 0.7H), 4.15 -4.06 (m, 2H),2.45 (s, 3H), 2.35 - 2.20 (m, 1H), 2.04 - 1.82 (m, 4.2H), 1.74 - 1.68 (m, 0.8H), 1.55 -1.46 (m, 3H), 1.28 - 1.20 (m, 3H).
87%	With N,N-dimethyl-4-aminopyridine; triethylamine In dichloromethane at 0℃; for 18h;	1.1 Step 1: ethyl 4-(p-tolylsulfonyloxy)cyclohexanecarboxylate (C87) To a solution of ethyl 4-hydroxycyclohexanecarboxylate C86 (10.2 g, 59.23 mmol), DMAP (725 mg, 5.934 mmol) and Et3N (15 mL, 107.6 mmol) in DCM (100 mL), TsCl (13.6 g, 71.34 mmol) portionwise in 20 minutes while at 0 °C, and the reaction was stirred for 18 hours. DCM (150 mL) was added, the mixture was successively washed with an aqueous solution of NH4Cl and brine, dried and concentrated. Purification by silica gel chromatography (0 to 70% EtOAc in heptane) afforded a cis:trans (1:1) mixture of ethyl 4-(p- tolylsulfonyloxy)cyclohexanecarboxylate (16.9 g, 87%)1H NMR (300 MHz, Chloroform-d) δ 7.81 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 7.8 Hz, 2H), 4.73 (s, 0.5H), 4.43 (d, J = 4.0 Hz, 0.5H), 4.13 (p, J = 7.1 Hz, 2H), 2.47 (s, 3H), 2.31 (ddd, J = 14.5, 9.3, 5.2 Hz, 1H), 2.05 - 1.79 (m, 4H), 1.72 (dt, J = 8.7, 4.2 Hz, 1H), 1.64 - 1.44 (m, 3H), 1.25 (td, J = 7.1, 5.7 Hz, 3H).
87%	With N,N-dimethyl-4-aminopyridine; triethylamine In dichloromethane at 20℃; for 24h;	Step 1. Ethyl 4-(p-tolylsulfonyloxy)cyclohexanecarboxylate To a solution of ethyl 4-hydroxycyclohexanecarboxylate (1 g, 5.81 mmol) in dichloromethane (20 mL) was added 4-methylbenzenesulfonyl chloride (1.22 g, 6.39 mmol), triethylamine (646 mg, 6.39 mmol) and 4-dimethylaminopyridine (70.9 mg, 581 umol), the mixture was stirred at 20 °C for 24 h. On completion, the mixture was quenched with water (10 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate from 50/1 to 10/1) to give ethyl 4-(p- tolylsulfonyloxy)cyclohexanecarboxylate (1.7 g, 5.21 mmol, 87%) as a colorless oil. NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 4.17 - 4.08 (m, 2H), 3.25 (q, J = 7.2 Hz, 1H), 2.47 (s, 3H), 2.35 - 2.20 (m, 1H), 2.04 - 1.94 (m, 3H), 1.92 - 1.85 (m, 1H), 1.77 - 1.67 (m, 1H), 1.55 - 1.43 (m, 3H), 1.26 (q, J = 7.2 Hz, 3H)

47%	With triethylamine In dichloromethane at 23℃; for 4h;	38.1 Step 1. ethyl 4-(tosyloxy)cyclohexanecarboxylate A 250-mE round-bottom flask was charged with ethyl 4-hydroxycyclohexane-1-carboxylate (3 g, 17.42 mmol), 4-methylbenzene-1 -sulfonyl chloride (5 g, 26.23 mmol), dichloromethane (50 mE) and triethylamine (5.28 g, 52.18 mmol). The resulting solution was stirred for 4 hat 23° C. The reaction was then quenched with water (50 mE). The mixture was extracted with dichloromethane (2x50 mE) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:10 v/v) to afford ethyl 4-(to- syloxy)cyclohexanecarboxylate as a yellow solid (2.7 g, 47%). ECMS: (ESI) mlz 327 [M+H].
	With pyridine at 15 - 25℃; for 24h; Cooling with ice;	i Step (i) 4-Toluenesulfonyl chloride (18.29 g, 96 mmol) was added in several portions to a solution of ethyl 4-hydroxycyclohexanecarboxylate (ca. 1 : 1 mixture of cis and trans ring isomers) (29.5 g, 90 mmol) in pyridine (100 niL) in an ice-water bath, and the mixture stirred, allowing to warm to RT. After the solid had dissolved, the mixture was allowed to stand. After 24 h, the mixture was concentrated and the residue partitioned between water and EtOAc (100 ml. each). The organic phase was dried and concentrated to give ethyl 4- (tosyloxy)cyclohexanecarboxylate (ca. 1 : 1 mixture of cis and trans ring isomers) (crude, 29.5 g) as a colourless oil which was used in the next step without further purification. NMR (400 MHz, CDC13) δ ppm 1.20-1.30 (m, 3H) 1 .44-2.08 (m, 81 ) 2.2 1 -2.43 (m, 111 ) 2.48 (s, 31 1) 4.08-4.20 (m, 211 ) 4.40-4.50 and 4.70-4.78 (both m, total 1H) 7.28-7.40 (m, 2H) 7.78-7.86 (m, 2H)
	With pyridine at 0 - 20℃; for 24h;	4-Toluenesulfonyl chloride (18.29 g, 96 mmol) was added in several portions to a solution of ethyl 4-hydroxycyclohexanecarboxylate (ca. 1:1 mixture of cis and trans ring isomers) (29.5 g, 90 mmol) in pyridine (100 mL) in an ice-water bath, and the mixture stirred, allowing to warm to RT. After the solid had dissolved, the mixture was allowed to stand. After 24 h, the mixture was concentrated and the residue partitioned between water and EtOAc (100 mL each). The organic phase was dried and concentrated to give ethyl 4-(tosyloxy)cyclohexanecarboxylate (ca. 1:1 mixture of cis and trans ring isomers) (crude, 29.5 g) as a colourless oil which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 1.20-1.30 (m, 3H) 1.44-2.08 (m, 8H) 2.21-2.43 (m, 1H) 2.48 (s, 3H) 4.08-4.20 (m, 2H) 4.40-4.50 and 4.70-4.78 (both m, total 1H) 7.28-7.40 (m, 2H) 7.78-7.86 (m, 2H)

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2019/1420, 2019, A1 Location in patent: Page/Page column 106
[2]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2021/203010, 2021, A1 Location in patent: Paragraph 00158; 00247
[3]Current Patent Assignee: BLACK DIAMOND THERAPEUTICS INC - WO2022/170122, 2022, A1 Location in patent: Paragraph 0952-0953
[4]Current Patent Assignee: VALO HEALTH INC - US2016/185785, 2016, A1 Location in patent: Paragraph 2121; 2122
[5]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2015/25164, 2015, A1 Location in patent: Page/Page column 78-79
[6]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2015/57298, 2015, A1 Location in patent: Paragraph 0535

38
[ 17159-80-7 ]
[ 74-88-4 ]
[ 223677-02-9 ]

Yield	Reaction Conditions	Operation in experiment
74%	Stage #1: 4-hydroxycyclohexyl carboxylic acid ethyl ester With sodium hydride In tetrahydrofuran at 0℃; for 0.333333h; Stage #2: methyl iodide In tetrahydrofuran at 0 - 20℃;	Compound 300.1. Ethyl 4-methoxycyclohexanecarboxylate Compound 300.1. Ethyl 4-methoxycyclohexanecarboxylate. Into a 100-mL round- bottom flask, was placed a solution of ethyl 4-hydroxycyclohexane-l-carboxylate (1 g, 5.81 mmol) in tetrahydrofuran (20 mL). Sodium hydride (349 mg, 8.72 mmol, 60%) was added to the reaction at 0 °C in portions, then stirred for 20 min. This was followed by the addition of CH3I (865 μ, 11.6 mmol) at 0 °C. The reaction mixture was stirred overnight at room temperature, quenched with 6 mL of brine and extracted with 3 x 40 mL of ether. The combined organic layers were washed with 2 x 20 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 800 mg (74%) of the title compound as a colorless oil.
27.74%	Stage #1: 4-hydroxycyclohexyl carboxylic acid ethyl ester In N,N-dimethyl-formamide at 20 - 25℃; for 0.5h; Stage #2: methyl iodide In N,N-dimethyl-formamide at 25℃; for 5h;	28.1 Step 1: 19-1 To a mixture of 14-1 (10 g, 58.06 mmol) in DMF (100 mL) was added NaH (4.64 g, 116.13 mmol, 60%purity) while the internal temperature was kept below 20 . After addition, the resulting mixture was warmed up to 25 and stirred for 30 min, and then iodomethane (9.89 g, 69.68 mmol) was added. The reaction mixture was stirred at 25 for further 5 hr, poured into water (500 mL) and extracted with ethyl acetate (200 mL × 3) . The combined organic layers were dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column eluted with petroleum ether/ethyl acetate = 3/1 to give 19-1 (3 g, 27.74%yield) .1H NMR (400 MHz, Chloroform-d) δ 4.12 (qd, J = 7.1, 2.0 Hz, 2H) , 3.33 (d, J = 17.1 Hz, 3H) , 3.13-3.09 (m, 1H) , 2.25 (tt, J = 11.7, 3.7 Hz, 1H) , 2.15-2.06 (m, 1H) , 2.06-1.96 (m, 2H) , 1.95-1.77 (m, 2H) , 1.65 (dq, J = 14.3, 5.1 Hz, 1H) , 1.57-1.40 (m, 2H) , 1.25 (td, J = 7.1, 4.7 Hz, 3H) ppm.
	Stage #1: 4-hydroxycyclohexyl carboxylic acid ethyl ester With sodium hydride In tetrahydrofuran at 0℃; Inert atmosphere; Stage #2: methyl iodide In tetrahydrofuran at 20℃;	123.1 [0644] Step 1: [0645] Compound ethyl 4-hydroxycyclohexyl formate 88 (1.0 g, 5.81 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL). Sodium hydride (60%, 348 mg, 8.71 mmol) was added at 0 °C under nitrogen protection, and the mixture was stirred for 10 min. Iodomethane (1.64 g, 11.61 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 h. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated to afford crude compound 89 .

Stage #1: 4-hydroxycyclohexyl carboxylic acid ethyl ester With sodium hydride In tetrahydrofuran at 0℃; Inert atmosphere; Stage #2: methyl iodide In tetrahydrofuran at 20℃;

123.1 [0644] Step 1: [0645] Compound ethyl 4-hydroxycyclohexyl formate 88 (1.0 g, 5.81 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL). Sodium hydride (60%, 348 mg, 8.71 mmol) was added at 0 °C under nitrogen protection, and the mixture was stirred for 10 min. Iodomethane (1.64 g, 11.61 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 h. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated to afford crude compound 89 .

Reference： [1]Current Patent Assignee: SAGIMET BIOSCIENCES INC. - WO2015/95767, 2015, A1 Location in patent: Page/Page column 355
[2]Current Patent Assignee: ECCOGENE SHANGHAI - WO2021/83209, 2021, A1 Location in patent: Paragraph 00388
[3]Current Patent Assignee: SHANGHAITECH UNIVERSITY - EP4056570, 2022, A1 Location in patent: Paragraph 0644-0645
[4]Current Patent Assignee: SHANGHAITECH UNIVERSITY - EP4056570, 2022, A1 Location in patent: Paragraph 0644-0645

39
[ 17159-80-7 ]
[ 32315-10-9 ]
[ 1838668-20-4 ]
[ 1838664-53-1 ]

Yield	Reaction Conditions	Operation in experiment
62%	Stage #1: 4-hydroxycyclohexyl carboxylic acid ethyl ester; bis(trichloromethyl) carbonate With triethylamine In dichloromethane at 20℃; for 3h; Stage #2: 1-(4-chloro-2-fluorobenzyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine With triethylamine In dichloromethane at 20℃;	4-1 Example 4-1 4-(Ethoxycarbonyl)cyclohexyll-(4-chloro-2-fluorobenzyl)-3-(trifluoromethyl)-4,5- dihydro- lH-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate Example 4-1 4-(Ethoxycarbonyl)cyclohexyll-(4-chloro-2-fluorobenzyl)-3-(trifluoromethyl)-4,5- dihydro- lH-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate To a stirred mixture of ethyl 4-hydroxycyclohexanecarboxylate (52 mg, 0.3 mmol) and triphosgene (45 mg, 0.15 mmol) in DCM (2 mL) was added TEA (30 mg, 0.3 mmol). The mixture was stirred at room temperature for 3 h. l-(4-chloro-2-fluorobenzyl)-3- (trifluoromethyl)-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine (110 mg, 0.3 mmol) was added, and followed by TEA (30 mg, 0.3 mmol, 1.0 eq) with stirring at room temperature overnight. The solvent was removed in vacuum and the crude was purified by prep. HPLC (MeCN and H20 with 0.225% (v/v) HCOOH as mobile phase) to provide 4- (ethoxycarbonyl)cyclohexyl l-(4-chloro-2-fluorobenzyl)-3-(trifluoromethyl)-4,5-dihydro- lH-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (90 mg, yield 62%) as a white solid. 1H NMR (400 MHz, Methanol-d4) δ: 7.30-7.15 (m, 3H), 5.36 (s, 2H), 4.60-4.57 (m, 3H), 4.14-4.08 (m, 2H), 3.69-3.67 (m, 2H), 2.67-2.66 (m, 2H), 2.44-2.34 (m, 1H), 2.00-1.22 (m, 11H); LCMS (ESI) m/z 531.9 [M+H]+

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - WO2015/188051, 2015, A1 Location in patent: Page/Page column 141; 142

40
[ 142-08-5 ]
[ 17159-80-7 ]
[ 1959557-00-6 ]

Yield	Reaction Conditions	Operation in experiment
46%	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 23℃; for 16h; Inert atmosphere;	62.1 Step 1. Ethyl4-(pyridin-2-yloxy)cyclohexane- 1 -carboxylate A 100-mE 3-necked round-bottom flask equipped with a nitrogen balloon was charged with ethyl 4-hydroxycy- clohexane-1-carboxylate (1.81 g, 10.51 mmol), pyridin-2-ol (500 mg, 5.26 mmol), triphenylphosphine (2.76 g, 10.52 mmol) and tetrahydrofuran (20 mE). A solution of diethyl azodicarboxylate (1.83 g, 10.51 mmol) intetrahydrofuran (5 mE) was added at 00 C. The resulting solution was stirred 16 hat 23° C. and then concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:30 to 1:10 v/v) to afford ethyl 4-(pyridin-2-yloxy)cyclohexane-1 -carboxylate (600 mg, 46%). LCMS: (ESI) mlz 250 [M+H].

Reference： [1]Current Patent Assignee: VALO HEALTH INC - US2016/185785, 2016, A1 Location in patent: Paragraph 2213; 2214

41
[ 1722-12-9 ]
[ 17159-80-7 ]
[ 1228087-19-1 ]

Yield	Reaction Conditions	Operation in experiment
24%	With copper(l) iodide; 1,10-Phenanthroline; caesium carbonate In toluene at 120℃; for 24h; Inert atmosphere;	64.1 Step 1. Ethyl4-(pyrimidin-2-yloxy)cyclohexanecarboxylate A 1 00-mE 3-necked round-bottom flask fitted with a nitrogen balloon, magnetic stir bar, condenser and thermomIntermediate eter was charged with ethyl 4-hydroxycyclohexane- 1-car- boxylate (1 g, 5.81 mmol), Cul (111mg, 0.58 mmol), Cs2CO3 (3.79 g, 11.6 mmol), toluene (25 mE), 2-chloropyrimidine (665 mg, 5.81 mmol), 1,10-phenanthroline (209 mg, 1.16 mmol). The resulting solution was stirred for 24 hat 120° C. in an oil bath. The resulting solution was cooled to 20° C. and quenched with water (50 mE). The product was extracted with ethyl acetate (5x50 mE). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/hexane (1:4, v/v) to afford ethyl 4-(pyrimidin-2-yloxy)cyclohexane- 1-car- boxylate (0.356 g, 24%). ECMS: (ESI) mlz 251 [M+H].

Reference： [1]Current Patent Assignee: VALO HEALTH INC - US2016/185785, 2016, A1 Location in patent: Paragraph 2221; 2222

42
[ 75-77-4 ]
[ 17159-80-7 ]
[ 201419-11-6 ]

Yield	Reaction Conditions	Operation in experiment
85%	With 1H-imidazole In N,N-dimethyl-formamide at 0 - 25℃; for 2.08333h; Inert atmosphere;	72.1 Step 1. Ethyl4-[(trimethylsilyl)oxy]cyclohexane-1 -carboxylate A 50-mE 3-necked round-bottom flask fitted with a nitrogen balloon, magnetic stir bar and thermometer was charged with ethyl 4-hydroxycyclohexane- 1 -carboxylate (500 mg, 2.90 mmol), 1H-imidazole (480 mg, 7.05 mmol) and N,N-dimethylformamide (9 mE) followed by chiorotrimethyl silane (382 mg, 3.52 mmol) added dropwise with stirring at 00 C. over 5 mm. The resulting solution was warmed to 25° C. and stirred for 2 h. The reaction was quenched with water (20 mE). The product was extracted with tert-butyl methyl ether (3x20 mE). The combined organic layers were washed with brine (2x20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford ethyl 4-[(trimethylsilyl)oxy]cyclohexane- 1 -carboxylate as light yellow oil (600 mg, 85%). GCMS: mlz 244.

Reference： [1]Current Patent Assignee: VALO HEALTH INC - US2016/185785, 2016, A1 Location in patent: Paragraph 2254; 2255

43
[ 17159-80-7 ]
[ 80522-42-5 ]
[ 1352615-11-2 ]

Yield	Reaction Conditions	Operation in experiment
87.5%	With 2,6-dimethylpyridine In dichloromethane at 0 - 5℃; for 1h; Inert atmosphere;	Example 5 Ethyl 4-hydroxycyclohexylcarboxylate (s36) (26.0 g), 2,6-lutidine (23.3 g) and methylene chloride (200 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to 0° C. Triisopropylsilyltrifluoromefhanesulfonate (50 g) was added dropwise in the temperature range of 0° C. to 5° C. After 1 hour of stirring at 0° C, the reaction mixture was allowed to come to room temperature, and the stirring was continued for another 8 hours. Methanol was added to the reaction mixture to terminate the reaction.The reaction mixture was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with waterthree times, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure,and the residue was purified by column chromatography with toluene as an eluentand silica gel as a stationary phase powder to give ethyl 4-triisopropylsilyloxy-cyclohexylcarboxylate (37) (43.4 g). The yield based onthe compound (s36) was 87.5%.

Reference： [1]Current Patent Assignee: CHISSO CORPORATION - JP5849664, 2016, B2 Location in patent: Paragraph 0188; 0189

44
[ 17159-80-7 ]
[ 1226365-05-4 ]
[ 2098654-03-4 ]

Yield	Reaction Conditions	Operation in experiment
46%	Stage #1: 4-hydroxycyclohexyl carboxylic acid ethyl ester With aluminium(III) triflate at 20℃; for 0.25h; Inert atmosphere; Stage #2: (5-fluoro-2-methoxyphenyl)ethylene oxide at 0 - 20℃; for 2h; Inert atmosphere; Stage #3: With carbon dioxide In isopropyl alcohol for 0.1h; Resolution of racemate;	212 Isolation of 212.4 Into a 2-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 4-hydroxycyclohexane-1-carboxylate (93 g, 540.00 mmol, 3.00 equiv). This was followed by the addition of Al(OTf)3 (8.75 g, 18.45 mmol, 0.10 equiv). The mixture was stirred for 15 min at room temperature. To this was added 212.1 (31 g, 184.34 mmol, 1.00 equiv) dropwise with stirring at 0-10° C. The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of 500 mL of NH4Cl (aq). The resulting solution was extracted with 2×1000 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18; mobile phase, CH3CN:H2O=10:90 increasing to CH3CN:H2O=100:0 within 35 min; Detector, UV 254 nm. This resulted in 15 g (crude) of 212.2 and 8.3 g (13%) of 212.3 as colorless oils.Enantiomer mixture 212.3 (4 g) was purified by Prep-SFC with the following conditions (Prep SFC350-2): Column, CHIRALPAK AD-H SFC, 5*25 cm, 5 um; mobile phase, CO2 and IPA (hold 20.0% IPA in 6 min, retention time: 4.9 min); Detector, 220 nm. This resulted in 1.82 g (46%) of 212.4 as colorless oil.

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - US2017/166584, 2017, A1 Location in patent: Paragraph 1334; 1337; 1338

45
[ 17159-80-7 ]
[ 1351564-76-5 ]
[ 1351621-16-3 ]

Yield	Reaction Conditions	Operation in experiment
89%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 2h;	8.14. 4-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1Hindazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]cyclohexanecarboxylic acid (26) (A) To a solution of indazolydinylthiazolidine-2,4-dione 5b(500 mg; 1.14 mmol), ethyl 4-hydroxycyclohexanecarboxylate(368 mL; 2.28 mmol) and triphenylphosphine (599 mg;2.28 mmol) in THF (20 mL) was added a solution of diisopropylazidodicarboxylate (450 mL; 2.28 mmol) in a dropwise fashion.After stirring at room temperature for 2 h, additional portions(1.14 mmol each) of alcohol, triphenylphosphine and diisopropylazidodicarboxylate were added and stirring was continued for anadditional 2 h, at which time LCMS analysis indicated completeconsumption of 5b. The reaction was concentrated and the residuewas taken up in DCM and purified by silica gel chromatographyeluting with (0-40%) EtOAc/hexanes to afford [(5Z)-5-({1-[-2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]cyclohexanecarboxylic acid ethyl ester(600 mg; 89%) as a white solid (following recrystallization fromMeCN), which was used directly.(B) A mixture of the above ester (450 mg; 0.76 mmol), 10% HCl(5 mL) and dioxane (10 mL) was heated at 100 °C for 12 h, thencooled to 0 °C, upon which the product precipitated as a white solid.The precipitate was filtered, washed with water and air-dried toafforded pure carboxylic acid 26 (410 mg; 96%) as a white powder,which was directly converted to the corresponding ethanolaminesalt.(C) A portion of the above carboxylic acid (300 mg;0.53 mmol) was dissolved in hot THF (1.5 mL) and ethanolamine(48 mL; 0.8 mmol) was added, resulting in the formation of aheavy precipitate. After cooling to room temperature, the reactionwas treated with ether (20 mL) and filtered to furnish thecorresponding ethanolamine salt (307 mg, 92%). 1H NMR (DMSO-d6) δ 8.36 (s, 1H), 8.15 (s, 1H), 8.04 (s, 1H), 7.89 (s, 1H), 7.80 (d,J 8.61 Hz, 1H), 7.60-7.74 (m, 2H), 6.77 (d, J 8.61 Hz, 1H), 5.86(s, 2H), 4.13 (t, J 12.33 Hz, 1H), 3.43 (t, J 5.48 Hz, 2H, ethanolamine),2.66 (t, J 5.28 Hz, 2H, ethanolamine), 1.92e2.22 (m,5H), 1.73 (d, J 10.96 Hz, 2H), 1.28e1.48 (m, 2H). LCMS (APCI)m/z: mass calcd. for C26H21ClF3N3O4S: 563.09, found: 564.0[(M)].

Reference： [1]Patch, Raymond J.; Huang, Hui; Patel, Sharmila; Cheung, Wing; Xu, Guozhang; Zhao, Bao-Ping; Beauchamp, Derek A.; Rentzeperis, Dionisios; Geisler, John G.; Askari, Hossein B.; Liu, Jianying; Kasturi, Jyotsna; Towers, Meghan; Gaul, Micheal D.; Player, Mark R. [European Journal of Medicinal Chemistry, 2017, vol. 138, p. 830 - 853]

46
[ 2295-31-0 ]
[ 17159-80-7 ]
[ 2130009-12-8 ]

Yield	Reaction Conditions	Operation in experiment
39%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 70℃;	8.10. 4-[(5Z)-5-({1-[4-Methoxy-2-(trifluoromethyl)benzyl]-1Hindazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]cyclohexanecarboxylic acid (22) (A) To a solution of 1,3-thiazolidine-2,4-dione (585 mg;5 mmol), ethyl 4-hydroxycyclohexanecarboxylate (1.03 g; 6 mmol)and triphenylphosphine (1.57 g; 6 mmol) in THF (10 mL) was addeda solution of diisopropyl azidodicarboxylate (1.18 mL; 6 mmol) inTHF (5 mL) in dropwise fashion. Upon complete addition, the reactionwas heated to 70° C and allowed to stir overnight. Aftercooling to room temperature, the reaction was concentrated andthe residual mixture was purified by silica gel chromatographyeluting with DCM to afford ethyl 4-(2,4-dioxothiazolidin-3-yl)cyclohexanecarboxylate (528 mg, 39%) as a colorless syrup that wasused directly.(B) A mixture of ethyl 4-(2,4-dioxothiazolidin-3-yl)cyclohexanecarboxylate(528 mg; 1.95 mmol), carboxaldehyde 3a(600 mg; 1.8 mmol) and NH4OAc (277 mg; 3.6 mmol) in HOAc washeated at 110° C for 12 h. After cooling to rt, the reaction wasconcentrated and the residual mixture was purified by silica gelchromatography (0-2% MeOH/DCM) to afford [(5Z)-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]cyclohexanecarboxylic acidethyl ester (391 mg; 37%) as a pale yellow solid, which was useddirectly.(C) A mixture of the above ester (391 mg; 0.67 mmol), 10% HCl(5 mL) and dioxane (10 mL) was heated at 95 °C for 24 h, thenconcentrated under reduced pressure. The residue was trituratedwith minimal MeCN/ether (1:2), filtered and washed with ether toafford pure carboxylic acid 22 (304 mg; 82%) as a pale yellowpowder. 1H NMR (400 MHz, DMSO-d6) δ12.25 (br s, 1H), 8.33 (s,1H), 8.14 (d, J 2.74 Hz, 1H), 8.03 (d, J 6.26 Hz, 1H), 7.76 (d,J 9.00 Hz, 1H), 7.65 (ddd, J 1.57, 3.52, 9.00 Hz, 1H), 7.27 (d,J 2.74 Hz, 1H), 7.14 (dd, J 2.54, 8.80 Hz, 1H), 6.80 (d, J 8.61 Hz,1H), 5.78 (s, 2H), 4.05e4.27 (m, 1H), 3.80 (s, 3H), 1.94e2.30 (m, 5H),1.69e1.85 (m, 1H), 1.31e1.68 (m, 3H). LCMS (APCI) m/z: masscalcd. for C27H24F3N3O5S: 559.14, found: 560.0 [(M+H)+].

Reference： [1]Patch, Raymond J.; Huang, Hui; Patel, Sharmila; Cheung, Wing; Xu, Guozhang; Zhao, Bao-Ping; Beauchamp, Derek A.; Rentzeperis, Dionisios; Geisler, John G.; Askari, Hossein B.; Liu, Jianying; Kasturi, Jyotsna; Towers, Meghan; Gaul, Micheal D.; Player, Mark R. [European Journal of Medicinal Chemistry, 2017, vol. 138, p. 830 - 853]

47
[ 3618-04-0 ]
[ 2042-14-0 ]
ethyl 4-(4-methyl-3-nitrophenoxy)cyclohexane-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 16h;	To a 25 0-mL round-bottom flask was placed a solution of <strong>[2042-14-0]4-methyl-3-nitrophenol</strong> (2 g,13.06 mmol) in THF(100 mL) then ethyl 4-hydroxycyclohexane-1-carboxylate (2.5 g,14.52 mmol),PPh3 (5.11 g,19.48 mmol) were added. The solution was cooled to 0C then DIAD (4.04 g,19.98 mmol) was added dropwise with stirring. The reaction was stirred for 16 h at rt then concentrated under reduced pressure. The residue was purified by column chromatography eluting with petroleum ether/ethyl acetate (15:1) affording 2.1 g (52%) of the title compound as a yellowoil.

Reference： [1]Patent: WO2017/62581,2017,A1 .Location in patent: Paragraph 0279

48
[ 2222300-61-8 ]
[ 17159-80-7 ]
[ CAS Unavailable ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
49.5%	With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃; for 2h;	61.61a; 74.74a Example 61a ethyl trans-4- ( (5-bromo-1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) oxy) cyclohexane-1-carboxylate Example 74a ethyl cis-4- [ (5-bromo-1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) oxy] cyclohexane-1-carboxylate A mixture of Example 1c (0.824 g, 4 mmol) and trans-ethyl 4-hydroxycyclohexanecarboxylate (0.758 g, 4.40 mmol) in tetrahydrofuran (20 mL) was cooled to 0 C. To this solution was added potassium 2-methylpropan-2-olate (5.20 mL, 5.20 mmol) . The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate three times. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The residue was purified by column chromatography on silica gel eluting with 100% ethyl acetate to give the title compound as the first eluting isomer (0.71 g, 1.982 mmol, 49.5 % yield) . Example 74a was isolated as the second eluting isomer in the preparation of Example 61a.

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2018/68283, 2018, A1 Location in patent: Paragraph 00403; 00430

49
[ 17159-80-7 ]
[ 58479-61-1 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
75.77%	With 1H-imidazole In dichloromethane at 25℃; for 16h;	24.1 Step 1: 14-2 To a mixture of 14-1 (1.55 g, 9.00 mmol) in DCM (30 mL) was added tert-butylchlorodiphenylsilane (4.95 g, 18.0 mmol) , Imidazole (1.53 g, 22.5 mmol) . After stirred at 25 for 16 hr, the reaction mixture was poured into 50 mL water, extracted with DCM (50 mL × 3) . The combined organic layers were washed with water (50 mL) and brine (50 mL) , dried over Na2SO4and filtered. The filtrated was concentrated under reduced pressure. The residue was purified by silica gel column eluted with petroleum ether/ethyl acetate (20/1) to afford 14-2 (2.8 g, 75.77%yield) .

Reference： [1]Current Patent Assignee: ECCOGENE SHANGHAI - WO2021/83209, 2021, A1 Location in patent: Paragraph 00357

50
[ 14508-49-7 ]
[ 17159-80-7 ]
[ 1228087-20-4 ]

Yield	Reaction Conditions	Operation in experiment
15%	With methanesulfinic acid sodium salt; potassium carbonate In N,N-dimethyl-formamide at 120℃;	General Procedure 2-II: Sodium methanesulfinate mediated arylation General procedure: To a solution of a 4-hydroxy-cyclohexanecarboxylic acid ester of formula II (1 eq) and a heteroaryl chloride derivative (1 eq) in dry N,N-dimethylformamide (1 M) are added consecutively sodium methanesulfinate (85%, 0.25 - 1 eq) and potassium carbonate (1.5 eq). After completed addition the reaction mixture is stirred at 120 °C for 3-18 h. After cooling to room temperature the reaction mixture is partitioned between tert-butyl methyl ether and water. The layers are separated and the aqueous layer is extracted with one to two portions of tert-butyl methyl ether. The combined organic layers are washed with one to two portions of water, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash-chromatography gives a 4-heteroaryloxy- cyclohexanecarboxylic acid ester of formula III.
15%	With methanesulfinic acid sodium salt; potassium carbonate In N,N-dimethyl-formamide at 120℃;	General Procedure 2-II: Sodium methanesulfinate mediated arylation General procedure: To a solution of a 4-hydroxy-cyclohexanecarboxylic acid ester of formula II (1 eq) and a heteroaryl chloride derivative (1 eq) in dry N,N-dimethylformamide (1 M) are added consecutively sodium methanesulfinate (85%, 0.25 - 1 eq) and potassium carbonate (1.5 eq). After completed addition the reaction mixture is stirred at 120 °C for 3-18 h. After cooling to room temperature the reaction mixture is partitioned between tert-butyl methyl ether and water. The layers are separated and the aqueous layer is extracted with one to two portions of tert-butyl methyl ether. The combined organic layers are washed with one to two portions of water, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash-chromatography gives a 4-heteroaryloxy- cyclohexanecarboxylic acid ester of formula III.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2022/18121, 2022, A1 Location in patent: Page/Page column 51; 53-54
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2022/18121, 2022, A1 Location in patent: Page/Page column 51; 53-54

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	17159-80-7	MDL No. :	MFCD00192156
Formula :	C₉H₁₆O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	172.22	Pubchem ID :	-
Synonyms :

Num. heavy atoms :	12
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.89
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	45.71
TPSA :	46.53 Å²

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.61 cm/s

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

[ CAS No. 17159-80-7 ] {[proInfo.proName]}

Quality Control of [ 17159-80-7 ]

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Product Details of [ 17159-80-7 ]

Calculated chemistry of [ 17159-80-7 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 17159-80-7 ]

Application In Synthesis of [ 17159-80-7 ]

[ 17159-80-7 ] Synthesis Path-Downstream 1~50

Related Functional Groups of
[ 17159-80-7 ]

Aliphatic Cyclic Hydrocarbons

Alcohols

Esters

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Log Po/w (iLOGP) :	2.2
Log Po/w (XLOGP3) :	1.04
Log Po/w (WLOGP) :	1.1
Log Po/w (MLOGP) :	1.0
Log Po/w (SILICOS-IT) :	1.23
Consensus Log Po/w :	1.32

Log S (ESOL) :	-1.36
Solubility :	7.43 mg/ml ; 0.0432 mol/l
Class :	Very soluble
Log S (Ali) :	-1.61
Solubility :	4.25 mg/ml ; 0.0247 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.99
Solubility :	17.7 mg/ml ; 0.103 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.73

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

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P321
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P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
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P401
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P422
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P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
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P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling