Name: 720720-96-7|5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride|97%
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SKU: A291325
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1
6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid lithium salt [ No CAS ]
[ 720720-96-7 ]

Yield	Reaction Conditions	Operation in experiment
67.8%	Stage #1: 6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid lithium salt With pyrographite In ethanol at 40 - 50℃; for 0.333333h; Stage #2: With hydrogenchloride In water at 0 - 5℃;	7 Example 7 Synthesis of 4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridine-2-carboxylate hydrochloride Add 90% ethanol (800g) to the reaction flask, add 109C6-10 (200g, 979.6mmol) obtained in Example 6; while stirring, heat to 40-50°C to completely dissolve the materials; then add activated carbon (20g 30g), stir and decolorize for about 20min, hot filter, rinse the filter residue with absolute ethanol, collect the filtrate, cool to 05, control the temperature not to exceed 5, add hydrochloric acid dropwise to adjust pH=12; keep warm at 0 Crystallize at 5°C for 2~3hr. Filter, rinse the filter cake with absolute ethanol, and collect the solids; control the temperature not to exceed 40°C and blow dry to obtain about 156 g of 109C6-20 dry product (theoretical amount: 230.0 g). Yield: 67.8%.
	With hydrogenchloride In ethanol at 20℃; for 1h;	14 To lithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate (3.00 g) was added 1N HCl in ethanol (36 mL), and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, and were washed with ethanol (9 mL). The wet crystal was dried at room temperature under reduced pressure, to thereby give 2.76 g of the title compound. 1H-NMR (D2O)δppm: 4.82-4.88 (d,1H, J=16.0Hz), 4.51-4.57(d,1H,J=16.0Hz), 3.88-3.96(m,1H), 3.60-3.70(m,1H), 3.22-3.33(m,2H), 3.15 (s, 3H). Elementary analysis: as C8H11ClN2O2S, Calculated: C,40.94;H,4.72;N,11.94;S,13.66 Found: C,40.51;H,4.65;N,11.79;S,13.53
	With hydrogenchloride In ethanol at 20℃; for 1h;	6 [Reference Example 6] 5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbox ylic acid hydrochloride [Reference Example 6] 5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbox ylic acid hydrochloride To the compound obtained in Reference Example 5 (3.00 g), a 1 N ethanol solution of hydrochloric acid (36 ml) was added, and the mixture was stirred at room temperature for 1 hour. The precipitating crystals were filtered and washed with ethanol (9 ml). The wet product was dried at room temperature under reduced pressure, to obtain the title compound (2.76 g). 1H-NMR(D2O)δ:4.82-4.88(1H, d, J=16.0Hz), 4.51-4.57(1H, d, J=16.0Hz), 3.88-3.96(1H, m), 3.60-3.70(1H, m), 3.22-3.33(2H, m), 3.15(3H, s).

With hydrogenchloride In ethanol at 20℃; for 1h;

323 A 1N hydrochloric acid ethanol solution (36 ml) was added to the compound (3.00 g) obtained in Referential Example 5. The resulting mixture was stirred at room temperature for 1 hour. The crystals thus precipitated were collected by filtration and washed with ethanol (9 ml). The wet crystals were dried at room temperature under reduced pressure, whereby the title compound (2.76 g) was obtained as slightly reddish brown crystals.1H-NMR (D2O) δ: 3.15 (3H, s), 3.22-3.33 (2H,m), 3.60-3.70 (1H, m) 3.88-3.96(1H, m), 4.51-4.57(1H,d,J=16.0Hz), 4.82-4.88(1H, d, J=16.0Hz).

Reference： [1]Current Patent Assignee: INNER MONGOLIA JINGDONG PHARMACEUTICAL - CN111393456, 2020, A Location in patent: Paragraph 0068-0073
[2]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP1683800, 2006, A1 Location in patent: Page/Page column 58
[3]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP1864982, 2007, A1 Location in patent: Page/Page column 59
[4]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP1577302, 2005, A1 Location in patent: Page/Page column 190

2
[ 720720-96-7 ]
C₁₂H₁₇ClN₄O₃ [ No CAS ]
N₁-(5-chloropyridin-2-yl)-N₂-((2S)-3-hydroxy-3-methyl-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}butyl)ethanediamide hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloric acid salt; C₁₂H₁₇ClN₄O₃ With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In DMF (N,N-dimethyl-formamide) at 20℃; for 13h; Stage #2: With hydrogenchloride In ethanol	53 The compound (360 mg) obtained in Referential Example 387 was dissolved in methylene chloride (10 ml) and to the resulting solution, 4N hydrochloric acid/dioxane (20 ml) was added. The resulting mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. To the residue were added N,N-dimethylformamide (10 ml), the compound (253 mg) obtained in Referential Example 323, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (345 mg), 1-hydroxybenzotriazole (61 mg) and triethylamine (373 µl) . The resulting mixture was stirred at room temperature for 13 hours. The solvent was distilled off under reduced pressure, and methylene chloride and a saturated aqueous solution of sodium bicarbonate were added to the residue to separate the layers. The organic layers were combined and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by chromatography (methylene chloride:methanol = 47:3) on a silica gel column, whereby a colorless amorphous substance (383 mg) was obtained. The resulting amorphous substance was dissolved in methanol (5 ml). To the resulting solution were added 1N hydrochloric acid/ethanol (796 µl) and water (5 ml). The solvent was distilled off under reduced pressure, whereby the title compound was obtained as a pale yellow solid (391 mg).1H-NMR(DMSO-d6)δ: 1.10(3H,s), 1.23(3H,s), 2.92(3H,s), 3.07-3.50(4H,m), 3.68(2H,br s), 4.09(1H,s), 4.42(1H,s), 4.68(1H,s), 4.97(1H,br s), 7.95-8.07(3H,m), 8.45(1H,s), 8.95-9.10(1H,m),10.19(1H,s), 11.44(1H,s). MS (ESI)m/z: 481(M+H)+.

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP1577302, 2005, A1 Location in patent: Page/Page column 256-257

3
[ 76-02-8 ]
[ 259809-24-0 ]
5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloric acid salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (1.00 g) was dissolved in toluene (10 mL) at room temperature, and triethylamine (1.81 mL) and trichloroacetyl chloride (1.45 mL) were sequentially added thereto at room temperature, followed by stirring at room temperature for 4 hours. To the resultant mixture was added a solution of lithium hydroxide monohydrate (1.22 g) in water (10 mL), to thereby perform hydrolysis. The organic layer was separated from the aqueous layer, and was further extracted with water (10 mL). The aqueous layers were combined, and the combined aqueous layer was concentrated in a bath at 50 C under reduced pressure. Ethanol (10 mL) was added thereto, and the resultant mixture was again concentrated under reduced pressure. Ethanol (15 mL) was added to the concentrated residue, and the resultant mixture was cooled with ice-water. Concentrated hydrochloric acid (2.7 mL) was added dropwise thereto, to thereby form a hydrochloride salt, and the resultant mixture was stirred at the same temperature for 1.5 hours. The precipitated crystals were collected by filtration, and were washed with ethanol (4 mL). The wet matter was dried at room temperature under reduced pressure, to thereby give 1.25 g of the title compound. 1H-NMR (D2O) deltappm: 4.82-4.88(d,1H,J=16.OHz),4.51-4.57(d,1H,J=16.0Hz), 3.88-3.96(m,1H), 3.60-3.70(m,1H), 3.22-3.33(m,2H), 3.15(s,3H) MS(FAB)m/z: 199(M+H)+

Reference： [1]Patent: EP1683800,2006,A1 .Location in patent: Page/Page column 54; 55

4
[ 124-38-9 ]
[ 720720-96-7 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-bromo-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine p-toluenesulfonate With sodium hydroxide In water at 20℃; for 0.5h; Stage #2: In tetrahydrofuran; hexane at -30℃; for 1h; Stage #3: carbon dioxide With hydrogenchloride more than 3 stages;	15 2-Bromo-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine p-toluenesulfonic acid salt (40.00 g) was mixed with 1N aqueous sodium hydroxide (200 mL) at room temperature, and the mixture was stirred for 30 minutes. The aqueous layer was extracted with toluene twice (400 mL W 2), and the organic layers were combined. The combined organic layer was washed with 5% brine (200 mL), and was concentrated to 80 mL at an external temperature of 50 °C or lower under reduced pressure. A sample for water content measurement was taken from the resultant mixture (weight of the mixture after concentration: 91.03 g, weight of the mixture after sampling: 87.68 g). The sample of the concentrated mixture was subjected to water content measurement with Karl-Fischer Moisture Titrator, and the water content was found to be 0.0231% (on a weight-to-weight ratio). The remaining portion of the concentrated mixture after sampling was dissolved in anhydrous tetrahydrofuran (231 mL). After the system was purged with argon, the reaction mixture was cooled to an internal temperature of -30 °C or lower, and to the solution was added dropwise n-butyllithium (as 1.59 mol/L n-hexane solution, 61.7 mL) while the internal temperature was kept at or below -30 °C, followed by stirring at the same temperature for 1 hour. After passing carbon dioxide gas through the resultant mixture while the internal temperature was kept at or below -30 °C, the reaction mixture was stirred under carbon dioxide atmosphere for 1 hour. The resultant mixture was heated to an internal temperature of 15 °C, and methanol (193 mL) was added thereto, to thereby dissolve the precipitated solid, and concentrated hydrochloric acid (19.3 mL) was added dropwise thereto while the internal temperature was kept at or below 20 °C. The resultant mixture was cooled to an internal temperature of 10 °C or lower, and was stirred at the same temperature for 1 hour. The precipitated crystals were collected by filtration, and were washed with methanol (58 mL). The wet crystal was dried at room temperature under reduced pressure, to thereby give 21.20 g of the title compound. 1H-NMR(D2O) δppm: 4.82-4.88(d, 1H,J=16.0Hz), 4.51-4.57 (d,1H,J=16.0Hz), 3.88-3.96(m,1H), 3.60-3.70(m,1H), 3.22-3.33 (m, 2H), 3.15(s,3H). MS(EI)m/z: 198(M)+ Elementary analysis: as C8H11ClN2O2S, Calculated: C,40.94;H,4.72;Cl,15.11;N,11.94;S,13.66 Found: C,40.83;H,4.56;Cl,14.81;N,11.91;S,13.87

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP1683800, 2006, A1 Location in patent: Page/Page column 58; 59

5
[ 480452-37-7 ]
[ 720720-96-7 ]
edoxaban [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77.2%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In acetonitrile at 0 - 20℃;	53 Example 53 Synthesis of N¹-(5-chloro-2-pyridyl)-N²-[(1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[[(4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridin-2-yl)carbonyl]amino]cyclohexyl]ethanediamide(Edoxaban) To 18 g (48.93 mmol) of the residue 109T2-01 obtained in Example 50, 270 g of acetonitrile was added. Stir and dissolve, Add 12g (118.6mmol) of triethylamine, stir and cool to 0 ~ 5 ° C; Further, 12.6 g (53.69 mmol) of 109C6-20, 10.5 g (68.56 mmol) of HOBt·H 2 O, 13.0 g (67.81 mmol) of EDCI·HCl were added; and the reaction was stirred at room temperature for about 20 to 24 hr. After the reaction is completed, 180 g of water is added to the reaction system; After stirring uniformly, the mixture was filtered to remove insoluble matter, and the residue was rinsed with 120 g of dichloromethane; The filtrate was collected, and then 300 g of dichloromethane was added thereto, and the mixture was thoroughly stirred; The aqueous phase was extracted once more with 200 g of dichloromethane, and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, the residue was washed with dichloromethane, and the filtrate was collected and concentrated under reduced pressure to give a residue. Add 25g of methanol to the residue, heat to 40 ~ 50 ° C to disperse evenly, cooled to 5 ~ 10 ° C, heat crystallization for about 2 ~ 3hr; Filtration, the filter cake was rinsed with methanol, and the solid was collected; After drying, about 109 g of dry product of 109TM-01 was obtained (theoretical amount: 26.82 g). Yield: 77.2%.
75.5%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine at 15 - 25℃;	2 Comparative example 2. N1-(5-chloro-2-pyridyl)-N2-[(1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-[[(4,5,6, Synthesis of 7-tetrahydro-5-methylthiazolo[5,4-c]pyridin-2-yl)carbonyl]amino]cyclohexyl]oxalamide (Edoxaban) Add acetonitrile (2850g) to the reaction flask, add 109T1-01 (190g, 406.0mmol) obtained in Comparative Example 1, add methanesulfonic acid (200g, 2081.2mmol), stir and react for 16-20hr; after the reaction is complete, cool down; Add triethylamine (315g, 3113.0mmol); add 109C6-20 (105g, 447.4mmol) obtained in Example 7, add HOBt (60kg, 444.0mmol), add EDCI·HCl (108g, 563.4mmol); addition is complete Then, control the temperature to 15-25, and stir the reaction for about 20-30hr; after the reaction is complete, add drinking water (1500g); stir evenly, filter, and collect the solid for use; collect the filtrate; add methylene chloride (4000g) to the collected filtrate ), stirring and extracting, standing for liquid separation; the aqueous phase was extracted with dichloromethane (3000g) once; the organic phases were combined, and the solid collected by the above filtration was added; stirring for 2-3hr; filtered, collected the filtrate, concentrated to dryness Add methanol to the residue, stir and disperse, heat to 4050 for hot beating, cool to 510, and crystallize for 34hr. Filter and collect the obtained solid; dry to obtain about 168 g of 109TM-01 dry product (theoretical amount: 222.5 g). Yield: 75.5%.
	Stage #1: N¹-[(1S,2R,4S)-2-amino-4-[(dimethylamino)carbonyl]cyclohexyl]-N²-(5-chloro-2-pyridyl)ethanediamide; 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloric acid salt With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl acetamide at 20℃; for 13h; Stage #2: With triethylamine In N,N-dimethyl acetamide; water	16 N1-{(1S, 2R, 4S)-2-Amino-4-[(dimethylamino)carbonyl]cyclohexyl}-N2-(5-chloropyridin-2-yl)ethanediamide (553.4 mg) was dissolved in dimethylacetamide (7 mL), and to the solution were added 1-hydroxybenzotriazole monohydrate (245.1 mg), 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (386.0 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (345.0 mg) at room temperature. The resultant mixture was stirred for 13 hours, and triethylamine and water were added thereto. The precipitated crystals were collected by filtration, and were dried, to thereby give 674.1 mg of the title compound. 1H-NMR(CDCl3)δppm: 1.60-1.98(3H,m), 2.00-2.16(3H,m), 2.52 (3H,s), 2.78-2.90 (3H,m), 2.92-2.98(2H,m), 2.95(3H,s), 3.06 (3H,s), 3.69(1H,d,J=15.4Hz), 3.75(1H,d,J=15.4Hz) 4.07-4.15 (1H,m), 4.66-4.72 (1H,m), 7.40 (1H,d,J=8.8,0.6Hz), 7.68 (1H,dd,J=8.8,2.4Hz), 8.03 (1H,d,J=7.8Hz), 8.16 (1H,dd,J=8.8,0.6Hz), 8.30(1H,dd,J=2.4,0.6Hz), 9.72(1H,s). MS(ESI)m/z; 548(M+H)+.

0.317 g

With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine at 20℃; for 16h; Cooling with ice;

1 Synthesis of N1- (5-chloropyridin-2-yl) -N2 - ((1S, 2R, 4S) -4 - [(dimethylamino) carbonyl]2 - [(5-methyl-4,5,6,7-tetrahydrothiazole[5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide Take 0.30g of t-butyl (1R, 2S, 5S) -2 - ({2 - ((5-chloropyridin-2-yl)2-glyoxylic acid} amino) -5 - [(dimethylamino) carbonyl]Cyclohexanecarbamate was suspended in 6 ml of acetonitrile,0.21 ml of methanesulfonic acid was added and the mixture was stirred at room temperature for about 2 hours.Under ice bath, 0.49 ml of triethylamine,0.164 g of 5-methyl-4,5,6,7-tetrahydro [1,3]Thiazole [5,4-c] pyridine-2-carboxylic acid hydrochloride,0.117 g of hydroxybenzotriazole monohydrate,0.149 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added to the mixture,And the mixture was stirred at room temperature for 16 hours. Then add triethylamine and water,And the mixture was stirred under ice-cooling for 1 hour.The crystals were then collected by filtration to obtain 0.317 g of the title compound(Equivalent recovery rate of 87%).

Reference： [1]Current Patent Assignee: INNER MONGOLIA JINGDONG PHARMACEUTICAL; BEIJING SIHUAN KEBAO PHARMACEUTICAL - CN109942600, 2019, A Location in patent: Paragraph 0239-0241
[2]Current Patent Assignee: INNER MONGOLIA JINGDONG PHARMACEUTICAL - CN111393456, 2020, A Location in patent: Paragraph 0091-0096
[3]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP1683800, 2006, A1 Location in patent: Page/Page column 59; 60
[4]Current Patent Assignee: CHUNGWHA CHEMICAL SYNTHESIS BIOTECH; CHINA CHEMICAL PHARMACEUTICAL GROUP - TWI571460, 2017, B Location in patent: Paragraph 0040-0041

6
2-cyano-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine hydrochloride [ No CAS ]
[ 720720-96-7 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-cyano-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine hydrochloride With lithium hydroxide; water In ethanol at 50℃; for 7 - 10h; Stage #2: With hydrogenchloride In ethanol; water at 0℃; for 1.5h;	3; 4 To 2-cyano-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine hydrochloride monohydrate (500.61 mg) were added ethanol (5 mL) and 4N aqueous lithium hydroxide (1.34 mL) at room temperature, and the resultant mixture was stirred at 50 °C for 7 hours. After the reaction mixture was cooled with ice-water, 1N HCl in ethanol (7.5 mL) was added thereto, to thereby form a hydrochloride salt, followed by stirring at the same temperature for 1.5 hours. The precipitated crystals were collected by filtration, and were washed with ethanol (2 mL). The wet crystal was dried at room temperature under reduced pressure, to thereby give 466.98 mg of the title compound. 1H-NMR (D2O) δppm: 4.82-4.88(d,1H,J=16.0Hz), 4.51-4.57(d,1H,J=16.0Hz), 3.88-3.96(m,1H), 3.60-3.70(m,1H), 3.22-3.33(m,2H), 3.15(s,3H). MS(EI)m/z: 198(M)+ Elementary analysis: as C8H11ClN2O2S, Calculated: C,40.94;H,4.72;Cl,15.11;N,11.94;S,13.66 Found: C,40.50;H,4.66;Cl,15.31;N,11.97;S,13.68

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP1683800, 2006, A1 Location in patent: Page/Page column 53

7
[ 720720-96-7 ]
[ 480452-36-6 ]
N¹-(5-chloropyridin-2-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99.69%	Stage #1: tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate With 3-butyl-1-methyl-1H-imidazol-3-ium hydroxide; methanesulfonic acid In acetonitrile for 10h; Stage #2: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride With pyridine; benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In acetonitrile at 10℃; for 20h;	2; 5-8 2. Preparation of DXB-ABC 100 g of DXB-AC and 2 L of acetonitrile were added to the three-necked flask, and the mixture was stirred, and the system was white turbid. About 1.65 g of 1-butyl-3-methylimidazolium hydroxide and 102.7 g of methanesulfonic acid were added in about 5 min, and the system was dissolved to be transparent, and then gradually turned into white turbidity, and stirred for 10 hours. The ice water bath was cooled to 10 ° C, and 97.3 g of triethylamine and 16.9 g of pyridine were added under stirring, and then 57.4 g were sequentially added.EDCI, 39.3g HoBt, 55.2g DXB-B, after the addition, the ice bath was withdrawn, stirred for 20h, TLC (DCM: MeOH = 10:1 UV, using the deboc reaction solution as a control point), the basic reaction was complete. The ice water bath was cooled to 10 ° C, 21.6 g of triethylamine was added, and the mixture was stirred for about 30 minutes. Filter by suction and rinse with 100 ml of acetonitrile. The filter cake was dried by blasting at 45 ° C to obtain a white solid, the yield was 97%, and the purity was 98.05%; 3. Refinement of DXB_ABCThe DXB-ABC crude product and 2 L of dichloromethane were added to a 5 L three-necked flask, and the mixture was stirred for 20-30 min, and the solid was substantially dissolved. After suction filtration, the filtrate was transferred to a 10 L bottle, and 4 L of n-hexane was added thereto with stirring, stirred for 30 min, and suction filtered. The filter cake was dried by blasting at 45 ° C to obtain a pale yellow to off-white solid powder;The above white solid was added to a 2 L bottle, 1275 ml of methanol was added, stirred at room temperature for 10-15 h, suction filtered, and the filter cake was blast dried to constant weight at 45 ° C to obtain a pale yellow to off-white solid;The above white solid was added to a 2 L bottle, 1125 ml of methanol was added, stirred at room temperature for 10-15 h, suction filtered, and the filter cake was air-dried at 45 °C. A white solid is obtained. The HPLC purity was 99.69%, single impurity <0.1%, total impurity <0.5%. For the product obtained (DXB-ABC)Perform structural characterization:
96.4%	Stage #1: tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate With methanesulfonic acid In acetonitrile at 20 - 60℃; for 3h; Large scale; Stage #2: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride With triethylamine; ethyl (hydroxyimino)cyanoacetate; diisopropyl-carbodiimide In acetonitrile at 0 - 25℃; for 5h; Large scale;	3 Example 3. Synthesis of N- (5-chloropyridin-2-yl ) -N' - ( (IS, 2R, 4S) - 4- (dimethylcarbamoyl) -2- ( (5-methyl-4, 5, 6, 7- tetrahydrothiazol [5, 4-c] pyridin-2-carbonyl) amino) cyclohexyl ) oxamide of formula (II) 1000 g (2.14 mol) of tert-butyl N- ( (1R, 2S, 5S ) -2- ( (2- ( (5- chloropyridin-2-yl ) amino) -2-oxoacetyl) amino) -5-(dimethylcarbamoyl ) cyclohexyl ) carbamate (of formula (I)), obtained according to any one of the methods described in Examples 1 or 2, were mixed with 12.5 L of acetonitrile. The temperature of the resulting mixture was maintained between 20 and 25 °C during the subsequent addition of 278 mL (411.4 g, 4.28 mol, 2 molar eq. ) of methanesulfonic acid. The resulting mixture was heated at a temperature of about 60 °C and kept under stirring for 3 hours at the indicated temperature. The reaction mixture was then cooled at a temperature of between 0 and 5 °C and 625 mL (453.7 g, 4.49 mol, 2.10 molar eq.) of triethylamine were slowly added, maintaining the temperature below 5 °C. The mass reaction temperature was controlled to keep it between 20 and 25 °C, and then 527 g (2.24 mol, 1.05 molar eq.) of the 5-methyl-4, 5, 6, 7- tetrahydrothiazol [5, 4-c] pyridin-2-carboxylic acid hydrochloride salt, 30.4 g of OximaPure (cyano (hydroxyimino) ethyl acetate) (0.214 mol, 0.1 molar eq. ) , and 384 mL (313 g, 2.48 mol, 1.16 molar eq. ) of diisopropylcarbodiimide were added, while keeping the temperature between 20 and 25 °C. The reaction mixture was kept under stirring for 5 hours in said temperature range. 2 L of triethylamine were then added, keeping the temperature between 20 and 25 °C, and subsequently 5 L of water were added in the same temperature range. The resulting mixture was cooled at a temperature of about 3 °C and filtered. The resulting solid was washed three times 1 L of water each, and subsequently dried. 1129.0 g (yield of 96.4%) of a white solid corresponding to N- (5-chloropyridin-2-yl ) -N' - ( (IS, 2R, 4S ) -4-(dimethylcarbamoyl ) -2- ( (5-methyl-4, 5, 6, 7-tetrahydrothiazol [5, 4- c] pyridin-2-carbonyl ) amino ) cyclohexyl ) oxamide were thereby obtained. Product purity was analyzed by means of HPLC, obtaining a value of 98.19%.
85%	Stage #1: tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate With methanesulfonic acid In dichloromethane at 20℃; for 2h; Stage #2: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 18h; Cooling with ice;	11 Example 11: Preparationof Edoxaban: A solution offormula (XI) (7.0g, 0.014moles) inmethylene dichloride(56ml) andmethane sulfonic acid (4.85ml, 0.074 moles) was stirred for 2 hours at room temperature. After completion of the reaction, triethylamine( 15.63ml,0.1 12moles),5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4- c]pyridine-2-carboxylic acid hydrochloride^.86 g,0.0164moles),N-(3-dimethylaminopropyl)-N'- ethylcarbodiimidehydrochloride (3.44g,0.017moles),and 1-hydroxybenzotriazole (0162) (2.43g,0.0158moles) was added while the reaction mixture was cooled with ice. Thereaction mixture was stirred for 18 hours at room temperature after which water (35ml)and methylene dichloride(70ml) was added. The layers were separated the layers and organic layer was concentrated under reduced pressure to get Edoxabanas a solid (7.0g, yield: 85%, HPLC Purity: >99%).

85.13%	Stage #1: tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate With hydrogenchloride; lithium hydroxide monohydrate In propan-2-one at 0.25 - 0.3℃; for 2h; Stage #2: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide In dichloromethane at 0.35 - 0.4℃; for 0.5h;	3E Example 3E: Preparation of Edoxaban Free base (compound of formula I-A) directly from Carbamic acid, N-[(1R, 2S, 5S)-2-[[2-[(5-chloro-2-pyridinyl) amino]-2-oxoacetyl] amino] -5- [(dime thy lamino) carbonyl] cyclohexyl]-l, 1- dimethylethyl ester (compound of formula IV): The compound of formula IV (25.0g) obtained from example IB was added to acetone(250 mL) and concentrated hydrochloric acid (50 mL) was then added to it. The reaction mass was then stirred for about 2 hours at about 25°C to 30°C. After completion of the reaction mass, filtered the slurry mass, washed with acetone and suck dried. The obtained wet cake was suspended in methylene dichloride (250 mL) and added 5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (compound of formula III, 15.05g, diisopropyl ethyl amine (34.5g), N,N- dicyclohexyl carbodiimide (DCC) ( 16.5 lg) and 1-hydroxybenzotriazole (HOBt, 3.62g). The reaction mass was heated to about 35°C to 40°C for about 5 hours. After completion ,the reaction mass was cooled to about 0°C to 5°C for about 1 hour, filtered. The combined filtrate was washed with 5% aq. NaHCCL followed by brine solution. The solvent was distilled to obtain the crude product (compound of formula I-A) to which methanol (200 mL) was added and heated to 60°C to 65 °C for about 1 hour then cooled to 25 °C to 30°C for 1 hour, filtered, washed with methanol to obtained wet cake which was dried in tray drier at 40°C to 45 °C to obtain compound of formula I- A (24.90g, 85.13%), HPLC purity 99.47.
	Stage #1: tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate With methanesulfonic acid In acetonitrile at 20℃; for 2h; Stage #2: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In acetonitrile at 0 - 20℃; for 17h;	2 Referential Example 2: N-(5-Chloropyridin-2-yl)-N'-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl]ethanediamide Methanesulfonic acid (66 mL) was added at room temperature to a suspension of t-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate (95.1 g) in acetonitrile (1,900 mL), and the mixture was stirred at the same temperature for 2 hours. Triethylamine (155 mL), 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (52.5 g), 1-hydroxybenzotriazole (33.0 g), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46.8 g) were added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 16 hours. Triethylamine and water were added thereto, followed by stirring under ice-cooling for 1 hour. The formed crystals were recovered by filtration, to thereby yield 103.2 g of the title compound. 1H-NMR(CDCl3)δ:1.60-1.98(3H,m),2.00-2.16(3H,m),2.52(3H,s), 2.78-2.90(3H,m),2.92-2.98(2H,m),2.95(3H,s),3.06(3H,s), 3.69(1H,d,J=15.4Hz),3.75(1H,d,J=15.4Hz),4.07-4.15(1H,m), 4.66-4.72(1H,m),7.40(1H,dd,J=8.8,0.6Hz), 7.68(1H,dd,J=8.8,2.4Hz),8.03(1H,d,J=7.8Hz), 8.16(1H,dd,J=8.8,0.6Hz),8.30(1H,dd,J=2.4,0.6Hz),9.72(1H,s).
	Stage #1: tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate With methanesulfonic acid In acetonitrile at 20℃; for 2h; Stage #2: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In acetonitrile at 20℃; for 16h; Cooling with ice;	6 (Reference Example 6) N1-(5-Chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide (A) Methanesulfonic acid (66 ml) was added to a suspension of tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate (8) (95.1 g) in acetonitrile (1900 ml) at room temperature, and the mixture was stirred at this temperature for 2 hours. To the reaction solution, triethylamine (155 ml), 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (10) (52.5 g), 1-hydroxybenzotriazole (33.0 g), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46.8 g) were added under ice cooling, and the mixture was stirred at room temperature for 16 hours. Triethylamine and water were added thereto, and the mixture was stirred for 1 hour under ice cooling. Then, crystals were collected by filtration to obtain the title compound (A) (103.2 g). 1H-NMR (CDCl3) δ: 1.60-1.98 (3H, m), 2.00-2.16 (3H, m), 2.52 (3H, s), 2.78-2.90 (3H, m), 2.92-2.98 (2H, m), 2.95 (3H, s), 3.06 (3H, s), 3.69 (1H, d, J=15.4 Hz), 3.75 (1H, d, J=15.4 Hz), 4.07-4.15 (1H, m), 4.66-4.72 (1H, m), 7.40 (1H, dd, J=8.8, 0.6 Hz), 7.68 (1H, dd, J=8.8, 2.4 Hz), 8.03 (1H, d, J=7.8 Hz), 8.16 (1H, dd, J=8.8, 0.6 Hz), 8.30 (1H, dd, J=2.4, 0.6 Hz), 9.72 (1H, s). MS (ESI) m/z: 548 (M+H)+.
	Stage #1: tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate With methanesulfonic acid In acetonitrile at 20℃; for 2h; Stage #2: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In acetonitrile at 20℃; for 16h; Cooling with ice;	4 (Reference Example 4) N1-(5-Chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide (A) Methanesulfonic acid (66 ml) was added to a suspension of tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbanyl)cyclohexyl]carbamate (1) (95.1 g) in acetonitrile (1900 ml) at room temperature, and the mixture was stirred at this temperature for 2 hours. To the reaction solution, triethylamine (155 ml), 5-methyl-4,5,6,7-tetrahydro[1,3]thiazalo[5,4-c]pyridine-2-carboxylic acid hydrochloride (8) (52.5 g), 1-hydroxybenzotriazole (33.0 g), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46.8 g) were added under ice cooling, and the mixture was stirred at room temperature for 16 hours. Triethylamine and water were added thereto, and the mixture was stirred for 1 hour under ice cooling. Then, crystals were collected by filtration to obtain the title compound (103.2 g). 1H-NMR (CDCI3) δ: 1.60-1.98 (3H, m), 2.00-2.16 (3H, m), 2.52 (3H, s), 2.78-2.90 (3H, m), 2.92-2.98 (2H, m), 2.95 (3H, s), 3.06 (3H, s), 3.69 (1H, d, J=15.4 Hz), 3.75 (1H, d, J=15.4 Hz), 4.07-4.15 (1H, m), 4.66-4.72 (1H, m), 7.40 (1H, dd, J=8.8, 0.6 Hz), 7.68 (1H, dd, J=8.8, 2.4 Hz), 8.03 (1H, d, J=7.8 Hz), 8.16 (1H, dd, J=8.8, 0.6 Hz), 8.30 (1H, dd, J=2.4, 0.6 Hz), 9.72 (1H, s). MS (ESI) m/z: 548 (M+H)+.
103.2 g	Stage #1: tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate With methanesulfonic acid In acetonitrile at 20℃; for 2h; Stage #2: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In acetonitrile at 20℃; for 16h; Cooling with ice;	6 (Reference Example 6) N1-(5-Chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide (X) (production method described in the pamphlet of International Publication No. WO 2007/032498) Methanesulfonic acid (66 ml) was added to a suspension of tert-butyl [(1R,2,S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate (5) (95.1 g) in acetonitrile (1900 ml) at room temperature, and the mixture was stirred at this temperature for 2 hours. To the reaction solution, triethylamine (155 ml), 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyrzdine-2-carboxylic acid hydrochloride (8) (52.5 g), 1-hydroxybenzotriazole (33.0 g), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46.8 g) were added under ice cooling, and the mixture was stirred at room temperature for 16 hours. Triethylamine and water were added thereto, and the mixture was stirred for 1 hour under ice cooling. Then, crystals were collected by filtration to obtain the title compound (X) (103.2 g). 1H-NMR (CDCl3) δ : 1.60-1.98 (3H, m), 2.00-2.16 (3H, m), 2.52 (3H, s), 2.78-2.90 (3H, m), 2.92-2.98 (2H, m), 2.95 (3H, s), 3.06 (3H, s), 3.69 (1H, d, J = 15.4 Hz), 3.75 (1H, d, J = 15.4 Hz), 4.07-4.15 (1H, m), 4.66-4.72 (1H, m), 7.40 (1H, dd, J = 8.8, 0.6 Hz), 7. 68 (1H, dd, J = 8.8, 2.4 Hz), 8.03 (1H, d, J = 7.8 Hz), 8.16 (1H, dd, J = 8.8, 0.6 Hz), 8.30 (1H, dd, J = 2. 4, 0.6 Hz), 9.72 (1H, s). MS (ESI) m/z: 548 (M+H)+.
103.2 g	Stage #1: tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate With methanesulfonic acid In acetonitrile at 20℃; for 2h; Stage #2: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In acetonitrile at 20℃; for 17h; Cooling with ice;	3 Referential Example 3 N¹- (5-Chloropyridin-2-yl) -N²- [ (IS, 2R, 4S) -4- (dimethylcarbamoyl) -2 - { [ (5-methyl-4 , 5,6, 7-tetrahydro [1,3] thiazolo [5 , 4-c] yridin-2 -yl ) carbonyl] amino} cyclohexyl] ethanediamide (Edoxaban) Referential Example 3 N1- (5-Chloropyridin-2-yl) -N2- [ (IS, 2R, 4S) -4- (dimethylcarbamoyl) -2 - { [ (5-methyl-4 , 5,6, 7-tetrahydro [1,3] thiazolo [5 , 4-c] yridin-2 -yl ) carbonyl] amino} cyclohexyl] ethanediamide (Edoxaban) Methanesulfonic acid (66 mL) was added at room temperature to a suspension of ' tert-butyl [ (1R, 2S, 5S) -2- ( { [ (5-chloropyridin-2-yl) amino] (oxo)acet yl }amino) -5- (dimethylaminocarbonyl) cyclohexyl] carbamate (95.1 g) in acetonitrile (1,900 mL) , and the mixture was stirred at the same temperature for 2 hours. Triethylamine (155 mL) , 5-methyl-4 ,5,6, 7-tetrahydro [1,3] thiazolo [5 , 4-c] pyridine-2 -carbox ylic acid hydrochloride (52.5 g) , 1 -hydroxybenzotriazole (33.0 g) , and l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (46.8 g) were added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 16 hours. Triethylamine and water were added thereto, followed by stirring under ice-cooling for 1 hour. The formed crystals were recovered by filtration, to thereby yield 103.2 g of the title compound.
103.2 g	Stage #1: tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate With methanesulfonic acid In acetonitrile at 20℃; for 2h; Stage #2: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride With N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In acetonitrile at 20℃; for 16h;	5 Reference Example 5N’-(5-Chloropyridin-2-yl)-N2-[(1 S,2R,45)-4-(dim- ethylcarbamoyl)-2-{ [(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl]ethanediamide [edoxaban] (X) 10098] tert-Hutyl[(1R,25,55)-2-([(5-chloropyridin-2-yl)amino] (oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cy-clohexyl]carbamate (12) (95.1 g) was suspended in acetonitrile (1900 mE), and methanesulfonic acid (66 mE) was addedto the suspension at room temperature. The obtained mixturewas stirred at the same temperature as described above for 2hours. While the reaction mixture was stirred under coolingon ice, triethylamine (155 mE), 5-methyl-4,5,6,7-tetrahydro[1 ,3]thiazolo[5,4-c]pyridine-2-carboxylate hydrochloride(52.5 g), 1-hydroxybenzotriazole (33.0 g), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46.8 g)were added to the mixture. The reaction mixture was stirred atroom temperature for 16 hours. Triethylamine and water wereadded to the reaction mixture, and the obtained mixture wasthen stirred under cooling on ice for 1 hout A precipitatedcrystal was collected by filtration and was dried to obtain103.2 g of the title product.
103.2 g	Stage #1: tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate With methanesulfonic acid In acetonitrile at 20℃; for 2h; Stage #2: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In lithium hydroxide monohydrate; acetonitrile at 20℃; for 17h;	10 N¹-(5-chloropyridin-2-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolone[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide The tert-butyl [. (1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl} amino)-5-(dimethylaminocarbonyl)cyclohexyl carbamate (A-9) (95.1g), to the acetonitrile (1900 ml) suspension of a under a room temperature, Methanesulfonic acid (66 ml) was added and it stirred at a temperature as it is for 2 hours. The bottom of ice-cooling to reaction mixture, triethylamine (155 ml), 5-methyl-4,5,6,7-tetrahydro [1,3]thiazolo [5,4-c]pyridin-2-carboxylic acid hydrochloride (52.5g), 1-hydroxybenzotriazol (33.0g) and a 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46.8g) were added, and it stirred at the room temperature for 16 hours. Triethylamine and water were added, the crystal was separated the bottom of ice-cooling, and after 1-hour stirring, and title compound (X) (103.2g) was obtained.
125.3 g	Stage #1: tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate With methanesulfonic acid In acetonitrile at 25℃; for 2h; Stage #2: With triethylamine In acetonitrile at 10℃; for 0.166667h; Stage #3: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In acetonitrile at 25℃; for 18h;	2 Example 2 N- (5-Chloropyridin-2-yl)-N '- ((1S, 2R, 4S)-4 - [(dimethylamino) carbonyl] -2 - [(5-methyl-4,5,6,7-tetrahydrothiazole[5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide, Preparation of Compound (1) A 10 L reaction flask was charged with 2560 mL of acetonitrile, 128.0 g of (1R, 2S, 5S) -2 - ({2- [5-chloropyridin-Yl] -2-oxoacetyl} amino) -5 - [(dimethylamino) carbonyl] cyclohexylcarbamate was added with stirring and 131.4 g of methanesulfonic acid was added with stirring at 25 ± 2 ° C. The reaction was incubated for 2 h , TLC no raw material point, cooling, 10.2 ° C was added 152.2g triethylamine, stirred 10min, followed by addition of 70.6g 5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid hydrochloride,40.7 g of 1-hydroxybenzotriazole and 62.9 g1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride,Warming to 25 , 25 ± 2 reaction 18h. TLC detection of raw material point. Developing solvent: dichloromethane: methanol = 10: 1.After the reaction, lowering the temperature to 10 °C, add saturated aqueous solution of sodium bicarbonate, 10 ± 2 °C insulation crystallization 1h, filtered, the filter cake washing, 45 °C drying by blowing 12h, shall 125.3g white solid
103.2 g	Stage #1: tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate With methanesulfonic acid In acetonitrile at 20℃; for 2h; Stage #2: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride With triethylamine In acetonitrile at 20℃; for 16h; Cooling with ice;	4 {Tert-Butyl [(1R, 2S, 5S) -2-({(5-chloropyridin-2-yl) amino} (oxo) acetyl) amino] -5-dimethylaminocarbonyl in acetonitrile (1900 ml)Cyclohexyl] carbamate(95.1g), Methanesulfonic acid (66 ml) is added at room temperature,The mixture was stirred at room temperature for 2 hours,The reaction solution, trimethylamine (155 ml),5-Methyl-4,5,6,7-tetrahydro [1,3] thiazo [5,4-c] pyridine-2-carboxylic acid hydrochloride (46.8 g) was added under ice cooling, and the mixture was added. Stirred at room temperature for 16 hours.Triethylamine and water were added thereto, and the mixture was stirred under ice cooling for 1 hour. Thereafter, the crystals were collected by filtration to obtain the title compound (103.2 g).
103.2 g	Stage #1: tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate With methanesulfonic acid In acetonitrile at 20℃; for 2h; Stage #2: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In acetonitrile at 20℃; for 16h; Cooling with ice;	1-2; 1-15 Refer to the technical scheme disclosed in patent US8686189B2, selectN-(5-chloropyridin-2-yl)-N'-[(1S,2R,4S)-4-(N,N-dimethylformylamino)-2-(5-methyl-4, 5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide)cyclohexyl]oxalamide as a raw material,Prepare compound (1): At room temperature, toN-(5-Chloropiperidin-2-yl)-N'-[(1S,2R,4S)-4-(N,N-dimethylformylamino)-2-(amino tert-butoxycarbonyl ) Cyclohexyl] oxamide (95.1g) in acetonitrile (1900ml) suspension was added with methanesulfonic acid (66ml),Stir at this temperature for 2 hours.Under ice cooling, triethylamine (155ml), 4,5,6,7-tetrahydro-5-methyl-thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride ( 52.5g), 1-hydroxybenzotriazole (33.0g), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (46.8g), stirred at room temperature for 16 hours . Triethylamine and water were added, and after stirring for 1 hour under ice cooling, the crystals were filtered out to obtain 103.2 g of compound (1)
	Stage #1: tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate With hydrogenchloride In dichloromethane; lithium hydroxide monohydrate at 20℃; for 1.16h; Stage #2: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride With N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In ethanol at 20℃;	1-2 Example 1 (5-chloropyridin-2-yl)-N2-((1S,2R,4S)-2-[(tert-Butoxycarbonyl)Amino]-4-[(dimethylamino) carbonyl]-cyclohexyl)oxalamide (Formula 2) 11.0 g is added to MC 146.3g and stirred at room temperature. 4.9 g of 35% hydrochloric acid is added, and the mixture is stirred until the reaction is completed, and when the reaction is completed, it is completely concentrated. TEA 7.1g and ethanol 39.5g were added to the concentrate and stirred at room temperature. 4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (Formula 4) 6.1g and EDCI 5.5g are added and stirred until the reaction is complete. 292.6 g of MC and 220 mL of water are added, stirred, and the MC layer is first separated. After the separation, 146.3 g of MC was added to the water layer again, stirred, and then the layers were separated a second time. 110 mL of water is added to the entire MC layer separated from the first and second water layers, stirred, and then the third layer is separated again. After the tertiary MC layer was concentrated, 35.1 g of MC, 9.2 g of ethanol, and 6 mL of water were added to the concentrate and stirred. Add 5.7 g of benzenesulfonic acid and stir at room temperature for about 10 minutes. After adding 110 mL of ethyl acetate to the stirred reaction solution, the mixture was stirred for 1 hour. After cooling the mixed solution in which crystals are formed by the stirring to 0-5° C., the mixture is stirred again for 1 hour to completely form crystals from the mixed solution. The resulting crystals were filtered and dried under vacuum at 50° C. for 12 hours to obtain the title crystals (yield: 89%, purity: 99.980%)

Reference： [1]Current Patent Assignee: BEIJING SUN NOVO PHARMACEUTICAL RES - CN108484641, 2018, A Location in patent: Paragraph 0050-0055; 0089-0096
[2]Current Patent Assignee: MOEHS IBERICA S L - WO2019/158550, 2019, A1 Location in patent: Page/Page column 15-16
[3]Current Patent Assignee: VIATRIS INC - WO2018/11823, 2018, A1 Location in patent: Page/Page column 27
[4]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2021/1728, 2021, A1 Location in patent: Page/Page column 17-18
[5]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP1925611, 2008, A1 Location in patent: Page/Page column 47-48
[6]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP2407450, 2012, A1 Location in patent: Page/Page column 21
[7]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP2407457, 2012, A1 Location in patent: Page/Page column 16
[8]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP2589590, 2013, A1 Location in patent: Paragraph 0144; 0145
[9]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - WO2014/81047, 2014, A1 Location in patent: Page/Page column 22
[10]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - US2015/353577, 2015, A1 Location in patent: Paragraph 0097; 0098
[11]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - JP5801011, 2015, B2 Location in patent: Page/Page column 0210-0212
[12]Current Patent Assignee: SHANDONG KEXING BIOPRODUCTS; SHENZHEN KEXING BIOTECH - CN104761571, 2017, B Location in patent: Paragraph 0049; 0050; 0051; 0052; 0053
[13]Current Patent Assignee: GAPI BIO; DONGBANG FTL; GABI BIO - JP2019/210273, 2019, A Location in patent: Paragraph 0043; 0048
[14]Current Patent Assignee: ZHEJIANG SUPOR PHARMACEUTICALS CO LTD - CN111606927, 2020, A Location in patent: Paragraph 0023-0062
[15]Current Patent Assignee: PHARMACOSTECH CO LTD - KR2021/152213, 2021, A Location in patent: Paragraph 0055-0057; 0060; 0062

8
[ 720720-96-7 ]
C₁₅H₁₇ClN₆O₃*ClH [ No CAS ]
N-(5-chloropyridin-2-yl)-N'-[(1S,2R,4S)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-4-(1,3,4-oxazol-2-yl)cyclohexyl]ethanediamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 18h;	6 Referential Example 6: N-(5-Chloropyridin-2-yl)-N'-[(1S,2R,4S)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-4-(1,3,4-oxazol-2-yl)cyclohexyl]ethanediamide The residue was dissolved in N,N-dimethylformamide (50 mL), and 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (160 mg), 1-hydroxybenzotriazole monohydrate (120 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (150 mg) were added to the solution. The mixture was stirred at room temperature for 18 hours, and the solvent was evaporated under reduced pressure. Ethyl acetate and water were added to the residue, and the organic layer was washed with saturated brine, followed by drying over magnesium sulfate anhydrate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (methanol: methylene chloride = 2: 23 to 1: 9), to thereby yield 181.3 mg of the title compound. 1H-NMR(CDCl3)δ:1.72-2.00(2H,m),2.13-2.23(2H,m),2.28-2.36(1H,m), 2.39-2.46(1H,m),2.53(3H,s),2.80-2.91(2H,m), 2.93-3.00 (2H,m), 3.28-3.38(1H,m), 3.69-3.79(2H,m), 4.14-4.24(1H,m),4.68-4.77(1H,m),4.68-4.77(1H,m), 7.51(1H,d,J=8.3Hz),7.70(1H,dd,J=8.8,2.5Hz),8.14(1H,d,J=7.8Hz), 8.18(1H,d,J=8.8Hz),8.31(1H,d,J=2.5Hz),9.72(1H,s).

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP1925611, 2008, A1 Location in patent: Page/Page column 49

9
[ 720720-96-7 ]
C₁₁H₁₀ClN₃OS [ No CAS ]
[ 1057855-15-8 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide

Reference： [1]Location in patent: scheme or table Mochizuki, Akiyoshi; Nagata, Tsutomu; Kanno, Hideyuki; Suzuki, Makoto; Ohta, Toshiharu [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1623 - 1642]

10
[ 720720-96-7 ]
[ 1247659-09-1 ]
[ 1286182-17-9 ]

Yield	Reaction Conditions	Operation in experiment
185 mg	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 72h;	5.1.3. N-{3-[(5-Chlorothiophen-2-yl)carbonylamino]propyl}-5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide hydrochloride (1A) To the mixed solution of 3A (200 mg, 0.627 mmol) in dioxane (3.0 mL) and MeOH (1.0 mL) was added 4 M HCl solution in dioxane (3.0 mL), and the mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the obtained residue was dissolved in DMF (4.0 mL). To the solution were added 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (176 mg, 0.750 mmol), HOBt (102 mg, 0.755 mmol), EDC·HCl (153 mg, 0.798 mmol) and triethylamine (322 μL, 2.29 mmol). After stirring at room temperature for 3 d, the solvent was evaporated. To the residue were added CH2Cl2 and saturated NaHCO3 aqueous solution. After extraction with CH2Cl2, combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH = 20:1) and the obtained crude product was washed with AcOEt to give the free form of the title compound (185 mg, 0.464 mmol, 74%) as a white solid. 1H NMR (CDCl3) δ: 1.78-1.87 (2H, m), 2.53 (3H, s), 2.84 (2H, t, J = 5.7 Hz), 2.93 (2H, t, J = 5.4 Hz), 3.42-3.49 (2H, m), 3.52-3.59 (2H, m), 3.74 (2H, s), 6.89 (1H, d, J = 4.2 Hz), 7.43 (1H, d, J = 4.2 Hz), 7.52-7.63 (2H, m). ESI-MS m/z: 399 [(M+H)+, 35Cl], 401 [(M+H)+, 37Cl].To the solution of the free form of the title compound (185 mg) in EtOH (20 mL) was added 1 M HCl solution in EtOH (500 μL) and the solvent was evaporated. Water was added to the residue and evaporated, and then dried in vacuo at room temperature for 14 h to obtain the title compound (202 mg) as a white solid. MP: 84-87 °C (Dec.). IR (ATR) cm-1: 3400, 2931, 1639, 1549, 1520, 1427, 1292, 1140. 1H NMR (DMSO-d6) δ: 1.68-1.80 (2H, m), 2.91 (3H, s), 3.04-3.34 (6H, m), 3.39-3.54 (1H, m), 3.61-3.82 (1H, m), 4.35-4.49 (1H, m), 4.63-4.77 (1H, m), 7.17 (1H, d, J = 4.2 Hz), 7.63 (1H, d, J = 4.2 Hz), 8.68 (1H, t, J = 5.5 Hz), 8.93 (1H, t, J = 6.1 Hz), 11.56 (1H, br s). FAB-MS m/z: 399 [(M+H)+, 35Cl], 401 [(M+H)+, 37Cl]. Anal. Calcd for C16H19ClN4O2S2·1.1HCl·H2O: C, 42.05; H, 4.87; Cl, 16.29; N, 12.26; S, 14.03. Found: C, 42.25; H, 5.23; Cl, 16.37; N, 12.26; S, 14.10.

Reference： [1]Location in patent: experimental part Mochizuki, Akiyoshi; Nagata, Tsutomu; Kanno, Hideyuki; Suzuki, Makoto; Ohta, Toshiharu [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1623 - 1642]

11
[ 720720-96-7 ]
[ 1247659-09-1 ]
C₁₆H₁₉ClN₄O₂S₂*1.1ClH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / N,N-dimethyl-formamide / 72 h / 20 °C 2: hydrogenchloride / ethanol

Reference： [1]Mochizuki, Akiyoshi; Nagata, Tsutomu; Kanno, Hideyuki; Suzuki, Makoto; Ohta, Toshiharu [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1623 - 1642]

12
[ 720720-96-7 ]
[ 1250550-99-2 ]
[ 1286182-18-0 ]

Yield	Reaction Conditions	Operation in experiment
223 mg	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 72h;	5.1.5. N-{1-[(5-Methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)carbonyl]piperidin-4-yl}-5-chlorothiophene-2-carboxamide hydrochloride (1B) General procedure: To the mixed solution of 3A (200 mg, 0.627 mmol) in dioxane (3.0 mL) and MeOH (1.0 mL) was added 4 M HCl solution in dioxane (3.0 mL), and the mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the obtained residue was dissolved in DMF (4.0 mL). To the solution were added 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (176 mg, 0.750 mmol), HOBt (102 mg, 0.755 mmol), EDC·HCl (153 mg, 0.798 mmol) and triethylamine (322 μL, 2.29 mmol). After stirring at room temperature for 3 d, the solvent was evaporated. To the residue were added CH2Cl2 and saturated NaHCO3 aqueous solution. After extraction with CH2Cl2, combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH = 20:1) and the obtained crude product was washed with AcOEt to give the free form of the title compound (185 mg, 0.464 mmol, 74%) as a white solid.

Reference： [1]Location in patent: experimental part Mochizuki, Akiyoshi; Nagata, Tsutomu; Kanno, Hideyuki; Suzuki, Makoto; Ohta, Toshiharu [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1623 - 1642]

13
[ 720720-96-7 ]
[ 1057651-04-3 ]
[ 1057650-46-0 ]

Yield	Reaction Conditions	Operation in experiment
62%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 23h;	5.1.10. N-(2-{3-[(5-Chlorothiophen-2-yl)carbonylamino]methyl}phenyl)-5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide (1D) To the solution of compound 43 (253 mg, 0.948 mmol) in DMF (10.0 mL) were added 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (260 mg, 1.11 mmol), HOBt (140 mg, 1.04 mmol), EDC·HCl (234 mg, 1.22 mmol) and triethylamine (320 μL, 2.30 mmol). After stirring at room temperature for 23 h, the solvent was evaporated. To the residue were added 10% MeOH solution in CH2Cl2 and saturated NaHCO3 aqueous solution. After extraction with CH2Cl2, combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. After washing the crude product with AcOEt (3.0 mL), precipitate was collected by filtration and washed with Et2O to obtain the free form of the title compound (262 mg, 0.586 mmol, 62%) as a pale yellow solid. 1H NMR (CDCl3) δ: 2.53 (3H, s), 2.85 (2H, t, J = 5.6 Hz), 2.94 (2H, t, J = 5.6 Hz), 3.75 (2H, s), 4.58 (2H, d, J = 5.9 Hz), 6.86 (1H, d, J = 3.9 Hz), 6.97-7.08 (1H, m), 7.21-7.32 (2H, m), 7.33-7.40 (1H, m), 7.46 (1H, d, J = 7.6 Hz), 7.65 (1H, d, J = 7.8 Hz), 9.40 (1H, s). ESI-MS m/z: 447 [(M+H)+, 35Cl], 449 [(M+H)+, 37Cl].To the solution of the free form of the title compound (262 mg) in EtOH (10.0 mL) was added 1 M HCl solution in EtOH (600 μL) and the solvent was evaporated. Water was added to the residue and evaporated, and the resultant matter was dried in vacuo at room temperature for 18 h to obtain the title compound (282 mg) as a white solid. MP: 259-266 °C (Dec.). IR (ATR) cm-1: 3317, 2366, 1662, 1637, 1591, 1556, 1539, 1504, 1454, 1427, 1298, 1273, 1122, 1078. 1H NMR (DMSO-d6) δ: 2.93 (3H, s), 3.08-3.33 (2H, br), 3.42-3.81 (2H, br), 4.31-4.87 (2H, br), 4.42 (2H, d, J = 5.9 Hz), 7.19 (1H, d, J = 4.2 Hz), 7.22-7.39 (3H, m), 7.48 (1H, d, J = 7.6 Hz), 7.71 (1H, d, J = 4.2 Hz), 9.22 (1H, t, J = 5.9 Hz), 10.67 (1H, s), 11.38-11.64 (1H, br). ESI-MS m/z: 447 [(M+H)+, 35Cl], 449 [(M+H)+, 37Cl]. Anal. Calcd for C20H19ClN4O2S2·HCl·0.2H2O: C, 49.32; H, 4.22; Cl, 14.56; N, 11.50; S, 13.17. Found: C, 49.40; H, 4.01; Cl, 14.33; N, 11.51; S, 13.21.

Reference： [1]Location in patent: experimental part Mochizuki, Akiyoshi; Nagata, Tsutomu; Kanno, Hideyuki; Suzuki, Makoto; Ohta, Toshiharu [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1623 - 1642]

14
[ 720720-96-7 ]
C₁₂H₁₇ClN₂OS [ No CAS ]
N-[(1RS,2SR)-2-([(5-chlorothiophen-2-yl)carbonyl]amino}methyl)cyclohexyl]-5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide

Reference： [1]Location in patent: scheme or table Mochizuki, Akiyoshi; Nagata, Tsutomu; Kanno, Hideyuki; Suzuki, Makoto; Ohta, Toshiharu [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1623 - 1642]

15
[ 720720-96-7 ]
C₁₂H₁₇ClN₂OS [ No CAS ]
N-[(1RS,2SR)-2-([(5-chlorothiophen-2-yl)carbonyl]amino}methyl)cyclohexyl]-5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / N,N-dimethyl-formamide 2: hydrogenchloride / ethanol

Reference： [1]Mochizuki, Akiyoshi; Nagata, Tsutomu; Kanno, Hideyuki; Suzuki, Makoto; Ohta, Toshiharu [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1623 - 1642]

16
[ 720720-96-7 ]
C₁₂H₁₇ClN₂OS [ No CAS ]
N-[(1RS,2RS)-2-([(5-chlorothiophen-2-yl)carbonyl]amino}methyl)cyclohexyl]-5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide

Reference： [1]Location in patent: scheme or table Mochizuki, Akiyoshi; Nagata, Tsutomu; Kanno, Hideyuki; Suzuki, Makoto; Ohta, Toshiharu [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1623 - 1642]

17
[ 720720-96-7 ]
C₁₂H₁₇ClN₂OS [ No CAS ]
N-[(1RS,2RS)-2-([(5-chlorothiophen-2-yl)carbonyl]amino}methyl)cyclohexyl]-5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / N,N-dimethyl-formamide 2: hydrogenchloride / ethanol

Reference： [1]Mochizuki, Akiyoshi; Nagata, Tsutomu; Kanno, Hideyuki; Suzuki, Makoto; Ohta, Toshiharu [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1623 - 1642]

18
[ 720720-96-7 ]
[ 1057650-82-4 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride for 1h; Reflux;	5.1.23. tert-Butyl [(2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyridin-3-yl)methyl]carbamate (3H) 5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (469 mg, 2.00 mmol) was suspended in thionylchloride (10 mL). The mixture was refluxed for 1 h and concentrated in vacuo to obtain the corresponding acylchloride as a solid. To the obtained solid were added pyridine (10 mL) and CH2Cl2 (10 mL) containing compound 2H (223 mg, 1.00 mmol). The mixture was stirred at room temperature overnight and stirred at 50 °C overnight. To the mixture was added further prepared acylchloride that is obtained by treating 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (469 mg, 2.00 mmol) and thionylchloride (10 mL) as described before. The mixture was stirred at room temperature for another 3 d. Solvent was distilled off in vacuo and the residue was partitioned between CH2Cl2 (50 mL) and saturated NaHCO3 aqueous solution (50 mL). Organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (8% MeOH-CH2Cl2) to obtain the title compound (211 mg, 0.523 mmol, 52%) as a white powder. 1H NMR (CDCl3) δ: 1.45 (9H, s), 2.60 (3H, s), 2.96 (2H, br s), 3.05 (2H, br s), 3.86 (2H, br s), 4.34 (2H, d, J = 6.1 Hz), 5.59 (1H, br s), 7.24 (1H, dd, J = 7.6, 4.9 Hz), 7.91 (1H, d, J = 7.6 Hz), 8.39 (1H, d, J = 4.9 Hz), 9.40 (1H, br s). ESI-MS m/z: 404 (M+H)+.
	With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1h; Reflux;	5 Example 5: Production of edoxaban 1 In a flask, 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid 2 (5.0 g, 21.3 mmol) was added to dichloromethane (25 ml). . To this was added a catalytic amount of N, N-dimethylformamide. ThenThionyl chloride (5.07 g, 42.6 mmol) was slowly added to the flask at room temperature. The reaction mixture was then heated to reflux for 1 hour and the solvent was distilled off under rotary vacuum. The obtained solid, 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carbonyl chloride 11, was added to 25 ml of dichloromethane. Then cooled to 0-5 ° C. To this was added amine 3 (7.83 g, 21.3 mmol), followed by Et3N (8.6 g, 85.21 mmol) at the same temperature. After stirring for 1 hour, the cooling bath was removed and the mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction by TLC,Dichloromethane (15 mL) and purified water (50 mL) were added.After stirring at room temperature for 30 minutes, the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate (1 g) and concentrated under reduced pressure.Crystallize from isopropyl alcohol (25 mL) to give the title compound 1.

Reference： [1]Location in patent: experimental part Mochizuki, Akiyoshi; Nagata, Tsutomu; Kanno, Hideyuki; Suzuki, Makoto; Ohta, Toshiharu [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1623 - 1642]
[2]Current Patent Assignee: GAPI BIO; DONGBANG FTL; GABI BIO - JP2019/210273, 2019, A Location in patent: Paragraph 0038; 0039

19
[ 720720-96-7 ]
C₁₄H₂₂N₄OS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / N,N-dimethyl-formamide / 18 h / 20 °C 2: hydrogenchloride; methanol / 1,4-dioxane / 14 h / 20 °C

Reference： [1]Mochizuki, Akiyoshi; Nagata, Tsutomu; Kanno, Hideyuki; Suzuki, Makoto; Ohta, Toshiharu [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1623 - 1642]

20
[ 720720-96-7 ]
[ 1286182-19-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / N,N-dimethyl-formamide / 18 h / 20 °C 2: hydrogenchloride; methanol / 1,4-dioxane / 14 h / 20 °C 3: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / N,N-dimethyl-formamide / 19 h / 20 °C

Reference： [1]Mochizuki, Akiyoshi; Nagata, Tsutomu; Kanno, Hideyuki; Suzuki, Makoto; Ohta, Toshiharu [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1623 - 1642]

21
[ 720720-96-7 ]
[ 1286182-02-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / N,N-dimethyl-formamide / 18 h / 20 °C 2: hydrogenchloride; methanol / 1,4-dioxane / 14 h / 20 °C 3: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / N,N-dimethyl-formamide / 19 h / 20 °C 4: hydrogenchloride / ethanol

Reference： [1]Mochizuki, Akiyoshi; Nagata, Tsutomu; Kanno, Hideyuki; Suzuki, Makoto; Ohta, Toshiharu [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1623 - 1642]

22
[ 720720-96-7 ]
N-(2-aminobenzyl)-5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / N,N-dimethyl-formamide / 18 h / 20 °C 2: iron(III) chloride; water; zinc / N,N-dimethyl-formamide / 1 h / Reflux

Reference： [1]Mochizuki, Akiyoshi; Nagata, Tsutomu; Kanno, Hideyuki; Suzuki, Makoto; Ohta, Toshiharu [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1623 - 1642]

23
[ 720720-96-7 ]
[ 1286182-20-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / N,N-dimethyl-formamide / 18 h / 20 °C 2: iron(III) chloride; water; zinc / N,N-dimethyl-formamide / 1 h / Reflux 3: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 20 °C

Reference： [1]Mochizuki, Akiyoshi; Nagata, Tsutomu; Kanno, Hideyuki; Suzuki, Makoto; Ohta, Toshiharu [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1623 - 1642]

24
[ 720720-96-7 ]
[ 1286182-04-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / N,N-dimethyl-formamide / 18 h / 20 °C 2: iron(III) chloride; water; zinc / N,N-dimethyl-formamide / 1 h / Reflux 3: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 20 °C 4: hydrogenchloride / ethanol

Reference： [1]Mochizuki, Akiyoshi; Nagata, Tsutomu; Kanno, Hideyuki; Suzuki, Makoto; Ohta, Toshiharu [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1623 - 1642]

25
[ 720720-96-7 ]
[ 1057650-81-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: thionyl chloride / 1 h / Reflux 2: pyridine / dichloromethane / 20 - 50 °C

Reference： [1]Mochizuki, Akiyoshi; Nagata, Tsutomu; Kanno, Hideyuki; Suzuki, Makoto; Ohta, Toshiharu [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1623 - 1642]

26
[ 720720-96-7 ]
[ 1057653-13-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: thionyl chloride / 1 h / Reflux 2: pyridine / dichloromethane / 20 - 50 °C 3: hydrogenchloride / 1,4-dioxane; dichloromethane 4: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / N,N-dimethyl-formamide

Reference： [1]Mochizuki, Akiyoshi; Nagata, Tsutomu; Kanno, Hideyuki; Suzuki, Makoto; Ohta, Toshiharu [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1623 - 1642]

27
[ 720720-96-7 ]
[ 1057653-12-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: thionyl chloride / 1 h / Reflux 2: pyridine / dichloromethane / 20 - 50 °C 3: hydrogenchloride / 1,4-dioxane; dichloromethane

Reference： [1]Mochizuki, Akiyoshi; Nagata, Tsutomu; Kanno, Hideyuki; Suzuki, Makoto; Ohta, Toshiharu [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1623 - 1642]

28
[ 720720-96-7 ]
C₁₉H₁₈ClN₅O₂S₂*1.9ClH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: thionyl chloride / 1 h / Reflux 2: pyridine / dichloromethane / 20 - 50 °C 3: hydrogenchloride / 1,4-dioxane; dichloromethane 4: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / N,N-dimethyl-formamide 5: hydrogenchloride / ethanol

Reference： [1]Mochizuki, Akiyoshi; Nagata, Tsutomu; Kanno, Hideyuki; Suzuki, Makoto; Ohta, Toshiharu [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1623 - 1642]

29
[ 720720-96-7 ]
[ 1057650-84-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: thionyl chloride / 1 h / Reflux 2: pyridine

Reference： [1]Mochizuki, Akiyoshi; Nagata, Tsutomu; Kanno, Hideyuki; Suzuki, Makoto; Ohta, Toshiharu [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1623 - 1642]

30
[ 720720-96-7 ]
C₁₄H₁₇N₅OS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: thionyl chloride / 1 h / Reflux 2: pyridine 3: hydrogenchloride / 1,4-dioxane; dichloromethane

Reference： [1]Mochizuki, Akiyoshi; Nagata, Tsutomu; Kanno, Hideyuki; Suzuki, Makoto; Ohta, Toshiharu [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1623 - 1642]

31
[ 720720-96-7 ]
[ 1057855-14-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: thionyl chloride / 1 h / Reflux 2: pyridine 3: hydrogenchloride / 1,4-dioxane; dichloromethane 4: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / N,N-dimethyl-formamide

Reference： [1]Mochizuki, Akiyoshi; Nagata, Tsutomu; Kanno, Hideyuki; Suzuki, Makoto; Ohta, Toshiharu [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1623 - 1642]

32
[ 720720-96-7 ]
C₁₉H₁₈ClN₅O₂S₂*1.5ClH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: thionyl chloride / 1 h / Reflux 2: pyridine 3: hydrogenchloride / 1,4-dioxane; dichloromethane 4: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / N,N-dimethyl-formamide 5: hydrogenchloride / ethanol

Reference： [1]Mochizuki, Akiyoshi; Nagata, Tsutomu; Kanno, Hideyuki; Suzuki, Makoto; Ohta, Toshiharu [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1623 - 1642]

33
[ 720720-96-7 ]
C₁₁H₁₀ClN₃OS [ No CAS ]
[ 1057653-16-3 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide

Reference： [1]Location in patent: scheme or table Mochizuki, Akiyoshi; Nagata, Tsutomu; Kanno, Hideyuki; Suzuki, Makoto; Ohta, Toshiharu [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1623 - 1642]

34
[ 720720-96-7 ]
C₁₁H₁₀ClN₃OS [ No CAS ]
C₁₉H₁₈ClN₅O₂S₂*1.9ClH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / N,N-dimethyl-formamide 2: hydrogenchloride / ethanol

Reference： [1]Mochizuki, Akiyoshi; Nagata, Tsutomu; Kanno, Hideyuki; Suzuki, Makoto; Ohta, Toshiharu [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1623 - 1642]

35
[ 720720-96-7 ]
[ 1904-78-5 ]
[ 1286182-25-9 ]

Yield	Reaction Conditions	Operation in experiment
76%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 18h;	5.1.11. N-(2-Nitrobenzyl)-5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide (3E) General procedure: To the solution of tert-butyl (piperidin-3-yl)methylcarbamate (252 mg, 1.18 mmol) in DMF (10 mL) were added 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (330 mg, 1.41 mmol), HOBt (188 mg, 1.39 mmol), EDC·HCl (288 mg, 1.50 mmol) and triethylamine (406 μL, 2.91 mmol). After stirring at room temperature for 18 h, the solvent was evaporated. To the residue were added CH2Cl2 and saturated NaHCO3 aqueous solution. After extraction with CH2Cl2, combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (CH2Cl2/MeOH = 30:1→20:1→10:1) and dried in vacuo at room temperature for 2 h to obtain the title compound (436 mg, 1.11 mmol, 94%) as a pale yellow solid.

Reference： [1]Location in patent: experimental part Mochizuki, Akiyoshi; Nagata, Tsutomu; Kanno, Hideyuki; Suzuki, Makoto; Ohta, Toshiharu [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1623 - 1642]

36
5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloric acid salt [ No CAS ]
[ 142643-29-6 ]
[ 1286182-24-8 ]

Yield	Reaction Conditions	Operation in experiment
94%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 18h;	To the solution of tert-butyl (piperidin-3-yl)methylcarbamate (252 mg, 1.18 mmol) in DMF (10 mL) were added 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (330 mg, 1.41 mmol), HOBt (188 mg, 1.39 mmol), EDC·HCl (288 mg, 1.50 mmol) and triethylamine (406 muL, 2.91 mmol). After stirring at room temperature for 18 h, the solvent was evaporated. To the residue were added CH2Cl2 and saturated NaHCO3 aqueous solution. After extraction with CH2Cl2, combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (CH2Cl2/MeOH = 30:1?20:1?10:1) and dried in vacuo at room temperature for 2 h to obtain the title compound (436 mg, 1.11 mmol, 94%) as a pale yellow solid. 1H NMR (CDCl3) delta: 1.45 (9H, s), 1.50-1.98 (5H, m), 2.55 (3H, s), 2.80-3.48 (7H, m), 3.69-3.83 (0.25H, m), 3.76 (2H, s), 3.89-4.04 (1H, m), 4.08-4.32 (1.25H, m), 4.62-4.77 (0.25H, m), 4.81-4.99 (0.25H, br), 5.99-6.14 (1H, br). ESI-MS m/z: 395 (M+H)+.

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 1623 - 1642

37
[ 720720-96-7 ]
[ 162046-50-6 ]
[ 1057651-77-0 ]

Yield	Reaction Conditions	Operation in experiment
2.93 g	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃;	5.1.40. tert-Butyl {2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-carbonyl)amino]benzyl}carbamate (38) Compound 37 (2.23 g, 8.84 mmol) was dissolved in AcOEt (50 mL), and wet 10% palladium on carbon (50% water containing, 70 mg) was added to this solution. After stirring for 1 h under hydrogen atmosphere, catalyst was removed by filtration. Filtrate was concentrated in vacuo to obtain a white solid. This solid was dissolved in DMF (30 mL), and to this solution were added 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (2.49 g, 10.6 mmol), HOBt (1.19 g, 8.84 mmol), EDC·HCl (2.54 g, 13.3 mmol) and triethylamine (2.46 mL, 17.7 mmol). The mixture was stirred overnight at room temperature. After removing the solvent in vacuo, the residue was partioned between AcOEt (200 mL) and saturated NaHCO3 aqueous solution (200 mL). Organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. Obtained pale yellow powder was washed with Et2O to obtain the title compound (2.93 g, 7.28 mmol, 82%) as a pale yellow solid. 1H NMR (CDCl3) δ: 1.45 (9H, s), 2.52 (3H, s), 2.86 (2H, t, J = 5.8 Hz), 2.99 (2H, t, J = 5.8 Hz), 3.72 (2H, s), 4.34 (2H, d, J = 5.9 Hz), 5.13 (1H, br s), 7.19 (1H, td, J = 7.8, 1.2 Hz), 7.31-7.38 (2H, m), 7.92 (1H, dd, J = 7.8, 1.2 Hz), 9.52 (1H, br s). ESI-MS m/z: 403 (M+H)+.

Reference： [1]Location in patent: experimental part Mochizuki, Akiyoshi; Nagata, Tsutomu; Kanno, Hideyuki; Suzuki, Makoto; Ohta, Toshiharu [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1623 - 1642]

38
[ 1445-73-4 ]
[ 720720-96-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: acetic acid; hydrogen bromide; bromine / water / 20 - 25 °C 2.1: ethanol / 75 - 80 °C 3.1: hydrogen bromide; sodium nitrite / water / 3 h / 10 - 25 °C 4.1: triethylamine / toluene / 25 - 35 °C 5.1: lithium hydroxide monohydrate / water / 25 - 30 °C 5.2: 0 - 5 °C
	Multi-step reaction with 6 steps 1.1: acetic acid; hydrogen bromide; bromine / water / 20 - 25 °C 2.1: ethanol / 75 - 80 °C 3.1: hydrogen bromide; sodium nitrite / water / 3 h / 10 - 25 °C 4.1: sodium dithionite / water; ethanol / 50 - 70 °C 5.1: triethylamine / toluene / 25 - 35 °C 6.1: lithium hydroxide monohydrate / water / 25 - 30 °C 6.2: 0 - 5 °C

Reference： [1]Current Patent Assignee: INNER MONGOLIA JINGDONG PHARMACEUTICAL; BEIJING SIHUAN KEBAO PHARMACEUTICAL - CN109942600, 2019, A
[2]Current Patent Assignee: INNER MONGOLIA JINGDONG PHARMACEUTICAL; BEIJING SIHUAN KEBAO PHARMACEUTICAL - CN109942600, 2019, A

39
2-amino-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine dihydrobromide [ No CAS ]
[ 720720-96-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: hydrogen bromide; sodium nitrite / water / 3 h / 10 - 25 °C 2.1: triethylamine / toluene / 25 - 35 °C 3.1: lithium hydroxide monohydrate / water / 25 - 30 °C 3.2: 0 - 5 °C
	Multi-step reaction with 4 steps 1.1: hydrogen bromide; sodium nitrite / water / 3 h / 10 - 25 °C 2.1: sodium dithionite / water; ethanol / 50 - 70 °C 3.1: triethylamine / toluene / 25 - 35 °C 4.1: lithium hydroxide monohydrate / water / 25 - 30 °C 4.2: 0 - 5 °C

Reference： [1]Current Patent Assignee: INNER MONGOLIA JINGDONG PHARMACEUTICAL; BEIJING SIHUAN KEBAO PHARMACEUTICAL - CN109942600, 2019, A
[2]Current Patent Assignee: INNER MONGOLIA JINGDONG PHARMACEUTICAL; BEIJING SIHUAN KEBAO PHARMACEUTICAL - CN109942600, 2019, A

40
[ 480452-36-6 ]
[ 720720-96-7 ]
[ 480449-70-5 ]

Yield	Reaction Conditions	Operation in experiment
103.2 g	Stage #1: carbamic acid, N-[(1R,2S,5S)-2-[[2-[(5-chloro-2-pyridinyl)amino]-2-oxoacetyl]amino]-5-[(dimethylamino)carbonyl]cyclohexyl]-1,1-dimethylethyl ester With methanesulfonic acid In acetonitrile at 20℃; for 2h; Stage #2: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In acetonitrile at 20℃; for 16h; Cooling with ice;	7 N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide (E) Reference Example 7 N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide (E) Methanesulfonic acid (66 ml) was added to a suspension of tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate (17) (95.1 g) in acetonitrile (1900 ml) at room temperature, and the mixture was stirred at this temperature for 2 hours. To the reaction solution, triethylamine (155 ml), 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (13a) (52.5 g), 1-hydroxybenzotriazole (33.0 g), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46.8 g) were added under ice cooling, and the mixture was stirred at room temperature for 16 hours. Triethylamine and water were added thereto, and the mixture was stirred for 1 hour under ice cooling. Then, the crystals were collected by filtration to obtain the title compound (E) (103.2 g). 1H-NMR (CDCl3) δ: 1.60-1.98 (3H, m), 2.00-2.16 (3H, m), 2.52 (3 H, s), 2.78-2.90 (3H, m), 2.92-2.98 (2H, m), 2.95 (3H, s), 3.06 (3H, s), 3.69 (1H, d, J=15.4 Hz), 3.75 (1H, d, J=15.4 Hz), 4.07-4.15 (1H, m), 4.66-4.72 (1H, m), 7.40 (1H, dd, J=8.8, 0.6 Hz), 7.68 (1H, dd, J=8.8, 2.4 Hz), 8.03 (1H, d, J=7.8 Hz), 8.16 (1H, dd, J=8.8, 0.6 Hz), 8.30 (1H, dd, J=2.4, 0.6 Hz), 9.72 (1 H, s). MS (ESI) m/z: 548 (M+H)+.

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - US2013/144061, 2013, A1 Location in patent: Paragraph 0260; 0261; 0262; 0263

41
[ 720720-96-7 ]
edoxaban [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With methanesulfonic acid; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In water; acetonitrile	R.10 N1-(5-Chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide (X) (the production method described in the pamphlet of International Publication No. WO 2007/032498) Reference Example 10 N1-(5-Chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide (X) (the production method described in the pamphlet of International Publication No. WO 2007/032498) Methanesulfonic acid (66 ml) was added to a suspension of tert-butyl[(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate (A-9) (95.1 g) in acetonitrile (1900 ml) at room temperature, and the mixture was stirred at this temperature for 2 hours. To the reaction solution, triethylamine (155 ml), 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (52.5 g), 1-hydroxybenzotriazole (33.0 g), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46.8 g) were added under ice cooling, and the mixture was stirred at room temperature for 16 hours. Triethylamine and water were added thereto, and the mixture was stirred for 1 hour under ice cooling. Then, crystals were collected by filtration to obtain the title compound (X) (103.2 g).
	Multi-step reaction with 2 steps 1.1: triethylamine / dichloromethane / 0.17 h / 25 °C 1.2: 7 h / 25 °C 2.1: triethylamine / 24 h / 25 °C
	Multi-step reaction with 2 steps 1.1: triethylamine; pyridine / dichloromethane / 3 h / -15 - -10 °C / Inert atmosphere 2.1: dichloromethane / 0.5 h 2.2: 2 h / -15 - -10 °C

	Multi-step reaction with 2 steps 1.1: picoline; triethylamine / dichloromethane; N,N-dimethyl acetamide / 2 h / -40 - -35 °C / Inert atmosphere 2.1: triethylamine / dichloromethane / 0.5 h / -40 - -35 °C 2.2: 1 h / -40 - -35 °C
	Multi-step reaction with 2 steps 1: triethylamine; triphenylphosphine / dichloromethane / 5 h / 0 - 10 °C / Inert atmosphere 2: triethylamine / dichloromethane; isopropyl alcohol; water / 2 h / 0 - 10 °C

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - US2016/16974, 2016, A1
[2]Current Patent Assignee: JILIN YATAI (GROUP) CO., LTD. - CN107641131, 2018, A
[3]Current Patent Assignee: ZHUHAI HAIRUIDE NEW MATERIAL TECH; ZHUHAI HAIRUIDE NEW MATERIALS TECH - CN111763222, 2020, A
[4]Current Patent Assignee: ZHUHAI HAIRUIDE NEW MATERIAL TECH; ZHUHAI HAIRUIDE NEW MATERIALS TECH - CN111763222, 2020, A
[5]Current Patent Assignee: ZHUHAI HAIRUIDE NEW MATERIAL TECH - CN111848647, 2020, A

42
[ 852291-42-0 ]
[ 1864-94-4 ]
5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloric acid salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86.5%		5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (1-c-hc1) To a 100 mL autoclave, compound (1-br-ts) (5.0 g, 12.34 mmol), Pd(OAc)2 (2.8 mg, 0.0123 mmol), and xantphos (14.3 mg, 0.0247 mmol) were added. In a glove box under a current of nitrogen, a solution containing <strong>[1864-94-4]phenyl formate</strong> (2.26 g, 18.50 mmol) and Et3N (5.1 mL, 36.99 mmol) in degassed Me3CN (20 mL: the degassing was carried out by repeated reduction in pressure and purging with nitrogen three times) was added to the reaction mixture. After sealing, the mixture was stirred at 60 C. for 39 hours. After cooling of the reaction solution, toluene (50 mL) was added thereto, and the mixture was washed with 1% NaOH (50 mL) and 20% saline (25 mL) and concentrated into 10 mL under reduced pressure. To the residue, THF (20 mL), H2O (2 mL), and LiOH.H2O (1.04 g, 2.0 equiv) were added, and the mixture was stirred at room temperature for 2 hours. To the reaction solution, c-HCl (3.86 g, 3.5 eq.) and MeOH (50 mL) were added, and the slurry was stirred at room temperature for 1 hour and then under ice cooling for 1 hour and filtered. The crystals obtained were washed with MeOH (10 mL) of 0 to 5 C. and dried under reduced pressure to obtain the title compound (2.51 g, 86.5%) as white crystals. 1H-NMR (500 Hz, DMSO-d6) delta: 4.63-4.55 (m, 2H), 3.62-3.57 (m, 2H), 3.23-3.14 (m, 2H), 2.94 (s, 3H).

Reference： [1]Patent: US2017/50983,2017,A1 .Location in patent: Paragraph 0197; 0198; 0199; 0200

43
[ 852291-42-0 ]
[ 124-38-9 ]
[ 720720-96-7 ]

Yield	Reaction Conditions	Operation in experiment
21.2 g	Stage #1: 2-bromo-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine p-toluenesulfonate With sodium hydroxide In water at 20℃; for 0.5h; Stage #2: With n-butyllithium In tetrahydrofuran; hexane at -30℃; for 1h; Inert atmosphere; Stage #3: carbon dioxide Further stages;	6 Reference Example 6 5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (1-c-hc1) (method described in International Patent Publication No. WO 2005/047296) 5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (1-c-hc1) (method described in International Patent Publication No. WO 2005/047296) Compound (1-br-ts) (40.00 g) and a 1 N aqueous NaOH solution (200 mL) were mixed at room temperature and stirred for 30 minutes, followed by extraction with toluene twice (400 mL*2). The extracts were washed with 5% saline (200 mL) and then concentrated into 80 mL under reduced pressure at an external temperature of 50° C. or lower (solution weight after concentration: 91.03 g). A sample for moisture content measurement was collected from the concentrate (solution weight after sampling: 87.68 g). The moisture content of the sampled concentrate was measured using a Karl Fischer moisture titrator and consequently was 0.0231% (weight ratio). The concentrate after the sampling was dissolved in anhydrous THF (231 mL), and the atmosphere in the flask containing the solution was converted to an argon atmosphere. The solution was cooled to an internal temperature of -30° C. or lower. Then, while the internal temperature was kept at -30° C. or lower, n-butyllithium (1.59 mol/L solution in n-hexane, 61.7 mL) was added dropwise thereto. The mixture was further stirred at the same temperature as above for 1 hour. While the internal temperature was kept at -30° C. or lower, CO2 was absorbed to the reaction mixture. The reaction mixture was further stirred for 1 hour under a CO2 atmosphere. The internal temperature was raised to 15° C. Then, the deposited solid was dissolved by the addition of MeOH (193 mL). While the internal temperature was kept at 20° C. or lower, concentrated hydrochloric acid (19.3 mL) was added dropwise to the reaction mixture. The mixture was cooled to an internal temperature of 10° C. or lower and then stirred at the same temperature as above for 1 hour. The deposited crystals were filtered, washed with MeOH (58 mL), and then dried under reduced pressure at room temperature to obtain the title compound (21.20 g). 1H-NMR (D2O) δ ppm: 4.82-4.88 (d, 1H, J=16.0 Hz), 4.51-4.57 (d, 1H, J=16.0 Hz), 3.88-3.96 (m, 1H), 3.60-3.70 (m, 1H), 3.22-3.33 (m, 2H), 3.15 (s, 3H). MS(EI) m/z: 198 (M)+

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - US2017/50983, 2017, A1 Location in patent: Paragraph 0160; 0161; 0162; 0163; 0164; 0165; 0166-0172

44
[ 720720-96-7 ]
2-methyl-2-hexanyl [(1S,2R,4S)-2-amino-4-(dimethylcarbamoyl)cyclohexyl]carbamate [ No CAS ]
2-methylhexan-2-yl {(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.11 g	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In acetonitrile at 20 - 25℃; for 0.2h;	25 Example 25 Preparation of 2-methylhexan-2-yl {(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}carbamate (Formula (9-A) Wherein R²=2-methyl-2-hexanyl or Formula (9-A2)) Example 25 Preparation of 2-methylhexan-2-yl {(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}carbamate (Formula (9-A) Wherein R2=2-methyl-2-hexanyl or Formula (9-A2)) To a suspension of 2-methyl-2-hexanyl(1S,2R,5R))-2-amino-4-[(dimethylamino) carbonyl)] cyclohexylcarbamate (1.0 g, ca. 90% purity by 1HNMR, 2.8 mmol), 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloric acid salt (1.0 g, 4.26 mmol), N-(3-dimethylaminopropyl)-W-ethylcarbodiimide hydrochloride (850 mg, 4.43 mmol) and 1-hydroxybenzotriazole (100 mg, 0.74 mmol) in acetonitrile (5 mL), was added triethylamine (1.4 mL, 9.66 mmol). The reaction mixture was stirred at room temperature for about 20 hours. Following completion of the reaction (TLC), solvent was evaporated in vacuo and the residue was dissolved in dichloromethane (30 mL). The solution was washed twice with saturated aqueous sodium bicarbonate solution (15 mL), and the aqueous layer was extracted with dichloromethane (10 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography over silica gel (2*18 cm), using 30% to 50% methanol-ethylacetate mixture, to afford 2-methylhexan-2-yl {(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}carbamate (1.11 g, 78% yield) as a solid. 1H-NMR (CDCl3, 300 MHz) δ: 0.88 (3H, t, J=6.5 Hz), 1.13-1.28 (4H, m), 1.46 (6H, broad s), 1.46-1.56 (1H, m), 1.69-1.97 (6H, m), 2.06-2.10 (2H, m), 2.52 (3H, s), 2.69-2.81 (1H, m), 2.83-2.85 (2H, m), 2.88 (3H, m), 2.88-2.95 (1H, m), 2.96 (3H, m), 3.69-3.77 (3H, m), 4.57-4.61 (1H, m), 4.89 (1H, m), 7.25-7.29 (1H, m).

Reference： [1]Current Patent Assignee: APOTEX INC - US2018/179226, 2018, A1 Location in patent: Paragraph 0324; 0325; 0326

45
[ 720720-96-7 ]
2-(trimethylsilyl)ethyl [(1S,2R,4S)-2-amino-4-(dimethylcarbamoyl)cyclohexyl]carbamate [ No CAS ]
2-(trimethylsilyl)ethyl {(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20 - 25℃; for 17h;	28 Example 28 Preparation of 2-(trimethylsilyl)ethyl {(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}carbamate (Formula (9-A) Wherein R²=2-trimethylsilylethyl) or Formula (9-A3) Example 28 Preparation of 2-(trimethylsilyl)ethyl {(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}carbamate (Formula (9-A) Wherein R2=2-trimethylsilylethyl) or Formula (9-A3) A suspension of 2-(trimethylsilyl)ethyl [(1S,2R,4S)-2-amino-4-(dimethylcarbamoyl)cyclohexyl]carbamate (0.77 g, 2.34 mmol), 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloric acid salt (0.66 g, 2.80 mmol), EDC-HCl (0.58 g, 3.04 mm), hydroxybenzotriazole (0.32 g, 2.34 mmol), dichloromethane (6 mL), and triethylamine (0.71 g, 7.02 mmol) was stirred at room temperature for 17 hours. Following the completion of the reaction, the thin suspension was washed with a saturated aqueous sodium bicarbonate solution (23 mL). The organic phase was then washed with a saturated aqueous sodium chloride solution (3 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo at about 35° C. to dryness to yield 1.06 g of a yellow solid. To the flask containing the yellow solid was added acetonitrile (2.3 mL) to form a thin suspension which was stirred at room temperature for 1 hour. The suspension was diluted with methyl tert-butyl ether (0.8 mL) and cooled to about 0° C. for 3.5 hours. The product was then collected by filtration, washed with methyl tert-butyl ether (21.5 mL), and dried in vacuo at room temperature to afford 2-(trimethylsilyl)ethyl {(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}carbamate (0.45 g, 38% yield). 1H-NMR (CDCl3, 300 mHz) δ: 0.00 (9H, s), 0.94 (2H, t, J=8.1 Hz), 1.48 (1H, apparent dq, J=4.3 Hz, 12.8 Hz), 1.61-2.19 (6H, m), 2.51 (3H, s), 2.65-2.79 (1H, m), 2.80-2.88 (2H, m), 2.91 (4H, s), 2.99 (3H, s), 3.70 (1H, s), 3.79 (2H, broad s), 4.11 (2H, t, J=8.1 Hz), 4.57 (1H, apparent dd, J=3.7 Hz, 8.1 Hz), 5.10 (1H, s), 7.28 (1H, d, J=8.6 Hz).

Reference： [1]Current Patent Assignee: APOTEX INC - US2018/179226, 2018, A1 Location in patent: Paragraph 0333; 0334; 0335

46
[ 720720-96-7 ]
1-methylcyclohexyl {(1S,2R,4S)-2-amino-4-[(dimethylamino) carbonyl]cyclohexyl}carbamate [ No CAS ]
1-methylcyclohexyl {(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20 - 25℃; for 0.2h;	33 Example 33 Preparation of 1-methylcyclohexyl {(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}carbamate (Formula (9-A) Example 33 Preparation of 1-methylcyclohexyl {(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}carbamate (Formula (9-A) Wherein R2=1-methylcyclohexyl or Formula (9-A4)) To a suspension of 1-methyl cyclohexyl {(1S,2R,4S)-2-amino-4-[(dimethylamino) carbonyl] cyclohexyl}carbamate (6.5 g, ca. 97% purity by 1HNMR, 19.37 mmol), 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloric acid salt (5.46 g, 23.25 mmol), N-(3-dimethylaminopropyl)-WV-ethylcarbodiimide hydrochloride (4.83 g, 25.18 mmol) and 1-hydroxybenzotriazole (2.62 g, 19.37 mmol) in dichloromethane (42 mL), was added triethylamine (8.1 mL, 58.11 mmol). The reaction mixture was stirred at room temperature for about 20 hours. Following completion of the reaction (TLC), the reaction mixture was washed twice with saturated aqueous sodium bicarbonate solution (25 mL), and then with brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to dryness to yield a foam (11.08 g). The crude product was dissolved in acetonitrile (20 mL) and immediately a thick suspension was formed. Methyl t-butyl ether (5 mL) was added and the suspension was cooled in an ice bath and stirred for 1 hour. The solids were filtered and washed with cold (about 0° C.) methyl t-butyl ether (8 mL). The damp cake was dried in vacuo at room temperature for 18 hours to afford 1-methylcyclohexyl {(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}carbamate as a crystalline solid (7.28 g, 74% yield; HPLC=99.9 area %). A second crop of 600 mg, 6% yield was obtained from acetonitrile (3 mL). 1H-NMR (CDCl3, 300 MHz) δ: 1.21-1.26 (1H, m), 1.35-1.59 (11H, m), 1.75-2.01 (3H, m), 2.06-2.10 (4H, m), 2.52 (3H, s), 2.69-2.88 (3H, m), 2.90 (3H, s), 2.90-2.94 (2H, m), 2.96 (3H, s), 3.0-3.78 (3H, m), 4.59-4.63 (1H, m), 4.96 (broad s, 1H), 7.33-7.35 (1H, m).

Reference： [1]Current Patent Assignee: APOTEX INC - US2018/179226, 2018, A1 Location in patent: Paragraph 0355; 0356; 0357

47
[ 720720-96-7 ]
tert-butyl-(3aRS,5SR,7aSR)-5-(dimethylcarbamoyl)-2,2-dioxooctahydro-1H-2,1,3-benzothiadiazole-1-carboxylate [ No CAS ]
tert-butyl {(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In acetonitrile at 20 - 25℃; for 0.14h;	22 Example 22 Preparation of tert-butyl {(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}carbamate (Formula (9-A) Wherein R²=t-butyl or Formula (9-A1)) Example 22 Preparation of tert-butyl {(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}carbamate (Formula (9-A) Wherein R2=t-butyl or Formula (9-A1)) To a suspension of racemic tert-butyl-(3aRS,5SR,7aSR)-5-(dimethylcarbamoyl)-2,2-dioxooctahydro-1H-2,1,3-benzothiadiazole-1-carboxylate (100 mg, 0.35 mmol), 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo [5,4-c]pyridine-2-carboxylic acid hydrochloric acid salt (100 mg, 0.42 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (85 mg, 0.42 mmol) and 1-hydroxybenzotriazole (10 mg, 0.07 mmol) in acetonitrile (2 mL), was added triethylamine (0.15 mL, 1.05 mmol). The reaction mixture was stirred at room temperature for about 14 hours. Following completion of the reaction (TLC), the solvent was evaporated in vacuo and the residue was dissolved in dichloromethane (15 mL). The solution was washed twice with saturated aqueous sodium bicarbonate solution (5 mL), and the organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to dryness to afford the crude product, racemic tert-butyl {(1 SR,2RS,4SR)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}carbamate as a foam (160 mg, 98% yield). 1H-NMR (CDCl3, 300 MHz) δ: 1.42 (9H, s), 1.69-2.09 (6H, m), 2.52 (3H, s), 2.71-2.97 (5H, m), 2.92 (3H, s), 3.01 (3H, s), 3.72-3.80 (3H, m), 4.57-4.61 (1H, m), 5.07 (1H, broad s), 7.35-7.38 (1H, m).

Reference： [1]Current Patent Assignee: APOTEX INC - US2018/179226, 2018, A1 Location in patent: Paragraph 0315; 0316; 0317

48
[ 720720-96-7 ]
tert-butyl-(3aRS,5SR,7aSR)-5-(dimethylcarbamoyl)-2,2-dioxooctahydro-1H-2,1,3-benzothiadiazole-1-carboxylate [ No CAS ]
N₁-(5-chloropyridin-2-yl)-N₂-{(1SR,2RS,4SR)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro [1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}ethanediamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; triethylamine / acetonitrile / 0.14 h / 20 - 25 °C 2.1: methanesulfonic acid / acetonitrile / 6 h / 20 - 25 °C 2.2: 11 h / 70 °C

Reference： [1]Current Patent Assignee: APOTEX INC - US2018/179226, 2018, A1

49
[ 720720-96-7 ]
[ 530-62-1 ]
C₁₁H₁₂N₄OS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloric acid salt With triethylamine In dichloromethane at 25℃; for 0.166667h; Stage #2: 1,1'-carbonyldiimidazole In dichloromethane at 25℃; for 7h;	2 Example 2 22.0 g of Compound C and 220 mL of dichloromethane were added to the reaction flask and stirred.Add 9.5 g of triethylamine,Stir at 25 ± 5 °C for 10 minutes.Add 16.7g CDI,Continue to stir at 25 ± 5 ° C for 7 hours.This system is System 1.39.4 g of Compound 1 and 800 mL of dichloromethane were added to another reaction flask.40.5 g of methanesulfonic acid was added dropwise.Stir at 10±5°C for 5 hours.This system is System 2.To the system 2, 42.7 g of triethylamine was added dropwise.After the addition is completed,System 2 is dropped into System 1,Stir at 25 ± 5 ° C for 24 hours.Add 1L of water to the system,The mixture was stirred for 15 minutes.The organic phase was dried over anhydrous magnesium sulfate.Concentrated under reduced pressure at 50 ° C to no fraction.The residue was added to 1 L of ethanol.Stir at reflux for 1 hour.Filter after cooling,The filter cake was dried to give compound 4, 38.2 g.The yield was 82.7% and the purity was 99.5%.

Reference： [1]Current Patent Assignee: JILIN YATAI (GROUP) CO., LTD. - CN107641131, 2018, A Location in patent: Paragraph 0032; 0033; 0034; 0035; 0038

50
[ 720720-96-7 ]
tert-butyl N-[(1S,2R,4S)-2-amino-4-(dimethylcarbamoyl)cyclohexyl]carbamate oxalate [ No CAS ]
[(1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[[(4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridine -2-yl)carbonyl]amino]cyclohexyl]carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: tert-butyl N-[(1S,2R,4S)-2-amino-4-(dimethylcarbamoyl)cyclohexyl]carbamate oxalate With potassium carbonate In dichloromethane; water at 5 - 15℃; Stage #2: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloric acid salt With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine at 0 - 25℃;	46 Example 46 Synthesis of [(1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[[(4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridine -2-yl)carbonyl]amino]cyclohexyl]carbamic acid tert-butyl ester Add 32g (85.24mmol) of 109E9-21 to the reaction flask. Add 160g of dichloromethane, Add 80g of water, Cool to 5 to 15 ° C, Slowly add a solution of 25 g (180.9 mmol) of anhydrous potassium carbonate and 100 g of water. Stirring and stirring, and standing still; The aqueous phase was extracted again with dichloromethane (80 g x 2); Combining the dichloromethane phase, adding anhydrous sodium sulfate and stirring and drying; Filtration, the filter residue was rinsed with dichloromethane, and the filtrate was collected; Add 22 g (217.4 mmol) of triethylamine to the filtrate, and cool to 0 to 5 ° C with stirring; Add 22g (93.74mmol) of 109C6-20, 14g (103.6mmol) HOBt, 22g (114.8mmol) EDCI.HCl; The temperature was returned to 20 to 25 ° C, and the reaction was stirred for about 16 to 20 hr. After the reaction is completed, Add 10g (98.82mmol) of triethylamine to the reaction system, and add 240g of water; Stir well and let stand for liquid separation; The aqueous phase was extracted again with dichloromethane (160 g x 2); The organic phases were combined and dried over anhydrous sodium sulfate; Filter and collect the filtrate. A 109T5-01/dichloromethane solution was obtained (subject to a theoretical amount of 39.69 g without further treatment).

Reference： [1]Current Patent Assignee: INNER MONGOLIA JINGDONG PHARMACEUTICAL; BEIJING SIHUAN KEBAO PHARMACEUTICAL - CN109942600, 2019, A Location in patent: Paragraph 0218-0220

51
[ 89580-42-7 ]
[ 720720-96-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: ethanol / 75 - 80 °C 2.1: hydrogen bromide; sodium nitrite / water / 3 h / 10 - 25 °C 3.1: triethylamine / toluene / 25 - 35 °C 4.1: lithium hydroxide monohydrate / water / 25 - 30 °C 4.2: 0 - 5 °C
	Multi-step reaction with 5 steps 1.1: ethanol / 75 - 80 °C 2.1: hydrogen bromide; sodium nitrite / water / 3 h / 10 - 25 °C 3.1: sodium dithionite / water; ethanol / 50 - 70 °C 4.1: triethylamine / toluene / 25 - 35 °C 5.1: lithium hydroxide monohydrate / water / 25 - 30 °C 5.2: 0 - 5 °C

Reference： [1]Current Patent Assignee: INNER MONGOLIA JINGDONG PHARMACEUTICAL; BEIJING SIHUAN KEBAO PHARMACEUTICAL - CN109942600, 2019, A
[2]Current Patent Assignee: INNER MONGOLIA JINGDONG PHARMACEUTICAL; BEIJING SIHUAN KEBAO PHARMACEUTICAL - CN109942600, 2019, A

52
[ 143150-92-9 ]
5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloric acid salt [ No CAS ]

Reference： [1]Patent: CN109942600,2019,A

53
[ 259809-24-0 ]
5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloric acid salt [ No CAS ]

Reference： [1]Patent: CN109942600,2019,A

54
2,2,2-trichloro-1-(4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridin-2-yl)ethanone [ No CAS ]
[ 720720-96-7 ]

Yield	Reaction Conditions	Operation in experiment
73 g	Stage #1: 2,2,2-trichloro-1-(4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridin-2-yl)ethanone With lithium hydroxide monohydrate In water at 25 - 30℃; Stage #2: With hydrogenchloride In ethanol; water at 0 - 5℃;	42; 43; 44 Example 42 Synthesis of 4,5,6,7-tetrahydro-5-methylthiazole [5,4-c]pyridin-2-carboxylate lithium salt Add 200g (667.6mmol) of 109C5-00 obtained in Example 41 to the reaction flask; Under stirring, the temperature control does not exceed 25 ° C. Adding a solution of 70 g (1.668 mol) of lithium hydroxide monohydrate and 420 g of water, The temperature was kept at 20 to 30 ° C, and the reaction was stirred overnight. After the reaction is completed, impurities (200 g × 3) are extracted by adding toluene, and the aqueous phase is retained; The aqueous phase is concentrated under reduced pressure to give a residue; Add 400g of absolute ethanol to the residue, stir and heat to 40 ~ 50 ° C, so that the material is completely dissolved; Ethanol is concentrated under reduced pressure to give a residue; 150 g of tetrahydrofuran was added to the residue, and the mixture was stirred and dispersed, and then concentrated to dryness under reduced vacuo. About 142g (Theoretical amount: 136.3g). Yield: >100% (containing part of lithium hydroxide). 96 g (451.3 mmol) obtained in Example 42 was added to the reaction flask. According to the theoretical yield conversion) 109C6-10; Add 400g of absolute ethanol, Stir under stirring, heat to 40 ~ 50 ° C, so that the material is completely dissolved; Add 12g of activated carbon, stir and discolor for about 20min, heat filter, filter residue with anhydrous ethanol, and collect the filtrate; The collected filtrate was cooled to 0 to 5 ° C, the temperature control was not more than 5 ° C, and 96 g (-947.9 mmol) of 36% concentrated hydrochloric acid was added dropwise; The crystallization was carried out at 0 to 5 ° C for 2 to 3 hr. Filtration, the filter cake was rinsed with absolute ethanol, and the solid was collected; Dry to obtain about 73 g of 109 C6-20 dry product (theoretical amount: 105.6 g, converted according to the theoretical yield). Yield: 69.1%.

Reference： [1]Current Patent Assignee: INNER MONGOLIA JINGDONG PHARMACEUTICAL; BEIJING SIHUAN KEBAO PHARMACEUTICAL - CN109942600, 2019, A Location in patent: Paragraph 0206-0211

55
[ 720720-96-7 ]
N-[(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl]-4,5,6,7-tetrahydro-5-methylthiazolo[5 ,4-c]pyridin-2-carboxamide dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: potassium carbonate / water; dichloromethane / 5 - 15 °C 1.2: 0 - 25 °C 2.1: hydrogenchloride / water; dichloromethane / 20 - 30 °C

Reference： [1]Current Patent Assignee: INNER MONGOLIA JINGDONG PHARMACEUTICAL; BEIJING SIHUAN KEBAO PHARMACEUTICAL - CN109942600, 2019, A

56
[ 720720-96-7 ]
[ 480449-71-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: potassium carbonate / water; dichloromethane / 5 - 15 °C 1.2: 0 - 25 °C 2.1: hydrogenchloride / water; dichloromethane / 20 - 30 °C 3.1: triethylamine / acetonitrile / 40 - 75 °C 3.2: 75 - 80 °C

Reference： [1]Current Patent Assignee: INNER MONGOLIA JINGDONG PHARMACEUTICAL; BEIJING SIHUAN KEBAO PHARMACEUTICAL - CN109942600, 2019, A

57
[ 720720-96-7 ]
[ 98-59-9 ]
C₁₅H₁₆N₂O₄S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; triethylamine In dichloromethane at -15 - -10℃; for 3h; Inert atmosphere;	4-5 Example 5 Under the protection of nitrogen, put 23.47g (0.1mol) in a 500ml three-necked flask5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylate hydrochloride,250ml dichloromethane, 10ml pyridine. Adjust the temperature to -10 to -15°C, and slowly add 20.24g (0.2mol) triethylamine dropwise. Control the temperature from -10 to -15°C, and add p-toluenesulfonyl chloride 19.06 (0.1 mol) all at once. The temperature is controlled at -10 to -15°C and the reaction is stirred for 3 hours to obtain solution A, which is kept at -10 to -15°C for later use. Solution A needs to be freshly prepared and stored at low temperature.

Reference： [1]Current Patent Assignee: ZHUHAI HAIRUIDE NEW MATERIAL TECH; ZHUHAI HAIRUIDE NEW MATERIALS TECH - CN111763222, 2020, A Location in patent: Paragraph 0109-0111; 0116-0118

58
[ 720720-96-7 ]
[ 75-36-5 ]
C₁₀H₁₂N₂O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With picoline; triethylamine In dichloromethane; N,N-dimethyl acetamide at -15 - -10℃; for 2h; Inert atmosphere;	6 Example 6 Under the protection of nitrogen, in a 500ml three-necked bottle,Put in 23.47g (0.1mol)5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid Hydrochloride,250ml dichloromethane, 20ml N,N-dimethylacetamide, 2ml 4-picoline. Adjust the temperature to -10 to -15°C, and slowly add 20.24g (0.2mol) triethylamine dropwise. Control the temperature from -10 to -15°C, and add 8.0 g (0.1 mol) of acetyl chloride dropwise. After the addition is completed, the temperature is controlled at -10 to -15°C and stirred for 2 hours to obtain solution A, which is kept at -10 to -15°C for later use. Solution A needs to be freshly prepared and stored at low temperature.

Reference： [1]Current Patent Assignee: ZHUHAI HAIRUIDE NEW MATERIAL TECH; ZHUHAI HAIRUIDE NEW MATERIALS TECH - CN111763222, 2020, A Location in patent: Paragraph 0123-0124

59
[ 720720-96-7 ]
[ 3282-30-2 ]
C₁₃H₁₈N₂O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With picoline; triethylamine In dichloromethane; N,N-dimethyl acetamide at -40 - -35℃; for 2h; Inert atmosphere;	1-3; 7-8 Example 2 Under the protection of nitrogen, put 23.47g (0.1mol) in a 500ml three-necked flask5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylate hydrochloride,250ml dichloromethane, 20ml N,N-dimethylacetamide, 2ml 4-picoline. Adjust the temperature to -35 to -40°C, and slowly add 20.24g (0.2mol) triethylamine dropwise. Control the temperature from -35 to -40°C, and add 12.06g (0.1mol) of pivaloyl chloride dropwise. After the dripping is completed, the temperature is controlled at -35 to -40°C and the reaction is stirred for 2 hours to obtain solution A, which is kept at -35 to -40°C for later use. Solution A needs to be freshly prepared and stored at low temperature.

Reference： [1]Current Patent Assignee: ZHUHAI HAIRUIDE NEW MATERIAL TECH; ZHUHAI HAIRUIDE NEW MATERIALS TECH - CN111763222, 2020, A Location in patent: Paragraph 0087-0089; 0095-0097; 0102-0104; 0129-0131; 0136

60
[ 720720-96-7 ]
[ 120-78-5 ]
5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-thiocarboxylic acid S-benzothiazol-2-yl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88.09%	With triethylamine; triphenylphosphine In dichloromethane at 0 - 10℃; for 5h; Inert atmosphere;	1-2 Under the protection of nitrogen, put 300ml of dichloromethane into a 500ml three-necked flask,23.47g (0.1mol) 5- methyl-4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine-2-carboxylic acid hydrochloride (1-b),Adjust the temperature to 010.10.12g (0.1mol) triethylamine was slowly added dropwise with stirring to fully dissolve the solid.Add 33.25g (0.1mol) Dibenzothiazyl disulfide (DM) to the reaction flask,Adjust the temperature to 0-5°C, and add 26.23g (0.1mol) of triphenylphosphine in 4 portions.Control the temperature at 05 and react for 5 hours.After the reaction is over, the reaction system is filtered and the filter cake is collected.The filter cake was beaten and washed with 100 ml of dichloromethane. The slurry was filtered again, and the filter cake was rinsed with 100ml of dichloromethane,40-45 vacuum drying obtains compound (I) (its chemical name is 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-thiocarboxylic acid S-benzothiazol-2-yl ester)30.61 g of light yellow solid powder, with a yield of 88.09%.

Reference： [1]Current Patent Assignee: ZHUHAI HAIRUIDE NEW MATERIAL TECH - CN111848647, 2020, A Location in patent: Paragraph 0078-0084

61
[ 720720-96-7 ]
ethanediamide, N¹-[(1S,2R,4S)-2-amino-4-[(dimethylamino)carbonyl]cyclohexyl]-N²-(5-chloro-2-pyridinyl)-, dihydrochloride [ No CAS ]
[ 104-15-4 ]
[ 480449-71-6 ]

Yield	Reaction Conditions	Operation in experiment
100 g	Stage #1: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloric acid salt; ethanediamide, N¹-[(1S,2R,4S)-2-amino-4-[(dimethylamino)carbonyl]cyclohexyl]-N²-(5-chloro-2-pyridinyl)-, dihydrochloride With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In 1,4-dioxane at 0 - 0.3℃; for 0.18h; Stage #2: toluene-4-sulfonic acid In water; dimethyl sulfoxide at 0.25 - 0.7℃; for 0.01h;	3A-3D Example 3A: Preparation of Ethanediamide, V^/- 5-chloro-2-pyridinyl)-V²-f(lS, 2R,4S) -4- [(dimethylamino)carbonyl] -2- [ [(4, 5, 6, 7 -tetrahydro-5-methy lthiazolo[5,4,c]pyridin-2-yl)carbonyl]amino]cylohexyl]-,4-methylbenzenesulfonate, hydrate (1:1:1) (compound of formula I) The compound of formula II-A (50.0g) was added to 1, 4-dioxane and the obtained reaction mass was cooled to about 0°C to 5°C. Triethyl amine (50.0g), 5-Methyl-4, 5, 6, 7-tetrahydrothiazolo [5,4-c]pyridine-2-carboxylic acid hydrochloride (compound of formula III, 34.0g), 1 -hydroxybenzotriazole (HOBt, 20.0g) and l-ethyl-3-(3- dimethylaminopropyl) carbodiimide hydrochloride (EDC.HC1, 35. Og) was added to the reaction mass. The temperature of the reaction mass was then raised to about 25°C to 30°C and the reaction mass was stirred for about 18 hours. Water was added to the reaction mass and the reaction mass was cooled to about 0°C to 5°C. The reaction mass was then filtered to obtain the product (compound of formula I-A). The product obtained was washed with water. The obtained product was then added to dimethyl sulfoxide-water mixture and p-toluene sulfonic acid (17.33g) was added to it and the reaction mass was stirred at about 25 °C to 30°C. The reaction mass was then heated to about 60°C to 70°C to get clear solution. The obtained clear solution was stirred for about 60 min and filtered hot to remove undissolved impurities. The filtrate was then cooled to about 25°C to 30°C and further to about 0°C to 5°C and maintained at same temperature for about 60 min. The reaction mass was then filtered to obtain the product. The product obtained dried at about 50°C to 60°C for about 12 hours to get compound of formula I. Yield: lOO.Og, HPLC purity: 99.25%

Reference： [1]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2021/1728, 2021, A1 Location in patent: Page/Page column 14-17

62
[ 720720-96-7 ]
C₁₆H₂₂ClN₅O₃*C₇H₈O₃S [ No CAS ]
[ 480449-71-6 ]

Yield	Reaction Conditions	Operation in experiment
9.2 g	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran; water; acetonitrile for 15h;	1.S11 S11. Add 15.3g of compound (XII) to 153ml of tetrahydrofuran, add 153ml of water, stir, adjust pH=8, separate, dry and concentrate the organic phase, add acetonitrile, 12.6g of triethylamine, 7.7g of HOBT, and 10.9g of EDCI to 153ml , 10.6g 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride for 15h, concentrate the reaction solution, add 153ml dichloromethane, divide Liquid, dry, concentrate, add absolute ethanol, stir and crystallize at 2030 for 23h, filter with suction, The filter cake was air-dried at 45-55 °C to obtain 12.1g, 3.9g toluenesulfonic acid monohydrate was added, 44ml absolute ethanol was added, the temperature was raised to 80, activated carbon was decolorized, hot suction filtration, the temperature was reduced to 20-30°C, and suction filtration After drying, 12.8 g of solid was obtained, which was recrystallized twice and dried at 45-55°C to obtain 9.2 g of compound (XIII), i.e. idoxaban tosylate (1S,2R,4S).

Reference： [1]Current Patent Assignee: NANJING ANHONG YUANHUA PHARMACEUTICAL INDUSTRY INVESTMENT PARTNERSHIP (LIMITED PARTNERSHIP) - CN112321613, 2021, A Location in patent: Paragraph 0071; 0093-0100

63
[ 720720-96-7 ]
C₁₆H₂₂ClN₅O₃*C₇H₈O₃S [ No CAS ]
N₁-(5-chloropyridin-2-yl)-N₂-{(1R,2R,4S)-4-(dimethylaminocarbonyl)-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carboxamido]cyclohexyl}oxalamide p-toluenesulfonic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.8 g	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran; water; acetonitrile for 15h;	2.S11 S11. Add 4.5g of compound (XII) to 153ml of tetrahydrofuran, add 153ml of water, stir, adjust pH=8, separate the liquids, dry and concentrate the organic phase, 153ml add acetonitrile, 3.8g triethylamine, 2.3g HOBT, 3.3g EDCI, 3.2g 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride was reacted for 15h, the reaction solution was concentrated, 153ml of dichloromethane was added, and the liquids were separated , Dry, concentrate, add absolute ethanol, Stir and crystallize at 20-30°C for 23h, filter with suction, and air-dried the filter cake at 45-55°C to obtain 3.6g, Add 1.2g of toluenesulfonic acid monohydrate, add 44ml of absolute ethanol, increase the temperature to 80°C, decolorize with activated carbon, heat suction filter, The temperature was lowered to 20-30°C, suction filtration was dried to obtain 3.8 g of solid, which was recrystallized twice, and dried at 45-55°C to obtain 2.8 g of compound (XIII). That is, the epimer of Idoxaban tosylate (1R,2R,4S),

Reference： [1]Current Patent Assignee: NANJING ANHONG YUANHUA PHARMACEUTICAL INDUSTRY INVESTMENT PARTNERSHIP (LIMITED PARTNERSHIP) - CN112321613, 2021, A Location in patent: Paragraph 0101; 0114-0121

64
[ 720720-96-7 ]
C₁₆H₂₂ClN₅O₃*C₇H₈O₃S [ No CAS ]
N₁-(5-chloropyridin-2-yl)-N₂-{(1R,2S,4R)-4-(dimethylaminocarbonyl)-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carboxamido]cyclohexyl}oxalamide p-toluenesulfonic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
9.2 g	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran; water; acetonitrile for 15h;	3.S11 S11. Add 15.3g of compound (XII) to 153ml of tetrahydrofuran, add 153ml of water, stir, adjust pH=8, separate, dry and concentrate the organic phase, add acetonitrile, 12.6g of triethylamine, 7.7g of HOBT, and 10.9g of EDCI to 153ml , 10.6g 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride reacted for 15h, concentrated the reaction solution, added 153ml dichloromethane, divided Liquid, dry, concentrate, add absolute ethanol, stir and crystallize at 20-30°C for 23h, filter with suction, The filter cake was air-dried at 45-55°C to obtain 12.1g, 3.9g toluenesulfonic acid monohydrate was added, 44ml absolute ethanol was added, the temperature was raised to 80, activated carbon was decolorized, hot suction filtration, the temperature was reduced to 2030, and suction filtration After drying, 12.8 g of solid was obtained, which was recrystallized twice and dried at 45-55°C to obtain 9.2 g of compound (XIII), which is the enantiomer of idoxaban tosylate (1R,2S,4R),

Reference： [1]Current Patent Assignee: NANJING ANHONG YUANHUA PHARMACEUTICAL INDUSTRY INVESTMENT PARTNERSHIP (LIMITED PARTNERSHIP) - CN112321613, 2021, A Location in patent: Paragraph 0122; 0145-0152

65
[ 720720-96-7 ]
C₁₆H₂₂ClN₅O₃*C₇H₈O₃S [ No CAS ]
N₁-(5-chloropyridin-2-yl)-N₂-{(1S,2S,4R)-4-(dimethylaminocarbonyl)-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carboxamido]cyclohexyl}oxalamide p-toluenesulfonic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.8 g	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran; water; acetonitrile for 15h;	4.S11 S11. Add 4.5g of compound (XII) to 153ml of tetrahydrofuran, add 153ml of water, stir, adjust pH=8, separate, dry and concentrate the organic phase, add 153ml of acetonitrile, 3.8g of triethylamine, 2.3g of HOBT, and 3.3g of EDCI , 3.2g 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride reacted for 48h, concentrated the reaction solution, added 153ml dichloromethane, divided Liquid, dry, concentrate, add absolute ethanol, stir and crystallize at 20-30°C for 23h, filter with suction, The filter cake was air-dried at 45-55°C to obtain 3.6g, HPLC93%, 1.2g toluenesulfonic acid monohydrate was added, 44ml absolute ethanol was added, the temperature was raised to 80°C, activated carbon was decolorized, hot suction filtration, and the temperature was lowered to 20-30 °C, Suction filtration and drying to obtain 3.8 g of solid, recrystallize twice, and dry at 45-55°C to obtain 2.8 g of compound (XIII), i.e. Idoxaban tosylate epimer (1S, 2S, 4R).

Reference： [1]Current Patent Assignee: NANJING ANHONG YUANHUA PHARMACEUTICAL INDUSTRY INVESTMENT PARTNERSHIP (LIMITED PARTNERSHIP) - CN112321613, 2021, A Location in patent: Paragraph 0153; 0155-0173

66
[ 480452-37-7 ]
[ 720720-96-7 ]
[ 104-15-4 ]
[ 480449-71-6 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: N¹-[(1S,2R,4S)-2-amino-4-[(dimethylamino)carbonyl]cyclohexyl]-N²-(5-chloro-2-pyridyl)ethanediamide With methanesulfonic acid In dichloromethane at 20℃; for 2h; Stage #2: With triethylamine In dichloromethane at 20℃; for 0.5h; Stage #3: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride; toluene-4-sulfonic acid Further stages;	2 To N-(5-chloropiperidin-2-yl)-N'-[(1S,2R,4S)-4-(N,N-dimethylformamido)-2-(amino-tert-butoxy Carbonyl)cyclohexyl]oxalamide, that is, the compound of formula (II) (15g) in dichloromethane (179g) was added with methanesulfonic acid (15.4g), stirred at room temperature for 2h, triethylamine (17.8 g) was added to the reaction solution, stirred at room temperature for 0.5 h, and 4,5,6,7-tetrahydro-5-methyl-thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride was added in sequence the compound of formula (III) (8.3g), 1-Hydroxybenzotriazole (5.5g) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.7g), stirred at room temperature for 2h, After the reaction was completed, water (110 g) was added to wash, and the organic phase was collected and divided into 3 parts. Add 4 times equivalent of formic acid (7.4g), acetic acid (9.6g) and propionic acid (11.8g) respectively, stir well, concentrate under reduced pressure, add p-toluenesulfonic acid monohydrate (6.1g) and dissolve in ethanol (91g) , at room temperature for 1 h, Precipitate to dryness under reduced pressure, add 85% ethanol aqueous solution (220 g) to the residue, keep at 65±5 °C for 2 h, Naturally lowered to room temperature, continued stirring for 5h, filtered, and dried by blasting to constant weight to obtain a white solid of formula (I), and its purity was detected respectively.

Reference： [1]Current Patent Assignee: JIANGSU VCARE PHARMATECH CO LTD - CN114349770, 2022, A Location in patent: Paragraph 0063-0069

67
[ 480452-37-7 ]
[ 720720-96-7 ]
[ 64-19-7 ]
C₂₄H₃₀ClN₇O₄S*3C₂H₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79.9%	Stage #1: N¹-[(1S,2R,4S)-2-amino-4-[(dimethylamino)carbonyl]cyclohexyl]-N²-(5-chloro-2-pyridyl)ethanediamide With methanesulfonic acid In dichloromethane at 20℃; for 3h; Stage #2: With triethylamine In dichloromethane at 20℃; for 0.5h; Stage #3: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride; glacial acetic acid Further stages;	3 Example 3 To N-(5-chloropiperidin-2-yl)-N'-[(1S,2R,4S)-4-(N,N-dimethylformamido)-2-(amino-tert-butoxy Carbonyl)cyclohexyl]oxalamide, that is, to a solution of the compound of formula (II) (33.2g) in dichloromethane (396g) was added methanesulfonic acid (34.1g), Stir at room temperature for 3h, add triethylamine (39.5g) to the reaction solution, stir at room temperature for 0.5h, 4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride, that is, the compound of formula (III) (18.3g), was successively added. 1-Hydroxybenzotriazole (12.1g) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (17.1g), stirred at room temperature for 6h, after the reaction was completed, water (220 g) was added to wash three times, acetic acid (174 g) was added and stirred evenly, and the dichloromethane was removed by concentration under reduced pressure. Methyl tert-butyl ether (182 g) was added to the residue, a solid was precipitated, aged at room temperature overnight, filtered, and dried by blowing to constant weight to obtain 51.7 g of formula (V) with a yield of 79.9%.

Reference： [1]Current Patent Assignee: JIANGSU VCARE PHARMATECH CO LTD - CN114349770, 2022, A Location in patent: Paragraph 0072-0073

68
[ 720720-96-7 ]
[ 2770688-74-7 ]
[ 480449-70-5 ]

Yield	Reaction Conditions	Operation in experiment
99%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In acetonitrile at 30℃; for 7h;	3: Preparation of compound (VI) In the 5000mL there-necked flask, add 1799mL acetonitrile, compound (IV) 150g, 111mL triethylamine,Compound (V) 75.5g, (1-ethyl-3(3-dimethylpropylamine) carbodiimide (EDCI) 79.3g, 1-hydroxybenzotriazole (HOBT) 52g, react at 30°C for 7h, HPLC monitored that no raw material remained, filtered with suction, washed the filter cake with 375 mL×3 times of acetonitrile, and dried under reduced pressure at 55° C. to obtain an off-white solid with a molar yield of 99%.
84%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In acetonitrile at 20℃; for 16h;	2.3-2.4 Example 2.3 Preparation of Edoxaban 2.0 g (3.25 mmol, assay 91.7%, 1.0 eq) of CPDC·2MSA·2.5H2O obtained in Example 2.2 was diluted and stirred with ACN 20mL (10v/v). 1.14 mL (8.13 mmol, 2.5 eq) of triethylamine was added. MTPC 0.84g (3.58mmol, 1.1eq), EDCI 0.75g (3.90mmol, 1.2eq), HOBt 0.053g (0.39mmol, 0.12eq) was added and stirred at room temperature for 16 hours. After 0.95 mL (6.8 mmol, 2.0eq) of triethylamine was added, 20 mL of purified water was added, followed by stirring at 10°C or less for 1 hour. The solid product was filtered and washed with 20 mL of purified water. The filtrate was dried at 45° C. to obtain 1.50 g (2.73 mmol, 84% yield) of a white solid compound.
84 %	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In acetonitrile at 20℃;	2.3-2.4 Example 2.3 Preparation of Edoxaban 2.0 g (3.25 mmol, assay 91.7%, 1.0 eq) of CPDC·2MSA·2.5H2O obtained in Example 2.2 was diluted and stirred with ACN 20mL (10v/v). 1.14 mL (8.13 mmol, 2.5 eq) of triethylamine was added. MTPC 0.84g (3.58mmol, 1.1eq), EDCI 0.75g (3.90mmol, 1.2eq), HOBt 0.053g (0.39mmol, 0.12eq) was added and stirred at room temperature for 16 hours. After 0.95 mL (6.8 mmol, 2.0eq) of triethylamine was added, 20 mL of purified water was added, followed by stirring at 10°C or less for 1 hour. The solid product was filtered and washed with 20 mL of purified water. The filtrate was dried at 45° C. to obtain 1.50 g (2.73 mmol, 84% yield) of a white solid compound.

84 %

With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In acetonitrile at 20℃;

2.3-2.4 Example 2.3 Preparation of Edoxaban 2.0 g (3.25 mmol, assay 91.7%, 1.0 eq) of CPDC·2MSA·2.5H2O obtained in Example 2.2 was diluted and stirred with ACN 20mL (10v/v). 1.14 mL (8.13 mmol, 2.5 eq) of triethylamine was added. MTPC 0.84g (3.58mmol, 1.1eq), EDCI 0.75g (3.90mmol, 1.2eq), HOBt 0.053g (0.39mmol, 0.12eq) was added and stirred at room temperature for 16 hours. After 0.95 mL (6.8 mmol, 2.0eq) of triethylamine was added, 20 mL of purified water was added, followed by stirring at 10°C or less for 1 hour. The solid product was filtered and washed with 20 mL of purified water. The filtrate was dried at 45° C. to obtain 1.50 g (2.73 mmol, 84% yield) of a white solid compound.

Reference： [1]Current Patent Assignee: HARBIN PHARMACEUTICAL GROUP CO., LTD. - CN114736218, 2022, A Location in patent: Paragraph 0038-0039; 0050-0052
[2]Current Patent Assignee: BORYUNG PHARM CO.,LTD.; BORYUNG - WO2022/103239, 2022, A1 Location in patent: Paragraph 48; 154; 165-170
[3]Current Patent Assignee: BORYUNG PHARM CO.,LTD.; BORYUNG - WO2022/103239, 2022, A1 Location in patent: Paragraph 48; 154; 165-170
[4]Current Patent Assignee: BORYUNG PHARM CO.,LTD.; BORYUNG - WO2022/103239, 2022, A1 Location in patent: Paragraph 48; 154; 165-170

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	720720-96-7	MDL No. :	MFCD25542379
Formula :	C₈H₁₁ClN₂O₂S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ZWIYEBIMFPQYDI-UHFFFAOYSA-N
M.W :	234.70	Pubchem ID :	11149031
Synonyms :

Num. heavy atoms :	14
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.5
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	60.28
TPSA :	81.67 Å²

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-8.24 cm/s

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	-0.72
Log Po/w (WLOGP) :	1.1
Log Po/w (MLOGP) :	0.17
Log Po/w (SILICOS-IT) :	1.81
Consensus Log Po/w :	0.47

[ CAS No. 720720-96-7 ] {[proInfo.proName]}

Quality Control of [ 720720-96-7 ]

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Physicochemical Properties

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[ 720720-96-7 ] Synthesis Path-Downstream 1~68

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[ 720720-96-7 ]

Carboxylic Acids

Related Parent Nucleus of
[ 720720-96-7 ]

Other Aromatic Heterocycles

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

Log S (ESOL) :	-1.04
Solubility :	21.4 mg/ml ; 0.0912 mol/l
Class :	Very soluble
Log S (Ali) :	-0.52
Solubility :	71.0 mg/ml ; 0.303 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.23
Solubility :	13.9 mg/ml ; 0.0594 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.81

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

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
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
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

[ CAS No. 720720-96-7 ] {[proInfo.proName]}

Quality Control of [ 720720-96-7 ]

Related Doc. of [ 720720-96-7 ]

Product Details of [ 720720-96-7 ]

Calculated chemistry of [ 720720-96-7 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 720720-96-7 ]

Application In Synthesis of [ 720720-96-7 ]

[ 720720-96-7 ] Synthesis Path-Downstream 1~68

Related Functional Groups of [ 720720-96-7 ]

Carboxylic Acids

Related Parent Nucleus of [ 720720-96-7 ]

Other Aromatic Heterocycles

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 720720-96-7 ]

Related Parent Nucleus of
[ 720720-96-7 ]