10177-24-9|5-Chloro-2-(chloromethyl)pyridine| Ambeed

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Quality Control of [ 10177-24-9 ] Purity: 95% SDS Specification

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Product Details of [ 10177-24-9 ]

CAS No. :	10177-24-9
Formula :	C₆H₅Cl₂N
M.W :	162.02
SMILES Code :	ClCC1=NC=C(Cl)C=C1
MDL No. :	MFCD10697588
InChI Key :	JTTKXEIHKDSIRC-UHFFFAOYSA-N
Pubchem ID :	14517151

Safety of [ 10177-24-9 ]

GHS Pictogram:
Signal Word:	Danger
Hazard Statements:	H302-H314
Precautionary Statements:	P261-P280-P305+P351+P338-P310
Class:	8
UN#:	1760
Packing Group:	Ⅲ

Application In Synthesis of [ 10177-24-9 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 10177-24-9 ]

[ 10177-24-9 ] Synthesis Path-Downstream 1~35

1
[ 209526-98-7 ]
[ 10177-24-9 ]

Yield	Reaction Conditions	Operation in experiment
89%	With thionyl chloride;N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 4h;	5-chloro-2(chloromethyl)pyridine; [00372] To a 0 C solution of 5-chloropicolinic acid (3.00 g, 19.0 mmol) indichloromethane (20 mL) was added sulfurous dichloride (2.78 mL, 38.1 mmol), after which the reaction was warmed to room temperature and stirred at that temperature for 4 hours. The reaction was then concentrated to dryness, then reconstituted in dichloromethane (5 mL). Methanol (10 mL) was added to the reaction mixture, and the reaction was allowed to stir at room temperature for 12 hours, after which it was then diluted with water, extracted with ethyl acetate (3 x 50 mL), washed with water, then washed with saturated sodium bicarbonate solution, dried (magnesium sulfate), filtered and concentrated. Purification was achieved by silica gel chromatography (ISCO 80g) using 0 to 80% ethyl acetate in hexanes to afford methyl 5-chloropicolinate was as an off-white solid (2.75 g, 15.2 mmol, 80% yield ).[00373] To a 0 C solution of methyl 5-chloropicolinate (2.70 g, 15.7 mmol) in methanol (50 mL) was added sodium borohydride (1.79 g, 47.2 mmol), after which the reaction was warmed to room temperature and stirred at that temperature for 4 hours. The reaction mixture was then concentrated to a residue which was treated with 1M hydrochloric acid solution (15 mL), extracted with ethyl acetate (3 x 100 mL), washed with water, then washed with saturated sodium bicarbonate solution, dried (magnesium sulfate), filtered and concentrated. Purification was achieved by silica gel chromatography (ISCO 80g) using 0 to 60% ethyl acetate in hexanes to afford (5-chloropyridin-2-yl)methanol was as an off-white solid (2.15 g, 14.9 mmol, 95% yield).[00374] To a 0 C solution of (5-chloropyridin-2-yl)methanol (2.10 g, 14.6 mmol) in dichloromethane (10 mL) was added sulfurous dichloride (1.60 mL, 21.9 mmol) followed by N,N-dimethylformamide (50 μ), after which the reaction was warmed to room temperature and stirred at that temperature for 4 hours. The reaction mixture was then concentrated to a residue which was reconstituted in water (15 mL), ethyl acetate (15 mL), and saturated sodium bicarbonate solution (15 mL). The organic layers were separated and washed with saturated sodium chloride solution, dried (magnesium sulfate), filtered and concentrated. Purification was achieved by silica gel chromatography (ISCO 40g) using 0 to 50% ethyl acetate in hexanes to afford 5-chloro-2(chloromethyl)pyridine as an light brown oil (2.11 g, 13.0 mmol, 89% yield).
78%		To a mixture of (5-chloro-pyridine-2-yl)-methanol (706 mg, 4.92 mmol) described in Manufacturing Example 63-1-1 and dichloromethane (70 mL) was added thionyl chloride (539 μL, 7.38 mmol), which was stirred for 1 hour at room temperature. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (620.0 mg, 78%). 1H-NMR Spectrum (CDCl3) δ (ppm): 4.66 (2H, s), 7.45 (1H, d, J=8.0 Hz), 7.71 (1H, dd, J=2.8, 8.0 Hz), 8.54 (1H, d, J=2.8 Hz).
	With thionyl chloride;N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 1h;	C. Preparation of 5-chloro-2-(chloromethyl)pyridine To a stirring solution of (5-chloropyridin-2-yl)methanol (840 mg, 5.8 mmol) in dichloromethane (10 mL) at 0 C. under argon was added thionyl chloride (0.64 mL, 8.77 mmol), followed by 4 drops of DMF (white precipitate formed). The reaction mixture was allowed to stir at room temperature for 1 h. The reaction mixture was concentrated to a white solid. The solid thus obtained was cooled in an ice bath before EtOAc (20 mL) and water (20 mL) and then 10% aqueous Na2CO3 solution (20 mL) were added. The organic layer was separated, washed with saturated aqueous NaCl, dried (MgSO4), filtered and concentrated to obtain 840 mg of the title compound as a light brown gum. HPLC/MS: retention time=2.392 min, [M+H]30 =162.

With thionyl chloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 1h;

C. Preparation of 5-chloro-2-(chloromethyl)pyridine To a stirring solution of (5-chloropyridin-2-yl)methanol (840 mg, 5.8 mmol) in dichloromethane (10 mL) at 0 C. under argon was added thionyl chloride (0.64 mL, 8.77 mmol), followed by 4 drops of DMF (white precipitate formed). The reaction mixture was allowed to stir at room temperature for 1 h. The reaction mixture was concentrated to a white solid. The solid thus obtained was cooled in an ice bath before EtOAc (20 mL) and water (20 mL) and then 10% aqueous Na2CO3 solution (20 mL) were added. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated to obtain 840 mg of the title compound as a light brown gum. HPLC/MS: retention time=2.392 min, [M+H]+=162.

References: [1]Patent: WO2012/88469,2012,A1 .Location in patent: Page/Page column 152-153.
[2]Patent: US2007/105904,2007,A1 .Location in patent: Page/Page column 115.
[3]Journal of Medicinal Chemistry,1992,vol. 35,p. 438 - 450.
[4]Patent: US2006/287341,2006,A1 .Location in patent: Page/Page column 48.
[5]Journal of Medicinal Chemistry,2011,vol. 54,p. 8013 - 8029.
[6]Patent: US2007/4772,2007,A1 .Location in patent: Page/Page column 83.
[7]Journal of Medicinal Chemistry,2021,vol. 64,p. 12738 - 12760.

2
[ 10177-24-9 ]
[ 90070-09-0 ]
[ 122307-50-0 ]

References: [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 438 - 450.

3
[ 10177-24-9 ]
[ 399559-99-0 ]
5-[1-[3-(6-Chloro-pyridin-3-ylmethyl)-2-oxo-imidazolidin-1-yl]-meth-(Z)-ylidene]-amino}-3-methylsulfanyl-1-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester [ No CAS ]

References: [1]Journal of Heterocyclic Chemistry,2001,vol. 38,p. 1035 - 1038.

4
[ 31181-73-4 ]
[ 10177-24-9 ]

References: [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 438 - 450.

5
[ 10177-24-9 ]
[ 122307-51-1 ]

References: [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 438 - 450.

6
[ 52313-58-3 ]
[ 10177-24-9 ]

References: [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 438 - 450.

7
[ 133258-71-6 ]
[ 10177-24-9 ]
1-(2-chloro-5-pyridylmethyl)-5-methyl-2-cyanoimino-hexahydro-1,3,5-triazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetonitrile; for 10h;Heating / reflux;	Example 3 A mixture consisting of 5-methyl-2-cyanoimino-hexahydro-1,3,5-triazine (6.0 g), 5-chloro-2-chloromethylpyridine (7.0 g), anhydrous potassium carbonate (6.6 g) and acetonitrile (80 ml) was heated under reflux for a period of 10 hours.. After having been allowed to cool, the separated solid substance was filtered off from the mixture and the filtrate was concentrated under reduced pressure, followed by purification of the resulting residue by column chromatography (eluant: ethanol chloroform=1:20) to obtain the desired 1-(2-chloro-5-pyridylmethyl)-5-neath-2-cyanoimino-hexahydro-1,3,5-triazine (7.5 g) having a melting point in the range of from 198 to 202 C.

References: [1]Patent: US6344453,2002,B1 .Location in patent: Page column 8-9.

8
[ 133258-71-6 ]
[ 10177-24-9 ]
1-(2-chloro-5-pyridylmethyl)-5-methyl-2-cyanoimino-hexahydro-1,3,5-triazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetonitrile;	EXAMPLE 3 STR14 A mixture consisting of 5-methyl-2-cyanoimino-hexahydro-1,3,5-triazine (6.0 g), 5-chloro-2-chloromethylpyridine (7.0 g), anhydrous potassium carbonate (6.6 g) and acetonitrile (80 ml) was heated under reflux for a period of 10 hours. After having been allowed to cool, the separated solid substance was filtered off from the mixture and the filtrate was concentrated under reduced pressure, followed by purification of the resulting residue by column chromatography (eluant:ethanol:chloroform=1:20) to obtain the desired 1-(2-chloro-5-pyridylmethyl)-5-methyl-2-cyanoimino-hexahydro-1,3,5-triazine (7.5 g) having a melting point in the range of from 198 to 202 C.

References: [1]Patent: US5032589,1991,A .

9
C₁₅H₁₂N₃O₂^(1-)*Na⁽¹⁺⁾ [ No CAS ]
[ 10177-24-9 ]
3-(3-(4-(5-Chloro-pyridin-2-ylmethoxy)-benzyl)-isoxazol-5-yl)-pyridin-2-ylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide; at 60℃; for 1h;	Tetrahydrofuran (3 mL) and a 5 N aqueous sodium hydroxide solution (22.4 μL, 0.11 mmol) were added to 4-(5-(2-amino-pyridine-3-yl)-isoxazole-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 5-1-1, which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was then concentrated under a reduced pressure to obtain a white solid. An N,N-dimethylformamide (1 mL) solution of 5-chloro-2-chloromethyl-pyridine (20 mg, 0.12 mmol) described in Manufacturing Example 63-1-2 was added to a suspension of this solid and N,N-dimethylformamide (1 mL), and stirred for 1 hour at 60 C. This mixture was cooled to room temperature and partitioned into water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (41.1 mg, 93%). 1H-NMR Spectrum (DMSO-d6) δ (ppm): 3.97 (2H, s), 5.17 (2H, s), 6.26 (2H, brs), 6.68-6.72 (1H, m), 6.80 (1H, s), 6.99 (2H, d, J=8.4 Hz), 7.26 (2H, d, J=8.8 Hz), 7.55 (1H, d, J=8.4 Hz), 7.87 (1H, dd, J=1.6, 8.0 Hz), 7.97 (1H, dd, J=2.4, 8.4 Hz), 8.09 (1H, d, J=1.6, 4.8 Hz), 8.64 (1H, d, J=2.4 Hz).

References: [1]Patent: US2007/105904,2007,A1 .Location in patent: Page/Page column 115.

10
4-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)phenol [ No CAS ]
[ 10177-24-9 ]
3-(3-(4-(5-Chloro-pyridin-2-ylmethoxy)-benzyl)-isoxazol-5-yl)-pyridin-2-ylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%		Reference Example 63 3-(3-(4-(5-Chloro-pyridin-2-ylmethoxy)-benzyl)-isoxazol-5-yl)-pyridin-2-ylamine; Tetrahydrofuran (3 mL) and a 5 N aqueous sodium hydroxide solution (22.4 μL, 0.11 mmol) were added to 4-(5-(2-amino-pyridine-3-yl)-isoxazole-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 5-1-1, which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was then concentrated under a reduced pressure to obtain a white solid. An N,N-dimethylformamide (1 mL) solution of 5-chloro-2-chloromethyl-pyridine (20 mg, 0.12 mmol) described in Manufacturing Example 63-1-2 was added to a suspension of this solid and N,N-dimethylformamide (1 mL), and stirred for 1 hour at 60 C. This mixture was cooled to room temperature and partitioned into water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (41.1 mg, 93%).1H-NMR Spectrum (DMSO-d6) δ (ppm): 3.97 (2H, s), 5.17 (2H, s), 6.26 (2H, brs), 6.68-6.72 (1H, m), 6.80 (1H, s), 6.99 (2H, d, J=8.4 Hz), 7.26 (2H, d, J=8.8 Hz), 7.55 (1H, d, J=8.4 Hz), 7.87 (1H, dd, J=1.6, 8.0 Hz), 7.97 (1H, dd, J=2.4, 8.4 Hz), 8.09 (1H, d, J=1.6, 4.8 Hz), 8.64 (1H, d, J=2.4 Hz).

References: [1]Patent: US2009/82403,2009,A1 .Location in patent: Page/Page column 114-115.

11
4-((5-(2,6-diaminopyridin-3-yl)isoxazol-3-yl)methyl)phenol [ No CAS ]
[ 10177-24-9 ]
[ 936341-01-4 ]

Yield	Reaction Conditions	Operation in experiment
89%		Reference Example 122 3-(3-(4-(5-Chloro-pyridin-2-ylmethoxy)-benzyl)-isoxazol-5-yl)-pyridin-2,6-diamine; To a tetrahydrofuran (3 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 18-1-1 was added a 5 N sodium hydroxide aqueous solution (21.2 μL, 0.11 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. An N,N-dimethylformamide (1 mL) solution of 5-chloro-2-chloromethyl-pyridine (18.9 mg, 0.12 mmol) described in manufacturing Example 63-1-2 was added to a suspension of this solid in N,N-dimethylformamide (1 mL), which was stirred for 1 hour at 60 C. The reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (38.4 mg, 89%).1H-NMR Spectrum (DMSO-d6) δ (ppm): 3.88 (2H, s), 5.16 (2H, s), 5.79 (2H, brs), 5.82 (1H, d, J=8.4 Hz), 6.11 (2H, brs), 6.34 (1H, s), 6.97 (2H, d, J=8.8 Hz), 7.23 (2H, d, J=8.8 Hz), 7.51 (1H, d, J=8.4 Hz), 7.54 (1H, d, J=8.4 Hz), 7.96 (1H, dd, J=2.4, 8.4 Hz), 8.63 (1H, d, J=2.8 Hz).

References: [1]Patent: US2009/82403,2009,A1 .Location in patent: Page/Page column 170.

12
potassium cyanide [ No CAS ]
[ 10177-24-9 ]
[ 185315-51-9 ]

Yield	Reaction Conditions	Operation in experiment
69%	In ethanol; at 100℃; for 1h;	To the solution of <strong>[10177-24-9]5-chloro-2-(chloromethyl)pyridine</strong> (CGenetech) (0.99 g, 6.1 mmol) in ethanol (8 mL) and H2O (6 mL) was added KCN (1.03 g, 15.9 mmol). The reaction mixture was heated at 100 C. for 1 h. The mixture was cooled, and extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:3) to give (5-chloro-pyridin-2-yl)acetonitrile as a yellow oil (0.64 g, 69%).
57%	In ethanol; water; at 100℃; for 1h;	Step 2-1. preparation of 2-(5-chloropyridin-2-v0acetonitrile: Into a 250-mL round- bottom flask, were placed <strong>[10177-24-9]5-chloro-2-(chloromethyl)pyridine</strong> (8.0 g, 49 mmol), potassium cyanide (4.5 g, 69 mmol), EtOH (80 mL) and LbO (60 mL). The resulting mixture was stirred at 100 C for 1 h and cooled to room temperature. The reaction was quenched with water (200 mL) and then extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 : 1) to afford the title compound (4.3 g, 57%) as a yellow oil. LCMS (M+H)+= 153.2.

References: [1]Patent: US2011/118283,2011,A1 .Location in patent: Page/Page column 10.
[2]Patent: WO2021/126693,2021,A1 .Location in patent: Paragraph 00346.

13
[ 86873-60-1 ]
[ 10177-24-9 ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 8013 - 8029.
[2]Patent: WO2012/88469,2012,A1 .

14
[ 132308-19-1 ]
[ 10177-24-9 ]

References: [1]Patent: WO2012/88469,2012,A1 .
[2]Patent: US2007/4772,2007,A1 .

15
[ 128073-03-0 ]
[ 10177-24-9 ]

References: [1]Patent: WO2012/88469,2012,A1 .

16
[ 10177-24-9 ]
1-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrazolo[3,4-b]azepin-4(1H)-one [ No CAS ]
[ 1448437-81-7 ]

Yield	Reaction Conditions	Operation in experiment
42%		To a solution of l-(4-methoxybenzyl)-5, 6,7,8- tetrahydropyrazolo[3,4-]azepin-4(lH)-one (0.50 g, 1.84 mmol) in THF (9.2 mL) were added consecutively 15-crown-5 (0.61 g, 2.76 mmol), NaOtBu (0.35 g, 3.69 mmol) and after stirring for 10 min, <strong>[10177-24-9]5-chloro-2-(chloromethyl)pyridine</strong> (0.33 g, 2.00 mmol). The mixture was stirred at reflux for 4 h. The reaction was quenched with water and the mixture was diluted with EtOAc. The separated aqueous layer was extracted with EtOAc. The organic layers were combined, dried over Na2S04, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel using cyclohexane/EtOAc (100:0 to 30:70) as eluent to afford the title compound (304 mg, 42%) as a yellow oil. UPLC-MS (Ml): RT = 0.98 min; MS m/z ES+= 397-399.
42%		8((5-Chloropyridin-2-yl)methyl)-1-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrazolo[3,4-b]azepin-4(1H)-one According to Scheme 3, Step 1: To a solution of 1-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrazolo[3,4-b]azepin-4(1H)-one (0.50 g, 1.84 mmol) in THF (9.2 mL) were added consecutively 15-crown-5 (0.61 g, 2.76 mmol), NaOtBu (0.35 g, 3.69 mmol) and after stirring for 10 min, <strong>[10177-24-9]5-chloro-2-(chloromethyl)pyridine</strong> (0.33 g, 2.00 mmol). The mixture was stirred at reflux for 4 h. The reaction was quenched with water and the mixture was diluted with EtOAc. The separated aqueous layer was extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel using cyclohexane/EtOAc (100:0 to 30:70) as eluent to afford the title compound (304 mg, 42%) as a yellow oil. UPLC-MS (M1): RT=0.98 min; MS m/z ES+=397-399.

References: [1]Patent: WO2013/107862,2013,A1 .Location in patent: Page/Page column 63.
[2]Patent: US2014/349994,2014,A1 .Location in patent: Paragraph 0556; 0557.

17
[ 10177-24-9 ]
3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione [ No CAS ]
7-((5-chloropyridin-2-yl)methyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetra-(n-butyl)ammonium iodide; potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 8h;	Step 1 7-((5-chloropyridin-2-yl)methyl)-3-methyl- 1 -(3-(tetrahydro-2H-pyran-2-yloxy)propyl)- -(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-lH-purine-2,6(3H,7H)-dione To a solution of 3-methyl-l-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(2-(3- (trifluoromethoxy)phenoxy)ethoxy)-lH-purine-2,6(3H,7H)-dione (60 mg, 0.14 mmol, intermediate 17) in DMF (5 mL) was added <strong>[10177-24-9]5-chloro-2-(chloromethyl)pyridine</strong> (33 mg, 0.20 mmol), potassium carbonate (37 mg, 0.27 mmol) and TBAI (2 mg, 0.02 mmol). The reaction was heated at 50 C for 8 h. The mixture was cooled and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give crude product, which was used without purification. LCMS MH+-THP 570.

References: [1]Patent: WO2014/143799,2014,A2 .Location in patent: Page/Page column 487; 488.

18
[ 10177-24-9 ]
C₁₇H₂₁N₃O₃S₂ [ No CAS ]
(S)-5-((5-chloropyridin-2-yl)methyl)-4-isopropyl-N-(4-(methylsulfonyl)benzyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazole-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3.90 mg	With sodium hydrogencarbonate; In acetonitrile; at 20℃;	(S)-5-((5-chloropyridin-2-yl)methyl)-4-isopropyl-N-(4-(methylsulfonyl)benzyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazole-2-carboxamide (1-Ki) [00252] To a solution of VI-5 (which is deprotected VI-3) (crude 36 mg, 0.076 mmol) in CH3CN (4 mL) was added <strong>[10177-24-9]5-chloro-2-(chloromethyl)pyridine</strong> (15 mg, 0.091 mmol) and NaHCO3 (32 mg, 0.38 mmol). The mixture was stirred at rt overnight. The mixture was concentrated under reduced pressure. Water (10 mL) and ethyl acetate (10 mL) were added to the mixture. After partition, the aqueous layer was extracted with ethyl acetate (3 X 10 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC with petroleum ether / ethyl acetate 1/1 to afford 1-Ki (3.90 mg, 10%) as a white solid. LC-MS tR = 0.744 mm in 5-95AB_1.5 mm chromatography (Welch MK RP18e 25-2 mm), MS (ESI) m/z 504.9 [M + H]. ‘H NMR (CD3OD): (58.48 (d, J = 2.4 Hz, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.74 (dd, J = 2.4, 8.4 Hz, 1H), 7.63 (t, J = 8.4 Hz, 3H), 4.67 (s, 2H), 4.33 (dd, J= 4.0, 10.8 Hz, 1H), 4.24 (d, J= 15.2 Hz, 1H), 4.07-4.01 (m, 2H), 3.84 (dd, J = 2.4, 14.8 Hz, 1H), 3.10 (s, 3H), 2.08-2.03 (m, 1H), 1.13 (d, J= 6.8 Hz, 3H), 0.92 (d, J= 6.8 Hz, 3H). Isomer SFC tR = 4.209 mm in 8 mm chromatography (Column: AS-H; Method Name: AS-H_S_5_5_40_3ML_8MIN_15C, ee = 100%).

References: [1]Patent: WO2014/179564,2014,A1 .Location in patent: Paragraph 00251; 00252.

19
[ 10177-24-9 ]
N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide [ No CAS ]
1-((5-chloropyridin-2-yl)methyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
13 mg	With caesium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 40℃;	A mixture of N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Intermediate 13), (110 mg), <strong>[10177-24-9]5-chloro-2-(chloromethyl)pyridine</strong> (65 mg), sodium iodide (1 mg) and cesium carbonate (302 mg) in DMF (3.6 mL) was stirred at 40 C. overnight. The reaction mixture was diluted with EtOAc and filtered and the filtrate was reduced in vacuo. The residue was purified by column chromatography to give the desired compound (13 mg). LCMS: m/z 399.62 [M+H]+. 1H NMR (400 MHz, CDCl3) ppm 1.23-1.65 (m, 4H) 1.70-1.92 (m, 2H) 2.09-2.29 (m, 2H) 2.49 (s, 3H) 3.57 (td, J=9.8, 4.5 Hz, 1H) 3.76-4.03 (m, 1H) 5.53-5.71 (m, 2H) 6.59 (d, J=8.3 Hz, 1H) 6.90 (d, J=4.9 Hz, 1H) 7.54 (dd, J=8.4, 2.3 Hz, 1H) 8.06 (s, 1H) 8.33 (d, J=4.7 Hz, 1H) 8.54 (d, J=2.2 Hz, 1H) 9.25 (d, J=6.6 Hz, 1H)
13 mg	With caesium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 40℃;	A mixture of N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Intermediate 13), (110 mg), <strong>[10177-24-9]5-chloro-2-(chloromethyl)pyridine</strong> (65 mg), sodium iodide (1 mg) and cesium carbonate (302 mg) in DMF (3.6 mL) was stirred at 40 C. overnight. The reaction mixture was diluted with EtOAc and filtered and the filtrate was reduced in vacuo. The residue was purified by column chromatography to give the desired compound (13 mg). LCMS: m/z 399.62 [M+H]+. 1H NMR (400 MHz, CDCl3) ppm 1.23-1.65 (m, 4H) 1.70-1.92 (m, 2H) 2.09-2.29 (m, 2H) 2.49 (s, 3H) 3.57 (td, J=9.8, 4.5 Hz, 1H) 3.76-4.03 (m, 1H) 5.53-5.71 (m, 2H) 6.59 (d, J=8.3 Hz, 1H) 6.90 (d, J=4.9 Hz, 1H) 7.54 (dd, J=8.4, 2.3 Hz, 1H) 8.06 (s, 1H) 8.33 (d, J=4.7 Hz, 1H) 8.54 (d, J=2.2 Hz, 1H) 9.25 (d, J=6.6 Hz, 1H)

References: [1]Patent: US2015/94328,2015,A1 .Location in patent: Paragraph 0820-0822.
[2]Patent: WO2015/49574,2015,A1 .Location in patent: Page/Page column 102; 103.

20
[ 10177-24-9 ]
(S)-N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide [ No CAS ]
C₂₅H₂₇ClN₄O₃S*(x)ClH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31%	With potassium carbonate; In acetonitrile; at 20℃; for 2h;	[00128] (S)-N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo [3 ,4-b]pyridine- 3-carboxamide (11.3 mg, 29.2 jimol), 4-(trifluoromethyl)benzyl bromide (10.5 mg, 43.9 jimol), and potassium carbonate (8.1 mg, 58.6 imol) were stuffed together in CH3CN (1 mL) at rt for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (5 mL) and extracted with EtOAc (10 mL). The organic phase was separated, washed with brine (5 mL), dried over anhydrous Mg504, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 50% EtOAc in hexanes, gradient to 100%), then further purified by reverse-phase HPLC to yield 5.2 mg of the HC1 salt of (S)-N(4-(ethylsulfonyl)benzyl)-7-isopropyl-6- (4-(trifluoromethyl)benzyl)-6,7-dihydro-5H-pyrrolo [3,4- b]pyridine-3-carboxamide (1, 3 1%)

References: [1]Patent: WO2015/116904,2015,A1 .Location in patent: Paragraph 0128; 00174.

21
[ 10177-24-9 ]
[ 149-30-4 ]
C₁₃H₉ClN₂S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Preparation of 2-(((5-chloropyridin-2-yl)methyl)sulfonyl)benzo[d]thiazole (5A). Aqueous sodium hydroxide (2M, 5 mL, 10 mmol) was added to a suspension of 2- mercaptobenzothiazole (1.60 g, 9.57 mmol) in MeOH (25 mL), and the mixture was stirred for 2-3 minutes, during which time the suspension became a solution. 5-Chloro-2- (chloromethyl)pyridine (1.17 mL, 9.57 mmol) was added via syringe, and the mixture was stirred for 5 hours at room temperature. The solvent was then removed in vacuo and the resulting solid was dissolved in 1 : 1 DCM/water. The layers were separated and the aqueous layer was extracted with DCM. The combined extracts were dried over anhydrous MgSO/i, filtered, and concentrated in vacuo to give an oil. The oil was purified by silica gel chromatography (0 to 50% EtO Ac/heptane gradient) to give a white solid that was taken directly to the next step. The solid prepared above was then dissolved in DCM (20 mL) and 3- chloroperbenzoic acid (5.36 g, 23.9 mmol) was added. This mixture was stirred for 3 hours at room temperature, during which time a suspension formed. Saturated aqueous sodium bicarbonate solution was added and the mixture was then stirred until the suspension dissipated. The biphasic mixture was separated and the aqueous layer was extracted with DCM (2x). The combined extracts were dried over anhydrous MgSO/i, filtered, and concentrated in vacuo to give a white solid that was purified by silica gel chromatography (0 to 50% EtO Ac/heptane gradient) to give 2-(((5-chloropyridin-2- yl)methyl)sulfonyl)benzo[d]thiazole (5A) (0.83 g, 27% yield for 2 steps) as a white solid. MS m/z = 325 [M+H]+.

References: [1]Patent: WO2017/24180,2017,A1 .Location in patent: Page/Page column 109-110.

22
[ 10177-24-9 ]
[ 130783-02-7 ]
2-(((3,5-bis(trifluoromethyl)phenyl)thio)methyl)-5-chloropyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Preparation of 2-(((3,5-bis(trifluoromethyl)phenyl)thio)methyl)-5-chloropyridine (6A). Sodium hydroxide (2N, aqueous, 5.46 mL, 10.9 mmol) was added dropwise to a solution of 3,5-bis-trifluoromethyl benzenethiol (1.83 mL, 10.9 mmol) in MeOH (3 mL). This mixture was stirred for 5 minutes and then <strong>[10177-24-9]5-chloro-2-(chloromethyl)pyridine</strong> (1.77 g, 10.9 mmol) was added as a solution in MeOH (10 mL). This mixture was stirred 2 hours at r.t. and then it was concentrated to about half volume in vacuo. EtOAc and half saturated aqueous ammonium chloride were added, the layers were separated, and the aqueous layer was extracted with EtOAc (lx). The combined organic layers were dried over anhydrous MgSO/i, filtered, and concentrated in vacuo to give 2-(((3,5- bis(trifluoromethyl)phenyl)thio)methyl)-5-chloropyridine (6A) as a solid (4.1 g, 101% yield). MS m/z = 372 [M+H]+. NMR (400 MHz, CDC13) δ ppm 8.49 (d, J=2.35 Hz, 1 H) 7.75 (s, 2 H) 7.61 - 7.65 (m, 2 H) 7.32 (d, J=8.08 Hz, 1 H) 4.32 (s, 2 H).
4.1 g		Sodium hydroxide (5.4 mL of 2 N solution, 10.8 mmol) was added dropwise to a solution of 3,5-bis-trifluoromethyl benzenethiol ( Sigma- Aldrich Chemical Company, Inc., St. Louis, MO, USA) (1.8 mL, 11 mmol) in MeOH (3 mL) at room temperature. This mixture was stirred for 5 minutes and then <strong>[10177-24-9]5-chloro-2-(chloromethyl)pyridine</strong> (Sigma-Aldrich Chemical Company, Inc., St. Louis, MO, USA) (1.8 g, 11 mmol) was added as a solution in MeOH (10 mL). This mixture was stirred for 2 hours at room temperature and then it was concentrated to about half volume in vacuo. EtOAc and half saturated aqueous ammonium chloride were added, the layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO/t, filtered, and concentrated in vacuo to give 2-(((3,5-bis(trifluoromethyl)phenyl)thio)methyl)-5- chloropyridine (8a) (4.1 g, 101% yield) as a solid. MS m/z = 372 [M+H]+. NMR (400 MHz, CDC13) δ ppm 8.49 (d, J = 2.35 Hz, 1H) 7.75 (s, 2H) 7.61 - 7.65 (m, 2H) 7.32 (d, J = 8.08 Hz, 1H) 4.32 (s, 2H).
	With sodium hydroxide; In methanol; water; at 20℃; for 2h;	Sodium hydroxide (2 N, aqueous, 5.4 mL, 10.8 mmol) was added dropwise to a solution of 3,5-bis-trifluoromethyl benzenethiol (Sigma-Aldrich Chemical Company, Inc., St. Louis, MO, USA) (1.8 mL, 10.9 mmol) in MeOH (3 mL). This mixture was stirred for 5 min and then <strong>[10177-24-9]5-chloro-2-(chloromethyl)pyridine</strong> (Sigma-Aldrich Chemical Company, Inc., St. Louis, MO, USA) (1.77 g, 10.9 mmol) was added as a solution in MeOH (10 mL). This mixture was stirred for 2 h at RT and then it was concentrated to about half volume in vacuo. EtOAc and half saturated aqueous ammonium chloride were added, the layers were separated, and the aqueous layer was extracted with EtOAc (1 x). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give 2-(((3,5-bis(trifluoromethyl)phenyl)thio)methyl)-5-chloropyridine (33a) as a solid (4.1 g, 101% yield). MS m/z = 372 [M+H]+. 1H NMR (400 MHz, CDCl3) ^ ^ppm 8.49 (d, J = 2.35 Hz, 1 H) 7.75 (s, 2 H) 7.61 - 7.65 (m, 2 H) 7.32 (d, J = 8.08 Hz, 1 H) 4.32 (s, 2 H).

References: [1]Patent: WO2017/24180,2017,A1 .Location in patent: Page/Page column 111.
[2]Patent: WO2018/112081,2018,A1 .Location in patent: Page/Page column 53-54.
[3]Patent: WO2018/112094,2018,A1 .Location in patent: Page/Page column 124-125.

23
[ 10177-24-9 ]
(1S,5S,6S)-methyl 3-amino-5-(5-((Z)-2-(5-chloropyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate [ No CAS ]