[(1R,2R)-2-aminocyclohexyl]methanol

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 6-(trifluoromethyl)pyridine-3-sulfonyl chloride (190 mg, 0.78 mmol) in 2 mL dichloromethane was added dropwise to a solution of ((1R,2R)-2-aminocyclohexyl)methanol (100 mg, 0.78 mmol) and triethylamine (320 μL, 2.3 mmol) in 10 mL dichloromethane at 0° C. The reaction was stirred at 0° C. for 1 h, then concentrated and purified by flash chromatography on silica gel with 0 to 60% ethyl acetate in hexane to yield N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)-6-(trifluoromethyl)pyridine-3-sulfonamide (150 mg, 57%). 1H NMR (400 MHz, CDCl3) δ ppm 9.18 (d, J=2.01 Hz, 1H), 8.37 (dd, J=8.06, 1.76 Hz, 1H), 7.83 (d, J=8.31 Hz, 1H), 5.83 (d, J=6.80 Hz, 1H), 3.77 (ddd, J=11.21, 3.78, 3.65 Hz, 1H), 3.36 (dt, J=11.33, 5.67 Hz, 1H), 2.97-3.15 (m, 1H), 2.37 (t, J=5.41 Hz, 1H), 1.73-1.87 (m, 1H), 1.67 (d, J=2.01 Hz, 1H), 1.56-1.66 (m, 2H), 1.33-1.46 (m, 1H), 1.05-1.30 (m, 4H). MS [M+H]+=339. MS [M+Na]+=361. concentrated purified by flash chromatography on silica gel with 0 to 60% ethyl acetate in hexane

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of (1R,2R)-2-aminocyclohexanecarboxylic acid (500 mg, 3.49 mmol) in anhydrous THF (3 mL) at 0° C. was added dropwise a solution of LAH (2M solution in THF, 7 mL, 13.99 mmol). The reaction vessel was sealed and the mixture was stirred at 85° C. for 24 h. The mixture was cooled to 0° C. and diluted with THF (6 mL). To the reaction mixture was added sequentially water (0.5 mL), 1M aq NaOH (0.5 mL), and water (1.5 mL). To the mixture was added MgSO4 and the mixture was stirred at rt for 10 min. The mixture was then diluted with THF (10 mL) and filtered, and the filtrate was concentrated under reduced pressure to afford ((1R,2R)-2-aminocyclohexyl)methanol (326 mg, 70%) as an oil. 1H NMR (300 MHz, DMSO-d6) δ 3.27-3.52 (m, 3H), 2.29 (dt, J=10.1, 4.0 Hz, 1H), 1.53-1.78 (m, 4H), 0.98-1.21 (m, 4H), 0.87 (m, 1H). The reaction vessel was sealed The mixture was cooled to 0° C. the mixture was stirred at rt for 10 min filtered the filtrate was concentrated under reduced pressure

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 4:1 mixture of 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole and 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfonyl)benzo[d]thiazole (120 mg) from Step 2 of Example 63 was dissolved in anhydrous DMA (2 mL), and then ((1R,2R)-2-aminocyclohexyl)methanol (180 mg, 1.40 mmol) from Step 1 of this Example and DIEA (188 mg, 1.46 mmol) were added. The reaction vessel was sealed and the mixture was heated with stirring at 120° C. for 4.5 h. After cooling to rt, the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford ((1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)methanol. The reaction vessel was sealed the mixture was heated After cooling to rt the mixture was purified directly by reverse-phase a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of LiAlH4 (796 mg, 20.97 mmol) in anhydrous THF (20 mL) at rt was added portion-wise (1R,2R)-2-aminocyclohexanecarboxylic acid (1 g, 6.99 mmol). The mixture was heated at 80° C. for 4 h before it was cooled to 0° C. Water (1 mL), 1M aq NaOH (1 mL), and water (3 mL) were added sequentially. The mixture was filtered and the filtrate partitioned between a mixture of DCM, 1M aq NaOH, and saturated aq sodium potassium tartrate. The organic layer was separated and washed with 1M aq NaOH. The organic layer was separated, dried over MgSO4, filtered, and under reduced pressure to afford ((1R,2R)-2-aminocyclohexyl)methanol (180 mg) which was not purified further. LCMS (ESI) m/z 130 (M+H)+. was cooled to 0° C The mixture was filtered the filtrate partitioned between a mixture of DCM, 1M aq NaOH, and saturated aq sodium potassium tartrate The organic layer was separated washed with 1M aq NaOH The organic layer was separated dried over MgSO4 filtered

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4sulfonyl chloride, and [(1R,2R)-2-aminocyclohexyl]methanol, the title compound was obtained in 40% purity by HPLC. MS(ESI+): m/z=486.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and [(1R,2R)-2-aminocyclohexyl]methanol, the title compound was obtained in 65% purity by HPLC. MS(ESI+): m/z=450.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-cyano[1,1′-biphenyl]-4-carboxylic acid, and [(1R,2R)-2-aminocyclohexyl]methanol, the title compound was obtained in 78% purity by HPLC. MS(ESI+): m/z=475.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methoxy[1,1′-biphenyl]-4-carboxylic acid, and [(1R,2R)-2-aminocyclohexyl]methanol, the title compound was obtained in 68% purity by HPLC. MS(ESI+): m/z=480.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-sulfonyl chloride, and [(1R,2R)-2-aminocyclohexyl]methanol, the title compound was obtained in 40% purity by HPLC. MS(ESI+): m/z=486.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and [(1R,2R)-2-aminocyclohexyl]methanol, the title compound was obtained in 65% purity by HPLC. MS(ESI+): m/z=450.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 6-(trifluoromethyl)pyridine-3-sulfonyl chloride (190 mg, 0.78 mmol) in 2 mL dichloromethane was added dropwise to a solution of ((1R,2R)-2-aminocyclohexyl)methanol (100 mg, 0.78 mmol) and triethylamine (320 μL, 2.3 mmol) in 10 mL dichloromethane at 0° C. The reaction was stirred at 0° C. for 1 h, then concentrated and purified by flash chromatography on silica gel with 0 to 60% ethyl acetate in hexane to yield N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)-6-(trifluoromethyl)pyridine-3-sulfonamide (150 mg, 57%). 1H NMR (400 MHz, CDCl3) δ ppm 9.18 (d, J=2.01 Hz, 1H), 8.37 (dd, J=8.06, 1.76 Hz, 1H), 7.83 (d, J=8.31 Hz, 1H), 5.83 (d, J=6.80 Hz, 1H), 3.77 (ddd, J=11.21, 3.78, 3.65 Hz, 1H), 3.36 (dt, J=11.33, 5.67 Hz, 1H), 2.97-3.15 (m, 1H), 2.37 (t, J=5.41 Hz, 1H), 1.73-1.87 (m, 1H), 1.67 (d, J=2.01 Hz, 1H), 1.56-1.66 (m, 2H), 1.33-1.46 (m, 1H), 1.05-1.30 (m, 4H). MS [M+H]+=339. MS [M+Na]+=361. concentrated purified by flash chromatography on silica gel with 0 to 60% ethyl acetate in hexane