(2R)-2-amino-2-cyclohexylethanol

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

Procedure: To a solution of (R)-2-Amino-2-cyclohexyl-ethanol.HCl salt (1.0 g, 5.57 mmol, 1.0 equiv) in CH2Cl2 (30.0 mL) at 0° C. was added DIPEA (1.94 mL, 11.1 mmol, 2.0 equiv) followed by triphosgene (4.95 g, 16.7 mmol, 3.0 equiv) and the resulting solution was stirred at room temperature for 12 hours. The solution was then concentrated and the residue was diluted with EtOAc. The solution was washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, (EtOAc 100%) to give product 520 mg. The solution was then concentrated the residue was diluted with EtOAc The solution was washed with water, brine dried over Na2SO4 concentrated The residue was purified by silica gel column chromatography, (EtOAc 100%)

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

Procedure: To a solution containing 3.8 g (26.5 mmol, 1.0 equiv) of (R)-2-amino-2-cyclohexyl-ethanol in 100 mL of THF was added sodium hydride (1.4 g, 58.4 mmol, 60% in mineral oil, 2.2 equiv). The reaction mixture was stirred at 25° C. for 30 minutes, at which time hydrogen evolution had ceased. The mixture was cooled at 0° C. and was added ethyl chloroacetate (3.3 g, 26.5 mmol, 1.0 equiv), dropwise, over 5 minutes. The reaction mixture was stirred for 1 hour at 25° C. and then 2 hours at reflux. The solvent was removed under vacuum and to the residue was added 1.0 N HCl aq. solution until pH=6. The mixture was extracted with ethyl acetate. The resulting organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was recrystallized from EtOAc/heptane to give product 2.8 g. The mother liquid was concentrated and the residue was purified by silica gel column chromatography (acetone/heptane 50%) to give product 1.3 g. Combined yield 4.1 g (84%) 2 hours at reflux The solvent was removed under vacuum and to the residue was added 1.0 N HCl aq. solution until pH=6 The mixture was extracted with ethyl acetate The resulting organic extracts were washed with brine dried over sodium sulfate concentrated in vacuo The residue was recrystallized from EtOAc/heptane

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

Procedure: To a solution containing 3.8 g (26.5 mmol, 1.0 equiv) of (R)-2-amino-2-cyclohexyl-ethanol in 100 mL of THF was added sodium hydride (1.4 g, 58.4 mmol, 60% in mineral oil, 2.2 equiv). The reaction mixture was stirred at 25° C. for 30 minutes, at which time hydrogen evolution had ceased. The mixture was cooled at 0° C. and was added ethyl chloroacetate (3.3 g, 26.5 mmol, 1.0 equiv), dropwise, over 5 minutes. The reaction mixture was stirred for 1 hour at 25° C. and then 2 hours at reflux. The solvent was removed under vacuum and to the residue was added 1.0 N HCl aq. solution until pH=6. The mixture was extracted with ethyl acetate. The resulting organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was recrystallized from EtOAc/heptane to give product 2.8 g. The mother liquid was concentrated and the residue was purified by silica gel column chromatography (acetone/heptane 50%) to give product 1.3 g. Combined yield 4.1 g (84%) 2 hours at reflux The solvent was removed under vacuum and to the residue was added 1.0 N HCl aq. solution until pH=6 The mixture was extracted with ethyl acetate The resulting organic extracts were washed with brine dried over sodium sulfate concentrated in vacuo The residue was recrystallized from EtOAc/heptane

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

Procedure: Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, (R)-1-cyclohexyl-2-hydroxy-ethylamine and DIEA to give 2-((R)-1-cyclohexyl-2-hydroxy-ethylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 382 (MH+).

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 (R)-2-amino-2-cyclohexylethanol (209 mg, 1.46 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 15 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 (R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2-cyclohexylethanol (18 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.38 (m, 1H), 8.09 (dd, J=1.0, 8.0 Hz, 1H), 7.85 (d, J=8.9 Hz, 1H), 7.66 (s, 1H), 7.18-7.32 (m, 3H), 5.48 (s, 2H), 4.70 (br s, 1H), 3.72 (m, 1H), 3.50 (m, 2H), 1.54-1.77 (m, 6H), 0.94-1.23 (m, 5H). LCMS (ESI) m/z 408 (M+H)+. 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 (724 mg, 19.08 mmol) in anhydrous THF (20 mL) at rt was added portionwise 2-cyclohexyl-D-glycine (1 g, 6.36 mmol). The mixture was heated at 80° C. for 4 h. The mixture was cooled to 0° C. and then water (1 mL), 1M aq NaOH (1 mL), and water (3 mL) were added sequentially. The mixture was filtered and the filtrate was partitioned between a mixture of DCM, 1M aq NaOH, and saturated aq sodium potassium tartrate. The organic layer was separated and further washed with 1M aq NaOH. The organic was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to afford (R)-2-amino-2-cyclohexylethanol (400 mg) which was not purified further. LCMS (ESI) m/z 144 (M+H)+. The mixture was cooled to 0° C. The mixture was filtered the filtrate was partitioned between a mixture of DCM, 1M aq NaOH, and saturated aq sodium potassium tartrate The organic layer was separated further washed with 1M aq NaOH The organic was separated dried over MgSO4 filtered concentrated under reduced pressure

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

Procedure: To a solution of (R)-2-Amino-2-cyclohexyl-ethanol.HCl salt (1.0 g, 5.57 mmol, 1.0 equiv) in CH2Cl2 (30.0 mL) at 0° C. was added DIPEA (1.94 mL, 11.1 mmol, 2.0 equiv) followed by triphosgene (4.95 g, 16.7 mmol, 3.0 equiv) and the resulting solution was stirred at room temperature for 12 hours. The solution was then concentrated and the residue was diluted with EtOAc. The solution was washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, (EtOAc 100%) to give product 520 mg. The solution was then concentrated the residue was diluted with EtOAc The solution was washed with water, brine dried over Na2SO4 concentrated The residue was purified by silica gel column chromatography, (EtOAc 100%)

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

Procedure: To a solution containing 3.8 g (26.5 mmol, 1.0 equiv) of (R)-2-amino-2-cyclohexyl-ethanol in 100 mL of THF was added sodium hydride (1.4 g, 58.4 mmol, 60% in mineral oil, 2.2 equiv). The reaction mixture was stirred at 25° C. for 30 minutes, at which time hydrogen evolution had ceased. The mixture was cooled at 0° C. and was added ethyl chloroacetate (3.3 g, 26.5 mmol, 1.0 equiv), dropwise, over 5 minutes. The reaction mixture was stirred for 1 hour at 25° C. and then 2 hours at reflux. The solvent was removed under vacuum and to the residue was added 1.0 N HCl aq. solution until pH=6. The mixture was extracted with ethyl acetate. The resulting organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was recrystallized from EtOAc/heptane to give product 2.8 g. The mother liquid was concentrated and the residue was purified by silica gel column chromatography (acetone/heptane 50%) to give product 1.3 g. Combined yield 4.1 g (84%) 2 hours at reflux The solvent was removed under vacuum and to the residue was added 1.0 N HCl aq. solution until pH=6 The mixture was extracted with ethyl acetate The resulting organic extracts were washed with brine dried over sodium sulfate concentrated in vacuo The residue was recrystallized from EtOAc/heptane