(1S,2R)-2-aminocyclohexan-1-ol

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

Procedure: 2-[3-(Ethylsulfanyl)phenoxy]-5-fluoronicotinic acid (250 mg, 0.85 mmol) was dissolved in dimethylformamide (5 ml) and triethylamine (475 μl, 3.41 mmol) was added followed by (1S,2R)-2-aminocyclohexanol hydroformate (144 mg, 0.89 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (180 mg, 0.94 mmol) and 1-hydroxybenzotriazole (127 mg, 0.94 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between water (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography using dichloromethane:methanol:0.880 ammonia (98:2:0.2) as eluant to give 2-[3-(ethylsulfanyl)phenoxy]-5-fluoro-N-[(1R,2S)-2-hydroxycyclohexyl]nicotinamide (60 mg) as a colourless oil. the solvent was removed under reduced pressure The residue was partitioned between water (5 ml) and ethyl acetate (10 ml) the aqueous phase was extracted with ethyl acetate (3×10 ml) The combined organic extracts were washed with brine (5 ml) dried over MgSO4 the solvent was removed under reduced pressure The residue was purified by flash column chromatography

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

Procedure: 2-[3-(Ethylsulfanyl)phenoxy]-5-fluoronicotinic acid (250 mg, 0.85 mmol) was dissolved in dimethylformamide (5 ml) and triethylamine (475 μl, 3.41 mmol) was added followed by (1S,2R)-2-aminocyclohexanol hydroformate (144 mg, 0.89 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (180 mg, 0.94 mmol) and 1-hydroxybenzotriazole (127 mg, 0.94 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between water (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography using dichloromethane:methanol:0.880 ammonia (98:2:0.2) as eluant to give 2-[3-(ethylsulfanyl)phenoxy]-5-fluoro-N-[(1R,2S)-2-hydroxycyclohexyl]nicotinamide (60 mg) as a colourless oil. the solvent was removed under reduced pressure The residue was partitioned between water (5 ml) and ethyl acetate (10 ml) the aqueous phase was extracted with ethyl acetate (3×10 ml) The combined organic extracts were washed with brine (5 ml) dried over MgSO4 the solvent was removed under reduced pressure The residue was purified by flash column chromatography

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

Procedure: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (294 mg, 1.53 mmol) was added to a solution of 2-(3-methylsulfanyl-phenoxy)-nicotinic acid (200 mg, 0.765 mmol), (1S,2R)-2-aminocyclohexanol hydroformate [8151/194/1] (128 mg, 0.765 mmol), 1-hydroxybenzotriazole (114 mg, 0.842 mmol) and triethylamine (430□l, 3.10 mmol) in dimethylformamide (5 ml) under nitrogen at room temperature. The reaction was stirred for 18 h and partitioned between diethyl ether (25 ml) and water (25 ml). The organic phase was washed with brine (30 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of ethyl acetate: cyclohexane (35:65 to 50:50) to give an off-white solid which was purified by flash column chromatography using ethyl acetate:cyclohexane (50:50 as eluant) to give N-[(1R,2S)-2-hydroxycyclohexyl]-2-[3-(methylsulfanyl)phenoxy]nicotinamide (133 mg) as a gum. partitioned between diethyl ether (25 ml) and water (25 ml) The organic phase was washed with brine (30 ml) dried over MgSO4 the solvent was removed under reduced pressure The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of ethyl acetate: cyclohexane (35:65 to 50:50) to give an off-white solid which was purified by flash column chromatography

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

Procedure: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (294 mg, 1.53 mmol) was added to a solution of 2-(3-methylsulfanyl-phenoxy)-nicotinic acid (200 mg, 0.765 mmol), (1S,2R)-2-aminocyclohexanol hydroformate [8151/194/1] (128 mg, 0.765 mmol), 1-hydroxybenzotriazole (114 mg, 0.842 mmol) and triethylamine (430□l, 3.10 mmol) in dimethylformamide (5 ml) under nitrogen at room temperature. The reaction was stirred for 18 h and partitioned between diethyl ether (25 ml) and water (25 ml). The organic phase was washed with brine (30 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of ethyl acetate: cyclohexane (35:65 to 50:50) to give an off-white solid which was purified by flash column chromatography using ethyl acetate:cyclohexane (50:50 as eluant) to give N-[(1R,2S)-2-hydroxycyclohexyl]-2-[3-(methylsulfanyl)phenoxy]nicotinamide (133 mg) as a gum. partitioned between diethyl ether (25 ml) and water (25 ml) The organic phase was washed with brine (30 ml) dried over MgSO4 the solvent was removed under reduced pressure The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of ethyl acetate: cyclohexane (35:65 to 50:50) to give an off-white solid which was purified by flash column chromatography

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

Procedure: 2-[3-(Ethylsulfanyl)phenoxy]-5-fluoronicotinic acid (250 mg, 0.85 mmol) was dissolved in dimethylformamide (5 ml) and triethylamine (475 μl, 3.41 mmol) was added followed by (1S,2R)-2-aminocyclohexanol hydroformate (144 mg, 0.89 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (180 mg, 0.94 mmol) and 1-hydroxybenzotriazole (127 mg, 0.94 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between water (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography using dichloromethane:methanol:0.880 ammonia (98:2:0.2) as eluant to give 2-[3-(ethylsulfanyl)phenoxy]-5-fluoro-N-[(1R,2S)-2-hydroxycyclohexyl]nicotinamide (60 mg) as a colourless oil. the solvent was removed under reduced pressure The residue was partitioned between water (5 ml) and ethyl acetate (10 ml) the aqueous phase was extracted with ethyl acetate (3×10 ml) The combined organic extracts were washed with brine (5 ml) dried over MgSO4 the solvent was removed under reduced pressure The residue was purified by flash column chromatography

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

Procedure: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (294 mg, 1.53 mmol) was added to a solution of 2-(3-methylsulfanyl-phenoxy)-nicotinic acid (200 mg, 0.765 mmol), (1S,2R)-2-aminocyclohexanol hydroformate [8151/194/1] (128 mg, 0.765 mmol), 1-hydroxybenzotriazole (114 mg, 0.842 mmol) and triethylamine (430□l, 3.10 mmol) in dimethylformamide (5 ml) under nitrogen at room temperature. The reaction was stirred for 18 h and partitioned between diethyl ether (25 ml) and water (25 ml). The organic phase was washed with brine (30 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of ethyl acetate: cyclohexane (35:65 to 50:50) to give an off-white solid which was purified by flash column chromatography using ethyl acetate:cyclohexane (50:50 as eluant) to give N-[(1R,2S)-2-hydroxycyclohexyl]-2-[3-(methylsulfanyl)phenoxy]nicotinamide (133 mg) as a gum. partitioned between diethyl ether (25 ml) and water (25 ml) The organic phase was washed with brine (30 ml) dried over MgSO4 the solvent was removed under reduced pressure The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of ethyl acetate: cyclohexane (35:65 to 50:50) to give an off-white solid which was purified by flash column chromatography