(1R,2R)-2-aminocyclohexan-1-ol;hydrochloride

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

Procedure: As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using (1R,2R)-2-amino-cyclohexanol hydrochloride (1:1) instead of 2-aminoethyl isopropylether, to the title compound (240 mg, 91%) which was obtained as a white solid. MS: m/e=406.2 [M−H]−.

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

Procedure: As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using (1R,2R)-2-amino-cyclohexanol hydrochloride (1:1) instead of 2-aminoethyl isopropylether, to the title compound (240 mg, 91%) which was obtained as a white solid. MS: m/e=406.2 [M−H]−.

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

Procedure: An ice-cooled solution of 2.28 g (10.0 mmol) of 5-Bromo-2,4-dichloropyrimidine and 3.4 ml (24.0 mmol) of triethylamine in 10 ml of acetonitrile is mixed with 1.82 g (12.1 mmol) of trans-2-aminocyclohexanol hydrochloride. After 16 hours at room temperature the batch is filtrated and the filtrate is concentrated by evaporation. The remaining residue is purified by chromatography (hexane/ethyl acetate: 1:1). 1.61 g (5.3 mmol, corresponding to 53% of theory) of the product is obtained. After 16 hours at room temperature the batch is filtrated the filtrate is concentrated by evaporation The remaining residue is purified by chromatography (hexane/ethyl acetate: 1:1) 1.61 g (5.3 mmol, corresponding to 53% of theory) of the product is obtained

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

Procedure: An ice-cooled solution of 2.28 g (10.0 mmol) of 5-Bromo-2,4-dichloropyrimidine and 3.4 ml (24.0 mmol) of triethylamine in 10 ml of acetonitrile is mixed with 1.82 g (12.1 mmol) of trans-2-aminocyclohexanol hydrochloride. After 16 hours at room temperature the batch is filtrated and the filtrate is concentrated by evaporation. The remaining residue is purified by chromatography (hexane/ethyl acetate: 1:1). 1.61 g (5.3 mmol, corresponding to 53% of theory) of the product is obtained. After 16 hours at room temperature the batch is filtrated the filtrate is concentrated by evaporation The remaining residue is purified by chromatography (hexane/ethyl acetate: 1:1) 1.61 g (5.3 mmol, corresponding to 53% of theory) of the product is obtained

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

Procedure: In a 20-mL screw-cap vial, 182 mg (0.5 mmol) 2-(2,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-imidazole-4-carboxylic acid, 145 mg (0.55 mmol) TFFH, and 5.0 equiv. PS-DIEA (loading level: 3.50 mmol/g, 716 mg, 2.5 mmol) were heated in 10 mL 1,2-dichloroethane at 35° C. overnight. The formation of acyl fluoride was monitored by LC-MS. To the mixture, 1.1 equiv. (84 mg, 0.55 mmol) trans-2-aminocyclohexanol hydrochloride was added and the reaction continued overnight. The mixture was filtered through a filter tube (polypropylene frit), and the filtrate was evaporated under reduced pressure. The crude product was redissolved in 1 mL MeOH and purified by preparative HPLC to give 53 mg of 2-(2,4-dichlorophenyl)-N-(trans-2-hydroxycyclohexyl)-1-(4-methoxyphenyl)-1H-imidazole-4-carboxamide (amber oil, 23% yield). 1H NMR (400 MHz, CD2Cl2) δ 7.90 (s, 1 H), 7.30-7.50 (m, 4 H), 7.10 (d, 2 H), 6.90 (d, 2 H), 3.85 (s, 3 H), 3.80 (m, 1 H), 3.50 (m, 1 H), 3.25 (bs, 1 H), 2.0 (m, 2 H), 1.75 (m, 2 H), 1.30-1.50 (m, 4 H); LC-MS m/z 460.2 (MH+), retention time 3.31 min (method 2). In a 20-mL screw-cap vial the reaction continued overnight The mixture was filtered through a filter tube (polypropylene frit) the filtrate was evaporated under reduced pressure The crude product was redissolved in 1 mL MeOH purified by preparative HPLC

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

Procedure: Tetrahydrofuran (100 mL) was added to racemic trans-2-amino-cyclohexanol hydrochloride (4.28 g, 28.2 mmol) and potassium carbonate (12.1 g, 88 mmol). The mixture was cooled at 0° C. before 2,4,5-trichloropyrimidine (2 mL, 17.4 mmol) was added. After 3 hours, the mixture was partitioned between water and ethyl acetate, the aq. layer was extracted and the combined extracts were dried and conc. in vacuo. The crude product was taken up in ethyl acetate and washed with 10% w/v citric acid, then with sodium bicarbonate, dried over sodium sulfate and conc. in vacuo to give rel-(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexanol (2.27 g, 50%) as a white solid. m.p.=139-142° C.; LCMS (m/e) 262 (M+1); 1H-NMR (DMSO-d6, 400 MHz) δ 8.12 (s, 1H), 7.45 (m, 1H), 68 (m, 1H), 3.81 (m, 1H), 3.55 (m, 1H), 1.92 (m, 1H), 1.81 (m, 1H), 1.67 (m, 2H), 1.41 (m, 1H), 1.26 (m, 3H). was added the mixture was partitioned between water and ethyl acetate the aq. layer was extracted the combined extracts were dried and conc. in vacuo washed with 10% w/v citric acid with sodium bicarbonate, dried over sodium sulfate and conc. in vacuo

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

Procedure: To a suspension of 3-((4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)(methyl)carbamoyl)-5-(trifluoromethyl)phenylboronic acid (0.1 g, 223 μmol, example 235, intermediate) in 2-propanol (1.0 mL) were added tert-butyl 3-iodoazetidine-1-carboxylate (63.2 mg, 223 μmol), (1R,2R)-2-aminocyclohexanol hydrochloride (2.03 mg, 13.4 μmol, CAS RN 13374-31-7), nickel(II) iodide (4.18 mg, 13.4 μmol) and sodium hexamethyldisilazan (40.9 mg, 223 μmol) and the suspension was heated in a microwave oven at 80° C. for 50 minutes. The reaction mixture was poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). The product (light brown solid, 0.048 g) was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless solid (0.008 g; 6%). MS (ESI): m/z=560.22 [M+H]+. the layers were separated The aqueous layer was extracted twice with EtOAc The organic layers were dried over MgSO4 filtered treated with silica gel evaporated The compound was purified by silica gel chromatography on a 10 g column eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100) The product (light brown solid, 0.048 g) was purified by preparative HPLC (Gemini NX column)

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

Procedure: To a suspension of 3-((4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)(methyl)carbamoyl)-5-(trifluoromethyl)phenylboronic acid (0.1 g, 223 μmol) in 2-propanol (1 mL) were added 3-iodooxetane (41.0 mg, 223 μmol), (1R,2R)-2-aminocyclohexanol hydrochloride (2.03 mg, 13.4 μmol), nickel(II) iodide (4.18 mg, 13.4 μmol) and sodium hexamethyldisilazan (40.9 mg, 223 μmol) and the suspension was heated in a microwave oven at 80° C. for 20 minutes. The reaction mixture was poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). The mixture was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless solid (0.004 g; 3%). MS (ESI): m/z=461.15 [M+H]+. the layers were separated The aqueous layer was extracted twice with EtOAc The organic layers were dried over MgSO4 filtered treated with silica gel evaporated The compound was purified by silica gel chromatography on a 10 g column eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100) The mixture was purified by preparative HPLC (Gemini NX column)

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

Procedure: A mixture of (5-bromopyridin-3-yl)boronic acid (330 mg, 1.6 mmol), nickel(II) iodide (15 mg, 0.049 mmol), trans-2-amino-cyclohexanol hydrochloride (7 mg, 0.049 mmol) and sodium bis(trimethylsilyl)amide solution in THF (1M; 1.6 mL, 1.6 mmol) in 2-propanol (2 mL) is stirred under Ar for 10 min. 3-Iodo-oxetane (150 mg, 0.82 mmol) is added and the mixture is heated at 80° C. for 90 min. After cooling to room temperature, the mixture is filtered through diatomaceous earth, rinsing thoroughly with EtOH. The filtrate is concentrated to give crude product. Purification by flash column chromatography affords 50 mg of 3-bromo-5-oxetan-3-yl-pyridine. After cooling to room temperature the mixture is filtered through diatomaceous earth rinsing thoroughly with EtOH The filtrate is concentrated to give crude product Purification by flash column chromatography

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

Procedure: 2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 3-iodooxetane in a CEM microwave vial with nickel(II)iodide, trans-2-aminocyclohexanol hydrochloride and sodium hexamethyldisilazane to give 529. MS(ESI+) 383.1. 1H NMR (400 MHz, DMSO) δ 8.34 (d, J=8.2 Hz, 1H), 7.27 (dd, J=8.2, 1.4 Hz, 1H), 7.08 (d, J=1.3 Hz, 1H), 5.76 (hept, J=6.8 Hz, 1H), 4.94 (dd, J=8.3, 5.9 Hz, 2H), 4.63 (t, J=6.3 Hz, 2H), 4.37 (t, J=5.0 Hz, 2H), 4.31-4.20 (m, 1H), 3.43 (t, J=5.0 Hz, 2H), 2.32 (s, 3H), 1.52 (d, J=6.6 Hz, 6H)

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

Procedure: 2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 3-iodooxetane in a CEM microwave vial with nickel(II)iodide, trans-2-aminocyclohexanol hydrochloride and sodium hexamethyldisilazane to give 529. MS(ESI+) 383.1. 1H NMR (400 MHz, DMSO) δ 8.34 (d, J=8.2 Hz, 1H), 7.27 (dd, J=8.2, 1.4 Hz, 1H), 7.08 (d, J=1.3 Hz, 1H), 5.76 (hept, J=6.8 Hz, 1H), 4.94 (dd, J=8.3, 5.9 Hz, 2H), 4.63 (t, J=6.3 Hz, 2H), 4.37 (t, J=5.0 Hz, 2H), 4.31-4.20 (m, 1H), 3.43 (t, J=5.0 Hz, 2H), 2.32 (s, 3H), 1.52 (d, J=6.6 Hz, 6H)

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

Procedure: To a solution of 3-chloro-2-ethenyl-4-methoxy-5-[4-(1H-pyrazol-1-yl)benzyl]benzoic acid (0.06 g), trans-2-aminocyclohexanol hydrochloride (0.04 g), 1-hydroxybenzotriazole (0.03 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.05 g) in dichloromethane (10.0 mL) was added triethylamine (0.03 g), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.08 g). the mixture was extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate the solvent was evaporated under reduced pressure