2-(2,6-difluorophenyl)ethanol

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

Procedure: 2,2,6,6-Tetramethylpiperidine (5 mL) was added to a solution of butyllithium (1.6M in hexanes, 19 mL) in THF (25 mL) at −70° C. A solution of 2-(2,6-difluorophenyl)ethanol (example 45, step a) (1.6 g) in THF (25 mL) was added dropwise and the resulting mixture stirred for 2 h. DMF (3.9 mL) was then added and the mixture stirred for 1 h at −70° C. The mixture was then allowed to warm to RT and stirred for 70 h. The reaction was quenched with HCl solution (2M, 50 mL), diluted with ethyl acetate (100 mL) and the layers separated. The aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organics were washed with brine (100 mL), dried over magnesium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with 4:1 to 2:1 isohexane:ether gradient. The fractions containing product were combined and evaporated. The resulting oil was dissolved in ethyl acetate (50 mL) and washed with HCl solution (2M, 30 mL), brine (30 mL), dried over magnesium sulphate, filtered and evaporated to give the subtitled compound as a clear oil. Yield 1.1 g. the mixture stirred for 1 h at −70° C stirred for 70 h The reaction was quenched with HCl solution (2M, 50 mL) diluted with ethyl acetate (100 mL) the layers separated The aqueous phase was extracted with ethyl acetate (2×50 mL) The combined organics were washed with brine (100 mL) dried over magnesium sulphate filtered evaporated The residue was purified by silica gel chromatography eluting with 4:1 to 2:1 isohexane The fractions containing product evaporated The resulting oil was dissolved in ethyl acetate (50 mL) washed with HCl solution (2M, 30 mL), brine (30 mL) dried over magnesium sulphate filtered evaporated

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

Procedure: 2,2,6,6-Tetramethylpiperidine (5 mL) was added to a solution of butyllithium (1.6M in hexanes, 19 mL) in THF (25 mL) at −70° C. A solution of 2-(2,6-difluorophenyl)ethanol (example 45, step a) (1.6 g) in THF (25 mL) was added dropwise and the resulting mixture stirred for 2 h. DMF (3.9 mL) was then added and the mixture stirred for 1 h at −70° C. The mixture was then allowed to warm to RT and stirred for 70 h. The reaction was quenched with HCl solution (2M, 50 mL), diluted with ethyl acetate (100 mL) and the layers separated. The aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organics were washed with brine (100 mL), dried over magnesium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with 4:1 to 2:1 isohexane:ether gradient. The fractions containing product were combined and evaporated. The resulting oil was dissolved in ethyl acetate (50 mL) and washed with HCl solution (2M, 30 mL), brine (30 mL), dried over magnesium sulphate, filtered and evaporated to give the subtitled compound as a clear oil. Yield 1.1 g. the mixture stirred for 1 h at −70° C stirred for 70 h The reaction was quenched with HCl solution (2M, 50 mL) diluted with ethyl acetate (100 mL) the layers separated The aqueous phase was extracted with ethyl acetate (2×50 mL) The combined organics were washed with brine (100 mL) dried over magnesium sulphate filtered evaporated The residue was purified by silica gel chromatography eluting with 4:1 to 2:1 isohexane The fractions containing product evaporated The resulting oil was dissolved in ethyl acetate (50 mL) washed with HCl solution (2M, 30 mL), brine (30 mL) dried over magnesium sulphate filtered evaporated

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

Procedure: A solution of borane dimethyl sulfide complex (2M in THF, 26 mL) was added cautiously to a solution of 2-(2,6-difluorophenyl)acetic acid (3 g) in THF (50 mL) at 0° C. The reaction was then allowed to warm to RT and stirred for 3 h. The reaction was cooled in an ice bath and cautiously quenched with methanol (10 mL). The solvent was evaporated and the residue purified by silica gel chromatography eluting with 9:1 to 4:1 isohexane:ethyl acetate gradient. The fractions containing product were combined and evaporated to give the subtitled compound as a clear oil. Yield 2.2 g. The reaction was cooled in an ice bath cautiously quenched with methanol (10 mL) The solvent was evaporated the residue purified by silica gel chromatography eluting with 9:1 to 4:1 isohexane The fractions containing product evaporated

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

Procedure: 6-(4-(Trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (50.0 mg, 0.169 mmol), 2-(2,6-difluorophenyl)ethanol (40.1 mg, 0.2535 mmol, 1.5 equiv.) and PPh3 (66.5 mg, 0.2535 mmol, 1.5 equiv.) were dissolved in THF (3 mL) under nitrogen atmosphere in a 50 mL round bottomed flask. This mixture was treated with diethyl azodicarboxylate (40% toluene solution, d=0.956, 0.12 mL, 0.2535 mmol, 1.5 equiv.) at room temperature. After stirring for 5 h, the mixture was directly loaded onto preparative HPLC. The HPLC purification gave compound 63 as colorless crystals (38.6 mg, 0.0887 mmol, 52.5%). LCMS (EI: 70 eV) 458 (M++Na), 436 (M++1). FTIR (ATR) 1701 (O═C). The HPLC purification

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

Procedure: 6-(4-(Trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (50.0 mg, 0.169 mmol), 2-(2,6-difluorophenyl)ethanol (40.1 mg, 0.2535 mmol, 1.5 equiv.) and PPh3 (66.5 mg, 0.2535 mmol, 1.5 equiv.) were dissolved in THF (3 mL) under nitrogen atmosphere in a 50 mL round bottomed flask. This mixture was treated with diethyl azodicarboxylate (40% toluene solution, d=0.956, 0.12 mL, 0.2535 mmol, 1.5 equiv.) at room temperature. After stirring for 5 h, the mixture was directly loaded onto preparative HPLC. The HPLC purification gave compound 63 as colorless crystals (38.6 mg, 0.0887 mmol, 52.5%). LCMS (EI: 70 eV) 458 (M++Na), 436 (M++1). FTIR (ATR) 1701 (O═C). The HPLC purification

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

Procedure: 2,2,6,6-Tetramethylpiperidine (5 mL) was added to a solution of butyllithium (1.6M in hexanes, 19 mL) in THF (25 mL) at −70° C. A solution of 2-(2,6-difluorophenyl)ethanol (example 45, step a) (1.6 g) in THF (25 mL) was added dropwise and the resulting mixture stirred for 2 h. DMF (3.9 mL) was then added and the mixture stirred for 1 h at −70° C. The mixture was then allowed to warm to RT and stirred for 70 h. The reaction was quenched with HCl solution (2M, 50 mL), diluted with ethyl acetate (100 mL) and the layers separated. The aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organics were washed with brine (100 mL), dried over magnesium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with 4:1 to 2:1 isohexane:ether gradient. The fractions containing product were combined and evaporated. The resulting oil was dissolved in ethyl acetate (50 mL) and washed with HCl solution (2M, 30 mL), brine (30 mL), dried over magnesium sulphate, filtered and evaporated to give the subtitled compound as a clear oil. Yield 1.1 g. the mixture stirred for 1 h at −70° C stirred for 70 h The reaction was quenched with HCl solution (2M, 50 mL) diluted with ethyl acetate (100 mL) the layers separated The aqueous phase was extracted with ethyl acetate (2×50 mL) The combined organics were washed with brine (100 mL) dried over magnesium sulphate filtered evaporated The residue was purified by silica gel chromatography eluting with 4:1 to 2:1 isohexane The fractions containing product evaporated The resulting oil was dissolved in ethyl acetate (50 mL) washed with HCl solution (2M, 30 mL), brine (30 mL) dried over magnesium sulphate filtered evaporated

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

Procedure: A solution of borane dimethyl sulfide complex (2M in THF, 26 mL) was added cautiously to a solution of 2-(2,6-difluorophenyl)acetic acid (3 g) in THF (50 mL) at 0° C. The reaction was then allowed to warm to RT and stirred for 3 h. The reaction was cooled in an ice bath and cautiously quenched with methanol (10 mL). The solvent was evaporated and the residue purified by silica gel chromatography eluting with 9:1 to 4:1 isohexane:ethyl acetate gradient. The fractions containing product were combined and evaporated to give the subtitled compound as a clear oil. Yield 2.2 g. The reaction was cooled in an ice bath cautiously quenched with methanol (10 mL) The solvent was evaporated the residue purified by silica gel chromatography eluting with 9:1 to 4:1 isohexane The fractions containing product evaporated

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

Procedure: 2,2,6,6-Tetramethylpiperidine (5 mL) was added to a solution of butyllithium (1.6M in hexanes, 19 mL) in THF (25 mL) at −70° C. A solution of 2-(2,6-difluorophenyl)ethanol (example 45, step a) (1.6 g) in THF (25 mL) was added dropwise and the resulting mixture stirred for 2 h. DMF (3.9 mL) was then added and the mixture stirred for 1 h at −70° C. The mixture was then allowed to warm to RT and stirred for 70 h. The reaction was quenched with HCl solution (2M, 50 mL), diluted with ethyl acetate (100 mL) and the layers separated. The aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organics were washed with brine (100 mL), dried over magnesium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with 4:1 to 2:1 isohexane:ether gradient. The fractions containing product were combined and evaporated. The resulting oil was dissolved in ethyl acetate (50 mL) and washed with HCl solution (2M, 30 mL), brine (30 mL), dried over magnesium sulphate, filtered and evaporated to give the subtitled compound as a clear oil. Yield 1.1 g. the mixture stirred for 1 h at −70° C stirred for 70 h The reaction was quenched with HCl solution (2M, 50 mL) diluted with ethyl acetate (100 mL) the layers separated The aqueous phase was extracted with ethyl acetate (2×50 mL) The combined organics were washed with brine (100 mL) dried over magnesium sulphate filtered evaporated The residue was purified by silica gel chromatography eluting with 4:1 to 2:1 isohexane The fractions containing product evaporated The resulting oil was dissolved in ethyl acetate (50 mL) washed with HCl solution (2M, 30 mL), brine (30 mL) dried over magnesium sulphate filtered evaporated

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

Procedure: A solution of borane dimethyl sulfide complex (2M in THF, 26 mL) was added cautiously to a solution of 2-(2,6-difluorophenyl)acetic acid (3 g) in THF (50 mL) at 0° C. The reaction was then allowed to warm to RT and stirred for 3 h. The reaction was cooled in an ice bath and cautiously quenched with methanol (10 mL). The solvent was evaporated and the residue purified by silica gel chromatography eluting with 9:1 to 4:1 isohexane:ethyl acetate gradient. The fractions containing product were combined and evaporated to give the subtitled compound as a clear oil. Yield 2.2 g. The reaction was cooled in an ice bath cautiously quenched with methanol (10 mL) The solvent was evaporated the residue purified by silica gel chromatography eluting with 9:1 to 4:1 isohexane The fractions containing product evaporated