sodium;2,2,2-trifluoroethanolate

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

Procedure: To a solution of sodium trifluoroethoxide, prepared from trifluoroethanol (2 ml) and sodium hydride (37 mg, 0.84 mmol) at 0-5° C., was added dropwise a solution of ethyl 5-bromo-2-(methylsulfonyl)pyrimidine-4-carboxylic acid ethyl ester (200 mg, 0.65 mmol; example 126, step 1) dissolved in trifluoroethanol (2 ml) at the same temperature. The ice bath was removed after 15 min and the mixture was stirred at r.t. for 4 h. The reaction mixture was poured into ethyl acetate (20 ml) and extracted with potassium hydrogen sulfate (10%, 10 ml). The organic phase was washed with water and brine and the aqueous layers were back-extracted with ethyl acetate. The combined organic layers were dried and evaporated and the product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as colorless oil (186 mg, 87%). The ice bath was removed after 15 min The reaction mixture was poured into ethyl acetate (20 ml) extracted with potassium hydrogen sulfate (10%, 10 ml) The organic phase was washed with water and brine the aqueous layers were back-extracted with ethyl acetate The combined organic layers were dried evaporated the product was obtained after purification by silica gel chromatography

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

Procedure: To a solution of sodium trifluoroethoxide, prepared from trifluoroethanol (2 ml) and sodium hydride (37 mg, 0.84 mmol) at 0-5° C., was added dropwise a solution of ethyl 5-bromo-2-(methylsulfonyl)pyrimidine-4-carboxylic acid ethyl ester (200 mg, 0.65 mmol; example 126, step 1) dissolved in trifluoroethanol (2 ml) at the same temperature. The ice bath was removed after 15 min and the mixture was stirred at r.t. for 4 h. The reaction mixture was poured into ethyl acetate (20 ml) and extracted with potassium hydrogen sulfate (10%, 10 ml). The organic phase was washed with water and brine and the aqueous layers were back-extracted with ethyl acetate. The combined organic layers were dried and evaporated and the product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as colorless oil (186 mg, 87%). The ice bath was removed after 15 min The reaction mixture was poured into ethyl acetate (20 ml) extracted with potassium hydrogen sulfate (10%, 10 ml) The organic phase was washed with water and brine the aqueous layers were back-extracted with ethyl acetate The combined organic layers were dried evaporated the product was obtained after purification by silica gel chromatography

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

Procedure: A solution of (S)-2-(1-{[2-chloro-4-(4-fluorophenyl)quinolin-7-yl]methyl}-1H-1,2,3-triazol-4-yl)-1,1,1-trifluorobutan-2-ol (60 mg, 0.13 mmol) and sodium trifluoroethoxide (79 mg, 0.65 mmol) in DMF (3 mL) was stirred at 120° C. for 1.5 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure. Purification on silica gel (eluting with ethyl acetate/hexanes, 3:7) gave the title compound. MS (+ESI): 529 (M+H)+. The reaction was quenched with saturated aqueous NH4Cl extracted with EtOAc The combined organic layers were washed with brine dried over Na2SO4 filtered concentrated Purification on silica gel (eluting with ethyl acetate/hexanes, 3:7)

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

Procedure: A solution of (S)-2-(1-{[2-chloro-4-(4-fluorophenyl)quinolin-7-yl]methyl}-1H-1,2,3-triazol-4-yl)-1,1,1-trifluorobutan-2-ol (60 mg, 0.13 mmol) and sodium trifluoroethoxide (79 mg, 0.65 mmol) in DMF (3 mL) was stirred at 120° C. for 1.5 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure. Purification on silica gel (eluting with ethyl acetate/hexanes, 3:7) gave the title compound. MS (+ESI): 529 (M+H)+. The reaction was quenched with saturated aqueous NH4Cl extracted with EtOAc The combined organic layers were washed with brine dried over Na2SO4 filtered concentrated Purification on silica gel (eluting with ethyl acetate/hexanes, 3:7)

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

Procedure: A solution of (S)-2-(1-{[2-chloro-4-(4-fluorophenyl)quinolin-7-yl]methyl}-1H-1,2,3-triazol-4-yl)-1,1,1-trifluorobutan-2-ol (60 mg, 0.13 mmol) and sodium trifluoroethoxide (79 mg, 0.65 mmol) in DMF (3 mL) was stirred at 120° C. for 1.5 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure. Purification on silica gel (eluting with ethyl acetate/hexanes, 3:7) gave the title compound. MS (+ESI): 529 (M+H)+. The reaction was quenched with saturated aqueous NH4Cl extracted with EtOAc The combined organic layers were washed with brine dried over Na2SO4 filtered concentrated Purification on silica gel (eluting with ethyl acetate/hexanes, 3:7)

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

Procedure: The following example was synthesized using the procedure described for Example 43 from Intermediate 5 using a solution of sodium 2,2,2-trifluoroethanolate in 2,2,2-trifluoroethanol:

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

Procedure: To a solution of sodium trifluoroethoxide, prepared from trifluoroethanol (2 ml) and sodium hydride (37 mg, 0.84 mmol) at 0-5° C., was added dropwise a solution of ethyl 5-bromo-2-(methylsulfonyl)pyrimidine-4-carboxylic acid ethyl ester (200 mg, 0.65 mmol; example 126, step 1) dissolved in trifluoroethanol (2 ml) at the same temperature. The ice bath was removed after 15 min and the mixture was stirred at r.t. for 4 h. The reaction mixture was poured into ethyl acetate (20 ml) and extracted with potassium hydrogen sulfate (10%, 10 ml). The organic phase was washed with water and brine and the aqueous layers were back-extracted with ethyl acetate. The combined organic layers were dried and evaporated and the product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as colorless oil (186 mg, 87%). The ice bath was removed after 15 min The reaction mixture was poured into ethyl acetate (20 ml) extracted with potassium hydrogen sulfate (10%, 10 ml) The organic phase was washed with water and brine the aqueous layers were back-extracted with ethyl acetate The combined organic layers were dried evaporated the product was obtained after purification by silica gel chromatography

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

Procedure: To a solution of sodium trifluoroethoxide, prepared from trifluoroethanol (2 ml) and sodium hydride (37 mg, 0.84 mmol) at 0-5° C., was added dropwise a solution of ethyl 5-bromo-2-(methylsulfonyl)pyrimidine-4-carboxylic acid ethyl ester (200 mg, 0.65 mmol; example 126, step 1) dissolved in trifluoroethanol (2 ml) at the same temperature. The ice bath was removed after 15 min and the mixture was stirred at r.t. for 4 h. The reaction mixture was poured into ethyl acetate (20 ml) and extracted with potassium hydrogen sulfate (10%, 10 ml). The organic phase was washed with water and brine and the aqueous layers were back-extracted with ethyl acetate. The combined organic layers were dried and evaporated and the product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as colorless oil (186 mg, 87%). The ice bath was removed after 15 min The reaction mixture was poured into ethyl acetate (20 ml) extracted with potassium hydrogen sulfate (10%, 10 ml) The organic phase was washed with water and brine the aqueous layers were back-extracted with ethyl acetate The combined organic layers were dried evaporated the product was obtained after purification by silica gel chromatography

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

Procedure: To a solution of sodium trifluoroethoxide, prepared from trifluoroethanol (2 ml) and sodium hydride (37 mg, 0.84 mmol) at 0-5° C., was added dropwise a solution of ethyl 5-bromo-2-(methylsulfonyl)pyrimidine-4-carboxylic acid ethyl ester (200 mg, 0.65 mmol; example 126, step 1) dissolved in trifluoroethanol (2 ml) at the same temperature. The ice bath was removed after 15 min and the mixture was stirred at r.t. for 4 h. The reaction mixture was poured into ethyl acetate (20 ml) and extracted with potassium hydrogen sulfate (10%, 10 ml). The organic phase was washed with water and brine and the aqueous layers were back-extracted with ethyl acetate. The combined organic layers were dried and evaporated and the product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as colorless oil (186 mg, 87%). The ice bath was removed after 15 min The reaction mixture was poured into ethyl acetate (20 ml) extracted with potassium hydrogen sulfate (10%, 10 ml) The organic phase was washed with water and brine the aqueous layers were back-extracted with ethyl acetate The combined organic layers were dried evaporated the product was obtained after purification by silica gel chromatography

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

Procedure: To a three neck 0.5 liter round bottom flask fitted with mechanical stirrer, nitrogen inlet and dropping funnel is added 4-[5-(2,4-Difluoro-phenyl)-4-hydroxymethyl-oxazol-2-yl]-piperidine-1-carboxylic acid benzyl ester, methane sulfonic anhydride (5.87 g, 33.7 mmol), and 150 mL of dry tetrahydrofuran. The mixture is stirred and cooled to 0° C., followed by dropwise addition of diisopropyl ethylamine (8.4 mL, 48 mmol). The mixture is stirred for 1 hour at 0° C. and then allowed to warm to room temperature. To the resultant mixture is then added sodium iodide (7.75 g, 51.7 mmol), and the mixture is stirred for an additional three hours. The sodium 2,2,2-trifluoroethoxide (0.151 mmol in 80 mL of dry tetrahydrofuran) is added dropwise over a 15 minute period and the resulting mixture is stirred for an additional 1 hour. The mixture is cooled to 0° C. and carefully quenched with 125 mL of water. After the addition was complete, the mixture is extracted with water and methylene chloride. The aqueous is washed with an additional three portions of methylene chloride, using 300 mL volumes. The organics are combined, washed with brine, dried over magnesium sulfate and concentrated to a thick residue. The residue is purified by preparative medium performance liquid chromatography to give upon concentration the desired fractions of the title compound. To a three neck 0.5 liter round bottom flask fitted with mechanical stirrer, nitrogen inlet The mixture is stirred for 1 hour at 0° C. to warm to room temperature the resulting mixture is stirred for an additional 1 hour The mixture is cooled to 0° C. carefully quenched with 125 mL of water After the addition the mixture is extracted with water and methylene chloride The aqueous is washed with an additional three portions of methylene chloride washed with brine dried over magnesium sulfate concentrated to a thick residue The residue is purified by preparative medium performance liquid chromatography

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

Procedure: To a three neck 0.5 liter round bottom flask fitted with mechanical stirrer, nitrogen inlet and dropping funnel is added 4-[5-(2,4-Difluoro-phenyl)-4-hydroxymethyl-oxazol-2-yl]-piperidine-1-carboxylic acid benzyl ester, methane sulfonic anhydride (5.87 g, 33.7 mmol), and 150 mL of dry tetrahydrofuran. The mixture is stirred and cooled to 0° C., followed by dropwise addition of diisopropyl ethylamine (8.4 mL, 48 mmol). The mixture is stirred for 1 hour at 0° C. and then allowed to warm to room temperature. To the resultant mixture is then added sodium iodide (7.75 g, 51.7 mmol), and the mixture is stirred for an additional three hours. The sodium 2,2,2-trifluoroethoxide (0.151 mmol in 80 mL of dry tetrahydrofuran) is added dropwise over a 15 minute period and the resulting mixture is stirred for an additional 1 hour. The mixture is cooled to 0° C. and carefully quenched with 125 mL of water. After the addition was complete, the mixture is extracted with water and methylene chloride. The aqueous is washed with an additional three portions of methylene chloride, using 300 mL volumes. The organics are combined, washed with brine, dried over magnesium sulfate and concentrated to a thick residue. The residue is purified by preparative medium performance liquid chromatography to give upon concentration the desired fractions of the title compound. To a three neck 0.5 liter round bottom flask fitted with mechanical stirrer, nitrogen inlet The mixture is stirred for 1 hour at 0° C. to warm to room temperature the resulting mixture is stirred for an additional 1 hour The mixture is cooled to 0° C. carefully quenched with 125 mL of water After the addition the mixture is extracted with water and methylene chloride The aqueous is washed with an additional three portions of methylene chloride washed with brine dried over magnesium sulfate concentrated to a thick residue The residue is purified by preparative medium performance liquid chromatography

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

Procedure: To a three neck 0.5 liter round bottom flask fitted with mechanical stirrer, nitrogen inlet and dropping funnel is added 4-[5-(2,4-Difluoro-phenyl)-4-hydroxymethyl-oxazol-2-yl]-piperidine-1-carboxylic acid benzyl ester, methane sulfonic anhydride (5.87 g, 33.7 mmol), and 150 mL of dry tetrahydrofuran. The mixture is stirred and cooled to 0° C., followed by dropwise addition of diisopropyl ethylamine (8.4 mL, 48 mmol). The mixture is stirred for 1 hour at 0° C. and then allowed to warm to room temperature. To the resultant mixture is then added sodium iodide (7.75 g, 51.7 mmol), and the mixture is stirred for an additional three hours. The sodium 2,2,2-trifluoroethoxide (0.151 mmol in 80 mL of dry tetrahydrofuran) is added dropwise over a 15 minute period and the resulting mixture is stirred for an additional 1 hour. The mixture is cooled to 0° C. and carefully quenched with 125 mL of water. After the addition was complete, the mixture is extracted with water and methylene chloride. The aqueous is washed with an additional three portions of methylene chloride, using 300 mL volumes. The organics are combined, washed with brine, dried over magnesium sulfate and concentrated to a thick residue. The residue is purified by preparative medium performance liquid chromatography to give upon concentration the desired fractions of the title compound. To a three neck 0.5 liter round bottom flask fitted with mechanical stirrer, nitrogen inlet The mixture is stirred for 1 hour at 0° C. to warm to room temperature the resulting mixture is stirred for an additional 1 hour The mixture is cooled to 0° C. carefully quenched with 125 mL of water After the addition the mixture is extracted with water and methylene chloride The aqueous is washed with an additional three portions of methylene chloride washed with brine dried over magnesium sulfate concentrated to a thick residue The residue is purified by preparative medium performance liquid chromatography