1-bromo-4-(1,1-difluoroethyl)benzene

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A solution of 2.98 g (13.3 mmol) of the compound from Example 68A in toluene (25.0 ml) was admixed under argon at RT with 3.62 g (16.7 mmol) of the compound from Example 29A in ethanol (8.4 ml) and 2.03 g (14.7 mmol) of potassium carbonate. After stirring for 10 min, 1.54 g (1.34 mmol) of tetrakis(triphenylphosphine)palladium and then 2.33 g (40.0 mmol) of potassium fluoride in water (5.8 ml) were added. The mixture was stirred under reflux for 8 h, and the reaction solution was cooled and diluted with ethyl acetate. The reaction solution was washed in water, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by means of column chromatography (silica gel, dichloromethane/methanol 100:1→80:1). Yield: 2.62 g (69% of theory, 4:1 mixture of methyl and ethyl ester) The mixture was stirred under reflux for 8 h the reaction solution was cooled The reaction solution was washed in water the organic phase was dried over magnesium sulphate filtered concentrated under reduced pressure The residue was purified by means of column chromatography (silica gel, dichloromethane/methanol 100:1→80:1) Yield: 2.62 g (69% of theory, 4:1 mixture of methyl and ethyl ester)

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

Procedure: A solution of 2.98 g (13.3 mmol) of the compound from Example 48A in toluene (25.0 ml) was admixed under argon at RT with 3.62 g (16.7 mmol) of the compound from Example 33A in ethanol (8.4 ml) and 2.03 g (14.7 mmol) of potassium carbonate. After stirring for 10 min, 1.54 g (1.34 mmol) of tetrakis(triphenylphosphine)palladium and then 2.33 g (40.0 mmol) of potassium fluoride in water (5.8 ml) were added. The mixture was stirred under reflux for 8 h, and the reaction solution was cooled and diluted with ethyl acetate. The reaction solution was washed in water, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by means of column chromatography (silica gel, dichloromethane/methanol 100:1→80:1). Yield: 2.62 g (69% of theory, 4:1 mixture of methyl and ethyl ester) The mixture was stirred under reflux for 8 h the reaction solution was cooled The reaction solution was washed in water the organic phase was dried over magnesium sulphate filtered concentrated under reduced pressure The residue was purified by means of column chromatography (silica gel, dichloromethane/methanol 100:1→80:1) Yield: 2.62 g (69% of theory, 4:1 mixture of methyl and ethyl ester)

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

Procedure: A solution of 2.98 g (13.3 mmol) of the compound from Example 48A in toluene (25.0 ml) was admixed under argon at RT with 3.62 g (16.7 mmol) of the compound from Example 33A in ethanol (8.4 ml) and 2.03 g (14.7 mmol) of potassium carbonate. After stirring for 10 min, 1.54 g (1.34 mmol) of tetrakis(triphenylphosphine)palladium and then 2.33 g (40.0 mmol) of potassium fluoride in water (5.8 ml) were added. The mixture was stirred under reflux for 8 h, and the reaction solution was cooled and diluted with ethyl acetate. The reaction solution was washed in water, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by means of column chromatography (silica gel, dichloromethane/methanol 100:1→80:1). Yield: 2.62 g (69% of theory, 4:1 mixture of methyl and ethyl ester) The mixture was stirred under reflux for 8 h the reaction solution was cooled The reaction solution was washed in water the organic phase was dried over magnesium sulphate filtered concentrated under reduced pressure The residue was purified by means of column chromatography (silica gel, dichloromethane/methanol 100:1→80:1) Yield: 2.62 g (69% of theory, 4:1 mixture of methyl and ethyl ester)

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

Procedure: A solution of 2.98 g (13.3 mmol) of the compound from Example 48A in toluene (25.0 ml) was admixed under argon at RT with 3.62 g (16.7 mmol) of the compound from Example 33A in ethanol (8.4 ml) and 2.03 g (14.7 mmol) of potassium carbonate. After stirring for 10 min, 1.54 g (1.34 mmol) of tetrakis(triphenylphosphine)palladium and then 2.33 g (40.0 mmol) of potassium fluoride in water (5.8 ml) were added. The mixture was stirred under reflux for 8 h, and the reaction solution was cooled and diluted with ethyl acetate. The reaction solution was washed in water, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by means of column chromatography (silica gel, dichloromethane/methanol 100:1→80:1). Yield: 2.62 g (69% of theory, 4:1 mixture of methyl and ethyl ester) The mixture was stirred under reflux for 8 h the reaction solution was cooled The reaction solution was washed in water the organic phase was dried over magnesium sulphate filtered concentrated under reduced pressure The residue was purified by means of column chromatography (silica gel, dichloromethane/methanol 100:1→80:1) Yield: 2.62 g (69% of theory, 4:1 mixture of methyl and ethyl ester)

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

Procedure: To a solution of 1-bromo-4-(1,1-difluoroethyl)benzene (1.00 g) in tetrahydrofuran (10.0 mL), n-butyl lithium (2.69 mol/L, solution in n-hexane, 1.68 mL) was added at −80° C. and the mixture was stirred at that temperature for 5 minutes. Subsequently, N,N-dimethylformamide (0.522 mL) was added at −80° C. and after stirring the mixture at that temperature for 20 minutes, 2 mol/L hydrochloric acid (2.50 mL) was added. After bringing the reaction mixture to room temperature, two extractions were conducted with ethyl acetate and the combined organic layers were washed with water. After drying over anhydrous magnesium sulfate and the desiccant was removed by filtration; the filtrate was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-90:10) to give the titled compound as a colorless oil (510 mg). after stirring the mixture at that temperature for 20 minutes to room temperature two extractions the combined organic layers were washed with water After drying over anhydrous magnesium sulfate the desiccant was removed by filtration the filtrate was then concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-90:10)

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

Procedure: A solution of 2.98 g (13.3 mmol) of the compound from Example 68A in toluene (25.0 ml) was admixed under argon at RT with 3.62 g (16.7 mmol) of the compound from Example 29A in ethanol (8.4 ml) and 2.03 g (14.7 mmol) of potassium carbonate. After stirring for 10 min, 1.54 g (1.34 mmol) of tetrakis(triphenylphosphine)palladium and then 2.33 g (40.0 mmol) of potassium fluoride in water (5.8 ml) were added. The mixture was stirred under reflux for 8 h, and the reaction solution was cooled and diluted with ethyl acetate. The reaction solution was washed in water, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by means of column chromatography (silica gel, dichloromethane/methanol 100:1→80:1). Yield: 2.62 g (69% of theory, 4:1 mixture of methyl and ethyl ester) The mixture was stirred under reflux for 8 h the reaction solution was cooled The reaction solution was washed in water the organic phase was dried over magnesium sulphate filtered concentrated under reduced pressure The residue was purified by means of column chromatography (silica gel, dichloromethane/methanol 100:1→80:1) Yield: 2.62 g (69% of theory, 4:1 mixture of methyl and ethyl ester)

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

Procedure: A solution of 2.98 g (13.3 mmol) of the compound from Example 48A in toluene (25.0 ml) was admixed under argon at RT with 3.62 g (16.7 mmol) of the compound from Example 33A in ethanol (8.4 ml) and 2.03 g (14.7 mmol) of potassium carbonate. After stirring for 10 min, 1.54 g (1.34 mmol) of tetrakis(triphenylphosphine)palladium and then 2.33 g (40.0 mmol) of potassium fluoride in water (5.8 ml) were added. The mixture was stirred under reflux for 8 h, and the reaction solution was cooled and diluted with ethyl acetate. The reaction solution was washed in water, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by means of column chromatography (silica gel, dichloromethane/methanol 100:1→80:1). Yield: 2.62 g (69% of theory, 4:1 mixture of methyl and ethyl ester) The mixture was stirred under reflux for 8 h the reaction solution was cooled The reaction solution was washed in water the organic phase was dried over magnesium sulphate filtered concentrated under reduced pressure The residue was purified by means of column chromatography (silica gel, dichloromethane/methanol 100:1→80:1) Yield: 2.62 g (69% of theory, 4:1 mixture of methyl and ethyl ester)