1-bromo-2-chloro-4-fluorobenzene

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

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

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 1-bromo-2-chloro-4-fluorobenzene (4.19 g, 20 mmoles), piperazine (10.32 g, 120 mmoles), sodium tert-butoxide (2.3 g, 1.5 mmoles), tris(dibenzylideneacetone)dipalladium (366 mg, 0.4 mmoles) and racemic (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (747 mg, 1.2 mmoles) in toluene (2 mL) was heated to 120° C. overnight. The mixture was cooled, filtered and the filtrate concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0-5% 2N methanolic ammonia in DCM) to provide the title compound. The mixture was cooled filtered the filtrate concentrated under reduced pressure The crude residue was purified by column chromatography (silica gel, 0-5% 2N methanolic ammonia in DCM)

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

Procedure: The title compound was prepared according to the procedure described for example AX from 1-bromo-2-chloro-4-fluorobenzene and N-Boc-piperazine (10%, off white solid, MS (m/e): 315.1 (M+H, 100%)

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

Procedure: The title compound was prepared according to the procedure described for example AX from 1-bromo-2-chloro-4-fluorobenzene and N-Boc-piperazine (10%, off white solid, MS (m/e): 315.1 (M+H, 100%)

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

Procedure: A solution of 24.0 g (115 mmol) of 2-chloro-4-fluorobromobenzene in 20 ml of diethyl ether was added dropwise to 2.92 g (120 mmol) of magnesium turnings in 780 ml of diethyl ether, activated by adding a few drops of dibromoethane, and the reaction mixture was heated under reflux overnight. The reaction solution was added dropwise under argon to a solution of 17.7 g (68.8 mmol) of the compound from Example 73A in 300 ml of THF, and the reaction mixture was stirred initially at RT overnight and then under reflux for 8 h. It was concentrated and taken up in ethyl acetate and saturated aqueous ammonium chloride solution, the phases were separated, and the organic phase was washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) to result in 2.20 g (14% of theory) of the title compound. the reaction mixture was heated under reflux overnight under reflux for 8 h It was concentrated saturated aqueous ammonium chloride solution, the phases were separated the organic phase was washed with water and saturated aqueous sodium bicarbonate solution dried over magnesium sulfate filtered concentrated The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient)

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

Procedure: A solution of 24.0 g (115 mmol) of 2-chloro-4-fluorobromobenzene in 20 ml of diethyl ether was added dropwise to 2.92 g (120 mmol) of magnesium turnings in 780 ml of diethyl ether, activated by adding a few drops of dibromoethane, and the reaction mixture was heated under reflux overnight. The reaction solution was added dropwise under argon to a solution of 17.7 g (68.8 mmol) of the compound from Example 73A in 300 ml of THF, and the reaction mixture was stirred initially at RT overnight and then under reflux for 8 h. It was concentrated and taken up in ethyl acetate and saturated aqueous ammonium chloride solution, the phases were separated, and the organic phase was washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) to result in 2.20 g (14% of theory) of the title compound. the reaction mixture was heated under reflux overnight under reflux for 8 h It was concentrated saturated aqueous ammonium chloride solution, the phases were separated the organic phase was washed with water and saturated aqueous sodium bicarbonate solution dried over magnesium sulfate filtered concentrated The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a reaction vessel were added 1-bromo-2-chloro-4-fluorobenzene (25 g), ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (46 g), toluene (125 ml), water (125 ml) and tripotassium phosphate (50.5 g), and purged with argon. To this mixture was added dichlorobis(triphenylphosphine)palladium(II) (1.67 g) and the mixture was stirred in an oil bath at 110° C. for 3 hr. The oil bath was removed, and water (125 ml) was added to the reaction mixture. The mixture was stirred at room temperature for 1 hr, and filtered through celite. The filtrate was partitioned in a separatory funnel. The aqueous layer was extracted with toluene, and the organic layers were combined. The organic layer was washed twice with water (125 ml), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound (41.8 g). The obtained solid was directly used for the next reaction without further purification. purged with argon To this mixture was added dichlorobis(triphenylphosphine)palladium(II) (1.67 g) The oil bath was removed water (125 ml) was added to the reaction mixture The mixture was stirred at room temperature for 1 hr filtered through celite The filtrate was partitioned in a separatory funnel The aqueous layer was extracted with toluene The organic layer was washed twice with water (125 ml) dried over anhydrous magnesium sulfate filtered The filtrate was concentrated under reduced pressure

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a reaction vessel were added 1-bromo-2-chloro-4-fluorobenzene (25 g), ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (46 g), toluene (125 ml), water (125 ml) and tripotassium phosphate (50.5 g), and purged with argon. To this mixture was added dichlorobis(triphenylphosphine)palladium(II) (1.67 g) and the mixture was stirred in an oil bath at 110° C. for 3 hr. The oil bath was removed, and water (125 ml) was added to the reaction mixture. The mixture was stirred at room temperature for 1 hr, and filtered through celite. The filtrate was partitioned in a separatory funnel. The aqueous layer was extracted with toluene, and the organic layers were combined. The organic layer was washed twice with water (125 ml), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound (41.8 g). The obtained solid was directly used for the next reaction without further purification. purged with argon To this mixture was added dichlorobis(triphenylphosphine)palladium(II) (1.67 g) The oil bath was removed water (125 ml) was added to the reaction mixture The mixture was stirred at room temperature for 1 hr filtered through celite The filtrate was partitioned in a separatory funnel The aqueous layer was extracted with toluene The organic layer was washed twice with water (125 ml) dried over anhydrous magnesium sulfate filtered The filtrate was concentrated under reduced pressure

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

Procedure: To a solution of 1-bromo-2-chloro-4-fluorobenzene (24.8 g, 119 mmol) and ethanethiol (10.6 mL, 143 mmol) in N,N-dimethylformamide (150 mL) was added sodium hydride (60% in oil, 6.00 g, 150 mmol) at room temperature by small portions, and the resulting mixture was stirred for 4 hr. The reaction mixture was diluted with ethyl acetate, washed twice with water and once with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane) to give the title compound (19.4 g, yield 65%) as a colorless oil. washed twice with water and once with saturated brine dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (hexane)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 1-bromo-2-chloro-4-fluorobenzene (4.19 g, 20 mmoles), piperazine (10.32 g, 120 mmoles), sodium tert-butoxide (2.3 g, 1.5 mmoles), tris(dibenzylideneacetone)dipalladium (366 mg, 0.4 mmoles) and racemic (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (747 mg, 1.2 mmoles) in toluene (2 mL) was heated to 120° C. overnight. The mixture was cooled, filtered and the filtrate concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0-5% 2N methanolic ammonia in DCM) to provide the title compound. The mixture was cooled filtered the filtrate concentrated under reduced pressure The crude residue was purified by column chromatography (silica gel, 0-5% 2N methanolic ammonia in DCM)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 1-bromo-2-chloro-4-fluorobenzene (4.19 g, 20 mmoles), piperazine (10.32 g, 120 mmoles), sodium tert-butoxide (2.3 g, 1.5 mmoles), tris(dibenzylideneacetone)dipalladium (366 mg, 0.4 mmoles) and racemic (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (747 mg, 1.2 mmoles) in toluene (2 mL) was heated to 120° C. overnight. The mixture was cooled, filtered and the filtrate concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0-5% 2N methanolic ammonia in DCM) to provide the title compound. The mixture was cooled filtered the filtrate concentrated under reduced pressure The crude residue was purified by column chromatography (silica gel, 0-5% 2N methanolic ammonia in DCM)