3-bromo-4-fluorobenzonitrile

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Prepared according to the method described in Example 12b) from (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-ylbutoxyl]enzeneboronic acid (0.20 g, Example 33), 3-bromo-4-fluorobenzonitrile (0.27 g), 2M aqueous sodium carbonate (0.76 ml) and tetrakis(triphenylphosphine)palladium (0) (0.019 g) in ethanol (5 ml) with heating at 90° C. for 4 hours. After work up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as an oil (0.22 g). Prepared After work up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-10% ethanol in dichloromethane

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Bromo-4-fluorobenzonitrile (10.0 g, 50 mmol, 1 eq) and imidazole (5.1 g, 75 mmol, 1.5 eq) are dissolved in dimethylformamide (100 ml) and carefully admixed with sodium hydride (60% in mineral oil, 3.0 g, 75 mmol, 1.5 eq) under nitrogen at room temperature. The mixture is stirred at 100° C. for 4 hours. After cooling to room temperature, water (10 ml) is added and the mixture is evaporated to dryness. The residue is washed with water and petroleum ether and purified by column chromatography (silica gel, methyl tert-butyl ether/ethyl acetate gradient). After cooling to room temperature the mixture is evaporated to dryness The residue is washed with water and petroleum ether purified by column chromatography (silica gel, methyl tert-butyl ether/ethyl acetate gradient)

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

Procedure: 3-Bromo-4-fluorobenzonitrile (2.00 g, 10 mmol) was coupled to 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (4.01 g, 15 mmol) following the procedure described in Example 14 part a), affording 6,2′-difluoro-5′-nitrobiphenyl-3-carbonitrile as a brown solid (2.60 g, 100%). δH (360 MHz, CDCl3) 7.38 (2H, q, J 8.8), 7.77-7.82 (2H, m), 8.33-8.38 (2H, m).

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

Procedure: 765 g (3.5 moles) of 3-bromo-4-fluoro-benzoic acid amide was added, at 25° C., to 1,150 g (9.7 moles) of thionyl chloride and the mixture was heated under reflux at 85° to 90° C., while stirring, until virtually no further evolution of gas took place. The excess thionyl chloride was then distilled off and the residue was fractionated in a short column. 630 g (91% of theory) of 3-bromo-4-fluoro-benzonitrile with a boiling point of 115°-116° C./20 mm Hg were obtained. the mixture was heated under reflux at 85° to 90° C. The excess thionyl chloride was then distilled off

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

Procedure: A mixture of 85 g of Raney nickel, which had been washed thoroughly with water, 500 ml of formic acid and 100 g (0.5 mole) of 3-bromo-4-fluoro-benzonitrile was stirred for 24 hours at 90°-100° C. under an atmosphere of a blanketing gas (nitrogen or argon). After cooling to room temperature, 1 liter of water was added and the mixture was extracted twice with 300 ml of toluene. The combined toluene solutions were washed with 200 ml of water, with 200 ml of saturated sodium bicarbonate solution and again with 200 ml of water and then dried by incipient distillation. 1.5 g of air-dried ion exchanger SPC 118, 16 g (0.5 mole) of methanol and 58.5 g (0.55 mole) of orthoformic acid trimethyl ester were then added to the solution, the mixture was stirred for a further 1 hour without a bath and was then warmed at 50° C. for 2 hours. The reaction mixture was cooled, filtered to remove the ion exchanger and washed with 200 ml of 5% strength potassium carbonate solution. The solvent was then stripped off and the residue was distilled in vacuo. 93 g (75% of theory) of 3-bromo-4-fluoro-benzaldehyde dimethyl acetal were obtained in this way, in the form of a colorless liquid with a boiling point of 67°-68° C./0.1 mm Hg. the mixture was extracted twice with 300 ml of toluene The combined toluene solutions were washed with 200 ml of water, with 200 ml of saturated sodium bicarbonate solution and again with 200 ml of water dried by incipient distillation the mixture was stirred for a further 1 hour without a bath was then warmed at 50° C. for 2 hours The reaction mixture was cooled filtered to remove the ion exchanger washed with 200 ml of 5% strength potassium carbonate solution the residue was distilled in vacuo

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

Procedure: A mixture of 85 g of Raney nickel, which had been washed thoroughly with water, 500 ml of formic acid and 100 g (0.5 mole) of 3-bromo-4-fluoro-benzonitrile was stirred for 24 hours at 90°-100° C. under an atmosphere of a blanketing gas (nitrogen or argon). After cooling to room temperature, 1 liter of water was added and the mixture was extracted twice with 300 ml of toluene. The combined toluene solutions were washed with 200 ml of water, with 200 ml of saturated sodium bicarbonate solution and again with 200 ml of water and then dried by incipient distillation. 1.5 g of air-dried ion exchanger SPC 118, 16 g (0.5 mole) of methanol and 58.5 g (0.55 mole) of orthoformic acid trimethyl ester were then added to the solution, the mixture was stirred for a further 1 hour without a bath and was then warmed at 50° C. for 2 hours. The reaction mixture was cooled, filtered to remove the ion exchanger and washed with 200 ml of 5% strength potassium carbonate solution. The solvent was then stripped off and the residue was distilled in vacuo. 93 g (75% of theory) of 3-bromo-4-fluoro-benzaldehyde dimethyl acetal were obtained in this way, in the form of a colorless liquid with a boiling point of 67°-68° C./0.1 mm Hg. the mixture was extracted twice with 300 ml of toluene The combined toluene solutions were washed with 200 ml of water, with 200 ml of saturated sodium bicarbonate solution and again with 200 ml of water dried by incipient distillation the mixture was stirred for a further 1 hour without a bath was then warmed at 50° C. for 2 hours The reaction mixture was cooled filtered to remove the ion exchanger washed with 200 ml of 5% strength potassium carbonate solution the residue was distilled in vacuo

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

Procedure: 17.0 g of a 50% strength alkaline suspension of Raney nickel were filtered under a nitrogen atmosphere and the material on the filter was washed until neutral. The Raney nickel obtained by this method was suspended in 150 ml of formic acid. 20.0 g (0.1 mole) of 3-bromo-4-fluoro-benzonitrile were added to this suspension. The mixture was heated at 80° to 90° C. for 3 to 5 hours and the reaction mixture was then cooled and poured into 300 ml of water. After filtering, the filtrate was twice extracted with, in each case, 200 ml of toluene. The toluene phase was dried over sodium sulphate and then concentrated. 17.2 g (85% of theory) of 3-bromo-4-fluoro-benzaldehyde with a boiling point of 63°-65° C./0.3 mm Hg were obtained. were filtered under a nitrogen atmosphere the material on the filter was washed until neutral The Raney nickel obtained by this method The mixture was heated at 80° to 90° C. for 3 to 5 hours the reaction mixture was then cooled After filtering the filtrate was twice extracted with, in each case, 200 ml of toluene The toluene phase was dried over sodium sulphate concentrated

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

Procedure: 17.0 g of a 50% strength alkaline suspension of Raney nickel were filtered under a nitrogen atmosphere and the material on the filter was washed until neutral. The Raney nickel obtained by this method was suspended in 150 ml of formic acid. 20.0 g (0.1 mole) of 3-bromo-4-fluoro-benzonitrile were added to this suspension. The mixture was heated at 80° to 90° C. for 3 to 5 hours and the reaction mixture was then cooled and poured into 300 ml of water. After filtering, the filtrate was twice extracted with, in each case, 200 ml of toluene. The toluene phase was dried over sodium sulphate and then concentrated. 17.2 g (85% of theory) of 3-bromo-4-fluoro-benzaldehyde with a boiling point of 63°-65° C./0.3 mm Hg were obtained. were filtered under a nitrogen atmosphere the material on the filter was washed until neutral The Raney nickel obtained by this method The mixture was heated at 80° to 90° C. for 3 to 5 hours the reaction mixture was then cooled After filtering the filtrate was twice extracted with, in each case, 200 ml of toluene The toluene phase was dried over sodium sulphate concentrated

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

Procedure: 3-Bromo-4-flurobenzonitrile (3.00 g, 15 mmol), benzyl alcohol (1.71 ml, 16.5 mmol) and THF (40 ml) are combined and treated with 60% sodium hydride in oil (0.66 g, 16.5 mmol). The reaction mixture is heated to reflux under nitrogen for 3 hours. Aqueous workup and chromatographic purification (cyclohexane:dichloromethane, 3:1) yields 4-benzyloxy-3-bromobenzonitrile as a white solid (3.88 g, 13.5 mmol). A portion of this material (2.64 g, 9.16 mmol) in THF (25 ml) is treated with a 1 M solution of borane in THF (18.3 ml, 18.3 mmol). After the exotherm subsides the reaction is refluxed a couple of days under nitrogen. The excess borane is destroyed by the addition of methanol and 4-benzyloxy-3-bromobenzylamine is precipitated as the hydrochloride salt (1.58 g, 4.8 mmol). This material is suspended in dichloromethane (30 ml) and treated successively with triethyl amine (1.68 ml, 12.02 mmol) and di-tert-butyl dicarbonate (1.26 g, 5.77 mmol). The reaction mixture is stirred under nitrogen four hours; aqueous workup and chromatographic purification (ethyl acetate:cyclohexane, 3:7) yields the title compound as a white solid (1.69 g, 4.3 mmol). MS(EI): 394(M+). The reaction mixture is heated to reflux under nitrogen for 3 hours Aqueous workup and chromatographic purification (cyclohexane:dichloromethane, 3:1)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Prepared according to the method described in Example 12b) from (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-ylbutoxyl]enzeneboronic acid (0.20 g, Example 33), 3-bromo-4-fluorobenzonitrile (0.27 g), 2M aqueous sodium carbonate (0.76 ml) and tetrakis(triphenylphosphine)palladium (0) (0.019 g) in ethanol (5 ml) with heating at 90° C. for 4 hours. After work up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as an oil (0.22 g). Prepared After work up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-10% ethanol in dichloromethane

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Bromo-4-fluorobenzonitrile (10.0 g, 50 mmol, 1 eq) and imidazole (5.1 g, 75 mmol, 1.5 eq) are dissolved in dimethylformamide (100 ml) and carefully admixed with sodium hydride (60% in mineral oil, 3.0 g, 75 mmol, 1.5 eq) under nitrogen at room temperature. The mixture is stirred at 100° C. for 4 hours. After cooling to room temperature, water (10 ml) is added and the mixture is evaporated to dryness. The residue is washed with water and petroleum ether and purified by column chromatography (silica gel, methyl tert-butyl ether/ethyl acetate gradient). After cooling to room temperature the mixture is evaporated to dryness The residue is washed with water and petroleum ether purified by column chromatography (silica gel, methyl tert-butyl ether/ethyl acetate gradient)

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

Procedure: 3-Bromo-4-fluorobenzonitrile (25 g, 0.125 mol) was dissolved in concentrated sulfuric acid (200 ml), and at 0° C., fuming nitric acid was dropwise added at 0° C., taking 1 hour. After stirred for 30 minutes at the same temperature, this was heated up to room temperature, taking 1.5 hours. This was gradually poured into ice. The formed precipitate was collected by filtration with washing with water, and dried under reduced pressure. The collected yellow powder was fractionated with chloroform and aqueous 1 M sodium hydroxide solution. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was well dried under reduced pressure to obtain the entitled compound (14.7 g, 48%) as a yellow powder. at 0° C. was dropwise added at 0° C. taking 1.5 hours This was gradually poured into ice The formed precipitate was collected by filtration with washing with water dried under reduced pressure The organic layer was washed with saturated brine dried over anhydrous sodium sulfate The solvent was evaporated away the resulting residue was well dried under reduced pressure