methyl 4-bromo-2-cyanobenzoate

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

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

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

Procedure: Methyl 4-bromo-2-cyanobenzoate (8.53 g) described in Preparation Example 75 was dissolved in dimethoxyethane (140 mL), a solution of lithium hydroxide 1 hydrate (2.24 g) in water (54 mL) was added dropwise under ice-cooling, and the mixture was stirred at the same temperature for 30 min. To the reaction mixture was added dropwise 1N hydrochloric acid (60 mL) under ice-cooling, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated to give the title compound (7.97 g). cooling cooling the mixture was extracted with ethyl acetate The organic layer was washed with saturated brine dried over sodium sulfate the solvent was evaporated

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of methyl 4-bromo-2-iodobenzoate (3.52 g) described in Preparation Example 74 and copper cyanide (1.16 g) was added N-methylpyrrolidone (21 mL), and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was cooled, a solution of saturated aqueous ammonium chloride solution and aqueous ammonia (1:1) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a solution of saturated aqueous ammonium chloride solution and aqueous ammonia (1:1), saturated aqueous ammonium chloride solution, and saturated brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated to give the title compound (2.39 g). The reaction mixture was cooled the mixture was extracted with ethyl acetate The organic layer was washed with a solution of saturated aqueous ammonium chloride solution and aqueous ammonia (1:1), saturated aqueous ammonium chloride solution, and saturated brine The organic layer was dried over sodium sulfate the solvent was evaporated

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of methyl 4-bromo-2-iodobenzoate (3.52 g) described in Preparation Example 74 and copper cyanide (1.16 g) was added N-methylpyrrolidone (21 mL), and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was cooled, a solution of saturated aqueous ammonium chloride solution and aqueous ammonia (1:1) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a solution of saturated aqueous ammonium chloride solution and aqueous ammonia (1:1), saturated aqueous ammonium chloride solution, and saturated brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated to give the title compound (2.39 g). The reaction mixture was cooled the mixture was extracted with ethyl acetate The organic layer was washed with a solution of saturated aqueous ammonium chloride solution and aqueous ammonia (1:1), saturated aqueous ammonium chloride solution, and saturated brine The organic layer was dried over sodium sulfate the solvent was evaporated

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of methyl 4-bromo-2-iodobenzoate (3.52 g) described in Preparation Example 74 and copper cyanide (1.16 g) was added N-methylpyrrolidone (21 mL), and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was cooled, a solution of saturated aqueous ammonium chloride solution and aqueous ammonia (1:1) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a solution of saturated aqueous ammonium chloride solution and aqueous ammonia (1:1), saturated aqueous ammonium chloride solution, and saturated brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated to give the title compound (2.39 g). The reaction mixture was cooled the mixture was extracted with ethyl acetate The organic layer was washed with a solution of saturated aqueous ammonium chloride solution and aqueous ammonia (1:1), saturated aqueous ammonium chloride solution, and saturated brine The organic layer was dried over sodium sulfate the solvent was evaporated

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

Procedure: A mixture of methyl 4-bromo-2-cyanobenzoate (230 mg, 0.96 mmol), allyl-tributyl-stannane (381 mg, 1.2 mmol), LiCl (126 mg, 2.87 mmol) and Pd(PPh3)4 (23 mg) in anhydrous toluene was refluxed under N2 overnight. Distilled off the solvent under reduce pressure, the residue was purified with prep-TLC to give the product methyl 2-cyano-4-(prop-2-en-1-yl)benzoate. was refluxed under N2 overnight Distilled off the solvent the residue was purified with prep-TLC

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of methyl 2-amino-4-bromobenzoate (500 mg, 2.2 mmol) in 2 mL of conc. HCl was added 5 mL of water and a solution of NaNO2 (159 mg, 2.3 mmol) in water (1 mL) was added over a 10-minute period at 0° C. This diazonium solution was then brought to pH 6 with aqueous NaHCO3. In a separated vail, a solution of CuSO4 (660 mg, 2.75 mmol) in water (2 mL) was added dropwise to a solution of KCN (657 mg, 10.11 mmol) in water (2 mL) at 0° C., then toluene (5 mL) was added and the mixture was stirred and heated to 60° C. The previously prepared diazonium solution was added dropwise to the brown CuCN solution at 60° C. over 40 min. The reaction mixture was heated to 70° C. for 1 hour and cooled to room temperature, and EtOAc (100 mL) was added. The organic phase was washed with brine (20 mL) and concentrated. The crude product was purified via cprep-TLC to afford the methyl 4-bromo-2-cyanobenzoate. 1H-NMR (400 MHz, CDCl3) δ 7.75-7.95 (m, 3H), 3.93 (s, 3H). The reaction mixture was heated to 70° C. for 1 hour cooled to room temperature The organic phase was washed with brine (20 mL) concentrated The crude product was purified via cprep-TLC

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

Procedure: To methyl 4-bromo-2-cyanobenzoate (4.76 g) described in Preparation Example 191 was added dimethoxyethane (78 mL), a solution obtained by dissolving lithium hydroxide monohydrate (1.25 g) in water (30 mL) under ice-cooling was added dropwise, and the mixture was stirred for 1 hr. Under ice-cooling, the mixture was neutralized with 1N hydrochloric acid and dimethoxyethane was evaporated. Water was added and the mixture was stirred under ice-cooling. The precipitated crystals were collected by filtration to give the title compound (4.19 g). a solution obtained cooling was added dropwise Under ice-cooling was evaporated Water was added the mixture was stirred under ice- cooling The precipitated crystals were collected by filtration

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To methyl 4-bromo-2-iodobenzoate (3.52 g) described in Preparation Example 190 were added copper cyanide (1.16 g) and N-methylpyrrolidone (21 mL) and the mixture was stirred at 60° C. for 1 hr. Under cooling with water, ethyl acetate, saturated aqueous ammonium chloride solution and aqueous ammonia were added and the mixture was extracted with ethyl acetate. The organic layer was washed once with saturated aqueous ammonium chloride solution and aqueous ammonia, once with saturated aqueous ammonium chloride solution and once with saturated brine, and dried over sodium sulfate. The solvent was evaporated to give the title compound (2.39 g). were added the mixture was extracted with ethyl acetate The organic layer was washed once with saturated aqueous ammonium chloride solution and aqueous ammonia, once with saturated aqueous ammonium chloride solution and once with saturated brine dried over sodium sulfate The solvent was evaporated