2-bromo-4-(bromomethyl)benzonitrile

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

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

Procedure: To a solution of 2-bromo-4-(bromomethyl)benzonitrile (18.0 g, 65.5 mmol) in DMF (60 mL), potassium phthalide (18.2 g, 98.2 mmol) was added, and then the mixture was stirred under reflux for 4 h. The reaction was allowed to cool to room temperature. After removing DMF under reduced pressure, the residue was dissolved in CH2Cl2 (200 mL), and washed with water (50 mL×2). The organic layer was dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was recrystallized from toluene and EtOH to give the product, 2-bromo-4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzonitrile (13.5 g, 61%). under reflux for 4 h After removing DMF under reduced pressure the residue was dissolved in CH2Cl2 (200 mL) washed with water (50 mL×2) The organic layer was dried over anhydrous sodium sulfate After evaporation of the solvent the residue was recrystallized from toluene and EtOH

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

Procedure: To a solution of 2-bromo-4-(bromomethyl)benzonitrile (18.0 g, 65.5 mmol) in DMF (60 mL), potassium phthalide (18.2 g, 98.2 mmol) was added, and then the mixture was stirred under reflux for 4 h. The reaction was allowed to cool to room temperature. After removing DMF under reduced pressure, the residue was dissolved in CH2Cl2 (200 mL), and washed with water (50 mL×2). The organic layer was dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was recrystallized from toluene and EtOH to give the product, 2-bromo-4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzonitrile (13.5 g, 61%). under reflux for 4 h After removing DMF under reduced pressure the residue was dissolved in CH2Cl2 (200 mL) washed with water (50 mL×2) The organic layer was dried over anhydrous sodium sulfate After evaporation of the solvent the residue was recrystallized from toluene and EtOH

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

Procedure: A mixture of 2-bromo-4-methylbenzonitrile (13.3 g, 81.4 mmol), NBS (14.4 g, 84.4 mmol) and BPO (0.20 g) in CCl4 (150 mL) was heated for 4 h at reflux. The reaction mixture was cooled to room temperature and filtered. Then the solid was washed with CCl4 (20 mL×2) and the combined filtrates were washed successively with saturated sodium bicarbonate (50 mL), water (2×100 mL) and sodium thiosulfate (50 mL). The organic phase was dried over NaSO4 and concentrated in vacuum afforded the titled compound, 2-bromo-4-(bromomethyl)benzonitrile (18.7 g, 100%). was heated for 4 h at reflux filtered Then the solid was washed with CCl4 (20 mL×2) the combined filtrates were washed successively with saturated sodium bicarbonate (50 mL), water (2×100 mL) and sodium thiosulfate (50 mL) The organic phase was dried over NaSO4 concentrated in vacuum

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

Procedure: To a solution of 2-bromo-4-(bromomethyl)benzonitrile (18.0 g, 65.5 mmol) in DMF (60 mL), potassium phthalide (18.2 g, 98.2 mmol) was added, and then the mixture was stirred under reflux for 4 h. The reaction was allowed to cool to room temperature. After removing DMF under reduced pressure, the residue was dissolved in CH2Cl2 (200 mL), and washed with water (50 mL×2). The organic layer was dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was recrystallized from toluene and EtOH to give the product, 2-bromo-4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzonitrile (13.5 g, 61%). under reflux for 4 h After removing DMF under reduced pressure the residue was dissolved in CH2Cl2 (200 mL) washed with water (50 mL×2) The organic layer was dried over anhydrous sodium sulfate After evaporation of the solvent the residue was recrystallized from toluene and EtOH

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

Procedure: A mixture of 2-bromo-4-methylbenzonitrile (13.3 g, 81.4 mmol), NBS (14.4 g, 84.4 mmol) and BPO (0.20 g) in CCl4 (150 mL) was heated for 4 h at reflux. The reaction mixture was cooled to room temperature and filtered. Then the solid was washed with CCl4 (20 mL×2) and the combined filtrates were washed successively with saturated sodium bicarbonate (50 mL), water (2×100 mL) and sodium thiosulfate (50 mL). The organic phase was dried over NaSO4 and concentrated in vacuum afforded the titled compound, 2-bromo-4-(bromomethyl)benzonitrile (18.7 g, 100%). was heated for 4 h at reflux filtered Then the solid was washed with CCl4 (20 mL×2) the combined filtrates were washed successively with saturated sodium bicarbonate (50 mL), water (2×100 mL) and sodium thiosulfate (50 mL) The organic phase was dried over NaSO4 concentrated in vacuum

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

Procedure: A mixture of 2-bromo-4-methylbenzonitrile (13.3 g, 81.4 mmol), NBS (14.4 g, 84.4 mmol) and BPO (0.20 g) in CCl4 (150 mL) was heated for 4 h at reflux. The reaction mixture was cooled to room temperature and filtered. Then the solid was washed with CCl4 (20 mL×2) and the combined filtrates were washed successively with saturated sodium bicarbonate (50 mL), water (2×100 mL) and sodium thiosulfate (50 mL). The organic phase was dried over NaSO4 and concentrated in vacuum afforded the titled compound, 2-bromo-4-(bromomethyl)benzonitrile (18.7 g, 100%). was heated for 4 h at reflux filtered Then the solid was washed with CCl4 (20 mL×2) the combined filtrates were washed successively with saturated sodium bicarbonate (50 mL), water (2×100 mL) and sodium thiosulfate (50 mL) The organic phase was dried over NaSO4 concentrated in vacuum

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

Procedure: To a solution of 2-bromo-4-(bromomethyl)benzonitrile (18.0 g, 65.5 mmol) in DMF (60 mL), potassium phthalide (18.2 g, 98.2 mmol) was added, and then the mixture was stirred under reflux for 4 h. The reaction was allowed to cool to room temperature. After removing DMF under reduced pressure, the residue was dissolved in CH2Cl2 (200 mL), and washed with water (50 mL×2). The organic layer was dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was recrystallized from toluene and EtOH to give the product, 2-bromo-4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzonitrile (13.5 g, 61%). under reflux for 4 h After removing DMF under reduced pressure the residue was dissolved in CH2Cl2 (200 mL) washed with water (50 mL×2) The organic layer was dried over anhydrous sodium sulfate After evaporation of the solvent the residue was recrystallized from toluene and EtOH

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

Procedure: To a solution of 2-bromo-4-(bromomethyl)benzonitrile (18.0 g, 65.5 mmol) in DMF (60 mL), potassium phthalide (18.2 g, 98.2 mmol) was added, and then the mixture was stirred under reflux for 4 h. The reaction was allowed to cool to room temperature. After removing DMF under reduced pressure, the residue was dissolved in CH2Cl2 (200 mL), and washed with water (50 mL×2). The organic layer was dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was recrystallized from toluene and EtOH to give the product, 2-bromo-4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzonitrile (13.5 g, 61%). under reflux for 4 h After removing DMF under reduced pressure the residue was dissolved in CH2Cl2 (200 mL) washed with water (50 mL×2) The organic layer was dried over anhydrous sodium sulfate After evaporation of the solvent the residue was recrystallized from toluene and EtOH

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

Procedure: A mixture of 2-bromo-4-methylbenzonitrile (13.3 g, 81.4 mmol), NBS (14.4 g, 84.4 mmol) and BPO (0.20 g) in CCl4 (150 mL) was heated for 4 h at reflux. The reaction mixture was cooled to room temperature and filtered. Then the solid was washed with CCl4 (20 mL×2) and the combined filtrate was washed successively with saturated sodium bicarbonate (50 mL), water (2×100 mL) and sodium thiosulfate (50 mL). The organic phase was dried over Na2SO4 and concentrated in vacuum afforded the titled compound, 2-bromo-4-(bromomethyl)benzonitrile (18.7 g, 100%). was heated for 4 h at reflux filtered Then the solid was washed with CCl4 (20 mL×2) the combined filtrate was washed successively with saturated sodium bicarbonate (50 mL), water (2×100 mL) and sodium thiosulfate (50 mL) The organic phase was dried over Na2SO4 concentrated in vacuum

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

Procedure: To tert-butyl-4-{3-[(3R)-3-{[(1S)-1-(5-hydroxypyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (100 mg, 0.18 mmol) in DMF (3 mL) was added sodium hydride (8 mg, 60% 0.2 mmol). The solution was cooled to 0° C. and 2-bromo-4-(bromomethyl)benzonitrile (55 mg, 0.2 mmol) while stirring. The mixture was warmed to room temperature and quenched by addition of water and ethyl acetate after 45 minutes. Phases were separated and the water phase was extracted with ethyl acetate. Combined organic extracts were concentrated in vacuum and the residue was purified by preparative HPLC to yield 46 mg of tert-butyl-4-{3-[(3R)-3-{[(1S)-1-{5-[(3-bromo-4-cyanobenzyl)oxy]pyridin-3-yl}-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate. The mixture was warmed to room temperature quenched by addition of water and ethyl acetate after 45 minutes Phases were separated the water phase was extracted with ethyl acetate Combined organic extracts were concentrated in vacuum the residue was purified by preparative HPLC

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