2-phenylmethoxybenzonitrile

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Titanium(IV) isopropoxide (1.62 mL) was added to a stirred solution of 2-(benzyloxy)benzonitrile (1.05 g) in diethyl ether (25 mL) cooled to −78° C. under N2 followed by the dropwise addition of ethylmagnesium bromide (3.67 mL of a 3M solution in diethylether). The resulting mixture was stirred at −78° C. for 10 min and then warmed to rt over 1 h. Boron trifluoride diethyl etherate (1.27 mL) was added dropwise and the mixture was stirred for 1 h. The reaction was quenched with 1M HCl (30 mL). Diethyl ether (30 mL) was added and the organic layer separated. To the aqueous layer was added aqueous 10% NaOH (50 mL) and diethyl ether and this was filtered through celite to remove solids (which were washed with further diethyl ether). This mixture was extracted with diethyl ether (2×70 mL) and dichloromethane (70 mL). All the organic layers were combined, dried (Na2SO4) and the solvents removed in vacuo. The residue was dissolved in dichloromethane and loaded on to an 10 g SCX cartridge. The impurities were washed through with methanol (50 mL) and discarded. Elution with 7N methanolic ammonia (25 mL) and evaporation in vacuo gave the subtitle compound as a brown oil (0.625 g). warmed to rt over 1 h the mixture was stirred for 1 h The reaction was quenched with 1M HCl (30 mL) Diethyl ether (30 mL) was added the organic layer separated To the aqueous layer was added aqueous 10% NaOH (50 mL) and diethyl ether this was filtered through celite to remove solids (which were washed with further diethyl ether) This mixture was extracted with diethyl ether (2×70 mL) and dichloromethane (70 mL) dried (Na2SO4) the solvents removed in vacuo The residue was dissolved in dichloromethane The impurities were washed through with methanol (50 mL) Elution with 7N methanolic ammonia (25 mL) and evaporation in vacuo

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

Procedure: 2-Hydroxy-4-nitro-benzonitrile (11.2 g, 68 mmole) was dissolved in DMF (200 ml). Potassium carbonate (11 g. 80 mmole) and benzyl bromide (9 ml, 75 mmole) were added. The reaction was stirred at room temperature overnight. The DMF was removed in vacuo and the residue taken up in ethyl acetate and water. The organic layer was separated, washed with 1 N NaOH, then with water, and dried over sodium sulfate. The crude product (5 g) was dissolved in ethyl acetate (75 ml) and added to a flask containing 5% Pt/C (500 mg). The reaction was placed under a hydrogen atmosphere (balloon) and stirred vigorously for several hours until the reaction was done (TLC). The catalyst was filtered off and the solvent removed. The product was purified by flash chromatography to yield 4.12 g of 4-amino, 2-benzyloxybenzonitrile. The DMF was removed in vacuo The organic layer was separated washed with 1 N NaOH with water, and dried over sodium sulfate The crude product (5 g) was dissolved in ethyl acetate (75 ml) added to a flask containing 5% Pt/C (500 mg) stirred vigorously for several hours until the reaction The catalyst was filtered off the solvent removed The product was purified by flash chromatography

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

Procedure: 2-Hydroxy-4-nitro-benzonitrile (11.2 g, 68 mmole) was dissolved in DMF (200 ml). Potassium carbonate (11 g. 80 mmole) and benzyl bromide (9 ml, 75 mmole) were added. The reaction was stirred at room temperature overnight. The DMF was removed in vacuo and the residue taken up in ethyl acetate and water. The organic layer was separated, washed with 1 N NaOH, then with water, and dried over sodium sulfate. The crude product (5 g) was dissolved in ethyl acetate (75 ml) and added to a flask containing 5% Pt/C (500 mg). The reaction was placed under a hydrogen atmosphere (balloon) and stirred vigorously for several hours until the reaction was done (TLC). The catalyst was filtered off and the solvent removed. The product was purified by flash chromatography to yield 4.12 g of 4-amino, 2-benzyloxybenzonitrile. The DMF was removed in vacuo The organic layer was separated washed with 1 N NaOH with water, and dried over sodium sulfate The crude product (5 g) was dissolved in ethyl acetate (75 ml) added to a flask containing 5% Pt/C (500 mg) stirred vigorously for several hours until the reaction The catalyst was filtered off the solvent removed The product was purified by flash chromatography

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

Procedure: 2-Hydroxy-4-nitro-benzonitrile (11.2 g, 68 mmole) was dissolved in DMF (200 ml). Potassium carbonate (11 g. 80 mmole) and benzyl bromide (9 ml, 75 mmole) were added. The reaction was stirred at room temperature overnight. The DMF was removed in vacuo and the residue taken up in ethyl acetate and water. The organic layer was separated, washed with 1 N NaOH, then with water, and dried over sodium sulfate. The crude product (5 g) was dissolved in ethyl acetate (75 ml) and added to a flask containing 5% Pt/C (500 mg). The reaction was placed under a hydrogen atmosphere (balloon) and stirred vigorously for several hours until the reaction was done (TLC). The catalyst was filtered off and the solvent removed. The product was purified by flash chromatography to yield 4.12 g of 4-amino, 2-benzyloxybenzonitrile. The DMF was removed in vacuo The organic layer was separated washed with 1 N NaOH with water, and dried over sodium sulfate The crude product (5 g) was dissolved in ethyl acetate (75 ml) added to a flask containing 5% Pt/C (500 mg) stirred vigorously for several hours until the reaction The catalyst was filtered off the solvent removed The product was purified by flash chromatography

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

Procedure: 2-Hydroxy-4-nitro-benzonitrile (11.2 g, 68 mmole) was dissolved in DMF (200 ml). Potassium carbonate (11 g. 80 mmole) and benzyl bromide (9 ml, 75 mmole) were added. The reaction was stirred at room temperature overnight. The DMF was removed in vacuo and the residue taken up in ethyl acetate and water. The organic layer was separated, washed with 1 N NaOH, then with water, and dried over sodium sulfate. The crude product (5 g) was dissolved in ethyl acetate (75 ml) and added to a flask containing 5% Pt/C (500 mg). The reaction was placed under a hydrogen atmosphere (balloon) and stirred vigorously for several hours until the reaction was done (TLC). The catalyst was filtered off and the solvent removed. The product was purified by flash chromatography to yield 4.12 g of 4-amino, 2-benzyloxybenzonitrile. The DMF was removed in vacuo The organic layer was separated washed with 1 N NaOH with water, and dried over sodium sulfate The crude product (5 g) was dissolved in ethyl acetate (75 ml) added to a flask containing 5% Pt/C (500 mg) stirred vigorously for several hours until the reaction The catalyst was filtered off the solvent removed The product was purified by flash chromatography

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Titanium(IV) isopropoxide (1.62 mL) was added to a stirred solution of 2-(benzyloxy)benzonitrile (1.05 g) in diethyl ether (25 mL) cooled to −78° C. under N2 followed by the dropwise addition of ethylmagnesium bromide (3.67 mL of a 3M solution in diethylether). The resulting mixture was stirred at −78° C. for 10 min and then warmed to rt over 1 h. Boron trifluoride diethyl etherate (1.27 mL) was added dropwise and the mixture was stirred for 1 h. The reaction was quenched with 1M HCl (30 mL). Diethyl ether (30 mL) was added and the organic layer separated. To the aqueous layer was added aqueous 10% NaOH (50 mL) and diethyl ether and this was filtered through celite to remove solids (which were washed with further diethyl ether). This mixture was extracted with diethyl ether (2×70 mL) and dichloromethane (70 mL). All the organic layers were combined, dried (Na2SO4) and the solvents removed in vacuo. The residue was dissolved in dichloromethane and loaded on to an 10 g SCX cartridge. The impurities were washed through with methanol (50 mL) and discarded. Elution with 7N methanolic ammonia (25 mL) and evaporation in vacuo gave the subtitle compound as a brown oil (0.625 g). warmed to rt over 1 h the mixture was stirred for 1 h The reaction was quenched with 1M HCl (30 mL) Diethyl ether (30 mL) was added the organic layer separated To the aqueous layer was added aqueous 10% NaOH (50 mL) and diethyl ether this was filtered through celite to remove solids (which were washed with further diethyl ether) This mixture was extracted with diethyl ether (2×70 mL) and dichloromethane (70 mL) dried (Na2SO4) the solvents removed in vacuo The residue was dissolved in dichloromethane The impurities were washed through with methanol (50 mL) Elution with 7N methanolic ammonia (25 mL) and evaporation in vacuo

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Titanium(IV) isopropoxide (1.62 mL) was added to a stirred solution of 2-(benzyloxy)benzonitrile (1.05 g) in diethyl ether (25 mL) cooled to −78° C. under N2 followed by the dropwise addition of ethylmagnesium bromide (3.67 mL of a 3M solution in diethylether). The resulting mixture was stirred at −78° C. for 10 min and then warmed to rt over 1 h. Boron trifluoride diethyl etherate (1.27 mL) was added dropwise and the mixture was stirred for 1 h. The reaction was quenched with 1M HCl (30 mL). Diethyl ether (30 mL) was added and the organic layer separated. To the aqueous layer was added aqueous 10% NaOH (50 mL) and diethyl ether and this was filtered through celite to remove solids (which were washed with further diethyl ether). This mixture was extracted with diethyl ether (2×70 mL) and dichloromethane (70 mL). All the organic layers were combined, dried (Na2SO4) and the solvents removed in vacuo. The residue was dissolved in dichloromethane and loaded on to an 10 g SCX cartridge. The impurities were washed through with methanol (50 mL) and discarded. Elution with 7N methanolic ammonia (25 mL) and evaporation in vacuo gave the subtitle compound as a brown oil (0.625 g). warmed to rt over 1 h the mixture was stirred for 1 h The reaction was quenched with 1M HCl (30 mL) Diethyl ether (30 mL) was added the organic layer separated To the aqueous layer was added aqueous 10% NaOH (50 mL) and diethyl ether this was filtered through celite to remove solids (which were washed with further diethyl ether) This mixture was extracted with diethyl ether (2×70 mL) and dichloromethane (70 mL) dried (Na2SO4) the solvents removed in vacuo The residue was dissolved in dichloromethane The impurities were washed through with methanol (50 mL) Elution with 7N methanolic ammonia (25 mL) and evaporation in vacuo

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Titanium(IV) isopropoxide (1.62 mL) was added to a stirred solution of 2-(benzyloxy)benzonitrile (1.05 g) in diethyl ether (25 mL) cooled to −78° C. under N2 followed by the dropwise addition of ethylmagnesium bromide (3.67 mL of a 3M solution in diethylether). The resulting mixture was stirred at −78° C. for 10 min and then warmed to rt over 1 h. Boron trifluoride diethyl etherate (1.27 mL) was added dropwise and the mixture was stirred for 1 h. The reaction was quenched with 1M HCl (30 mL). Diethyl ether (30 mL) was added and the organic layer separated. To the aqueous layer was added aqueous 10% NaOH (50 mL) and diethyl ether and this was filtered through celite to remove solids (which were washed with further diethyl ether). This mixture was extracted with diethyl ether (2×70 mL) and dichloromethane (70 mL). All the organic layers were combined, dried (Na2SO4) and the solvents removed in vacuo. The residue was dissolved in dichloromethane and loaded on to an 10 g SCX cartridge. The impurities were washed through with methanol (50 mL) and discarded. Elution with 7N methanolic ammonia (25 mL) and evaporation in vacuo gave the subtitle compound as a brown oil (0.625 g). warmed to rt over 1 h the mixture was stirred for 1 h The reaction was quenched with 1M HCl (30 mL) Diethyl ether (30 mL) was added the organic layer separated To the aqueous layer was added aqueous 10% NaOH (50 mL) and diethyl ether this was filtered through celite to remove solids (which were washed with further diethyl ether) This mixture was extracted with diethyl ether (2×70 mL) and dichloromethane (70 mL) dried (Na2SO4) the solvents removed in vacuo The residue was dissolved in dichloromethane The impurities were washed through with methanol (50 mL) Elution with 7N methanolic ammonia (25 mL) and evaporation in vacuo

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Titanium(IV) isopropoxide (1.62 mL) was added to a stirred solution of 2-(benzyloxy)benzonitrile (1.05 g) in diethyl ether (25 mL) cooled to −78° C. under N2 followed by the dropwise addition of ethylmagnesium bromide (3.67 mL of a 3M solution in diethylether). The resulting mixture was stirred at −78° C. for 10 min and then warmed to rt over 1 h. Boron trifluoride diethyl etherate (1.27 mL) was added dropwise and the mixture was stirred for 1 h. The reaction was quenched with 1M HCl (30 mL). Diethyl ether (30 mL) was added and the organic layer separated. To the aqueous layer was added aqueous 10% NaOH (50 mL) and diethyl ether and this was filtered through celite to remove solids (which were washed with further diethyl ether). This mixture was extracted with diethyl ether (2×70 mL) and dichloromethane (70 mL). All the organic layers were combined, dried (Na2SO4) and the solvents removed in vacuo. The residue was disolved in dichloromethane and loaded on to an 10 g SCX cartridge. The impurities were washed through with methanol (50 mL) and discarded. Elution with 7N methanolic ammonia (25 mL) and evaporation in vacuo gave the subtitle compound as a brown oil (0.625 g). warmed to rt over 1 h the mixture was stirred for 1 h The reaction was quenched with 1M HCl (30 mL) Diethyl ether (30 mL) was added the organic layer separated To the aqueous layer was added aqueous 10% NaOH (50 mL) and diethyl ether this was filtered through celite to remove solids (which were washed with further diethyl ether) This mixture was extracted with diethyl ether (2×70 mL) and dichloromethane (70 mL) dried (Na2SO4) the solvents removed in vacuo The impurities were washed through with methanol (50 mL) Elution with 7N methanolic ammonia (25 mL) and evaporation in vacuo

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

Procedure: The title compound was prepared in a similar manner to that described in Reference Example 20 using 2-cyanophenol instead of tert-butyl N-(3′-hydroxybiphenyl-4-ylmethyl)-carbamate and benzyl bromide instead of 1-bromopropane.

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Titanium(IV) isopropoxide (1.62 mL) was added to a stirred solution of 2-(benzyloxy)benzonitrile (1.05 g) in diethyl ether (25 mL) cooled to −78° C. under N2 followed by the dropwise addition of ethylmagnesium bromide (3.67 mL of a 3M solution in diethylether). The resulting mixture was stirred at −78° C. for 10 min and then warmed to rt over 1 h. Boron trifluoride diethyl etherate (1.27 mL) was added dropwise and the mixture was stirred for 1 h. The reaction was quenched with 1M HCl (30 mL). Diethyl ether (30 mL) was added and the organic layer separated. To the aqueous layer was added aqueous 10% NaOH (50 mL) and diethyl ether and this was filtered through celite to remove solids (which were washed with further diethyl ether). This mixture was extracted with diethyl ether (2×70 mL) and dichloromethane (70 mL). All the organic layers were combined, dried (Na2SO4) and the solvents removed in vacuo. The residue was dissolved in dichloromethane and loaded on to an 10 g SCX cartridge. The impurities were washed through with methanol (50 mL) and discarded. Elution with 7N methanolic ammonia (25 mL) and evaporation in vacuo gave the subtitle compound as a brown oil (0.625 g). warmed to rt over 1 h the mixture was stirred for 1 h The reaction was quenched with 1M HCl (30 mL) Diethyl ether (30 mL) was added the organic layer separated To the aqueous layer was added aqueous 10% NaOH (50 mL) and diethyl ether this was filtered through celite to remove solids (which were washed with further diethyl ether) This mixture was extracted with diethyl ether (2×70 mL) and dichloromethane (70 mL) dried (Na2SO4) the solvents removed in vacuo The residue was dissolved in dichloromethane The impurities were washed through with methanol (50 mL) Elution with 7N methanolic ammonia (25 mL) and evaporation in vacuo

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

Procedure: 2-Hydroxy-4-nitro-benzonitrile (11.2 g, 68 mmole) was dissolved in DMF (200 ml). Potassium carbonate (11 g, 80 mmole) and benzyl bromide (9 ml, 75 mmole) were added. The reaction was stirred at room temperature overnight. The DMF was removed in vacuo and the residue taken up in ethyl acetate and water. The organic layer was separated, washed with 1 N NaOH, then with water, and dried over sodium sulfate. The crude product (5 g) was dissolved in ethyl acetate (75 ml) and added to a flask containing 5% Pt/C (500 mg). The reaction was placed under a hydrogen atmosphere (balloon) and stirred vigorously for several hours until the reaction was done (TLC). The catalyst was filtered off and the solvent removed. The product was purified by flash chromatography to yield 4.12 g of 4-amino, 2-benzyloxybenzonitrile. The DMF was removed in vacuo The organic layer was separated washed with 1 N NaOH with water, and dried over sodium sulfate The crude product (5 g) was dissolved in ethyl acetate (75 ml) added to a flask containing 5% Pt/C (500 mg) stirred vigorously for several hours until the reaction The catalyst was filtered off the solvent removed The product was purified by flash chromatography