3-bromo-2-methylbenzonitrile

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

Procedure: To a stirred and refluxing Grignard-complex, previously prepared starting from 7.3 parts of magnesium, 52.6 parts of methyl iodide in 160 parts of ether, is added dropwise a solution of 19.6 parts of 3'-bromo-2'-methylbenzonitrile in 40 parts of ether. Upon completion, stirring at reflux is continued for 20 hours. The reaction mixture is cooled to 0° C and poured onto 500 parts of ice-water while stirring vigorously. The ethereal phase is separated, dried and evaporated. The residue is boiled in 60 parts of a 6N hydrochloric acid solution for 10 minutes. The separated oil is extracted with ether. The extract is washed with water, dried and evaporated. The residue is distilled, yielding 3'-bromo-2'-methylacetophenone; bp. 125°-128° C at 10 mm. pressure. refluxing Grignard-complex previously prepared Upon completion, stirring at reflux while stirring vigorously The ethereal phase is separated dried evaporated The residue is boiled in 60 parts of a 6N hydrochloric acid solution for 10 minutes The separated oil is extracted with ether The extract is washed with water dried evaporated The residue is distilled

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

Procedure: To a stirred and refluxing Grignard-complex, previously prepared starting from 7.3 parts of magnesium, 52.6 parts of methyl iodide in 160 parts of ether, is added dropwise a solution of 19.6 parts of 3'-bromo-2'-methylbenzonitrile in 40 parts of ether. Upon completion, stirring at reflux is continued for 20 hours. The reaction mixture is cooled to 0° C and poured onto 500 parts of ice-water while stirring vigorously. The ethereal phase is separated, dried and evaporated. The residue is boiled in 60 parts of a 6N hydrochloric acid solution for 10 minutes. The separated oil is extracted with ether. The extract is washed with water, dried and evaporated. The residue is distilled, yielding 3'-bromo-2'-methylacetophenone; bp. 125°-128° C at 10 mm. pressure. refluxing Grignard-complex previously prepared Upon completion, stirring at reflux while stirring vigorously The ethereal phase is separated dried evaporated The residue is boiled in 60 parts of a 6N hydrochloric acid solution for 10 minutes The separated oil is extracted with ether The extract is washed with water dried evaporated The residue is distilled

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

Procedure: In a microwave vial, methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (200 mg), 3-bromo-2-methylbenzonitrile (169 mg), K3PO4 (274 mg), Palladium-(II)-acetate (10 mg) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (S-Phos) (18 mg) are suspended in toluene (10 mL) and water (2 mL) and purged for 10 minutes with argon. The vial is sealed and the mixture is stirred at 100° C. for 4 hours. After cooling to ambient temperature the mixture is partitioned between ethyl acetate and water. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10) to give the title compound. Yield: 124 mg; LC (method 20): tR=8.09 min; Mass spectrum (ESI+): m/z=558 [M+−H]+. water (2 mL) and purged for 10 minutes with argon The vial is sealed After cooling to ambient temperature the mixture is partitioned between ethyl acetate and water The organic phase is dried (MgSO4) concentrated The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10)

Conditions: temp:47.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Bromo-2-methylbenzonitrile (810 mg, 4.13 mmol) was stirred in THF (5 mL) at 0° C. under argon, and methylmagnesium bromide (1.6 mL, 4.8 mmol) (3.0 M solution in Et2O). The reaction was stirred at 45-50° C. for 2 h. The reaction was cooled to 0° C. and 6 N HCl (5 mL) was added carefully. The reaction mixture was stirred at 40-50° C. for 2 h. After cooling, the mixture was extracted with Et2O (2×). The organic layers were washed with H2O, brine, dried over MgSO4, filtered and concentrated to give Intermediate 12A (600 mg, 2.82 mmol, 68.2% yield) as yellowish oil. LCMS=1.27 min [M+1]=211.9, 213.9 (Method B). The reaction was cooled to 0° C. The reaction mixture was stirred at 40-50° C. for 2 h After cooling the mixture was extracted with Et2O (2×) The organic layers were washed with H2O, brine dried over MgSO4 filtered concentrated

Conditions: temp:47.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Bromo-2-methylbenzonitrile (810 mg, 4.13 mmol) was stirred in THF (5 mL) at 0° C. under argon, and methylmagnesium bromide (1.6 mL, 4.8 mmol) (3.0 M solution in Et2O). The reaction was stirred at 45-50° C. for 2 h. The reaction was cooled to 0° C. and 6 N HCl (5 mL) was added carefully. The reaction mixture was stirred at 40-50° C. for 2 h. After cooling, the mixture was extracted with Et2O (2×). The organic layers were washed with H2O, brine, dried over MgSO4, filtered and concentrated to give Intermediate 12A (600 mg, 2.82 mmol, 68.2% yield) as yellowish oil. LCMS=1.27 min [M+1]=211.9, 213.9 (Method B). The reaction was cooled to 0° C. The reaction mixture was stirred at 40-50° C. for 2 h After cooling the mixture was extracted with Et2O (2×) The organic layers were washed with H2O, brine dried over MgSO4 filtered concentrated

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

Procedure: To a stirred and refluxing Grignard-complex, previously prepared starting from 7.3 parts of magnesium, 52.6 parts of methyl iodide in 160 parts of ether, is added dropwise a solution of 19.6 parts of 3'-bromo-2'-methylbenzonitrile in 40 parts of ether. Upon completion, stirring at reflux is continued for 20 hours. The reaction mixture is cooled to 0° C and poured onto 500 parts of ice-water while stirring vigorously. The ethereal phase is separated, dried and evaporated. The residue is boiled in 60 parts of a 6N hydrochloric acid solution for 10 minutes. The separated oil is extracted with ether. The extract is washed with water, dried and evaporated. The residue is distilled, yielding 3'-bromo-2'- methylacetophenone; bp. 125°-128°C at 10 mm. pressure. refluxing Grignard-complex previously prepared Upon completion, stirring at reflux while stirring vigorously The ethereal phase is separated dried evaporated The residue is boiled in 60 parts of a 6N hydrochloric acid solution for 10 minutes The separated oil is extracted with ether The extract is washed with water dried evaporated The residue is distilled

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

Procedure: To a stirred and refluxing Grignard-complex, previously prepared starting from 7.3 parts of magnesium, 52.6 parts of methyl iodide in 160 parts of ether, is added dropwise a solution of 19.6 parts of 3'-bromo-2'-methylbenzonitrile in 40 parts of ether. Upon completion, stirring at reflux is continued for 20 hours. The reaction mixture is cooled to 0° C and poured onto 500 parts of ice-water while stirring vigorously. The ethereal phase is separated, dried and evaporated. The residue is boiled in 60 parts of a 6N hydrochloric acid solution for 10 minutes. The separated oil is extracted with ether. The extract is washed with water, dried and evaporated. The residue is distilled, yielding 3'-bromo-2'- methylacetophenone; bp. 125°-128°C at 10 mm. pressure. refluxing Grignard-complex previously prepared Upon completion, stirring at reflux while stirring vigorously The ethereal phase is separated dried evaporated The residue is boiled in 60 parts of a 6N hydrochloric acid solution for 10 minutes The separated oil is extracted with ether The extract is washed with water dried evaporated The residue is distilled

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

Procedure: To a stirred and refluxing Grignard-complex, previously prepared starting from 7.3 parts of magnesium, 52.6 parts of methyl iodide in 160 parts of ether, is added dropwise a solution of 19.6 parts of 3'-bromo-2'-methylbenzonitrile in 40 parts of ether. Upon completion, stirring at reflux is continued for 20 hours. The reaction mixture is cooled to 0° C and poured onto 500 parts of ice-water while stirring vigorously. The ethereal phase is separated, dried and evaporated. The residue is boiled in 60 parts of a 6N hydrochloric acid solution for 10 minutes. The separated oil is extracted with ether. The extract is washed with water, dried and evaporated. The residue is distilled, yielding 3'-bromo-2'-methylacetophenone; bp. 125°-128° C at 10 mm. pressure. refluxing Grignard-complex previously prepared Upon completion, stirring at reflux while stirring vigorously The ethereal phase is separated dried evaporated The residue is boiled in 60 parts of a 6N hydrochloric acid solution for 10 minutes The separated oil is extracted with ether The extract is washed with water dried evaporated The residue is distilled

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

Procedure: In a microwave vial, methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (200 mg), 3-bromo-2-methylbenzonitrile (169 mg), K3PO4 (274 mg), Palladium-(II)-acetate (10 mg) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (S-Phos) (18 mg) are suspended in toluene (10 mL) and water (2 mL) and purged for 10 minutes with argon. The vial is sealed and the mixture is stirred at 100° C. for 4 hours. After cooling to ambient temperature the mixture is partitioned between ethyl acetate and water. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10) to give the title compound. Yield: 124 mg; LC (method 20): tR=8.09 min; Mass spectrum (ESI+): m/z=558 [M+−H]+. water (2 mL) and purged for 10 minutes with argon The vial is sealed After cooling to ambient temperature the mixture is partitioned between ethyl acetate and water The organic phase is dried (MgSO4) concentrated The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10)

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

Procedure: This compound was prepared in a manner similar to that described for 3-bromo-5-fluorobenzonitrile from commercially available 2,6-dibromotoluene (1.80 g, 7.20 mmol), DMF (11 mL), pyridine (1.1 mL), and copper (I) cyanide (0.52 g, 5.76 mmol). The crude product was purified by flash column chromatography (100 mL silica, hexane) to afford 50 mg (35%) of 3-bromo-2-methylbenzonitrile. Data for 3-bromo-2-methylbenzonitrile: 1H NMR (400 MHz, acetone-d6) 7.88 (d, J=8.0, 1H), 7.73 (d, J=8.0, 1H), 7.32 (t, J=15.8, 7.9, 1H), 2.58 (s, 3H). This compound was prepared in a manner similar to The crude product was purified by flash column chromatography (100 mL silica, hexane)

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

Procedure: This compound was prepared in a manner similar to that described for 3-bromo-5-fluorobenzonitrile from commercially available 2,6-dibromotoluene (1.80 g, 7.20 mmol), DMF (11 mL), pyridine (1.1 mL), and copper (I) cyanide (0.52 g, 5.76 mmol). The crude product was purified by flash column chromatography (100 mL silica, hexane) to afford 50 mg (35%) of 3-bromo-2-methylbenzonitrile. Data for 3-bromo-2-methylbenzonitrile: 1H NMR (400 MHz, acetone-d6) 7.88 (d, J=8.0, 1H), 7.73 (d, J=8.0, 1H), 7.32 (t, J=15.8, 7.9, 1H), 2.58 (s, 3H). This compound was prepared in a manner similar to The crude product was purified by flash column chromatography (100 mL silica, hexane)

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

Procedure: This compound was prepared in a manner similar to that described for 3-bromo-5-fluorobenzonitrile from commercially available 2,6-dibromotoluene (1.80 g, 7.20 mmol), DMF (11 mL), pyridine (1.1 mL), and copper (I) cyanide (0.52 g, 5.76 mmol). The crude product was purified by flash column chromatography (100 mL silica, hexane) to afford 50 mg (35%) of 3-bromo-2-methylbenzonitrile. Data for 3-bromo-2-methylbenzonitrile: 1H NMR (400 MHz, acetone-d6) 7.88 (d, J=8.0, 1H), 7.73 (d, J=8.0, 1H), 7.32 (t, J=15.8, 7.9, 1H), 2.58 (s, 3H). This compound was prepared in a manner similar to The crude product was purified by flash column chromatography (100 mL silica, hexane)