4-Bromo-2-chloro-5-fluorotoluene

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-bromo-5-chloro-2-fluoro-4-methylbenzene (10 g, 44.7 mmol) in 200 mL of methanol were added 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphine)-dichloropalladium (1:1) (358 mg, 0.447 mmol) and N,N-diethylethanamine (8.11 mL, 58.2 mmol). The resulting reaction mixture was placed in a bomb, pressurised to 80 psi of carbon monoxide and heated at 80° C. for 18 hours. The reaction mixture was concentrated in vacuo to yield a semi-solid which was dissolved in EtOAc (300 mL) and washed with water (200 mL). The organic layer was separated, dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting crude product was purified by silica gel chromatography eluting with 0 to 20% EtOAc in heptane to afford the title compound as a white crystalline solid (8.47 g, 93%). The resulting reaction mixture The reaction mixture was concentrated in vacuo to yield a semi-solid which washed with water (200 mL) The organic layer was separated dried over magnesium sulfate filtered evaporated in vacuo The resulting crude product was purified by silica gel chromatography eluting with 0 to 20% EtOAc in heptane

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-bromo-5-chloro-2-fluoro-4-methylbenzene (Comm, 10 g, 44.7 mmol) in methanol (200 mL) was added 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphine)-dichloropalladium (1:1) (358 mg, 0.447 mmol) and N,N-diethylethanamine (8.11 mL, 58.2 mmol). The resulting mixture was placed in a bomb and pressurized with carbon monoxide to 80 psi and heated at 80° C. for 18 hours. The reaction mixture was then concentrated in vacuo to yield a semi-solid, which was dissolved in EtOAc (300 mL) and washed with water (200 mL). The organic layer was separated, dried over magnesium sulphate, filtered and concentrated in vacuo to yield an orange oil, which solidified on standing (9.87 g). The solid was purified by silica gel chromatography eluting with 0 to 20% EtOAc in heptane to afford the title compound as a crystalline white solid (8.47 g, 93%). The reaction mixture was then concentrated in vacuo to yield a semi-solid, which washed with water (200 mL) The organic layer was separated dried over magnesium sulphate filtered concentrated in vacuo to yield an orange oil, which The solid was purified by silica gel chromatography eluting with 0 to 20% EtOAc in heptane

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-bromo-2-chloro-5-fluorotoluene (997 mg, 4.46 mmol), N-bromosuccinimide (837 mg, 4.70 mmol) and benzoyl peroxide (35 mg, 0.14 mmol) in carbon tetrachloride (20 mL) was heated to reflux at 85° C. for 18.5 hours under nitrogen. The reaction mixture was concentrated in vacuo to afford a cream solid residue. The residue was suspended in heptane (40 mL), filtered and the filtrate then concentrated in vacuo to afford the title compound a clear oil (1.35 g, 100%). The compound was used without further purification in the next step. The reaction mixture was concentrated in vacuo to afford a cream solid residue filtered the filtrate then concentrated in vacuo

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-bromo-5-chloro-2-fluoro-4-methylbenzene (10 g, 44.7 mmol) in methanol (200 mL) was added 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphine)-dichloropalladium (1:1) (358 mg, 0.447 mmol) and N,N-diethylethanamine (8.11 mL, 58.2 mmol). The resulting mixture was placed in a bomb and pressurized with carbon monoxide to 80 psi and heated at 80° C. for 18 hours. The cooled reaction mixture was then concentrated in vacuo to yield a semi-solid, which was dissolved in EtOAc (300 mL) and washed with water (200 mL). The organic layer was separated, dried over magnesium sulphate, filtered and concentrated in vacuo to yield an orange oil, which solidified on standing (9.87 g). The solid was purified by silica gel column chromatography eluting with 0 to 20% EtOAc in heptane to afford the title compound as a crystalline white solid (8.47 g, 93%): The cooled reaction mixture was then concentrated in vacuo to yield a semi-solid, which washed with water (200 mL) The organic layer was separated dried over magnesium sulphate filtered concentrated in vacuo to yield an orange oil, which The solid was purified by silica gel column chromatography eluting with 0 to 20% EtOAc in heptane

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

Procedure: To a solution of 1-bromo-5-chloro-2-fluoro-4-methylbenzene (11.3 g, 50 mmol) in dry THF (100 mL) was added isopropylmagnesium chloride (30 mL, 2 M) dropwise. After stirring at room temperature for 30 min, dry CO2 was added and the mixture was stirred at room temperature for additional 30 min. The reaction was quenched by sat. NH4Cl and extracted with EtOAc (100 mL×3). The combined organic layers were washed with water (50 mL×3), dried over anhydrous Na2SO4, filtered and concentrated to give the desired product (4.7 g, 49%). LCMS (ESI) m/z: 187.0 [M−H]−. the mixture was stirred at room temperature for additional 30 min The reaction was quenched by sat. NH4Cl extracted with EtOAc (100 mL×3) The combined organic layers were washed with water (50 mL×3) dried over anhydrous Na2SO4 filtered concentrated

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

Procedure: To a solution of 1-bromo-5-chloro-2-fluoro-4-methylbenzene (11.3 g, 50 mmol) in dry THF (100 mL) was added isopropylmagnesium chloride (30 mL, 2 M) dropwise. After stirring at room temperature for 30 min, dry CO2 was added and the mixture was stirred at room temperature for additional 30 min. The reaction was quenched by sat. NH4Cl and extracted with EtOAc (100 mL×3). The combined organic layers were washed with water (50 mL×3), dried over anhydrous Na2SO4, filtered and concentrated to give the desired product (4.7 g, 49%). LCMS (ESI) m/z: 187.0 [M−H]−. the mixture was stirred at room temperature for additional 30 min The reaction was quenched by sat. NH4Cl extracted with EtOAc (100 mL×3) The combined organic layers were washed with water (50 mL×3) dried over anhydrous Na2SO4 filtered concentrated

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-bromo-5-chloro-2-fluoro-4-methylbenzene (10 g, 44.7 mmol) in 200 mL of methanol were added 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphine)-dichloropalladium (1:1) (358 mg, 0.447 mmol) and N,N-diethylethanamine (8.11 mL, 58.2 mmol). The resulting reaction mixture was placed in a bomb, pressurised to 80 psi of carbon monoxide and heated at 80° C. for 18 hours. The reaction mixture was concentrated in vacuo to yield a semi-solid which was dissolved in EtOAc (300 mL) and washed with water (200 mL). The organic layer was separated, dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting crude product was purified by silica gel chromatography eluting with 0 to 20% EtOAc in heptane to afford the title compound as a white crystalline solid (8.47 g, 93%). The resulting reaction mixture The reaction mixture was concentrated in vacuo to yield a semi-solid which washed with water (200 mL) The organic layer was separated dried over magnesium sulfate filtered evaporated in vacuo The resulting crude product was purified by silica gel chromatography eluting with 0 to 20% EtOAc in heptane

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-bromo-5-chloro-2-fluoro-4-methylbenzene (Comm, 10 g, 44.7 mmol) in methanol (200 mL) was added 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphine)-dichloropalladium (1:1) (358 mg, 0.447 mmol) and N,N-diethylethanamine (8.11 mL, 58.2 mmol). The resulting mixture was placed in a bomb and pressurized with carbon monoxide to 80 psi and heated at 80° C. for 18 hours. The reaction mixture was then concentrated in vacuo to yield a semi-solid, which was dissolved in EtOAc (300 mL) and washed with water (200 mL). The organic layer was separated, dried over magnesium sulphate, filtered and concentrated in vacuo to yield an orange oil, which solidified on standing (9.87 g). The solid was purified by silica gel chromatography eluting with 0 to 20% EtOAc in heptane to afford the title compound as a crystalline white solid (8.47 g, 93%). The reaction mixture was then concentrated in vacuo to yield a semi-solid, which washed with water (200 mL) The organic layer was separated dried over magnesium sulphate filtered concentrated in vacuo to yield an orange oil, which The solid was purified by silica gel chromatography eluting with 0 to 20% EtOAc in heptane

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-bromo-2-chloro-5-fluorotoluene (997 mg, 4.46 mmol), N-bromosuccinimide (837 mg, 4.70 mmol) and benzoyl peroxide (35 mg, 0.14 mmol) in carbon tetrachloride (20 mL) was heated to reflux at 85° C. for 18.5 hours under nitrogen. The reaction mixture was concentrated in vacuo to afford a cream solid residue. The residue was suspended in heptane (40 mL), filtered and the filtrate then concentrated in vacuo to afford the title compound a clear oil (1.35 g, 100%). The compound was used without further purification in the next step. The reaction mixture was concentrated in vacuo to afford a cream solid residue filtered the filtrate then concentrated in vacuo