2-bromo-4-chloro-1-methylbenzene

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: To a 2 L round bottle flask equipped with reflux condenser, stir bar, nitrogen feed, and oil bath were added 2-bromo-4-chlorotoluene (20.67 g, 98.59 mmol), 3-biphenylboronic acid (20.50 g 103.52 mmol), sodium carbonate (158 mL, 315 mmol), Aliquat 336 (4.00 g) and toluene (600 mL). Solution was purged with nitrogen for 20 minutes before adding tetrakis(triphenylphospine)palladium(0) (1.14 g, 0.98 mmol) and purged for another 10 minute. The reaction was then heated under nitrogen for 18 hour. After cooing to ambient temperature, the organic phase was separated, washed with 10% HCl (200 mL), water (200 mL) and saturated brine (200 mL). This solution was dried with magnesium sulfate (50 g) for 3 hour and the solvent was removed by rotary evaporation. The crude product was filtered, washing with hexane. Product containing fractions were identified by UPLC and collected. Low boiling point is impurities and solvents were removed by Kruger-Rohr distillation to give the product as colorless oil (20.2 g, 77%). To a 2 L round bottle flask equipped with reflux condenser Solution was purged with nitrogen for 20 minutes purged for another 10 minute The reaction was then heated under nitrogen for 18 hour After cooing to ambient temperature the organic phase was separated washed with 10% HCl (200 mL), water (200 mL) and saturated brine (200 mL) This solution was dried with magnesium sulfate (50 g) for 3 hour the solvent was removed by rotary evaporation The crude product was filtered washing with hexane Product containing fractions collected were removed by Kruger-Rohr distillation

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

Procedure: To a 2 L round bottle flask equipped with reflux condenser, stir bar, nitrogen feed, and oil bath were added 2-bromo-4-chlorotoluene (20.67 g, 98.59 mmol), 3-biphenylboronic acid (20.50 g 103.52 mmol), sodium carbonate (158 mL, 315 mmol), Aliquat 336 (4.00 g) and toluene (600 mL). Solution was purged with nitrogen for 20 minutes before adding tetrakis(triphenylphospine)palladium(0) (1.14 g, 0.98 mmol) and purged for another 10 minute. The reaction was then heated under nitrogen for 18 hour. After cooing to ambient temperature, the organic phase was separated, washed with 10% HCl (200 mL), water (200 mL) and saturated brine (200 mL). This solution was dried with magnesium sulfate (50 g) for 3 hour and the solvent was removed by rotary evaporation. The crude product was filtered, washing with hexane. Product containing fractions were identified by UPLC and collected. Low boiling point is impurities and solvents were removed by Kruger-Rohr distillation to give the product as colorless oil (20.2 g, 77%). To a 2 L round bottle flask equipped with reflux condenser Solution was purged with nitrogen for 20 minutes purged for another 10 minute The reaction was then heated under nitrogen for 18 hour After cooing to ambient temperature the organic phase was separated washed with 10% HCl (200 mL), water (200 mL) and saturated brine (200 mL) This solution was dried with magnesium sulfate (50 g) for 3 hour the solvent was removed by rotary evaporation The crude product was filtered washing with hexane Product containing fractions collected were removed by Kruger-Rohr distillation

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

Procedure: To 2-bromo-4-chloro toluene (20.0 g; 97.3 mmol) in 300 mL of THF at −78° C. was added n-BuLi 2.5M (40.8 mL) dropwise. After 20 min. 1-formylpiperidine (11.4 mL; 103.0 mmol) in 10 mL of THF was added dropwise. After 30 min the reaction mixture was brought to 0° C. and quenched with HCl (10%) and diluted with EtOAc. The organic phase was collected, dry and the solvent evaporated to yield 13.3 g (89%) of 5-chloro-2-methylbenzaldehyde. This crude aldehyde was mixed with 1.1 equivalent of triethyl phosphonoacetate in THF. Sodium hydride 80% (1.3 equivalent ) was added portionwise and 1 h later the reaction was quenched with 25% NH4Cl. The reaction mixture was diluted with EtOAc and the organic phase collected, dried and the solvent removed. The crude oil was purified on a short pad of silica gel using 5% EtOAc in hexane to afford 16.67 g of the title compound. After 30 min the reaction mixture was brought to 0° C. quenched with HCl (10%) diluted with EtOAc The organic phase was collected dry the solvent evaporated

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

Procedure: To a solution of 2-bromo-4-chlorotoluene (20.0 g; 97.3 mmol) in 300 mL of THF at −78° C. was added dropwise a 2.5 M solution of n-BuLi (102.2 mmol). After 30 min of stirring at that temperature, 1-formylpiperidine (11.4 mL) in 10 mL of THF was added and the solution left for 1 h. It was brought to 0° C. , quenched with NH4OAc (25%) and diluted with EtOAc. The organic phase was dried over Na2SO4, filtered and the solvent removed to yield 13.3 g of the title compound. was added was brought to 0° C. quenched with NH4OAc (25%) diluted with EtOAc The organic phase was dried over Na2SO4 filtered the solvent removed

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

Procedure: To a solution of 2-bromo-4-chlorotoluene (20.0 g; 97.3 mmol) in 300 mL of THF at −78° C. was added dropwise a 2.5 M solution of n-BuLi (102.2 mmol). After 30 min of stirring at that temperature, 1-formylpiperidine (11.4 mL) in 10 mL of THF was added and the solution left for 1 h. It was brought to 0° C. , quenched with NH4OAc (25%) and diluted with EtOAc. The organic phase was dried over Na2SO4, filtered and the solvent removed to yield 13.3 g of the title compound. was added was brought to 0° C. quenched with NH4OAc (25%) diluted with EtOAc The organic phase was dried over Na2SO4 filtered the solvent removed

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

Procedure: Treatment of 2-bromo-4-chlorotoluene (20 mL, 0.15 mol) with 2-fluoro-6-methoxybenzene boronic acid (10.0 g, 58.8 mmol) in DME-water (5:1, 300 mL) according to the procedure described for Example 69, Step 1 provided 21.0 g of 4-chloro-2′-fluoro-6′-methoxy-2-methylbiphenyl as a colorless oil.

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

Procedure: 5-chloro-2-methylbenzenamine (50 g, 0.355 mol) was dissolved in HBr solution (1.5 M, 100 mL) and cooled to 0° C., a solution of NaNO2 (27.6 g, 0.4 mol) in water (200 mL) was added dropwise. After addition, the mixture was stirred for 1 hr. In another flask CuBr (30 g, 0.21 mol) was added to HBr solution (1.5 M, 30 mL) and heated to 60° C., then the mixture was added to the above solution. The mixture was heated to reflux for 1 hr then cooled to rt. The reaction was quenched with water (500 mL), the aqueous layer was extracted 3 times with CH2Cl2, dried over Na2SO4, solvent removal and purification by column chromatography afforded 2-bromo-4-chloro-1-methylbenzene (53 g, 0.26 mol). 1H NMR (CDCl3, 400 MHz) δ 7.53 (s, 1H), 7.20-7.10 (m, 2H), 2.36 (s, 3H). After addition heated to 60° C. the mixture was added to the above solution The mixture was heated to reflux for 1 hr then cooled to rt The reaction was quenched with water (500 mL) the aqueous layer was extracted 3 times with CH2Cl2 dried over Na2SO4, solvent removal and purification by column chromatography

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

Procedure: To a solution of 2-bromo-4-chloro-1-methylbenzene (53 g, 0.26 mol) in anhydrous THF (600 mL) at −78° C. under nitrogen was added dropwise a solution of 2.5 M n-BuLi in hexane (103 mL, 0.26 mol). After stirring for 1 hr at −78° C., a solution of the (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (67 g, 0.246 mol) in anhydrous THF (300 mL) was added dropwise. After addition, the reaction mixture was allowed to warm to rt and stirred for 2 hr. The mixture was quenched with saturated NH4Cl solution (500 mL) and extracted with EtOAc (3×400 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give crude (R)-tert-butyl 3-(5-chloro-2-methylbenzoyl)piperidine-1-carboxylate (86 g), which was used immediately in the next step without purification. After addition to warm to rt stirred for 2 hr The mixture was quenched with saturated NH4Cl solution (500 mL) extracted with EtOAc (3×400 mL) The combined organic layers were washed with brine dried over Na2SO4 concentrated in vacuo

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

Procedure: To a solution of 2-bromo-4-chloro-1-methylbenzene (53 g, 0.26 mol) in anhydrous THF (600 mL) at −78° C. under nitrogen was added dropwise a solution of 2.5 M n-BuLi in hexane (103 mL, 0.26 mol). After stirring for 1 hr at −78° C., a solution of the (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (67 g, 0.246 mol) in anhydrous THF (300 mL) was added dropwise. After addition, the reaction mixture was allowed to warm to rt and stirred for 2 hr. The mixture was quenched with saturated NH4Cl solution (500 mL) and extracted with ethyl acetate (3×400 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give crude (R)-tert-butyl 3-(5-chloro-2-methylbenzoyl)piperidine-1-carboxylate (86 g), which was used immediately in the next step without purification. After addition to warm to rt stirred for 2 hr The mixture was quenched with saturated NH4Cl solution (500 mL) extracted with ethyl acetate (3×400 mL) The combined organic layers were washed with brine dried over Na2SO4 concentrated in vacuo

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

Procedure: To a solution of 2-bromo-4-chloro-1-methylbenzene (53 g, 0.26 mol) in anhydrous THF (600 mL) at −78° C. under nitrogen was added dropwise a solution of 2.5 M n-BuLi in hexane (103 mL, 0.26 mol). After stirring for 1 hr at −78° C., a solution of the (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (67 g, 0.246 mol) in anhydrous THF (300 mL) was added dropwise. After addition, the reaction mixture was allowed to warm to rt and stirred for 2 hr. The mixture was quenched with saturated NH4Cl solution (500 mL) and extracted with ethyl acetate (3×400 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give crude (R)-tert-butyl 3-(5-chloro-2-methylbenzoyl)piperidine-1-carboxylate (86 g), which was used immediately in the next step without purification. After addition to warm to rt stirred for 2 hr The mixture was quenched with saturated NH4Cl solution (500 mL) extracted with ethyl acetate (3×400 mL) The combined organic layers were washed with brine dried over Na2SO4 concentrated in vacuo