4-bromo-1-chloro-2-fluorobenzene

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

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

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: Prepared following the procedure described in Intermediate 13, starting from 4-bromo-1-chloro-2-fluorobenzene, where the crude product was purified by column chromatography (PE: EtOAc=100:1) to afford Intermediate 16 (200 mg, yield 18.2%). Prepared was purified by column chromatography (PE: EtOAc=100:1)

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

Procedure: To a solution of 1-bromo-4-chloro-3-fluorobenzene (2.09 g, 10 mmol) in dry diethyl ether (12.0 ml) was added a solution of n-BuLi (1.55M in hexane, 6.77ml, 10.5 mmol) at −78° C. under nitrogen atmosphere. The mixture was allowed to warm to −20_C stirred for 45 min. A solution of N,N-dimethylacetamide (1.04 ml, 11.2 mmol) in diethyl ether (1.5 ml) was added and the mixture stirred for an additional 1 h. The mixture was then allowed to warm to room temperature. After stirring for 3 h, the reaction mixture was poured into saturated aqueous ammonium chloride (20 ml) and extracted with diethyl ether (30 ml×3). The combined organic layers were washed with 2N aqueous HCl (20 ml), saturated aqueous sodium bicarbonate (20 ml), brine (20 ml), and dried (MgSO4). Removal of solvent gave the title compound as a yellow oil (quant.). to warm the mixture stirred for an additional 1 h After stirring for 3 h extracted with diethyl ether (30 ml×3) The combined organic layers were washed with 2N aqueous HCl (20 ml), saturated aqueous sodium bicarbonate (20 ml), brine (20 ml) dried (MgSO4) Removal of solvent

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 mixture of 4-bromo-1-chloro-2-fluorobenzene (11.7 g, 56.0 mmol) and magnesium turnings (2.1 g, 84 mmol) in THF (150 mL) at RT was added a few drops of 1,2-dibromoethane (1.1 g, 5.6 mmol). The mixture was stirred at RT for 1.5 h. After cooling to −78° C., (R,E)-2-methyl-N-((1-methyl-1H-pyrazol-4-yl)methylene)propane-2-sulfinamide (4.00 g, 18.7 mmol) was added and stirred at −78° C. for 6 h. The reaction was quenched with aq. NH4Cl solution and extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (150:1) to afford the 2.9 g (45%) of (R)—N—((S)-(4-chloro-3-fluorophenyl)(1-methyl-1H-pyrazol-4-yl)methyl)-2-methylpropane-2-sulfinamide (48). LCMS (ESI) m/z: 344.1 [M+H]+. After cooling to −78° C. stirred at −78° C. for 6 h The reaction was quenched with aq. NH4Cl solution extracted with EtOAc The combined organic layers were dried (MgSO4) filtered concentrated The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (150:1)

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

Procedure: To a mixture of 4-bromo-1-chloro-2-fluorobenzene (11.7 g, 56.0 mmol) and magnesium turnings (2.1 g, 84 mmol) in THF (150 mL) at RT was added a few drops of 1,2-dibromoethane (1.1 g, 5.6 mmol). The mixture was stirred at RT for 1.5 h. After cooling to −78° C., (R,E)-2-methyl-N-((1-methyl-1H-pyrazol-4-yl)methylene)propane-2-sulfinamide (4.00 g, 18.7 mmol) was added and stirred at −78° C. for 6 h. The reaction was quenched with aq. NH4Cl solution and extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (150:1) to afford the 2.9 g (45%) of (R)—N—((S)-(4-chloro-3-fluorophenyl)(1-methyl-1H-pyrazol-4-yl)methyl)-2-methylpropane-2-sulfinamide (48). LCMS (ESI) m/z: 344.1 [M+H]+. After cooling to −78° C. stirred at −78° C. for 6 h The reaction was quenched with aq. NH4Cl solution extracted with EtOAc The combined organic layers were dried (MgSO4) filtered concentrated The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (150:1)

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

Procedure: Magnesium (2.43 g) and iodine (10 mg) were added to tetrahydrofuran (40 ml) and a solution of 4-bromo-1-chloro-2-fluorobenzene (21.0 g) in tetrahydrofuran (40 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hr to give a Grignard's reagent. The reaction mixture was ice-cooled and copper iodide (1.90 g) was added. 3-Chloro-2-methyl-1-propene (14.8 ml) was added and the mixture was stirred at room temperature for 1 hr. The reaction mixture was ice-cooled and saturated aqueous ammonium chloride solution (10 ml) was added. The mixture was stirred at room temperature for 20 min and magnesium sulfate (40 g) was added. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Hexane (100 ml) was added to the obtained residue and insoluble materials were filtered off. The resulting solution was concentrated under reduced pressure to give the title compound (16.9 g). to give a Grignard's reagent cooled the mixture was stirred at room temperature for 1 hr cooled The mixture was stirred at room temperature for 20 min The reaction mixture was filtered the filtrate was concentrated under reduced pressure Hexane (100 ml) was added to the obtained residue and insoluble materials were filtered off The resulting solution was concentrated under reduced pressure

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

Procedure: Magnesium (2.43 g) and iodine (10 mg) were added to tetrahydrofuran (40 ml) and a solution of 4-bromo-1-chloro-2-fluorobenzene (21.0 g) in tetrahydrofuran (40 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hr to give a Grignard's reagent. The reaction mixture was ice-cooled and copper iodide (1.90 g) was added. 3-Chloro-2-methyl-1-propene (14.8 ml) was added and the mixture was stirred at room temperature for 1 hr. The reaction mixture was ice-cooled and saturated aqueous ammonium chloride solution (10 ml) was added. The mixture was stirred at room temperature for 20 min and magnesium sulfate (40 g) was added. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Hexane (100 ml) was added to the obtained residue and insoluble materials were filtered off. The resulting solution was concentrated under reduced pressure to give the title compound (16.9 g). to give a Grignard's reagent cooled the mixture was stirred at room temperature for 1 hr cooled The mixture was stirred at room temperature for 20 min The reaction mixture was filtered the filtrate was concentrated under reduced pressure Hexane (100 ml) was added to the obtained residue and insoluble materials were filtered off The resulting solution was concentrated under reduced pressure