4-bromo-1-fluoro-2-(trifluoromethyl)benzene

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

Procedure: A mixture of 1-bromo-4-fluoro-3-(trifluoromethyl)benzene (5.02 g) and potassium cyanide (1.38 g) in DMSO (20 ml) was heated at 80° C. for 14 h. Water was added and the mixture was extracted ether, the organic extracts were dried (MgSO4) and evaporated to give a brown oil. This was dissolved in DMSO (10 ml) and 4 M NaOH (10 ml) and heated at 100° C. for 16 h. 2 M Hcl (20 ml) was added and the mixture was extracted with DCM (three times), the organic extracts were dried (MgSO4), evaporated and purified by chromatography (silica, CH2Cl2-MeOH—AcOH as eluent) to give the sub-title compound (1.99 g). the mixture was extracted ether the organic extracts were dried (MgSO4) evaporated to give a brown oil 2 M Hcl (20 ml) was added the mixture was extracted with DCM (three times) the organic extracts were dried (MgSO4) evaporated purified by chromatography (silica, CH2Cl2-MeOH—AcOH as eluent)

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

Procedure: A mixture of 1-bromo-4-fluoro-3-(trifluoromethyl)benzene (5.02 g) and potassium cyanide (1.38 g) in DMSO (20 ml) was heated at 80° C. for 14 h. Water was added and the mixture was extracted ether, the organic extracts were dried (MgSO4) and evaporated to give a brown oil. This was dissolved in DMSO (10 ml) and 4 M NaOH (10 ml) and heated at 100° C. for 16 h. 2 M Hcl (20 ml) was added and the mixture was extracted with DCM (three times), the organic extracts were dried (MgSO4), evaporated and purified by chromatography (silica, CH2Cl2-MeOH—AcOH as eluent) to give the sub-title compound (1.99 g). the mixture was extracted ether the organic extracts were dried (MgSO4) evaporated to give a brown oil 2 M Hcl (20 ml) was added the mixture was extracted with DCM (three times) the organic extracts were dried (MgSO4) evaporated purified by chromatography (silica, CH2Cl2-MeOH—AcOH as eluent)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of sodium thiomethoxide (317 mg) and 5-bromo-2-fluorobenzotrifluoride (1.0 g) in DMF (4 ml) was heated at 50° C. for 1 h then poured into water and extracted with isohexane. The organics were washed with brine, dried and concentrated in vacuo to give the tip sub-title compound (762 mg). extracted with isohexane The organics were washed with brine dried concentrated in vacuo

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of sodium thiomethoxide (317 mg) and 5-bromo-2-fluorobenzotrifluoride (1.0 g) in DMF (4 ml) was heated at 50° C. for 1 h then poured into water and extracted with isohexane. The organics were washed with brine, dried and concentrated in vacuo to give the tip sub-title compound (762 mg). extracted with isohexane The organics were washed with brine dried concentrated in vacuo

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

Procedure: First, 4-(4-fluoro-3-trifluoromethyl-phenyl)-pyridine 73 was prepared as follows. To a suspension of pyridine-4-boronic acid (2.59 g, 21.1 mmol) in 1-propanol (60 mL) was added 5-bromo-2-fluorobenzotrifluoride (5.12 g, 21.1 mmol) and triphenylphosphine (0.160 g, 0.610 mmol), followed by sodium carbonate in water (2.0 M, 12 mL). The mixture was purged with nitrogen gas for 10 minutes. To it was added palladium(II) acetate (0.044 g, 0.196 mmol) and it was then heated under reflux for 4 hours. The reaction mixture was partitioned between ethyl acetate (200 mL) and water (200 mL). The organic layer was separated, washed with brine (3×200 mL), dried over MgSO4, then filtered. After evaporating the solvent, the crude material was loaded to a silica gel column, eluting with 60% ethyl acetate in hexane to give a white solid 73 (2.73 g, 54%). 1H-NMR (CDCl3, 400 MHz) δ 7.34-7.42 (m, 1H), 7.61-7.65 (m, 2H), 7.80-7.93 (m, 2H), 8.73-8.84 (m, 2H); MS (DCI) m/z 242, 243 (M+H)+. First, 4-(4-fluoro-3-trifluoromethyl-phenyl)-pyridine 73 was prepared The mixture was purged with nitrogen gas for 10 minutes was then heated under reflux for 4 hours The reaction mixture was partitioned between ethyl acetate (200 mL) and water (200 mL) The organic layer was separated washed with brine (3×200 mL) dried over MgSO4 filtered After evaporating the solvent eluting with 60% ethyl acetate in hexane

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

Procedure: First, 4-(4-fluoro-3-trifluoromethyl-phenyl)-pyridine 73 was prepared as follows. To a suspension of pyridine-4-boronic acid (2.59 g, 21.1 mmol) in 1-propanol (60 mL) was added 5-bromo-2-fluorobenzotrifluoride (5.12 g, 21.1 mmol) and triphenylphosphine (0.160 g, 0.610 mmol), followed by sodium carbonate in water (2.0 M, 12 mL). The mixture was purged with nitrogen gas for 10 minutes. To it was added palladium(II) acetate (0.044 g, 0.196 mmol) and it was then heated under reflux for 4 hours. The reaction mixture was partitioned between ethyl acetate (200 mL) and water (200 mL). The organic layer was separated, washed with brine (3×200 mL), dried over MgSO4, then filtered. After evaporating the solvent, the crude material was loaded to a silica gel column, eluting with 60% ethyl acetate in hexane to give a white solid 73 (2.73 g, 54%). 1H-NMR (CDCl3, 400 MHz) δ 7.34-7.42 (m, 1H), 7.61-7.65 (m, 2H), 7.80-7.93 (m, 2H), 8.73-8.84 (m, 2H); MS (DCI) m/z 242, 243 (M+H)+. First, 4-(4-fluoro-3-trifluoromethyl-phenyl)-pyridine 73 was prepared The mixture was purged with nitrogen gas for 10 minutes was then heated under reflux for 4 hours The reaction mixture was partitioned between ethyl acetate (200 mL) and water (200 mL) The organic layer was separated washed with brine (3×200 mL) dried over MgSO4 filtered After evaporating the solvent eluting with 60% ethyl acetate in hexane

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

Procedure: Beginning with 5-bromo-2-fluorobenzotrifluoride and cis-2,6-dimethyl-1-propyl-piperazine, the title compound was recovered by the procedure described in Preparation 9: m.p. 221° C. (HCl), MS m/z (rel. intensity, 70 eV)) 318 (M+, 32), 289 (74), 112 (bp), 70 (71), 56 (85). the title compound was recovered by the procedure described in Preparation 9

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

Procedure: Sodium hydride (247 mmol, 9.88 g) was stirred in DMF (100 ml) at room temperature. triethylamine (165 mmol, 22.88 ml, 16.66 g) was added. tert-butyl 2-hydroxyethyl(methyl)carbamate (173 mmol, 30.3 g) was added dropwise in DMF. 4-bromo-1-fluoro-2-(trifluoromethyl)benzene (165 mmol, 40 g) was added in one portion and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with water. The organic was dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by flash chromatography eluting with heptane—60/40 heptane/EtOAc. Fractions were collected and combined to afford tert-butyl 2-(4-bromo-2-(trifluoromethyl)phenoxy)-ethyl(methyl)carbamate. (18.44 g) washed with water The organic was dried over sodium sulfate concentrated in vacuo The resulting residue was purified by flash chromatography eluting with heptane—60/40 heptane/EtOAc Fractions were collected