1-bromo-2-(bromomethyl)-4-(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:; See reaction.notes.procedure_details.

Procedure: To a solution of N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine (3.9 g, 12 mmol) in THF (50 mL) at room temperature was added potassium tert-butoxide (KOtBu) (13.2 ml of 1M solution, 13.2 mmol) followed by 1-bromo-2-(bromomethyl)-4-(trifluoromethyl)benzene (4 g, 12.6 mmol). The mixture was stirred at room temperature for 16 hours. Additional KOtBu in THF (13.2 mL of 1M solution, 13.2 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between water (50 mL) and ethyl acetate (3×50 mL). The combined organic layers were washed with saturated NaCl (50 mL), dried (MgSO4) and concentrated. The residue was purified by flash chromatography (silica gel) (eluted with 3:1 hexane-ethyl acetate) to yield the title compound (4.72 g). 1H NMR (400 MHz, CDCl3) δ 4.2 (s, 3 H) 4.8 (s, 2 H) 4.9 (s, 2 H) 7.4 (dd, J=8.2, 1.7 Hz, 1 H) 7.5 (d, J=1.7 Hz, 1 H) 7.7 (m, 3 H) 7.8 (s, 1 H). MS (ES+) Calc: 561.02, Found: 561.7 (M+1). the mixture was stirred at room temperature for 2 hours The reaction mixture was partitioned between water (50 mL) and ethyl acetate (3×50 mL) The combined organic layers were washed with saturated NaCl (50 mL) dried (MgSO4) concentrated The residue was purified by flash chromatography (silica gel) (eluted with 3:1 hexane-ethyl acetate)

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (2-bromo-5-(trifluoromethyl)phenyl)methanol (4.7 g, 18 mmol) in methylene chloride (50 mL) at −10° C. was added carbon tetrabromide (CBr4) (7.17 g, 21.6 mmol). The resulting mixture was stirred at −10° C. for 15 minutes. Triphenylphosphine (5.61 g, 21.4 mmol) was then slowly added portion-wise. This mixture was stirred at room temperature for 16 hours. The mixture was partitioned between saturated ammonium chloride (NH4Cl) (50 ml) and methylene chloride (2×50 mL). The combined organic layers were washed with saturated NaCl (50 mL), dried (MgSO4) and concentrated. The residue was purified by flash chromatography (silica gel) (eluted with 3:1 hexanes-ethyl acetate) to yield the title compound as a white solid (4.01 g), 1H NMR (400 MHz, CDCl3) δ4.6 (s, 2 H) 7.5 (dd, J=8.3, 1.6 Hz, 1 H) 7.8 (m, 2 H). This mixture was stirred at room temperature for 16 hours The mixture was partitioned between saturated ammonium chloride (NH4Cl) (50 ml) and methylene chloride (2×50 mL) The combined organic layers were washed with saturated NaCl (50 mL) dried (MgSO4) concentrated The residue was purified by flash chromatography (silica gel) (eluted with 3:1 hexanes-ethyl acetate)

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

Procedure: To (4S,5R)-5-(3,5-bis-trifluoromethyl-phenyl)-4-methyl-oxazolidin-2-one (0.246 g, 0.79 mmol) in THF (10 mL) at mom temperature was added sodium hexamethyldisilazane (1M in THF; 1.02 mL, 1.02 mmol), and the reaction was stirred for 15 minutes. 2-Bromo-5-(trifluoromethyl)benzyl bromide (0.250 g, 0.79 mmol) was added, and the reaction was stirred overnight at room temperature. The mixture was worked-up with EtOAc and H2O, and the crude material was purified by silica gel chromatography to give the title compound. the reaction was stirred overnight at room temperature the crude material was purified by silica gel chromatography

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

Procedure: Prepared according to the procedure described in Example 6, Step 3, using the following starting materials: 2-bromo-5-(trifluoromethyl)benzyl bromide and (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone. Prepared

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

Procedure: Prepared according to the procedure described in Example 6, Step 3, using the following starting materials: 2-bromo-5-(trifluoromethyl)benzyl bromide and (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone. Prepared

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

Procedure: To (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone (0.386 g, 2.13 mmol) in THY (7 mL) at −78° C. under N2 was added n-butyllithium (2.5M in hexanes; 0.94 mL, 2.35 mmol), and the mixture was stirred at −78° C. for 30 minutes. 2-Bromo-5-(trifluoromethyl)benzyl bromide (0.678 g, 2.13 mmol) was added, and the reaction was warmed to room temperature and stirred overnight. Once no starting material was seen by analytical LCMS, the mixture was transferred to a separatory funnel and partitioned between EtOAc and H2O. The organic layer was separated and washed with brine, dried over MgSO4, filtered, and concentrated to give the title compound. the reaction was warmed to room temperature stirred overnight the mixture was transferred to a separatory funnel partitioned between EtOAc and H2O The organic layer was separated washed with brine dried over MgSO4 filtered concentrated

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

Procedure: To 2-oxazolidone (0.110 g, 1.26 mmol) in DMF (4 mL) was added sodium hydride (60% in mineral oil; 0.056 g, 1.39 mmol), and the mixture was stirred at 0° C. for 10 minutes. 2-Bromo-5-(trifluoromethyl)benzyl bromide (0.420 g, 1.26 mmol) was added, and the reaction was stirred at 0° C. for 1 hour. The mixture was diluted with EtOAc and H2O, and the aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound. the reaction was stirred at 0° C. for 1 hour the aqueous layer was separated extracted with EtOAc The combined organic layers were washed with brine dried over MgSO4 filtered concentrated the residue was purified by silica gel chromatography (0-50% EtOAc in hexanes)

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

Procedure: To 2-oxazolidone (0.110 g, 1.26 mmol) in DMF (4 mL) was added sodium hydride (60% in mineral oil; 0.056 g, 1.39 mmol), and the mixture was stirred at 0° C. for 10 minutes. 2-Bromo-5-(trifluoromethyl)benzyl bromide (0.420 g, 1.26 mmol) was added, and the reaction was stirred at 0° C. for 1 hour. The mixture was diluted with EtOAc and H2O, and the aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound. the reaction was stirred at 0° C. for 1 hour the aqueous layer was separated extracted with EtOAc The combined organic layers were washed with brine dried over MgSO4 filtered concentrated the residue was purified by silica gel chromatography (0-50% EtOAc in hexanes)

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

Procedure: To a solution of N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine (3.9 g, 12 mmol) in THF (50 mL) at room temperature was added potassium tert-butoxide (KOtBu) (13.2 ml of 1M solution, 13.2 mmol) followed by 1-bromo-2-(bromomethyl)-4-(trifluoromethyl)benzene (4 g, 12.6 mmol). The mixture was stirred at room temperature for 16 hours. Additional KOtBu in THF (13.2 mL of 1M solution, 13.2 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between water (50 mL) and ethyl acetate (3×50 mL). The combined organic layers were washed with saturated NaCl (50 mL), dried (MgSO4) and concentrated. The residue was purified by flash chromatography (silica gel) (eluted with 3:1 hexane-ethyl acetate) to yield the title compound (4.72 g). 1H NMR (400 MHz, CDCl3) δ 4.2 (s, 3 H) 4.8 (s, 2 H) 4.9 (s, 2 H) 7.4 (dd, J=8.2, 1.7 Hz, 1 H) 7.5 (d, J=1.7 Hz, 1 H) 7.7 (m, 3 H) 7.8 (s, 1 H). MS (ES+) Calc: 561.02, Found: 561.7 (M+1). the mixture was stirred at room temperature for 2 hours The reaction mixture was partitioned between water (50 mL) and ethyl acetate (3×50 mL) The combined organic layers were washed with saturated NaCl (50 mL) dried (MgSO4) concentrated The residue was purified by flash chromatography (silica gel) (eluted with 3:1 hexane-ethyl acetate)

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (2-bromo-5-(trifluoromethyl)phenyl)methanol (4.7 g, 18 mmol) in methylene chloride (50 mL) at −10° C. was added carbon tetrabromide (CBr4) (7.17 g, 21.6 mmol). The resulting mixture was stirred at −10° C. for 15 minutes. Triphenylphosphine (5.61 g, 21.4 mmol) was then slowly added portion-wise. This mixture was stirred at room temperature for 16 hours. The mixture was partitioned between saturated ammonium chloride (NH4Cl) (50 ml) and methylene chloride (2×50 mL). The combined organic layers were washed with saturated NaCl (50 mL), dried (MgSO4) and concentrated. The residue was purified by flash chromatography (silica gel) (eluted with 3:1 hexanes-ethyl acetate) to yield the title compound as a white solid (4.01 g), 1H NMR (400 MHz, CDCl3) δ4.6 (s, 2 H) 7.5 (dd, J=8.3, 1.6 Hz, 1 H) 7.8 (m, 2 H). This mixture was stirred at room temperature for 16 hours The mixture was partitioned between saturated ammonium chloride (NH4Cl) (50 ml) and methylene chloride (2×50 mL) The combined organic layers were washed with saturated NaCl (50 mL) dried (MgSO4) concentrated The residue was purified by flash chromatography (silica gel) (eluted with 3:1 hexanes-ethyl acetate)