1-bromo-3-ethynylbenzene

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: A solution of 4-iodo-1H-pyrrole-2-carbaldehyde (0.50 g; 2.262 mmol) and bis(triphenylphosphine)palladium-(II)chloride (0.079 g; 0.113 mmol)) in DMF (15 mL; degassed with nitrogen for 30 minutes) was stirred at ambient temperature for 15 minutes. Then the following were added: 1-bromo-3-ethynylbenzene (0.61 g; 3.394 mmol), copper iodide (43 mg; 0.226), and triethylamine (1.58 mL, 11.3 mmol). The course of the reaction was followed with TLC (4:1, hexane:ethyl acetate). After 2 hours the reaction mixture was diluted with water and the organic material was extracted into dichloromethane. The organic extracts were washed with water and brine, dried over MgSO4, filtered, and evaporated. The residue was chromatographed on silica gel using 3:1 hexane:ethyl acetate to yield 0.58 g (93%) of the title compound as a yellow crystalline solid, mp 152-156° C.; MS (ES) m/z 272.0, [M−H]−. Then the following were added the organic material was extracted into dichloromethane The organic extracts were washed with water and brine dried over MgSO4 filtered evaporated The residue was chromatographed on silica gel using 3:1 hexane

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

Procedure: To a solution of 4-iodo-1-(2,2,2-trifluoroethyl)-1H-pyrazole (4.14 g, 15 mmol) in triethylamine (53 mL) is added tetrakis(triphenylphosphine)paddadium (1.20 g, 1.04 mmol), copper iodide (0.28 g, 1.46 mmol) and a solution of 1-bromo-3-ethynylbenzene (2.78 g, 15 mmol) in acetonitrile (15 mL) at room temperature. After heating for 1 hour at 80° C., the reaction mixture is cooled and concentrated. The crude material is purified by chromatography (silica gel, EtOAc/hexane:5/95) to give the title compound as a solid (4.91 g, 99%). mp: 107-109° C. MS (+) EI: 328 M+. at room temperature the reaction mixture is cooled concentrated The crude material is purified by chromatography (silica gel, EtOAc/hexane:5/95)

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

Procedure: A solution of N-triisopropylsilylpyrrole (3.49 g, 1 mmol), 3-bromo-1-ethynylbenzene (1.81 g, 1 mmol), Pd(PPh3)4 (800 mg) and CuI (185 mg) in CH3CN (15 ml) and triethylamine (35 ml) is refluxed for 5 h. The reaction mixture is cooled to room temperature and the solvent is evaporated on a rotary evaporator. The crude material is purified by flash chromatographied (silica gel, 100% hexane) to afford 3-[(3-bromophenyl)ethynyl]-1-(triisopropylsilyl)-1H-pyrrole (2.7 g, 85%) as a clear oil. the solvent is evaporated on a rotary evaporator The crude material is purified by flash

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

Procedure: To a mixture of 1-bromo-3-ethynylbenzene (0.430 g; 2.38 mmol; Note 1), and azidomethyl 2,2-dimethylpropanoate (0.391 g; 2.49 mmol; Note 2) in t-BuOH/water (3.5/3.0 mL respectively) at room temperature was added a solution of CuSO4.5H2O in water (0.030 g/0.5 mL), followed by sodium ascorbate (0.141 g; 0.71 mmol) in one portion. The mixture was stirred 25 h at room temperature, diluted with water and extracted with EtOAc (×3). Combined organics were washed (5% NH4OH, water, brine), dried over Na2SO4 and concentrated in vacuo affording the title compound as a tan solid which was used without further purification. LC/MS (method B) 2.77 min, m/z 338, 340 (M+H, Br isotopes). extracted with EtOAc (×3) Combined organics were washed (5% NH4OH, water, brine) dried over Na2SO4 concentrated in vacuo

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

Procedure: Using essentially the same procedure described in Example 1, steps a-d, and employing 1-bromo-3-ethynylbenzene in step a, the racemic mixture of 2-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one was obtained and separated by chiral chromatography technique (Chiralcel OJ, 2×25 cm, using 5% ethanol in 95% hexane and diethylamine as the mobile phase) to give the title enantiomer, MS m/e (M+H)+ 332; 1H NMR (400 MHz, DMSO-d6) 2.94 (s, 3H), 6.72 (brs, 2H), 7.1 (d, J=8.66 Hz, 2H), 7.13-7.35 (m, 2H), 7.38-7.43 (m, 4H), 7.56 (t, J=1.72 Hz, 1H); [a]25=−4 (C=1% in MeOH). was obtained separated by chiral chromatography technique (Chiralcel OJ, 2×25 cm to give the title enantiomer, MS m/e (M+H)+ 332

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

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

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