2-bromo-1,3,5-trifluorobenzene

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

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

Procedure: This compound was synthesized from (3,5-dimethoxy-4-1-propylphenyl)ethene and 1-bromo-2,4,6-trifluorobenzene in 58% yield in the same procedure as described in preparation of 31B. 1HNMR (CDCl3, ppm): δ 1.32 (d, J=7.0 Hz, 6H), 3.62 (qint, J=7.1 Hz, 1H), 3.89 (s, 6H), 6.73 (s, 2H), 6.79-7.55 (m, 4H).

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

Procedure: This compound was synthesized from (3,5-dimethoxy-4-1-propylphenyl)ethene and 1-bromo-2,4,6-trifluorobenzene in 58% yield in the same procedure as described in preparation of 31B. 1HNMR (CDCl3, ppm): δ 1.32 (d, J=7.0 Hz, 6H), 3.62 (qint, J=7.1 Hz, 1H), 3.89 (s, 6H), 6.73 (s, 2H), 6.79-7.55 (m, 4H).

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

Procedure: This compound was synthesized from (3,5-dimethoxy-4-1-propylphenyl)ethene and 1-bromo-2,4,6-trifluorobenzene in 58% yield in the same procedure as described in preparation of 31B. 1HNMR (CDCl3, ppm): δ 1.32 (d, J=7.0 Hz, 6H), 3.62 (qint, J=7.1 Hz, 1H), 3.89 (s, 6H), 6.73 (s, 2H), 6.79-7.55 (m, 4H).

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

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

Procedure: This compound was synthesized from (3,5-dimethoxy-4-i-propylphenyl)ethene and 1-bromo-2,4,6-triflurobenzene in 58% yield in the same procedure as described in preparation of 31B. 1HNMR (CDCl3, ppm): δ 1.32 (d, J=7.0 Hz, 6H), 3.62 (qint, J=7.1 Hz, 1H), 3.89 (s, 6H), 6.73 (s, 2H), 6.79-7.55 (m, 4H).

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

Procedure: To a cooled (1.3° C.) mixture of 1-bromo-2,4,6-trifluorobenzene (30.0 g, 142 mmol) and H2SO4 (115 mL) was added HNO3 (68%, 102 mL) over 1.5 h at such a rate that the internal temperature was <8° C. After stirring at 0° C. for 2 h, the resulting mixture was poured into ice water (1850 mL), stirred vigorously for 30 min and extracted with CH2Cl2 (3×600 mL). The combined organic layers were washed with water (2×600 mL), dried over MgSO4, filtered and concentrated in vacuo to give the desired product as a clear yellow oil (35.0 g, 99% yield). 1H NMR (CDCl3) δ 7.01 (ddd, J=2.4, 7.8, 9.3 Hz, 1H); 19F NMR (CDCl3) δ −116.20 to −116.10, −107.73 to −107.71, −93.80 to −93.70. To a cooled was <8° C stirred vigorously for 30 min extracted with CH2Cl2 (3×600 mL) The combined organic layers were washed with water (2×600 mL) dried over MgSO4 filtered concentrated in vacuo

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 1-bromo-2,4,6-trifluorobenzene (0.01 ml, 0.12 mmol) in diethyl ether (0.5 mL) at −78° C. was added n-butyllithium (0.13 mL, 0.14 mmol, 1.6 M in hexanes). After 30 tert-butyl 6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(pyrazine-2-carbonyl)-1H-benzo[d]imidazole-1-carboxylate (36.6 mg, 0.08 mmol) in diethyl ether (1 mL) was added drop-wise to the reaction. After 90 minutes, the reaction was warmed, quenched with saturated NH4Cl(aq) (10 mL), extracted with ethyl acetate (3×10 mL), dried over Na2SO4, and concentrated in vacuo. To the crude residue in ethanol (1.5 mL) was added hydrochloric acid (0.20 mL, 0.79 mmol, 4 M in 1,4-dioxane) and the mixture was heated to 70° C. in a microwave reactor for 45 minutes. Purification by reverse-phase HPLC (35-50% acetonitrile/water with 0.01% trifluoroacetic acid, Gemini C18 5μ) afforded 6-(3,5-dimethylisoxazol-4-yl)-4-(hydroxy(pyrazin-2-yl)(2,4,6-trifluorophenyl)methyl)-1H-benzo[d]imidazol-2(3H)-one as a pale yellow solid. to the reaction the reaction was warmed quenched with saturated NH4Cl(aq) (10 mL) extracted with ethyl acetate (3×10 mL) dried over Na2SO4 concentrated in vacuo Purification by reverse-phase HPLC (35-50% acetonitrile/water with 0.01% trifluoroacetic acid, Gemini C18 5μ)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 1-bromo-2,4,6-trifluorobenzene (0.02 ml, 0.16 mmol) in diethyl ether (0.52 mL) at −78° C. was added n-butyllithium (0.12 mL, 0.18 mmol, 1.6 M in hexanes). After 30 minutes, tert-butyl 6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(5-fluoropicolinoyl)-1H-benzo[d]imidazole-1-carboxylate (50 mg, 0.10 mmol) in diethyl ether (1 mL) was added drop-wise to the reaction. After 60 minutes, the reaction was warmed, quenched with saturated NH4Cl(aq) (10 mL), extracted with ethyl acetate (3×10 mL), dried over Na2SO4, and concentrated in vacuo. To the crude residue in ethanol (3.5 mL) was added hydrochloric acid (0.35 mL, 1.4 mmol, 4 M in 1,4-dioxane) and the mixture was heated to 70° C. in a microwave reactor for 45 minutes. Purification by reverse-phase HPLC (40-50% acetonitrile/water with 0.01% trifluoroacetic acid, Gemini C18 5μ) afforded 6-(3,5-dimethylisoxazol-4-yl)-4-((5-fluoropyridin-2-yl)(hydroxy)(2,4,6-trifluorophenyl)methyl)-1H-benzo[d]imidazol-2(3H)-one as a white solid. to the reaction After 60 minutes the reaction was warmed quenched with saturated NH4Cl(aq) (10 mL) extracted with ethyl acetate (3×10 mL) dried over Na2SO4 concentrated in vacuo Purification by reverse-phase HPLC (40-50% acetonitrile/water with 0.01% trifluoroacetic acid, Gemini C18 5μ)

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diethyl malonate (0.49 mol) was added to a mixture of sodium hydride (0.51 mol) and 1,4-dioxane (140 ml) at 55 to 60° C. within 2 hours. A mixture of 1,4-dioxane (50 ml) and diethyl malonate (0.13 mol) was added. The mixture was stirred for 10 minutes at 55° C. and copper(I) bromide (0.05 mol) was added. After 15 min. a mixture of 2-bromo-1,3,5-trifluorobenzene (0.25 mol) and 1,4-dioxane (10 ml) was added. The reaction mixture was heated at 100° C. for 15 hours and cooled to 15° C. Hydrochloric acid (12N, 35 ml) was added slowly at 15 to 20° C. The precipitate was filtered off. The filtrate was extracted with diethylether. The organic Phase was separated, dried with anhydrous sodium sulphate and filtered. The filtrate was evaporated under reduced Pressure to yield the product. was added was added The reaction mixture was heated at 100° C. for 15 hours cooled to 15° C The precipitate was filtered off The filtrate was extracted with diethylether The organic Phase was separated dried with anhydrous sodium sulphate filtered The filtrate was evaporated under reduced Pressure to yield the product

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Alternatively, combine trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (1.93 g, 3.60 mmol), cesium fluoride (5.0 g, 33 mmol), bis(neopentyl glycolato)diboron (1.0 g, 4.4 mmol), bis(tricyclohexylphosphine)palladium (0.50 g, 0.75 mmol) and acetonitrile (50 mL). Heat the mixture to 90° C. for 20 minutes to obtain a dark-colored solution. Add 2-bromo-1,3,5-trifluoro-benzene (5 g, 23.7 mmol) and heat at 90° C. for 2 hours. Add bis(tricyclohexylphosphine)palladium (0.50 g, 0.75 mmol) and 2-bromo-1,3,5-trifluoro-benzene (5.0 g, 23 mmol) and heat at 90° C. for 4 hours. Cool to room temperature and filter through a pad of celite and evaporate the solvent. Purify the residue over silica gel, eluting the material with methanol in dichloromethane (0 to 5%), to give 1.30 g (67%) of title compound: mass spectrum (ion spray) m/z=520.2 (M+H). to obtain a dark-colored solution Cool to room temperature filter through a pad of celite evaporate the solvent Purify the residue over silica gel eluting the material with methanol in dichloromethane (0 to 5%)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a mixture of 4.8 g of sodium hydride (60% in oil) and 100 ml of 1,4-dioxane, 19.2 g of diethyl malonate were added dropwise at room temperature, and then 17.2 g of cuprous bromide and 21.1 g of 1-bromo-2,4,6-trifluorobenzene were subsequently added thereto at 40° C. and refluxed for 26 hours under heating. To the reaction mixture, conc. hydrochloric acid was added under ice-cooling, and then tert-butyl methyl ether and water were added. The organic layer was separated, washed with aqueous sodium hydroxide solution, dil. hydrochloric acid and water subsequently, dried over sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 12.6 g of diethyl (2,4,6-trifluorophenyl)malonate. were added dropwise at room temperature under heating cooling The organic layer was separated washed with aqueous sodium hydroxide solution, dil. hydrochloric acid and water subsequently dried over sodium sulfate concentrated