2-(bromomethyl)-1,3,5-trifluorobenzene

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 mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. Potassium carbonate (740 mg, 5.35 mmoles) and 2,4,6-trifluorobenzyl bromide (337 mg, 1.5 mmoles) in dimethylformamide (5 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate. The organic solution was washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (1.0 mL) and 6 molar sodium hydroxide solution (1.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated to give the title compound (240 mg, 53%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.06 (br. s, 1 H), 10.08 (br. s, 1 H), 7.11-7.19 (m, 2 H), 5.06 (s, 2 H), 4.61 (t, J=12.00 Hz, 1 H), 4.12 (d, J=5.81 Hz, 2 H), 2.19-2.30 (m, J=12.25, 12.25, 12.13, 2.53 Hz, 2 H), 1.78 (d, J=12.88 Hz, 2 H), 1.59 (t, J=13.01 Hz, 3 H), 1.28 (q, J=12.88 Hz, 2 H), 1.06-1.17 (m, 1 H). extracted with ethyl acetate The organic solution was washed with 1 molar hydrochloric acid evaporated The residue was purified by flash chromatography (10-50% ethyl acetate in hexane) the required fractions evaporated dissolved in ethanol (5 mL) 1 molar sodium hydroxide solution (1.0 mL) and 6 molar sodium hydroxide solution (1.0 mL) added extracted with ethyl acetate (×2) the combined extracts washed with 1 molar hydrochloric acid dried evaporated

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

Procedure: Then a solution of 3-pyridin-2-yl-7-(trifluoromethyl)-2H-indazole (0.183 g, 0.7 mmol) and 2,4,6-trifluorobenzyl bromide (0.203 g, 0.9 mmol) in DMF (5 mL) was heated at 120° C. After 5 days, the reaction mixture was partitioned with EtOAc and water. Organics were washed with water (3×), then brine and dried over MgSO4, then stripped and the resulting crude product was flashed by reverse phase HPLC to afford the title compound (0.033 g, 5%). the reaction mixture was partitioned with EtOAc and water Organics were washed with water (3×) brine and dried over MgSO4

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

Procedure: A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. Potassium carbonate (740 mg, 5.35 mmoles) and 2,4,6-trifluorobenzyl bromide (337 mg, 1.5 mmoles) in dimethylformamide (5 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate. The organic solution was washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (1.0 mL) and 6 molar sodium hydroxide solution (1.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated to give the title compound (240 mg, 53%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.06 (br. s, 1 H), 10.08 (br. s, 1 H), 7.11-7.19 (m, 2 H), 5.06 (s, 2 H), 4.61 (t, J=12.00 Hz, 1 H), 4.12 (d, J=5.81 Hz, 2 H), 2.19-2.30 (m, J=12.25, 12.25, 12.13, 2.53 Hz, 2 H), 1.78 (d, J=12.88 Hz, 2 H), 1.59 (t, J=13.01 Hz, 3 H), 1.28 (q, J=12.88 Hz, 2 H), 1.06-1.17 (m, 1 H). extracted with ethyl acetate The organic solution was washed with 1 molar hydrochloric acid evaporated The residue was purified by flash chromatography (10-50% ethyl acetate in hexane) the required fractions evaporated dissolved in ethanol (5 mL) 1 molar sodium hydroxide solution (1.0 mL) and 6 molar sodium hydroxide solution (1.0 mL) added extracted with ethyl acetate (×2) the combined extracts washed with 1 molar hydrochloric acid dried evaporated

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

Procedure: A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. Potassium carbonate (740 mg, 5.35 mmoles) and 2,4,6-trifluorobenzyl bromide (337 mg, 1.5 mmoles) in dimethylformamide (5 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate. The organic solution was washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (1.0 mL) and 6 molar sodium hydroxide solution (1.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated to give the title compound (240 mg, 53%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.06 (br. s, 1 H), 10.08 (br. s, 1 H), 7.11-7.19 (m, 2 H), 5.06 (s, 2 H), 4.61 (t, J=12.00 Hz, 1 H), 4.12 (d, J=5.81 Hz, 2 H), 2.19-2.30 (m, J=12.25, 12.25, 12.13, 2.53 Hz, 2 H), 1.78 (d, J=12.88 Hz, 2 H), 1.59 (t, J=13.01 Hz, 3 H), 1.28 (q, J=12.88 Hz, 2 H), 1.06-1.17 (m, 1 H). extracted with ethyl acetate The organic solution was washed with 1 molar hydrochloric acid evaporated The residue was purified by flash chromatography (10-50% ethyl acetate in hexane) the required fractions evaporated dissolved in ethanol (5 mL) 1 molar sodium hydroxide solution (1.0 mL) and 6 molar sodium hydroxide solution (1.0 mL) added extracted with ethyl acetate (×2) the combined extracts washed with 1 molar hydrochloric acid dried evaporated

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

Procedure: The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2,4,6-trifluorobenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.41 (s, 1 H), 7.20 (d, J=10.0 Hz, 1 H), 7.08 (t, J=4.0 Hz, 1 H), 6.91 (dd, J=5.6, 8.3 Hz, 1 H), 6.71 (t, J=8.1 Hz, 2 H), 6.23-6.16 (m, 1 H), 5.61-5.42 (m, 3 H), 4.31-4.24 (m, 2 H), 2.94-2.76 (m, 2 H), 2.72 (s, 3 H), 2.13-2.05 (m, 2 H), 0.96 (s, 9 H); LC/MS (m/z) ES+=539.33 (M+1).

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

Procedure: The title compound was prepared from methyl 2-(tert-butoxy)-2-(6-methyl-4-(p-tolyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2-(bromomethyl)-1,3,5-trifluorobenzene in a manner similar to that described in Example 25 as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=7.63 (d, J=7.6 Hz, 1 H), 7.40-7.30 (m, 3 H), 7.07 (d, J=3.5 Hz, 1 H), 6.78-6.69 (m, 2 H), 6.25 (d, J=3.5 Hz, 1 H), 5.71-5.56 (m, 2 H), 5.53 (s, 1 H), 2.84 (s, 3 H), 2.47 (s, 3 H), 0.95 (s, 9 H); LCMS (m/z) ES+=497 (M+1).

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

Procedure: The title compound is prepared by alkylation of the (RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester with 2,4,6-trifluorobenzyl bromide giving the (RS)-5-oxo-1-[4-(3,4,5-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid methyl ester as a white solid (99% of theory) which, thereupon, by treatment with methylamine in ethanol at 50° C. yields the (RS)-5-oxo-1-[4-(3,4,5-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid methylamide. Yield: 99% of theory as a white solid; MS: m/e=379 (M+H)+.

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

Procedure: The title compound is prepared by alkylation of the (RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester with 2,4,6-trifluorobenzyl bromide giving the (RS)-5-oxo-1-[4-(2,4,6-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid methyl ester which, thereupon, by treatment with methylamine yields the (RS)-5-oxo-1-[4-(2,4,6-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid methylamide. Yield: 97% of theory as a white solid. MS: m/e=379 (M+H)+.

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

Procedure: The title compound was prepared from 2-(4,5-dimethoxypyrimidin-2-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide (IntA32) (50 mg, 0.15 mmol), 2,4,6-trifluorobenzyl bromide (41 mg, 0.18 mmol) and K2CO3 (62 mg, 0.45 mmol) in DMF (1.5 mL) using the methods of (115). After purification by gradient column chromatography further purification by preparative HPLC (method C) yielded the title compound (8 mg, 0.02 mmol). After purification by gradient column chromatography further purification by preparative HPLC (method C)

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

Procedure: The title compound (103 mg, 0.21 mmol) was prepared from (IntA19) (84 mg, 0.25 mmol), K2CO3 (104 mg, 0.75 mmol) and 2,4,6-trifluorobenzyl bromide (68 mg, 0.30 mmol) in DMF (2 mL) using the methods of (115).