1-(bromomethyl)-2-fluoro-3-(trifluoromethyl)benzene

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

Procedure: To a suspension of 5-(2-chloro-3-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione 7e (2.2 g, 8.7 mmol) in acetonitrile (25 mL) was added bis(trimethylsilyl)acetamide (4.3 mL, 17.4 mmol), and the resulting solution was refluxed for 1.5 hours. The mixture was cooled to room temperature, 2-fluoro-3-trifluoromethylbenzyl bromide (2.7 g, 10.5 mmol) was added, and reflux was resumed for 16 hours. The reaction was quenched by addition of MeOH (25 mL) and stirring for 2 hours. After concentration, the residue was purified by column chromatography on silica gel with ethyl acetate/hexanes 1/1 to afford 5-(2-chloro-3-methoxyphenyl)-1-[1-fluoro-6-(trifluoromethyl)benzyl]pyrimidine-2,4(1H,3H)-dione 7f (3.3 g, 88%) as a white solid. MS (CI) m/z 429.0, 431.0 (MH+). the resulting solution was refluxed for 1.5 hours reflux The reaction was quenched by addition of MeOH (25 mL) After concentration the residue was purified by column chromatography on silica gel with ethyl acetate/hexanes 1/1

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of {3-[3-(2,2-diphenyl-ethylamino)-propoxy]-phenyl}-acetic acid methyl ester (3) (0.7 g, 0.002 mol) in DMF (10 mL), was added 2-fluoro-3-(trifluoromethyl)benzyl bromide (0.5 g, 0.002 mol) and powdered potassium carbonate (1.93 g, 0.014 mol), the reaction mixture was heated and stirred at 45° C. for 18 hours. After cooling, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, concentrated to an oil, which was purified by flash chromatography (8:2 Hexanes/EtOAc) to give the desired product as oil 0.84 g in 72% yield. 1H NMR (CDCl3) δ 7.35 (t, 1H), 7.17 (m, 12H), 6.85 (t, 2H), 6.63 (s, 1H), 6.59 (t, 1H), 4.16 (t, 1H), 3.69 (s, 3H), 3.68 (s, 2H), 3.63 (t, 2H), 3.57 (d, 2H), 3.10 (d, 2H), 2.67 (t, 2H), 1.82 (t, 2H). 13C NMR (CDCl3) δ 173.4, 160.4, 144.8, 136.6, 130.8, 130.8, 129.7, 129.6, 129.4, 127.7, 126.8, 124.9, 123.1, 122.8, 116.8, 114.5, 66.3, 61.4, 53.5, 52.4, 51.8, 51.1, 42.7, 28.3. the reaction mixture was heated After cooling extracted with EtOAc (3×25 mL) The combined organic extracts were washed with brine (15 mL) dried over Na2SO4 concentrated to an oil, which was purified by flash chromatography (8:2 Hexanes/EtOAc)

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

Procedure: To a suspension of 5-(2-chloro-3-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione 7e (2.2 g, 8.7 mmol) in acetonitrile (25 mL) was added bis(trimethylsilyl)acetamide (4.3 mL, 17.4 mmol), and the resulting solution was refluxed for 1.5 hours. The mixture was cooled to room temperature, 2-fluoro-3-trifluoromethylbenzyl bromide (2.7 g, 10.5 mmol) was added, and reflux was resumed for 16 hours. The reaction was quenched by addition of MeOH (25 mL) and stirring for 2 hours. After concentration, the residue was purified by column chromatography on silica gel with ethyl acetate/hexanes 1/1 to afford 5-(2-chloro-3-methoxyphenyl)-1-[1-fluoro-6-(trifluoromethyl)benzyl]pyrimidine-2,4(1H,3H)-dione 7f (3.3 g, 88%) as a white solid. MS (CI) m/z 429.0, 431.0 (MH+). the resulting solution was refluxed for 1.5 hours reflux The reaction was quenched by addition of MeOH (25 mL) After concentration the residue was purified by column chromatography on silica gel with ethyl acetate/hexanes 1/1

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

Procedure: To a suspension of 5-(2-chloro-3-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione 7e (2.2 g, 8.7 mmol) in acetonitrile (25 mL) was added bis(trimethylsilyl)acetamide (4.3 mL, 17.4 mmol), and the resulting solution was refluxed for 1.5 hours. The mixture was cooled to room temperature, 2-fluoro-3-trifluoromethylbenzyl bromide (2.7 g, 10.5 mmol) was added, and reflux was resumed for 16 hours. The reaction was quenched by addition of MeOH (25 mL) and stirring for 2 hours. After concentration, the residue was purified by column chromatography on silica gel with ethyl acetate/hexanes 1/1 to afford 5-(2-chloro-3-methoxyphenyl)-1-[1-fluoro-6-(trifluoromethyl)benzyl]pyrimidine-2,4(1H,3H)-dione 7f (3.3 g, 88%) as a white solid. MS (CI) m/z 429.0, 431.0 (MH+). the resulting solution was refluxed for 1.5 hours reflux The reaction was quenched by addition of MeOH (25 mL) After concentration the residue was purified by column chromatography on silica gel with ethyl acetate/hexanes 1/1

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of {3-[3-(2,2-diphenyl-ethylamino)-propoxy]-phenyl}-acetic acid methyl ester (3) (0.7 g, 0.002 mol) in DMF (10 mL), was added 2-fluoro-3-(trifluoromethyl)benzyl bromide (0.5 g, 0.002 mol) and powdered potassium carbonate (1.93 g, 0.014 mol), the reaction mixture was heated and stirred at 45° C. for 18 hours. After cooling, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, concentrated to an oil, which was purified by flash chromatography (8:2 Hexanes/EtOAc) to give the desired product as oil 0.84 g in 72% yield. 1H NMR (CDCl3) δ 7.35 (t, 1H), 7.17 (m, 12H), 6.85 (t, 2H), 6.63 (s, 1H), 6.59 (t, 1H), 4.16 (t, 1H), 3.69 (s, 3H), 3.68 (s, 2H), 3.63 (t, 2H), 3.57 (d, 2H), 3.10 (d, 2H), 2.67 (t, 2H), 1.82 (t, 2H). 13C NMR (CDCl3) δ 173.4, 160.4, 144.8, 136.6, 130.8, 130.8, 129.7, 129.6, 129.4, 127.7, 126.8, 124.9, 123.1, 122.8, 116.8, 114.5, 66.3, 61.4, 53.5, 52.4, 51.8, 51.1, 42.7, 28.3. the reaction mixture was heated After cooling extracted with EtOAc (3×25 mL) The combined organic extracts were washed with brine (15 mL) dried over Na2SO4 concentrated to an oil, which was purified by flash chromatography (8:2 Hexanes/EtOAc)