4-bromo-2-(trifluoromethyl)benzonitrile

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:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-[(2-propenyloxy)methyl]-4-(3-methylphenyl)imidazolidine-2,5-dione (899 mg) and 4-bromo-2-(trifluoromethyl)benzonitrile (863 mg) in DMAC (5 mL) is added copper (I) oxide (395 mg). The mixture is refluxed overnight at 130° C. The mixture is concentrated, taken in ethyl acetate, washed with a 10% aqueous ammonia solution and brine. The organic phase is dried over magnesium sulfate, concentrated under vacuum and purified on silica gel (ethyl acetate/cyclohexane 0/100 to 50/50) to give the desired compound. The mixture is concentrated washed with a 10% aqueous ammonia solution and brine The organic phase is dried over magnesium sulfate concentrated under vacuum purified on silica gel (ethyl acetate/cyclohexane 0/100 to 50/50)

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-[(2-propenyloxy)methyl]-4-(3-trifluoromethylphenyl)imidazolidin-2,5-dione (1.45 g) and 4-bromo-2-(trifluoromethyl)benzonitrile (1.15 g) in DMAC (7 mL) is added copper oxide (528 mg). The mixture is refluxed overnight at 130° C. The mixture is concentrated, taken in ethyl acetate, washed with a 10% aqueous ammonia solution and brine. The organic phase is dried over magnesium sulfate, concentrated under vacuum and purified on silica gel (ethyl acetate/cyclohexane 0/100 to 50/50) to give the desired compound. The mixture is concentrated washed with a 10% aqueous ammonia solution and brine The organic phase is dried over magnesium sulfate concentrated under vacuum purified on silica gel (ethyl acetate/cyclohexane 0/100 to 50/50)

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 579 mg of 3-[2,5-dioxo-4-[(2-propenyloxy)methyl]imidazolidin-4-yl]benzonitrile and 534 mg of 4-bromo-2-(trifluoromethyl)benzonitrile in DMAC (2.5 mL), 183 mg of copper oxide are added. The mixture is refluxed overnight at 130° C. The mixture is concentrated, taken in DCM, washed with a solution of 10% aqueous ammonia solution and brine. The organic phase is dried over magnesium sulfate, concentrated under vacuum and purified on silica gel (ethyl acetate/cyclohexane 0/100 to 50/50) to give the desired compound. The mixture is concentrated washed with a solution of 10% aqueous ammonia solution and brine The organic phase is dried over magnesium sulfate concentrated under vacuum purified on silica gel (ethyl acetate/cyclohexane 0/100 to 50/50)

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 675 mg of 4-[2,5-dioxo-4-[(2-propenyloxy)methyl]imidazolidin-4-yl]benzonitrile and 622 mg of 4-bromo-2-trifluoromethylbenzonitrile in DMAC (2.5 mL) 214 mg of copper (I) oxide is added. The mixture is refluxed overnight at 130° C. The mixture is concentrated, taken in DCM, washed with a 10% aqueous ammonia solution and brine. The organic phase is dried over magnesium sulfate, concentrated under vacuum and purified on silica gel (ethyl acetate/cyclohexane: 0/100 to 50/50) to give the desired compound. The mixture is concentrated washed with a 10% aqueous ammonia solution and brine The organic phase is dried over magnesium sulfate concentrated under vacuum purified on silica gel (ethyl acetate/cyclohexane: 0/100 to 50/50)

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 0.33 g of copper (I) oxide and 0.95 g of 4-bromo-2-trifluoromethylbenzonitrile are added to a solution of 1 g 4-(4-fluorophenyl)-4-[(2-propenyloxy)methyl]imidazolidine-2,5-dione obtained in step 3 in 3 mL of DMAC. The mixture is heated at 160° C. for 3 hours. After cooling, the mixture is diluted with a 50% aqueous ammonia solution and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and evaporated. The crude product is purified by chromatography over silica gel while eluting with 2/1 heptane/ethyl acetate. After cooling extracted with ethyl acetate The organic layer is dried over sodium sulfate filtered evaporated The crude product is purified by chromatography over silica gel while eluting with 2/1 heptane/ethyl acetate

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 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (10 mg, 0.024 mmol), 4-bromo-2-(trifluoromethyl)benzonitrile (6.09 mg, 0.024 mmol), Pd2(dba)3 (2.231 mg, 2.436 μmol), Xantphos (1.410 mg, 2.436 μmol) and Cs2CO3 (15.88 mg, 0.049 mmol) in 1,4-dioxane (1 mL) was stirred at 120° C. for 1 h. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo. The residue was dissolved in EA (20 mL) and washed with H2O (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by preparative TLC (PE/EA=1/1) to yield a white solid of N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (15 mg, 0.013 mmol, 51.4% yield): 1H NMR (400 MHz, CD3OD) δ 8.23 (s, 1H), 7.98 (m, 1H), 7.94-7.90 (m, 2H), 7.44-7.37 (m, 6H), 6.90 (d, J=8.4 Hz, 2H), 5.32 (s, 2H), 4.16-4.11 (m, 2H), 2.85 (s, 2H), 3.77 (s, 3H), 1.41 (t, J=7.2 Hz, 3H); ES-LCMS m/z 460.1 (M−120). the solvent was removed in vacuo The residue was dissolved in EA (20 mL) washed with H2O (10 mL) and brine (10 mL) The organic layer was dried over Na2SO4 filtered concentrated The crude material was purified by preparative TLC (PE/EA=1/1)

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

Procedure: A solution of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (10 mg, 0.024 mmol), 4-bromo-2-(trifluoromethyl)benzonitrile (6.09 mg, 0.024 mmol), Pd2(dba)3 (2.231 mg, 2.436 μmol), Xantphos (1.410 mg, 2.436 μmol) and Cs2CO3 (15.88 mg, 0.049 mmol) in 1,4-dioxane (1 mL) was stirred at 120° C. for 1 h. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo. The residue was dissolved in EA (20 mL) and washed with H2O (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by preparative TLC (PE/EA=1/1) to yield a white solid of N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (15 mg, 0.013 mmol, 51.4% yield): 1H NMR (400 MHz, CD3OD) δ 8.23 (s, 1H), 7.98 (m, 1H), 7.94-7.90 (m, 2H), 7.44-7.37 (m, 6H), 6.90 (d, J=8.4 Hz, 2H), 5.32 (s, 2H), 4.16-4.11 (m, 2H), 2.85 (s, 2H), 3.77 (s, 3H), 1.41 (t, J=7.2 Hz, 3H); ES-LCMS m/z 460.1 (M−120). the solvent was removed in vacuo The residue was dissolved in EA (20 mL) washed with H2O (10 mL) and brine (10 mL) The organic layer was dried over Na2SO4 filtered concentrated The crude material was purified by preparative TLC (PE/EA=1/1)