1-(4-fluorophenyl)imidazolidin-2-one

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

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

Procedure: Triphosgene (209.2, 0.47 mmol) was added to a solution of 1-(4-fluorophenyl)imidazolidin-2-one (209.2 mg, 0.71 mmol) in THF (4.7 mL) and the mixture was heated to reflux for 6 h. 1-(4-(7-(4-Amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone 270 (120.0 mg, 0.31 mmol) and DIPEA (0.1 mL, 0.5 mmol) were added and the mixture was stirred for 1 h at room temperature. The reaction mixture was transferred to a silica gel flash chromatography column and eluted with 3% MeOH in DCM affording 264 (97.6 mg, 0.16 mmol, 52% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.55 (s, 1H), 8.47 (d, 5.5 Hz, 1H), 7.84 (dd, J=2.4 Hz, 13.1 Hz, 1H), 7.71-7.63 (m, 2H), 7.54 (m, 1H), 7.48-7.42 (m, 2H), 7.31-7.27 (m, 2H), 6.63 (m, 1H), 6.42 (m, 1H), 4.21 (br, 1H), 4.15 (br, 1H), 3.96-3.93 (m, 4H), 3.71-3.65 (m, 2H), 2.70 (br, 1H), 2.59 (br, 1H), 2.09 (s, 1.5H), 2.05 (s, 1.5H). MS (m/z): (M+1) 590.2 (100%). the mixture was heated to reflux for 6 h

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

Procedure: Triphosgene (209.2, 0.47 mmol) was added to a solution of 1-(4-fluorophenyl)imidazolidin-2-one (209.2 mg, 0.71 mmol) in THF (4.7 mL) and the mixture was heated to reflux for 6 h. 1-(4-(7-(4-Amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone 270 (120.0 mg, 0.31 mmol) and DIPEA (0.1 mL, 0.5 mmol) were added and the mixture was stirred for 1 h at room temperature. The reaction mixture was transferred to a silica gel flash chromatography column and eluted with 3% MeOH in DCM affording 264 (97.6 mg, 0.16 mmol, 52% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.55 (s, 1H), 8.47 (d, 5.5 Hz, 1H), 7.84 (dd, J=2.4 Hz, 13.1 Hz, 1H), 7.71-7.63 (m, 2H), 7.54 (m, 1H), 7.48-7.42 (m, 2H), 7.31-7.27 (m, 2H), 6.63 (m, 1H), 6.42 (m, 1H), 4.21 (br, 1H), 4.15 (br, 1H), 3.96-3.93 (m, 4H), 3.71-3.65 (m, 2H), 2.70 (br, 1H), 2.59 (br, 1H), 2.09 (s, 1.5H), 2.05 (s, 1.5H). MS (m/z): (M+1) 590.2 (100%). the mixture was heated to reflux for 6 h

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

Procedure: Triphosgene (209.2, 0.47 mmol) was added to a solution of 1-(4-fluorophenyl)imidazolidin-2-one (209.2 mg, 0.71 mmol) in THF (4.7 mL) and the mixture was heated to reflux for 6 h. 1-(4-(7-(4-Amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone 270 (120.0 mg, 0.31 mmol) and DIPEA (0.1 mL, 0.5 mmol) were added and the mixture was stirred for 1 h at room temperature. The reaction mixture was transferred to a silica gel flash chromatography column and eluted with 3% MeOH in DCM affording 264 (97.6 mg, 0.16 mmol, 52% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.55 (s, 1H), 8.47 (d, 5.5 Hz, 1H), 7.84 (dd, J=2.4 Hz, 13.1 Hz, 1H), 7.71-7.63 (m, 2H), 7.54 (m, 1H), 7.48-7.42 (m, 2H), 7.31-7.27 (m, 2H), 6.63 (m, 1H), 6.42 (m, 1H), 4.21 (br, 1H), 4.15 (br, 1H), 3.96-3.93 (m, 4H), 3.71-3.65 (m, 2H), 2.70 (br, 1H), 2.59 (br, 1H), 2.09 (s, 1.5H), 2.05 (s, 1.5H). MS (m/z): (M+1) 590.2 (100%). the mixture was heated to reflux for 6 h

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

Procedure: To a solution of 1-(4-fluorophenyl)-2-imidazolidinone (0.12 g, 0.65 mmol) dissolved in 10 mL dimethylformamide cooled in an ice bath was added NaH (60% dispersion in mineral oil, 39.0 mg, 0.98 mmol). The mixture was stirred at room temperature for 30 minutes and then cooled in ice bath. 1-Bromo-6-(4-bromophenoxy)heptane (0.22 g, 0.65 mmol) was added, and the mixture was stirred at room temperature for additional 4 hours. The reaction was quenched with methanol, and the solvents were removed under reduced pressure. 5 mL of saturated NH4Cl water solution and 10 mL of dichloromethane were added to the residue. The dichloromethane layer was dried over MgSO4, filtered, evaporated, and purified by column chromatography (ethyl acetate:MeOH=10:1) to give the product (i.e., Compound 7) as a white solid (0.14 g, 48%). cooled in an ice bath cooled in ice bath the mixture was stirred at room temperature for additional 4 hours The reaction was quenched with methanol the solvents were removed under reduced pressure 5 mL of saturated NH4Cl water solution and 10 mL of dichloromethane were added to the residue The dichloromethane layer was dried over MgSO4 filtered evaporated purified by column chromatography (ethyl acetate:MeOH=10:1)

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

Procedure: To a solution of 1-(4-fluorophenyl)-2-imidazolidinone (0.12 g, 0.65 mmol) dissolved in 10 mL dimethylformamide cooled in an ice bath was added NaH (60% dispersion in mineral oil, 39.0 mg, 0.98 mmol). The mixture was stirred at room temperature for 30 minutes and then cooled in ice bath. 1-Bromo-6-(4-bromophenoxy)heptane (0.22 g, 0.65 mmol) was added, and the mixture was stirred at room temperature for additional 4 hours. The reaction was quenched with methanol, and the solvents were removed under reduced pressure. 5 mL of saturated NH4Cl water solution and 10 mL of dichloromethane were added to the residue. The dichloromethane layer was dried over MgSO4, filtered, evaporated, and purified by column chromatography (ethyl acetate:MeOH=10:1) to give the product (i.e., Compound 7) as a white solid (0.14 g, 48%). cooled in an ice bath cooled in ice bath the mixture was stirred at room temperature for additional 4 hours The reaction was quenched with methanol the solvents were removed under reduced pressure 5 mL of saturated NH4Cl water solution and 10 mL of dichloromethane were added to the residue The dichloromethane layer was dried over MgSO4 filtered evaporated purified by column chromatography (ethyl acetate:MeOH=10:1)

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

Procedure: Triphosgene (209.2, 0.47 mmol) was added to a solution of 1-(4-fluorophenyl)imidazolidin-2-one (209.2 mg, 0.71 mmol) in THF (4.7 mL) and the mixture was heated to reflux for 6 h. 1-(4-(7-(4-Amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone 270 (120.0 mg, 0.31 mmol) and DIPEA (0.1 mL, 0.5 mmol) were added and the mixture was stirred for 1 h at room temperature. The reaction mixture was transferred to a silica gel flash chromatography column and eluted with 3% MeOH in DCM affording 264 (97.6 mg, 0.16 mmol, 52% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.55 (s, 1H), 8.47 (d, 5.5 Hz, 1H), 7.84 (dd, J=2.4 Hz, 13.1 Hz, 1H), 7.71-7.63 (m, 2H), 7.54 (m, 1H), 7.48-7.42 (m, 2H), 7.31-7.27 (m, 2H), 6.63 (m, 1H), 6.42 (m, 1H), 4.21 (br, 1H), 4.15 (br, 1H), 3.96-3.93 (m, 4H), 3.71-3.65 (m, 2H), 2.70 (br, 1H), 2.59 (br, 1H), 2.09 (s, 1.5H), 2.05 (s, 1.5H). MS (m/z): (M+1) 590.2 (100%). the mixture was heated to reflux for 6 h

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred suspension of (S)-4-[(E)-2-(4-iodo-phenyl)-vinyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (250 mg, example 3(a)), 1-(4-fluorophenyl)imidazoline-2-one (320 mg, CAS 53159-75-4), caesium carbonate (418 mg), trans-1,2-diaminocyclohexane (0.14 ml), dibenzylideneacetone (54 mg) and copper(I) triflate benzene complex (58 mg) in dioxane (3 ml) under an atmosphere of argon in a sealed tube was heated at 180° C. for 40 min under microwave irradiation. The mixture was then cooled to room temperature and was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-4-((E)-2-{4-[3-(4-fluoro-phenyl)-2-oxo-imidazolidin-1-yl]-phenyl}-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (187 mg, 67%) as an off-white solid. MS (ISP): 504.2 ([M+Na]+), 426.2 ([M+H—C4H8]+). The mixture was then cooled to room temperature was purified by column chromatography (SiO2; gradient: heptane/EtOAc)

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

Procedure: Triphosgene (209.2, 0.47 mmol) was added to a solution of 1-(4-fluorophenyl)imidazolidin-2-one (209.2 mg, 0.71 mmol) in THF (4.7 mL) and the mixture was heated to reflux for 6 h. 1-(4-(7-(4-Amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone 270 (120.0 mg, 0.31 mmol) and DIPEA (0.1 mL, 0.5 mmol) were added and the mixture was stirred for 1 h at room temperature. The reaction mixture was transferred to a silica gel flash chromatography column and eluted with 3% MeOH in DCM affording 264 (97.6 mg, 0.16 mmol, 52% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.55 (s, 1H), 8.47 (d, 5.5 Hz, 1H), 7.84 (dd, J=2.4 Hz, 13.1 Hz, 1H), 7.71-7.63 (m, 2H), 7.54 (m, 1H), 7.48-7.42 (m, 2H), 7.31-7.27 (m, 2H), 6.63 (m, 1H), 6.42 (m, 1H), 4.21 (br, 1H), 4.15 (br, 1H), 3.96-3.93 (m, 4H), 3.71-3.65 (m, 2H), 2.70 (br, 1H), 2.59 (br, 1H), 2.09 (s, 1.5H), 2.05 (s, 1.5H). MS (m/z): (M+1) 590.2 (100%). the mixture was heated to reflux for 6 h

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

Procedure: To a solution of 1-(4-fluorophenyl)-2-imidazolidinone (0.12 g, 0.65 mmol) dissolved in 10 mL dimethylformamide cooled in an ice bath was added NaH (60% dispersion in mineral oil, 39.0 mg, 0.98 mmol). The mixture was stirred at room temperature for 30 minutes and then cooled in ice bath. 1-Bromo-6-(4-bromophenoxy)heptane (0.22 g, 0.65 mmol) was added, and the mixture was stirred at room temperature for additional 4 hours. The reaction was quenched with methanol, and the solvents were removed under reduced pressure. 5 mL of saturated NH4Cl water solution and 10 mL of dichloromethane were added to the residue. The dichloromethane layer was dried over MgSO4, filtered, evaporated, and purified by column chromatography (ethyl acetate:MeOH=10:1) to give the product (i.e., Compound 7) as a white solid (0.14 g, 48%). cooled in an ice bath cooled in ice bath the mixture was stirred at room temperature for additional 4 hours The reaction was quenched with methanol the solvents were removed under reduced pressure 5 mL of saturated NH4Cl water solution and 10 mL of dichloromethane were added to the residue The dichloromethane layer was dried over MgSO4 filtered evaporated purified by column chromatography (ethyl acetate:MeOH=10:1)