ethyl (E)-3-(4-aminophenyl)prop-2-enoate

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

Procedure: 2-(3-Benzyl-ureido)-thiazole-4-carboxylic acid is coupled with ethyl (E)-3-(4-amino-phenyl)-acrylate in analogy to Example 11 After chromatography on silica gel with methylene chloride-ethanol 98:2 and crystallization from ether there is obtained ethyl (E)-3-[4-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-phenyl]-acrylate, m.p. 207° C., MS: 451 (M+H)+. with methylene chloride-ethanol 98:2 and crystallization from ether

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

Procedure: (E)-ethyl (3-(4-(1-aminocyclopentanecarboxamido)phenyl)acrylate. EEDQ (593 mg, 2.4 mmol) was added to a solution of (E)-ethyl 3-(4-aminophenyl)acrylate (417 mg, 2.18 mmol) and 1-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (500 mg, 2.18 mmol) in THF (6 mL). The solution was stirred at reflux for 3–4 hours. The mixture was concentrated and the residue partitioned between dichloromethane and water. The organic layer was washed sequentially with dilute HCl, water, and brine. The solution was dried over Na2SO4 and filtered. Dilution of the filtrate with hexanes resulted in the crystallization of (E)-ethyl 3-(4-(1-(tert-butoxycarbonylamino)cyclopentanecarboxamido)phenyl)acrylate as a pale yellow solid (360 mg, 37% yield). ESI-MS m/z 403 (MH+). at reflux for 3–4 hours The mixture was concentrated the residue partitioned between dichloromethane and water The organic layer was washed sequentially with dilute HCl, water, and brine The solution was dried over Na2SO4 filtered

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

Procedure: The title compound was prepared following the procedure A using 4-dec-1-ynyl-benzaldehyde and ethyl (2E)-3-(4-aminophenyl)acrylate. (purification by flash chromatography on SiO2, EtOAc/c-Hex 1/7 to 1/6 in about 30 min.) as a yellow solid (61%). 1H NMR (CDCl3) δ: 7.59 (d, J=15.8 Hz, 1H), 7.36 (m, 4H), 7.26 (m, 2H), 6.57 (d, J=8.7 Hz, 2H), 6.21 (d, J=15.8 Hz, 1H), 4.35 (s, 2H), 4.23 (dd, J1=7.2 Hz, J2=14.3 Hz, 2H), 2.39 (t, J=7.2 Hz, 2H), 1.66-1.52 (m, 2H), 1.50-1.39 (m, 2H), 1.38-1.24 (m, 11H), 0.87 (m, 3H). M+ (ESI): 418.1; M− (ESI): 416.2. HPLC, Rt: 6.1 min (purity: 98.7%). (purification by flash chromatography on SiO2, EtOAc/c-Hex 1/7 to 1/6 in about 30 min.) as a yellow solid (61%)

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

Procedure: The title compound was prepared following the procedure A using 4-dec-1-ynyl-benzaldehyde and ethyl (2E)-3-(4-aminophenyl)acrylate. (purification by flash chromatography on SiO2, EtOAc/c-Hex 1/7 to 1/6 in about 30 min.) as a yellow solid (61%). 1H NMR (CDCl3) δ: 7.59 (d, J=15.8 Hz, 1H), 7.36 (m, 4H), 7.26 (m, 2H), 6.57 (d, J=8.7 Hz, 2H), 6.21 (d, J=15.8 Hz, 1H), 4.35 (s, 2H), 4.23 (dd, J1=7.2 Hz, J2=14.3 Hz, 2H), 2.39 (t, J=7.2 Hz, 2H), 1.66-1.52 (m, 2H), 1.50-1.39 (m, 2H), 1.38-1.24 (m, 11H), 0.87 (m, 3H). M+ (ESI): 418.1; M− (ESI): 416.2. HPLC, Rt: 6.1 min (purity: 98.7%). (purification by flash chromatography on SiO2, EtOAc/c-Hex 1/7 to 1/6 in about 30 min.) as a yellow solid (61%)

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

Procedure: 2-(3-Benzyl-ureido)-thiazole-4-carboxylic acid is coupled with ethyl (E)-3-(4-amino-phenyl)-acrylate in analogy to Example 11 After chromatography on silica gel with methylene chloride-ethanol 98:2 and crystallization from ether there is obtained ethyl (E)-3-[4-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-phenyl]-acrylate, m.p. 207° C., MS: 451 (M+H)+. with methylene chloride-ethanol 98:2 and crystallization from ether

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

Procedure: 2-(3-Benzyl-ureido)-thiazole-4-carboxylic acid is coupled with ethyl (E)-3-(4-amino-phenyl)-acrylate in analogy to Example 11 After chromatography on silica gel with methylene chloride-ethanol 98:2 and crystallization from ether there is obtained ethyl (E)-3-[4-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-phenyl]-acrylate, m.p. 207° C., MS: 451 (M+H)+. with methylene chloride-ethanol 98:2 and crystallization from ether

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

Procedure: To a suspension of sodium hydride (36 mg, 0.89 mmol) in DMSO (2 mL) was added the solid trimethyl sulfoxonium iodide (185 mg, 1.05 mmol). The mixture was stirred for 25 min before a solution of ethyl (E)-3-(4-aminophenyl)prop-2-enoate (100 mg, 0.52 mmol) in DMSO (2 mL) was added quickly at RT. The mixture was left to stir overnight. The bulk mixture was quenched with NH4Cl (sat.) and the mixture diluted with water and EtOAc. The layers were separated and the aqueous layer extracted into EtOAc (3×30 mL). The organic fractions were combined, dried with brine then MgSO4 and the solvent removed. Flash chromatography on silica gel, eluting with 20-50% ethyl acetate gradient in n-heptane, gave ethyl (1R,2R)-2-(4-aminophenyl)cyclopropanecarboxylate, 70 mg. 1H NMR (400 MHz, CDCl3) δ 6.96-6.89 (m, 2H), 6.68-6.61 (m, 2H), 4.17 (q, J=7.1 Hz, 2H), 2.44 (ddd, J=9.2, 6.6, 4.2 Hz, 1H), 1.80 (ddd, J=8.4, 5.2, 4.2 Hz, 1H), 1.53 (ddd, J=9.2, 5.2, 4.5 Hz, 1H), 1.28 (t, J=7.1 Hz, 3H), 1.24 (ddd, J=8.3, 6.6, 4.5 Hz, 1H). was added quickly at RT The mixture was left The bulk mixture was quenched with NH4Cl (sat.) the mixture diluted with water and EtOAc The layers were separated the aqueous layer extracted into EtOAc (3×30 mL) dried with brine MgSO4 and the solvent removed Flash chromatography on silica gel, eluting with 20-50% ethyl acetate gradient in n-heptane

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

Procedure: (E)-ethyl (3-(4-(1-aminocyclopentanecarboxamido)phenyl)acrylate. EEDQ (593 mg, 2.4 mmol) was added to a solution of (E)-ethyl 3-(4-aminophenyl)acrylate (417 mg, 2.18 mmol) and 1-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (500 mg, 2.18 mmol) in THF (6 mL). The solution was stirred at reflux for 3-4 hours. The mixture was concentrated and the residue partitioned between dichloromethane and water. The organic layer was washed sequentially with dilute HCl, water, and brine. The solution was dried over Na2SO4 and filtered. Dilution of the filtrate with hexanes resulted in the crystallization of (E)-ethyl 3-(4-(1-(tert-butoxycarbonylamino)cyclopentanecarboxamido)phenyl)acrylate as a pale yellow solid (360 mg, 37% yield). ESI-MS m/z 403 (MH+). at reflux for 3-4 hours The mixture was concentrated the residue partitioned between dichloromethane and water The organic layer was washed sequentially with dilute HCl, water, and brine The solution was dried over Na2SO4 filtered

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

Procedure: (E)-ethyl (3-(4-(1-aminocyclopentanecarboxamido)phenyl)acrylate. EEDQ (593 mg, 2.4 mmol) was added to a solution of (E)-ethyl 3-(4-aminophenyl)acrylate (417 mg, 2.18 mmol) and 1-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (500 mg, 2.18 mmol) in THF (6 mL). The solution was stirred at reflux for 3–4 hours. The mixture was concentrated and the residue partitioned between dichloromethane and water. The organic layer was washed sequentially with dilute HCl, water, and brine. The solution was dried over Na2SO4 and filtered. Dilution of the filtrate with hexanes resulted in the crystallization of (E)-ethyl 3-(4-(1-(tert-butoxycarbonylamino)cyclopentanecarboxamido)phenyl)acrylate as a pale yellow solid (360 mg, 37% yield). ESI-MS m/z 403 (MH+). at reflux for 3–4 hours The mixture was concentrated the residue partitioned between dichloromethane and water The organic layer was washed sequentially with dilute HCl, water, and brine The solution was dried over Na2SO4 filtered

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

Procedure: The title compound was prepared following the procedure A using 4-dec-1-ynyl-benzaldehyde and ethyl (2E)-3-(4-aminophenyl)acrylate. (purification by flash chromatography on SiO2, EtOAc/c-Hex 1/7 to 1/6 in about 30 min.) as a yellow solid (61%). 1H NMR (CDCl3) δ: 7.59 (d, J=15.8 Hz, 1H), 7.36 (m, 4H), 7.26 (m, 2H), 6.57 (d, J=8.7 Hz, 2H), 6.21 (d, J=15.8 Hz, 1H), 4.35 (s, 2H), 4.23 (dd, J1=7.2 Hz, J2=14.3 Hz, 2H), 2.39 (t, J=7.2 Hz, 2H), 1.66-1.52 (m, 2H), 1.50-1.39 (m, 2H), 1.38-1.24 (m, 11H), 0.87 (m, 3H). M+ (ESI): 418.1; M− (ESI): 416.2. HPLC, Rt: 6.1 min (purity: 98.7%). (purification by flash chromatography on SiO2, EtOAc/c-Hex 1/7 to 1/6 in about 30 min.) as a yellow solid (61%)

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

Procedure: 2-(3-Benzyl-ureido)-thiazole-4-carboxylic acid is coupled with ethyl (E)-3-(4-amino-phenyl)-acrylate in analogy to Example 11 After chromatography on silica gel with methylene chloride-ethanol 98:2 and crystallization from ether there is obtained ethyl (E)-3-[4-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-phenyl]-acrylate, m.p. 207° C., MS: 451 (M+H)+. with methylene chloride-ethanol 98:2 and crystallization from ether