3-chloro-4-isothiocyanatobenzonitrile

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

Procedure: 2-Hydroxyethylamine was reacted with 4-chlorobenzyl bromide according to Method B2a to give N-(4-chlorobenzyl)-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-(4-chlorobenzyl)-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-chloro-4-cyanophenyl isothiocyanate to give 2-(2-chloro-4-cyanophenylimino)-3-(4-chlorobenzyl)-1,3-thiazolidine.

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

Procedure: 2-Hydroxyethylamine was reacted with 4-chlorobenzyl bromide according to Method B2a to give N-(4-chlorobenzyl)-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-(4-chlorobenzyl)-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-chloro-4-cyanophenyl isothiocyanate to give 2-(2-chloro-4-cyanophenylimino)-3-(4-chlorobenzyl)-1,3-thiazolidine.

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

Procedure: 2-Hydroxyethylamine was reacted with 4-chlorobenzyl bromide according to Method B2a to give N-(4-chlorobenzyl)-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-(4-chlorobenzyl)-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-chloro-4-cyanophenyl isothiocyanate to give 2-(2-chloro-4-cyanophenylimino)-3-(4-chlorobenzyl)-1,3-thiazolidine.

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3k (370 mg, 2 mmol, prepared by a method similar to the synthesis of 3d) and 6h (384 mg, 2 mmol, prepared by a method similar to the synthesis of 6b) in DMF (10 mL) was heated under microwave irradiation at 150° C. for 5 h. To this mixture was added ethanol (10 mL) and aqueous HCl solution (2N, 5 mL). The resulting mixture was heated at reflux for 1 h. The solution was poured into ice-cold water and extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over MgSO4, and concentrated in vacuo. The residue was purified with Pre-HPLC, affording the title compound (Example 25, 150 mg, 19.8% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.93-7.91 (m, 2H), 7.26-7.09 (m, 3H), 2.35 (s, 3H), 1.58 (s, 6H). ESI-MS (M+H)+: 379. The resulting mixture was heated at reflux for 1 h The solution was poured into ice-cold water extracted with ethyl acetate (3×30 mL) dried over MgSO4 concentrated in vacuo The residue was purified with Pre-HPLC

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3k (370 mg, 2 mmol, prepared by a method similar to the synthesis of 3d) and 6g (348 mg, 2 mmol, prepared by a method similar to the synthesis of 6b) in DMF (10 mL) was heated under microwave irradiation at 150° C. for 5 h. To this mixture was added ethanol (10 mL) and aqueous HCl solution (2N, 5 mL). The resulting mixture was heated at reflux for 1 h. The solution was poured into ice-cold water and extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over MgSO4, and concentrated in vacuo. The residue was purified with Pre-HPLC, affording the title compound (Example 24, 60 mg, 8.3% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.93 (m, 2H), 7.35 (d, J=8 Hz, 2H), 7.16 (d, J=8 Hz, 2H), 2.44 (s, 3H), 1.58 (s, 6H). ESI-MS (M+H)+: 361. The resulting mixture was heated at reflux for 1 h The solution was poured into ice-cold water extracted with ethyl acetate (3×30 mL) dried over MgSO4 concentrated in vacuo The residue was purified with Pre-HPLC

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3k (370 mg, 2 mmol, prepared by a method similar to the synthesis of 3d) and 6g (348 mg, 2 mmol, prepared by a method similar to the synthesis of 6b) in DMF (10 mL) was heated under microwave irradiation at 150° C. for 5 h. To this mixture was added ethanol (10 mL) and aqueous HCl solution (2N, 5 mL). The resulting mixture was heated at reflux for 1 h. The solution was poured into ice-cold water and extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over MgSO4, and concentrated in vacuo. The residue was purified with Pre-HPLC, affording the title compound (Example 24, 60 mg, 8.3% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.93 (m, 2H), 7.35 (d, J=8 Hz, 2H), 7.16 (d, J=8 Hz, 2H), 2.44 (s, 3H), 1.58 (s, 6H). ESI-MS (M+H)+: 361. The resulting mixture was heated at reflux for 1 h The solution was poured into ice-cold water extracted with ethyl acetate (3×30 mL) dried over MgSO4 concentrated in vacuo The residue was purified with Pre-HPLC

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3k (370 mg, 2 mmol, prepared by a method similar to the synthesis of 3d) and 6a (494 mg, 2 mmol) in DMF (10 mL) was heated under microwave irradiation at 110° C. for 12 h. To this mixture was added ethanol (10 mL) and aqueous HCl solution (2N, 5 mL). The resulting mixture was heated at reflux for 1 h. The solution was poured into ice-cold water and extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over MgSO4, and concentrated in vacuo. The residue was purified with silica gel column chromatography using petroleum ether:ethyl acetate (1:1), affording the title compound (Example 9, 200 mg, 23% yield). 1H NMR (CDCl3, 500 MHz): δ 8.39 (1H, t, J=9.0 Hz), 8.00 (1H, d, J=2.0 Hz), 7.90 (2H, m.br), 7.26 (1H, m.br), 7.18 (1H, dd, J=11.5, 2.0 Hz), 6.71 (1H, br s), 3.00 (3H, d, J=5 Hz), 2.70 (2H, m), 2.52 (2H, m), 2.26 (1H, m), 1.62 (1H, m, br). MS (ES-API positive): 434 (M+H)+. The resulting mixture was heated at reflux for 1 h The solution was poured into ice-cold water extracted with ethyl acetate (3×30 mL) dried over MgSO4 concentrated in vacuo The residue was purified with silica gel column chromatography

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3e (380 mg, 2 mmol, prepared by a method similar to the synthesis of 3d) and 6a (494 mg, 2 mmol) in DMF (10 mL) was heated under microwave irradiation at 110° C. for 12 h. After cooled to room temperature, to the reaction mixture was added ethanol (10 mL) and aqueous HCl solution (2N, 5 mL). The resulting mixture was heated at reflux for 1 h. The solution was poured into ice-cold water and the mixture was extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over MgSO4, and concentrated in vacuo. The residue was purified with silica gel column chromatography using Petroleum ether:Ethyl acetate (1:1), affording the title compound (Example 2, 180 mg, 20% yield). 1H NMR (CDCl3, 500 MHz): δ 8.39 (1H, t, J=9.0 Hz), 7.62 (1H, d, J=8.0 Hz), 7.26 (1H, m.br), 7.18 (1H, d, J=10.0 Hz), 7.10 (2H, m), 6.71 (1H, br s), 3.97 (3H, s), 3.00 (3H, d, J=5 Hz), 2.70 (2H, m), 2.52 (2H, m), 2.26 (1H, m), 1.69 (1H, m, br). MS (ES-API positive): 439 (M+H)+. After cooled to room temperature, to the reaction mixture The resulting mixture was heated at reflux for 1 h The solution was poured into ice-cold water the mixture was extracted with ethyl acetate (3×30 mL) dried over MgSO4 concentrated in vacuo The residue was purified with silica gel column chromatography

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 6a (388 mg, 2 mmol) and 3d (494 mg, 2 mmol) in DMF (10 mL) was heated under microwave irradiation at 110° C. for 12 h. To this mixture is added ethanol (10 mL) and HCl (2N, 5 mL). The resulting mixture was refluxed for 1 h. After being cooled to room temperature, the reaction mixture was poured into cold water and extracted with ethyl acetate (3×100 mL). Combined organic layers were dried over MgSO4, concentrated. The residue was purified by silica gel column chromatography using petroleum ether:ethyl acetate (1:1), to give the title compound (Example 1, 200 mg, 23% yield). 1H NMR (CDCl3, 500 MHz): δ 8.39 (1H, t, J=9.0 Hz), 7.89 (1H, s), 7.72 (1H, dd, m), 7.54 (1H, d, J=8.0 Hz), 7.26 (1H, m.br), 7.20 (1H, d, J=11 Hz), 6.71 (1H, br s), 3.00 (3H, d, J=5 Hz), 2.70 (2H, m), 2.52 (2H, m), 2.26 (1H, m), 1.69 (1H, m, br). MS (ES-API positive): 443 (M+H)+. The resulting mixture was refluxed for 1 h After being cooled to room temperature extracted with ethyl acetate (3×100 mL) Combined organic layers were dried over MgSO4 concentrated The residue was purified by silica gel column chromatography

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

Procedure: To a suspension of thiophosgene (2 mL) in water (5 mL) was added 4-amino-3-chloro-benzonitrile (1 g, 7 mmol) in small portions over a period of 1 h at 25° C. The mixture was extracted with ethyl acetate (3×25 mL). Combined organic phase was washed with brine (1×50 mL), dried (MgSO4) and concentrated to dryness in vacuo. The title compound 3d was obtained as a tan solid (1.3 g, 96% yield). The mixture was extracted with ethyl acetate (3×25 mL) Combined organic phase was washed with brine (1×50 mL) dried (MgSO4) concentrated to dryness in vacuo

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

Procedure: 2-Hydroxyethylamine was reacted with 4-chlorobenzyl bromide according to Method B2a to give N-(4-chlorobenzyl)-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-(4-chlorobenzyl)-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-chloro-4-cyanophenyl isothiocyanate to give 2-(2-chloro-4-cyanophenylimino)-3-(4-chlorobenzyl)-1,3-thiazolidine.