3-methylsulfanylpropanoyl chloride

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

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

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

Procedure: 3-(Methylsulphenyl)propanoyl isothiocyanate was prepared using commercially available 3-(methylsulphenyl)propanoyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-(methylsulphenyl)propanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (41 mg, yield 56%). The reaction solution was concentrated the residue was purified by chromatography on silica gel

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

Procedure: 3-(Methylsulfanyl)propanoyl isothiocyanate was prepared using commercially available 3-(methylsulfanyl)propanoyl chloride (80 mg) as a starting compound according to the description of the literature. 3-(Methylsulfanyl)propanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-3-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (38 mg, yield 50%). to prepare a solution The reaction solution was concentrated the residue was purified by chromatography on silica gel

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

Procedure: 3-(Methylsulfanyl)propanoyl isothiocyanate was prepared using commercially available 3-(methylsulfanyl)propanoyl chloride (80 mg) as a starting compound according to the description of the literature. 3-(Methylsulfanyl)propanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (43 mg, yield 57%). to prepare a solution The reaction solution was concentrated the residue was purified by chromatography on silica gel

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

Procedure: Dissolved in 4 ml of dimethylformamide were 1.46 g of triethylamine and 1.52 g of 4-(3-ethoxy-2-hydroxypropoxy)aniline. A 1.10 g quantity of 3-methylmercaptopropionyl chloride was added to the solution with ice-cooling. The mixture was stirred at room temperature for 12 hours and the reaction mixture was concentrated. The residue was extracted with chloroform and the chloroform layer was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and water and concentrated. Ether was added to the residue and the crystals formed were filtered off to give 1.52 g of 2-{4-(3-ethoxy-2-hydroxypropoxy)phenylcarbamoyl}ethyl methyl sulfide in 67.4%, M.P. 79° to 81° C. cooling the reaction mixture was concentrated The residue was extracted with chloroform the chloroform layer was washed successively with 1N hydrochloric acid a saturated aqueous solution of sodium hydrogencarbonate and water and concentrated Ether was added to the residue the crystals formed were filtered off

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

Procedure: Dissolved in 4 ml of dimethylformamide were 1.46 g of triethylamine and 1.52 g of 4-(3-ethoxy-2-hydroxypropoxy)aniline. A 1.10 g quantity of 3-methylmercaptopropionyl chloride was added to the solution with ice-cooling. The mixture was stirred at room temperature for 12 hours and the reaction mixture was concentrated. The residue was extracted with chloroform and the chloroform layer was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and water and concentrated. Ether was added to the residue and the crystals formed were filtered off to give 1.52 g of 2-{4-(3-ethoxy-2-hydroxypropoxy)phenylcarbamoyl}ethyl methyl sulfide in 67.4%, M.P. 79° to 81° C. cooling the reaction mixture was concentrated The residue was extracted with chloroform the chloroform layer was washed successively with 1N hydrochloric acid a saturated aqueous solution of sodium hydrogencarbonate and water and concentrated Ether was added to the residue the crystals formed were filtered off

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (2,4-dichloro-thiazol-5-yl)-carbamic acid tert-butyl ester (1.0 g, 3.7 mmol) in dichloroethane (20 mL) stirring at room temperature was added triethylamine (935 mg, 9.25 mmol), followed by dropwise addition of methylsulfanyl-propionyl chloride (776 mg, 5.6 mmol) and the mixture was stirred for 5 min before DMAP (45 mg, 0.37 mmol) was added. The mixture was stirred at 75° C. for 4 h. The reaction mixture was cooled, quenched with H2O (30 mL). The organic layer was separated and the aqueous layer extracted with dichloromethane (20 mL). The combined organic layer was dried over Na2SO4 and purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to give product as a colorless oil (1.11 g, 81%): 1H NMR (300 MHz, CDCl3) δ 3.32 (t, J=7.3 Hz, 2H), 2.83 (t, J=7.3 Hz, 2H), 2.16 (s, 3H), 1.46 (s, 9H); ESIMS m/z 371.2 (M+1). was added The reaction mixture was cooled quenched with H2O (30 mL) The organic layer was separated the aqueous layer extracted with dichloromethane (20 mL) The combined organic layer was dried over Na2SO4 purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes)

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

Procedure: To a nitrogen-purged solution of 4-(methylthio)-5-nitro-2-(pyridin-3-yl)thiazole (253 mg, 1 mmol) in ethyl acetate (50 mL) in a Parr bottle were added glacial acetic acid (601 mg, 10 mmol), followed by Pd on carbon (35 mg, 10% (w)). Hydrogen was added and the mixture was shaken in a Parr shaker for 2 hours and filtered through a bed of Celite®. The filtrate was concentrated under vacuum to give 4-(methylthio)-2-(pyridin-3-yl)thiazol-5-amine as a pale yellow solid, which was placed under high vacuum to remove residual acetic acid. This crude was found to be 95% pure by GC-MS. The crude 4-(methylthio)-2-(pyridin-3-yl)thiazol-5-amine was used without further purification to prepare 3-(methylthio)-N-(4-(methylthio)-2-(pyridin-3-yl)thiazol-5-yl)propanamide. To a solution of 4-(methylthio)-2-(pyridin-3-yl)thiazol-5-amine (100 mg, 0.45 mmol) in methylene chloride (2 mL) were added dimethylaminopyridine (137 mg, 1.12 mmol) followed by 3-(methylthio)propanoyl chloride (68 mg, 0.49 mmol). The mixture was stirred at room temperature for 30 min. The mixture was diluted with dichloromethane (10 mL) and water (5 mL). The organic phase was separated, rinsed with brine, dried over MgSO4 and concentrated in vacuo to give a yellow solid. This solid was purified by silica gel chromatography (methylene chloride-methanol) to give 3-(methylthio)-N-(4-(methylthio)-2-(pyridin-3-yl)thiazol-5-yl)propanamide as a yellow solid (32 mg, 22%): mp 72-74° C., 1H NMR (300 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.08 (m, 1H), 8.64 (d, J=4.8 Hz, 1H), 8.32 (d, J=9.0 Hz, 1H), 7.57 (dd, J=5.1 Hz, 8.4 Hz, 1H), 3.25 (s, 3H), 2.85 (m, 2H), 2.73 (m, 2H), 2.07 (s, 3H); ESIMS m/z 326.1 (M+1), 324.1 (M−1). to remove residual acetic acid The crude 4-(methylthio)-2-(pyridin-3-yl)thiazol-5-amine was used without further purification to prepare 3-(methylthio)-N-(4-(methylthio)-2-(pyridin-3-yl)thiazol-5-yl)propanamide The organic phase was separated rinsed with brine dried over MgSO4 concentrated in vacuo to give a yellow solid This solid was purified by silica gel chromatography (methylene chloride-methanol)

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

Procedure: To a nitrogen-purged solution of 4-(methylthio)-5-nitro-2-(pyridin-3-yl)thiazole (253 mg, 1 mmol) in ethyl acetate (50 mL) in a Parr bottle were added glacial acetic acid (601 mg, 10 mmol), followed by Pd on carbon (35 mg, 10% (w)). Hydrogen was added and the mixture was shaken in a Parr shaker for 2 hours and filtered through a bed of Celite®. The filtrate was concentrated under vacuum to give 4-(methylthio)-2-(pyridin-3-yl)thiazol-5-amine as a pale yellow solid, which was placed under high vacuum to remove residual acetic acid. This crude was found to be 95% pure by GC-MS. The crude 4-(methylthio)-2-(pyridin-3-yl)thiazol-5-amine was used without further purification to prepare 3-(methylthio)-N-(4-(methylthio)-2-(pyridin-3-yl)thiazol-5-yl)propanamide. To a solution of 4-(methylthio)-2-(pyridin-3-yl)thiazol-5-amine (100 mg, 0.45 mmol) in methylene chloride (2 mL) were added dimethylaminopyridine (137 mg, 1.12 mmol) followed by 3-(methylthio)propanoyl chloride (68 mg, 0.49 mmol). The mixture was stirred at room temperature for 30 min. The mixture was diluted with dichloromethane (10 mL) and water (5 mL). The organic phase was separated, rinsed with brine, dried over MgSO4 and concentrated in vacuo to give a yellow solid. This solid was purified by silica gel chromatography (methylene chloride-methanol) to give 3-(methylthio)-N-(4-(methylthio)-2-(pyridin-3-yl)thiazol-5-yl)propanamide as a yellow solid (32 mg, 22%): mp 72-74° C., 1H NMR (300 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.08 (m, 1H), 8.64 (d, J=4.8 Hz, 1H), 8.32 (d, J=9.0 Hz, 1H), 7.57 (dd, J=5.1 Hz, 8.4 Hz, 1H), 3.25 (s, 3H), 2.85 (m, 2H), 2.73 (m, 2H), 2.07 (s, 3H); ESIMS m/z 326.1 (M+1), 324.1 (M−1). to remove residual acetic acid The crude 4-(methylthio)-2-(pyridin-3-yl)thiazol-5-amine was used without further purification to prepare 3-(methylthio)-N-(4-(methylthio)-2-(pyridin-3-yl)thiazol-5-yl)propanamide The organic phase was separated rinsed with brine dried over MgSO4 concentrated in vacuo to give a yellow solid This solid was purified by silica gel chromatography (methylene chloride-methanol)

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

Procedure: A solution of 3-methylsulfanyl-propionyl chloride (120 mg, 0.9 mmol) in DCE (1 mL) was pipetted at a dropwise rate into an ice-cold suspension of methyl-(2-pyridin-3-yl-thiazol-5-yl)-amine (114 mg, 0.6 mmol) in DCE (5 mL), and the mixture was stirred for 5 min before adding a solution of DMAP (80 mg, 0.6 mmol) in DCE (1 mL). The ice bath was removed after 30 min, and the mixture was stirred at reflux under nitrogen for 15 min. The reaction mixture was cooled, diluted with DCE (70 mL), washed with saturated aqueous NaHCO3 (50 mL), dried over MgSO4 and purified by silica gel chromatography (3:1 ethyl acetate/hexanes) to afford a fine yellow powder (131 mg, 75%): mp 116-118° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.08 (d, J=2.0 Hz, 1H), 8.61 (dd, J=4.8, 1.4 Hz, 1H), 8.24 (dt, J=9.8, 1.8 Hz, 1H), 7.81 (s, 1H), 7.51 (dd, J=7.7, 4.7 Hz, 1H), 3.56 (s, 3H), 3.02 (t, J=7.0 Hz, 2H), 2.76 (t, J=7.2 Hz, 2H), 2.12 (s, 3H); ESIMS m/z 294 (M+1). The ice bath was removed after 30 min the mixture was stirred at reflux under nitrogen for 15 min The reaction mixture was cooled diluted with DCE (70 mL) washed with saturated aqueous NaHCO3 (50 mL) dried over MgSO4 purified by silica gel chromatography (3:1 ethyl acetate/hexanes)

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

Procedure: To a solution of 4-chloro-N-cyclopropyl-2-(pyridin-3-yl)thiazol-5-amine HCl salt (288 mg, 1 mmol) and DMAP (305 mg, 2.500 mmol) in CH2ClCH2Cl (1 mL) was added 3-(methylthio)propanoyl chloride (166 mg, 1.200 mmol), and the mixture stirred at room temperature for 1 h. The mixture was diluted with ethyl acetate, mixed with aqueous NaHCO3 (10 mL). The organic phase was separated, rinsed with brine (2×), dried over MgSO4 and concentrated in vacuo to give a yellow gum. This gum was purified on reverse phase column chromatography (C-18, CH3CN/H2O) to give N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-cyclopropyl-3-(methylthio)propanamide (82 mg, 22%) as a brown gum: 1H NMR (400 MHz, CDCl3) δ 9.10 (s, 0.6H), 9.02 (s, 0.4H), 8.71 (s, 6H), 8.61 (d, J=3.4 Hz, 0.4H), 8.21 (d, J=7.6 Hz, 1H), 8.19-8.10 (m, 1H), 7.41 (d, J=5.6, 0.6H), 7.35 (dd, J=8.3, 4.5 Hz, 0.4H), 3.16 (bs, 1H), 2.91 (s, 3H), 2.88-2.72 (m, 2H), 2.11 (m, 2H), 0.85 (m, 4H); ESIMS (m/z) 354.56 ([M+H]+). The organic phase was separated rinsed with brine (2×) dried over MgSO4 concentrated in vacuo to give a yellow gum This gum was purified on reverse phase column chromatography (C-18, CH3CN/H2O)