1,5-dichloro-2-isothiocyanato-3-methylbenzene

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3-amino-2-[(2-hydroxyethyl)amino]benzoate (521 mg, 2.48 mmol) and 2,4-dichloro-6-methylphenylisothiocyanate (595 mg, 2.73 mmol) in tetrahydrofuran (25 mL) was stirred at room temperature for 18 hr. The mixture was warmed to 50° C. and it was stirred at 50° C. for 24 hr. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 20-80% ethyl acetate/n-hexane gradient mixture to give the title compound (959.9 mg) as a colorless amorphous. The reaction mixture was concentrated in vacuo The residue was purified by flash chromatography on silica gel eluting with a 20-80% ethyl acetate/n-hexane gradient mixture

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of methyl 3-amino-4-chloro-2-[(2-hydroxyethyl)amino]benzoate (290 mg, 1.19 mmol) and 2,4-dichloro-6-methylphenylisothiocyanate (284.4 mg, 1.3 mmol) in tetrahydrofuran (12 mL) was stirred at 45° C. for 62 hr. The mixture was warmed to 60° C. and stirred at 60° C. for 24 hr. 2,4-Dichloro-6-methylphenylisothiocyanate (104 mg, 0.48 mmol) was added to the reaction mixture and the mixture was stirred at 60° C. for 26 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on NH-silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture give a red amorphous (261.4 mg). To a mixture of the amorphous (261.4 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (119 mg, 0.62 mmol) in tetrahydrofuran (11.2 mL) was added triethylamine (0.0866 mL, 0.62 mmol) at room temperature. The mixture was stirred at 50° C. for 16 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound (156.3 mg, 0.36 mmol, 30%) as a pale yellow solid. the mixture was stirred at 60° C. for 26 hr the mixture was extracted with ethyl acetate The organic layer was washed with brine dried over anhydrous magnesium sulfate concentrated in vacuo The residue was purified by flash chromatography on NH-silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture give a red amorphous (261.4 mg) The mixture was stirred at 50° C. for 16 hr the mixture was extracted with ethyl acetate The organic layer was washed with water and brine dried over anhydrous magnesium sulfate concentrated in vacuo

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

Procedure: Thiophosgene (17.0 g, 148 mmol) was added dropwise to a stirred mixture of 2,4-dichloro-6-methylaniline (20.0 g, 114 mmol) in tetrahydrofuran (100 mL) and saturated aqueous sodium hydrogen carbonate (100 mL) at 0° C., and the mixture was stirred at room temperature for 90 minutes. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with n-hexane to give the title compound as a colorless powder (14.4 g, 66.0 mmol, 58%). extracted with ethyl acetate The combined organic layer was washed with brine dried over anhydrous magnesium sulfate filtered concentrated in vacuo The residue was washed with n-hexane

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (1.50 g, 5.80 mmol) and 1,5-dichloro-2-isothiocyanato-3-methylbenzene (1.64 g, 7.52 mmol) in tetrahydrofuran (15 mL) was stirred at 60° C. for 17 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with diisopropyl ether to give the title compound as a brown powder (2.18 g, 4.57 mmol, 79%). extracted with ethyl acetate The combined organic layer was washed with brine dried over anhydrous magnesium sulfate filtered concentrated in vacuo The residue was washed with diisopropyl ether

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3-amino-2-[(2-hydroxyethyl)amino]benzoate (521 mg, 2.48 mmol) and 2,4-dichloro-6-methylphenylisothiocyanate (595 mg, 2.73 mmol) in tetrahydrofuran (25 mL) was stirred at room temperature for 18 hr. The mixture was warmed to 50° C. and it was stirred at 50° C. for 24 hr. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 20-80% ethyl acetate/n-hexane gradient mixture to give the title compound (959.9 mg) as a colorless amorphous. The reaction mixture was concentrated in vacuo The residue was purified by flash chromatography on silica gel eluting with a 20-80% ethyl acetate/n-hexane gradient mixture

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of methyl 3-amino-4-chloro-2-[(2-hydroxyethyl)amino]benzoate (290 mg, 1.19 mmol) and 2,4-dichloro-6-methylphenylisothiocyanate (284.4 mg, 1.3 mmol) in tetrahydrofuran (12 mL) was stirred at 45° C. for 62 hr. The mixture was warmed to 60° C. and stirred at, 60° C. for 24 hr. 2,4-Dichloro-6-methylphenylisothiocyanate (104 mg, 0.48 mmol) was added to the reaction mixture and the mixture was stirred at 60° C. for 26 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on NH-silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture give a red amorphous (261.4 mg). To a mixture of the amorphous (261.4 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (119 mg, 0.62 mmol) in tetrahydrofuran (11.2 mL) was added triethylamine (0.0866 mL, 0.62 mmol) at room temperature. The mixture was stirred at 50° C. for 16 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound (156.3 mg, 0.36 mmol, 30%) as a pale yellow solid. the mixture was stirred at 60° C. for 26 hr the mixture was extracted with ethyl acetate The organic layer was washed with brine dried over anhydrous magnesium sulfate concentrated in vacuo The residue was purified by flash chromatography on NH-silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture give a red amorphous (261.4 mg) The mixture was stirred at 50° C. for 16 hr the mixture was extracted with ethyl acetate The organic layer was washed with water and brine dried over anhydrous magnesium sulfate concentrated in vacuo

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

Procedure: Thiophosgene (17.0 g, 148 mmol) was added dropwise to a stirred mixture of 2,4-dichloro-6-methylaniline (20.0 g, 114 mmol) in tetrahydrofuran (100 mL) and saturated aqueous sodium hydrogen carbonate (100 mL) at 0° C., and the mixture was stirred at room temperature for 90 minutes. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with n-hexane to give the title compound as a colorless powder (14.4 g, 66.0 mmol, 58%). extracted with ethyl acetate The combined organic layer was washed with brine dried over anhydrous magnesium sulfate filtered concentrated in vacuo The residue was washed with n-hexane

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (1.50 g, 5.80 mmol) and 1,5-dichloro-2-isothiocyanato-3-methylbenzene (1.64 g, 7.52 mmol) in tetrahydrofuran (15 mL) was stirred at 60° C. for 17 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with diisopropyl ether to give the title compound as a brown powder (2.18 g, 4.57 mmol, 79%). extracted with ethyl acetate The combined organic layer was washed with brine dried over anhydrous magnesium sulfate filtered concentrated in vacuo The residue was washed with diisopropyl ether