O-ethyl 2-amino-2-oxoethanethioate

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

Procedure: Compound V2 (yellow oil) was synthesized from compound U2 (23.87 g, 1 eq.) and ethyl thiooxamate (21.41 g, 1 eq.) in 64% yield, following the procedure as described for compound 36.

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

Procedure: 4-Cyclobutylthiazole-2-carboxylic acid ethyl ester 265b was synthesized from compound 264b (23.87 g, 1 eq.) and ethyl thiooxamate (21.41 g, 1 eq.) as a yellow oil in 64% yield, following the procedure as described for compound 212. 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 1.32 (t, J=7.12 Hz, 3H), 1.82-1.89 (m, 1H), 1.92-2.02 (m, 1H), 2.15-2.33 (m, 4H), 3.65-3.74 (m, 1H), 4.36 (q, J=7.12 Hz, 2H), 7.76 (d, J=0.64 Hz, 1H); MS (ESI, EI+): m/z=212 (MH+).

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

Procedure: Ethyl thiooxamate (172 mg) was suspended in ethanol (5 ml) at 0° C., followed by the addition of hydrazine monohydrate (63 μl). While the resulting gas was suctioned, the resulting mixture was stirred for 30 minutes. Ethyl (pyridin-4-yl)glyoxylate hydrate (254 mg) was added to the reaction mixture and the mixture was stirred at room temperature for 30 minutes. After heating under reflux for 4 hours, the reaction mixture was concentrated. The yellow powder thus precipitated was collected by filtration and dried, whereby the title compound (140 mg) was obtained. the mixture was stirred at room temperature for 30 minutes After heating under reflux for 4 hours the reaction mixture was concentrated The yellow powder thus precipitated was collected by filtration dried

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An adaptation of the method of Burrell et al., J. Chem. Soc. Perkin I. 2707 (1973), was used. A mixture of 4,5-dichloro-1,2-phenylenediamine (354 mg, 2.00 mmol; Aldrich Co.) and ethyl thiooxamate (333 mg, 2.50 mmol; Aldrich Co.) in 5 mL of ethanol was heated to reflux. The resulting brown solution was stirred under reflux for 10 h. The resulting brown suspension was cooled down to 25° C. A brown precipitate appeared. The mixture was vacuum filtered and the brown solid was washed with EtOH (5×2 mL) and dried in vacuum at 60° C. overnight to yield 92 mg (20%) of 6,7-dichloro-3-aminoquinoxalin-2(1H)-one: mp dec.>350° C. 1H NMR (300 MHz, DMSO-d6) δ 12.261 (br s, 1H, NH), 7.421 (s, 1H, H-5), 7.252 (s, 1H, H-8). Mass: calcd. for C8H5Cl2N3O (M+) M/z 228.9810, found 228.9820. was heated to reflux under reflux for 10 h filtered the brown solid was washed with EtOH (5×2 mL) dried in vacuum at 60° C. overnight

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An adaptation of the method of Burrell et al., J. Chem. Soc. Perkin I. 2707 (1973), was used. A mixture of 3-bromo-5-trifluoromethyl-1,2-phenylenediamine (384 mg, 1.50 mmol; Maybridge Co.) and ethyl thiooxamate (220 mg, 1.70 mmol; Aldrich Co.) in 4 mL of 1-butanol was heated to reflux. The resulting solution was stirred under reflux for 6 h. The resulting suspension was cooled to 25 ° C. A pale yellow precipitate appeared. The mixture was vacuum filtered and the solid was washed with EtOH (5×2 mL) and dried in vacuum at 60° C. overnight to yield 125 mg (27.1%) of 5-bromo-7-trifluoromethyl-3-aminoquinoxalin-2(1H)-one (tentatively named as this since the regiochemistry is not sure) as a pale yellow solid of a new compound: mp dec.>267° C. 1H NMR (300 MHz, DMSO-d6) δ 7.680 (s, 1H, H-7), 7.495 (s, 1H, H-5). LRMS: 307 (M+, 100%), 280 (50%). was heated to reflux under reflux for 6 h filtered the solid was washed with EtOH (5×2 mL) dried in vacuum at 60° C. overnight

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An adaptation of the method of Burrell et al., J. Chem. Soc. Perkin I. 2707 (1973), was used. A mixture of 3-chloro-5-trifluoromethyl-1,2-phenylenediamine (420 mg, 2.00 mmol; Maybridge Co.) and ethyl thiooxamate (293 mg, 2.20 mmol; Aldrich Co.) in 4 mL of 1-butanol was heated to reflux. The resulting solution was stirred under reflux for 6 h. The resulting suspension was cool to 25° C. A pale yellow precipitate appeared. The mixture was vacuum filtered and the solid was washed with EtOH (5×2 mL) and dried in vacuum at 60° C. overnight to yield 50 mg (9.5%) of 5-chloro-7-trifluoromethyl-3-aminoquinoxalin-2(1H)-one (tentatively named as this since the regiochemistry is not sure) as a pale yellow solid: mp 270°-272° C. 1H NMR (300 MHz, DMSO-d6) δ 12.043 (br s, 1H, NH), 7.561 (s, 1H, H-7), 7.463 (s, 1H, H-5). LRMS: 263 (M+, 100%), 235 (50%). was heated to reflux under reflux for 6 h filtered the solid was washed with EtOH (5×2 mL) dried in vacuum at 60° C. overnight

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An adaptation of the method of Burrell et al., J. Chem. Soc. Perkin I. 2707 (1973), was used. A mixture of 1,2-phenylenediamine (324 mg, 3.00 mmol; Aldrich Co.) and ethyl thiooxamate (400 mg, 3.00 mmol; Aldrich Co.) in 7.5 mL of ethanol was heated to reflux. The resulting solution was stirred under reflux for 3 h. The resulting suspension was cool to 25° C. A pale yellow precipitate appeared. The mixture was vacuum filtered and the solid was washed with EtOH (5×2 mL) and dried in vacuum at 60° C. overnight to yield 85 mg (18%) of 3-aminoquinoxalin-2(1H)-one as a pale yellow solid (McKillop et al., Tetrahedron Lett. 23:3357 (1982)): mp dec.>320° C. 1H NMR (300 MHz, DMSO-d6) δ 7.261-7.075 (m, 4H, H-5+H-6+H-7+H-8). LRMS: 161 (M+, 100%), 133 (50%). was heated to reflux under reflux for 3 h filtered the solid was washed with EtOH (5×2 mL) dried in vacuum at 60° C. overnight

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

Procedure: Ethyl thiooxamate (3.0 g, 22 mmol) was dissolved in ethanol (30 mL) under argon. Chloroacetone (1.8 mL, 22 mmol) was added and the resultant solution was heated at 80° C. for 16 h. The reaction mixture was concentrated in vacuo, adsorbed onto silica gel, and purified by column chromatography on silica gel eluting with 97:3, then 95:5 hexane:ethyl acetate to afford ethyl 4-methyl-1,3-thiazole-2-carboxylate (850 mg, 22% yield) as an oil. 1H NMR (CDCl3, 300 MHz) 7.20 (s, 1H), 4.48 (q, J=7.1 Hz), 2.56 (s, 3H), 1.47 (s, 3H). MS (EI ionization) 171 (M+). The reaction mixture was concentrated in vacuo purified by column chromatography on silica gel eluting with 97:3

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

Procedure: 4-Cyclobutylthiazole-2-carboxylic acid ethyl ester 265b was synthesized from compound 264b (23.87 g, 1 eq.) and ethyl thiooxamate (21.41 g, 1 eq.) as a yellow oil in 64% yield, following the procedure as described for compound 212. 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 1.32 (t, J=7.12 Hz, 3H), 1.82-1.89 (m, 1H), 1.92-2.02 (m, 1H), 2.15-2.33 (m, 4H), 3.65-3.74 (m, 1H), 4.36 (q, J=7.12 Hz, 2H), 7.76 (d, J=0.64 Hz, 1H); MS (ESI, EI+): m/z=212 (MH+).

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

Procedure: To a solution of ethyl thiooxamate (29.6 g, 0.22 mol) in DCM (260 mL) at RT was added trimethyloxonium tetrafluoroborate (34.5 g, 0.23 mol) and the mixture stirred at RT for 2 h. During this time the yellow colour faded and a thick white precipitate was formed. Acetic acid N′-isopropylhydrazide (27.1 g, 0.23 mol) and TEA (30.9 mL, 0.22 mol) were added as a solution in DCM (75 mL) causing the precipitate to dissolve. The reaction mixture was stirred at reflux for 5 h then at RT for 10 h. The reaction mixture was washed with water, and the aqueous layer extracted with DCM (2×50 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-100% ethyl acetate in cyclohexane) to give 2-Isopropyl-5-methyl-2H-[1,2,4]triazole-3-carboxylic acid ethyl ester as a pale yellow oil which crystallised on standing (15.6 g, 32%). 1H NMR 400 MHz (CDCl3) δ: 5.49 (1H, sept, J=6.7 Hz), 4.45 (2H, t, J=7.2 Hz), 2.43 (3H, s), 1.50 (6H, d, J=6.7 Hz), 1.44 (3H, t, J=7.2 Hz) a thick white precipitate was formed to dissolve The reaction mixture was stirred at reflux for 5 h at RT for 10 h The reaction mixture was washed with water the aqueous layer extracted with DCM (2×50 mL) The combined organic extracts were washed with brine dried (MgSO4) concentrated in vacuo

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

Procedure: To a solution of ethyl thiooxamate (29.6 g, 0.22 mol) in DCM (260 mL) at RT was added trimethyloxonium tetrafluoroborate (34.5 g, 0.23 mol) and the mixture stirred at RT for 2 h. During this time the yellow colour faded and a thick white precipitate was formed. Acetic acid N′-isopropylhydrazide (27.1 g, 0.23 mol) and TEA (30.9 mL, 0.22 mol) were added as a solution in DCM (75 mL) causing the precipitate to dissolve. The reaction mixture was stirred at reflux for 5 h then at RT for 10 h. The reaction mixture was washed with water, and the aqueous layer extracted with DCM (2×50 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-100% ethyl acetate in cyclohexane) to give 2-Isopropyl-5-methyl-2H-[1,2,4]triazole-3-carboxylic acid ethyl ester as a pale yellow oil which crystallised on standing (15.6 g, 32%). 1H NMR 400 MHz (CDCl3) δ: 5.49 (1H, sept, J=6.7 Hz), 4.45 (2H, t, J=7.2 Hz), 2.43 (3H, s), 1.50 (6H, d, J=6.7 Hz), 1.44 (3H, t, J=7.2 Hz) a thick white precipitate was formed to dissolve The reaction mixture was stirred at reflux for 5 h at RT for 10 h The reaction mixture was washed with water the aqueous layer extracted with DCM (2×50 mL) The combined organic extracts were washed with brine dried (MgSO4) concentrated in vacuo

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

Procedure: 4-Cyclobutylthiazole-2-carboxylic acid ethyl ester 265b was synthesized from compound 264b (23.87 g, 1 eq.) and ethyl thiooxamate (21.41 g, 1 eq.) as a yellow oil in 64% yield, following the procedure as described for compound 212. 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 1.32 (t, J=7.12 Hz, 3H), 1.82-1.89 (m, 1H), 1.92-2.02 (m, 1H), 2.15-2.33 (m, 4H), 3.65-3.74 (m, 1H), 4.36 (q, J=7.12 Hz, 2H), 7.76 (d, J=0.64 Hz, 1H); MS (ESI, EI+): m/z=212 (MH+).