ethyl (2E)-2-amino-2-hydroxyiminoacetate

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

Procedure: Water (600 ml) is added dropwise over a period of two hours to a vigorously stirred, room temperature mixture of ethyl cyanoformate (99 g, 1 mol), hydroxylamine hydrochloride (105 g, 1.5 mol ) and sodium carbonate (82 g, 0.77 mol ) in ethanol (1 L.) The resulting solution is stirred until the starting material has been consumed. When the reaction is complete, most of the solvent is removed in vacuo and the resulting residue is extracted with methylene chloride (3×200 ml.) The combined organic extracts are washed with brine (250 ml), dried (Na2SO4), filtered and concentrated to afford 120.1 g (91%) of compound 2a as a white solid. Further purification can be achieved by crystallization from chloroform and hexanes. 1H NMR (CDCl3): δ9.15 (br s, OH), 5.12 (br s, 2H), 4.32 (q, 2H), 1.42 (t, J=7.1 Hz, 3H). 13C NMR (CDCl3): δ161.4, 144.4, 62.8, 14.3. is stirred until the starting material has been consumed is removed in vacuo the resulting residue is extracted with methylene chloride (3×200 ml.) The combined organic extracts are washed with brine (250 ml) dried (Na2SO4) filtered concentrated

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

Procedure: Water (600 ml) is added dropwise over a period of two hours to a vigorously stirred, room temperature mixture of ethyl cyanoformate (99 g, 1 mol), hydroxylamine hydrochloride (105 g, 1.5 mol ) and sodium carbonate (82 g, 0.77 mol ) in ethanol (1 L.) The resulting solution is stirred until the starting material has been consumed. When the reaction is complete, most of the solvent is removed in vacuo and the resulting residue is extracted with methylene chloride (3×200 ml.) The combined organic extracts are washed with brine (250 ml), dried (Na2SO4), filtered and concentrated to afford 120.1 g (91%) of compound 2a as a white solid. Further purification can be achieved by crystallization from chloroform and hexanes. 1H NMR (CDCl3): δ9.15 (br s, OH), 5.12 (br s, 2H), 4.32 (q, 2H), 1.42 (t, J=7.1 Hz, 3H). 13C NMR (CDCl3): δ161.4, 144.4, 62.8, 14.3. is stirred until the starting material has been consumed is removed in vacuo the resulting residue is extracted with methylene chloride (3×200 ml.) The combined organic extracts are washed with brine (250 ml) dried (Na2SO4) filtered concentrated

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

Procedure: N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.32 g, 10 mmol) was added in one portion to a stirred solution of ethyl 2-amino-2-(hydroxyimino)acetate (1.32 g, 10 mmol) plus 3,5-dibromo-4-hydroxybenzoic acid (2.95 g, 10 mmol) in pyridine (20 mL), the resulting solution was stirred at room temperature for 2 h and then at 90° C. for 5 h. After standing at room temperature overnight the pyridine was evaporated in vacuo and the residue was purified by flash chromatography (silica gel, 10% ethyl acetate/dichloromethane) to give the title compound (0.48 g, 12%) as a colourless solid. 1H NMR δ (ppm) (DMSO-d6): 1.48 (3H, t), 4.47 (2H, d), 8.13 (2H, s), 11.54 (1H, s, br). at 90° C. for 5 h After standing at room temperature overnight the pyridine was evaporated in vacuo the residue was purified by flash chromatography (silica gel, 10% ethyl acetate/dichloromethane)

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

Procedure: This compound was prepared according to General method 2 with (step I) 2-(2,4,6-trifluorophenyl)acetic acid (0.360 g; 1.89 mmol) and oxalyl chloride (0.176 mL; 2.08 mmol) in dichloromethane (12 mL) with few drops of DMF and (step II) ethyl 2-amino-2-(hydroxyimino)acetate (0.250 g; 1.89 mmol) and N,N diisopropylethylamine (0.527 mL; 3.03 mmol) in dichloromethane (10 mL) and (step III) pyridine (18 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.1002 g (19%) of ethyl 5-(2,4,6-trifluorobenzyl)-1,2,4-oxadiazole-3-carboxylate as a white solid. This compound was prepared The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane)

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

Procedure: This compound was prepared according to general method 2 with (step I) 2-(2,3,4-trifluorophenyl)acetic acid (0.360 g; 1.89 mmol) and oxalyl chloride (0.176 mL; 2.08 mmol) in dichloromethane (12 mL) with few drops of DMF and (step II) ethyl 2-amino-2-(hydroxyimino)acetate (0.250 g; 1.89 mmol) and N,N diisopropylethylamine (0.527 mL; 3.03 mmol) in dichloromethane (10 mL) and (step III) pyridine (18 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.065 g (12%) of ethyl 5-(2,3,4-trifluorobenzyl)-1,2,4-oxadiazole-3-carboxylate as a white solid. This compound was prepared The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane)

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

Procedure: This compound was prepared according to general method 2 with (step I) 2-(4-fluoro-2-(trifluoromethyl)phenyl)acetic acid (0.420 g; 1.89 mmol) and oxalyl chloride (0.176 mL; 2.08 mmol) in dichloromethane (12 mL) with few drops of DMF and (step II) ethyl 2-amino-2-(hydroxyimino)acetate (0.250 g; 1.89 mmol) and N,N diisopropylethylamine (0.527 mL; 3.03 mmol) in dichloromethane (10 mL) and (step III) pyridine (18 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.063 g (10%) of ethyl 5-(4-fluoro-2-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxylate as a white solid. This compound was prepared The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane)

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

Procedure: This compound was prepared according to general method 2 with (step I) 2-(2-fluoro-5-(trifluoromethyl)phenyl)acetic acid (0.420 g; 1.89 mmol) and oxalyl chloride (0.176 mL; 2.08 mmol) in dichloromethane (12 mL) with few drops of DMF and (step II) ethyl 2-amino-2-(hydroxyimino)acetate (0.250 g; 1.89 mmol) and N,N diisopropylethylamine (0.527 mL; 3.03 mmol) in dichloromethane (10 mL) and (step III) pyridine (18 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.116 g (20%) of ethyl 5-(2-fluoro-5-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxylate as a white solid. This compound was prepared The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane)

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

Procedure: This compound was prepared according to general method 2 with (step I) 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid (0.420 g; 1.89 mmol) and oxalyl chloride (0.176 mL; 2.08 mmol) in dichloromethane (12 mL) with few drops of DMF and (step II) ethyl 2-amino-2-(hydroxyimino)acetate (0.250 g; 1.89 mmol) and N,N diisopropylethylamine (0.527 mL; 3.03 mmol) in dichloromethane (10 mL) and (step III) pyridine (18 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.085 g (14%) of ethyl 5-(2-fluoro-3-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxylate as a white solid. This compound was prepared The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane)

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

Procedure: This compound was prepared according to general method 2 with (step I) 2-(5-methyl-2-phenyloxazol-4-yl)acetic acid (0.411 g; 1.89 mmol) and oxalyl chloride (0.176 mL; 2.08 mmol) in dichloromethane (12 mL) with few drops of DMF and (step II) ethyl 2-amino-2-(hydroxyimino)acetate (0.250 g; 1.89 mmol) and N,N diisopropylethylamine (0.527 mL; 3.03 mmol) in dichloromethane (10 mL) and (step III) pyridine (18 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.076 g (13%) of ethyl 5-((5-methyl-2-phenyloxazol-4-yl)methyl)-1,2,4-oxadiazole-3-carboxylate as a white solid. This compound was prepared The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane)

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

Procedure: Benzoyl chloride (0.219 mL; 1.89 mmol) was added to a mixture of ethyl 2-amino-2-(hydroxyimino)acetate (0.250 g; 1.89 mmol) and N,N diisopropylethylamine (0.527 mL; 3.03 mmol) in dichloromethane (18 mL) at −15° C. The reaction mixture was stirred at room temperature overnight and poured into a mixture of ice and water. The aqueous layer was extracted with dichloromethane, and the combined organic extracts were dried and concentrated under reduced pressure. The residue was refluxed in a sealed tube with pyridine (6 mL) for 20 hours and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.239 (60%) of ethyl 5-phenyl-1,2,4-oxadiazole-3-carboxylate as a yellow solid. The aqueous layer was extracted with dichloromethane the combined organic extracts were dried concentrated under reduced pressure The residue was refluxed in a sealed tube with pyridine (6 mL) for 20 hours concentrated under reduced pressure The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane)

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

Procedure: 2-phenyl acetyl chloride (1.0 mL; 7.57 mmol) was added to a mixture of ethyl 2-amino-2-(hydroxyimino)acetate (0.5 g; 3.78 mmol) and N,N diisopropylethylamine (1.05 mL; 6.06 mmol) in dichloromethane (15 mL) at −15° C. The reaction mixture was stirred at room temperature overnight and poured into a mixture of ice and water. The formed precipitate was filtered off, suspended in pyridine (18 mL) and refluxed in a sealed tube for 20 h and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.308 g (35%) of the title compound as a white solid. The formed precipitate was filtered off refluxed in a sealed tube for 20 h concentrated under reduced pressure The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane)

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

Procedure: This compound was prepared according to general method 2 with (step I) 2-(3-fluorophenyl)acetic acid (1.03 g; 7.57 mmol) and oxalyl chloride (0.704 mL; 8.33 mmol) in dichloromethane (5 mL) and a few drops of DMF and (step II) ethyl 2-amino-2-(hydroxyimino)acetate (1.0 g; 7.57 mmol) and N,N diisopropylethylamine (2.11 mL; 12.11 mmol) in dichloromethane (10 mL) and (step III) pyridine (18 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.555 g (30%) of the title compound as a white solid. This compound was prepared The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane)