2-ethylhexyl carbonochloridate

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

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

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl 6-[amino(hydroxyimino)methyl]-4-{[tert-butyl(dimethyl)silyl]oxy}spiro[chroman-2,4′-piperidine]-1′-carboxylate in 80 mL of DMF were added 3.78 mL of pyridine and 8.4 mL of 2-Ethylhexyl chloroformate at 0° C., and the reaction mixture was stirred at 0° C. for 1.5 h. The reaction mixture was poured into ice-cold brine, and extracted with AcOEt twice. The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in reduced pressure to give a crude product, which was used in the next step without further purification. The reaction mixture was poured into ice-cold brine extracted with AcOEt twice The combined organic layers were washed with H2O and brine dried over Na2SO4 filtered concentrated in reduced pressure

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl 6-[amino(hydroxyimino)methyl]-4-{[tert-butyl(dimethyl)silyl]oxy}-spiro[chroman-2,4′-piperidine]-1′-carboxylate in 80 mL of DMF were added 3.78 mL of pyridine and 8.4 mL of 2-Ethylhexyl chloroformate at 0° C., and the reaction mixture was stirred at 0° C. for 1.5 h. The reaction mixture was poured into ice-cold brine, and extracted with AcOEt twice. The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in reduced pressure to give a crude product, which was used in the next step without further purification. The reaction mixture was poured into ice-cold brine extracted with AcOEt twice The combined organic layers were washed with H2O and brine dried over Na2SO4 filtered concentrated in reduced pressure

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a reactor, 117 g (0.6 mol) of N-methyl-D-glucamine were dissolved in a mixture of 800 ml of water and 400 ml of tetrahydrofuran, and 201.6 g (2.4 mol) of sodium hydrogen carbonate were then dispersed. While the temperature of the reaction mixture was maintained at 5° C., 115.6 g (0.6 mol) of 2-ethylhexyl chloroformate were added dropwise, and the mixture was then allowed to react for 3 hours with stirring at 5° C. and left standing overnight at room temperature. The reaction mixture was then filtered and concentrated; the pasty residue obtained was dissolved in 2 liters of acetone and then filtered after cooling to 5° C. The crystallized product collected was dried. 105 g (50% yield) of N-(2-ethylhexyloxycarbonyl)-N-methyl-D-glucamine, the melting point of which is 74° C., were obtained. were then dispersed to react for 3 hours left The reaction mixture was then filtered concentrated the pasty residue obtained filtered after cooling to 5° C The crystallized product collected was dried

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (1Z,2E)-N′-hydroxy-3-(4-((E)-2-phenyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylimidamide (51 mg, 0.1 mmol) in anhydrous DMF (0.4 mL) was added 2-ethylhexylchloroformate (20 μL, 0.1 mmol) followed by pyridine (9 μL, 0.11 mmol). The reaction mixture was stirred at 0° C. for 1 h and then partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (2×), and the combined organics were dried over MgSO4 and concentrated. The residue was dissolved in xylenes (1 mL), heated at 130° C. for 2 h, and then concentrated to afford 25 mg of the title compound. LCMS: 519 (M+H)+. partitioned between water and EtOAc The aqueous layer was extracted with EtOAc (2×) the combined organics were dried over MgSO4 concentrated The residue was dissolved in xylenes (1 mL) heated at 130° C. for 2 h concentrated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [4-(N-hydroxycarbamimidoyl)-phenyl]-amide (97 mg, 0.19 mmol) in dimethylformamide (2.0 mL) was treated with pyridine (0.020 mL, 0.20 mmol) and the mixture was cooled at 0° C. Chloroformic acid 2-ethylhexyl ester (36 mg, 0.19 mmol) was added dropwise and the mixture was stirred at 0° C. for 30 min. The mixture was diluted with water and extracted three times with ethyl acetate. The combined organic extracts were dried over sodium sulfate and evaporated. The residue was suspended in xylene (8.0 mL) and refluxed for 2 hours. Upon cooling to room temperature a solid precipitated, which was filtered and dried under high vacuum. 4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-amide was obtained as a white solid, 74 mg (73%), MS (ISP): m/e=541.1, 542.7 (M−H). extracted three times with ethyl acetate The combined organic extracts were dried over sodium sulfate evaporated refluxed for 2 hours Upon cooling to room temperature a solid precipitated which was filtered dried under high vacuum

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

Procedure: Under Ar, to a soln of the product of Example 242, 3-[8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-N-hydroxy-propionamidine (100 mg, 0.20 mmol), and pyridine (0.048 mL, 0.6 mmol), was added 2-ethylhexyl chloroformate (0.039 mL, 0.2 mmol). The mixture was stirred at room temperature for 2 h, then diluted with H2O and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting residue was diluted with xylene (10 mL) and heated to reflux for 18 h to give the crude material, which was purified by preparative hplc to give the desired product 28 mg (28%). LC-MS: 495.0 (MH+, m/z), 1.96 (Rt, min). extracted with EtOAc The organic layer was dried over sodium sulfate filtered concentrated The resulting residue was diluted with xylene (10 mL) heated to reflux for 18 h to give the crude material, which was purified by preparative hplc

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

Procedure: To a mixed liquid of 280 mg of (3RS,4RS)—N-({3-[amino(hydroxyimino)methyl]benzyl}oxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 10 ml of DMF were added 0.037 ml of pyridine and subsequently 0.084 ml of 2-ethylhexyl chloroformate under ice-cooling, followed by stirring under ice-cooling for 30 minutes. To the reaction solution was added ethyl acetate, followed by washing with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 305 mg of (3RS,4RS)—N-[(3-{amino[({[(2-ethyl hexyl)oxy]carbonyl}oxy)imino]methyl}benzyl)oxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white amorphous substance. To 290 mg of the present compound was added 6 ml of NMP, followed by stirring at 140° C. for 3 hours. The reaction solution was cooled, and 50 ml of water was then added thereto, followed by stirring. The precipitated solid was collected by filtration. This solid was purified by silica gel column chromatography (eluent: chloroform-methanol), then crystallized with acetonitrile-water, and collected by filtration to obtain 101 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-{[3-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzyl]oxy}-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal. cooling cooling for 30 minutes by washing with water The organic layer was dried over anhydrous magnesium sulfate the solvent was then evaporated under reduced pressure The obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl 6-[amino(hydroxyimino)methyl]-4-{[tert-butyl(dimethyl)silyl]oxy}spiro[chroman-2,4′-piperidine]-1′-carboxylate in 80 mL of DMF were added 3.78 mL of pyridine and 8.4 mL of 2-Ethylhexyl chloroformate at 0° C., and the reaction mixture was stirred at 0° C. for 1.5 h. The reaction mixture was poured into ice-cold brine, and extracted with AcOEt twice. The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in reduced pressure to give a crude product, which was used in the next step without further purification. The reaction mixture was poured into ice-cold brine extracted with AcOEt twice The combined organic layers were washed with H2O and brine dried over Na2SO4 filtered concentrated in reduced pressure

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl 6-[amino(hydroxyimino)methyl]-4-{[tert-butyl(dimethyl)silyl]oxy}spiro[chroman-2,4′-piperidine]-1′-carboxylate in 80 mL of DMF were added 3.78 mL of pyridine and 8.4 mL of 2-Ethylhexyl chloroformate at 0° C., and the reaction mixture was stirred at 0° C. for 1.5 h. The reaction mixture was poured into ice-cold brine, and extracted with AcOEt twice. The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in reduced pressure to give a crude product, which was used in the next step without further purification. The reaction mixture was poured into ice-cold brine extracted with AcOEt twice The combined organic layers were washed with H2O and brine dried over Na2SO4 filtered concentrated in reduced pressure

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