ethyl 2-hydrazinylacetate;hydrochloride

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

Procedure: A mixture of 18.45 g of 4-[6-(2-chloro-4-methoxyphenoxy)hexyl]-3,5-heptanedione, 7.73 g of carbethoxymethylhydrazine hydrochloride and 5 g of triethylamine in 100 ml of absolute ethanol was heated at reflux for 8 hours. The product was isolated and distilled to give 16.7 g of ethyl 4-[6-(2-chloro-4-methoxyphenoxy)hexyl]-3,5-diethyl-1H-pyrazol-1-acetate as a pale yellow oil, b.p. 205°-210° C. (0.05 mm); MIC=6-12 microg/ml (herpes 1 and 2). was heated at reflux for 8 hours The product was isolated distilled

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 155 ml of THF are added with stirring to a mixture of 5.17 g of 2,4,6-tri-chloropyrimidine-5-carbaldehyde and 5.85 g of ethyl hydrazinoacetate hydrochloride. The mixture is cooled to 10° C., and 6.78 ml of triethylamine are added dropwise. The mixture is stirred at RT for a further 1 h. The deposited precipitate is separated off (not the product). The filtrate, which contains the product, is subjected to conventional work-up, giving 3 g of ethyl (4,6-dichloropyrazolo[3,4-d]pyrimidin-1-yl)acetate (“12”). The deposited precipitate is separated off (not the product)

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

Procedure: 5-Hydroxy-4-methylfuran-2(5H)-one (1.19 g, 10.4 mmol) and ethyl hydrazinoacetate hydrochloride (1.61 g, 10.4 mmol) in 95% ethanol (20 mL) was refluxed for 2 h. Removal of the solvent in vacuo followed by purification using a Biotage Horizon® system (0-50% ethyl acetate/hexanes mixture) gave ethyl [4-methyl-6-oxopyridazin-1(6H)-yl]acetate as a yellow crystalline. LC/MS 219.2 (M+23). Removal of the solvent in vacuo followed by purification

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

Procedure: 5-Hydroxy-4-methylfuran-2(5H)-one (1.19 g, 10.4 mmol) and ethyl hydrazinoacetate hydrochloride (1.61 g, 10.4 mmol) in 95% ethanol (20 mL) was refluxed for 2 h. Removal of the solvent in vacuo followed by purification using a Biotage Horizon® system (0-50% ethyl acetate/hexanes mixture) gave ethyl [4-methyl-6-oxopyridazin-1(6H)-yl]acetate as a yellow crystalline. LC/MS 219.2 (M+23). Removal of the solvent in vacuo followed by purification

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

Procedure: To a mixture of ethyl hydrazinoacetate hydrochloride (2.8 g, 18.1 mmol) and triethylamine (9.2 g, 91 mmol) in a solution of ethanol (20 mL) and N,N-dimethylformamide (1 mL), a solution of crude 4,4-dichloro-1,1,1-trifluoro-3-buten-2-one in dichloromethane (20 mL) was added dropwise while keeping the temperature of the reaction mixture below 10° C. After stirring a further 2 h at below 10° C., the reaction mixture was concentrated under reduced pressure. The residue was diluted with diethyl ether, and the mixture was filtered. The resulting filtrate was concentrated to give 4.34 g of the title compound as a solid. This compound was of sufficient purity to use in subsequent reactions. the temperature of the reaction mixture below 10° C the reaction mixture was concentrated under reduced pressure The residue was diluted with diethyl ether the mixture was filtered The resulting filtrate was concentrated

Conditions: temp:190.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of cyclohexane-1,3-dione (50.7 g, 45.2 mmol) in N,N-dimethylformamide (700 mL) was added ethyl hydrazinoacetate hydrochloride (70 g, 45.2 mmol). The reaction mixture was stirred for 5 minutes, then dimethoxymethyl-dimethyl-amine (53.9 g, 45.2 mmol) was added. The reaction mixture was divided into 50 vials, which were heated in a microwave at 190° C. for 2 minutes. After cooling to room temperature, the combined reaction mixture was concentrated in vacuo to remove most of N,N-dimethylformamide. Water (200 mL) was added, and the resulting dark brown mixture was extracted with ethyl acetate (200 mL×3). The organic layers were combined, washed with brine (600 mL), dried over sodium sulfate and concentrated in vacuo to afford a brown oil, which was placed in a fridge overnight. The resulting yellow precipitate was filtered and washed with petroleum ether to give (4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (79 g, 79%) as yellow crystals. 1H NMR (400 MHz, CDCl3) δ ppm 7.92 (s, 1 H), 4.89 (s, 2 H), 4.26 (m, 2 H), 2.80 (t, J=6.4 Hz, 2 H), 2.51 (t, J=6.4 Hz, 2 H), 2.20 (t, J=6.4 Hz, 2 H), 1.31 (t, J=7.2 Hz, 3 H). MS calcd. for C11H14N2O3 222, obsd. (ESI+) (M+H)+223. After cooling to room temperature the combined reaction mixture was concentrated in vacuo to remove most of N,N-dimethylformamide Water (200 mL) was added the resulting dark brown mixture was extracted with ethyl acetate (200 mL×3) washed with brine (600 mL) dried over sodium sulfate concentrated in vacuo to afford a brown oil, which was placed in a fridge overnight The resulting yellow precipitate was filtered washed with petroleum ether

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

Procedure: 6.0 g of chloro-2-(5-chloro-2-hydroxyphenyl)benz[e][1,3]oxazin-4-one (Example 16), 3.0 ml of triethylamine and 3.3 g of ethyl hydrazinoacetate hydrochloride are boiled under reflux for 2 h in 60 ml of ethanol. On cooling, the product precipitates in crystalline form. It is filtered off and washed with ethanol. After drying, ethyl [3,5-bis(5-chloro-2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate is obtained as colorless crystals of m.p. 195-200° C. On cooling the product precipitates in crystalline form It is filtered off washed with ethanol After drying

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

Procedure: 51.5 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one, 30.5 ml of triethylamine and 33.4 g of ethyl hydrazinoacetate hydrochloride are boiled under reflux for 0.5 h in 450 ml of ethanol. On cooling, the product precipitates in crystalline form. It is filtered off and washed with ethanol. After drying, ethyl [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate remains as colorless crystals of m.p. 172-174° C. On cooling the product precipitates in crystalline form It is filtered off washed with ethanol After drying

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

Procedure: 5-Hydroxy-4-methylfuran-2(5H)-one (1.19 g, 10.4 mmol) and ethyl hydrazinoacetate hydrochloride (1.61 g, 10.4 mmol) in 95% ethanol (20 mL) was refluxed for 2 h. Removal of the solvent in vacuo followed by purification using a Biotage Horizon® system (0-50% ethyl acetate/hexanes mixture) gave ethyl[4-methyl-6-oxopyridazin-1(6H)-yl]acetate as a yellow crystalline. LC/MS 219.2 (M+23). Removal of the solvent in vacuo followed by purification

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

Procedure: 5-Hydroxy-4-methylfuran-2(5H)-one (1.19 g, 10.4 mmol) and ethyl hydrazinoacetate hydrochloride (1.61 g, 10.4 mmol) in 95% ethanol (20 mL) was refluxed for 2 h. Removal of the solvent in vacuo followed by purification using a Biotage Horizon® system (0-50% ethyl acetate/hexanes mixture) gave ethyl[4-methyl-6-oxopyridazin-1(6H)-yl]acetate as a yellow crystalline. LC/MS 219.2 (M+23). Removal of the solvent in vacuo followed by purification

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

Procedure: A mixture of ethyl 2-hydrazinylacetate hydrochloride (0.309 g, 2 mmol), NaHC O3 (0.185 g, 2.2 mmol), and 4,4-dimethyl-3-oxopentanenitrile (0.250 g, 2 mmol) in EtOH (10 mL) was heated at 60° C. overnight. The reaction was quenched with water and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure to afford ethyl 2-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)acetate as solid (0.369 g, 82%). 1H NMR (300 MHz, CDCl3) δ 5.50 (s, 1H), 4.75 (s, 2H), 4.23 (q, 2H), 3.57 (br, 2H), 1.29 (t, 3H), 1.25 (s, 9H); LC-MS (ESI) m/z 226 (M+H)+. The reaction was quenched with water extracted with CH2Cl2 Extracts were dried over MgSO4 concentrated under reduced pressure

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

Procedure: To a solution of diphenylmethyl 3-formyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate (155 mg) in tetrahydrofuran (15 ml) is added a solution of carbethoxymethylhydrazine hydrochloride (69 mg) in water (2.5 ml), and the mixture is kept at room temperature for 2 days. The crystals obtained by concentration of the reaction mixture are collected by filtration, washed with ether and water, and dried to give diphenylmethyl 7-(2-thienylacetamido)-3-(2-carbethoxymethylhydrazono)methyl-3-cephem-4-carboxylate (129 mg). m.p. 70°-75° C. Yield: 69%. IR: νmaxNujol 3270, 1780, 1745, 1670; 1540cm-1. NMR: δd 6-DMSO (60MHz) 1.435 (6Hz) 3H, 3.52ABq (24; 17Hz) 2H, 3.48s2H, 3.60s2H, 4.17 quintet (6Hz) 2H, 4.95d(5Hz)1H, 5.70dd(8;4Hz)1H, 6.67-7.63m16H, 8.03s1H. [ α]D24.5 - 144° (c=0.340, CHCl3). The crystals obtained by concentration of the reaction mixture are collected by filtration washed with ether and water dried