ethyl 2-(3-ethoxy-2-oxocyclohex-3-en-1-yl)-2-oxoacetate

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

Procedure: 1 g (4.2 mmol) of ethyl (3-ethoxy-2-oxocyclohex-3-en-1-yl)(oxo)acetate were dissolved in mL of ethanol, 0.21 mL of hydrazine hydrate were added and the solution stirred at reflux for a day. The solvent was then evaporated and the residue redissolved with dichloromethane. The organic layer was washed with water, dried over Na2SO4 and concentrated. The crude was triturated with diethyl ether and filtered to give (70% yield) the title compound. were added at reflux for a day The solvent was then evaporated the residue redissolved with dichloromethane The organic layer was washed with water dried over Na2SO4 concentrated The crude was triturated with diethyl ether filtered

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

Procedure: 1 g (4.2 mmol) of ethyl (3-ethoxy-2-oxocyclohex-3-en-1-yl)(oxo)acetate were dissolved in mL of ethanol, 0.21 mL of hydrazine hydrate were added and the solution stirred at reflux for a day. The solvent was then evaporated and the residue redissolved with dichloromethane. The organic layer was washed with water, dried over Na2SO4 and concentrated. The crude was triturated with diethyl ether and filtered to give (70% yield) the title compound. were added at reflux for a day The solvent was then evaporated the residue redissolved with dichloromethane The organic layer was washed with water dried over Na2SO4 concentrated The crude was triturated with diethyl ether filtered

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

Procedure: 1.2 g (5 mmol) of ethyl (3-ethoxy-2-oxocyclohex-3-en-1-yl)(oxo)acetate were dissolved in 20 mL of ethanol and 25 mL (5.2 mmol) of hydrazine hydrate 98% were added dropwise. The solution was stirred at room temperature for 5 hours, then heated at 60° C. for further 5 hours. The solvent was removed in vacuo and the residue taken up with diethyl ether and the resulting precipitate collected by filtration giving 0.8 g of the title compound, that was employed in the next step without any further purification. heated at 60° C. for further 5 hours The solvent was removed in vacuo the resulting precipitate collected by filtration

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

Procedure: 1.2 g (5 mmol) of ethyl (3-ethoxy-2-oxocyclohex-3-en-1-yl)(oxo)acetate were dissolved in 20 mL of ethanol and 25 mL (5.2 mmol) of hydrazine hydrate 98% were added dropwise. The solution was stirred at room temperature for 5 hours, then heated at 60° C. for further 5 hours. The solvent was removed in vacuo and the residue taken up with diethyl ether and the resulting precipitate collected by filtration giving 0.8 g of the title compound, that was employed in the next step without any further purification. heated at 60° C. for further 5 hours The solvent was removed in vacuo the resulting precipitate collected by filtration

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

Procedure: 30 g (0.125 mol) of ethyl (3-ethoxy-2-oxocyclohex-3-en-1-yl)(oxo)acetate were dissolved in 150 mL of glacial acetic acid and 6.5 mL of methylhydrazine were added. The mixture was stirred at room temperature for 6 hours. The solvent was then evaporated and the crude redissolved with water, the solution made basic with 30% NH4OH and extracted with chlorform. The organic layer was then dried over Na2SO4 and concentrated. The residue was chromatographed on a silica gel column (eluant: chloroform) and crystallized from a mixture n-hexane/diethyl ether (TLC chloroform; 63% yield as a white solid). The solvent was then evaporated the crude redissolved with water extracted with chlorform The organic layer was then dried over Na2SO4 concentrated The residue was chromatographed on a silica gel column (eluant: chloroform) crystallized from a mixture n-hexane/diethyl ether (TLC chloroform

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

Procedure: 41.40 g (0.29 mol) of 2-ethoxycyclohex-2-en-1-one were dissolved in 310 mL of diethyl ether and 325 mL of 1M LiN(TMS)2 in tetrahydrofuran were added dropwise at −50° C. After 30 minutes at the same temperature, 44.2 mL of diethyloxalate were also added under stirring. The solution was kept at room temperature overnight (TLC chloroform). 300 mL of water were then added, the pH adjusted to 4-5 by adding 1 N HCl and the resulting solution extracted with ethyl acetate. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude was purified by chromatography on a silica gel column eluted by chloroform (76% yield as an oil). the resulting solution extracted with ethyl acetate The organic layer was dried over Na2SO4 evaporated to dryness The crude was purified by chromatography on a silica gel column eluted by chloroform (76% yield as an oil)

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

Procedure: 41.40 g (0.29 mol) of 2-ethoxycyclohex-2-en-1-one were dissolved in 310 mL of diethyl ether and 325 mL of 1M LiN(TMS)2 in tetrahydrofuran were added dropwise at −50° C. After 30 minutes at the same temperature, 44.2 mL of diethyloxalate were also added under stirring. The solution was kept at room temperature overnight (TLC chloroform). 300 mL of water were then added, the pH adjusted to 4-5 by adding 1 N HCl and the resulting solution extracted with ethyl acetate. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude was purified by chromatography on a silica gel column eluted by chloroform (76% yield as an oil). the resulting solution extracted with ethyl acetate The organic layer was dried over Na2SO4 evaporated to dryness The crude was purified by chromatography on a silica gel column eluted by chloroform (76% yield as an oil)

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

Procedure: To a solution of ethyl (3-ethoxy-2-oxocyclohex-3-en-1-yl)(oxo)acetate 5.0 g (20.73 mmol) in 20 mL of EtOH and 5 mL of AcOH, 1.3 mL (20.78 mmol) of HONH2.H2O (50% wt/wt) was added. The mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the crude solid was purified by flash chromatography on silica gel (eluant: AcOEt/Hexane:3/7) to afford 1.35 g (25% yield) as a white solid of ethyl 7-ethoxy-7a-hydroxy-3a,4,5,7a-tetrahydro-1,2-benzisoxazole-3-carboxylate The solvent was removed under reduced pressure the crude solid was purified by flash chromatography on silica gel (eluant: AcOEt/Hexane:3/7)

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

Procedure: To a solution of ethyl (3-ethoxy-2-oxocyclohex-3-en-1-yl)(oxo)acetate 5.0 g (20.73 mmol) in 20 mL of EtOH and 5 mL of AcOH, 1.3 mL (20.78 mmol) of HONH2.H2O (50% wt/wt) was added. The mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the crude solid was purified by flash chromatography on silica gel (eluant: AcOEt/Hexane:3/7) to afford 1.35 g (25% yield) as a white solid of ethyl 7-ethoxy-7a-hydroxy-3a,4,5,7a-tetrahydro-1,2-benzisoxazole-3-carboxylate The solvent was removed under reduced pressure the crude solid was purified by flash chromatography on silica gel (eluant: AcOEt/Hexane:3/7)

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

Procedure: To a solution of ethyl (3-ethoxy-2-oxocyclohex-3-en-1-yl)(oxo)acetate 10 g (42.6 mmol) and acetic acid 5 ml in absolute ethanol (150 ml) at room temperature was added tert-butyl hydrazine hydrochloride 6 g (48 mmol). The mixture was stirred at 60° C. for 3 hours. The volatiles were removed under vacuum, the residue was diluted with DCM and washed with sat. aqueous solution of NaHCO3, and with brine. The organic phase was dried with sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography eluting with ethyl acetate and hexane (1:2) to give ethyl 1-tert-butyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate in 90% yield. LC/MS (254 nm) HPLC method 2 Rt 6.08 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.18 (q, J=6.83 Hz, 2H) 2.93-2.30 (3 m, 6H) 1.58 (s, 9H), 1.16 (t, J=6.83 Hz, 3H). HRMS (ESI) calcd for C14H20N2O3 [M+H]+ 287.1366 found 287.1356. The volatiles were removed under vacuum the residue was diluted with DCM washed with sat. aqueous solution of NaHCO3 The organic phase was dried with sodium sulfate filtered concentrated The crude material was purified by silica gel column chromatography eluting with ethyl acetate and hexane (1:2)

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

Procedure: 1 g (4.2 mmol) of ethyl (3-ethoxy-2-oxocyclohex-3-en-1-yl)(oxo)acetate were dissolved in 10 mL of ethanol, 0.21 mL of hydrazine hydrate were added and the solution stirred at reflux for a day. The solvent was then evaporated and the residue redissolved with dichloromethane. The organic layer was washed with water, dried over Na2SO4 and concentrated. The crude was triturated with diethyl ether and filtered to give (70% yield) the title compound. at reflux for a day The solvent was then evaporated the residue redissolved with dichloromethane The organic layer was washed with water dried over Na2SO4 concentrated The crude was triturated with diethyl ether filtered

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

Procedure: 1.2 g (5 mmol) of ethyl (3-ethoxy-2-oxocyclohex-3-en-1-yl)(oxo)acetate were dissolved in 20 mL of ethanol and 25 mL (5.2 mmol) of hydrazine hydrate 98% were added dropwise. The solution was stirred at room temperature for 5 hours, then heated at 60° C. for further 5 hours. The solvent was removed in vacuo and the residue taken up with diethyl ether and the resulting precipitate collected by filtration giving 0.8 g of the title compound, that was employed in the next step without any further purification. heated at 60° C. for further 5 hours The solvent was removed in vacuo the resulting precipitate collected by filtration