ethyl 2,4-dioxohexanoate

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

Procedure: Reaction of ethyl 2,4-dioxohexanoate with dimethylmethylene ammonium chloride and ammonia, analogous to the procedure in Preparation 8, gave the title compound as an amorphous solid. 1H nmr (250 MHz, DMSO-d6) δ0.99 (t, J=7.3 Hz, 3H), 2.75 (q, J=7.3 Hz, 2H), 3.81 (s, 2H), 8.84 (s, 1H). analogous to the procedure in Preparation 8

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

Procedure: Ethyl 2,4-dioxohexanoate (12 g) in glacial acetic acid (75 ml) was cooled in an ice-bath and treated with methylhydrazine (3.21 g) in a dropwise fashion over 5-10 m. On complete addition the ice cooling was removed and the yellow homogeneous solution stirred at room temperature for ca. 2 h. The acetic acid was then removed in vacuo and the residual oil re-dissolved in ethyl acetate (~ 100 mls). The ethyl acetate solution was washed with saturated sodium hydrogen carbonate (3×) and brine. After drying over anhydrous magnesium sulphate the solvent was evaporated. The crude material was purified by silica gel chromatography eluting with 20-70% ethyl acetate/hexane giving the title compound as a pale yellow oil, (6.656 g, 52%); dH (CDCl3) 1.28 (3H, t, J7.6 Hz), 1.38 (3H, t, J7.1 Hz), 2.61 (2H, q, J7.6 Hz), 3.84 (3H, s), 4.38 (2H, q, J7.1 Hz) and 6.58 (1H, s). was removed The acetic acid was then removed in vacuo the residual oil re-dissolved in ethyl acetate (~ 100 mls) The ethyl acetate solution was washed with saturated sodium hydrogen carbonate (3×) and brine After drying over anhydrous magnesium sulphate the solvent was evaporated The crude material was purified by silica gel chromatography eluting with 20-70% ethyl acetate/hexane giving the title compound as a pale yellow oil, (6.656 g, 52%)

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

Procedure: Ethyl 2,4-dioxohexanoate (21.5 g) in glacial acetic acid (125 ml) was cooled in an ice-bath and treated with N-ethylhydrazine oxalate (18.75 g) over 15 minutes. After addition was complete the mixture was stirred for 3 hours at room temperature. The acetic acid was then removed by evaporation in vacuo. The orange oily residue was dissolved in EtOAc and the solution washed repeatedly with saturated aqueous NaHCO3 and once with brine. Following drying over MgSO4 the solvent was evaporated in vacuo to give ethyl 1,5-diethylpyrazole-3-carboxylate as an oil (20.7 g); δ (CDCl3) 1.25-1.45 (9H, 3×3H,t, J 7 Hz), 2.62 (2H, q, J 7 Hz), 4.17 (2H, q, J 7 Hz), 4.38 (2H, q, J 7 Hz) 6.57 (1H, s) ppm. After addition The acetic acid was then removed by evaporation in vacuo The orange oily residue was dissolved in EtOAc the solution washed repeatedly with saturated aqueous NaHCO3 and once with brine Following drying over MgSO4 the solvent was evaporated in vacuo

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

Procedure: The title compound was prepared in analogy to the procedure described in Step 60.1 using 3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-amine (Step 67.4), 4-chlorobenzaldehyde and ethyl 2,4-dioxohexanoate at 110° C. for 4 hr. tR: 0.79 min (LC-MS 2); ESI-MS: 411 [M+H]+, ESI-MS: 409 [M−H]− (LC-MS 2).

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

Procedure: The title compound was prepared in analogy to the procedure described in Step 57.1 using 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2), 4-chlorobenzaldehyde and ethyl 2,4-dioxohexanoate under reflux for 7 hr. The crude product was purified by silica gel chromatography (hexane/CH2Cl2/MeOH 40:60:10 to 0:60:10). tR: 0.82 min (LC-MS 2); ESI-MS: 387 [M+H]+ (LC-MS 2). under reflux for 7 hr The crude product was purified by silica gel chromatography (hexane/CH2Cl2/MeOH 40:60:10 to 0:60:10)

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

Procedure: The title compound was prepared in analogy to the procedure described in Step 57.1 using 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2), 4-chlorobenzaldehyde and ethyl 2,4-dioxohexanoate under reflux for 7 hr. The crude product was purified by silica gel chromatography (hexane/CH2Cl2/MeOH 40:60:10 to 0:60:10). tR: 0.82 min (LC-MS 2); ESI-MS: 387 [M+H]+ (LC-MS 2). under reflux for 7 hr The crude product was purified by silica gel chromatography (hexane/CH2Cl2/MeOH 40:60:10 to 0:60:10)

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of compound 2 (3.8 g, 22 mmol) in toluene (20 mL) was added methylhydrazine (1.8 g, 0.039 mol) cooled to −20° C. After completion of the reaction, the reaction liquid was washed with water and the solvent was removed by evaporation to obtain crude product, the crude product was purified by silica gel column chromatography (PE:EA=5:1) to give the desired product as a white oil. After completion of the reaction the reaction liquid was washed with water the solvent was removed by evaporation to obtain crude product the crude product was purified by silica gel column chromatography (PE:EA=5:1)

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of compound 2 (3.8 g, 22 mmol) in toluene (20 mL) was added methylhydrazine (1.8 g, 0.039 mol) cooled to −20° C. After completion of the reaction, the reaction liquid was washed with water and the solvent was removed by evaporation to obtain crude product, the crude product was purified by silica gel column chromatography (PE:EA=5:1) to give the desired product as a white oil. After completion of the reaction the reaction liquid was washed with water the solvent was removed by evaporation to obtain crude product the crude product was purified by silica gel column chromatography (PE:EA=5:1)

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

Procedure: To a solution of sodium ethoxide (2.33 g, 34 mmol) in absolute alcohol (40 mL) was added a mixture of 2-butanone (2.45 g, 34 mmol) and diethyl oxalate (5 g, 34 mmol) dropwise at −5° C. The reaction mixture was stirred at −5° C. overnight and then concentrated. The resulting residue was partitioned between water (20 mL) and ethyl acetate (70 mL*3). The aqueous layer was acidified to pH 2 with dilute H2SO4 and then extracted with ethyl acetate (50 ml*3). The combined organic phase was dried over anhydrous Na2SO4, The organic solvent was evaporated in vacuo, and the residue was used directly in the next step without further purification. concentrated The resulting residue was partitioned between water (20 mL) and ethyl acetate (70 mL*3) extracted with ethyl acetate (50 ml*3) The combined organic phase was dried over anhydrous Na2SO4 The organic solvent was evaporated in vacuo the residue was used directly in the next step without further purification

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

Procedure: Reaction of ethyl 2,4-dioxohexanoate with dimethylmethylene ammonium chloride and ammonia, analogous to the procedure in Preparation 8, gave the title compound as an amorphous solid. 1H nmr (250 MHz, DMSO-d6) δ0.99 (t, J=7.3 Hz, 3H), 2.75 (q, J=7.3 Hz, 2H), 3.81 (s, 2H), 8.84 (s, 1H). analogous to the procedure in Preparation 8

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

Procedure: The title compound was prepared in analogy to the procedure described in Step 57.1 using 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2), 4-chlorobenzaldehyde and ethyl 2,4-dioxohexanoate under reflux for 7 hr. The crude product was purified by silica gel chromatography (hexane/CH2Cl2/MeOH 40:60:10 to 0:60:10). tR: 0.82 min (LC-MS 2); ESI-MS: 387 [M+H]+ (LC-MS 2). under reflux for 7 hr The crude product was purified by silica gel chromatography (hexane/CH2Cl2/MeOH 40:60:10 to 0:60:10)

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

Procedure: A solution of ethyl 2,4-dioxohexanoate (Step 1, 2.0 g, 11.6 mmol) and 4-(methylbenzyl)-hydrazine dihydrochloride (Step 3 of Intermediate A, 2.67 g, 12.8 mmol) in acetic acid (15 mL) was stirred for 4 h at 90° C. After removal of the solvent (rotavapor), the residue was subjected to MPLC (silica, cyclohexane/ethyl acetate 5:1) to afford the title compound as a highly viscous oil (1.93 g, 61%): 1H NMR (400 MHz, CDCl3) δ 7.10 (d, 2H), 6.98 (d, 2H), 6.62 (s, 1H), 5.33 (s, 2H), 4.40 (quart, 2H), 2.48 (quart, 2H), 2.31 (s, 3H), 1.40 (t, 3H), 1.18 (t, 3H); DCI(NH3)-MS m/z 273 (MH)+; HPLC RT (Method I) 4.75 min. After removal of the solvent (rotavapor)