ethyl 4-cyclopropyl-2,4-dioxobutanoate

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2) (1.77 g, 12.78 mmol), 4-chlorobenzaldehyde (1.63 g, 11.62 mmol) and ethyl 4-cyclopropyl-2,4-dioxobutanoate (2 g, 11.62 mmol) in acetic acid (10 mL) was stirred for 2 h at 100° C. The reaction mixture was concentrated, diluted with CH2Cl2/1 N NaOH, and extracted with CH2Cl2. The combined organic extracts were discarded. The aqueous layer was acidified to pH 3 with 6 N HCl and extracted twice with CH2Cl2. The combined organic extracts were dried (Na2SO4) and concentrated to afford 3.06 g of the title compound as a beige foam. tR. 0.83 min (LC-MS 2); ESI-MS: 387.0 [M+H]+ (LC-MS 2). The reaction mixture was concentrated diluted with CH2Cl2/1 N NaOH extracted with CH2Cl2 extracted twice with CH2Cl2 The combined organic extracts were dried (Na2SO4) concentrated

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2) (1.77 g, 12.78 mmol), 4-chlorobenzaldehyde (1.63 g, 11.62 mmol) and ethyl 4-cyclopropyl-2,4-dioxobutanoate (2 g, 11.62 mmol) in acetic acid (10 mL) was stirred for 2 h at 100° C. The reaction mixture was concentrated, diluted with CH2Cl2/1 N NaOH, and extracted with CH2Cl2. The combined organic extracts were discarded. The aqueous layer was acidified to pH 3 with 6 N HCl and extracted twice with CH2Cl2. The combined organic extracts were dried (Na2SO4) and concentrated to afford 3.06 g of the title compound as a beige foam. tR. 0.83 min (LC-MS 2); ESI-MS: 387.0 [M+H]+ (LC-MS 2). The reaction mixture was concentrated diluted with CH2Cl2/1 N NaOH extracted with CH2Cl2 extracted twice with CH2Cl2 The combined organic extracts were dried (Na2SO4) concentrated

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 84.5 using 3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-amine (Step 67.4), 4-chlorobenzaldehyde and ethyl 4-cyclopropyl-2,4-dioxobutanoate. tR: 0.82 min (LC-MS 2); ESI-MS: 483 [M+H]+ (LC-MS 2); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.60-0.97 (m, 4H) 2.41 (s, 3H) 2.55-2.68 (m, 3H) 2.85-2.93 (m, 1H) 6.12 (s, 1H) 7.11-7.28 (m, 2H) 7.28-7.41 (m, 3H) 8.50 (s, 1H) —OH missing.

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 84.5 using 3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-amine (Step 67.4), 4-chlorobenzaldehyde and ethyl 4-cyclopropyl-2,4-dioxobutanoate. tR: 0.82 min (LC-MS 2); ESI-MS: 483 [M+H]+ (LC-MS 2); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.60-0.97 (m, 4H) 2.41 (s, 3H) 2.55-2.68 (m, 3H) 2.85-2.93 (m, 1H) 6.12 (s, 1H) 7.11-7.28 (m, 2H) 7.28-7.41 (m, 3H) 8.50 (s, 1H) —OH missing.

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

Procedure: The title compound was prepared in the same manner as described for intermediate 30 using 3-methyl-1-(4-pyridinyl)-1H-pyrazol-5-amine (310 mg, 1.780 mmol), ethyl 4-cyclopropyl-2,4-dioxobutanoate (328 mg, 1.780 mmol), benzene (50 mL), and acetic acid (25 mL). The final product was collected as 3.71 (71% overall). LCMS E-S (M+H)=323.5 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.22 (m, 4H), 1.41 (t, J=7.07 Hz, 3H), 2.64-2.69 (m, 4H), 4.47 (q, J=7.07 Hz, 2H), 7.74 (s, 1H), 8.27-8.36 (m, 2H), 8.66-8.71 (m, 2H). The final product was collected as 3.71 (71% overall)

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

Procedure: The title compound was prepared in the same manner as described for intermediate 30 using 3-methyl-1-(4-pyridinyl)-1H-pyrazol-5-amine (310 mg, 1.780 mmol), ethyl 4-cyclopropyl-2,4-dioxobutanoate (328 mg, 1.780 mmol), benzene (50 mL), and acetic acid (25 mL). The final product was collected as 3.71 (71% overall). LCMS E-S (M+H)=323.5 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.22 (m, 4H), 1.41 (t, J=7.07 Hz, 3H), 2.64-2.69 (m, 4H), 4.47 (q, J=7.07 Hz, 2H), 7.74 (s, 1H), 8.27-8.36 (m, 2H), 8.66-8.71 (m, 2H). The final product was collected as 3.71 (71% overall)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Methyl-1-(1-methyl-4-piperidinyl)-1H-pyrazol-5-amine (500 mg, 2.57 mmol) and ethyl 4-cyclopropyl-2,4-dioxobutanoate (474 mg, 2.57 mmol) were suspended in Toluene (10 mL) and heated at 70° C. for 5 h. The solvent was removed in vacuo and the crude residue was purified via silica gel chromatography (eluent: gradient of 0 to 10% MeOH:DCM). The final product was collected as a solid, 0.722 g (76%). LCMS E-S (M+H)=343.1 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.11 (m, 4H), 1.38 (t, J=7.07 Hz, 3H), 1.83 (d, J=6.06 Hz, 2H), 2.12-2.22 (m, 4H), 2.27 (s, 3H), 2.35 (m, J=7.83, 7.83, 5.05, 4.80 Hz, 1H), 2.54 (s, 3H), 2.94 (d, J=6.57 Hz, 2H), 4.42 (q, J=7.16 Hz, 2H), 4.57-4.73 (m, 1H), 7.46 (s, 1H). The solvent was removed in vacuo the crude residue was purified via silica gel chromatography (eluent: gradient of 0 to 10% MeOH:DCM) The final product was collected as a solid, 0.722 g (76%)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Methyl-1-(1-methyl-4-piperidinyl)-1H-pyrazol-5-amine (500 mg, 2.57 mmol) and ethyl 4-cyclopropyl-2,4-dioxobutanoate (474 mg, 2.57 mmol) were suspended in Toluene (10 mL) and heated at 70° C. for 5 h. The solvent was removed in vacuo and the crude residue was purified via silica gel chromatography (eluent: gradient of 0 to 10% MeOH:DCM). The final product was collected as a solid, 0.722 g (76%). LCMS E-S (M+H)=343.1 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.11 (m, 4H), 1.38 (t, J=7.07 Hz, 3H), 1.83 (d, J=6.06 Hz, 2H), 2.12-2.22 (m, 4H), 2.27 (s, 3H), 2.35 (m, J=7.83, 7.83, 5.05, 4.80 Hz, 1H), 2.54 (s, 3H), 2.94 (d, J=6.57 Hz, 2H), 4.42 (q, J=7.16 Hz, 2H), 4.57-4.73 (m, 1H), 7.46 (s, 1H). The solvent was removed in vacuo the crude residue was purified via silica gel chromatography (eluent: gradient of 0 to 10% MeOH:DCM) The final product was collected as a solid, 0.722 g (76%)

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

Procedure: The title compound was prepared in the same manner as described for intermediate 37 using 1-(1-cyclohexyl)-3-methyl-1H-pyrazol-5-amine (500 mg, 2.79 mmol) and ethyl 4-cyclopropyl-2,4-dioxobutanoate (514 mg, 2.79 mmol). The final product was collected as a solid, 0.827 g (91%). LCMS E-S (M+H)=328.3 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01-1.10 (m, 3H), 1.20-1.30 (m, 1H), 1.37 (t, J=7.07 Hz, 3H), 1.41-1.52 (m, 2H), 1.70 (d, 1H), 1.79-1.98 (m, 6H), 2.30-2.38 (m, 1H), 2.54 (s, 3H), 4.42 (q, J=7.07 Hz, 2H), 4.60-4.74 (m, 1H), 7.44 (s, 1H). The final product was collected as a solid, 0.827 g (91%)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-(1-Cyclopropylethyl)-3-methyl-1H-pyrazol-5-amine (500 mg, 3.03 mmol) and ethyl 4-cyclopropyl-2,4-dioxobutanoate (557 mg, 3.03 mmol) were suspended in Toluene (10 mL) and heated at 70° C. for 16 h. The solvent was removed in vacuo and the crude residue was purified via silica gel chromatography (eluent: gradient of 0 to 10% EtOAc:Hex). The final product was collected as a solid, 0.722 g (76%). LCMS E-S (M+H)=314.3 1H NMR (400 MHz, DMSO-d6) ppm 0.17-0.32 (m, 2H), 0.39 (m, J=9.69, 4.82, 4.82, 4.67 Hz, 1H), 0.51-0.62 (m, 1H), 0.94-1.11 (m, 4H), 1.28-1.41 (m, 4H), 1.58 (d, J=6.82 Hz, 3H), 2.30-2.38 (m, 1H), 2.56 (s, 3H), 4.19 (dq, J=9.44, 6.87 Hz, 1H), 4.43 (q, J=7.07 Hz, 2H), 7.48 (s, 1H) The solvent was removed in vacuo the crude residue was purified via silica gel chromatography (eluent: gradient of 0 to 10% EtOAc:Hex) The final product was collected as a solid, 0.722 g (76%)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-(1-Cyclopropylethyl)-3-methyl-1H-pyrazol-5-amine (500 mg, 3.03 mmol) and ethyl 4-cyclopropyl-2,4-dioxobutanoate (557 mg, 3.03 mmol) were suspended in Toluene (10 mL) and heated at 70° C. for 16 h. The solvent was removed in vacuo and the crude residue was purified via silica gel chromatography (eluent: gradient of 0 to 10% EtOAc:Hex). The final product was collected as a solid, 0.722 g (76%). LCMS E-S (M+H)=314.3 1H NMR (400 MHz, DMSO-d6) ppm 0.17-0.32 (m, 2H), 0.39 (m, J=9.69, 4.82, 4.82, 4.67 Hz, 1H), 0.51-0.62 (m, 1H), 0.94-1.11 (m, 4H), 1.28-1.41 (m, 4H), 1.58 (d, J=6.82 Hz, 3H), 2.30-2.38 (m, 1H), 2.56 (s, 3H), 4.19 (dq, J=9.44, 6.87 Hz, 1H), 4.43 (q, J=7.07 Hz, 2H), 7.48 (s, 1H) The solvent was removed in vacuo the crude residue was purified via silica gel chromatography (eluent: gradient of 0 to 10% EtOAc:Hex) The final product was collected as a solid, 0.722 g (76%)

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

Procedure: The title compound was prepared in the same manner as described for intermediate 33 using ethyl 4-cyclopropyl-2,4-dioxobutanoate (481 mg, 2.61 mmol), 1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-amine (400 mg, 2.61 mmol), and toluene (20 mL), wherein the reaction time was 3 h. The crude product was purified via silica gel chromatography (eluent: 0 to 10% EtOAc:Hex). The final product was collected as 0.24 g (30%). LCMS E-S (M+H)=302.5. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.02-1.23 (m, 4H) 1.47 (t, J=7.20 Hz, 3H) 1.79 (s, 9H) 2.19 (s, 1H) 2.66 (s, 3H) 4.49 (q, J=7.07 Hz, 2H) 7.44 (s, 1H). The crude product was purified via silica gel chromatography (eluent: 0 to 10% EtOAc:Hex) The final product was collected as 0.24 g (30%)