(2,5-dioxopyrrolidin-1-yl) 2-cyanoacetate

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

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

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

Procedure: A mixture of N-methyl-N-[(3R,4R)-4-methylpiperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine (43.0 mg, 0.000176 mol) and 3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxopropanenitrile (38 mg, 0.00021 mol) in ethanol (1 mL, 0.02 mol) was stirred overnight. The reaction mixture was partitioned between ethyl acetate/THF and sat. NaHCO3, and the organic layer was washed by sat. NaCl. The solvent was removed under vacuum to give 100 mg of an orange solid which was chromatographed with 7% MeOH/DCM, 0.7% NH4OH to give 17 mg of pale orange solid. The crude product was triturated with Et2O and the resulting solid was filtered and washed to give 9.4 mg of wet pale orange solid which was dried at from room temperature to about 60° C. for 3.5 h to give 6.5 mg of the final product. The reaction mixture was partitioned between ethyl acetate/THF and sat. NaHCO3 the organic layer was washed by sat. NaCl The solvent was removed under vacuum

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

Procedure: Triethylamine (8.2 μL, 0.059 mmol) and ethanol (1.0 mL) were added to a solution of (3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-N-methylpyrrolidin-3-amine (8.5 mg, 0.020 mmol) in methylene chloride (0.50 mL), followed by addition of 3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxopropanenitrile (7.2 mg, 0.039 mmol) and the mixture was stirred overnight at room temperature. The mixture was then diluted with methanol and purified by preparative LCMS using pH 10 buffer to give the title compound (1.4 mg, 14%). LCMS calc. for C27H28N7O3 (M+H)+: m/z=498.2. found: 498.3. purified by preparative LCMS

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

Procedure: Triethylamine (33 μL, 0.24 mmol) and 3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxopropane nitrile (prepared as described in BE875054(A1), 51 mg, 0.28 mmol) were added to a solution of (R)-3-(4-(piperidin-3-ylamino)pyrimidin-2-ylamino)pyridin-2(1H)-one (Preparation 19c, 67 mg, 0.23 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at ambient temperature for 24 hours and solvent was evaporated. Water was added and the mixture was extracted with dichloromethane. The organic layer was dried (MgSO4), evaporated under reduced pressure and the residue was purified by reverse phase chromatography (C-18 silica from Waters©, water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give the title compound (11 mg, 12%) as a solid. solvent was evaporated Water was added the mixture was extracted with dichloromethane The organic layer was dried (MgSO4) evaporated under reduced pressure the residue was purified by reverse phase chromatography (C-18 silica from Waters©, water/acetonitrile/methanol as eluents [0.1% v/v formic acid

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

Procedure: Triethylamine (33 μL, 0.24 mmol) and 3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxopropane nitrile (prepared as described in BE875054(A1), 51 mg, 0.28 mmol) were added to a solution of (R)-3-(4-(piperidin-3-ylamino)pyrimidin-2-ylamino)pyridin-2(1H)-one (Preparation 19c, 67 mg, 0.23 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at ambient temperature for 24 hours and solvent was evaporated. Water was added and the mixture was extracted with dichloromethane. The organic layer was dried (MgSO4), evaporated under reduced pressure and the residue was purified by reverse phase chromatography (C-18 silica from Waters©, water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give the title compound (11 mg, 12%) as a solid. solvent was evaporated Water was added the mixture was extracted with dichloromethane The organic layer was dried (MgSO4) evaporated under reduced pressure the residue was purified by reverse phase chromatography (C-18 silica from Waters©, water/acetonitrile/methanol as eluents [0.1% v/v formic acid

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

Procedure: A mixture of N-methyl-N-[(3R,4R)-4-methylpiperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine (43.0 mg, 0.000176 mol) and 3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxopropanenitrile (38 mg, 0.00021 mol) in ethanol (1 mL, 0.02 mol) was stirred overnight. The reaction mixture was partitioned between ethyl acetate/THF and sat. NaHCO3, and the organic layer was washed by sat. NaCl. The solvent was removed under vacuum to give 100 mg of an orange solid which was chromatographed with 7% MeOH/DCM, 0.7% NH4OH to give 17 mg of pale orange solid. The crude product was triturated with Et2O and the resulting solid was filtered and washed to give 9.4 mg of wet pale orange solid which was dried at from room temperature to about 60° C. for 3.5 h to give 6.5 mg of the final product. The reaction mixture was partitioned between ethyl acetate/THF and sat. NaHCO3 the organic layer was washed by sat. NaCl The solvent was removed under vacuum

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

Procedure: The desired compound was prepared according to the procedure of Example D94 using 6-chloro-12-(2-oxo-2-piperazin-1-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxopropanenitrile as the starting materials in 60% yield. LCMS for C26H26ClN8O3 (M+H)+: m/z=533.0.

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

Procedure: A mixture of N-methyl-N-[(3R,4R)-4-methylpiperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine (43.0 mg, 0.000176 mol) and 3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxopropanenitrile (38 mg, 0.00021 mol) in ethanol (1 mL, 0.02 mol) was stirred overnight. The reaction mixture was partitioned between ethyl acetate/THF and sat. NaHCO3, and the organic layer was washed by sat. NaCl. The solvent was removed under vacuum to give 100 mg of an orange solid which was chromatographed with 7% MeOH/DCM, 0.7% NH4OH to give 17 mg of pale orange solid. The crude product was triturated with Et2O and the resulting solid was filtered and washed to give 9.4 mg of wet pale orange solid which was dried at from room temperature to about 60° C. for 3.5 h to give 6.5 mg of the final product. The reaction mixture was partitioned between ethyl acetate/THF and sat. NaHCO3 the organic layer was washed by sat. NaCl The solvent was removed under vacuum

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

Procedure: A mixture of N-methyl-N-[(3R,4R)-4-methylpiperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine (43.0 mg, 0.000176 mol) and 3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxopropanenitrile (38 mg, 0.00021 mol) in ethanol (1 mL, 0.02 mol) was stirred overnight. The reaction mixture was partitioned between ethyl acetate/THF and sat. NaHCO3, and the organic layer was washed by sat. NaCl. The solvent was removed under vacuum to give 100 mg of an orange solid which was chromatographed with 7% MeOH/DCM, 0.7% NH4OH to give 17 mg of pale orange solid. The crude product was triturated with Et2O and the resulting solid was filtered and washed to give 9.4 mg of wet pale orange solid which was dried at from room temperature to about 60° C. for 3.5 h to give 6.5 mg of the final product. The reaction mixture was partitioned between ethyl acetate/THF and sat. NaHCO3 the organic layer was washed by sat. NaCl The solvent was removed under vacuum

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

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