1,3-diazinan-2-one

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

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

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

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

Procedure: 20.0 g of N,N'-trimethyleneurea are partially dissolved in 1000 ml of toluene under reflux and admixed with 20.2 g of triethylamine and then dropwise, in the course of 90 minutes, with a solution of 25.4 g of 3-chloropropionyl chloride. Subsequent stirring for 30 minutes, cooling down to 5° C., removal of undissolved matter by filtration and evaporating the filtrate in vacuo gives 24 g of chloropropionylurea of the formula ##STR70## as a beige powder. under reflux in the course of 90 minutes removal of undissolved matter by filtration evaporating the filtrate in vacuo

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: To a mixture of tetrahydro-2-pyrimidone (0.040 g, 0.4 mmol), 5-bromo-N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide (0.050 g, 0.13 mmol), and Cu2O (0.0095 g, 0.07 mmol) under an atmosphere of argon was added pyridine (1.0 mL) and the suspension was stirred at reflux for 16 hr. Cu2O (0.005 g, 0.04 mmol) was added and the reaction heated at 115 C for a further 16 hr. The reaction was allowed to cool to room temperature and the solvent evaporated in vacuo. The residue was treated with DMF (2 mL) and filtered to remove the solids. TFA (0.5 mL) was added to the filtrate which was purified by reverse phase HPLC. (Waters PrePak 500 cartridge C18, Gradient elution with Water:Acetonitrile 95:5 to 5:95 with 0.1% TFA at 75 mL/min over 45 mins). Lyophilization of the pure fractions afforded the title compound as an off white solid. at reflux for 16 hr the reaction heated at 115 C for a further 16 hr the solvent evaporated in vacuo The residue was treated with DMF (2 mL) filtered to remove the solids TFA (0.5 mL) was added to the filtrate which was purified by reverse phase HPLC (Waters PrePak 500 cartridge C18, Gradient elution with Water:Acetonitrile 95:5 to 5:95 with 0.1% TFA at 75 mL/min over 45 mins)

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

Procedure: To a solution of 5-bromo-1-methyl-1H-indazole (76 mg, 0.36 mmol) in 1,4-dioxane (5 mL) was added tetrahydropyrimidin-2(1H)-one (Aldrich, 216 mg, 2.16 mmol), followed by Pd2(dba)3 (16 mg, 0.02 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (31 mg, 0.06 mmol) and cesium carbonate (176 mg, 0.54 mmol). The reaction mixture was degassed with nitrogen and heated at 100° C. for 16 hours. The mixture was diluted with ethyl acetate, washed with water and brine, and dried over Na2SO4 and filtered. Concentration and purification by flash column chromatography (hexanes/EtOAc) yielded 1-(1-methyl-1H-indazol-5-yl)tetrahydropyrimidin-2(1H)-one. LCMS-ESI+: calc'd for C12H14N4O: 231.2 (M+H+); Found: 231.2 (M+H+). The reaction mixture was degassed with nitrogen The mixture was diluted with ethyl acetate washed with water and brine dried over Na2SO4 filtered Concentration and purification by flash column chromatography (hexanes/EtOAc)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 1-6 prepared in Example 1 (80 mg, 0.18 mmol), tetrahydro-2-pyrimidinone (54 mg, 0.54 mmol), 1,2-trans-diaminocyclohexane (13 μL, 0.11 mmol) and K3PO4 (100 mg, 0.47 mmol) in dioxane (1 mL) was degassed with Ar before being charged with CuI (20 mg, 0.11 mmol). The mixture in a sealed tube was heated at 110° C. overnight. It was then purified by HPLC to give the title compound (4 mg). MS 416.1 and 418.1 (M+H, Cl pattern). was degassed with Ar It was then purified by HPLC

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

Procedure: To a solution of 5-bromo-1-methyl-1H-indazole (76 mg, 0.36 mmol) in 1,4-dioxane (5 mL) was added tetrahydropyrimidin-2(1H)-one (Aldrich, 216 mg, 2.16 mmol), followed by Pd2(dba)3 (16 mg, 0.02 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (31 mg, 0.06 mmol) and cesium carbonate (176 mg, 0.54 mmol). The reaction mixture was degassed with nitrogen and heated at 100° C. for 16 hours. The mixture was diluted with ethyl acetate, washed with water and brine, and dried over Na2SO4 and filtered. Concentration and purification by flash column chromatography (hexanes/EtOAc) yielded 1-(1-methyl-1H-indazol-5-yl)tetrahydropyrimidin-2(1H)-one. LCMS-ESI+: calc'd for C12H14N4O: 231.2 (M+H+); Found: 231.2 (M+H+). The reaction mixture was degassed with nitrogen The mixture was diluted with ethyl acetate washed with water and brine dried over Na2SO4 filtered Concentration and purification by flash column chromatography (hexanes/EtOAc)

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

Procedure: To a solution of 5-bromo-1-methyl-1H-indazole (76 mg, 0.36 mmol) in 1,4-dioxane (5 mL) was added tetrahydropyrimidin-2(1H)-one (Aldrich, 216 mg, 2.16 mmol), followed by Pd2(dba)3 (16 mg, 0.02 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (31 mg, 0.06 mmol) and cesium carbonate (176 mg, 0.54 mmol). The reaction mixture was degassed with nitrogen and heated at 100° C. for 16 hours. The mixture was diluted with ethyl acetate, washed with water and brine, and dried over Na2SO4 and filtered. Concentration and purification by flash column chromatography (hexanes/EtOAc) yielded 1-(1-methyl-1H-indazol-5-yl)tetrahydropyrimidin-2(1H)-one. LCMS-ESI+: calc'd for C12H14N4O: 231.2 (M+H+); Found: 231.2 (M+H+). The reaction mixture was degassed with nitrogen The mixture was diluted with ethyl acetate washed with water and brine dried over Na2SO4 filtered Concentration and purification by flash column chromatography (hexanes/EtOAc)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 1-6 prepared in Example 1 (80 mg, 0.18 mmol), tetrahydro-2-pyrimidinone (54 mg, 0.54 mmol), 1,2-trans-diaminocyclohexane (13 μL, 0.11 mmol) and K3PO4 (100 mg, 0.47 mmol) in dioxane (1 mL) was degassed with Ar before being charged with CuI (20 mg, 0.11 mmol). The mixture in a sealed tube was heated at 110° C. overnight. It was then purified by HPLC to give the title compound (4 mg). MS 416.1 and 418.1 (M+H, Cl pattern). was degassed with Ar It was then purified by HPLC