aminourea;hydrochloride

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1672 g of semicarbazide hydrochloride is dissolved in 2 liters of water, and neutralised, with cooling, with 600 g of sodium hydroxide in 1 liter of water. After the addition dropwise of 795 g of acrylonitrile, the mixture is heated for 7 hours at 80° C. and then allowed to stand for 4 hours at 0° C.; the precipitated crystalline product is subsequently filtered off, and dried under vacuum. There is obtained 1152 g of white product having a melting point of 125°-128° C. the precipitated crystalline product is subsequently filtered off dried under vacuum

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

Procedure: To a stirred solution of 1-[(E)-2-(4-fluoro-2-nitrophenyl)ethenyl]pyrrolidine (77.25 g, 0.327 mol) in warm MeOH (500 mL) was added a solution of semicarbazide HCl (38.3 g, 0.343 mol) in warm water (200 mL). The reaction mixture was stirred at room temperature for 1 h and was then cooled in ice and filtered. The solid was washed with cold 1:1 MeOH/water (2×30 mL) and dried to give 71 g (90% over two steps) of the title compound. was then cooled in ice filtered The solid was washed with cold 1:1 MeOH/water (2×30 mL) dried

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

Procedure: 1-Chloro-3-(5-chloropyrid-2-yloxy)propan-2-one (400 mg.) was dissolved in ethanol (4 ml.) with warming, and stirred while a solution of semicarbazide hydrochloride (223 mg.) in water (2 ml.) was added. The mixture was cooled in ice for 11/2 hours and filtered, and the filter cake was washed with a 1:1 v/v mixture of ethanol and water (1 ml.), then with water (3 × 1 ml.). The product was dried in a desiccator over silica gel to give 1-chloro-3-(5-chloropyrid-2-yloxy)-2-semicarbazonopropane, RF = 0.72 (5% v/v methanol in ethyl acetate), m.p. 115°-117° C. with warming was added The mixture was cooled in ice for 11/2 hours filtered the filter cake was washed with a 1:1 v/v mixture of ethanol and water (1 ml.) The product was dried in a desiccator over silica gel

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

Procedure: A mixture of 50 g. (0.44 mole) of 2-chloropyridine and 98.22 g. (0.88 mole) of semicarbazide hydrocloride in 150 ml. of 2-ethoxyethanol was heated to reflux and then treated with a solution of 1 ml. of concentrated sulfuric acid (36 N) in 5 ml. of 2-ethoxyethanol. The resulting solution was refluxed for 18 hr., cooled to about 60°, and treated with 150 ml. of water. The mixture was stirred, cooled to 0°, and kept 0.5 hr. and the solid was collected on a filter. The solid was washed well with water and dried under reduced pressure, to give 35.0 g. (59%) of product, m.p. 230°-231°, which was sufficiently pure to be used for the next step. A mixture of 50 g to reflux treated with a solution of 1 ml The resulting solution was refluxed for 18 hr , cooled to about 60° treated with 150 ml cooled to 0° and the solid was collected on a filter The solid was washed well with water dried under reduced pressure to give 35.0 g

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

Procedure: To a 3 L round bottom flask was added (r)-Pulegone (300 g, 1.97 mol), anhydrous NaHCO3 (82 g, 0.99 mol) and Ether (1.5 L). The mixture was cooled to −5° C. ice-salt bath under N2. Then bromine (101 mL, 1.97 mol) was added dropwise over 45 minutes. The mixture was filtered and carefully added dropwise (addition is exothermic in nature) to NaOEt (20 wt %, 4.3 mol) cooled at 0° C. The reaction was allowed to stir with warming to ambient temperature overnight. Then 1 L of 5% HCl and 300 mL of ether was added. The aqueous phase was extracted with ether and the combined organic layers washed with brine, dried with MgSO4 and concentrated. The resulting brown oil diluted with EtOH was added to a warm solution of semicarbazide HCl (150 g, 1.3 mol), NaOAc (150 g, 1.8 mol) and H2O (2 L) to give a brownish solution. The mixture was then refluxed for 3 hours and stirred at ambient temperature overnight. The mixture was treated with 1 L of water and 500 mL of ether. The aqueous phase was extracted with ether. The combined organic layers were dried with MgSO4 and concentrated to give a brown oil. The oil was subject to vacuum distillation, and the title compound (247 g, 64% yield) was collected at 73-76° C. The mixture was filtered carefully added dropwise cooled at 0° C with warming to ambient temperature overnight The aqueous phase was extracted with ether the combined organic layers washed with brine dried with MgSO4 concentrated The resulting brown oil diluted with EtOH to give a brownish solution The mixture was then refluxed for 3 hours stirred at ambient temperature overnight The aqueous phase was extracted with ether The combined organic layers were dried with MgSO4 concentrated to give a brown oil The oil was subject to vacuum distillation

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

Procedure: A mixture of 3-[2-(2-oxocyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (231 mg), semicarbazide hydrochloride (101 mg), potassium carbonate (125 mg), water (2 ml), and ethanol (10 ml) was heated under reflux for 4 hours. Ethanol was evaporated in vacuo and the residue was partitioned between dichloromethane (30 ml) and saturated aqueous sodium bicarbonate (30 ml). After an additional extraction with dichloromethane, the combined extracts were washed with brine (20 ml), dried over anhydrous sodium sulfate, and evaporated in vacuo to give colorless crystals of 3-[2-(2-carbamoylhydrazonocyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (125.8 mg). was heated under reflux for 4 hours Ethanol was evaporated in vacuo the residue was partitioned between dichloromethane (30 ml) and saturated aqueous sodium bicarbonate (30 ml) After an additional extraction with dichloromethane the combined extracts were washed with brine (20 ml) dried over anhydrous sodium sulfate evaporated in vacuo

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

Procedure: A mixture of 3-[2-(2-oxocyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (231 mg), semicarbazide hydrochloride (101 mg), potassium carbonate (125 mg), water (2 ml), and ethanol (10 ml) was heated under reflux for 4 hours. Ethanol was evaporated in vacuo and the residue was partitioned between dichloromethane (30 ml) and saturated aqueous sodium bicarbonate (30 ml). After an additional extraction with dichloromethane, the combined extracts were washed with brine (20 ml), dried over anhydrous sodium sulfate, and evaporated in vacuo to give colorless crystals of 3-[2-(2-carbamoylhydrazonocyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (125.8 mg). was heated under reflux for 4 hours Ethanol was evaporated in vacuo the residue was partitioned between dichloromethane (30 ml) and saturated aqueous sodium bicarbonate (30 ml) After an additional extraction with dichloromethane the combined extracts were washed with brine (20 ml) dried over anhydrous sodium sulfate evaporated in vacuo

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

Procedure: To a mixture of 2.1 g. (0.0079 mole) of 2-nitro-3-phenylbenzofuran-7-carboxaldehyde in 70 ml. of ethanol is added 1.34 g. (0.012 mole) of semicarbazide hydrochloride and 1.07 g. (0.013 mole) of sodium acetate. The mixture is heated to its reflux temperature and maintained at reflux for 3 hours. The precipitated product is separated by filtration, washed with water and diethyl ether. The solid is washed with hot dichloroethane, separated by filtration, then dissolved in a mixture of 650 ml. of chloroform and 100 ml. of acetone by heating. This solution is washed twice with water, once with sodium bicarbonate solution, again with water, once with dilute hydrochloric acid, and twice with water. The solution is dried and the dry solution is evaporated to provide solid 2-nitro-3-phenylbenzofuran-7-carboxaldehyde semicarbazone, m.p. 249° C. (dec.). To a mixture of 2.1 g The mixture is heated to its reflux temperature maintained at reflux for 3 hours The precipitated product is separated by filtration washed with water and diethyl ether The solid is washed with hot dichloroethane separated by filtration dissolved in a mixture of 650 ml of acetone by heating This solution is washed twice with water, once with sodium bicarbonate solution, again with water, once with dilute hydrochloric acid The solution is dried the dry solution is evaporated

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

Procedure: To a mixture of 2.1 g. (0.0079 mole) of 2-nitro-3-phenylbenzofuran-7-carboxaldehyde in 70 ml. of ethanol is added 1.34 g. (0.012 mole) of semicarbazide hydrochloride and 1.07 g. (0.013 mole) of sodium acetate. The mixture is heated to its reflux temperature and maintained at reflux for 3 hours. The precipitated product is separated by filtration, washed with water and diethyl ether. The solid is washed with hot dichloroethane, separated by filtration, then dissolved in a mixture of 650 ml. of chloroform and 100 ml. of acetone by heating. This solution is washed twice with water, once with sodium bicarbonate solution, again with water, once with dilute hydrochloric acid, and twice with water. The solution is dried and the dry solution is evaporated to provide solid 2-nitro-3-phenylbenzofuran-7-carboxaldehyde semicarbazone, m.p. 249° C. (dec.). To a mixture of 2.1 g The mixture is heated to its reflux temperature maintained at reflux for 3 hours The precipitated product is separated by filtration washed with water and diethyl ether The solid is washed with hot dichloroethane separated by filtration dissolved in a mixture of 650 ml of acetone by heating This solution is washed twice with water, once with sodium bicarbonate solution, again with water, once with dilute hydrochloric acid The solution is dried the dry solution is evaporated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 11 g (0.05 mol) of 3,5-dimethyl-4-hydroxybenzenesulphonic acid chloride and 6 g (0.05mol) of semicarbazide hydrochloride are first introduced into 50 ml of dimethylacetamide. 10 ml of 10 N sodium hydroxide solution are added dropwise to this white suspension over the course of 15 minutes at 40° C., whilst stirring. Since the reaction is exothermic, slight cooling must be applied. The mixture is then stirred for a further 4 hours at 40° C. After cooling to 0° C., the sodium chloride which has precipitated is filtered off and the filtrate is concentrated completely under reduced pressure. The residue is dissolved in a small amount of water and is cooled to 0°-5° C. Hereupon, 3.5-dimethyl-4-hydroxybenzenesulphonylsemicarbazide, of melting point 243° C. (with decomposition), crystallises out. slight cooling must The mixture is then stirred for a further 4 hours at 40° C the sodium chloride which has precipitated is filtered off the filtrate is concentrated completely under reduced pressure The residue is dissolved in a small amount of water is cooled to 0°-5° C Hereupon, 3.5-dimethyl-4-hydroxybenzenesulphonylsemicarbazide, of melting point 243° C. (with decomposition), crystallises out

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 11 g (0.05 mol) of 3,5-dimethyl-4-hydroxybenzenesulphonic acid chloride and 6 g (0.05mol) of semicarbazide hydrochloride are first introduced into 50 ml of dimethylacetamide. 10 ml of 10 N sodium hydroxide solution are added dropwise to this white suspension over the course of 15 minutes at 40° C., whilst stirring. Since the reaction is exothermic, slight cooling must be applied. The mixture is then stirred for a further 4 hours at 40° C. After cooling to 0° C., the sodium chloride which has precipitated is filtered off and the filtrate is concentrated completely under reduced pressure. The residue is dissolved in a small amount of water and is cooled to 0°-5° C. Hereupon, 3.5-dimethyl-4-hydroxybenzenesulphonylsemicarbazide, of melting point 243° C. (with decomposition), crystallises out. slight cooling must The mixture is then stirred for a further 4 hours at 40° C the sodium chloride which has precipitated is filtered off the filtrate is concentrated completely under reduced pressure The residue is dissolved in a small amount of water is cooled to 0°-5° C Hereupon, 3.5-dimethyl-4-hydroxybenzenesulphonylsemicarbazide, of melting point 243° C. (with decomposition), crystallises out

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

Procedure: A mixture of 600 mg (2.25 mmol) 17g and 329 mg (2.92 mmol) semicarbazide hydrochloride in 20 ml acetonitrile was heated 14 h under reflux. After that time, TLC indicated complete conversion of the starting product. After evaporation of the solvent, the crude product was recrystallised from aqueous ethanol, and compound 43 was obtained in slightly greenish crystals (90%). 1H-NMR (d6-DMSO, 400 MHz): δ (ppm)=7.40 (sl, 1H); 7.70 (sl, 1H); 7.71 (d, J=8 Hz, 1H); 8.17 (d, J=8 Hz, 1H); 8.89 (s, 1H); 10.95 (s, 1H). ESI+MS: calcd for C14H6ClN7O: 323.70; found: 324 (MH+). was heated 14 h under reflux After evaporation of the solvent the crude product was recrystallised from aqueous ethanol