methylthiourea

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

Procedure: A solution of ethyl 3-(bromoacetyl)isoxazole-3-carboxylate (100 mg, 0.40 mmol) and methylthiourea (69 mg, 0.76 mmol) in acetic acid (3.0 mL) was heated at 150° C. in the microwave for 15 minutes. Solvent was removed in vacuo to give the crude which was used without purification. MF=C10H11N3O3S; LCMS calculated for C10H11N3O3S; (M+H)+: m/z=254. Solvent was removed in vacuo to give the crude which was used without purification

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

Procedure: A mixture containing 70.0 g (0.36 mol) of ethyl 3-(4-pyridinyl)-3-oxopropionate, 98.1 g (1.09 mol) of N-methylthiourea, 55.0 g (0.36 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 551 ml of ethanol is heated under reflux during 2 h. The cooled mixture is treated with 34.9 ml (0.36 mol) of methanesulfonic acid in 143.6 ml of water and the precipitate recovered by filtration to afford 60.4 g of pure product as a white solid. is heated under reflux during 2 h the precipitate recovered by filtration

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

Procedure: A mixture containing 70.0 g (0.36 mol) of ethyl 3-(4-pyridinyl)-3-oxopropionate, 98.1 g (1.09 mol) of N-methylthiourea, 55.0 g (0.36 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 551 ml of ethanol is heated under reflux during 2 h. The cooled mixture is treated with 34.9 ml (0.36 mol) of methanesulfonic acid in 143.6 ml of water and the precipitate recovered by filtration to afford 60.4 g of pure product as a white solid. is heated under reflux during 2 h the precipitate recovered by filtration

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 45 g (0.5 mol) of N-methylthiourea, 54 g (1 mol) of sodium methylate, 200 ml of methanol and 80 g (0.5 mol) of malonic acid diethyl ester was boiled for 3 hours under reflux. 71 g (0.5 mol) of methyl iodide were then added dropwise at about 50° C. and the mixture was stirred for a further 0.5 hour at 50° C. The salt which crystallized out was filtered off and was then dissolved in 400 ml of water. The solution was neutralized by adding glacial acetic acid, the precipitate was then filtered off, and 80 g (93% of theory) of 1,6-dihydro-4-hydroxy-1-methyl-2-methylthio-6-oxo-pyrimidine were thus obtained in the form of a colorless powder of melting point 198° C. under reflux The salt which crystallized out was filtered off was then dissolved in 400 ml of water by adding glacial acetic acid the precipitate was then filtered off

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 45 g (0.5 mol) of N-methylthiourea, 54 g (1 mol) of sodium methylate, 200 ml of methanol and 80 g (0.5 mol) of malonic acid diethyl ester was boiled for 3 hours under reflux. 71 g (0.5 mol) of methyl iodide were then added dropwise at about 50° C. and the mixture was stirred for a further 0.5 hour at 50° C. The salt which crystallized out was filtered off and was then dissolved in 400 ml of water. The solution was neutralized by adding glacial acetic acid, the precipitate was then filtered off, and 80 g (93% of theory) of 1,6-dihydro-4-hydroxy-1-methyl-2-methylthio-6-oxo-pyrimidine were thus obtained in the form of a colorless powder of melting point 198° C. under reflux The salt which crystallized out was filtered off was then dissolved in 400 ml of water by adding glacial acetic acid the precipitate was then filtered off

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

Procedure: A reaction mixture containing 11.4 g (0.035 mole) of N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-4-bromoacetoacetamide, 150 ml of ethanol and 3.3 g (0.036 mole) of N-methylthiourea was refluxed for four hours. The reaction solution was poured into 300 ml of water and treated with excess aqueous sodium bicarbonate. The product was isolated and dried. There was obtained 9.5 g (87.2%) of white solid, m.p. 198°-200° (dec.). N.M.R. (CDCl3) ∂ 1.4 [C(CH3)3 ], 3.0 (CH3), 3.8 (CH2), 6.4 (hetero-aromatic). was refluxed for four hours The product was isolated dried

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

Procedure: A reaction mixture containing 11.4 g (0.035 mole) of N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-4-bromoacetoacetamide, 150 ml of ethanol and 3.3 g (0.036 mole) of N-methylthiourea was refluxed for four hours. The reaction solution was poured into 300 ml of water and treated with excess aqueous sodium bicarbonate. The product was isolated and dried. There was obtained 9.5 g (87.2%) of white solid, m.p. 198°-200° (dec.). N.M.R. (CDCl3) ∂ 1.4 [C(CH3)3 ], 3.0 (CH3), 3.8 (CH2), 6.4 (hetero-aromatic). was refluxed for four hours The product was isolated dried

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

Procedure: A solution containing 32.4 g (0.10 mole) of 4-bromo-3'-trifluoromethylacetoacetanilide and 11.3 g (0.13 mole) of N-methylthiourea in 250 ml of ethanol was refluxed for four hours. The reaction mixture was poured into 700 ml of water and ethanol was added. A small quantity of insoluble material was removed by filtration and the filtrate was made strongly alkaline by the addition of ammonium hydroxide. The solution was cooled and an additional 400 ml of water was added. The precipitated solid was collected and dried in an oven. There was obtained 25.5 g (81%) of product, m.p. 153°-55°. N.M.R. (dimethyl-d6 sulfoxide) ∂ 2.8-2.9 (CH3, doublet), 3.5 (CH2), 6.3 (hetero-aromatic), 7.3-8.1 (aromatic, NH), 10.4 (HNC=0). was refluxed for four hours was added A small quantity of insoluble material was removed by filtration by the addition of ammonium hydroxide The solution was cooled an additional 400 ml of water was added The precipitated solid was collected dried in an oven

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

Procedure: A solution containing 32.4 g (0.10 mole) of 4-bromo-3'-trifluoromethylacetoacetanilide and 11.3 g (0.13 mole) of N-methylthiourea in 250 ml of ethanol was refluxed for four hours. The reaction mixture was poured into 700 ml of water and ethanol was added. A small quantity of insoluble material was removed by filtration and the filtrate was made strongly alkaline by the addition of ammonium hydroxide. The solution was cooled and an additional 400 ml of water was added. The precipitated solid was collected and dried in an oven. There was obtained 25.5 g (81%) of product, m.p. 153°-55°. N.M.R. (dimethyl-d6 sulfoxide) ∂ 2.8-2.9 (CH3, doublet), 3.5 (CH2), 6.3 (hetero-aromatic), 7.3-8.1 (aromatic, NH), 10.4 (HNC=0). was refluxed for four hours was added A small quantity of insoluble material was removed by filtration by the addition of ammonium hydroxide The solution was cooled an additional 400 ml of water was added The precipitated solid was collected dried in an oven

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

Procedure: To an ice-cooled solution of 5-(2-fluoro-4-biphenylyl)-4-oxohexanoic acid (500 mg, 1.52 mmoles) in diethyl ether (10 ml) was added dropwise bromine (243 mg, 1.52 mmoles) and the resulting mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated under reduced pressure. A mixture of the afforded residue, N-methylthiourea (164 mg, 1.82 mmoles) and methanol was stirred at 50° C. for 2 hours and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduce pressure. Purification of the residue by medium pressure silica gel column chromatography gave the desired ethyl 2-(4-(1-(2-fluoro-4-biphenylyl)ethyl)-2-methylamino-5-thiazolyl)acetate (209 mg, 0.524 mmole, yield 35%) as a yellow oil. The reaction mixture was concentrated under reduced pressure was stirred at 50° C. for 2 hours concentrated under reduced pressure The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate The organic layer was washed with water dried over sodium sulfate concentrated Purification of the residue by medium pressure silica gel column chromatography

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

Procedure: To an ice-cooled solution of 5-(2-fluoro-4-biphenylyl)-4-oxohexanoic acid (500 mg, 1.52 mmoles) in diethyl ether (10 ml) was added dropwise bromine (243 mg, 1.52 mmoles) and the resulting mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated under reduced pressure. A mixture of the afforded residue, N-methylthiourea (164 mg, 1.82 mmoles) and methanol was stirred at 50° C. for 2 hours and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduce pressure. Purification of the residue by medium pressure silica gel column chromatography gave the desired ethyl 2-(4-(1-(2-fluoro-4-biphenylyl)ethyl)-2-methylamino-5-thiazolyl)acetate (209 mg, 0.524 mmole, yield 35%) as a yellow oil. The reaction mixture was concentrated under reduced pressure was stirred at 50° C. for 2 hours concentrated under reduced pressure The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate The organic layer was washed with water dried over sodium sulfate concentrated Purification of the residue by medium pressure silica gel column chromatography

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

Procedure: A suspension of 3-(3-fluoropyridin-4-yl)-3-oxo-propionic acid ethyl ester (60.3 g, 286 mmol), N-methylthiourea (88 g, 976 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (48 g, 315 mmol) in toluene (600 ml) was heated at 100° C. for 5 hour. After addition of water (2000 ml) and methanesulfonic acid (30.3 g, 315 mmol) at room temperature and stirring for one hour, resulting precipitate was collected by filtration and dried to afford 6-(3-fluoropyridin-4-yl)-2-mercapto-3-methyl-3H-pyrimidin-4-one (46.3 g, 195 mmol, 68%) as white crystals. resulting precipitate was collected by filtration dried