N-ethylethanamine;hydrochloride

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

Procedure: 3-[5-(N-methylsulfamoyl)-1,3,4-thiadiazol-2-yl]-1,1-dimethylurea, from 4 g. of the carbamic acid, phenyl ester, above, and 3 g. of diethylamine hydrochloride. The product had a melting point of about 152°-153° C. and weighed 1.5 g.

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

Procedure: 3-[5-(N-methylsulfamoyl)-1,3,4-thiadiazol-2-yl]-1,1-dimethylurea, from 4 g. of the carbamic acid, phenyl ester, above, and 3 g. of diethylamine hydrochloride. The product had a melting point of about 152°-153° C. and weighed 1.5 g.

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

Procedure: O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.380 g, 1.0 mmol) was added to 2-amino-4-phenyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (0.187 g, 0.69 mmol). This mixture was suspended in dimethylformamide (DMF) (5.0 ml) and diisopropylethylamine (0.696 ml; 4.0 mmol) added to afford a yellow solution. Diethylamine hydrochloride (0.122 g; 5.0 mmol) was added and the reaction mixture was heated for ten minutes at 100° C. in a sealed vial in a microwave synthesiser. DMF was removed in vacuo and the residue was partitioned between ethyl acetate (30 ml) and water (30 ml). The phases were separated and the organic phase was washed with saturated sodium chloride solution and dried over sodium sulphate. Mixture was filtered and the filtrate solvents were removed in vacuo to leave a yellow solid which was adsorbed onto silica gel and purified by flash chromatography on silica gel (20 g), eluting with a solvent gradient of 15 to 50% ethyl acetate in hexane. This affords 2-amino-4-phenyl-thieno[2,3-d]pyrimidine-6-carboxylic acid ethylamide as a pale yellow solid (0.051 g; 25%). to afford a yellow solution DMF was removed in vacuo the residue was partitioned between ethyl acetate (30 ml) and water (30 ml) The phases were separated the organic phase was washed with saturated sodium chloride solution dried over sodium sulphate Mixture was filtered the filtrate solvents were removed in vacuo to leave a yellow solid which purified by flash chromatography on silica gel (20 g) eluting with a solvent gradient of 15 to 50% ethyl acetate in hexane

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

Procedure: A mixture containing 8.2 g. of 4-chloro-6-methyl-2-(4-pyridinyl)pyrimidine, 8.7 g. of diethylamine hydrochloride, 100 ml. of ethanol, 6 g. of potassium carbonate and 10 ml. of water was refluxed with stirring for eight hours and then concentrated in vacuo to dryness. The residue was swirled in water and the solid collected. The solid was dissolved in boiling isopropyl alcohol, the hot solution treated with decolorizing charcoal and filtered, and the hot filtrate allowed to cool. The filtrate was then saturated with gaseous hydrogen chloride, ether was added to turbidity and the mixture was allowed to stand. The separated solid was collected and dried in vacuo at 80° C. to yield 7.4 g. of N,N-diethyl-6-methyl-2-(4-pyridinyl)-4-pyrimidinamine dihydrochloride, m.p. 205°-208° C. A mixture containing 8.2 g concentrated in vacuo to dryness the solid collected The solid was dissolved the hot solution treated with decolorizing charcoal filtered to cool saturated with gaseous hydrogen chloride, ether was added to turbidity The separated solid was collected dried in vacuo at 80° C. to yield 7.4 g

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

Procedure: To a solution of 132.6 g of o-nitrobenzenesulfonyl chloride in 700 ml of tetrahydrofuran was added 88.5 g of diethylamine at 5°-15°. The reaction mixture was stirred at room temperature for 1 hour before the precipitated diethylamine hydrochloride was removed by filtration. The filtrate was evaporated to dryness in-vacuo and the residue dissolved in 1-chlorobutane. The 1-chlorobutane solution was washed with water, dried over magnesium sulfate and evaporated in-vacuo to give 122.4 g of o-nitro-N,N-diethylbenzenesulfonamide as a dark oil. was removed by filtration The filtrate was evaporated to dryness in-vacuo the residue dissolved in 1-chlorobutane The 1-chlorobutane solution was washed with water dried over magnesium sulfate evaporated in-vacuo

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

Procedure: 2-Formylvinyl phenyl ether is prepared by treating phenoxyacetaldehyde with formaldehyde and diethylamine hydrochloride salt. The ether is then reacting with a solution of diethylphosphonoacetic acid and n-butyllithium in anhydrous tetrahydrofuran (THF) to form 5-phenoxy-2,4-pentadienoic acid. 5-Phenyl-2,4-pentadienal is obtained by first converting the carboxylic acid to a Weinreb amide using oxalyl chloride followed by N,O-dimethylhydroxylamine. Subsequently, reduction of the Weinreb amide with lithium aluminum hydride (LAH) in THF leads to the formation of 5-phenoxy-2,4-pentadienal. The synthesis is summarized in Scheme II.

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

Procedure: A solution of diethylamine hydrochloride (1 g) in sulfuryl chloride (10 ml) was heated at 50° C. for 4 hours. The solution was allowed to cool to ambient temperature and sulfuryl cloride was evaporated in vacuo. To the residue were added ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give diethylsulfamoyl chloride (720 mg) as a colorless oil. sulfuryl cloride was evaporated in vacuo To the residue were added ethyl acetate and water The organic layer was washed with brine dried over anhydrous magnesium sulfate concentrated in vacuo

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diethylamine hydrochloride (0.33 g) was added to a stirred mixture of N-[5-(4-cyanobenzamido)-2-methylphenyl]-3-chloromethylbenzamide (0.4 g), potassium carbonate (0.5 g) and acetone (6 ml) and the reaction mixture was stirred and heated to 55° C. for 16 hours. The reaction mixture was evaporated and the residue was triturated under water. The solid was isolated and dried under vacuum at 55° C. to give the title compound (0.24 g); NMR spectrum: (DMSOd6) 0.95 (t, 6H), 2.19 (s, 3H), 3.58 (s, 2H), 7.22 (d, 1H), 7.5 (m, 3H), 7.85 (m, 3H), 7.99 (d, 2H), 8.12 (d, 2H); Mass Spectrum: M−H− 439. The reaction mixture was evaporated the residue was triturated under water The solid was isolated dried under vacuum at 55° C.

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diethylamine hydrochloride (0.33 g) was added to a stirred mixture of N-[5-(4-cyanobenzamido)-2-methylphenyl]-3-chloromethylbenzamide (0.4 g), potassium carbonate (0.5 g) and acetone (6 ml) and the reaction mixture was stirred and heated to 55° C. for 16 hours. The reaction mixture was evaporated and the residue was triturated under water. The solid was isolated and dried under vacuum at 55° C. to give the title compound (0.24 g); NMR spectrum: (DMSOd6) 0.95 (t, 6H), 2.19 (s, 3H), 3.58 (s, 2H), 7.22 (d, 1H), 7.5 (m, 3H), 7.85 (m, 3H), 7.99 (d, 2H), 8.12 (d, 2H); Mass Spectrum: M−H− 439. The reaction mixture was evaporated the residue was triturated under water The solid was isolated dried under vacuum at 55° C.

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diethylamine hydrochloride (0.024 g) was added to a stirred mixture of N-[5-(4-cyanoberizamido)-2-methylphenyl]-4-(chloromethyl)benzamide (0.06 g), potassium carbonate (0.082 g) and acetone (5 ml) and the reaction mixture was stirred and heated to 55° C. for 16 hours. Further portions of diethylamine hydrochloride and potassium carbonate (same quanities as before) were added and the mixture was heated to 55° C. for a further 4 days. The reaction mixture was evaporated and the residue was triturated with water. The solid was isolated and dried under vacuum at 55° C. to give the title compound as a solid (0.044 g); NMR Spectrum: (CDCl3) 1.06 (t, 6H), 2.28 (s, 3H), 2.53 (m, 4H), 3.63 (s, 2H), 7.2 (d, 1H), 7.5 (d, 2H), 7.74 (m, 4H), 7.81 (d, 2H), 7.97 (d, 2H), 8.15 (s, 1H), 8.27 (s, 1H); Mass Spectrum: M−H− 439. the mixture was heated to 55° C. for a further 4 days The reaction mixture was evaporated the residue was triturated with water The solid was isolated dried under vacuum at 55° C.

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

Procedure: A three-neck round-bottom flask with fitted KPG stirrer, reflux condenser and dropping funnel is initially charged with 44.0 g of paraformaldehyde (95%), 105.5 g of demineralized water and 233.4 g of diethylamine hydrochloride, followed by the addition of 100.1 g of ethylphosphonous acid (96.3%) (prepared according to example 1) during 6 h at 110° C. with stirring. The pH of the reaction solution is adjusted to below 1 with 8 g of 37% hydrochloric acid. After one hour of refluxing, a solution of ethyldiethylaminomethylphosphinic acid is obtained. A three-neck round-bottom flask with fitted KPG stirrer, reflux condenser After one hour of refluxing

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

Procedure: A three-neck round-bottom flask with fitted KPG stirrer, reflux condenser and dropping funnel is initially charged with 44.0 g of paraformaldehyde (95%), 105.5 g of demineralized water and 233.4 g of diethylamine hydrochloride, followed by the addition of 100.1 g of ethylphosphonous acid (96.3%) (prepared according to example 1) during 6 h at 110° C. with stirring. The pH of the reaction solution is adjusted to below 1 with 8 g of 37% hydrochloric acid. After one hour of refluxing, a solution of ethyldiethylaminomethylphosphinic acid is obtained. A three-neck round-bottom flask with fitted KPG stirrer, reflux condenser After one hour of refluxing