1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione

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

Procedure: 2-Benzylsulfanyl-3-nitro-pyridine (6 g, 24.39 mmol) was dissolved in dichloromethane (84 mL). Acetic acid (12 mL) and water (24 mL) were added. The mixture was chilled to 0° C. With vigorous stirring, 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione (14.4 g, 73.17 mmol) was added portionwise as a suspension in dichloromethane (48 mL). The mixture was allowed to slowly warm to 25° C. and continued to stir for 16 h. The mixture was poured into 5% aqueous sodium metabisulfite solution (100 mL) and shaken well. Dichloromethane (200 mL) and 20% aqueous dibasic potassium phosphate solution (100 mL) were added and the mixture was shaken well. The layers were separated. The crude desired product, 3-nitro-pyridine-2-sulfonyl chloride, dissolved in the organic layer was used directly in the next step without further isolation or characterization. to slowly warm to 25° C. shaken well the mixture was shaken well The layers were separated The crude desired product, 3-nitro-pyridine-2-sulfonyl chloride, dissolved in the organic layer

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

Procedure: A mixture of methyl 4-amino-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-picolinate (0.5 g, 1.52 mmol) and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.30 g, 1.52 mmol) in acetonitrile (10 mL) was heated to reflux for 1.5 h. Upon cooling to room temperature, the reaction mixture was concentrated under vacuum and then purified by silica gel chromatography (100% hexane to 100% EtOAc gradient) to give a light brown solid (0.53 g, 100%): mp 169-170.5° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.48 (d, J=8.4 Hz, 1H), 7.32 (t, J=7.7 Hz, 1H), 7.15 (s, 2H), 3.96 (s, 3H), 3.90 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 164.8 (s), 153.1 (d, J=253 Hz), 146.3 (s), 144.5 (d, J=4 Hz), 143.7 (s), 142.8 (dd, J=227, 14 Hz), 136.4 (d, J=13 Hz), 128.6 (d, J=3 Hz), 125.9 (s), 125.5 (d, J=4 Hz), 122.9 (dd, J=14, 4 Hz), 113.0 (d, J=3 Hz), 61.6 (d, J=4 Hz), 52.7 (s). Anal. Calcd for C14H10Cl2F2N2O3: C, 46.30; H, 2.78; N, 7.71. Found: C, 46.60; H, 2.68; N, 7.51. was heated to reflux for 1.5 h the reaction mixture was concentrated under vacuum purified by silica gel chromatography (100% hexane to 100% EtOAc gradient)

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

Procedure: 5 g (36.2 mmol) of anisyl alcohol, 3.0 g (36.6 mmol) of sodium acetate and 4.2 g (21.3 mmol) of dichlorodimethylhydantoin were suspended in 40 ml of methylene chloride in a 100 ml sulphonation flask. The suspension was cooled to 0° C. while stirring and treated with 10 mg (0.06 mmol) of TEMPO, whereupon the mixture was held at 0° C. for 16 hours. Thereafter, the reaction had finished without 4-chloro-anisole being formed in any amount worth mentioning. The white precipitate was filtered off and the filtrate was washed with sodium bicarbonate solution and with sodium chloride solution. Distillation of the crude product gave 4.49 g (91%) of anisaldehyde GC content: 88.8% (area percent). formed in any amount The white precipitate was filtered off the filtrate was washed with sodium bicarbonate solution and with sodium chloride solution Distillation of the crude product

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

Procedure: 2-Benzylsulfanyl-3-nitro-pyridine (6 g, 24.39 mmol) was dissolved in dichloromethane (84 mL). Acetic acid (12 mL) and water (24 mL) were added. The mixture was chilled to 0° C. With vigorous stirring, 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione (14.4 g, 73.17 mmol) was added portionwise as a suspension in dichloromethane (48 mL). The mixture was allowed to slowly warm to 25° C. and continued to stir for 16 h. The mixture was poured into 5% aqueous sodium metabisulfite solution (100 mL) and shaken well. Dichloromethane (200 mL) and 20% aqueous dibasic potassium phosphate solution (100 mL) were added and the mixture was shaken well. The layers were separated. The crude desired product, 3-nitro-pyridine-2-sulfonyl chloride, dissolved in the organic layer was used directly in the next step without further isolation or characterization. to slowly warm to 25° C. shaken well the mixture was shaken well The layers were separated The crude desired product, 3-nitro-pyridine-2-sulfonyl chloride, dissolved in the organic layer

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

Procedure: 2-Benzylsulfanyl-3-nitro-pyridine (6 g, 24.39 mmol) was dissolved in dichloromethane (84 mL). Acetic acid (12 mL) and water (24 mL) were added. The mixture was chilled to 0° C. With vigorous stirring, 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione (14.4 g, 73.17 mmol) was added portionwise as a suspension in dichloromethane (48 mL). The mixture was allowed to slowly warm to 25° C. and continued to stir for 16 h. The mixture was poured into 5% aqueous sodium metabisulfite solution (100 mL) and shaken well. Dichloromethane (200 mL) and 20% aqueous dibasic potassium phosphate solution (100 mL) were added and the mixture was shaken well. The layers were separated. The crude desired product, 3-nitro-pyridine-2-sulfonyl chloride, dissolved in the organic layer was used directly in the next step without further isolation or characterization. to slowly warm to 25° C. shaken well the mixture was shaken well The layers were separated The crude desired product, 3-nitro-pyridine-2-sulfonyl chloride, dissolved in the organic layer

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

Procedure: A mixture of 18 g (118 mmol) of methyl 3-aminoisonicotinate and 12 g (60 mmol) of 1,3-dichloro-5,5-dimethylhydantoin in 1500 mL of tetrachloroethylene was warmed slowly to 80° C. with stirring and held there for 3 hours. The solution was then cooled, filtered, washed with dilute aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain a dark oil. This oil was purified by careful column chromatography to give 6.7 g (30 percent of theory) of the title compound as a colorless solid melting at 91°-92° C. The solution was then cooled filtered washed with dilute aqueous sodium bicarbonate dried over magnesium sulfate filtered concentrated by evaporation under reduced pressure to obtain a dark oil This oil was purified by careful column chromatography

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

Procedure: A mixture of 18 g (118 mmol) of methyl 3-aminoisonicotinate and 12 g (60 mmol) of 1,3-dichloro-5,5-dimethylhydantoin in 1500 mL of tetrachloroethylene was warmed slowly to 80° C. with stirring and held there for 3 hours. The solution was then cooled, filtered, washed with dilute aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain a dark oil. This oil was purified by careful column chromatography to give 6.7 g (30 percent of theory) of the title compound as a colorless solid melting at 91°-92° C. The solution was then cooled filtered washed with dilute aqueous sodium bicarbonate dried over magnesium sulfate filtered concentrated by evaporation under reduced pressure to obtain a dark oil This oil was purified by careful column chromatography

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

Procedure: A solution of 8-amino-2-benzylthio[1,2,4]triazolo[1,5-a]pyridine (14.0 g, 0.0546 mol) and 1,3-dichloro-5,5-dimethylhydantoin (5.4 g, 0.0273 mol) were combined in 500 mL of dichloromethane and the mixture was heated at reflux with stirring for two hours. Additional 1,3-dichloro-5,5-dimethylhydantoin (5.0 g, 0.025 mol) was added and the reaction was heated with stirring for an additional hour. The reaction mixture was cooled and dilute aqueous sodium bisulfite was added with stirring and allowed to react for an hour. The mixture was then washed with water and the volatiles were removed by evaporation under reduced pressure. The residue obtained was chromatographed on silica gel eluting with dichloromethane to obtain 6.0 g (38 percent of theory) of the title compound as a light tan powder melting at 113°-114° C. the mixture was heated at reflux the reaction was heated with stirring for an additional hour The reaction mixture was cooled with stirring to react for an hour The mixture was then washed with water the volatiles were removed by evaporation under reduced pressure The residue obtained was chromatographed on silica gel eluting with dichloromethane

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

Procedure: 2-Benzylsulfanyl-3-nitro-pyridine (6 g, 24.39 mmol) was dissolved in dichloromethane (84 mL). Acetic acid (12 mL) and water (24 mL) were added. The mixture was chilled to 0° C. With vigorous stirring, 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione (14.4 g, 73.17 mmol) was added portionwise as a suspension in dichloromethane (48 mL). The mixture was allowed to slowly warm to 25° C. and continued to stir for 16 h. The mixture was poured into 5% aqueous sodium metabisulfite solution (100 mL) and shaken well. Dichloromethane (200 mL) and 20% aqueous dibasic potassium phosphate solution (100 mL) were added and the mixture was shaken well. The layers were separated. The crude desired product, 3-nitro-pyridine-2-sulfonyl chloride, dissolved in the organic layer was used directly in the next step without further isolation or characterization. to slowly warm to 25° C. shaken well the mixture was shaken well The layers were separated The crude desired product, 3-nitro-pyridine-2-sulfonyl chloride, dissolved in the organic layer