1-amino-3-ethylthiourea

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

Procedure: A solution of 7.0 g N-ethyl-N-[3-(6-chloro-3-pyridazinyl) phenyl]acetamide and 6.0 g 4-ethyl-3-thiosemicarbazide in 200 ml ethanol was refluxed for 18 hours. The mixture was then worked up and the product chromatographed as described in Example 70. Recrystalization of the product from dichloromethane-hexane afforded 2.1 g yellow flakes mp 171°-172° C. the product chromatographed Recrystalization of the product from dichloromethane-hexane afforded 2.1 g yellow flakes mp 171°-172° C.

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

Procedure: A solution of 6.0 g -N-methyl-N-[3-(6-chloro-3-pyridazinyl)phenyl]acetamide and 5.5 g 4-ethyl-3-thiosemicarbazide in 200 ml ethanol was refluxed for 18 hours and treated in similar fashion to Example 67. Chromatography on silica gel and recrystalization from dichloromethanehexane afforded 1.2 g yellow crystals, mp 225°-227° C. treated in similar fashion to Example 67 Chromatography on silica gel and recrystalization from dichloromethanehexane

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

Procedure: Utilizing the reaction conditions of Example 2, 9.3 g (0.04 mole) of 2,4-dichlorophenacyl chloride and 4.77 g (0.04 mole) of 4-ethylthiosemicarbazide are reacted in 200 ml of methanol to produce 6.5 g of 5-(2,4-dichlorophenyl)-N-ethyl-6H-1,3,4-thiadiazin-2-amine monohydrochloride after recrystallization which, in this case, was from methanol/ethyl acetate. m.p. 197°-198° C.

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

Procedure: 11.19 g of 4-ethyl-thiosemicarbazide and 17.6 g of 4-fluorophenacyl chloride are heated and stirred under reflux (65° C.) in 400 ml of methanol for 30 minutes in a one liter round bottom flask equipped with a magnetic stirring bar and a condenser protected by a CaCl2 drying tube. The solution is allowed to cool to room temperature and is then concentrated to a yellow solid residue. The residue is recrystallized from methanol/butanone yielding 21.0 g (75.5%) of N-ethyl-5-(4-fluorophenyl)-6H-1,3,4-thiadiazin-2-amine hydrochloride. m.p. 192°-193° C. The fluffy, yellowish white solid is dried under high vacuum at 65° C. equipped with a magnetic stirring bar and a condenser protected by a CaCl2 drying tube is then concentrated to a yellow solid residue The residue is recrystallized from methanol/butanone yielding 21.0 g (75.5%) of N-ethyl-5-(4-fluorophenyl)-6H-1,3,4-thiadiazin-2-amine hydrochloride The fluffy, yellowish white solid is dried under high vacuum at 65° C.

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

Procedure: To a suspension of (S)-4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (50 mg, 0.12 mmol) and N-ethylhydrazinecarbothioamide (21 mg, 0.18 mmol) in 1 ml 1,4-dioxane was added phosphorus (V) oxychloride (12.5 μL, 0.13 mmol). The mixture was stirred at 80° C. overnight. The solvent was evaporated and the residue was poured into water and ethyl acetate. The mixture was basified to pH 10 with sodium carbonate and extracted twice with ethyl acetate. The organics were combined and washed with water, brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was precipitated using diethyl ether, filtered, washed with cold diethyl ether and dried in a vacuum oven to obtain 14 mg (29% yield) of the title compound. The solvent was evaporated the residue was poured into water and ethyl acetate extracted twice with ethyl acetate washed with water, brine dried over sodium sulphate filtered evaporated under reduced pressure The residue was precipitated filtered washed with cold diethyl ether dried in a vacuum oven

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

Procedure: The title compound was prepared from 4-ethyl-3-thiosemicarbazide (100 mg, 0.838 mmol) and 2-pyridinecarboxaldehyde (80 μL, 0.838 mmol) similar to Example 3 and isolated as a white solid (137 mg, 78%). 1H NMR (DMSO-d6): 11.65 (s, 1H), 8.72 (t, J=5.4 Hz, 1H), 8.58-8.55 (m, 1H), 8.27 (dd, J=1.1, 8.1 Hz, 1H), 8.09 (s, 1H), 7.88-7.82 (m, 1H), 7.40-7.36 (m, 1H), 3.65-3.56 (m, 2H), 1.16 (t, J=7.1 Hz, 3H).

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

Procedure: Methoxyacetic acid 360 mg, 3.99 mmol), 4-ethyl-3-thiosemicarbazide (581 mg, 4.87 mmol), diisopropylcarbodiimide (615 mg, 4.87 mmol) and hydroxybenzotriazole (69.6 mg, 0.51 mmol) were mixed in dimethylformamide (10 ml) and stirred under argon at ambient temperatures for 19 h. After evaporation to dryness the crude was used directly in the next step. MS (ESI) m/z 192 (M+1). Step 2: 4-Ethyl-5-methoxymethyl-2,4-dihydro-[1,2,4]triazole-3-thione: N-Ethyl-2-(methoxyacetyl(hydrazinecarbothioamide (760 mg crude, 4 mmol) and sodium bicarbonate (560 mg, 6.6 mmol) were suspended in water (15 ml) and refluxed for 5 h. After cooling and filtration the filtrate was acidified with concentrated hydrochloric acid, followed by extraction with ethyl acetate. After evaporation to dryness the crude was recrystallized in ethyl acetate/heptane. Filtration and recrystallization of the mother liquor gave a combined yield of 325 mg (47%) of the title compound. 1H NMR (CDCl3), δ (ppm): 4.47 (s, 2H), 4.13 (q, 2H), 3.37 (s, 3H), 1.38 (t, 3H). After evaporation to dryness the crude refluxed for 5 h After cooling filtration the filtrate followed by extraction with ethyl acetate After evaporation to dryness the crude was recrystallized in ethyl acetate/heptane Filtration and recrystallization of the mother liquor

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

Procedure: Methoxyacetic acid 360 mg, 3.99 mmol), 4-ethyl-3-thiosemicarbazide (581 mg, 4.87 mmol), diisopropylcarbodiimide (615 mg, 4.87 mmol) and hydroxybenzotriazole (69.6 mg, 0.51 mmol) were mixed in dimethylformamide (10 ml) and stirred under argon at ambient temperatures for 19 h. After evaporation to dryness the crude was used directly in the next step. MS (ESI) m/z 192 (M+1). Step 2: 4-Ethyl-5-methoxymethyl-2,4-dihydro-[1,2,4]triazole-3-thione: N-Ethyl-2-(methoxyacetyl(hydrazinecarbothioamide (760 mg crude, 4 mmol) and sodium bicarbonate (560 mg, 6.6 mmol) were suspended in water (15 ml) and refluxed for 5 h. After cooling and filtration the filtrate was acidified with concentrated hydrochloric acid, followed by extraction with ethyl acetate. After evaporation to dryness the crude was recrystallized in ethyl acetate/heptane. Filtration and recrystallization of the mother liquor gave a combined yield of 325 mg (47%) of the title compound. 1H NMR (CDCl3), δ (ppm): 4.47 (s, 2H), 4.13 (q, 2H), 3.37 (s, 3H), 1.38 (t, 3H). After evaporation to dryness the crude refluxed for 5 h After cooling filtration the filtrate followed by extraction with ethyl acetate After evaporation to dryness the crude was recrystallized in ethyl acetate/heptane Filtration and recrystallization of the mother liquor

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

Procedure: The title compound (pale yellow solid, 16.7 g, 58%) was prepared from isonicotinoyl chloride hydrochloride (25.1 g, 140.8 mmol) and 4-ethyl-3-thiosemicarbazide (16.87 g, 141.5 mmol) in pyridine (185 ml) with sodium hydroxide (220 mL, 2M, 440 mmol) added to the intermediate formed to effect cyclization. 1H NMR (DMSO-d6) δ (ppm): 8.80 (dd, 2H), 7.72 (dd, 2H), 4.11 (q, 2H), 3.59 (t, 3H). added to the intermediate formed

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

Procedure: The title compound (pale yellow solid, 16.7 g, 58%) was prepared from isonicotinoyl chloride hydrochloride (25.1 g, 140.8 mmol) and 4-ethyl-3-thiosemicarbazide (16.87 g, 141.5 mmol) in pyridine (185 ml) with sodium hydroxide (220 mL, 2M, 440 mmol) added to the intermediate formed to effect cyclization. 1H NMR (DMSO-d6) δ (ppm): 8.80 (dd, 2H), 7.72 (dd, 2H), 4.11 (q, 2H), 3.59 (t, 3H). added to the intermediate formed

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

Procedure: The title compound was prepared from N-ethylhydrazine carbothioamide and 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone in analogy to the synthesis of example 1 in 53% yield. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.83 (d, 1H), 8.30 (d, 1H), 8.24 (d, 1H), 7.93 (m, 2H), 7.69 (m, 2H), 7.48 (q, 1H), 4.67 (s, 2H), 3.74 (q, 2H), 2.39 (s, 3H), 1.26 (t, 3H). LCMS (method A): [MH]+=422, tR=5.43 min.

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

Procedure: The title compound was prepared from N-ethylhydrazine carbothioamide and 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone in analogy to the synthesis of example 1 in 53% yield. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.83 (d, 1H), 8.30 (d, 1H), 8.24 (d, 1H), 7.93 (m, 2H), 7.69 (m, 2H), 7.48 (q, 1H), 4.67 (s, 2H), 3.74 (q, 2H), 2.39 (s, 3H), 1.26 (t, 3H). LCMS (method A): [MH]+=422, tR=5.43 min.