2-Amino-3-thiophenecarboxamide

Triethylamine (36 mL, 256 mmol) was added to the solution of 2- cyanoacetamide (10.8 g, 128 mmol) and [1, 4] -dithiane-2, 5-diol (19.5 g, 128 mmol) in ethanol (400 mL). The resulting reaction mixture was stirred at room temperature for 5 min, then heated at reflux for 2 h. After the reaction mixture is cooled to room temperature, it was filtered and concentrated under vacuum. The residue was then taken up into ethyl acetate (400 mL) and washed with aqueous sodium hydroxide (1 M, 1X200 mL), water (2X200 mL) and brine (1X200 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give the above titled compound as a light yellow solid (16 g, 113 mmol, 88percent yield). LC-MS [M+H]+ m/z 143.Step A: A stirred mixture of 2-cyanoacetamide (2 g, 23.8 mmol), 1, 4- dithiane-2, 5-diol (3.6 g, 23.8 mmol) and TEA (4.8 g, 47.6 mmol) in EtOH was heated at reflux for 5 h. After cooling to rt, the mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc (200 mL) and 1 M aq sodium hydroxide (300 mL). The organic layer was separated and washed with water and brine., dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 2-aminothiophene-3-carboxamide (2.78 g, 82percent). 1H NMR (400 MHz, DMSO- dStep 1 Step 1 l, 4-dithian-2, 5-diol (4.56g, 30mmole) and 2-cyanoacetamide (2.52 g, 30 mmole) were combined in ethanol (50 ml). Triethylamine (6 ml) was added and heated to 70°C for 1 hour. The volume of solvent was reduced under vacuum, and the product was isolated by filtration. Product was recrystallized from ethanol to give 2.7 Ig of product (yield 64percent)General procedure: In a 2–5 mL microwave vial was added the nitrile (0.22 mmol, 1 equiv) and trifluoroethanol (2 mL) which was stirring for 2 min to dissolve. Next, 1, 4-dithian-2, 5-diol (0.11 mmol, 0.5 equiv) was then added and stirred for 5 min before triethylamine(0.242 mmol; 1.1 equiv) was added and the mixture further stirred for 2 min. The vial was then sealed and heated in the microwave for 390 min at 60 °C. The solvent was evaporated under vacuo and the crude residue was then purified using flash chromatography on silica (EtOAc/hexanes).Example 15: Synthesis of 3-methylthiopheno[2, 3-d]l, 2, 3-triazin-4-one (compound 15); Step a:2-An.inothiophene-3-carboxan.ide: To a solution of 2, 5-dihydroxy-l, 4-dithiane (10 g, 65.78 mmol) in ethanol (200 mL) and triethylamine (2 mL) was added cyanoacetamide (5.52 g, 65.78 mmol) at rt for 5 min. The reaction mixture was refluxed for 3 h and attained to rt. Ethanol (appr. 150 mL) was removed under reduced pressure and poured the contents into ice cold water and stirred for 15 min. The solution was extracted with ethyl acetate (3 x 100 mL) and the combined EtOAc layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (95:5) as eluents to give the product as a pale yellow color solid (4.9 g, 53percent), mp 150-152 Step a:; 2-Aminothiophene-3-carboxamide:; To a solution of 2, 5-dihydroxy-1, 4-dithiane (10 g, 65.78 mmol) in ethanol (200 mL) and triethylamine (2 mL) was added cyanoacetamide (5.52 g, 65.78 mmol) at rt for 5 min. The reaction mixture was refluxed for 3 h and attained to rt. Ethanol (appr. 150 mL) was removed under reduced pressure and poured the contents into ice cold water and stirred for 15 min. The solution was extracted with ethyl acetate (3.x.100 mL) and the combined EtOAc layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (95:5) as eluents to give the product as a pale yellow color solid (4.9 g, 53percent), mp 150-152° C.Example 442-(2-(3-(trifluoromethyl)-4, 5, 6, 7-tetrahvdro--//-/-indazole-1-yl)acetamido)thiophene-3- carboxamidea) 2-aminothiophene-3-carboxamideA solution of 2, 5-dihydroxy-1 , 4-dithiane (5.83 g, 38.3 mmol), 2-cyanoacetamide (8.4 g, 99.1 mmol) and triethylamine (10 mL, 71.9 mmol) in EtOH (30 mL) was heated at 70 Step b:3H-Thiopheno[2, 3-d]l, 2, 3-triazin-4-one: To an ice cold solution (O0C) of 2- aminothiophene-3-carboxamide (5 g, 35.21 mmol) in concentrated sulfuric acid (40 mL) was added a cold (O0C) solution of sodium nitrite (2.5 g, 35.21 mmol) in concentrated sulfuric acid (30 mL) for 30 min (while adding, the temperature should keep between -5- O0C). After addition, the mixture was stirred at the same temperature (O0C) for 3 h. The mixture was poured into crushed ice slowly with stirring for 15 min and stirred at the same temperature for 15 min. The solution was extracted with ethyl acetate (4 x 200 mL) and the combined EtOAc layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (95:5) as eluents to give the product as a pale red color solid (1.0 g, 18%), mp 175-176 0C. 1H NMR (400 MHz, DMSOd6): delta 15.18 (IH, s), 8.16 (IH, d, J=5.6 Hz), 7.64 (IH, d, J=5.6 Hz); 13C NMR (100 MHz, DMSOd6): delta 159.1, 153.8, 132.0, 126.1, 121.2; LC-MS (negative ion mode): m/z 152 (M-H).Step b:; 3H-Thiopheno[2, 3-d]1, 2, 3-triazin-4-one:; To an ice cold solution (0 C.) of EXAMPLE 446 Preparation of Compound 624 in Table 28 An analogous reaction to that described in example 444 but starting with To a stirred solution of General procedure: A mixture of 4a (172mg, 1mmol), 5a or 5b (1mmol) and 2-morpholinoethanesulfonic acid (20mg, 0.1mmol) in 50% aq EtOH (10mL) was heated at 60C for 3h, and the solvent was removed under reduced pressure. The residue was extracted with EtOAc three times, and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (30/1) to afford A24 or A25, respectively.a. 2-Amino-thiophene-3-carboxylic Acid Amide A mixture of thioacetaldehyde and cyanoacetamide in ethanol is heated with trithylamine at reflux for 1 h. the reaction is filtered and the filtrate is taken into ethyl acetate, washed with 2 N NaOH, dried over magnesium sulfate and evaporated. Recrystallization from diethylether gives the above titled compound.a) A solution of 2-propoxybenzoyl chloride (0.99 g) in acetonitrile (7.5 ml) was added dropwise over 5 minutes to a cooled (0 C.), stirred mixture of a) A solution of 2-propoxybenzoyl chloride (0.99 g) in acetonitrile (7.5 ml) was added dropwise over 5 minutes to a cooled (0 C.), stirred mixture of N-(3-Carbamoylthiophen-2-yl)nicotinamide (iii-b) To a solution of To a solution of

Molecular Weight:142.18
XLogP3:0.7
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:142.02008399
Monoisotopic Mass:142.02008399
Topological Polar Surface Area:97.4
Heavy Atom Count:9
Complexity:128
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes