2-AMINO-5-(4-METHYLPHENYL)-1 3 4-THIADI&

General procedure: 5.1.1 General procedure: 4.2.2.1. 5-(4-Fluorophenyl)-1, 3, 4-thiadiazol-2-amine (2b). A mixture of 4-fluoro benzoic acid (5.0 g, 35.70 mmol), thiosemicarbazide (3.25 g, 35.70 mmol) and POClGeneral procedure: A mixture of appropriate carboxylic acid (5.0 g, 1 eq), thiosemicarbazide(1 eq) and POCl3 (1.85 eq) was heated to 75C andmaintained at the same temperature for 30 min under stirring. Thereaction mixture was then cooled to room temperature, water (11v) was added and the mixture was refluxed for 4 h. After cooling, the mixture was basified with 50percent NaOH to pH 8 by the drop wiseaddition under stirring. The obtained solid was filtered andrecrystallized from ethanol to give the target compounds 4b-gGeneral procedure: A mixture of aldehydes (1 mmol), thiosemicarbazide (1 mmol) in ethanol (10 mL) and tert-butyl hydroperoxide (TBHP, 70percent aqueous solution) (1 mmol) was stirred at room temperature for 4h. The progress of the reaction was monitored by TLC using hexane/ EtOAc as the mobile phase. After the completion of the reaction, ethanol was evaporated under vacuum to obtain a solid residue. To this solid residue, ethyl acetate (10 ml) and water (10 ml) were added followed by saturated sodium bicarbonate solution (10 mL). Separated organic layer was dried over anhydrous sodium sulfate and evaporated under vacuum to obtain the product, which was further purified using silica gel column chromatography (hexane/ethyl acetate).General procedure: Compound 1a (1.15g, 10mmol) was stirred in dry benzene (15mL). Chloroacetyl chloride (1.3mL, 16mmol, 1.6 equv.) in dry benzene (10mL) was added in a dropwise manner. The reaction mixture was refluxed for 3-5h. The reaction was monitored by TLC using ethyl acetate: hexane (1:1 v/v) system. The products were filtered while hot and washed with a small amount of cold methanol. The The reaction mixture was filtered while hot, washed with a small amount of cold methanol and recrystallized from dioxane-water to give white crystalline solid. Yield (89.5%); mp decompose at 236C; IR (cm-1, KBr): 3434(NH), 1698 (C=O), 1580 (C=N); 1H NMR (90MHz, delta ppm DMSO-d6): 2.6 (s, 3H, CH3), 4.4 (s, 2H, CH2), 12.9 (br. s, 1H, NH), Elemental analysis for C5H6ClN3OS (191.64): Calculated/Found: 31.34/31.49 (%C), 3.16/3.28 (%H), 21.93/21.87 (%N) and 16.73/16.94 (%S).General procedure: EDCI (1.5 equiv) was added to a solution of the acid (c1-c3, 1.1equiv), DIPEA (1.5 equiv) and HOBt (1.5 equiv) in DMF (10 mL) at0 C and stirred for 5 min. Then, the amine (f1-f35, 1.0 equiv) wasadded to the solution and the reaction mixture was stirred for48 h at room temperature. The mixture was poured into the icedwater. The precipitated solid was filtered and washed with icedwater. After the purification by a silica gel column chromatography, the target compound (11 or g1-g37) was produced. 4.1.5.1. 1-methyl-N-(5-ethyl-1, 3, 4-thiadiazol-2-yl)-4-hydroxy-2-oxo-1, 2-dihydroquinoline-3-carboxamide (11). Yield 14.1%, light yellowsolid. ESI-MS (m/z): 331.11[MH]. 1H NMR (400 MHz, DMSO-d6)delta 8.28-8.23 (m, 0H), 7.87-7.84 (m, 1H), 7.74-7.69 (m, 1H), 7.51-7.44(m, 1H), 7.32 (dd, J 16.5, 8.5 Hz, 1H), 3.60 (s, 3H), 1.29-1.17 (m, 2H), 0.98-0.85 (m, 3H). 13C NMR (100 MHz, DMSO-d6) delta 162.77, 161.79, 161.38, 143.29, 140.25, 133.39, 130.37, 123.04, 120.84, 115.87, 109.55, 98.89, 36.24, 29.68, 14.14. HRMS calcd for C15H15N4O3S [MH], 331.0865; found, 331.0859.To the mixtureof 3, 4-dihydroxybenzoic acid (2.00 mmol, 0.308 g) in drydichloromethane (8.0 ml), SOCl2 (20.00 mmol, 1.5 mL) wasslowly added, followed by two drops of DMF. The resultingmixture was then stirred for 2 h at room temperature. Afterward, the solvent was evaporated under reduced pressure, and the excess of SOCl2 was removed by azeotropicdistillation with toluene. Corresponding substituted 2-amino-1, 3, 4-thiadiazole, 2aeo (1.00 mmol), NaHCO3(2.00 mmol, 0.168 g), and dry dioxane (10.0 ml) were addedto the formed acid chloride, without previous isolation, andthe mixture was then refluxed for 24 h. Afterward, thesolvent was evaporated under reduced pressure, 15.0 mL ofH2O was added to the residue, as well as solid Na2CO3, untilpH 9 was reached, and the formed suspension was stirredfor 30 min at the room temperature, filtrated, washed withwater, and dried over CaCl2. The final compounds wereobtained with satisfactory purity, but to obtain compoundswith very high purity, they can be subjected to furtherpurification by recrystallization from a hot aqueous solutionof 50% EtOH, for 3l, 65% EtOH, for 3b and 3o, 70% EtOH, for 3a, 3c, 3f, and 3n, 75% EtOH, for 3m, 80% EtOH, for 3k, 85% EtOH, for 3d and 3e, 90% EtOH, for 3j and 3g, and 96%EtOH, for 3h and 3i.General procedure: Conventional heating method (A): To a stirred solution of compound (3, 0.526 mol) in ethanol (10 mL) was added substituted 1, 3, 4-thiadiazol-2-amine (4a-4h) (1.052 mmol) in ethanol (10 mL) and the mixture was heated under refluxed for a period of time indicated in Table 1. After completion of the reaction, the mixture was concentrated under reduced pressure and the residue was subjected to column chromatography eluting with 30% to 40% (EtOAc/hexane). MWI method (B): A mixture of compound (3, 0.526 mmol), substituted 1, 3, 4-thiadiazol-2-amine (4a-4h) (1.052 mmol) and ethanol (10 mL) were placed in a microwave tube and subjected to MWI at 180 W for 10-25 min. Workup and purification were conducted as described above.A mixture of 1, 3, 4-thiadiazoles (4a-i, 0.28mmol), N, N?-dicyclohexylcarbodiimide (DCC, 0.2mmol), 4-dimethylaminopyridine (DMAP, 0.04mmol), and matrinic acids (6a-c, 0.2mmol) in dry DCM (10mL) was stirred at room temperature. When the reaction was complete according to TLC analysis, the mixture was diluted by DCM (40mL), washed by water (20mL), 0.1mol/L aq. HCl (20mL), saturated aq. NaHCO3 (20mL) and brine (20mL), dried over anhydrous Na2SO4, concentrated in vacuo, and purified by preparative thin-layer chromatography (PTLC) to give compounds 7a-x in 26-78% yields. Exemplary data for compounds 7a and 7b are as follows:

Molecular Weight:191.26
XLogP3:2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:191.05171847
Monoisotopic Mass:191.05171847
Topological Polar Surface Area:80
Heavy Atom Count:13
Complexity:168
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes