Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:10])[CH2:4][C:5](=[O:9])[CH:6]([CH3:8])[CH3:7].[OH:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[OH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:3](=[O:10])[CH2:4][C:5](=[O:9])[CH:6]([CH3:7])[CH3:8])[CH2:14][CH2:13]1
Reactant: OC1CCNCC1
Reactant: COC(=O)CC(=O)C(C)C
Product: CC(C)C(=O)CC(=O)N1CCC(O)CC1
Yield: 94.8 %

Procedure:
0.351 mol (49.6 ml) of 4-methyl-3-oxovaleric acid methyl ester and 0.369 mol (37.3 g) of 4-hydroxypiperidine were stirred for 6 h at 120° C. in a Dean-Stark apparatus. 12 ml of methanol were collected. Subsequently, the excess starting materials were distilled off for 3 h on a rotary evaporator (80° C. water bath, 2 mbar). 71 g of the title compound were obtained.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1(C)C=CC(S(O[CH2:25][C:26]2([CH2:32]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:7][O:6][C:4]([C:3]1[C:2]2[O:1][CH2:32][C:26]3([CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH2:25][O:12][C:11]=2[C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:5]
Reactant: COC(=O)c1ccc(OC)c(O)c1O
Reactant: Cc1ccc(S(=O)(=O)OCC2(COS(=O)(=O)c3ccc(C)cc3)CCOCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(OC)c2c1OCC1(CCOCC1)CO2

Procedure:
Following the general procedure, dialkylation of compound 513 (95 mg, 0.48 mmol) with compound 519 (240 mg, 0.53 mmol) in DMSO (3 mL) in the presence of K2CO3 (166 mg, 1.2 mmol) afforded compound 520 as a white solid material after purification by column chromatography (45-65% EtOAc in light petroleum). LC-MS: RT=2.40 min.; 1H NMR (DMSO-d6): δ 7.34 (1H, d, J 8.8), 6.78 (1H, d, J 8.8), 3.99 (4H, s), 3.80 (3H, s), 3.76 (3H, s), 3.61 (4H, t, J 5.5), 1.54 (4H, t, J 5.5).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[C:5]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[O:13][C:14]([CH2:17][N:18]([CH3:20])[CH3:19])=[CH:15][CH:16]=1)=[O:6].[CH3:24][S:25][C:26](SC)=[CH:27][N+:28]([O-:30])=[O:29]>C(O)C>[CH3:24][S:25][C:26]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[C:5]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[O:13][C:14]([CH2:17][N:18]([CH3:19])[CH3:20])=[CH:15][CH:16]=1)=[O:6])=[CH:27][N+:28]([O-:30])=[O:29]
Reactant: CN(C)Cc1ccc(CSCCNC(=O)c2cccc(N)c2)o1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCO
Product: CSC(=C[N+](=O)[O-])Nc1cccc(C(=O)NCCSCc2ccc(CN(C)C)o2)c1
Yield: 65 %

Procedure:
According to the above procedure, by reacting 0.02 mol of 3-amino-N-[2-(5-dimethylaminomethylfuran-2-ylmethylthio)ethyl]benzamide and 0.02 mol of 1,1-bis-methylthio-2-nitroethene in 50 ml of ethanol, the 3-[N-(1-methylthio-2-nitroethenyl)amino]-N-[2-(5-dimethylaminomethylfuran-2-ylmethylthio)ethyl]benzamide is obtained in 65% yield, said compound being then dissolved in ethanol and treated with a 33% solution of methylamine in ethanol to give the 3-[N-(1-methylamino-2-nitroethenyl)amino]-N-[2-(5-dimethylaminomethylfuran-2-ylmethylthio)ethyl]benzamide as a practically pure oil. The product thus obtained is transformed into its oxalate in 95% ethanol. After crystallization from 200 ml of ethanol, the pure oxalate is obtained in 43% yield; m.p. 175°-177° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[CH:13]=2)=[O:10])[C:6]=1[O:7][CH3:8].[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:9]([C:5]2[C:6]([O:7][CH3:8])=[C:2]([C:30]3[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=3)[S:3][CH:4]=2)=[O:10])=[CH:13][C:14]=1[N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1
Reactant: OB(O)c1ccncc1
Reactant: COc1ccc(NC(=O)c2csc(Br)c2OC)cc1N1CCN(C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(NC(=O)c2csc(-c3ccncc3)c2OC)cc1N1CCN(C)CC1

Procedure:
2-Bromo-N-[4-methoxy-3-(4-methyl- 1-piperazinyl)phenyl]-3-methoxythiophene-4-carboxamide (0.20 g;0.45 mmol) was stirred with 4-pyridylboronic acid (0.056 g;0.45 mmol), tetrakis(triphenylphosphine)palladium(0) (0.024 g) and anhydrous sodium carbonate (0.053 g;0.50 mmol) in water (5 ml) and DME (5 ml) and the whole heated at reflux under Ar (18 hours). The reaction mixture was poured into 10% Na2CO3 (aq) (20 ml) and extracted into CHCl3. The organic extracts were combined, dried over Na2SO4, filtered and the filtrate evaporated in vacuo to a brown gum. The gum was purified by flash silica-gel chromatography and eluted with 4%MeOH/CHCl3 to yield a orange gum (0.088;44%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.O.O.O.O.O.O.[F:18][C:19]([F:27])([F:26])[C:20]([C:22]([F:25])([F:24])[F:23])=[O:21]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[NH2:1][C:2]1[C:11]([C:20]([OH:21])([C:22]([F:25])([F:24])[F:23])[C:19]([F:27])([F:26])[F:18])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: Nc1cccc2cnccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Nc1c(C(O)(C(F)(F)F)C(F)(F)F)ccc2cnccc12
Temperature: 150 °C
Yield: 21 %

Procedure:
5-Aminoisoquinoline (288 mg, 2.00 mmol) and p-toluenesulfonic acid (5 mg) were combined and treated with hexafluoroacetone hexahydrate (0.29 mL, 462 mg, 2.10 mmol). The mixture was stirred in a sealed pressure tube and heated to 150° C. for 18 hours. The reaction was allowed to cool to room temperature and partitioned between CH2Cl2 (20 mL) and water (10 mL). The organic layer was passed thru Na2SO4 and then filtered through activated charcoal. The charcoal was washed with methanol (3×10 mL) and the filtrate and washings were collected and concentrated under reduced pressure to provide the title compound (130 mg, 30%) as a yellow solid. MS (ESI+) m/z 311 (M+H)+; MS (ESI−) m/z 309 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 6.64 (br s, 2H), 7.30 (d, J 8.7, 1H), 7.40 (d, J 8.7, 1H), 8.09 (d, J 6.1, 1H), 8.49 (d, J 6.1, 1H), 9.14 (s, 1H); 13C NMR (DMSO, 100 MHz) δ 107.02, 110.60, 113.95 (1), 115.46 (1), 122.03, 124.92, 124.92, 125.94, 126.98 (1), 128.17, 142.43 (1), 144.82, 151.85 (1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C@@H:12]1[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C>C(O)C>[F:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:14][C@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNCC[C@H]1F
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2[N+](=O)[O-])CC[C@H]1F
Yield: 91 %

Procedure:
Method 1 of Example 1 was followed using 1 eq each of 4-chloro-3-nitropyridine, tert-butyl(3R,4R)-4-fluoropiperidin-3-ylcarbamate and triethylamine in ethanol yielding tert-butyl(3R,4R)-4-fluoro-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate, (91%). LCMS (m/z): 341.0 (MH+); LC Rt=2.37 min.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[C@H:3]([OH:16])[CH2:4][N:5]([CH3:15])[C:6](=[O:14])[O:7][CH2:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11].N1C=CC=CC=1.[Si:30](Cl)([CH3:33])([CH3:32])[CH3:31]>C1COCC1>[NH2:1][C@@H:2]([CH2:17][CH:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)[C@H:3]([O:16][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH2:4][N:5]([CH3:15])[C:6](=[O:14])[O:7][CH2:8][CH2:9][Si:10]([CH3:12])([CH3:13])[CH3:11]
Reactant: C[Si](C)(C)Cl
Reactant: CN(C[C@@H](O)[C@@H](N)CC1CCOCC1)C(=O)OCC[Si](C)(C)C
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CN(C[C@@H](O[Si](C)(C)C)[C@@H](N)CC1CCOCC1)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
A 100 mL flask was charged with 2-(trimethylsilyl)ethyl (2R,3S)-3-amino-2-hydroxy-4-(tetrahydro-2H-pyran-4-yl)butyl(methyl)carbamate (100 mg, 0.29 mmol) dissolved in THF (10 mL), pyridine (68 mg, 0.87 mmol) was added at 0° C. Me3SiCl (94 mg, 0.87 mmol) was added and the mixture was stirred for 2 h at rt. The mixture was quenched with 1% aq HCl and extracted with EtOAc (3×15 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography to give 2-(trimethylsilyl)ethyl (2R,3S)-3-amino-4-(tetrahydro-2H-pyran-4-yl)-2-(trimethylsilyloxy)butyl(methyl)carbamate (110 mg, 92%)
Reaction SMILES: [C:1]1([C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.ClCCl>Br.C(O)(=O)C>[C:1]1([C:7]2([C:14]3[S:13][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccsc1
Reactant: C1=C(c2ccccc2)CCCC1
Agent: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc(C2(c3cccs3)CCCCC2)cc1
Temperature: 25 °C

Procedure:
Phenyl cyclohexene (50 mg) and thiophene (100 mg) were dissolved in 33% HBr in acetic acid (0.5 mL). The mixture was stirred at room temperature over night. Tlc indicated full conversion of the starting material. Dichloromethane (10 mL) was added. The organic phase was washed with saturated NaHCO3 (3×10 mL), dried Na2SO4 and concentrated in vacuo. The desired product was afforded after flash chromatography (eluent: dichloromethane). Yield: 39 mg. LC/MS purity (UV/MS): 100/90%, Rt 6.22 min. M+1: 243
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([OH:14])(=O)[CH3:12]>N1C=CC=CC=1>[O:14]=[C:11]1[C:12]2[CH:8]=[CH:5][CH:4]=[CH:3][C:2]=2[N:7]=[C:2]2[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][N:7]12
Reactant: CC(=O)O
Reactant: O=C(O)c1ccc(Cl)nn1
Solvent: c1ccncc1
Product: O=C(O)c1ccc2nc3ccccc3c(=O)n2n1

Procedure:
A precipitate is obtained when a mixture of methyl anthraniliate (4.78 g, 31.6 mmol), 6-chloropyridazine-3-carboxylic acid (5.0 g, 31.6 mmol) and 50 ml of acetic acid is heated at reflux for 21 hrs; m.p. 246°-50° C. This crude material is recyrstallized from pyridine giving the anlytical sample, m.p. 239°-43° C. (dec.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[OH-].[Na+].O.Cl[C:11]1[N:16]=[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=2)[N:14]=[C:13]([NH:27][CH:28]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[N:12]=1>O1CCOCC1>[Cl:26][C:20]1[CH:19]=[C:18]([NH:17][C:15]2[N:14]=[C:13]([NH:27][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[N:12]=[C:11]([N:1]3[CH2:6][CH2:5][S:4][CH2:3][CH2:2]3)[N:16]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Reactant: C1CSCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(N3CCSCC3)n2)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of thiomorpholine (97 mg, 0.942 mmol), sodium hydroxide (31.4 mg, 0.785 mmol) and water (0.5 mL) in 1,4-dioxane (15 mL) was heated to reflux for 3 hours with stirring under nitrogen atmosphere and then cooled to 25° C. followed by the addition of compound 133 (0.30 g, 0.785 mmol) at same temperature. The mixture was heated to reflux for 12 hours, concentrated under vacuum and diluted with water (20 mL). The mixture was then extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (2×10 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The residue thus obtained was purified by column chromatography (10-20% EtOAc-Hexane) to afford the title compound E27 as a pale yellow solid (0.26 g, 74%). mp 78-80° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4; solvent B=CH3CN], A:B=20:80; 220 nm, Rt 20.36 min, 97.15% purity; MS (CI): m/z 449 (M+H, 100).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([CH:9]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]=1[NH:21][C:22](=O)[CH3:23])=O.[NH3:25]>CO>[N:16]1([CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]2[CH:8]=[C:3]3[C:4](=[CH:5][CH:6]=2)[N:21]=[C:22]([CH3:23])[N:25]=[CH:1]3)[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: N
Reactant: CC(=O)Nc1ccc(C(c2ccccc2)n2ccnc2)cc1C=O
Solvent: CO
Product: Cc1ncc2cc(C(c3ccccc3)n3ccnc3)ccc2n1
Yield: 14.7 %

Procedure:
A solution of 2.2 parts of N-(2-formyl-4-[(1H-imidazol-1-yl)phenylmethyl]phenyl]acetamide and 40 parts of methanol, saturated with ammonia was stirred for 1 hour at room temperature. After evaporation, dichloromethane was added. The solution was filtered and the filtrate was evaporated. The residue was purified by column chromatography over silica gel first using a mixture of dichloromethane and methanol (97:3 by volume) and then a mixture of dichloromethane and methanol (94:6 by volume) as eluents. The eluent of the desired fraction was evaporated and the residue was crystallized from 21 parts of 1,1'-oxybisethane. The product was filtered off and dried, yielding 0.3 parts (14.7%) of 6-[(1H-imidazol-1-yl)phenylmethyl]-2-methylquinazoline; mp. 129.6° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[N:16]1[CH2:21][CH2:20][CH:19]([CH:22]([N:24]([CH3:26])[CH3:25])[CH3:23])[CH2:18][CH2:17]1.[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[OH:34]>>[Cl:27][C:28]1[CH:29]=[C:30]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]3[N:16]2[CH2:17][CH2:18][CH:19]([CH:22]([N:24]([CH3:26])[CH3:25])[CH3:23])[CH2:20][CH2:21]2)[CH:31]=[CH:32][C:33]=1[OH:34]
Reactant: OB(O)c1ccc(O)c(Cl)c1
Reactant: CC(C1CCN(c2c(S(C)(=O)=O)cnc3ccc(Br)cc23)CC1)N(C)C
Product: CC(C1CCN(c2c(S(C)(=O)=O)cnc3ccc(-c4ccc(O)c(Cl)c4)cc23)CC1)N(C)C
Yield: 24.4 %

Procedure:
Following general procedure D, 1-{1-[6-bromo-3-(methylsulfonyl)quinolin-4-yl]piperidin-4-yl}-N,N-dimethylethanamine (35 mg, 0.079 mmol) was reacted with 3-chloro-4-hydroxyphenylboronic acid (26 mg, 0.150 mmol) to afford the desired product (9.4 mg, 24%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 9.23 (s, 1H), 8.39 (d, J=1.5 Hz, 1H), 8.24-8.13 (m, 2H), 7.74 (d, J=2.2 Hz, 1H), 7.58 (dd, J=8.4, 2.3 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 3.81-3.70 (m, 2H), 3.55 (s, 2H), 3.45 (s, 3H), 3.28-3.22 (m, 1H), 2.84 (s, 6H), 2.14 (d, J=7.9 Hz, 1H), 1.95 (d, J=11.0 Hz, 2H), 1.87-1.68 (m, 2H), 1.38 (d, J=6.7 Hz, 3H); ESI MS m/z 488 [C25H30ClN3O3S+H]+; HPLC>99% (AUC), tR=10.84 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[CH3:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([NH:29][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([CH3:23])=[CH:25][CH:26]=2)=[O:22])=[CH:18][CH:19]=1
Reactant: Cc1ccc(CN)cc1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: Cc1ccc(CNC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1

Procedure:
2′-Methyl-N-(4-methylbenzyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 4-methylbenzylamine using method N. NMR; δH [2H6]—DMSO 9.10,(1H, t), 7.99,(2H, d), 7.89,(1H, dd), 7.76,(1H, d), 7.56-7.51,(3H, m), 7.22,(2H, d), 7.13,(2H, d), 4.46,(2H, d), 2.56,(3H, s), 2.31,(3H, s), 2.27,(3H, s). LCMS; retention time 3.48 min, MH+ 398.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])=[C:9]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.CN(C)[CH2:28][CH2:29][CH2:30]N=C=NCC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[C:10]([O:11][CH2:12][C:13]([N:15]([CH2:16][CH3:17])[CH2:18][CH3:19])=[O:14])=[C:9]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:28]1[CH2:29][CH2:30][CH2:2][C:10](=[O:11])[CH:9]=1)=[O:5]
Reactant: CCN(CC)C(=O)COc1c(S(=O)(=O)CC)ccc(C(=O)O)c1Cl
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)C(=O)COc1c(S(=O)(=O)CC)ccc(C(=O)OC2=CC(=O)CCC2)c1Cl

Procedure:
0.500 g (1.30 mmol) of 2-chloro-3-(N,N-diethylaminocarbonylmethoxy)-4-ethylsulfonylbenzoic acid, 0.163 g (1.30 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide-hydrochloride and 0.002 g of DMAP were stirred for 10 hours at RT in 15 ml of CH2Cl2. The mixture was subsequently diluted with CH2Cl2 and washed with 0.5 N HCl, with water, with saturated NaHCO3 solution and again with water. After the organic phases had been dried over Na2SO4 and concentrated completely, the product was obtained in the form of a brown resin.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27]CC5C=CC(OC)=CC=5)=[O:26])[CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[CH:3]=[N:2]1.FC(F)(F)C(O)=O>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=[O:26])[CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[CH:3]=[N:2]1
Reactant: COc1ccc(COC(=O)c2ccc3nc(-c4ccc5oncc5c4)c(N(C)C(C)C)nc3c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc2oncc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
To a solution of (4-methoxyphenyl)methyl 2-(1,2-benzoxazol-5-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (50 mg, 0.10 mmol) in dichloromethane (10 mL) was added 2,2,2-trifluoroacetic acid (1 mL). The solution was stirred for 30 min at room temperature. Then the reaction was quenched by the addition of water (100 mL), extracted with dichloromethane (3×30 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with 5% dichloromethane in methanol to afford 2-(1,2-benzoxazol-5-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylic acid as a yellow solid (12.3 mg, 33%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[OH:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([O:15]CC)=[O:14]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([O:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[C:13]([OH:15])=[O:14])=[N:3][CH:4]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: CCOC(=O)c1cccc(O)c1
Product: O=C(O)c1cccc(Oc2ccc(Cl)cn2)c1

Procedure:
Prepared from 2,5-dichloropyridine and ethyl 3-hydroxybenzoate. 1H NMR (400 MHz, DMSO-d5) δ 13.17 (br. s., 1H), 8.22 (d, 1H), 8.00 (dd, 1H), 7.81 (dd, 1H), 7.60-7.64 (m, 1H), 7.58 (t, 1H), 7.43 (dd, 1H), 7.18 (d, 1H).
Reaction SMILES: [N:1]([O-])=O.[Na+].[C:5]([C:7]1[C:8]([S:17]([NH2:20])(=[O:19])=[O:18])=[C:9]([C:13]([NH:15][NH2:16])=[O:14])[S:10][C:11]=1[CH3:12])#[N:6]>O.Cl>[C:5]([C:7]1[C:8]([S:17](=[O:18])(=[O:19])[NH2:20])=[C:9]([C:13]([N:15]=[N+:16]=[N-:1])=[O:14])[S:10][C:11]=1[CH3:12])#[N:6]
Reactant: Cc1sc(C(=O)NN)c(S(N)(=O)=O)c1C#N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1sc(C(=O)N=[N+]=[N-])c(S(N)(=O)=O)c1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A solution of sodium nitrite (0.47 g) in 5 ml of water was added dropwise to a stirred solution of 4-cyano-2-hydrazinocarbonyl-5-methyl-thiophene-3-sulfonamide (1.6 g) in 38 ml of 1 M hydrochloric acid at 0° C. The resulting mixture was stirred for 30 min at 0° C. and then filtered. The filter cake was washed with water and dried in vacuum to give 1.35 g of the title compound; 1H-NMR (DMSO-d6), δ(ppm): 7.75 (br, 1H, NH2), 2.75 (s, 1H, CH3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([Br:16])[C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH3:2].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([Br:16])[C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH3:2]
Reactant: C1CCNCC1
Reactant: CCOC(=O)C(Br)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: CCOC(=O)C(Br)c1ccc(S(=O)(=O)N2CCCCC2)cc1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
Bromo-(4-chlorosulfonyl-phenyl)-acetic acid ethyl ester (2.08 gm, 6.38 mmol) was taken in DCM (63 ml) under argon atmosphere and cooled to 0-5° C., piperidine (0.56 ml, 5.74 mmol) was added dropwise to the mixture at 0-5° C. Reaction mixture was then stirred at room temperature for 30 min. Reaction mixture was washed with water followed by brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography over silica gel using 30-50% ethyl acetate in hexane as eluent to give bromo-[4-(piperidine-1-sulfonyl)-phenyl]-acetic acid ethyl ester (1.2 gm).
Reaction SMILES: [O:1]=[C:2]1[NH:21][C:5]2=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:11][C:12]=3[CH:13]=[C:4]2[NH:3]1.[CH2:22]([CH:24]([NH2:27])[CH2:25][CH3:26])[CH3:23]>>[O:1]=[C:2]1[NH:21][C:5]2=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][C:18]([NH:27][CH:24]([CH2:25][CH3:26])[CH2:22][CH3:23])=[O:20])=[CH:11][C:12]=3[CH:13]=[C:4]2[NH:3]1
Reactant: O=C(O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Reactant: CCC(N)CC
Product: CCC(CC)NC(=O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1

Procedure:
This compound, m.p. 312°-314° C., was prepared from 4-[(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butyric acid and 1-ethylpropylamine.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH:15]([C:17]1[N:22]2[N:23]=[CH:24][N:25]=[C:21]2[N:20]=[CH:19][CH:18]=1)[CH3:16]>COCCOC>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([O:9][CH:15]([C:17]2[N:22]3[N:23]=[CH:24][N:25]=[C:21]3[N:20]=[CH:19][CH:18]=2)[CH3:16])=[CH:7][CH:8]=1
Reactant: CC(Br)c1ccnc2ncnn12
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(Oc1ccc(C(F)(F)F)cc1)c1ccnc2ncnn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Trifluoromethylphenol (1.62 g) was added to a stirred suspension of sodium hydride (0.48 g) in dry 1,2-dimethoxyethane (35 ml). The mixture was stirred at room temperature for 30 minutes, then a solution of 7-(1-bromoethyl)-1,2,4-triazolo[1,5-a]pyrimidine (2.27 g, prepared in a similar manner to that described in Example 6 below) in dry 1,2-dimethoxyethane (85 ml) was added dropwise. The mixture was stirred at room temperature for 24 hours. The sodium bromide was removed from the mixture by filtration. The solvent was evaporated from the filtrate and the residue dissolved in dichloromethane and washed with 200 ml of a 5% aqueous solution of sodium hydroxide followed by water. The organic layer was dried over magnesium sulphate. Evaporation of the solvent afforded a crude product which was purified by column chromatography on silica gel using as eluent a mixture of petroleum ether and ethyl acetate (in the ratio 6:4 respectively), followed by recrystallisation from hexane, to give 7-[1-(4-trifluoromethylphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine. Yield 1.1 g, (mp 100°-102° C.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[C:11]1([C:17](=O)[C:18]([O:20]CC)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[O:10]=[C:2]1[C:3](=[C:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:18]([OH:20])=[O:19])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1]1
Reactant: CCOC(=O)C(=O)c1ccccc1
Reactant: O=C1Cc2ccccc2N1
Product: O=C(O)C(=C1C(=O)Nc2ccccc21)c1ccccc1
Yield: 25.1 %

Procedure:
Oxindole (390 mg, 3mmol) was condensed with ethyl phenylglyoxylate (540 mg) using method A to give 200 mg (25%) of the title compound as a yellow solid.