Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[C:14]1[O:15][CH2:16][C:17]([CH3:20])([CH3:19])[N:18]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH3:30])[CH:24]=1>CCCC(C)C.O1CCCC1>[CH2:29]([C:25]1[CH:24]=[C:23]([CH2:22][CH2:6][C:7]2[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=2[C:14]2[O:15][CH2:16][C:17]([CH3:20])([CH3:19])[N:18]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:30]
Reactant: Cc1ccc(C2=NC(C)(C)CO2)c(C)c1
Reactant: CCc1cccc(CBr)c1
Agent: [Li]CCCC
Solvent: CCCC(C)C
Solvent: C1CCOC1
Product: CCc1cccc(CCc2cc(C)ccc2C2=NC(C)(C)CO2)c1
Reaction time: 1 h

Procedure:
n-Butyllithium (16.8 ml of a 2.5M solution in isohexane) was added dropwise to a stirred solution of the product of step (iii) (8.13 g) in dry tetrahydrofuran (ISOml) at 0° C. under nitrogen. After 1 hour, the product of step (ii) (8.0 g) in tetrahydrofliran (60 ml) was added. After 1 hour, the reaction was quenched with aqueous ammonium chloride and partitioned between ethyl acetate and water. The organic solution was dried (MgSO4) and evaporated. Purification was by chromatography eluting with 5% ethyl acetate in isohexane. Yield 4.93 g.
Reaction SMILES: C([O:8][C:9]([C:11]1([N:16]([CH:34]=[CH:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1.[H][H]>C(O)C.O>[CH2:39]([O:38][C:36]([CH2:35][CH2:34][N:16]([S:17]([C:20]1[CH:21]=[CH:22][C:23]([O:26][C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)=[CH:24][CH:25]=1)(=[O:19])=[O:18])[C:11]1([C:9]([OH:10])=[O:8])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:37])[CH3:40]
Reactant: [H][H]
Reactant: CCOC(=O)C=CN(C1(C(=O)OCc2ccccc2)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCN(C1(C(=O)O)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1

Procedure:
A solution of 2.50 g (4.4 mmol) of 1-{(2-ethoxycarbonylvinyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}cyclopentanecarboxylic acid benzyl ester in 25 mL of ethanol was treated with 2.5 9 of 50% water wet 10% palladium on carbon catalyst and shaken under 53 psi of hydrogen for 21 hours. The catalyst was removed by filtration and washed with ethanol (4×25 mL). The filtrate and washings were combined and concentrated under vacuum to 1.74 g (82%) of crude 1-{(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}cyclopentanecarboxylic acid_ as a viscous oil.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][CH2:20]OS(C)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:28][NH:29][CH3:30]>>[CH3:28][N:29]([CH3:30])[CH2:20][CH2:19][CH2:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:27])([F:26])[F:1])=[CH:4][CH:5]=3)=[N:10][S:11][C:12]=2[CH:17]=1
Reactant: CNC
Reactant: CS(=O)(=O)OCCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Product: CN(C)CCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 17.1; Methanesulfonic acid 3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-propyl ester and Dimethylamine were converted to yield Dimethyl-{3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-propyl}-amine as light brown oil, MS: 365 (MH+).
Reaction SMILES: [CH:1]1([C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH2:8])[CH2:5][CH2:4][CH:3]=[CH:2]1.C(=O)(O)[O-].[Na+].[Cl:18][CH2:19][C:20](Cl)=[O:21]>C(Cl)Cl.O>[CH:1]1([C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH:8][C:20](=[O:21])[CH2:19][Cl:18])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: Nc1ccccc1C1C=CCC1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(CCl)Nc1ccccc1C1C=CCC1
Temperature: 0 °C
Yield: 77 %

Procedure:
A solution of 10.00 g (62.8 mmol) of 2-(cyclopent-2-enyl)aniline from Example 1 in 150 mL of methylene chloride and 5.28 g (62.8 mmol) of sodium bicarbonate in 15 mL of water were combined with rapid stirring and cooled 0° C. with the aid of an ice bath. A solution of 7.099 (62.8 mmol) of chloroacetyl chloride in 25 mL of methylene chloride was then added dropwise through the course of 20 min. After an additional hour of vigorous stirring. the layers were separated and the organic layer was dried over anhydrous magnesium sulfate. Evaporation of the solvent in the organic layer and recrystallization of the precipitate with ether afforded 11.41 g (77% yield) of N-[2-(cyclopent-2-enyl)phenyl]-2-chloroacetamide: mp 101°-102° C.
Reaction SMILES: [Na].[C:2]1([NH:8][CH2:9][C:10]([OH:12])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C=CC(O)=CC=1)O.[C:21]([O:26][CH2:27][CH:28]1[O:30][CH2:29]1)(=[O:25])[C:22]([CH3:24])=[CH2:23].Cl>O.CO>[OH:30][CH:28]([CH2:27][O:26][C:21](=[O:25])[C:22]([CH3:24])=[CH2:23])[CH2:29][N:8]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]([OH:12])=[O:11]
Reactant: O=C(O)CNc1ccccc1
Reactant: C=C(C)C(=O)OCC1CO1
Agent: Cl
Agent: Oc1ccc(O)cc1
Agent: [Na]
Solvent: O
Solvent: CO
Product: C=C(C)C(=O)OCC(O)CN(CC(=O)O)c1ccccc1

Procedure:
A sodium salt of N-phenylglycine of 50 g (0.29 mol) was dissolved in water of 50 g and methanol of 50 g and then hydroquinone of 18 mg were added to the resulting solution. This solution was heated up to temperatures of 45° to 50° C. and glycidyl methacrylate of 41 g (0.29 mol) was added dropwise for 20 minutes with stirring followed by stirring for further 2 hours. Water of 200 g was added to the resulting solution and acidified with hydrochloric acid followed by filtering and drying the resulting crystals. N-(2-hydroxy-3-methacryloxypropyl)-N-phenylglycine (hereinafter called GMA-NPG for short) of 45 g was obtained. Then GMA-NPG of 2.0 g, MMA (methyl methacrylate) of 14.0 g, EA (ethyl acrylate) of 2.4 g and MAA (methacrylic acid) of 1.6 g were dissolved in dimethylformamide of 80 g. 20 g of a 1 wt %-solution of benzoyl peroxide in dimethylformamide was added dropwise to the above described solution under an atmosphere of nitrogen at 70° C. followed by stirring for further 6 hours. After cooling, hexane of about 10 times in weight was added to dilute the solution, the resulting polymer being settled and collected, the collected polymer being dissolved in methalethylketone and settled again in hexane, and the settled material being fltered and dried in a vacuum. A white powdery polymer was obtained. The number mean molecular weight of the obtained polymer was 25,000 and its acid value was 75. In addition, it was confirmed from the existence of an absorption having a peak at 300 nm in the UV absorption spectrum of this polymer that GMA was copolymerized with NPG.
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[C:10]([CH3:14])[C:11]([CH3:13])=[CH:12][C:7]=2[NH:6][C:5]1=[O:15])([CH3:3])=[CH2:2].C([O-])([O-])=O.[K+].[K+].[CH3:22][N:23]1[C:31]2[C:26](=[C:27]([CH3:32])[CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:33][N+](C)(C)C)=[CH:24]1.[I-]>CN(C=O)C.C(OCC)(=O)C>[CH3:22][N:23]1[C:31]2[C:26](=[C:27]([CH3:32])[CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:33][N:6]2[C:7]3[CH:12]=[C:11]([CH3:13])[C:10]([CH3:14])=[CH:9][C:8]=3[N:4]([C:1]([CH3:3])=[CH2:2])[C:5]2=[O:15])=[CH:24]1
Reactant: C=C(C)n1c(=O)[nH]c2cc(C)c(C)cc21
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(C)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2cc(C)c(C)cc21
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of 1-Isopropenyl-5,6-dimethyl-1,3-dihydro-benzimidazol-2-one (0.25 g, 1.2 mmol) in DMF (10 mL) was added K2CO3 (0.51 g, 3.7 mmol). The reaction mixture was heated to 90° C. and stirred for 20 min. (1,4-Dimethyl-1H-indol-3-ylmethyl)-trimethyl-ammonium; iodide (0.64 g, 1.8 mmol) was then added to the reaction mixture and stirred for another 3 h. The reaction mixture was treated with ethyl acetate and washed with water. The resulting residue was purified by silica gel prep TLC using 4:1 Hexane:ethyl acetate as an eluent to afford 0.35 g the desired product as an off-white solid. LCMS (ESMS): m/z 360.33 (M+H+).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:2][CH3:3].[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.BrCC=CC1C=C(C=CC=1)C([O-])=O>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:3][CH:2]=[CH:1][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC=Cc1cccc(C(=O)OCC)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])c1cccc(C=CCBr)c1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cccc(C=CCBr)c1

Procedure:
A mixture of ethyl 3-(1-propenyl)benzoate (14.0 g., 0.074 mole), N-bromosuccinimide (14.9 g., 0.084 mole), benzoyl peroxide (150 mg.), and carbon tetrachloride (75 ml.) is stirred and heated at reflux for 46 hours. The mixture is cooled. Solids are filtered off and the filtrate is washed with water and dried over magnesium sulfate. The solvent is evaporated and the residual oil distilled to yield 10.2 g. (51%) of ethyl (3-(3-bromo-1-propenyl)benzoate, b.p. 129°-131° C. (0.05 mm.).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[CH:4][N:3]=1.[NH:10]1[CH:14]=[N:13][CH:12]=[N:11]1>CO.ClCCl>[CH2:8]([C:6]1[CH:7]=[C:2]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[N:3]=[CH:4][N:5]=1)[CH3:9]
Reactant: c1nc[nH]n1
Reactant: CCc1cc(Cl)ncn1
Solvent: CO
Solvent: ClCCl
Product: CCc1cc(-n2cncn2)ncn1
Temperature: 120 °C
Yield: 82.2 %

Procedure:
A mixture of 4-chloro-6-ethylpyrimidine (1.42 g, 10 mmol) and 1H-1,2,4-triazole (1.4 g, 20 mmol) was heated to 120° C. with stirring to give a yellow oil, which deposited an orange solid. The mixture was maintained at 120° C. for 0.2 hours, cooled to 70° C. and dissolved in methanol (10 ml). The solution was diluted with dichloromethane (50 ml) and was washed with saturated sodium bicarbonate solution (20 ml). The aqueous phase was extracted with dichloromethane (2×20 ml) and the combined organic layers were dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica by elution with ethyl acetate to give the title compound (1.44 g, 82%) as a yellow solid, m.p. 75-76° C., which was characterised by 1H-N.M.R. spectroscopy.
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.O.[NH2:22][NH2:23].O>C(O)C>[CH3:1][S:2][C:3]1[NH:23][N:22]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NN
Reactant: CSC(SC)=C(C(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCO
Product: CSc1[nH]nc(-c2ccccc2)c1-c1ccccc1
Yield: 89.3 %

Procedure:
To a suspension of 3,3-bis(methylthio)-1,2-diphenylprop-2-en-1-one (2.5 g, 8.32 mmol) in ethanol (20 mL), was added hydrazine hydrate (1.67 g, 33.3 mmol) at room temperature. The reaction was refluxed for 6 h. After cooling, the reaction was poured into water and extracted with ethyl acetate. The organic extract was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (1.98 g). LCMS m/z=267.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][S:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])=[CH:24][CH:23]=1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: COc1ccc(CN)cc1
Product: CCc1cc(-c2ccc(S(=O)(=O)NCc3ccc(OC)cc3)s2)c(C)[nH]c1=O

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 4-methoxy-benzyl amine as described in Step 5, Example 24 to give the title compound. MS: m/e 419 (M+H). 1H NMR (δ ppm): 11.83 (s, 1H); 8.33 (t, 1H, J=6.3 Hz); 7.49 (d, 1H, J=3.7 Hz); 7.28 (s, 1H); 7.16 (d, 2H, J=8.6 Hz); 7.10 (d, 1H, J=3.7 Hz); 6.84 (d, 1H; J=8.6 Hz); 4.05 (d, 2H, J=6.3 Hz); 3.70 (s, 3H); 2.40 (q, 2H, J=7.4 Hz); 2.28 (s, 3H); 1.10 (t, 3H, J=7.4 Hz).
Reaction SMILES: [C:1](OC=O)(=[O:3])C.[Cl:7][C:8]1[C:9]([NH:18][C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=2)=[CH:10][CH:11]=[C:12]2[C:17]=1[CH2:16][NH:15][CH2:14][CH2:13]2.CN(C1C=CC=CN=1)C>ClCCl>[CH:1]([N:15]1[CH2:14][CH2:13][C:12]2[C:17](=[C:8]([Cl:7])[C:9]([NH:18][C:19](=[O:32])[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([C:28]([F:29])([F:30])[F:31])[CH:21]=3)=[CH:10][CH:11]=2)[CH2:16]1)=[O:3]
Reactant: CC(=O)OC=O
Reactant: COc1ccc(C(=O)Nc2ccc3c(c2Cl)CNCC3)cc1C(F)(F)F
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccc3c(c2Cl)CN(C=O)CC3)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
Formic acetic anhydride (0.21 g) was added to N-(8-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide (0.15 g) and dimethylaminopyridine (0.05 g) in dichloromethane. The mixture was stirred at room temperature overnight and quenched with saturated aqueous sodium hydrogen carbonate (20 ml). The organic phase was separated and washed with brine, dried (MgSO4) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, ammonia/methanol/dichloromethane mixtures as eluant) to give the title compound (0.10 g)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:19][S:20][C:21](=[N:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26])SC.C(N(CC)CC)C>C(#N)C>[CH3:19][S:20][C:21]([N:10]1[CH2:11][CH:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9]1)=[N:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)(=[O:26])=[O:27]
Reactant: Clc1ccc(C2=NNCC2c2ccccc2)cc1
Reactant: CSC(=NS(=O)(=O)c1ccc(Cl)cc1)SC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CSC(=NS(=O)(=O)c1ccc(Cl)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Yield: 79.7 %

Procedure:
Part A: A stirred mixture of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole (12.0 gram, 46.8 mmol), [(4-chlorophenyl)sulfonyl]dithioimidocarbonic acid dimethyl ester (CAS: 13068-12-7) (9.20 gram, 31.1 mmol) and triethylamine (15 ml) in acetonitrile (200 ml) was heated at reflux temperature for 20 hours. An additional portion of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole (12.0 gram, 46.8 mmol) was added and the resulting mixture was heated at reflux temperature for another 16 hours. After concentration in vacuo, dichloromethane was added and the resulting solution was washed twice with water and dried over anhydrous Na2SO4. After filtration and evaporation in vacuo the residue was further purified by flash chromatography (diethyl ether/petroleum ether=1/1 (v/v)) to give 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboximidothioic acid methyl ester (12.5 gram, 80% yield based on [(4-chlorophenyl)sulfonyl]dithioimidocarbonic acid dimethyl ester) as an amorphous solid.
Reaction SMILES: [H][H].[F:3][C:4]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]>C(OCC)(=O)C.[Pd]>[NH2:15][C:13]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([F:3])[CH:14]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(N)cc1F

Procedure:
To a mixture of 2-fluoro-4-nitrotoluene (1.0 g, 6.4 mmol, Aldrich) and Na2Cr2O7 (2.74 g, 8.4 mmol) in 13.7 ml of HOAC was added slowly 6.83 ml of H2SO4. This mixture was slowly heated to 90° C. for 1 h to give a greenish heterogeneous solution. The mixture was cooled to room temperature and diluted with ethyl acetate. The PH of the solution was adjusted to 4 with NaOH (aq.). The mixture was extracted with more ethyl acetate. The organic layer was washed with NaHCO3 (sat.), then brine and dried over Na2SO4. After filtration, the solution was concentrated to dryness which then was dissolved in 6 ml of SOCl2, and heated at 80° C. for 1 h. The excess of SOCl2 was removed under reduced pressure and the residue was dissolved in 5 ml of CH2Cl2, 2 ml of EtOH and 2 ml of pyridine. The mixture was stirred at room temperature for 2 h and concentrated to dryness. Ethyl 2-fluoro-4-nitrobenzoate was obtained as a white solid after column chromatography of the residue with ethyl acetate/hexane (1/9). This solid was then dissolved in 10 ml of ethyl acetate, and Pd/C (50 mg) was added. Hydrogenation with a hydrogen balloon converted ethyl 2-fluoro-4-nitrobenzoate into the title compound.
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[N:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O>CC(O)=O>[C:1]1([C:7]2[C:8]([C:10]3[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=3)=[N:19][C:20]3[C:21]([CH:22]=2)=[CH:24][CH:25]=[CH:26][N:27]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ncccc1C=O
Reactant: O=C(O)c1ccc(C(=O)Cc2ccccc2)cc1
Solvent: CC(=O)O
Product: O=C(O)c1ccc(-c2nc3ncccc3cc2-c2ccccc2)cc1

Procedure:
4-(Phenylacetyl)benzoic acid (1.0 g, 4.16 mmole) and 2-aminonicotinaldehyde (508 mg, 4.16 mmole) were combined in HOAc (5 mL) in a sealed microwave vessel. The mixture was microwave irradiated to 200° C. internal temperature for 2 hr. The mixture was concentrated. Flash column (5% MeOH/CH2Cl2) gave the title compound as a pale yellow solid (9-1): 1H-NMR (500 MHz, DMSO-d6) δ 13.05 (bs, 1 H), 9.15 (dd, J=1.95, 2.20 Hz, 1 H), 8.58 (m, 2 H), 7.88 (d, J=8.06 Hz, 2 H), 7.71 (m, 1 H), 7.53 (d, J=8.05 Hz, 2 H), 7.36 (m, 3 H), 7.30 (m, 2 H).
Reaction SMILES: [C:1]([C:3]1[C:4]([O:16][CH3:17])=[CH:5][C:6]([O:14][CH3:15])=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)#[CH:2].C([Li])CCC.[CH:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)=[O:24]>C1COCC1>[CH3:32][O:31][C:29](=[O:30])[C:28]1[CH:33]=[CH:34][C:25]([CH:23]([OH:24])[C:2]#[C:1][C:3]2[CH:8]=[C:7]([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)[C:6]([O:14][CH3:15])=[CH:5][C:4]=2[O:16][CH3:17])=[CH:26][CH:27]=1
Reactant: C#Cc1cc(-c2cccs2)c(OC)cc1OC
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)C#Cc2cc(-c3cccs3)c(OC)cc2OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
Ex-1C: A solution of 2-(5-ethynyl-2,4-dimethoxy-phenyl)-thiophene (1.5 g, 6.14 mmol) from Ex-1B in THF (20 mL) was cooled to −78° C. n-Butyllithium (6.72 mmol, 4.2 mL of a 1.6 M solution in hexanes) was added dropwise while maintaining an internal temperature below −65° C. After aging for 30 min at −78° C., the reaction was transferred via cannula over 10 min to a cold (−78° C.) solution of methyl 4-formylbenzoate (1.07 g, 6.52 mmol) in THF (10 mL). The resulting solution was slowly warmed to 0° C. and then quenched with a saturated NH4Cl solution. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Silica gel chromatography (hexane/ethyl acetate, 3:1, 1:1) gave 2.2 g (88%) of the desired 4-[3-(2,4-dimethoxy-5-thiophen-2-yl-phenyl)-1-hydroxy-prop-2-ynyl]-benzoic acid methyl ester as a greenish yellow solid, m.p. 128–130° C. 1H-NMR (300 MHz, CDCl3) d 8.08 (d, 2H, J=8.3 Hz), 7.75 (d, 2H, J=8.3 Hz), 7.68 (s, 1H), 7.37 (dd, 1H, J=3.6 and 1.7 Hz), 7.28 (dd, 1H, J=5.1 and 1.7 Hz), 7.06 (dd, 1H, J=5.1 and 3.6 Hz), 5.79 (d, 1H, J=6.6 Hz), 3.96 (s, 3H), 3.94 (s, 3H), 3.93 (s, 3H), 2.53 (d, 1H, J=6.6 Hz).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[Br:12]Br.OO>C(O)(=O)C>[Br:12][C:10]1[C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=[C:3]([CH:11]=1)[CH:2]=[O:1]
Reactant: COc1cc(C=O)ccc1O
Reactant: BrBr
Agent: OO
Solvent: CC(=O)O
Product: COc1cc(C=O)cc(Br)c1O
Temperature: 20 °C
Yield: 152.9 %

Procedure:
Anhydrous acetic acid (20 ml) followed by vanillin (7.5 g; 0.05 mole) were charged into a 100-ml round glass flask equipped with a stirring system, thermometer, a dropping funnel and cooled with a water bath at 20° C. Stirring was begun and then, when the vanillin had dissolved, a solution of bromine (4.8 g; 0.03 mole) in acetic acid (10 ml) was added dropwise. The temperature gradually increased to 30° C. When the bromine addition was complete, acetic acid (20 ml) was added, followed, dropwise, by hydrogen peroxide at a concentration of 30% of H2O2 (2.26 g; 0.02 mole). Stirring was continued for 10 min upon completion of the addition and the heterogeneous reaction mixture was cooled to 20° C. It was next filtered and the cake was washed on the filter with fresh acetic acid (10 ml) followed by ice water (30 ml). After drying under vacuum, a product (10.8 g) melting at 162 ° C. was obtained, in which 5-bromovanillin (10.60 g) was determined by high pressure liquid chromatography. Unconverted vanillin (0.45 g) was determined in the filtrate and the acetic acid wash.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:8]3[N:9]2[C:12](=[O:15])[NH:13][N:14]=3)=[CH:4][CH:3]=1.Cl[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([N:16]3[CH2:17][CH2:18][N:19]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=4)[CH2:20][CH2:21]3)[C:8]3[N:9]2[C:12](=[O:15])[NH:13][N:14]=3)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: O=c1[nH]nc2c(N3CCNCC3)nc3ccc(F)cc3n12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: O=c1[nH]nc2c(N3CCN(c4ccc(C(F)(F)F)cn4)CC3)nc3ccc(F)cc3n12
Temperature: 25 °C

Procedure:
A solution of 40 mg of 8-fluoro-4-piperazin-1-yl-[1,2,4]triazolo[4,3-a]quinoxalin-1-one, 48 mg of 2-chloro-5-trifluoromethylpyridine, and 47 mg of sodium carbonate in n-butanol (1 mL) was heated to reflux for 24 hrs. The reaction mixture was cooled to room temperature, filtered through a plug of diatomaceous earth, and evaporated to dryness. The residue was separated by silica gel chromatography to provide a white solid. MS (M+H)+=434.0.
Reaction SMILES: F[C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].CCO[C:13]([S-:15])=[S:14].[K+]>CN(C)C=O.O.Cl>[I:9][C:7]1[CH:6]=[CH:5][C:3]2[N:4]=[C:13]([SH:15])[S:14][C:2]=2[CH:8]=1
Reactant: Nc1ccc(I)cc1F
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Sc1nc2ccc(I)cc2s1
Temperature: 95 °C
Reaction time: 5 h

Procedure:
A mixture of 2-fluoro-4-iodoaniline (24.19 g, 0.100 mole) and potassium ethylxanthogenate (35.27 g, 0.220 mole) in N,N-dimethylformamide (80 mL) was stirred at 95° C. for 5 hours. The reaction mixture was cooled to room temperature then diluted with water (150 mL) and 1 N aqueous HCl (200 mL). The mixture was stirred at room temperature overnight. The resulting precipitate was collected by filtration and rinsed with water. The solid was dried overnight at 85° C. in a vacuum oven to provide 6-iodobenzo[d]thiazole-2-thiol. 1H NMR (300 MHz, CD3OD) δ ppm 7.09 (d, J=8 Hz, 1H), 7.70 (dd, J=2, 8 Hz, 1H), 8.10 (d, J=2 Hz, 1H), 13.82 (sbroad, 1H); MS (DCI/NH3) m/z 294 (M+H)+.