Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]=1[NH:14][S:15]([C:18]1[S:19][CH:20]=[C:21]([CH3:23])[N:22]=1)(=[O:17])=[O:16].C(P(CCCC)CCCC)CCC.[F:37][C@@H:38]([CH3:41])[CH2:39]O.N(/C(N1CCCCC1)=O)=N\C(N1CCCCC1)=O>C1COCC1>[F:37][C@@H:38]([CH3:41])[CH2:39][N:14]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:5]=1[O:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][CH2:9]2)[S:15]([C:18]1[S:19][CH:20]=[C:21]([CH3:23])[N:22]=1)(=[O:17])=[O:16]
Reactant: COCOc1cc2c(cc1NS(=O)(=O)c1nc(C)cs1)CCC2
Reactant: C[C@H](F)CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COCOc1cc2c(cc1N(C[C@H](C)F)S(=O)(=O)c1nc(C)cs1)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
896 mg of N-[6-(methoxymethoxy)-2,3-dihydro-1H-inden-5-yl]-4-methyl-1,3-thiazole-2-sulfonamide, 665 mg of tributyl phosphine, and 257 mg of (2S)-2-fluoropropan-1-ol were dissolved in 8.96 mL of THF, and 829 mg of 1,1′-[(E)-diazen-1,2-diyldicarbonyl]dipiperidine was added thereto, followed by stirring overnight at room temperature. After the insoluble materials were removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10 to 50:50) to obtain 632 mg of N-[(2S)-2-fluoropropyl]-N-[6-(methoxymethoxy)-2,3-dihydro-1H-inden-5-yl]-4-methyl-1,3-thiazole-2-sulfonamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([NH2:13])[CH:7]=[CH:6]2.[Br:14]N1C(=O)CCC1=O>CC#N>[Br:14][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[NH2:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2cc(N)ccc2c1
Solvent: CC#N
Product: COc1ccc2c(Br)c(N)ccc2c1
Yield: 74.4 %

Procedure:
6-Methoxy-2-naphthylamine (400 mg, 1.6 mmol) was suspended in 20 mL of MeCN with 12 mg of NH4OAc (0.16 mmol) and stirred in an ice bath. N-Bromosuccinimide (299 mg, 1.68 mmol) was dissolved in 6 mL of dry MeCN and added slowly over 1 hour (h). The reaction was stirred for an additional hour at 0° C., then adsorbed onto Celite, concentrated under reduced pressure and subjected to silica gel chromatography eluting with 0→60% EtOAc in heptanes to yield 300 mg of an orange solid. 7.94 (d, 1H); 7.55 (d, 1H); 7.18 (dd, 1H); 7.09 (d, 1H); 7.02 (d, 1H); 4.29 (br s, 2H); 3.89 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[C:21]([O:26][CH2:27][CH3:28])=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:36](Cl)([Cl:38])=[O:37]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:36]([Cl:38])=[O:37])[C:10]([C:20]3[C:21]([O:26][CH2:27][CH3:28])=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: CCOc1ncccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ncccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
To a solution of 4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-1H-imidazole (475 mg, 1.152 mmol) and triethylamine (321 uL, 2.304 mmol) in methylene chloride (6 mL) cooled to 0° C. was added phosgene (895 uL, 1.728 mmol, 20% solution in toluene, Fluka). The reaction mixture was stirred at 0° C. for 30 min then concentrated to dryness. The residue was taken in ethyl acetate, and the solids were filtered off. The filtrate was concentrated to give crude 4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-imidazole-1-carbonyl chloride as yellow solids (450 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([OH:11])[CH2:9][CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=1.CS(C)=O.C(N(CC)CC)C>O>[F:1][C:2]1[C:7]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCC(O)c1cccnc1F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CCC(=O)c1cccnc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 87.3 %

Procedure:
To a mixture of 1-(2-fluoropyridin-3-yl)propan-1-ol (12.3 g), dimethyl sulfoxide (130 mL) and triethylamine (65 mL) was added a sulfur trioxide-pyridine complex (25.6 g), and the mixture was stirred at room temperature for 14 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give the title compound as a brown oil (yield 10.6 g, 87%).
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=2)[C:10]1=[O:24])(C)(C)C>C(OCC)(=O)C.C(Cl)(Cl)Cl>[ClH:1].[NH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2[CH:16]=[C:17]([F:23])[C:18]([F:22])=[C:19]([F:21])[CH:20]=2)[C:10]1=[O:24]
Reactant: CC(C)(C)OC(=O)NN1CCCC(c2cc(F)c(F)c(F)c2)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: NN1CCCC(c2cc(F)c(F)c(F)c2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4 N hydrochloric acid in ethyl acetate (1 mL) was added to a solution of tert-butyl[2-oxo-3-(3,4,5-trifluorophenyl)piperidin-1-yl]carbamate (134 mg) in chloroform (1 mL), and the reaction solution was stirred at room temperature for three hours. The reaction solution was concentrated under reduced pressure to obtain 109 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH:1]1([NH:7][N:8]2[NH:12][CH:11]=[C:10]([C:13]3[N:14]([CH3:21])[C:15]([N+:18]([O-:20])=[O:19])=[CH:16][N:17]=3)[S:9]2)[CH2:6]CCC[CH2:2]1.[C:22](N)(C)(C)C.C1(N)CCCCC1>>[C:1]([NH:7][N:8]1[NH:12][CH:11]=[C:10]([C:13]2[N:14]([CH3:21])[C:15]([N+:18]([O-:20])=[O:19])=[CH:16][N:17]=2)[S:9]1)([CH3:2])([CH3:6])[CH3:22]
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(NC2CCCCC2)S1
Reactant: CC(C)(C)N
Solvent: NC1CCCCC1
Product: Cn1c([N+](=O)[O-])cnc1C1=CNN(NC(C)(C)C)S1

Procedure:
The preparation of the above compound is accomplished essentially by the procedure described for the 2-cyclohexylamino derivative (Example 38), an equivalent of t-butylamine replacing the cyclohexylamine. Recrystallization of the crude product from a mixture of ethyl acetate and acetone gives the pure compound melting at 249°-251° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10].Cl[S:22]([C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[C:28]([O:30][CH3:31])=[O:29])(=[O:24])=[O:23]>C(Cl)Cl.N1C=CC=CC=1>[CH3:31][O:30][C:28](=[O:29])[C:27]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:25]([S:22](=[O:23])(=[O:24])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH:13]=2)(=[O:11])=[O:10])[CH:26]=1
Reactant: Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Reactant: COC(=O)c1ccc(OC)c(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)c(S(=O)(=O)Nc2ccccc2NS(=O)(=O)c2cc3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid (2-aminophenyl)-amide (1 mmol) in DCM (2 mL) and pyridine (2 mL), methyl 3-(chlorosulfonyl)-4-methoxybenzoate (1.1 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight. The reaction mixture was then diluted with DCM (10 mL). The organic phase was washed with 10% aqueous HCl (10 mL), water (10 mL) and brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to obtain 350 mg of 3-[2-(benzo[b]thiophene-2-sulfonylamino)phenylsulfamoyl]-4-methoxybenzoic acid methyl ester. Tr 1.10 min, MS: 533.7 (M+1)+. 1H NMR (CDCl3, 400 MHz): δ 3.84 (s, 3H), 4.18 (s, 3H), 7.0-7.2 (m, 5H), 7.4-7.6 (m, 3H), 7.66 (s, 1H), 7.80 (d, 1H), 7.83 (d, 1H), 8.22 (dd, 1H), 8.34 (d, 1H) ppm.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=O)[NH:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[C:3]([C:13]([O:15][CH3:16])=[O:14])[N:4]=1
Reactant: COC(=O)c1[nH]c(=O)c2ccccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1nc(Cl)c2ccccc2c1O
Temperature: 0 °C

Procedure:
2.84 g (13 mmol) of methyl 4-hydroxy-1 (2H)-isoquinolone-3-carboxylate (prepared as in M. Suzuki, SYNTHESIS, 461 (1978)) was stirred at 70° C. for 3 h in 25 ml of phosphorus oxychloride. After cooling, the mixture was added to 500 ml of ice water, the precipitate was filtered off with suction next morning and dried at 70° C. under an IR Lamp. 2.96 g of product were obtained; m.p. 168° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.O.[NH3:12]>>[N:10]1[CH:9]=[CH:8][N:6]2[C:5]=1[CH:4]=[CH:3][C:2]([NH2:12])=[N:7]2
Reactant: Clc1ccc2nccn2n1
Reactant: N
Solvent: O
Product: Nc1ccc2nccn2n1
Yield: 67.3 %

Procedure:
A solution of 6-chloroimidazo[1,2-b]pyridazine (5.00 g, 32.6 mmol) in a 25% aqueous ammonia water (50 ml) was stirred in a sealed tube at 180° C. for 8 hours, and the reaction solution was distilled off under reduced pressure. A form solid was separated by filtration, which was washed with water to give 2.94 g (67.3%) of the desired product as a solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][CH:11]1[N:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[C:15]2[CH:21]=[CH:22][CH:23]=[CH:24][C:14]=2[NH:13][C:12]1=[O:25])=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:26]([C:29]1[S:30][CH:31]=[CH:32][C:33]=1[CH2:34]Br)(=[O:28])[CH3:27]>CN(C)C=O>[C:26]([C:29]1[S:30][CH:31]=[CH:32][C:33]=1[CH2:34][N:13]1[C:14]2[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=2[C:16]([CH:18]([CH3:19])[CH3:20])=[N:17][CH:11]([NH:10][C:8]([O:7][C:3]([CH3:5])([CH3:6])[CH3:4])=[O:9])[C:12]1=[O:25])(=[O:28])[CH3:27]
Reactant: CC(=O)c1sccc1CBr
Reactant: CC(C)C1=NC(NC(=O)OC(C)(C)C)C(=O)Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1sccc1CN1C(=O)C(NC(=O)OC(C)(C)C)N=C(C(C)C)c2ccccc21
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
To a suspension of sodium hydride (0.065 g of a 65% dispersion in mineral oil) in dry N,N-dimethylformamide (5 ml) was added dropwise a solution of (3RS)-3-tert-butoxycarbonylamino-2,3-dihydro-5-isopropyl-1H-1, 4-benzodiazepin-2-one (0.508 g) in dry N,N-dimethylformamide (5 ml) under cooling in an ice-bath. The mixture was stirred under the same condition for 30 minutes and then at ambient temperature for 2 hours. To the mixture was added dropwise a solution of 2-acetyl-3-bromomethylthiophene (0.420 g) in dry N,N-dimethylformamide under cooling in an ice-bath. After completion of the addition, the mixture was stirred under the same condition for 30 minutes and then at ambient temperature overnight. The resultant mixture was concentrated in vacuo. The residue was treated with ethyl acetate (100 ml), washed with water (50 ml) and dried over anhydrous sodium sulfate. Filtration and evaporation gave a crude product. The product was purified by column chromatography on silica gel with an eluent of a mixture of chloroform and ethyl acetate (10: 1) to give (3RS)-1-(2-acetylthiophen-3-yl)methyl-3-tert-butoxycarbonylamino-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one (0.380 g).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[CH:5][O:4][C:3]=1[C:8]([OH:10])=[O:9].[Li+].CC([N-]C(C)C)C.[P:19](Cl)([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20]>C(OCC)C>[CH2:22]([O:21][P:19]([C:5]1[O:4][C:3]([C:8]([OH:10])=[O:9])=[C:2]([Cl:1])[C:6]=1[Cl:7])([O:24][CH2:25][CH3:26])=[O:20])[CH3:23]
Reactant: CCOP(=O)(Cl)OCC
Reactant: O=C(O)c1occ(Cl)c1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Product: CCOP(=O)(OCC)c1oc(C(=O)O)c(Cl)c1Cl

Procedure:
A solution of 3,4-dichloro-2-furoic acid (1 mmol) in diethyl ether was treated with LDA (3 mmol) at −78° C. for 30 min and then treated with diethyl chlorophosphate (3.5 mmol) at −78° C. for 1 h. The reaction was quenched and extracted to give 5-diethylphosphono-3,4-dichloro-2-furoic acid as a yellow foam.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:18]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)=[O:8].[N:19]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22][C@H:21]2[CH2:24][NH:25][CH2:26][C@@H:20]12>>[F:17][C:12]1[CH:11]=[C:10]([NH:9][C:7]([C:6]2[CH:18]=[C:2]([N:25]3[CH2:24][C@@H:21]4[CH2:22][CH2:23][N:19]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:20]4[CH2:26]3)[CH:3]=[N:4][CH:5]=2)=[O:8])[CH:15]=[C:14]([F:16])[CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2CNC[C@H]21
Reactant: O=C(Nc1cc(F)cc(F)c1)c1cncc(Br)c1
Product: CC(C)(C)OC(=O)N1CC[C@H]2CN(c3cncc(C(=O)Nc4cc(F)cc(F)c4)c3)C[C@H]21

Procedure:
The product from Example 53A and (3aS,6aS)-tert-butyl hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate (prepared as described in WO2001081347) were processed as described in Example 53B to provide the title compound. MS (APCI) m/z=445 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][NH2:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:14](OCC)(OCC)(OCC)[CH3:15]>>[Cl:1][C:2]1[C:11]2[N:10]([C:14]([CH3:15])=[N:13][N:12]=2)[C:9]2[C:4]([N:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: CCOC(C)(OCC)OCC
Reactant: NNc1nc2ccccc2nc1Cl
Product: Cc1nnc2c(Cl)nc3ccccc3n12
Temperature: 25 °C
Yield: 65 %

Procedure:
2-Chloro-3-hydrazinoquinoxaline (15.5 g., 0.080 mole), the product of Example 1, was stirred with triethyl orthoacetate for 3 hours at 100° C. The mixture was cooled to room temperature and the solid precipitate was collected by filtration, washed with ethanol and air dried to afford 11.4 g. (65% yield) of 4-chloro-1-methyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 215°-222° C. Mass spectrum: m/e, 218 (P).
Reaction SMILES: FC(F)(F)S(O[Si:7]([CH3:18])([CH3:17])[CH:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH3:15])=[C:9]1[CH3:16])(=O)=O.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[C-:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32]1.[Li+]>CCOCC>[CH3:17][Si:7]([CH3:18])([CH:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31]([C:22]2[CH:23]=[CH:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:21]=2)=[CH:32]1)[CH:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH3:15])=[C:9]1[CH3:16]
Reactant: c1ccc2cc(-[c-]3ccc4ccccc43)ccc2c1
Reactant: CC1=C(C)C([Si](C)(C)OS(=O)(=O)C(F)(F)F)C(C)=C1C
Agent: [Li+]
Solvent: CCOCC
Product: CC1=C(C)C([Si](C)(C)C2C=C(c3ccc4ccccc4c3)c3ccccc32)C(C)=C1C
Reaction time: 19 h

Procedure:
To a solution of dimethyl(2,3,4,5-tetramethylcyclopenta-2,4-dien-1-yl)silyl trifluoromethanesulfonate (Compound C, 7.50 g, 22.8 mmol, 1.00 eq.) in ether (25 mL) at −35° C. was added lithium (1-(2-naphthyl)indenide) (6.05 g, 24.4 mmol, 1.07 eq.). The reaction was stirred for 19 hours, and was then evaporated under vacuum. The residue was extracted with pentane (40 mL, then 2×20 mL) and the extract was filtered. The resulting solution was evaporated under vacuum to give a foam. The foam was extracted with pentane and the extracts were filtered to give a solution. The solution was evaporated under vacuum to give thick oil. Yield 9.44 g (98%). 1H NMR(C6D6): δ 8.20 (s, 1H), 7.84 (d, 1H), 7.76 (m, 2H), 7.70 (m, 2H) 7.51 (d, 1H), 7.27 (m, 4H), 6.71 (s, 1H), 3.75, (s, 1H), 2.94 (br s, 1H), 1.95 (s, 3H), 1.93 (s, 3H), 1.84 (s, 3H), 1.82 (s, 3H), −0.04 (s, 3H), −0.34 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[C:13]#[N:14].O>C1COCC1>[C:13]([C:6]1[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=1[CH2:4][C:3]([OH:15])=[O:2])#[N:14]
Reactant: COC(=O)Cc1ccc(OC)cc1C#N
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CC(=O)O)c(C#N)c1
Temperature: 55 °C
Yield: 76.9 %

Procedure:
The (2-cyano-4-methoxy-phenyl)-acetic acid methyl ester (120 mg, 0.585 mmol) was dissolved in 10 mL THF and 2 mL water and LiOH monohydrate (101 mg, 2.34 mmol) was added. The mixture was heated at 55° C. overnight. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in 30 mL water and adjusted to pH ˜14 with aqueous 1N NaOH. The aqueous layer was washed with 50 mL of ethyl acetate. The organic extract was discarded and the aqueous phase was treated with 1N HCl (aq.) to pH˜2-3. The aqueous solution was washed with 75 mL ethyl acetate and the organic solution was dried (MgSO4), filtered and concentrated to give 86 mg (77%) of the title compound (SM-1ah) as a yellow solid. MS (ES+) 192.2 (M+H)+ 1H NMR (CDCl3) δ 3.81 (s, 3H), 3.84 (s, 2H), 7.09 (dd, 1H), 7.13 (d, 1H), 7.30 (d, 1H), 10.22 (br s, 1H).
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:7]=[C:8]([C:12](=O)[CH:13]=O)[CH:9]=[CH:10][CH:11]=1)([F:4])[F:3].I.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:27][NH2:28])=[NH:26])=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[N:27]=[N:28][CH:13]=[C:12]([C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([S:5][C:2]([F:1])([F:3])[F:4])[CH:7]=3)[N:26]=2)=[CH:23][CH:24]=1
Reactant: O=CC(=O)c1cccc(SC(F)(F)F)c1
Reactant: COc1ccc(C(=N)NN)cc1
Agent: I
Product: COc1ccc(-c2nncc(-c3cccc(SC(F)(F)F)c3)n2)cc1

Procedure:
(3-Trifluoromethylsulfanylphenyl)oxoacetaldehyde was reacted with 4-methoxybenzenecarboximidic hydrazide hydriodide salt (1.11 g, 3.78 mmol) using the method described in Example 1 to give 3-(4-methoxyphenyl)-5-(3-trifluoromethylsulfanylphenyl)-[1,2,4]triazine as a yellow solid (820 g): δH (400 MHz, CDCl3) 3.92 (3H, s), 7.06-7.10 (2H, m), 7.67 (1H, t, J 7.8 Hz), 7.90 (1H, d, J 7.8 Hz), 8.35-8.39 (1H, m), 8.56 (1H, s), 8.60-8.64 (2H, m), 9.55 (1H, s); m/z (ES+) 364.
Reaction SMILES: [C:1]([O:6][CH:7]([O:9][C:10]([NH:12][CH2:13][C:14]1([CH2:20][C:21]([O:23]CC=C)=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].N1CCOCC1>C(#N)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:6][CH:7]([O:9][C:10]([NH:12][CH2:13][C:14]1([CH2:20][C:21]([OH:23])=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: C=CCOC(=O)CC1(CNC(=O)OC(C)OC(=O)C(C)C)CCCCC1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1COCCN1
Product: CC(OC(=O)NCC1(CC(=O)O)CCCCC1)OC(=O)C(C)C
Reaction time: 1 h

Procedure:
To a stirred solution of compound (15) (1 g, 2.7 mmol) in acetonitrile (10 mL) under nitrogen was added (10 mg, 0.008 mmol) of tetrakis(triphenylphosphine) palladium (0) followed by morpholine (0.28 mL, 0.28 g, 3.2 mmol). After one hour, the solvent was removed in vacuo. The resulting oil was dissolved in diethyl ether (50 mL) and the organic phase was washed with 2N HCl (20 mL), water (20 mL) and brine (20 mL). The ether layer was dried over anhydrous sodium sulfate and concentrated to give an oil, which was purified by column chromatography on silica gel, eluting with 30% ethyl acetate:hexane. The desired product (11) was isolated as a white crystalline solid (0.75 g, 84% yield), m.p 63-64° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:31]=[CH:30][CH:29]=[CH:28][C:8]=1[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH2:21])=O)[CH:17]=2)[C:12]([C:22](=[O:25])[CH2:23][CH3:24])=[C:11]1[CH2:26][CH3:27].O.N>CN(C)C=O>[Cl:6][C:7]1[CH:31]=[CH:30][CH:29]=[CH:28][C:8]=1[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[N:21])[CH:17]=2)[C:12]([C:22](=[O:25])[CH2:23][CH3:24])=[C:11]1[CH2:26][CH3:27]
Reactant: CCC(=O)c1c(CC)n(Cc2ccccc2Cl)c2cc(C(N)=O)ccc12
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)c1c(CC)n(Cc2ccccc2Cl)c2cc(C#N)ccc12
Reaction time: 0.25 h
Yield: 87.3 %

Procedure:
To a solution of phosphorus oxychloride (0.031 ml) in dimethylformamide (1.2 ml) was added 1-(2-chlorobenzyl)-2-ethyl-3-propionylindole-6-carboxamide (112 mg) at 0° C., and the mixture was stirred for 15 minutes. The resulting mixture was poured into ammonia water and ice, and then extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was triturated with a mixture of hexane and isopropyl ether to give 1-(2-chlorobenzyl)-2-ethyl-3-propionylindole-6-carbonitrile (93 mg) as a solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[CH3:27][CH:28]([CH3:31])[CH2:29][NH2:30]>C(#N)C>[CH3:27][CH:28]([CH3:31])[CH2:29][NH:30][CH2:12][CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:18][CH:19]=2)[O:14]1
Reactant: CC(C)CN
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CC(C)CNCC1CCc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 25: [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), 2-methylpropan-1-amine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 297 (M+, 6), 254 (33), 130 (7), 87 (7), 86 (bp), 57 (9).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([N+]([O-])=O)=[C:12]([CH:19]=[CH:20][N:21]3CCCC3)[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.O.NN>[Ni].C1COCC1>[NH:21]1[C:13]2[C:12](=[CH:11][C:10]([C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[O:9])=[CH:15][CH:14]=2)[CH:19]=[CH:20]1
Reactant: CN1CCN(C(=O)c2ccc([N+](=O)[O-])c(C=CN3CCCC3)c2)CC1
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(C(=O)c2ccc3[nH]ccc3c2)CC1

Procedure:
(4-Methylpiperazin-1-yl)-[4-nitro-3-(2-pyrrolidin-1-yl-vinyl)phenyl]methanone (2.907 mmol, 1.0 gram) (obtained from step (ii)) was taken in a 25 mL, two necked round bottom flask provided with a condenser, under nitrogen atmosphere. To this THF (7 mL) was added, followed by Raney-Nickel (Ra-Ni) (0.1 gram). Hydrazine hydrate (14.54 mmol, 0.73 gram) was added to the above reaction mixture in such a way that the reaction mixture starts refluxing. The reaction mixture was further refluxed for 3 hours. After the completion of reaction, Ra-Ni was removed by filtration, THF and methanol were distilled off and the concentrate was diluted with water (20 mL), basified with 20% sodium hydroxide solution to pH: 10 and the mixture was extracted with ethyl acetate (2×30 mL). The combined ethyl acetate extracts were then washed with water (2×30 mL), brine (30 Ml) and dried over anhydrous sodium sulfate. The volatiles were removed under the reduced pressure to obtain thick syrupy mass. This thick syrupy mass was purified over silica gel column, eluent being ethyl acetate and triethylamine (0.2 to 1.0%).