Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:10]2[S:9][N:8]=[CH:7][C:6]=2[C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].O1CCCC1.C([O-])(=O)C.[Na+]>Cl.O>[CH2:12]([O:11][C:5]1[C:6]2[CH:7]=[N:8][S:9][C:10]=2[CH:2]=[CH:3][CH:4]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc(OCc2ccccc2)c2cnsc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(COc2cccc3sncc23)cc1
Temperature: 25 °C
Yield: 59 %

Procedure:
54 g of 7-amino-4-benzyloxy-1,2-benzisothiazole are suspended in 400 ml of half-concentrated hydrochloric acid and diazotized at from 0° to 5° C. with a solution of 16 g of sodium nitrite in 60 ml of water. 500 ml of tetrahydrofuran, 400 ml of a saturated sodium acetate solution and 120 g of sodium acetate are then added and the mixture is allowed to warm up to room temperature. The two-phase reaction medium is then repeatedly extracted with methylene chloride. The combined extracts are dried over magnesium sulfate and then free from solvent under reduced pressure. The crude product is fractionated, giving 30 g (60% of theory) of 4-benzyloxy-1,2-benzisothiazole of melting point 47°-49° C. (boiling point 165° C./0.4 mm Hg).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([NH:8][CH3:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(CC)CC.[CH2:19]([O:26][CH2:27][C:28](Cl)=[O:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl.CCOC(C)=O>[CH2:19]([O:26][CH2:27][C:28]([N:8]([CH3:9])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1)=[O:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CNc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)COCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C(=O)COCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 70 %

Procedure:
To a suspension of 4-nitro-N-methylaniline in DCM (10 mL) was added at 0° C. was added Et3N (0.63 mL, 4.5 mmol) and 2-benzoxyacetyl chloride (0.513 mL, 3.3 mmol). After stirring for 15 h at room temperature, the reaction mixture was diluted with EtOAc, washed with Sat. NaHCO3, brine, dried and concentrated to give 2-benzoxy-N-methyl-N-(4-nitrophenyl)acetamide (0.63 g, 70%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[S:20](Cl)(=[O:22])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>ClCCl>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[S:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)(=[O:22])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1cc2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: C1CNCCN1
Solvent: ClCCl
Product: O=S(=O)(c1cc2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1)N1CCNCC1
Reaction time: 2 h

Procedure:
The requisite 1-(1-benzenesulphonyl-5-chloroindol-2-ylsulphonyl)piperazine starting material was prepared as follows. A solution of 1-benzenesulphonyl-5-chloroindol-2-ylsulphonyl chloride (10.0 g, 25.6 mmol) in dichloromethane (100 ml) was added dropwise to a stirred solution of piperazine (13.23 g, 6 eq.) in dichloromethane (200 ml), and the mixture stirred for a further 2 hrs. The reaction mixture was then washed with water (3×200 ml), dried (Phase-Separating paper) and evaporated to give a red oil which was purified by flash chromatography using Merck silica (Art. 9385), eluting with dichloromethane containing methanol (0-6%), to give 1-(1-benzene sulphonyl-5-chloroindol-2-ylsulphonyl)piperazine as a colourless solid, 1H NMR (CDCl3) 2.95 ppm (m, 4H), 3.4 ppm (m, 4H), 7.4 ppm (m, 4H), 7.55 ppm (m, 2H), 8.0 ppm (d, 2H), 8.0 ppm (d, 1H); MS (M+H)+ 440/442.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[C:8]([CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:10][CH2:11][CH3:12])=[O:9]>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][C:4](=[CH:13][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]1
Reactant: O=C1CCOCC1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C=C1CCOCC1
Yield: 56.4 %

Procedure:
A solution of tetrahydo-4H-pyran-4-one (5 g, 50 mmol) in CH2Cl2 (500 mL) was treated with (carbethoxymethylene)triphenylphosphorane (19.29 g, 55 mmol) stirred at reflux for 24 h, concentrated and purified via silica gel column chromatography eluting with 10% ethyl acetate/hexane to give 4.8 g of the title compound. MS (APCI): m/z 188 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:24]=[C:11]3[CH:12]=[C:13]([C:16]4[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=4)C=O)[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C1([Mg]Br)CC1.[O:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:24]=[C:11]3[CH:12]=[C:13]([C:16]4[CH:17]=[C:18]([C:33]5([CH2:34][OH:30])[CH2:31][CH2:32]5)[CH:21]=[CH:22][CH:23]=4)[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(-c2ccn3nc(-c4ccc(Cl)cc4)cc3c2)c1
Reactant: C1CCOC1
Agent: Br[Mg]C1CC1
Product: OCC1(c2cccc(-c3ccn4nc(-c5ccc(Cl)cc5)cc4c3)c2)CC1
Yield: 59 %

Procedure:
The procedure described in stage 6.2 is followed. Starting from 0.15 g (0.45 mmol) of 3-[2-(4-chlorophenyl)pyrazolo[1,5-a]pyridin-5-yl]benzaldehyde, obtained according to the process described in 6.1, in solution in 8 ml of tetrahydrofuran, followed by addition of 1.80 ml (0.9 mmol) of a cyclopropylmagnesium bromide solution (0.5M in tetrahydrofuran) and after chromatographing on silica gel, elution being carried out with a mixture of cyclohexane and ethyl acetate (8/2), 0.1 g (59%) of the expected product is obtained in the form of a beige powder.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].I[CH2:13][CH:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.CCOCC>[CH3:13][CH:14]([CH3:16])[CH2:15][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)CI
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CC(C)COc1ccc(C=O)cc1
Yield: 46 %

Procedure:
A 1000 mL, 1 neck, round-bottomed flask equipped with a magnetic stirrer and reflux condenser is charged with 4-hydroxybenzaldehyde (33.18 g, 0.272 mol), 100 ml of ethanol, and a solution of potassium hydroxide (20.42 g, 0.309 mol) in 100 mL of ethanol. The reaction mixture is heated with stirring for one-half hour. Next 1-iodo-2-methylpropane (100 g, 0.543 mol) is added and the mixture refluxed for 12 hours. After cooling, the solvents are removed by rotary evaporation to yield a brown solid which is added to a separatory funnel containing 500 mL ether and 500 mL of 5% aqueous sodium carbonate. The layers are separated and the aqueous phase is washed with ether (2×500 mL). The combined ether layers are washed with pH 12 sodium hydroxide solution (5×200 mL) until the washes are colorless. The organic solution is then washed with brine (100 mL) and dried over magnesium sulfate. After filtration and removal of the solvents by rotary evaporation, a viscous yellow liquid is obtained. This material is purified by Kugel-Rohr distillation to give 22.3 g (0.125 mol, 46%) of a colorless liquid.
Reaction SMILES: [C:1]([OH:6])(=O)[CH:2]([CH3:4])[CH3:3].[NH:7]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9][CH2:8]1>>[OH:14][CH2:13][CH:10]1[CH2:11][CH2:12][N:7]([C:1](=[O:6])[CH:2]([CH3:4])[CH3:3])[CH2:8][CH2:9]1
Reactant: CC(C)C(=O)O
Reactant: OCC1CCNCC1
Product: CC(C)C(=O)N1CCC(CO)CC1

Procedure:
Prepared as in Example 24a from isobutyric acid and piperidin-4-ylmethanol as a colorless oil (36%). MS 186 (MH+).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C@@H:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH:25]=[CH2:26])[CH:21]=2)[CH2:16]1)(C)(C)C>C(Cl)Cl>[CH:25]([C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C@H:15]([NH2:14])[CH2:24][CH2:23]2)=[CH2:26]
Reactant: C=Cc1ccc2c(c1)CC[C@@H](NC(=O)OC(C)(C)C)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=Cc1ccc2c(c1)CC[C@@H](N)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
TFA (0.7 mL, 9.07 mmol) was added dropwise to a solution of (6-vinyl-1,2,3,4-tetrahydro-naphthalen-2-(R)-yl)-carbamic acid tert-butyl ester (620 mg, 2.27 mmol) in CH2Cl2 (10 mL). After stirring at RT for 4 h, the mixture was evaporated to dryness. Et3N (1 mL) was added to the residue and evaporated again to give the crude which was directly used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH2:27][NH:28][CH2:29][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.Cl.[CH3:31][N:32]([CH3:39])[CH2:33]/[CH:34]=[CH:35]/[C:36](O)=[O:37]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH2:27][N:28]([C:36](=[O:37])/[CH:35]=[CH:34]/[CH2:33][N:32]([CH3:39])[CH3:31])[CH2:29][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CN(C)C/C=C/C(=O)O
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4sc5c(c34)CNC5)cc2Cl)c1
Agent: Cl
Product: CN(C)C/C=C/C(=O)N1Cc2sc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2C1

Procedure:
In analogy to Example 89, the title compound was prepared from N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6,7-dihydro-5H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-amine from Example 29A (46 mg, 0.11 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (25 mg, 0.15 mmol) to yield 19 mg (33%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][CH3:12])[C:8]([N+:13]([O-:15])=[O:14])=[CH:7][C:3]=1[C:4]([OH:6])=O.ClC(N(C)C)=C(C)C.[F:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][C:26]=1[Cl:32].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([N+:13]([O-:15])=[O:14])[C:9]([NH:11][CH3:12])=[CH:10][C:2]=2[F:1])=[CH:27][C:26]=1[Cl:32]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CNc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cc(F)c(C(=O)Nc2ccc(F)c(Cl)c2)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
A mixture of 2-fluoro-4-methylamino-5-nitro-benzoic acid (0.500 g, 2.34 mmol), (1-chloro-2-methyl-propenyl)-dimethylamine (0.371 mL, 2.80 mmol) and DCM (50 mL) is stirred for 30 min, then 4-fluoro-3-chloro-aniline (0.340 g, 2.34 mmol) and DIPEA (0.549 mL, 3.15 mmol) are added and it is stirred for 2 h. The mixture is concentrated, water is added and the precipitate is filtered, washed with water and dried to give the subtitle compound.
Reaction SMILES: [C:1]([O:4][CH:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:6])(=[O:3])[CH3:2].[CH:13]1(C(O)C)CCCC[CH2:14]1>>[C:1]([O:4][CH:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:6])(=[O:3])[CH2:2][CH2:13][CH3:14]
Reactant: CC(=O)OC(C)C1CCCCC1
Reactant: CC(O)C1CCCCC1
Product: CCCC(=O)OC(C)C1CCCCC1

Procedure:
1-cyclohexylethan-1-yl acetate; 1-cyclohexylethan-1-ol;
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[NH:10][C:11]1([C:14]#[N:15])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:17]=[N+:18]=[N-:19].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:16])[NH:10][C:11]1([C:14]2[NH:19][N:18]=[N:17][N:15]=2)[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1(NC(=O)OCc2ccccc2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NC1(c2nnn[nH]2)CC1)OCc1ccccc1
Temperature: 110 °C
Reaction time: 24 h
Yield: 63.4 %

Procedure:
To a round bottom flask was added (1-cyano-cyclopropyl)-carbamic acid benzyl ester (500 mg, 2.31 mmol) in DMF (4 ml), followed by the addition of NaN3 (195 mg, 3 mmol) and NH4Cl (161 mg, 3 mmol). The reaction mixture was stirred at 110° C. for 24 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc/water. The organic layer was separated, washed with brine, dried under any. Na2SO4, filtered and concentrated to afford 380 mg of [1-(1H-tetrazol-5-yl)-cyclopropyl]-carbamic acid benzyl ester as a off-white solid, m/z 260.8 [M+1]+.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[C:1]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])(=[O:8])[C:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH:3]=1
Reactant: O=C(Nc1ccccc1F)c1cccnc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(Nc1ccccc1F)C1=CNCCC1
Yield: 70 %

Procedure:
Fifty grams of N-nicotinoyl-2-fluoroaniline was dissolved in 700 ml of 10% hydrous ethanol. To the solution, 5 g of 10% palladium-on-carbon was added and the mixture was reduced with hydrogen at room temperature and at atmospheric pressure. When a stoichiometric amount of hydrogen was absorbed, the reaction was stopped and the catalyst was removed. the liquid reaction mixture was concentrated and the resulting crystal was recrystallized from hydrous methanol to give N-(1,4,5,6-tetrahydronicotinoyl)-2-fluoroaniline having a melting point of 137° to 140° C. Yield=70%.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][N:22]=2)=[CH:17][CH:16]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(NC(C)C)(C)C.O=O.[F:37][C:38]([F:48])([F:47])[CH:39]([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:40][CH2:41]I.[Cl-].[NH4+]>CCCCCC.C1COCC1>[CH2:6]([O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:41][CH2:40][CH:39]([C:38]([F:37])([F:48])[F:47])[CH2:43][CH2:44][CH2:45][CH3:46])=[CH:23][N:22]=2)=[CH:19][CH:20]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCC(CCI)C(F)(F)F
Reactant: CCCCCCCCOc1ccc(-c2ccc(C)cn2)cc1
Agent: O=O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCCCCCOc1ccc(-c2ccc(CCCC(CCCC)C(F)(F)F)cn2)cc1
Reaction time: 12 h

Procedure:
0.2 mol of a 1.6 N solution of n-butyllithium in hexane and subsequently, at -30° C. to -40° C., a solution of 0.19 mol of 2 (p-octyloxyphenyl)-5-methylpyridine in THF are added to 0.2 mol of diisopropylamine in 100 ml of THF with exclusion of atmospheric oxygen and moisture. The reaction mixture is allowed to warm slowly until a clear solution is produced, and 0.2 mol of 3-trifluoromethylheptyl iodide (optically active) is then added. After 12 hours, the reaction mixture is hydrolyzed using saturated ammonium chloride solution, and is then subjected to customary work-up, giving optically active 2-(p-octyloxyphenyl)-5-(4-trifluoromethyloctyl)pyridine.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])=[CH:3][N:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12]([OH:14])=[O:13])=[CH:3][N:2]=1
Reactant: CC(C)(C)OC(=O)Cc1cncc2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cc1cncc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a solution of tert-butyl 2-(isoquinolin-4-yl)acetate (1.8 g, 7.4 mmol) in DCM (10 mL) was added TFA (10 mL) dropwise. The reaction was stirred at room temperature overnight. After the reaction completed, the solvent was evaporated and the residue was neutralized with aqueous ammonia to pH 3-4, then the precipitate was filtered, washed with water and ether, and the ether extract was collected to give the title compound (1.3 g, 93%) LC-MS (0.05% TFA): [M+1]+ 188.1. 1H-NMR (DMSO-d6, 400 MHz): δ 9.39 (s, 1H), 8.48 (s, 1H), 8.24 (d, 1H, J=6.4 Hz), 7.93 (t, 1H), 7.79 (m, 1H), 4.11 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[CH:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=3)[N+:11]=2[O-:27])=[CH:6][CH:5]=1)([O-])=O.[S-2].[Na+].[Na+].O>C(O)C>[NH2:24][C:21]1[CH:20]=[CH:19][C:18]([CH:17]=[CH:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([CH:9]=[CH:8][C:7]3[CH:28]=[CH:29][C:4]([NH2:1])=[CH:5][CH:6]=3)[N+:11]=2[O-:27])=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2cccc(C=Cc3ccc([N+](=O)[O-])cc3)[n+]2[O-])cc1
Agent: [Na+]
Agent: [S-2]
Solvent: CCO
Solvent: O
Product: Nc1ccc(C=Cc2cccc(C=Cc3ccc(N)cc3)[n+]2[O-])cc1
Yield: 88.7 %

Procedure:
More specifically, the synthesizing procedure is as follows. 2,6-dimethylpyridine or a substituted product thereof, is reacted with p-nitrobenzenealdehyde or a substituted product according to a method described, for example, in Journal of Organic Chemistry, vol. 15, P. 1184 (1950) to synthesize 2,6-di(p-nitrostyryl)pyridine (K). 30 g of this nitro compound is reacted wtih 27 g of m-chloroperbenzoic acid in three liter of dichloromethane to obtain 24 g of 2,6-di(p-nitrostyryl)pyridine-N-oxide. 24 g of this pyridine-N-oxide is reacted with 90 g of sodium sulfide in a solution mixed four liter of water with four liter of ethanol to reduce nitro group selectively and form 18 g of 2,6-di(p-aminostyryl)pyridine-N-oxide (M). The N-oxide amino compound is converted into a diazo compound according to a conventional method, and thereby tetrazonium salt is isolated as 15 g of hydroborofluoric salt (N). 5.0 g of the tetrazonium salt (N) and 5.0 g of 2-hydroxy-3-phenylcarbamoylnaphthalene (O) were dissolved in one liter of DMF, to which aqueous sodium acetate solution (7 g/100 ml) was added to perform coupling reaction. After two hours of stirring, the resultant crystals were separated by filtration, and the crystals were rinsed three times respectively with five liter water, three times respectively with five liter THF, then dried, to obtain 4.0 g of the final product, azo compound (P - 1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:8]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=1)([O-])=O.[Cl-].[NH4+].C(OCC)(=O)C>[Fe].O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:8]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=1
Reactant: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1Oc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)Nc1cc(N)ccc1Oc1ccccc1
Temperature: 80 °C
Yield: 62.9 %

Procedure:
To 52.1 g of N-(5-nitro-2-phenoxyphenyl)methanesulfonamide was added 51 ml of an aqueous solution containing 2.7 g of ammonium chloride, and then 42.5 g of an iron powder was added thereto with heating at 80° C. with stirring, followed by stirring for 2 hours. To the reaction cooled to 50° C. were added ethyl acetate and water, and the precipitate was filtered. After extraction with ethyl acetate, the organic layer was successively washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethanol to give 29.6 g of N-(5-amino-2-phenoxyphenyl)methanesulfonamide.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[C:14]([F:21])=[CH:13][C:11]=2[N:12]=1.FC1C=CC2SC(C3C(C)=NNC=3N)=NC=2C=1.[N:39]1[CH:44]=[CH:43][C:42]([CH2:45][NH2:46])=[CH:41][CH:40]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N:39]1[CH:44]=[CH:43][C:42]([CH2:45][NH:46][S:17]([C:15]2[C:14]([F:21])=[CH:13][C:11]3[N:12]=[C:8]([C:3]4[C:4]([CH3:7])=[N:5][NH:6][C:2]=4[NH2:1])[S:9][C:10]=3[CH:16]=2)(=[O:19])=[O:18])=[CH:41][CH:40]=1
Reactant: Cc1n[nH]c(N)c1-c1nc2cc(F)c(S(=O)(=O)Cl)cc2s1
Reactant: NCc1ccncc1
Agent: Cc1n[nH]c(N)c1-c1nc2cc(F)ccc2s1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1n[nH]c(N)c1-c1nc2cc(F)c(S(=O)(=O)NCc3ccncc3)cc2s1
Yield: 24 %

Procedure:
The title compound (15 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-5-fluorobenzothiazole-6-sulfonyl chloride, which had been derived from the chlorosulfonation of 90 mg of 4-(5-fluorobenzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine, 32 mg (0.30 mmol) of C-pyridin-4-ylmethylamine, and triethylamine (0.50 mL) in chloroform. MS (m/z, ES+): 419.1 (M+1,100%), 210.0 (100%). Yield=24%.
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29]([C:34]([NH:36][C@@H:37]1[CH2:39][C@@H:38]1[NH2:40])=[O:35])=[CH:28]2.[CH3:41][N:42]1[CH2:47][CH2:46][C:45]2[N:48]=[C:49]([C:51]([O-])=[O:52])[S:50][C:44]=2[CH2:43]1.[Li+]>CN(C)C=O>[ClH:24].[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29]([C:34]([NH:36][C@@H:37]1[CH2:39][C@@H:38]1[NH:40][C:51]([C:49]1[S:50][C:44]3[CH2:43][N:42]([CH3:41])[CH2:47][CH2:46][C:45]=3[N:48]=1)=[O:52])=[O:35])=[CH:28]2
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Reactant: N[C@H]1C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCc2nc(C(=O)N[C@H]3C[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Reaction time: 192 h
Yield: 71.4 %

Procedure:
1-Hydroxybenzotriazole monohydrate (71 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (100 mg) were added to a solution with (±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclopropanediamine (108 mg) and lithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate (124 mg) dissolved in N,N-dimethylformamide (3 ml) at room temperature, and the mixture was stirred for 8 days. After concentrating the reaction mixture under reduced pressure using a vacuum pump, water (50 ml) and a saturated aqueous solution (50 ml) of sodium hydrogencarbonate were added to the residue to conduct extraction with dichloromethane. The resultant organic layers were collected and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by preparative thin-layer chromatography on silica gel (dichloromethane:methanol=10:1). After 1N hydrochloric acid, dichloromethane and methanol were added to the thus-obtained amorphous substance, the mixture was concentrated to obtain the title compound (72 mg) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]=[CH2:13])=[CH:6][CH:5]=1)=[O:3].[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH:18]=O>>[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH:18]=[CH:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]=[CH2:13])=[CH:6][CH:5]=1)=[O:3]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: C=CCOc1ccc(C(C)=O)cc1
Product: C=CCOc1ccc(C(=O)C=Cc2ccc(OC)cc2OC)cc1
Reaction time: 18 h
Yield: 92.2 %

Procedure:
17.6 g (0.1 mol) of 4-allyloxyacetophenone and 16.6 g (0.1 mol) of 2,4-dimethoxy-benzaldehyde were under an inert dry atmosphere (argon) dissolved in 100 ml of dry ethanol (freshly distilled from sodium under argon atmosphere). The solution was added 1 g of sodium hydroxide and left under stirring for 18 h. The reaction mixture was filtered to give 29.9 g (97%) of 2,4-dimethoxy-4′-prop-2-enyloxychalcone identical to that obtained in Example 2.22, m.p. 74.5-75° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][N:18]=[CH:17]2>O>[NH:19]1[C:20]2[C:16](=[CH:15][C:14]([N:13]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]3=[O:11])=[CH:22][CH:21]=2)[CH:17]=[N:18]1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=C1Nc2ccc(F)cc2C1=O
Solvent: O
Product: O=C1Nc2ccc(F)cc2C1=Nc1ccc2[nH]ncc2c1
Yield: 44.2 %

Procedure:
The title compound (62 mg, 43%) was synthesized as a brick red solid (instead of stirring at it, 1 mL of H2O was added to crash out the product) according to the method described for Example A74 using 5-fluoroisatin (82.5 mg, 0.5 mmol), 5-aminoindazole (66.5 mg, 0.5 mmol). 1H NMR indicated a 3:1 mixture of E/Z isomers. 1H NMR (400 MHz, DMSO-d6) δ 13.22 (s, 1H), 11.00 (s, 1H), 8.10 (s, 1H), 6.67 (d, J=8.8 Hz, 1H), 7.39 (s, 1H), 7.22 (dt, J=9.2 Hz, 2.4 Hz, 1H), 7.10 (dd, J=8.8 Hz, 1.6 Hz, 1H), 6.90 (dd, J=8.8 Hz, 4.4 Hz, 1H), 6.14 (dd, J=8.8 Hz, 2.8 Hz, 1H); MS ESI 281.0 [M+H]+, calcd for [C15H9FN4O+H]+ 281.1.