Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[CH2:20][C:21]1[N:25]2[N:26]=[C:27]([C:30](=O)[CH3:31])[CH:28]=[CH:29][C:24]2=[N:23][CH:22]=1>>[F:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[CH2:20][C:21]1[N:25]2[N:26]=[C:27](/[C:30](=[N:8]/[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)/[CH3:31])[CH:28]=[CH:29][C:24]2=[N:23][CH:22]=1
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Reactant: NNc1ccccc1
Product: C/C(=N\Nc1ccccc1)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Yield: 32 %

Procedure:
The title compound was prepared from phenyl hydrazine and 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone in analogy to the synthesis of example 1 in 32% yield as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.78 (s, 1H), 8.86 (dd, 1H), 8.32 (d, 1H), 7.98 (m, 3H), 7.78 (d, 1H), 7.61 (s, 1H), 7.47 (q, 1H), 7.30 (m, 4H), 6.83 (t, 1H), 4.57 (s, 2H), 2.31 (s, 3H). LCMS (method C): [MH]+=411, tR=4.57 min.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:5]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:6]=2[S:7][C:8]=1[CH:9]=[O:10].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1>CN(C)C=O>[CH3:16][O:15][C:13]1[C:12]([O:17][CH3:18])=[CH:11][C:6]2[S:7][C:8]([CH:9]=[O:10])=[C:4]([O:27][C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[C:5]=2[CH:14]=1
Reactant: COc1ccc(O)cc1
Reactant: COc1cc2sc(C=O)c(Cl)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Oc2c(C=O)sc3cc(OC)c(OC)cc23)cc1

Procedure:
1.1 equivalents of sodium hydride and then 0.033 mol of the product obtained in Step D are added at room temperature and under an inert atmosphere to a solution of 0.036 mol of 4-methoxyphenol in 250 ml of dimethylformamide. After 12 hours' reaction, the reaction mixture is concentrated under reduced pressure. The residue is then diluted in ethyl acetate, washed with water and then with an aqueous NaCl solution, dried over calcium sulphate, filtered and concentrated under reduced pressure. Chromatography over silica gel (dichloromethane/ethyl acetate: 98/2) enables 8.6 g of the expected product to be isolated.
Reaction SMILES: [C:1]([O:14][CH2:15][Cl:16])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH3:18]>CCOCC>[Cl-:16].[C:1]([O:14][CH2:15][N+:19]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:17][CH3:18])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCN(CC)CC
Reactant: CCCCCCCCCCCC(=O)OCCl
Solvent: CCOCC
Product: CCCCCCCCCCCC(=O)OC[N+](CC)(CC)CC
Product: [Cl-]
Temperature: 25 °C

Procedure:
2.49 g (0.01 mol) chloromethyl n-dodecanoate (1b) and 1.01 g (0.01 mol) triethylamine were mixed and heated together at 90° for three hr. On cooling to room temperature, anhydrous ether was added to the mixture and the mixture was triturated in anhydrous ether overnite. The solid was isolated by filtration under a nitrogen atmosphere and thoroughly washed with ether. After drying in vacuo over calcium sulfate at room temperature 0.6 g (0.002 mol 20%, 2h was obtained as a hygroscopic solid, mp 72°-77°.
Reaction SMILES: C([N:5]1[C:12](=O)[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6]1)CCC.N#C[Br:20]>ClCCl>[Br:20][C:12]1[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6][N:5]=1
Reactant: CCCCn1sc2nc3ccccc3n2c1=O
Reactant: N#CBr
Solvent: ClCCl
Product: Brc1nsc2nc3ccccc3n12
Temperature: 25 °C
Reaction time: 26 h
Yield: 81.4 %

Procedure:
A mixture of 2-butyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-one (5.0 g, 20.2 mmole) and cyanogen bromide (4.28 g, 40.4 mmole) in 100 mL of dichloromethane was stirred at room temperature for 26 h. The precipitate was filtered and washed with dichloromethane to yield 4.18 g (81%) of 3-bromo-1,2,4-thiadiazolo[4,5-a]benzimidazole as a white powder: mp 189-190° C.; 1H NMR (CDCl3)δ 8.23 (d, 1H), 7.82 (d, 1H), 7.52 (t, 1H), 7.42 (d, 1H) ppm; 13C NMR (1:1 CDCl3 :DMSO-d6):δ 162.78, 149.67, 129.22, 125.53, 122.25, 119.48, 117.25, 111.27 ppm; IR (KBr):ν 3025, 2925, 1601, 1493, 1451, 1028, 757, 701 cm-1 ; HRMS calcd for C8H4N3SBr 252.9309, found 252.9307. Anal. Calcd for C8H4N3SBr: C, 37.81;H, 1.59; N, 16.54. Found: C, 37.44; H, 1.33; N. 16.57.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([O:27][C:28](=[O:39])[NH:29][C:30]1[CH:35]=[C:34]([CH2:36][OH:37])[CH:33]=[C:32]([CH3:38])[N:31]=1)([CH3:26])([CH3:25])[CH3:24].O>ClCCl.N1C=CC=CC=1>[C:23]([O:27][C:28](=[O:39])[NH:29][C:30]1[CH:35]=[C:34]([CH:36]=[O:37])[CH:33]=[C:32]([CH3:38])[N:31]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1cc(CO)cc(NC(=O)OC(C)(C)C)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C=O)cc(NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
Dess-Martin periodinane (50.0 g, 0.118 mol, 1.34 eq) was portionwise added to a solution of 4 (21.0 g, 0.088 mol) in dichloromethane:pyridine 10:1 (1.1 L). The resulting solution was stirred at room temperature for 2 h and then water (700 mL) was added. The mixture was stirred for a further 5 min, and then the layers were separated. The aqueous layer was extracted with dichloromethane (1×11), the combined organic phase dried and the solvent evaporated to give a brown solid which was purified by column chromatography (EtOAc:hexane 1:2) to afford (4-formyl-6-methyl-pyridine-2-yl)-carbamic acid tert-butyl ester 5 (20.5 g, 99%) as a pale orange solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7](O)=[O:8])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.O.[NH2:30][NH2:31]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([NH:30][NH2:31])=[O:8])[CH3:2]
Reactant: CCOc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: NN
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOc1cc(C(=O)NN)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
3-Ethoxy-4-nitrobenzoic acid (PCT Int Appl. 2008003958, 1.06 g 5.02 mmole) was stirred with dry THF (10 mL) and triethylamine (0.86 mL, 6.1 mmol) and the solution was cooled in an ice bath. Ethyl chloroformate (0.56 mL, 5.85 mmol) was added dropwise and the reaction was stirred in the ice bath for 15 minutes. Hydrazine hydrate (1.27 mL, 26 mmol) was added in one portion and the reaction stirred in the ice bath for 5 minutes and then at 20° C. for 1 hour. The reaction was concentrated in vacuo, partitioned between EtOAc (100 mL) and saturated aqueous sodium bicarbonate (15 mL). The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound (1.07 g, 95%).
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCOCC>O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:1]([OH:3])(=[O:5])=[O:2]
Reactant: O=S(=O)(O)O
Reactant: COc1ccccc1
Solvent: O
Solvent: CCOCC
Product: COc1ccccc1S(=O)(=O)O
Temperature: 50 °C
Reaction time: 12 h

Procedure:
560 g of 98% sulfuric acid was dropped into 600 g of methoxybenzene while stirring. Then, while the stirring was continued, the temperature was raised at 45 to 55° C., reacting for 12 hours. After the reaction, 500 g of distillation water was added. Then, 200 g of ether was added. The lower phase (water phase) of the two separated phases was taken, into which a step of distillation for condensation and addition of water was repeated twice, so as to obtain methoxybenzenesulfonic acid. As a result of analysis, the methoxybenzenesulfonic acid included the para compound thereof at a concentration of 86 mole % in the total of the methoxybenzenesulfonic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:31]1[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=3)[CH2:33][CH2:32]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Reactant: COc1ccc(N2CCNCC2)cc1
Product: COc1ccc(N2CCN(C(=O)Nc3nc4ccc(Cl)cc4nc3OC)CC2)cc1
Yield: 90 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(4-methoxyphenyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 90%). 1H NMR (200 MHz, CDCl3): δ 3.17 (s, 4H), 3.78 (s, 7H), 4.15 (m, 3H), 6.85-6.96 (m, 4H), 7.29-7.49 (m, 2H), 7.74-7.77 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[NH2:14][C:15]1([CH2:20][OH:21])[CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([NH:14][C:15]2([CH2:20][OH:21])[CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: NC1(CO)CCCC1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Nc1cccc(S(=O)(=O)NC2(CO)CCCC2)c1
Yield: 59.2 %

Procedure:
A mixture of 3-nitro-benzenesulfonyl chloride (0.89 g, 4 mmol) and (1-amino-cyclopentyl)-methanol (0.46 g, 4 mmol) in dichloromethane (4 mL)/sat. sodium bicarbonate solution (4 mL) was stirred at 20° C. for 20 h. The mixture was diluted with dichloromethane (20 mL). The layers were separated and the organic layer was washed with water, dried (Na2SO4) and evaporated in vacuo. The solid residue was dissolved in ethanol (20 mL) and hydrogenated in the presence of 5% palladium-charcoal (0.2 g) to give the title compound (0.64 g, 59%). Off-white solid. MS (ISP) 271.4 [(M+H)+]; mp 130-132° C.
Reaction SMILES: [NH4+:1].[Cl-].C[Al](C)C.[C:7]12([CH:17]([CH2:20][CH3:21])[C:18]#[N:19])[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2.C(Cl)(Cl)[Cl:23]>C1(C)C=CC=CC=1>[ClH:23].[C:7]12([CH:17]([CH2:20][CH3:21])[C:18](=[NH:1])[NH2:19])[CH2:14][CH:13]3[CH2:12][CH:11]([CH2:10][CH:9]([CH2:15]3)[CH2:8]1)[CH2:16]2
Reactant: CCC(C#N)C12CC3CC(CC(C3)C1)C2
Reactant: [NH4+]
Reactant: ClC(Cl)Cl
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCC(C(=N)N)C12CC3CC(CC(C3)C1)C2
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A suspension of NH4Cl (1.38 g, 26 mmol) in dry toluene (8 mL) at 0° C. was treated dropwise with 2-M trimethylaluminium in toluene (13 mL, 26 mmol), allowed to warm to room temperature and stirred for 2 h. This solution was added to a solution of 2-(1-adamantyl)butanenitrile (0.44 g, 2.2 mmol) in dry toluene (10 mL) and the resulting solution refluxed for 4 days, cooled to room temperature and poured into a slurry of SiO2 (5 g) and CHCl3 (10 mL). The slurry was filtered, the filtrate treated with Na2SO4, concentrated in vacuo and the residue loaded on to the top of a silica column and purified by chromatography [SiO2; EtOAc-MeOH (9:1 to 4:1)] to give the title compound (0.38 g, 68%) as a white solid: mp 223° C. (dec); IR νmax (Nujol)/cm−1 3332, 3157, 3071, 2925, 2852, 1666, 1510, 1462, 1377 and 724; NMR δH (400 MHz, DMSO-d6) 0.81 (3H, t, J 7.2 Hz), 1.39 (2H, m), 1.56-1.69 (11H, br m), 1.96 (3H, m), 2.13 (1H, m) and 9.08 (4H, br m); NMR δC (100 MHz, DMSO-d6) 11.8, 17.0, 27.8, 34.1, 36.2, 39.5, 56.0 and 171.0.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1)=[CH2:9].[H-].[Na+].[C:18]1([C:24]2[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[C:18]1([C:24]2[CH:25]=[CH:26][C:27]([CH2:28][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:8]([CH2:10][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)=[CH2:9])=[CH:30][CH:31]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Reactant: C=C(Cn1ccnc1)c1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(Cn1ccnc1)c1ccccc1OCc1ccc(-c2ccccc2)cc1

Procedure:
2-(2-Hydroxyphenyl)-3-(imidazol-1-yl)-1-propene (400 mg, 2.0 mmole) was dissolved in dimethylformamide (5 ml) and sodium hydride (60% dispersion in oil)(110 mg, 2.75 mmole) was added to the solution with stirring and ice-cooling. After stirring for additional 30 minutes, 4-phenylbenzylchloride (490 mg, 2.42 mmole) was added and the mixture was stirred overnight at room temperature. Then, the mixture was poured into water (50 ml) and extracted with diethyl ether (75 ml×2). The extract was washed with water (50 ml×2) and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was subjected to chromatography on a silica gel column and eluted with methylene chloride/methanol to obtain the title compound (0.41 g, 55.9%), m.p. 90°-92° C. (recrystallized from ethyl acetate/n-hexane).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[C:4](=[O:13])[CH:3]=1.[N+:14]([O-])([OH:16])=[O:15]>C(O)(=O)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[C:4](=[O:13])[C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: Cn1c(=O)cc(O)c2ccccc21
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Cn1c(=O)c([N+](=O)[O-])c(O)c2ccccc21

Procedure:
A suspension of 4-hydroxy-1-methyl carbostyril (1.63g; 0.009 mole) in glacial acetic acid (10 ml) was stirred during the addition of concentrated nitric acid (2.5 ml; d, 1.42) and the mixture heated for a few minutes on a steam bath. On cooling the clear red solution deposited yellow crystals of the title compound which were diluted with ethanol, filtered, and washed well with ethanol, m.p. 159°-161° C (Found: C, 54.20; H 3.71; N, 12.42; C10H8N2O4 requires; C, 54.55 H, 3.66; N, 12.72%).
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[C:10]([O:23]C)=[N:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH3:22])[N:16]=3)[CH:14]=2)=[O:7])=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>CN1C(=O)CCC1>[CH3:22][NH:21][C:17]1[N:16]=[C:15]([C:13]2[CH:14]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:25]=[CH:26][C:2]([N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:3][CH:4]=3)[C:10](=[O:23])[NH:11][CH:12]=2)[CH:20]=[CH:19][N:18]=1
Reactant: CNc1nccc(-c2cnc(OC)c(NC(=O)c3ccc(Br)cc3)c2)n1
Reactant: C1CCNCC1
Solvent: CN1CCCC1=O
Product: CNc1nccc(-c2c[nH]c(=O)c(NC(=O)c3ccc(N4CCCCC4)cc3)c2)n1
Temperature: 160 °C
Yield: 45 %

Procedure:
4-Bromo-N-(2-methoxy-5-(2-(methylamino)pyrimidin-4-yl)pyridin-3-yl)benzamide (50 mg, 0.121 mmol) was placed in a microwave tube equipped with a stirrer bar. NMP (1.5 mL) was added, followed by piperidine (1.5 mL). The reaction vessel was heated at 160° C. for 2 hours in a microwave. After cooling, the solvent and excess piperidine were removed in vacuo. The crude compound was recrystallized from methanol to give the title compound as a white solid (22 mg, 45% yield).). MS (ES+) m/e=405. 1H NMR (DMSO-d6) δH 1.54-1.61 (6H, m), 2.85 (3H, br s), 3.28-3.36 (4H, m), 6.95-7.12 (4H, m), 7.77 (2H, d), 8.00 (1H, s), 8.27 (1H, d), 9.02 (1H, br s), 9.09 (1H, s), 12.53 (1H, br s).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-])=O)[CH:8]=[C:7]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:6]=1[OH:26])([CH3:4])([CH3:3])[CH3:2].O.Cl>CO.[Fe]>[NH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:12]=[CH:11][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]([OH:26])=[C:7]([C:22]([CH3:24])([CH3:23])[CH3:25])[CH:8]=1
Reactant: CC(C)(C)c1cc(C=Cc2ccccc2[N+](=O)[O-])cc(C(C)(C)C)c1O
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc(C=Cc2ccccc2N)cc(C(C)(C)C)c1O
Yield: 69.8 %

Procedure:
To a solution of 2,6-di-tert-butyl-4-(2-nitrostyryl)phenol (1.1 g, 3.1 mmol) in methanol (15 ml) was added water (4 ml), conc. hydrochloric acid (0.2 ml) and iron powder (1.7 g, 30 mmol) and the mixture was heated under reflux for 5 hrs. After filtration, followed by extraction with ethyl acetate and water, the extract was washed with water, dried over MgSO4 and concentrated. Purification of the residue by a silica gel column chromatography followed by recrystallization from hexane afforded 4-(2-aminostyryl)-2,6-di-tert-butylphenol (0.70 g, 70%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]2[CH:10]=[C:11]([CH3:15])[N:12]=[C:13](Br)[C:8]2=[N:7][C:6]=1[CH2:16][CH3:17])=[O:4].[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1B(O)O>C1(C)C=CC=CC=1.CO>[CH3:1][O:2][C:3]([C:5]1[N:9]2[CH:10]=[C:11]([CH3:15])[N:12]=[C:13]([C:22]3[CH:21]=[CH:20][C:19]([Cl:18])=[CH:24][C:23]=3[Cl:25])[C:8]2=[N:7][C:6]=1[CH2:16][CH3:17])=[O:4]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CCc1nc2c(Br)nc(C)cn2c1C(=O)OC
Solvent: CO
Solvent: Cc1ccccc1
Product: CCc1nc2c(-c3ccc(Cl)cc3Cl)nc(C)cn2c1C(=O)OC
Yield: 107.4 %

Procedure:
8-Bromo-2-ethyl-6-methylimidazo[1,2-a]pyrazine-3-carboxylic acid methyl ester (0.30 g, 1.0 mmol) was dissolved in a mixed solvent of toluene (5.6 mL) and methanol (1.4 mL). Then 2,4-dichlorobenzeneboronic acid (0.382 g, 2.0 mmol) and tetrakistriphenylphosphine palladium complex (116 mg, 0.1 mmol) were added thereto, and the mixture was heated under reflux for 4 hours under nitrogen atmosphere. After the reaction mixture was allowed to cool, the solvent was removed. Then the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to give the title compound (391 mg) as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][CH:23]=[CH:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=3)=[CH:17][C:16]=2[N+:33]([O-:35])=[O:34])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:43][C:44]([O:46][CH3:47])=[O:45]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:43][C:44]([O:46][CH3:47])=[O:45])[CH2:22][CH:23]=[CH:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=3)=[CH:17][C:16]=2[N+:33]([O-:35])=[O:34])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCC=Cc3cccc(C#N)c3)cc2[N+](=O)[O-])CC1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN(CC=Cc1cccc(C#N)c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c1
Temperature: 55 °C
Reaction time: 6 h

Procedure:
To 4-(N′-(t-butoxycarbonyl)piperidin-4-yl)oxy-3-nitro-N-(3-(3-cyanophenyl)prop-2-en-1-yl)benzenamine (0.39 g) and K2CO3 (0.56 g) in DMF was added methyl bromoacetate. The mixture was stirred at 55° C. for 6 hours. The reaction was cooled, diluted with water and extracted with ethyl acetate (3×). The organic layer was concentrated and purified on silica gel column to afford 4-(N′-(t-butoxycarbonyl)piperidin-4-yl)oxy-3-nitro-N-(methoxycarbonylmethyl)-N-(3-(3-cyanophenyl)prop-2-en-1-yl)benzenamine (0.15 g).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([O:23][CH2:24][CH3:25])=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[C@H:36]1[CH2:40][CH2:39][C@H:38]([NH2:41])[CH2:37]1>>[CH2:24]([O:23][C:19]1[C:17]2[O:18][C@@H:13]([CH2:12][NH:41][C@H:38]3[CH2:39][CH2:40][C@H:36]([C:30]4[C:29]5[C:33](=[CH:34][CH:35]=[C:27]([F:26])[CH:28]=5)[NH:32][CH:31]=4)[CH2:37]3)[CH2:14][O:15][C:16]=2[CH:22]=[CH:21][CH:20]=1)[CH3:25]
Reactant: N[C@H]1CC[C@H](c2c[nH]c3ccc(F)cc23)C1
Reactant: CCOc1cccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Product: CCOc1cccc2c1O[C@@H](CN[C@H]1CC[C@H](c3c[nH]c4ccc(F)cc34)C1)CO2
Yield: 57.3 %

Procedure:
This compound was prepared in the same manner as for Example 1, using [(2R)-8-ethoxy-2,3-dihydro-benzo[1,4]dioxin-2-yl]methyl 4-methylbenzenesulfonate (0.25 g, 0.68 mmol) and trans-3-(5-fluoro-1H-indol-3-yl)-cyclopentylamine (0.3 g, 1.38 mmol) to afford 0.16 g (64%) of the title compound as its hydrochloride salt: MS (ESI) m/z 411 [M+H]+.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]12[CH2:16][CH:12]3[CH2:13][CH:14]([CH2:15]1)[C:10]([NH2:17])([CH2:11]3)[CH2:9]2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C:34]#[N:35])=[O:28]>CS(C)=O.CCOC(C)=O>[O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]12[CH2:16][CH:12]3[CH2:11][C:10]([NH:17][CH2:26][C:27]([N:29]4[CH2:33][CH2:32][CH2:31][C@H:30]4[C:34]#[N:35])=[O:28])([CH2:9]1)[CH:14]([CH2:13]3)[CH2:15]2
Reactant: NC12CC3CC1CC(CN1CCCS1(=O)=O)(C3)C2
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(CN1CCCS1(=O)=O)(C3)C2
Reaction time: 3 h
Yield: 43.6 %

Procedure:
To a stirred mixture of the amine obtained in step IV (0.26 g, 0.96 mmol) and K2CO3 (0.42 g, 2.9 mmol) in DMSO (4.0 mL) at ice bath temperature was added under nitrogen atmosphere (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.17 g, 1.0 mmol). After stirring the reaction mixture for 3 h at r.t, it was diluted with EtOAc, washed with water and brine, dried over Na2SO4, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{N-[2-[(1,1-dioxidoisothiazolidin-2-yl)methyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as an off-white solid (0.17 g) in 43% yield. m/z (M+1) 407; 1H NMR (CDCl3) 300 MHz δ 4.87-4.76 (m, 1H), 3.70-3.40 (m, 2H), 3.44 (s, 2H), 3.32 (t, J=6.7 Hz, 2H), 3.10 (t, J=7.5 Hz, 2H), 2.93 (s, 2H), 2.41-2.10 (m, 8H), 1.90-1.46 (m, 7H), 1.43-1.35 (m, 1H).
Reaction SMILES: [ClH:1].[CH:2]1([C:5](=[O:33])[CH:6]([N:14]2[CH2:19][CH2:18][CH:17]([SH:20])/[C:16](=[CH:21]/[C:22]3[N:23]=[CH:24][N:25]([CH2:27][C:28]([O:30]CC)=[O:29])[CH:26]=3)/[CH2:15]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[CH2:4][CH2:3]1.O1CCCC1.[OH-].[Na+].Cl>O>[ClH:1].[C:28]([CH2:27][N:25]1[CH:26]=[C:22](/[CH:21]=[C:16]2\[CH2:15][N:14]([CH:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[F:13])[C:5]([CH:2]3[CH2:3][CH2:4]3)=[O:33])[CH2:19][CH2:18][CH:17]\2[SH:20])[N:23]=[CH:24]1)([OH:30])=[O:29]
Reactant: CCOC(=O)Cn1cnc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cn1cnc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S)c1
Yield: 80.9 %

Procedure:
To a solution of (E)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-{[1-(ethoxycarbonylmethyl)-1H-imidazol-4-yl]methylidene}-4-sulfanylpiperidine hydrochloride (72.6 mg) in a mixed solvent of tetrahydrofuran (2 ml) and water (1 ml) was added 1N aqueous sodium hydroxide solution (0.55 ml) with stirring under ice-cooling, and the resulting mixture was stirred at the same temperature for 3 minutes. To the reaction mixture was added 1N hydrochloric acid solution (1.00 ml). The reaction mixture was concentrated in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of methanol and dichloromethane (1:4) as the eluent to afford the title compound (55.4 mg, yield: 80%) as a pale yellow solid.