Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:10]([N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cn(Cc2ccccc2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 72 %

Procedure:
A mixture of thymine (7.68 g, 61 mmol), benzyl bromide (10.55 g, 61 mmol), potassium carbonate (17.05 g, 123 mmol) and DMF (90 mL) was stirred 12 hours at 25° C. The reaction mixture was poured into water (500 mL) and extracted with ethyl acetate (3×200 mL). The combined extract was washed with water (5×100 mL), dried (Na2SO4) and concentrated in vacuo. The residue was crystallized from hexane/ethyl acetate to give 1-benzyl-5-methyl-2,4(1H,3H)-pyrimidinedione (9.4 g, 43.9 mmol), m.p. 170°-173° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH2:18]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([O:11][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][C:2]=1[O:1][CH2:4][C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 155.8 %

Procedure:
2,4-dihydroxy-benzoic acid (35) (2 g, 13 mmol) in THF (250 mL) was mixed with cesium carbonate (16.9 g, 52 mmol) and benzyl bromide (6.2 mL, 52 mmol). The reaction mixture was refluxed overnight and then cooled down to room temperature. Cesium carbonate was filtered off through filter paper. The solvent was removed under reduced pressure. Liquid-liquid extraction was performed using 200 mL of CHCl3 and H2O (100 mL×3). The organic layer was dried over MgSO4. After filtering off the MgSO4, the organic layer was concentrated to give compound 36 (4.3 g) as a solid. LC-MS (ESI): m/e=425.2 [M+1]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[S:8])[NH:6][CH:7]=1.[CH3:9][N:10]=[C:11]=[O:12]>ClCCl>[CH3:9][NH:10][C:11]([S:8][C:5]1[N:6]=[CH:7][C:2]([Cl:1])=[CH:3][N:4]=1)=[O:12]
Reactant: CN=C=O
Reactant: S=c1ncc(Cl)c[nH]1
Solvent: ClCCl
Product: CNC(=O)Sc1ncc(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A mixture of 5-chloropyrimidine-2-thione (3 mmol) and methylisocyanate (4 mmol) in dichloromethane (15 ml) was stirred at room temperature for 2 h, the solvent was then distilled off and the residue was crystallised from CHCl3 : Pet. ether; yield 85%, m.p. 115° C. 1H NMR (CDCl3) δ3.03 (Me), 8.62 (H-4, H-6).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-])=O)=[CH:13][N:12]=2)=[CH:6][CH:5]=1.C(O)(=O)C>CO.[Zn]>[NH2:18][C:14]1[CH:15]=[C:16]([CH3:17])[C:11]([O:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:21])=[CH:9][CH:8]=2)=[N:12][CH:13]=1
Reactant: COC(=O)c1ccc(Oc2ncc([N+](=O)[O-])cc2C)cc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(Oc2ncc(N)cc2C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a mixture of 4-(3-methyl-5-nitro-pyridin-2-yloxy)-benzoic acid methyl ester (0.43 g, 1.49 mmol) from the previous step and zinc dust (0.932 g, 14.2 mmol) in methanol (15 ml) was added dropwise acetic acid (0.32 ml, 5.12 mmol). The mixture was stirred for 1 h at room temperature and filtered through a thin silica pad to remove inorganics. The filtrate was concentrated at reduced pressure to dryness to provide methyl 4-(5-amino-3-methylpyridin-2-yloxy)benzoate (0.346 g, 90% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([NH:14]C)[CH2:11][C@@H:10]([C:16](=[O:39])[N:17](C2CC2)[C:18]2[CH:19]=[CH:20][C:21]3[O:26][C:25]([CH3:28])([CH3:27])[C:24](=[O:29])[N:23]([CH2:30][CH2:31][CH2:32][O:33][CH3:34])[C:22]=3[CH:35]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:40]1([C:46]2([C:49]([OH:51])=O)[CH2:48][CH2:47]2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([NH:14][C:49]([C:46]2([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:47][CH2:48]2)=[O:51])[CH2:11][C@@H:10]([C:16](=[O:39])[NH:17][C:18]2[CH:19]=[CH:20][C:21]3[O:26][C:25]([CH3:27])([CH3:28])[C:24](=[O:29])[N:23]([CH2:30][CH2:31][CH2:32][O:33][CH3:34])[C:22]=3[CH:35]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN[C@H]1C[C@@H](C(=O)N(c2ccc3c(c2)N(CCCOC)C(=O)C(C)(C)O3)C2CC2)CN(C(=O)OC(C)(C)C)C1
Reactant: O=C(O)C1(c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCCN1C(=O)C(C)(C)Oc2ccc(NC(=O)[C@@H]3C[C@H](NC(=O)C4(c5ccccc5)CC4)CN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (3R,5S)-3-{Cyclopropyl-[4-(3-methoxy-propyl)-2,2-dimethyl-3-oxo-3,4-di hydro-2H-benzo[1,4]oxazin-6-yl]-carbamoyl}-5-methylamino-piperidine-1-carboxylic acid tert-butyl ester (110 mg, 0.2 mmol) and 1-phenyl-1-cyclopropanecarboxylic acid (40 mg, 0.24 mmol) in DMF (2 mL) are added EDCI. HCl (60 mg, 0.3 mmol) and HOAt (40 mg, 0.3 mmol) at 0° C. After stirred at rt overnight, the reaction mixture is diluted with EtOAc. The mixture is washed with water and dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography to afford (3R,5S)-3-[4-(3-Methoxy-propyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylcarbamoyl]-5-[(1-phenylcyclopropanecarbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a white amorphous, which is treated with 4 N HCl in 1,4-dioxane (3 mL). The solution is concentrated under reduced pressure to give the title compound as a yellow powder. MS: 589 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 3.01 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:17]2[C:12](=[CH:13][C:14](/[CH:18]=[CH:19]/[C:20](O)=[O:21])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:23][C:24]([F:38])([F:37])[CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1)[NH2:26].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CN(C=O)C.C(OCC)(=O)C>[O:21]=[C:20]([NH:26][CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=1)[C:24]([F:38])([F:37])[F:23])/[CH:19]=[CH:18]/[C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11]2
Reactant: CC(C)(C)OC(=O)NC1CCc2cc(/C=C/C(=O)O)ccc21
Reactant: NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCc2cc(/C=C/C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)ccc21
Temperature: 50 °C
Yield: 89.9 %

Procedure:
1.5 g (4.95 mmol) of (2E)-3-{1-[(tert-butoxycarbonyl)amino]-2,3-dihydro-1H-inden-5-yl}acrylic acid and 1.2 g (4.95 mmol) of 2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethanamine were dissolved in 100 ml of DMF, 1.5 g (5.44 mmol) of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride were added, and the reaction mixture was heated to 50° C. overnight. The reaction solution was diluted with ethyl acetate, washed with sat. NaHCO3 solution, 1N hydrochloric acid and sat. sodium chloride solution, dried over sodium sulphate, filtered and concentrated. Chromatographic purification gave 2.3 g (4.45 mmol) of tert-butyl {5-[(1E)-3-oxo-3-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}amino)prop-1-en-1-yl]-2,3-dihydro-1H-inden-1-yl}carbamate (87%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2=[N:6][C:7](=[O:9])[N:8]=[C:4]2[CH:3]=1.[I-].[K+].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CN(C=O)C>[CH2:15]([N:1]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])[C:2]1[CH:11]=[CH:10][C:5]2=[N:6][C:7](=[O:9])[N:8]=[C:4]2[CH:3]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCBr
Reactant: Nc1ccc2c(c1)=NC(=O)N=2
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCN(CCCCCCCCCCCC)c1ccc2c(c1)=NC(=O)N=2
Temperature: 60 °C
Reaction time: 72 h
Yield: 76.4 %

Procedure:
5-Aminobenzimidazolone (0.1348 g, 0.904 mmol), potassium iodide (0.1513 g, 0.911 mmol), and dry DMF (20 mL) are mixed in a 100 mL round bottom flask under an inert atmosphere. The reaction is heated to 60° C. and 1-bromododecane (0.45 mL, 1.88 mmol) is added. After 3 days at 60° C., the reaction is cooled to room temperature to give a brown suspension. The solid is filtered, washed with deionized water, and dried in vacuo to give 5-(didodecylamino)-2-benzimidazolone as a white solid (0.334 g). The product is identified by 1H and 13C NMR spectroscopy and ESI-MS and is of satisfactory purity.
Reaction SMILES: [Na].[O-]CC.[Na+].Cl.[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]([O:22]CC)=O)[C:16](=O)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[F:27][C:28]([F:39])([F:38])[C:29]1[N:34]=[CH:33][C:32]([C:35]([NH2:37])=[NH:36])=[CH:31][CH:30]=1>C(O)C>[CH2:7]([N:14]1[CH2:19][CH2:18][C:17]2[C:20]([OH:22])=[N:37][C:35]([C:32]3[CH:33]=[N:34][C:29]([C:28]([F:39])([F:27])[F:38])=[CH:30][CH:31]=3)=[N:36][C:16]=2[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N=C(N)c1ccc(C(F)(F)F)nc1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Oc1nc(-c2ccc(C(F)(F)F)nc2)nc2c1CCN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.8 %

Procedure:
A mixture of 258 mg (11.2 mmol) of sodium in 10 mL of absolute ethanol was stirred at ambient temperature for 1 h. To the resultant sodium ethoxide solution was added 893 mg (3.0 mmol) of ethyl 1-benzyl-3-oxopiperidine-4-carboxylate hydrochloride in portions followed by 840 mg (3.72 mmol) of 6-(trifluoromethyl)pyridine-3-amidine hydrochloride. The reaction mixture was heated at reflux for 18 h, then concentrated in vacuo. To the residue was added ˜30 mL of 1N aqueous sodium hydroxide solution and 15 mL of water to give an insoluble solid and a yellow solution. The solid was filtered off and washed with water to provide 496 mg of the title compound. The aqueous filtrate was acidified to ˜pH 5 with concentrated hydrochloric acid and the solid precipitate was collected to give an additional 334 mg of the title compound as a bright yellow powder (72% total yield). LC-MS 387.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([CH3:15])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[CH2:68]([NH2:75])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:68]([NH:75][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([CH3:15])[CH:3]=1)[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1
Reactant: Cc1cc(Br)ccc1C(=O)OC(C)(C)C
Reactant: NCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1cc(NCc2ccccc2)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
tert.-butyl 4-bromo-2-methyl-benzoate (12 g; 43.4 mmol), caesium carbonate (21.2 g, 65 mmol), palladium(II)-acetate (1 g, 4.45 mmol) and BINAP (2.37 g, 4.40 mmol) are suspended in 150 ml of toluene under a nitrogen atmosphere and stirred for 10 minutes at ambient temperature. Then benzylamine (5.7 ml, 52.1 mmol) is added dropwise and the mixture is heated to 100° C. for two days. The mixture is then cooled, filtered to remove undissolved matter and evaporated to dryness. The oily residue is purified by chromatography (silica gel, petroleum ether/ethyl acetate 98:2). White crystals are obtained.
Reaction SMILES: [OH-].[K+].[O:3]=[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([C:32]([O:34]CC)=[O:33])([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:26])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([C:16]([O:18]CC)=[O:17])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:10]>CCO>[CH2:14]([O:13][C:11]([C:9]([CH3:10])([CH2:8][CH2:7][CH2:6][CH2:5][C:4](=[O:3])[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])([CH3:26])[C:32]([OH:34])=[O:33])[C:16]([OH:18])=[O:17])=[O:12])[CH3:15]
Reactant: CCOC(=O)C(C)(CCCCC(=O)CCCCC(C)(C(=O)OCC)C(=O)OCC)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(CCCCC(=O)CCCCC(C)(C(=O)O)C(=O)OCC)C(=O)O
Reaction time: 54 h
Yield: 80.7 %

Procedure:
A solution of KOH (2.44 g, >85%, >37.0 mmol) in EtOH (80 mL) was added to 106h (9.00 g, 18.5 mmol). After stirring for 54 h, another portion of KOH (1.21 g, >85%, >18.5 mmol) was added and stirring was continued for 16 h. The reaction mixture was evaporated in vacuo and Et2O (250 mL) and H2O (250 mL) were added. The aqueous layer was separated, acidified with aqueous HCl (2 M, 50 mL) and extracted with Et2O (250 mL) and CH2Cl2 (250 mL). The combined organic layers were dried and the remaining residue was purified by column chromatography (silica, heptane:EtOAc:HOAc=3:2:0.01) and vacuum dried at 50° C. to give 107h (6.43 g, 81%) as a yellow oil. 1H NMR: δ 10.40 (br s, 2H), 4.21 (q, J=7.1 Hz, 4H), 2.42 (t, J=7.4 Hz, 4H), 1.90-1.84 (m, 4H), 1.59 (quintet, J=7.4 Hz, 4H), 1.43 (s, 6H), 1.32-1.19 (m, 4H), 1.27 (t, J=7.2 Hz, 6H). 13C NMR: δ 210.9, 177.7 (2×), 172.1 (2×), 61.5 (2×), 53.5 (2×), 42.2 (2×), 35.3 (2×), 23.8 (2×), 23.7 (2×), 19.8 (2×), 13.9 (2×). HRMS calcd for C21H35O9 (MH+): 431.2281, found: 431.2298.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[CH:4][C:3]=1[O:10][CH3:11].[CH3:12][O:13][C:14]1[CH:40]=[CH:39][C:17]([CH2:18][O:19][C:20](=[O:38])[C:21]2[CH:26]=[C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[CH:24]=[CH:23][C:22]=2I)=[CH:16][CH:15]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][O:19][C:20](=[O:38])[C:21]2[CH:26]=[C:25]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[CH:24]=[CH:23][C:22]=2/[CH:9]=[CH:8]/[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:10][CH3:11])[CH:4]=2)=[CH:39][CH:40]=1
Reactant: C=Cc1ccc(F)c(OC)c1
Reactant: COc1ccc(COC(=O)c2cc(OCc3ccc(OC)cc3)ccc2I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(COC(=O)c2cc(OCc3ccc(OC)cc3)ccc2/C=C/c2ccc(F)c(OC)c2)cc1

Procedure:
To a stirred solution of 1-fluoro-2-methoxy-4-vinylbenzene (INTERMEDIATE I.1) (4.49 g, 29.53 mmol) and 2-iodo-5-(4-methoxybenzyloxy)benzoic acid 4-methoxybenzyl ester (14.89 g, 29.53 mmol) in anhydrous acetonitrile (75 mL) was added triethylamine (8.2 mL, 59.06 mmol) and tri(o-tolyl)phosphine (1.17 g, 3.84 mmol). The mixture was sparged for 5 min with argon, and palladium(II) acetate (662 mg, 2.95 mmol) was added. The mixture was heated at reflux for 13 h and concentrated to give the crude product (E)-2-[2-(4-fluoro-3-methoxyphenyl)vinyl]-5-(4-methoxybenzyloxy)benzoic acid 4-methoxybenzyl ester as a dark brown residue, which was used without further purification.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[CH:26]=[CH:25][N:24]=[C:23]3[C:18]=2[C:19]2[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][C:20]=2[C:21](=[O:27])[NH:22]3)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:68][N:69]1[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]1>CN(C=O)C>[CH3:68][N:69]1[CH2:74][CH2:73][N:72]([C:32]([C:29]2[CH:30]=[CH:31][C:19]3[C:18]4[C:23](=[N:24][CH:25]=[CH:26][C:17]=4[NH:16][C:13]4[CH:12]=[CH:11][C:10]([NH:9][C:1](=[O:8])[C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[CH:15][CH:14]=4)[NH:22][C:21](=[O:27])[C:20]=3[CH:28]=2)=[O:33])[CH2:71][CH2:70]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc2c(c1)c(=O)[nH]c1nccc(Nc3ccc(NC(=O)c4ccccc4)cc3)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)c2ccc3c(c2)c(=O)[nH]c2nccc(Nc4ccc(NC(=O)c5ccccc5)cc4)c23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
268 (30 mg, 0.07 mmol), DIEA (25 mg, 0.2 mmol), HATU (31 mg, 0.08 mmol), and 1-methylpiperazine (20 mg, 0.2 mmol) were dissolved in DMF (1 mL), and stirred for 3 h at room temperature. The crude product was purified directlyl via HPLC to provide 269 (27 mg, 63% yield) as a solid. LC-MS (M+H=533, obsd.=533).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:14]=[C:13]([C:15]4[CH:16]=[CH:17][C:18]5[O:22][C:21]([CH3:23])=[CH:20][C:19]=5[CH:24]=4)[O:12][N:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(OC1C=C(C2ON=C(C3C=CC=C4C=3C=CN4)N=2)C=CC=1OCC)C>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:14]=[C:13]([C:15]4[CH:16]=[CH:17][C:18]5[O:22][C:21]([CH3:23])=[CH:20][C:19]=5[CH:24]=4)[O:12][N:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc2cc(-c3nc(-c4cccc5[nH]ccc45)no3)ccc2o1
Agent: CCOc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1OCC
Product: Cc1cc2cc(-c3nc(-c4cccc5c4CCN5)no3)ccc2o1
Yield: 100 %

Procedure:
When the product of Step D was substituted for 5-(3,4-diethoxyphenyl)-3-(1H-indol-4-yl)-1,2,4-oxadiazole in Example 34, Step C, the identical process afforded the title compound in 100% yield, as a colourless foam. 1H-NMR (CDCl3) 2.49 (s, 3H); 2.52 (broad s, 1H+H2O); 3.48 (tr, 2H, J=8.44 Hz); 3.68 (tr, 2H, J=8.44 Hz); 6.48 (s, 1H); 6.85 (d, 1H, J=7.75 Hz); 7.2 (tr, 2H, J=7.6 Hz); 7.38 (d, 1H, J=8.16 Hz); 7.51 (d, 1H, J=8.5 Hz); 8.06 (d, 1H, J=8.5 Hz); 8.32 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH:5]=[CH:6][CH:7]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+].[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1Nc1cccc(Br)c1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1Nc1cccc(Br)c1)c1ccccc1
Temperature: 25 °C

Procedure:
3.8 g (13 mmol) of (3-bromophenyl)-(2-nitrophenyl)amine was dissolved in 30 mL of tetrahydrofuran. A solution of 11 g (64 mmol) of sodium hydrosulfite in 30 mL of water was added dropwise to the solution while stirring the solution at room temperature in an argon atmosphere. After stirring the mixture for 5 hours, 20 mL of ethyl acetate was added to the mixture. A solution of 2.2 g (26 mmol) of sodium hydrogencarbonate in 20 mL of water was then added to the mixture. After the dropwise addition of a solution of 2.5 g (18 mmol) of benzoyl chloride in 10 mL of ethyl acetate, the mixture was stirred at room temperature for 1 hour. The mixture was then extracted with ethyl acetate, washed with a 10% potassium carbonate aqueous solution, water, and a saturated sodium chloride solution sequentially, and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure to obtain N-[2-(3-bromophenylamino)phenyl]benzamide.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:24]=[CH:23][C:13]3[S:14][C:15]4([C:21](=[O:22])[C:12]=3[CH:11]=2)[CH2:19][CH2:18]OC4=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C>[N:1]1([S:7]([C:10]2[CH:24]=[CH:23][C:13]3[S:14][C:15]4([C:21](=[O:22])[C:12]=3[CH:11]=2)[CH2:19][CH2:18]4)(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1OCCC12Sc1ccc(S(=O)(=O)N3CCCCC3)cc1C2=O
Solvent: CCO
Product: O=C1c2cc(S(=O)(=O)N3CCCCC3)ccc2SC12CC2

Procedure:
5-Piperidinosulfonylspiro[benzo[b]thiophene-2(3H),1'-cyclopropan]-3-one was prepared by a similar procedure to that of Example 8 except for the use of 5-piperidinosulfonyl 4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-dione obtained in Reference Example 17. Colorless prisms (from C2H5OH), mp 155.5°-157° C. Anal. Calcd. for C15H17NO3S: C, 55.70; H, 5.30; N, 4.33. Found: C, 55.74; H, 5.34; N, 4.50.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.CCCCCC>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCCCCC
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 93 %

Procedure:
A mixture of 5-fluoro-2-nitrotoluene (2 mL, 16.4 mmol), 1-tert-butoxycarbonyl piperazine (3.35 g, 18 mmol) and potassium carbonate (2.76 g, 20 mmol) in 7 mL of DMSO was stirred and heated at 100° C. for 2 h. Water (40 mL) and hexane (30 mL) were added and the bright yellow precipitate was collected, washed with water and hexane, and dried in vacuo to afford 4.9 g of 4-(3-methyl-4-nitrophenyl)-piperazine-1-carboxylic acid tert-butyl ester, m.p. 145-146° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]=[CH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.[I-].[Na+].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[OH-].[Na+]>CN(C)C=O.CCOCC.C(N(CC)CC)C>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[N:27]1[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][CH:4]=[CH:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]3)[CH2:31][CH2:32]1
Reactant: O=C1CCc2cc(C=CCCCl)ccc2N1
Reactant: Cc1cccc(Cl)c1N1CCNCC1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc(Cl)c1N1CCN(CCC=Cc2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
2.8 Grams of 6-(4-chloro-1-butenyl)-3,4- dihydrocarbostyril and 2.1 g of sodium iodide were dissolved in 40 ml of dimethylformamide and stirred at 50° C. for 1 hour. To this solution were added 2.7 g of 4-(2-chloro-6-methlphenyl)piperazine and 1.5 g of triethylamine and the mixture was further stirred at 50° C. for 5 hours. The reaction mixture was concentrated under a reduced pressure to dryness to obtain a residue. To the residue were added 10N-NaOH and ether and stirred at a room temperature for 30 minutes to precipitate crystals. The crystals were separated by a silica-gel chromatography and recrystallized from ethanol-acetone-chloroform to obtain 6-{4-[4-(2-chloro-6-methlphenyl)-1-piperazinyl]-1-butenyl}-3,4-dihydrocarbostyril in colorless prism-like crystals. Yield: 2.7 g. Melting point: 179°-180° C.