Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]=[C:11]([C:16](=[O:27])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][CH3:26])[CH:18]=3)[C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:3]=2[O:2]1>FC(F)(F)C(O)=O>[CH3:15][O:14][C:12]([CH:11]1[C:16](=[O:27])[C:17]2[C:22](=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][CH3:26])[CH:18]=2)[CH:10]1[C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)=[O:13]
Reactant: CCCOc1cccc(C(=O)C(=Cc2ccc3c(c2)OCO3)C(=O)OC)c1
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1ccc2c(c1)C(=O)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 868.7 %

Procedure:
Methyl 3-(3,4-methylenedioxyphenyl)-2-[3-(prop-1-yloxy)benzoyl]propenoate (7.4 g, 2.0 mmol) was dissolved in trifluoroacetic acid (50 mL) at 0° C. and the mixture stirred at room temperature for 20 min.. The trifluoroacetic acid was removed in vacuo to give the title compound (6.4 g, 87 %) as a white solid after trituration with warm isopropanol m.p. 106°-108° C. Anal. Calc. for C21H20O6 : C, 68.47; H, 5.47. Found: C, 68.12; H, 5.41.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>S(Cl)(Cl)=O.ClCCl>[CH2:11]([NH:18][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][N:10]=[C:2]([Cl:1])[CH:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(NCc1ccccc1)c1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
A solution of 2-chloroisonicotinic acid (5.00 g, 31.7 mmol) in thionyl chloride (25 mL) was refluxed for 30 minutes and concentrated in vacuo to dryness. The residue was dissolved in dichloromethane (100 mL) and added to a mixture of benzylamine (3.40 g, 31.7 mmol) and triethylamine (6.64 mL, 47.6 mmol) in dichloromethane (40 mL). The resulting solution was stirred at ambient temperature for 16 hours, washed with saturated sodium bicarbonate solution (30 mL), water (30 mL) and brine (30 mL). The separated organic solution was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with 60-80% ethyl acetate in hexanes to give N-benzyl-2-chloroisonicotinamide as a colorless solid (5.35 g, 49%): 1H NMR (300 MHz, DMSO-d6) δ 9.44-9.40 (m, 1H), 8.56 (d, J=5.1 Hz, 1H), 7.91 (s, 1H), 7.82-7.80 (m, 1H), 7.34-7.25 (m, 5H), 4.49 (d, J=5.1 Hz, 2H), MS (ES+) m/z 247.2 (M+1).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[N:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[N:10][CH:11]=1)=[O:5].C([Mg]Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[C:4]([C:6]1[CH:11]=[N:10][C:9]([N:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:16][CH2:17]2)=[N:8][CH:7]=1)(=[O:5])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Br[Mg]Cc1ccccc1
Reactant: CON(C)C(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)c3ccccc3)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
To a solution of tert-butyl 4-(5-(methoxy(methyl)carbamoyl)pyrimidin-2-yl)piperazine-1-carboxylate (2.6 g, 7.4 mmol) in dry THF (30 mL) was added benzylmagnesium bromide (1 M in THF, 29.6 mL) at 0° C. under N2, and the mixture was stirred at room temperature for 3 hours. LCMS showed the reaction was completed. The reaction mixture was quenched with 1 M HCl and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=5:1) to get tert-butyl 4-(5-benzoylpyrimidin-2-yl)piperazine-1-carboxylate (2 g, 73%) as a yellow solid. MS (ES+) C20H24N4O3 requires: 368, found: 313 [M-56+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]3[CH2:19][CH2:20][O:21][CH2:22][CH:23]=3)=[C:13](Cl)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[CH:29]1[CH2:31][CH2:30]1)CCC>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]3[CH2:19][CH2:20][O:21][CH2:22][CH:23]=3)=[C:13]([CH:29]3[CH2:31][CH2:30]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(C3=CCOCC3)cc2C1
Reactant: CCCC[Sn](CCCC)(CCCC)C1CC1
Product: CC(C)(C)OC(=O)N1Cc2cc(C3=CCOCC3)c(C3CC3)cc2C1

Procedure:
Prepared in analogy to Example A54(a) from 5-chloro-6-(3,6-dihydro-2H-pyran-4-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and tributylcyclopropylstannane. Yellow oil. MS (m/e): 286.1 ([M+H−Me2C═CH2]+, 100%).
Reaction SMILES: [Li+].[BH4-].[F:3][C:4]1([F:26])[CH2:8][N:7]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([C:18]([F:21])([F:20])[F:19])[CH:10]=2)[C@H:6]([C:22](OC)=[O:23])[CH2:5]1>C1COCC1.C(OCC)(=O)C>[F:26][C:4]1([F:3])[CH2:8][N:7]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([C:18]([F:20])([F:21])[F:19])[CH:10]=2)[C@H:6]([CH2:22][OH:23])[CH2:5]1
Reactant: COC(=O)[C@@H]1CC(F)(F)CN1c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(N2CC(F)(F)C[C@H]2CO)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a suspension of LiBH4 (55 mg, 2.54 mmol) in anhydrous THF (3 mL) was added a solution of (S)-methyl 4,4-difluoro-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidine-2-carboxylate (300 mg, 0.85 mmol) in anhydrous THF at 0° C. The reaction mixture was stirred at 0° C. for 20 min then allowed to come to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (50 mL), and then brine. The layers were separated, and the organic layer was dried over Na2SO4, filtered, and concentrated to afford (S)-(4,4-difluoro-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidin-2-yl)methanol as a yellow, viscous oil (275 mg, 100%). LC/MS: m/z 327.2 (M+H)+ at 1.54 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH2:13]([O:15][C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[O:18][CH2:19][CH2:20][NH2:21])[CH3:14].C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[ClH:1].[CH2:13]([O:15][C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[O:18][CH2:19][CH2:20][NH:21][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[CH3:14]
Reactant: CCOc1ccccc1OCCN
Reactant: Fc1ccc(OCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccccc1OCCNCCCOc1ccc(F)cc1
Product: Cl

Procedure:
A mixture of 1.9 g of 1-chloro-3-(4-fluorophenoxy)-propane, l.8 g of 2-(2-ethoxyphenoxy)ethylamine, 0.53 g of sodium carbonate and 60 ml of dimethylformamide was heated at 80°-90° C for 15 hours. After cooling, the reaction mixture was poured into water and extracted with benzene. The extract was washed with water and dried over sodium sulfate and evaporated under reduced pressure. The oily residue was dissolved in ether and treated with ethanolic hydrogen chloride under cooling. The precipitate was collected by filtration and dried to give N-{2-(2-ethoxyphenoxy)ethyl}-3-(4-fluorophenoxy)propylamine hydrochloride, M.P. 78°-82° C. Recrystallization from ethanol-benzene gave white crystals, M.P. 84°-86° C.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:18])[C@H:8]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27]>C(#N)C>[C:2]([O:6][C:7](=[O:18])[C@H:8]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[NH:9][CH2:27][CH:26]=[CH2:25])([CH3:4])([CH3:5])[CH3:3]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCN[C@@H](CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
L-aspartic acid di-tert-butyl ester hydrochloride (1.0 g, 3.5 mmol) was dissolved in acetonitrile (7 ml), potassium carbonate (0.98 g, 7.1 mmol) and allyl bromide (0.29 ml, 3.4 mmol) were added, and the mixture was stirred at room temperature overnight. The insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5) to give N-allyl-L-aspartic acid di-tert-butyl ester (0.50 g, 1.8 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][O:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.[CH3:18][O:19][N:20]([CH3:24])[C:21](Cl)=[O:22].N1C=CC=CC=1.[Cl-].[Na+]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][O:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][C:21]([N:20]([CH3:24])[O:19][CH3:18])=[O:22])=[CH:9][CH:8]=1
Reactant: CON(C)C(=O)Cl
Reactant: Nc1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CON(C)C(=O)Nc1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Yield: 36.8 %

Procedure:
4-(3,4-Dichlorobenzyloxy)aniline (26.7 g), N-methoxy-N-methylcarbamyl chloride (13.5 g) and pyridine (8.7 g) are dissolved in toluene (200 ml), and the reaction mixture is heated under reflux for 5 hours. Water is added to the reaction mixture to dissolve the by-produced sodium chloride. The toluene layer is washed with dilute hydrochloric acid and water in that order, dried and concentrated under reduced pressure. The residual crude crystals are recrystallized from ethanol to give N-[4-(3,4-dichlorobenzyloxy)phenyl]-N'-methyl-N'-methoxyurea (Compound No. 9) (13 g) as white plates. M.P., 114° to 115° C.
Reaction SMILES: OC[C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]([C:11]2[CH:16]=[CH:15][C:14](CO)=[CH:13][CH:12]=2)=[CH2:10])=[CH:5][CH:4]=1.[OH:21][CH2:22]C1C=CC(COC(C2C=CC=C(CO)C=2)=C)=CC=1>>[CH2:7]([O:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:21][CH3:22])=[CH:15][CH:16]=1)=[CH2:10])[C:6]1[CH:5]=[CH:4][CH:3]=[CH:20][CH:19]=1
Reactant: C=C(OCc1ccc(CO)cc1)c1ccc(CO)cc1
Reactant: C=C(OCc1ccc(CO)cc1)c1cccc(CO)c1
Product: C=C(OCc1ccccc1)c1ccc(OC)cc1

Procedure:
α-[4-(Hydroxymethyl)benzyloxy][4-(hydroxymethyl)styrene] and α-[4-(Hydroxymethyl)benzyloxy][3-(hydroxymethyl)styrene]
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:14]2[CH2:19][CH:18]([CH2:20]O)[CH2:17][N:16](/[C:22](=[CH:28]/[C:29]([O:31][CH2:32][CH3:33])=[O:30])/[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:15]2)[NH:9][C:10](=[O:13])[C:11]=1[OH:12])=[O:5])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[CH2:26]([O:25][C:23](=[O:24])[C:22]([N:16]1[CH2:17][CH:18]2[CH2:19][CH:14]([C:8]3[N:9]([C:10](=[O:13])[C:11]([OH:12])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=3)[CH2:20]2)[CH2:15]1)=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:27]
Reactant: CCOC(=O)/C=C(\C(=O)OCC)N1CC(CO)CC(c2nc(C(=O)OCC)c(O)c(=O)[nH]2)C1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C=C(C(=O)OCC)N1CC2CC(C1)c1nc(C(=O)OCC)c(O)c(=O)n1C2
Temperature: 23 °C
Reaction time: 3 h
Yield: 100.7 %

Procedure:
To diethyl 2-(3-(4-(ethoxycarbonyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidin-2-yl)-5-(hydroxymethyl)piperidin-1-yl)maleate (1.05 g, 2.32 mmol) in THF at 0° C. was added triethylamine (0.975 mL, 6.99 mmol) and methanesulfonyl chloride (0.541 mL, 6.99 mmol). The reaction mixture was stirred at 23° C. for 3 hours. H2O (50 mL) was then added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo. To the crude material dissolved in EtOH (40 mL) were added K2CO3 (0.643 g, 4.66 mmol) and H2O (1.7 mL). The reaction mixture was stirred at 23° C. for 36 hours. The solvent was removed in vacuo and the crude material was purified by silica gel column chromatography (Biotage flash chromatography system) using a gradient of ethyl acetate:methanol:AcOH (95:4:1) to (40:40:10) to afford 1.05 g (33% yield) of the title compound. 1H NMR (400 MHz, DMSO-D6) δ ppm 3.83-4.26 (7 H, m), 2.68-3.40 (6H, m), 2.02 (1 H, m), 1.79-1.89 (2 H, m), 1.07-1.31 (10 H, m). LCMS (+ESI, M+H+) m/z: 450.
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[S:22][C:12]2[CH2:13][N:14]([C:17]([CH:19]3[CH2:21][CH2:20]3)=[O:18])[CH2:15][CH2:16][C:11]=2[C:10]=1[C:23](=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30].C(=O)([O-])O.[Na+].[Br:37][CH:38]([CH3:42])[C:39](Br)=[O:40]>C(OCC)(=O)C.O>[Br:37][CH:38]([CH3:42])[C:39]([NH:8][C:9]1[S:22][C:12]2[CH2:13][N:14]([C:17]([CH:19]3[CH2:20][CH2:21]3)=[O:18])[CH2:15][CH2:16][C:11]=2[C:10]=1[C:23](=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30])=[O:40]
Reactant: CC(Br)C(=O)Br
Reactant: Nc1sc2c(c1C(=O)c1ccccc1Cl)CCN(C(=O)C1CC1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(Br)C(=O)Nc1sc2c(c1C(=O)c1ccccc1Cl)CCN(C(=O)C1CC1)C2

Procedure:
450 ml of toluene and 150 ml of water were added to 21.83 g of 2-amino-3-(2-chlorobenzoyl)-6-cyclopropanecarbonyl-4,5,6,7-tetrahydro-thieno [2,3-C]pyridine. 10.16 g of sodium hydrogencarbonate was further added, to which 9.5 ml of 2-bromopropionyl bromide was added while heating to 50° to 60° C. Moreover, a sodium hydrogencarbonate aqueous solution (10.6 g of sodium hydrogencarbonate and 150 ml of water) and 5 ml of 2-bromopropionyl bromide were added to complete the reaction. After the completion of the reaction, ethyl acetate was added and the reaction solution was washed once with a saturated saline solution and dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 29.9 g of the intended compound (at a quantitative yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[F:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C.O>[F:10][C:11]1[CH:16]=[C:15]([C:2]2[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: O=Cc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: O=Cc1ccc(-c2cccc(F)c2)cn1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 2 g of 5-bromopyridine-2-carbaldehyde, 1.96 g of 3-fluorophenylboronic acid, 11.2 g of K2CO3, 160 ml of toluene, 60 ml of water, 60 ml of ethanol and 0.93 mg of tetrakis(triphenylphosphine)palladium(0) is stirred at 100° C. under argon for 2 hours. The solvents are evaporated and the residue is dispersed in 100 ml of water, and the product is extracted with 2 portions of 30 ml of ethyl acetate. The organic phase is washed with 30 ml of sat. brine, dried over sodium sulfate and concentrated. The resulting residue is recrystallized from 28 ml of isopropanol.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[NH:28]1[C:32]([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)=[N:31][N:30]=[N:29]1>>[NH:31]1[C:32]([C:33]2[CH:39]=[CH:38][C:36]([NH:37]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=4)/[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:35][CH:34]=2)=[N:28][N:29]=[N:30]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Reactant: Nc1ccc(-c2nnn[nH]2)cc1
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(-c3nnn[nH]3)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and 4-tetrazol-5-yl-aniline
Reaction SMILES: [C:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)(=O)[CH3:2].N1C2C(=CC=CC=2)C=C1.P(Cl)(Cl)(Cl)=O>ClCCCl>[NH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[C:4]1[CH:1]=[CH2:2]
Reactant: CC(=O)c1cc2ccccc2[nH]1
Agent: c1ccc2[nH]ccc2c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: C=Cc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
This condensation reaction was studied in detail using the acetylindole (K5) and the indole (J6) using phosphoryl chloride as a condensing agent in 1,2-dichloroethane as solvent. A solution of acetylindole (K5) in 1,2-dichloroethane was cooled in an ice/salt bath and phosphoryl chloride was added slowly, keeping the temperature of the reaction mixture between 0° and 5° C. during the addition. This low temperature was preferred during the initial stages of this reaction to minimize the formation of unwanted byproducts. After 30 minutes stirring while the reaction mixture warmed to room temperature, indole (J6) in 1,2-dichloroethane was added. The reaction mixture was stirred overnight at room temperature and gas chromatographic analysis indicated that the condensation, though not complete, had taken place. The condensation reaction was driven to completion by refluxing the reaction mixture for one hour. The product, unsymmetrical indolylethene [Table 3, Entry 22], was isolated in good yield (74%, Example 11).
Reaction SMILES: [CH2:1]([SnH](CCCC)CCCC)CCC.[CH2:14]=[C:15]([NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C:16]([OH:18])=[O:17].[CH3:30][C:31]1(Br)[CH2:35][CH2:34][CH2:33][CH2:32]1.CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[CH3:1][O:17][C:16](=[O:18])[CH:15]([NH:19][C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[CH2:14][C:31]1([CH3:30])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC1(Br)CCCC1
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C=C(NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: COC(=O)C(CC1(C)CCCC1)NC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 38.6 %

Procedure:
Tributyltin hydride (37.8 g, 130 mmol) was added at reflux to a 500 mL of flask charged with benzene (200 mL) was added Z-dehydro-Ala-OH (15 g, 64 mmol), 1-methylcyclopentanyl-bromide (20.5 g) and AIBN (1.9 g). After 2 h, the solvent was removed and the residue was purified by column chromatograph to yield 2-benzyloxycarbonylamino-3-(1-methyl-cyclopentyl)-propionic acid methyl ester (7.9 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[O:16]1[C:24]2[C:19](=[CH:20][C:21]([CH2:25][NH:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[CH:22][CH:23]=2)[O:18][CH2:17]1>>[O:16]1[C:24]2[C:19](=[CH:20][C:21]([CH2:25][N:26]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C:13]([CH:10]3[C:11]4[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=4)[CH2:7][CH2:8][CH2:9]3)=[O:15])=[CH:22][CH:23]=2)[O:18][CH2:17]1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Reactant: COc1ccc(NCc2ccc3c(c2)OCO3)cc1
Product: COc1ccc(N(Cc2ccc3c(c2)OCO3)C(=O)C2CCCc3ccc(OC)cc32)cc1
Yield: 9.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.75 g) and [(1,3-dioxaindan-5-yl)methyl](4-methoxyphenyl)amine (0.93 g) as starting materials, N-[(1,3-dioxaindan-5-yl)methyl]-N-(4-methoxyphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.15 g) was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:26])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([O:24][CH3:25])[CH:16]=3)[N:10]=2)[CH:8]=1.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:26][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:30]([CH:27]2[CH2:29][CH2:28]2)=[O:31])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([O:24][CH3:25])[CH:16]=2)[N:10]=1
Reactant: COc1cc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)ccc1[N+](=O)[O-]
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared according to the procedure as described in step-2 Intermediate-30 by using 3-(5-(aminomethyl)-2-chlorophenyl)-1-(3-methoxy-4-nitrophenyl)-1H-1,2,4-triazol-5(4H)-one (0.500 g, 1.33 mmol), cyclopropylcarbonyl chloride (0.207 g, 1.99 mmol), DIPEA (2.0 mL) and THF (30 nit) to afford 0.300 g of crude product which was triturated with methanol: DEE to afford 0.300 g of pure product. 1H NMR (300 MHz, DMSO d6): δ 0.69 (s, 4H), 1.60 (m, 1H), 3.97 (s, 3H), 4.33 (d, J=5.4 Hz, 2H), 7.42-7.55 (m 3H), 7.70 (d, J=8.4 Hz, 1H), 7.87 (s, 1H), 8.12 (d, J=8.7 Hz, 1H), 8.69-8.71 (m, 1H), 12.83 (s, 1H); MS (m/z): 442.14 (M-FI).
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Br:11][C:12]1[CH:13]=[C:14](CN)[CH:15]=[CH:16][CH:17]=1.[CH2:20]([N:22](CC)CC)C.O>O1CCCC1>[Br:11][C:12]1[CH:13]=[C:14]([N:22]([CH3:20])[C:9]([NH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:10])[CH:15]=[CH:16][CH:17]=1
Reactant: CCCCCCCN=C=O
Reactant: CCN(CC)CC
Reactant: NCc1cccc(Br)c1
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCNC(=O)N(C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
3.2 mL (20 mmol, 1.5 eq) of heptyl isocyanate are added to a solution of 2.5 g (13 mmol, 1 eq) of (3-bromophenyl)methylamine in 10 ml of tetrahydrofuran in the presence of 2 ml of triethylamine. The reaction mixture is stirred for 12 hours at r.t. The reaction is stopped by addition of 2 mL of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). 3.4 g of 1-(3-bromophenyl)-3-heptyl-1-methylurea in solid form are obtained. Yield=77%
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:20]Br.[CH3:22][Si:23]([CH3:31])([CH3:30])[CH2:24][CH2:25][C:26]#[C:27][CH2:28]O>C(Cl)Cl.CCCCC>[Br:20][CH2:28][C:27]#[C:26][CH2:25][CH2:24][Si:23]([CH3:31])([CH3:30])[CH3:22]
Reactant: BrBr
Reactant: C[Si](C)(C)CCC#CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Solvent: ClCCl
Product: C[Si](C)(C)CCC#CCBr
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
To a flame dried flask was added PPh3 (1.76 g, 6.73 mmol) followed by dry CH2Cl2 (60 mL). The mixture was placed in an ice bath and bromine (0.34 mL, 6.41 mmol) was added dropwise. A small amount of PPh3 was added until the reaction went from yellow to clear in color. After 0.5 h at 0° C., 5-trimethylsilanylpent-2-yn-1-ol (1.0 g, 6.41 mmol) was dissolved in CH2Cl2 (5 mL) and added dropwise. After 4 h at 0° C., the reaction mixture was poured into a separatory funnel, diluted with pentane (250 mL) and extracted with H2O (100 mL) and sat. NaHCO3 (100 mL). The organic layer was dried (MgSO4), filtered and reduced in volume to 50 mL. The crude solution was chromatographed on a pad of silica gel with pentane (500 mL). After evaporation of the pentane, (5-bromopent-3-ynyl)trimethylsilane (1.2 g 87%) was obtained as a clear oil: IR (neat, cm-1) 2953, 2922, 2899, 2230, 1431, 1317, 1248, 1208, 852; 1H NMR (300 MHz, CDCl3) δ0.03 (s, 9H), 0.79 (t, J=8 Hz, 2H), 2.28 (tt, J1 =8 Hz, J2 =2 Hz, 2H), 3.92 (t, J=2 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ1.7, 13.6, 15.7, 15.8, 74.6, 90.2; HRMS (EI) m/z calcd for C7H12BrSi (M-CH3) 202.9892, found 202.9889 LRMS (EI) m/z 203 (M-CH3), 137, 73, 66.