Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]([CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][C:16]2=[O:21])([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl:31][C:32]1[CH:46]=[CH:45][C:35]2[C:36](=[O:44])[C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:38][O:39][C:34]=2[CH:33]=1>ClCCl>[C:1]([N:4]1[CH2:5][CH2:6][C:7]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:40]([C:37]3[C:36](=[O:44])[C:35]4[CH:45]=[CH:46][C:32]([Cl:31])=[CH:33][C:34]=4[O:39][CH:38]=3)(=[O:42])=[O:41])[CH2:17][C:16]2=[O:21])([C:10]([O:12][CH3:13])=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C1(CN2CCNCC2=O)CCN(C(C)=O)CC1
Reactant: O=c1c(S(=O)(=O)Cl)coc2cc(Cl)ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1(CN2CCN(S(=O)(=O)c3coc4cc(Cl)ccc4c3=O)CC2=O)CCN(C(C)=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
To a solution of 1-(1-acetyl-4-methoxycarbonylpiperidin-4-ylmethyl)-2-piperazinone (850 mg) and diisopropylethylamine (555 mg) in dichloromethane (15 ml) was gradually added dropwise at 0° C. a solution of 7-chloro-4-oxo-4H-benzopyran-3-sulfonyl chloride (960 mg) in dichloromethane (5 ml), and the mixture was stirred at 0° C. for 30 minutes. The reaction solution was diluted with dichloromethane, washed with water, citric acid solution, sodium bicarbonate solution and brine, dried and concentrated, and the residue was purified with silica gel column chromatography (ethyl acetate: methanol=10:1) to give pale yellow solid of 1-(1-acetyl-4-methoxycarbonylpiperidin-4-ylmethyl)-4-(7-chloro-4-oxo-4H-benzopyran-3-sulfonyl)-2-piperazinone (1.10 g).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])(O)=O.[C:12](=O)([O-:14])[O-:13].[K+].[K+].CI>CC(C)=O>[C:12]([CH2:1][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([OH:14])=[O:13]
Reactant: O=Cc1ccccc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: O=Cc1ccccc1CC(=O)O
Temperature: 56 °C
Reaction time: 72 h
Yield: 99.5 %

Procedure:
2-Carboxybenzaldehyde (4.53 g, 30 mmoles) was dissolved in acetone (100 mls) and anhydrous potassium carbonate (4.14 g, 30 mmoles) was added. After stirring methyl iodide (5.6 mls, 90 mmoles) was added and the reaction was heated (56° C.) for 30 minutes. The reaction became very thick so further acetone was added (50 mls) and stirring continued at room temperature for a further 72 hours. The reaction mixture was filtered through Celite and then evaporated to leave a viscous oil. The oil was then partitioned between water (30 ml) and ethyl acetate (30 ml). The aqueous layer was washed with further ethyl acetate (2×30 mls) and all the ethyl acetate extracts combined and washed with brine (30 mls) and then water (30 mls) dried over anhydrous magnesium sulphate and evaporated to leave a clear light yellow oil (4.9 g, 100% yield).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br>>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][O:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Reactant: Fc1cccc(CBr)c1
Product: O=Cc1cc([N+](=O)[O-])ccc1OCc1cccc(F)c1
Yield: 95 %

Procedure:
Prepared in analogy to example 8 from 2-hydroxy-5-nitrobenzaldehyde and 3-fluoro-benzylbromide. Colorless solid. Yield=95%. MS: m/e=275.1 (M+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:19]2[N:20]=[C:21]([CH3:23])[S:22][C:18]=2[CH:17]=1>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9](/[CH:10]=[CH:23]/[C:21]2[S:22][C:18]3[CH:17]=[C:16]([O:15][CH3:14])[CH:25]=[CH:24][C:19]=3[N:20]=2)=[CH:8][CH:7]=1
Reactant: COc1ccc2nc(C)sc2c1
Reactant: O=Cc1ccc(OCCCCl)cc1
Product: COc1ccc2nc(/C=C/c3ccc(OCCCCl)cc3)sc2c1
Yield: 27.8 %

Procedure:
The procedure of Example 28 was followed starting with 4-chloropropoxybenzaldehyde (5.0 g, 25 mmol) and using 6-methoxy-2-methylbenzothiazole (4.2 ml, 25 mmol) in place of 2-methylbenzothiazole to give (E)-2-[2-(4-chloropropoxyphenyl)ethenyl]-6-methoxybenzothiazole (2.5 g, 28% yield) as an amber oil. 1H NMR (CDCl3): δ 7.44-6.82 (m, 9H9, 4.21 (t, J=5.3 Hz, 2H), 3.93 (s, 3H), 3.41 (t, J=5.3 Hz, 2H), 2.51 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[H-].[Na+].[F:15][C:16]1[CH:17]=[C:18]([CH2:34][OH:35])[CH:19]=[C:20]([F:33])[C:21]=1[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1>CN(C=O)C>[F:15][C:16]1[CH:17]=[C:18]([CH:19]=[C:20]([F:33])[C:21]=1[O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=1)[CH2:34][O:35][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: OCc1cc(F)c(Oc2ccc(C(F)(F)F)cc2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1cc(F)c(Oc3ccc(C(F)(F)F)cc3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (30 mg, 0.162 mmol), sodium hydride (12.93 mg, 0.323 mmol) and (3,5-difluoro-4-(4-(trifluoromethyl)phenoxy)phenyl)methanol (49.2 mg, 0.162 mmol) in DMF (1.5 mL).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:15](=[O:17])[CH2:14][CH2:13][CH2:12][C:11]=3[O:10][C:9](=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][NH2:20]>>[CH3:19][N:20]1[C:11]2[CH2:12][CH2:13][CH2:14][C:15](=[O:17])[C:16]=2[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][C:9]1=[O:10]
Reactant: O=C1CCCc2oc(=O)cc(-c3ccccc3)c21
Reactant: CN
Product: Cn1c2c(c(-c3ccccc3)cc1=O)C(=O)CCC2

Procedure:
Prepared from 4-phenyl-5,6,7,8-tetrahydro-cumarin- 5-one and methanolic methylamine at ambient temperature.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.Cl[CH2:19][CH:20]([O:23][CH3:24])[O:21][CH3:22]>O1CCCC1>[CH3:22][O:21][CH:20]([O:23][CH3:24])[CH2:19][CH:1]([N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(CCl)OC
Reactant: c1ccc(Cn2cccn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(CC(c1ccccc1)n1cccn1)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-benzyl-1H-pyrazole (0.653 g) in tetrahydrofuran (5 mL) cooled to −78° C. was dropwise added 1.6M n-butyllithium (2.84 mL). The reaction mixture was stirred for 60 minutes, and 2-chloro-1,1-dimethoxyethane (0.517 mL) was added, and stirring continued for 3 hours. The reaction mixture was allowed to slowly warm up to room temperature, and was quenched with water, extracted with ether, dried over Na2SO4, filtered, and concentrated. The product was purified by chromatography on silica gel using 0-20% ethyl acetate/hexanes as the eluent to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][N:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:13][Si](C(C)C)(C(C)C)C(C)C)[CH:10]=2)[C:5]1=[O:24]>Cl.CO.O1CCCC1>[F:26][C:2]([F:1])([F:25])[CH2:3][N:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([SH:13])[CH:10]=2)[C:5]1=[O:24]
Reactant: CC(C)[Si](Sc1ccc2c(c1)CN(CC(F)(F)F)C2=O)(C(C)C)C(C)C
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=C1c2ccc(S)cc2CN1CC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(2,2,2-trifluoroethyl)-5-((triisopropylsilyl)sulfanyl)isoindolin-1-one was dissolved in a solution of hydrochloric acid in methanol (2 ml) and tetrahydrofuran (2 ml) and stirred at room temperature for 2 hours or until disappearance of starting material. Reaction mixture concentrated to give desired material (quant yield). ES+ 248
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[OH:16])[N:12]=[CH:11][CH:10]=[C:9]2[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][CH:28]2[CH2:30][CH2:29]2)=[O:26])=[C:20]([Cl:31])[CH:19]=1)=[O:5])[CH3:2].CC1C=CC(S(O[CH2:43][C@H:44]2[CH2:46][O:45]2)(=O)=O)=CC=1>>[CH2:1]([NH:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:43][C@H:44]1[CH2:46][O:45]1)[N:12]=[CH:11][CH:10]=[C:9]2[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][CH:28]2[CH2:30][CH2:29]2)=[O:26])=[C:20]([Cl:31])[CH:19]=1)=[O:5])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: CCNC(=O)c1cc2c(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)ccnc2cc1O
Product: CCNC(=O)c1cc2c(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)ccnc2cc1OC[C@H]1CO1
Yield: 47.4 %

Procedure:
The title compound (235.4 mg, 0.474 mmol, 47.4%) was obtained as light yellow crystals from N6-ethyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide) (440.9 mg, 1.00 mmol) and (2R)oxiran-2-ylmethyl 4-methyl-1-benzenesulfonate, by the same procedure as in Example 7.
Reaction SMILES: C([O-])(=O)C.[Na+].Br[CH:7](Br)[C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].Cl.[F:16][C:17]1[CH:22]=[C:21]([Cl:23])[C:20]([OH:24])=[CH:19][C:18]=1[NH:25][NH2:26]>O>[Cl:23][C:21]1[C:20]([OH:24])=[CH:19][C:18]([NH:25][N:26]=[CH:7][C:8](=[O:9])[C:10]([F:13])([F:12])[F:11])=[C:17]([F:16])[CH:22]=1
Reactant: O=C(C(Br)Br)C(F)(F)F
Reactant: NNc1cc(O)c(Cl)cc1F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(C=NNc1cc(O)c(Cl)cc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
Then, 49.2 g of sodium acetate and 40.5 g of 1,1-dibromo-3,3,3-trifluoroacetone were dissolved in 400 ml of water, and the solution was heated at 80° to 90° C. for 40 minutes. This solution was cooled to 0° C., to which 75 g of the crude crystals of 2-fluoro-4-chloro-5-hydroxyphenylhydrazine hydrochloride was added. The mixture was stirred at room temperature for 70 minutes, and the resulting crystals were collected by filtration, and dried under reduced pressure, which afforded 35.4 g of 3,3,3-trifluoro-2-oxopropanal 1-(4-chloro-2-fluoro-5-hydroxyphenylhydrazone).
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10]([S:12][CH3:13])[N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[F:22])[NH2:18]>O1CCOCC1>[Cl:14][C:15]1[CH:16]=[C:17]([NH:18][C:2]2[C:3]3[N:11]=[C:10]([S:12][CH3:13])[N:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: CSc1ncc2ncnc(Cl)c2n1
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: C1COCCO1
Product: CSc1ncc2ncnc(Nc3ccc(F)c(Cl)c3)c2n1

Procedure:
3.0 g of 4-chloro-6-methylthiopyrimido[5,4-d]pyrimidine, 3.8 g of 3-chloro-4-fluoroaniline and 10 ml of dioxane are heated at 80° C. for 2 hours. After cooling, the reaction mixture is concentrated and portions are triturated first with water and then with diethyl ether, filtered off with suction and dried.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[Br:16]C1C=C(C=CC=1)C(Cl)=O.N1CCOCC1>>[Br:16][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:2]=1)[C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:7]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: O=C(c1ccc(Br)cc1)N1CCOCC1
Solvent: C1COCCN1
Product: O=C(c1cccc(Br)c1)N1CCOCC1
Yield: 71 %

Procedure:
Following the general method as outlined in Intermediate 174, starting from 3-bromobenzoyl chloride and morpholine, the title compound was obtained as a colorless sticky solid in 71% yield.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH2:34]([O:33][C:31]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH2:26][CH:27]4[CH2:28][CH2:29]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)=[O:32])[CH3:35]
Reactant: CCOC(=O)Cl
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3ccccc3OCC3CC3)ncnc12
Product: CCOC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A162) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:10]=3[S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([C:8]2[S:9][C:10]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=3[C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc2c(-c3ccccc3)csc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2sc3cc(OC)ccc3c2-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To 500 ml. of 1,2-dichloroethane were added 24.0 g. (0.10 mole) of 3-phenyl-6-methoxybenzothiophene and 17.1 g. (0.10 mole) of p-methoxybenzoyl chloride. The mixture was cooled to 0° C., and 13.4 g. (0.10 mole) of aluminum chloride were added. The mixture was stirred for 1 hour, and ice then was added to the mixture. The organic layer was separated, washed with water, and evaporated. To the residue were added a mixture of methanol and 5N sodium hydroxide. The mixture was refluxed for 30 minutes and evaporated. To the residue were added ether and water. The ether layer was separated, washed with 1N sodium hydroxide, 1N hydrochloric acid, and aqueous sodium chloride solution. The ether layer then was dried over magnesium sulfate, filtered, and evaporated to give crude product which was recrystallized from methanol to obtain 34.2 g. (91 percent) of the title compound, m.p. 127°-128° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C@@H:4]([CH:5]=[CH2:6])[C@H:3]1[C:7]([OH:9])=[O:8].[CH2:11]([N:14]1[CH:18]=[CH:17][C:16]([CH2:19]O)=[C:15]1[C:21]([F:24])([F:23])[F:22])[C:12]#[CH:13]>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:10])[C@@H:4]([CH:5]=[CH2:6])[C@H:3]1[C:7]([O:9][CH2:19][C:16]1[CH:17]=[CH:18][N:14]([CH2:11][C:12]#[CH:13])[C:15]=1[C:21]([F:24])([F:23])[F:22])=[O:8]
Reactant: C=C[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: C#CCn1ccc(CO)c1C(F)(F)F
Solvent: Cc1ccccc1
Product: C#CCn1ccc(COC(=O)[C@@H]2[C@H](C=C)C2(C)C)c1C(F)(F)F
Yield: 99.9 %

Procedure:
Using the procedure of Example 1, 610 mg of (1R,cis) 2,2-dimethyl-3-ethenyl-cyclopropane carboxylic acid and with 800 mg of 1-(2-propynyl)-2-trifluromethyl-3-pyrrole-methanol were reacted to obtain 1.28 g of [2-trifluoromethyl-1-(2-propynyl)-1H-pyrrol-3-yl]-methyl (1R,cis) 2,2-dimethyl-3-ethenyl-cyclopropane carboxylate with a specific rotation of [α]D =+9° (0.2% toluene)
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:20](=[O:22])[CH3:21])[C:10]([O:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])=[CH:11][CH:12]=2)[O:7][C:6](=[O:23])[CH:5]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35])[CH:29]=O>C(O)C.O>[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:20](=[O:22])[CH:21]=[CH:29][C:28]3[CH:31]=[C:32]([O:36][CH3:37])[C:33]([O:34][CH3:35])=[C:26]([O:25][CH3:24])[CH:27]=3)[C:10]([O:14][CH2:15][CH:16]=[C:17]([CH3:18])[CH3:19])=[CH:11][CH:12]=2)[O:7][C:6](=[O:23])[CH:5]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: CC(=O)c1c(OCC=C(C)C)ccc2c(C)cc(=O)oc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(C=CC(=O)c2c(OCC=C(C)C)ccc3c(C)cc(=O)oc23)cc(OC)c1OC
Temperature: 25 °C
Yield: 37.3 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 4-methyl-7-(3-methylbut-2-enyloxy)-8-acetylcoumarin (2.14 g, 0.0075 mol) and 3,4,5-trimethoxy-benzaldehyde (1.47 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified. The precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 1.3 g of product m.p. 148-150° C., 1H-NMR (CDCl3) δ: 1.69 (s, 3H,); 1.72 (s, 3H); 2.44 (d, 3H, J=1.2 Hz); 3.74-3.88 (m, 9H); 4.65 (d, 2H, J=6.5 Hz); 5.34-5.38 (m, 1H); 6.16 (s, 1H); 6.93 (d, 1H, J=16 Hz); 6.95 (d, 1H, J=8.9 Hz); 7.25 (d, 1H, J=16 Hz); 7.63 (d, 1H, J=8.9 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=O)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.[NH2:48][CH2:49][CH2:50][O:51][C:52]1[CH:53]=[C:54]([CH:57]=[CH:58][CH:59]=1)[C:55]#[N:56]>Cl.O>[C:55]([C:54]1[CH:53]=[C:52]([CH:59]=[CH:58][CH:57]=1)[O:51][CH2:50][CH2:49][NH:48][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[CH:17][CH:16]=1)#[N:56]
Reactant: COC(=O)c1ccc(Cc2ccncc2)cc1
Reactant: N#Cc1cccc(OCCN)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Product: N#Cc1cccc(OCCNC(=O)c2ccc(Cc3ccncc3)cc2)c1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
262 mg (1.15 mmol) of methyl 4-[(pyridine-4-yl)methyl]benzoate was dissolved in 5 ml of concentrated hydrochloric acid. The solution was stirred at 70° C. for 15 hours. The solvent was evaporated, and the residue was dissolved in 5 ml of dichloromethane. 0.24 ml (1.73 mmol) of triethylamine, 243 mg (1.27 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 172 mg (1.27 mmol) of 1-hydroxybenzotriazole and 308 mg (1.27 mmol) of 3-(2-aminoethoxy)benzonitrile hydrochloride were added to the solution, and they were stirred for 15 hours. The reaction liquid was diluted with water. After the extraction with ethyl acetate, the organic layer was successively washed with water, 1 N sodium hydroxide and saturated aqueous NaCl solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[NH2:10][C@@H:11]([CH2:15][OH:16])[CH:12]([CH3:14])[CH3:13].C(O)(=O)C.C([BH3-])#N>CO>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:10][C@H:11]([CH:12]([CH3:14])[CH3:13])[CH2:15][OH:16])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](N)CO
Reactant: O=Cc1cccc(Br)n1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)[C@H](CO)NCc1cccc(Br)n1
Reaction time: 0.08 h
Yield: 59.7 %

Procedure:
To a solution of 6-bromopyridine-2-carbaldehyde (5.00 g, 26.9 mmol) in methanol (75 mL) at ambient temperature was added D-valinol (3.00 mL, 26.9 mmol) followed by acetic acid (6.2 mL, 110 mmol). After 5 minutes, MP-cyanoborohydride (2.49 mmol/g; 12 g) was added and stirred overnight. The mixture was filtered, concentrated. The residue was partitioned between 1N NaOH and CH2Cl2. The organic phase was dried (Na2SO4) and concentrated. The residue was purified by chromatography (50% ethyl acetate:CH2Cl2 to remove non polar impurites, then ethyl acetate to 20% acetone:ethyl acetate) to provide 4.39 g (60%) of the title compound. MS (DCI30 ) m/z 273/275 (M+H).
Reaction SMILES: C(O[C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17](=[O:34])[N:18]([CH3:33])[C:19]2[CH:20]=[N:21][C:22]([O:25][C:26]3[C:27]([CH3:32])=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:23][CH:24]=2)=[CH:9]1)=O)(C)(C)C.[H-].[Na+].CI>C1COCC1>[CH3:33][N:18]([C:19]1[CH:20]=[N:21][C:22]([O:25][C:26]2[C:27]([CH3:32])=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:23][CH:24]=1)[C:17]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([CH3:6])[CH:9]=1)=[O:34]
Reactant: Cc1ncccc1Oc1ccc(N(C)C(=O)c2cn(C(=O)OC(C)(C)C)c3ccccc23)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ncccc1Oc1ccc(N(C)C(=O)c2cn(C)c3ccccc23)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 61.7 %

Procedure:
The tert-butyl-3-(methyl(6-(2-methylpyridine-3-yloxy)pyridine-3-yl)carbamoyl)-1H-indole-1-carboxylate (40 mg, 0.087 mmol) in Example 12 was dissolved in THF (10 ml), and NaH (21 mg, 0.54 mmol) and methyl iodide (0.95 g, 0.67 mmol) were added to the solution. The reaction solution was stirred at room temperature for 5 hours, and then the product was washed and filtered to yield a target compound as a brown solid (20 mg, 12%) by chromatography (methanol:dichloromethane=1:20).
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-])=O.C([O-])([O-])=O.[K+].[K+].[C:21]([O:25][CH3:26])(=[O:24])[CH2:22][SH:23]>>[CH3:26][O:25][C:21]([C:22]1[S:23][C:4]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=2[CH:6]=1)=[O:24]
Reactant: COC(=O)CS
Reactant: O=Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cc2ccc([N+](=O)[O-])cc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2,4-dinitrobenzaldehyde (6.45 g, 32.9 mol) and K2CO3 (5.45 g, 39.4 mmol) in DMIF (60 mL) was slowly added methyl thioglycolate (3.0 mL, 32.9 mmol). The mixture was stirred at RT for 1 h, then at 50° C. for 2 h. The resultant mixture was poured into H2O/ice and stirred until a precipitate formed. The solid was filtered and triturated with hot MeOH. The pale brown solid was filtered. 1H NMR (DMSO-d6) δ 9.13 (s, 1H), 8.33 (s, 1H), 8.30-8.17 (m, 2H), 3.89 (s, 3H). MS (EI): cal'd (MH+) 238.01, exp (MH+) 238.10.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[F:23])[NH:19][C:18]([C:24]1[CH:25]=[CH:26][C:27]([O:31][CH3:32])=[C:28]([NH2:30])[CH:29]=1)=[CH:17]2.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([CH2:1][NH:30][C:28]2[CH:29]=[C:24]([C:18]3[NH:19][C:20]4[C:16]([CH:17]=3)=[CH:15][C:14]([F:13])=[C:22]([F:23])[CH:21]=4)[CH:25]=[CH:26][C:27]=2[O:31][CH3:32])=[CH:4][CH:5]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CNc2cc(-c3cc4cc(F)c(F)cc4[nH]3)ccc2OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.7 %

Procedure:
Methyl 4-formylbenzoate (0.21 g, 1.28 mmol) was added to a stirred mixture of 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.34 g, 1.24 mmol) in methylene chloride (125 mL), followed by acetic acid (0.3 g, 3.33 mmol). The resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.3 g, 1.42 mmol) was added in one portion, and the resulting homogeneous solution stirred at room temperature for 4 days. Saturated aqueous sodium bicarbonate solution (100 mL) was added and the mixture stirred for 2 hours. The mixture was shaken, the organic layer separated, and dried over Na2SO4. The solvent was evaporated to give a brown gum. Recrystallization from methanol gave the product as off-white crystals (140 mg), mp 168-170° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[F:33][C:34]([F:45])([F:44])[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42]N)=[CH:38][CH:37]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:42][C:39]3[C:40]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:41][C:36]([O:35][C:34]([F:45])([F:44])[F:33])=[CH:37][CH:38]=3)=[CH:6][CH:7]=1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Br)cc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(Br)cc4)[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS m/e: 642 (M+H)+.