Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][CH:35]=[CH:34][C:4]=1[CH2:5][C:6]1[C:7]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]=C)=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[N:8][CH:9]=[N:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1.[O-:38]I(=O)(=O)=O.[Na+].O>[Os](=O)(=O)(=O)=O.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:37]=[CH:36][CH:35]=[CH:34][C:4]=1[CH2:5][C:6]1[C:7]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]=[O:38])=[CH:28][CH:27]=2)(=[O:24])=[O:25])=[N:8][CH:9]=[N:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1
Reactant: C=Cc1ccc(S(=O)(=O)Nc2ncnc(OCCOC3CCCCO3)c2Cc2ccccc2OC)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1Cc1c(NS(=O)(=O)c2ccc(C=O)cc2)ncnc1OCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
318 mg of rac-N-[5-(o-methoxybenzyl)-6-[2-[(tetrahydro-2H-pyran-2-yl]oxy]ethoxy]-4-pyrimidinyl]-p-vinylbenzenesulfonamide, 5.3 mg of osmium tetroxide and 270 mg of sodium(meta)periodate were added in succession to a mixture of 1.5 ml of water and 4 ml of dioxane at room temperature. After stirring at room temperature for 1 hour, the dioxane was distilled under reduced pressure. Thereafter, the aqueous phase was extracted three times with ethyl acetate. The ethyl acetate was washed twice with water and once with NaCl solution (saturated), dried and distilled under reduced pressure. The residue was chromatographed over 30 g of SiO2 with CH2Cl2 /ethyl acetate and yielded 150 mg of rac-p-[[5-(o-methoxybenzyl)-6-[2-[(tetra-hydro-2H-pyran-2-yl)oxy]ethoxy]-4-pyrimidinyl]sulfamoyl]-benzaldehyde as white foam. MS: 527 (M); 443 ##STR12## (--OCH3 +SO2).
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([CH3:34])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:17]([CH3:32])=[N:18][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)=[CH:10][C:9]=1[CH3:33])[CH3:6])C.[OH-].[Na+]>C1COCC1.CCO>[CH3:34][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:17]([CH3:32])=[N:18][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)=[CH:10][C:9]=1[CH3:33])([CH3:6])[C:4]([OH:35])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OC(C)(C)C(=O)O
Reaction time: 4 h

Procedure:
0.221 g (0.453 mmol) of the above prepared 2-methyl-2-{2-methyl-4-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-phenoxy}-propionic acid ethyl ester was dissolved in 2.7 ml of THF/EtOH=1/1, treated with 1.35 ml (3 eq.) of 1N NaOH and kept at ambient temperature for 4 h. The reaction mixture was then poured onto crashed ice/AcOEt/HCl dil., the aqueous phase extracted again with AcOEt, the combined organic layers were washed with water, dried over sodium sulfate, and evaporated to dryness. Recrystallisation from AcOEt/hexane afforded finally 0.194 g of the title compound as white solid of mp. 164–165° C.
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([NH:19][NH2:20])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[C:11]([NH:19][N:20]=[CH:1][CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CC=Cc1ccccc1
Reactant: NNC(=O)c1ccccc1
Solvent: CO
Product: O=C(NN=CC=Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To 200 ml of methanol solution containing 13.2 g of cinnamaldehyde was added 13.6 g of benzoylhydrazine, followed by stirring for 30 minutes at room temperature, for the precipitation of crystals. The crystals were filtered off and dried. Thus there was obtained 22 g of cinnamaldehyde benzoyl hydrazone (mp. 192°-194° C.).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:7][C:8]1[CH:9]=[C:10]([CH:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][NH2:16])[CH:11]=[CH:12][CH:13]=1)[CH2:4][CH2:5][CH3:6].Cl[CH2:25][C:26]([N:28]([CH3:30])[CH3:29])=[O:27].O>CN(C=O)C>[CH2:3]([O:7][C:8]1[CH:9]=[C:10]([CH:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:15][NH:16][CH2:25][C:26]([N:28]([CH3:30])[CH3:29])=[O:27])[CH:11]=[CH:12][CH:13]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CN(C)C(=O)CCl
Reactant: CCCCOc1cccc(C(CN)C(=O)OC(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1cccc(C(CNCC(=O)N(C)C)C(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a suspension of NaH (60%, 2.0 g, 51 mmol) in dry DMF (125 ml) cooled at 0° C., a solution of 2-(3-butoxyphenyl)-(tert-butoxycarbonyl)ethylamine (7.5 g, 25.5 mmol) in dry DMF (125 ml) was added dropwise. After 1 h at room temperature, 2-chloro-N,N-dimethylacetamide (5.2 ml, 51 mmol) was added and the mixture was stirred for 16 h at room temperature. H2O (10 ml) was added and the solvent was evaporated under reduced pressure. The residue was dissolved in H2O (150 ml) and extracted with CH2Cl2 (2×150 ml). The collected organic phases were dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography (petroleum ether/EtOAc 4:6) affording the title compound (7.2 g, 75%) as light yellow oil. 1H NMR (300 MHz, DMSO-d6): δ 7.1 (m, 1H), 6.79-6.71 (m, 3H), 3.97 (t, J=6.0 Hz, 2H), 3.96 (s, 2H), 3.40 (dd, J=8.7 Hz, J=7.2 Hz, 2H), 2.88 (s, 6H), 2.76 (dd, J=7.9 Hz, J=6.4 Hz, 2H), 1.76 (m, 2H), 1.46 (m, 2H), 1.37 (s, 9H), 0.95 (t, J=7.3 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:12])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:13]1[CH:18]=[CH:17][C:16]([O:19][C:20](Cl)=[S:21])=[CH:15][CH:14]=1>C(Cl)Cl>[CH3:12][C:3]1[C:2]([NH:1][C:20](=[S:21])[O:19][C:16]2[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Cc1nc2ccccc2cc1N
Reactant: S=C(Cl)Oc1ccccc1
Solvent: ClCCl
Product: Cc1nc2ccccc2cc1NC(=S)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
3-Amino-2-methylquinoline(4 g, 25 mmol) and phenyl chlorothionoformate(4.32 g, 25 mmol) were dissolved in methylene chloride and then was stirred at room temperature for 2 hours. The mixture solution was concentrated under reduced pressure to remove methylene chloride and purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:21][C:20]=2[N+:32]([O-])=O)=[C:4]([Cl:17])[CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH:7]2[C:12]([O:14][CH2:15][CH3:16])=[O:13].[Cl-].[NH4+]>O1CCCC1.[Zn]>[NH2:32][C:20]1[CH:21]=[C:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH:23]=[CH:24][C:19]=1[O:18][C:3]1[C:2]([Br:1])=[C:11]2[C:6]([CH:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:9][O:10]2)=[CH:5][C:4]=1[Cl:17]
Reactant: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-])c2Br
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)OC(C)(C)C)cc1N)c2Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a stirred solution of ethyl 8-bromo-7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6-chlorochroman-4-carboxylate (2.00 g, 3.59 mmol) in tetrahydrofuran (15 mL) at ambient temperature was added zinc dust (4.70 g, 71.8 mmol), followed by saturated ammonium chloride solution (7.5 mL). The resulting mixture was stirred at ambient temperature for 1 hour. The mixture was filtered through a glass microfibre filter to remove the insoluble zinc solids, and the solids were washed twice with tetrahydrofuran. The combined filtrate and washings were concentrated to remove most of the tetrahydrofuran, and the residue was partitioned between ethyl acetate (100 mL) and water (50 mL). The organic layer was washed with brine (50 mL), then dried over sodium sulfate and concentrated to afford the desired compound as a light brown glass (1.61 g, 85% yield).
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][CH2:4][C:5](=O)[CH2:6][C:7]([O:9]CC)=[O:8].[N:14]([C:17]1[CH:27]=[CH:26][C:20]([C:21]([NH:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1)=[N+:15]=[N-:16].[O-]CC.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:24]([NH:23][C:21]([C:20]1[CH:26]=[CH:27][C:17]([N:14]2[C:5]([CH2:4][CH2:3][CH:2]([CH3:1])[CH3:13])=[C:6]([C:7]([OH:9])=[O:8])[N:16]=[N:15]2)=[CH:18][CH:19]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)CC(=O)CCC(C)C
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Agent: CC[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCC(C)C)cc1
Temperature: 60 °C
Reaction time: 17 h
Yield: 96.4 %

Procedure:
Ethyl 6-methyl-3-oxoheptanoate (1.08 g, 5.53 mmol, 1.25 eq.) obtained in Example 97a) and 4-azido-N-ethylbenzamide (0.842 g, 4.43 mmol) were dissolved in ethanol (25 ml), sodium ethoxide (418 mg, 5.53 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min and at 60° C. for 17 hr. 2% Aqueous sodium carbonate solution (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with water (20 ml) and washed with ethyl acetate-hexane (2:1, 40 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, acidified (pH<3) with 6N hydrochloric acid, and stood still at 0° C. The precipitate was collected by filtration and washed with cold water and dried to give the title compound as a grayish white powder (1.41 g, 4.27 mmol, 96.3%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][O:14][C:15]([C:17]1[C:22]2[C@@H:23]3[C@H:28]([CH2:29][CH2:30][C:21]=2[CH:20]=[CH:19][CH:18]=1)[NH:27][CH2:26][CH2:25][CH2:24]3)=[O:16]>C(Cl)Cl.CO>[CH3:13][O:14][C:15]([C:17]1[C:22]2[C@@H:23]3[C@H:28]([CH2:29][CH2:30][C:21]=2[CH:20]=[CH:19][CH:18]=1)[N:27]([C:10]([C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1)=[O:12])[CH2:26][CH2:25][CH2:24]3)=[O:16]
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: COC(=O)c1cccc2c1[C@H]1CCCN[C@H]1CC2
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccc2c1[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1CC2
Yield: 43 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-10-carboxylic acid methyl ester following a procedure analogous to that described in Example 1. Yield: 43% of theory; TLC: rf=0.30 (silica gel, CH2Cl2/MeOH/32% aqueous NH3 90:10:1); Mass spectrum (ESI+): m/z=390 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8](O)=O.[NH2:11][C:12]1[CH:13]=[C:14]([CH:23]=[CH:24][C:25]=1[NH2:26])[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>N1C=CC=CC=1>[C:15]([C:14]1[CH:23]=[CH:24][C:25]2[N:26]=[C:8]([C:3]3[NH:4][C:5]([CH3:7])=[CH:6][C:2]=3[CH3:1])[NH:11][C:12]=2[CH:13]=1)(=[O:16])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cc(C)c(C(=O)O)[nH]1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc(C)c(-c2nc3ccc(C(=O)c4ccccc4)cc3[nH]2)[nH]1
Temperature: 70 °C
Reaction time: 8 h
Yield: 15.2 %

Procedure:
3,5-Dimethylpyrrole-2-carboxylic acid (99 mg, 0.71 mmol) was added to a pyridine (3 ml) solution of 3,4-diaminobenzophenone (150 mg, 0.71 mmol). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (149 mg, 0.78 mmol) and 1-hydroxybenzotriazole monohydrate (119 mg, 0.78 mmol) were further added, and the mixture was heated to 70° C. and stirred overnight. The reaction mixture was allowed to cool to room temperature with stirring, and then the solvent was evaporated. The residue was purified using medium pressure silica gel flash column chromatography (NH silica gel, chloroform:methanol=98:2). The residue was dissolved in acetic acid (3 ml), and stirred for 8 hours at 100° C. The reaction mixture was allowed to cool to room temperature with stirring, and then the solvent was evaporated. The residue was purified using medium pressure silica gel flash column chromatography (NH silica gel, chloroform:methanol=98:2), to afford 5-benzoyl-2-(3,5-dimethylpyrrol-2-yl)-benzimidazole (34 mg, 15% in two steps) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8]C)[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[O:13][CH3:14].B(Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([OH:8])[CH:7]=1
Reactant: COc1cc([N+](=O)[O-])c(OC)cc1C
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])c(O)cc1C
Temperature: -20 °C
Reaction time: 20 h
Yield: 99.6 %

Procedure:
1-Methyl-2,5-bis(methyloxy)-4-nitrobenzene (3.96 g, 20 mmol) was dissolved in CH2Cl2 (20 mL) and cooled to −20° C. A solution of BCl3 (1.0 M) in CH2Cl2 (20 mL) was added to above solution drop wise over 5 minutes. A purple solution was obtained. The reaction mixture was slowly warmed to room temperature and stirred for 20 h. The mixture was then quenched with saturated Na2CO3, stirred for 10 minutes and then extracted with EtOAc (3×100 mL). The organic extracts were combined, washed with water, brine, and dried (Na2SO4). The solvent was removed via rotovap to give the title compound (3.65 g, 99%) as a yellow solid. MS (ES) m/e 184 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]1[O:15][C:14]2[C:9](=[C:10]([OH:16])[CH:11]=[CH:12][CH:13]=2)[O:8]1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][C:19]=1[C:41]#[N:42]>CN(C=O)C>[C:41]([C:19]1[CH:20]=[N:21][C:22]2[C:27]([C:18]=1[O:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]3[O:15][CH2:7][O:8][C:9]=13)=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH2:32][CH2:33][N:34]1[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]1)[CH:23]=2)#[N:42]
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCN1CCN(C)CC1
Reactant: Oc1cccc2c1OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cccc4c3OCO4)c(C#N)cnc2cc1OCCCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.3 %

Procedure:
Potassium carbonate-(0.055 g) was added to a solution of 2,3-methylenedioxyphenol (0.041 g) in DMF (3 ml) and the mixture was stirred at ambient temperature for 10 minutes. 4-Chloro-3-cyano-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline (0.1 g) was added and the mixture was stirred and heated to 95° C. for 2 hours. The resultant mixture was cooled to ambient temperature and filtered. The filtrate was evaporated and the residue was purified by colum chromatography on silica using initially increasingly polar mixtures of methylene chloride and methanol followed by increasingly polar mixtures of methylene chloride and a saturated methanolic ammonia solution as eluent. There was thus obtained the title compound as a solid (0.069 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 2.3-2.4 (m, 2H), 3.0 (s, 3H), 3.2-4.0 (m, 8H), 3.5 (m, 2H), 3.95 (s, 3H), 4.4 (m, 2H), 6.05 (s, 2H), 6.8 (m, 1H), 6.9 (m, 2H), 7.6 (s, 1H), 7.62 (s, 1H), 9.1 (s, 1H); Mass Spectrum: M+H+ 477.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:35][N:36]([CH3:42])[CH:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:39]4[CH2:40][CH2:41][CH:37]([N:36]([CH3:42])[CH3:35])[CH2:38]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1
Reactant: O=C(NCC1(O)CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CN(C)C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCN(c2ccc3c(C(=O)NCC4(O)CCC(F)(F)CC4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxycyclohexylmethyl)-amide, DIPEA and N,N-dimethylpyrrolidin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (m, 1H), 7.85 (1H), 7.48 (m, 2H), 6.69 (1H), 4.66 (s, 1H), 3.89 (m, 1H), 3.70 (m, 1H), 3.45 (m, 1H), 3.26 (m, 2H), 2.85 (m, 1H), 2.54 (m, 4H), 2.22 (s, 6H), 2.15 (m, 1H), 2.06 (m, 2H), 1.85 (m, 3H), 1.74-1.76 (m, 5H). m/z: 467 [M+H]
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:15]([CH3:21])[C:16]([O:18]CC)=O)[CH:8]=[CH:9][C:10]=1[O:11]C(=O)C)(=O)C.[CH3:22][NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:22][N:23]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:16](=[O:18])[CH:15]([C:7]1[CH:8]=[CH:9][C:10]([OH:11])=[C:5]([OH:4])[CH:6]=1)[CH3:21]
Reactant: CCOC(=O)C(C)c1ccc(OC(C)=O)c(OC(C)=O)c1
Reactant: CNCc1ccccc1
Product: CC(C(=O)N(C)Cc1ccccc1)c1ccc(O)c(O)c1

Procedure:
Ethyl 3,4-diacetoxyphenylpropionate and N-methylbenzylamine were used to obtain N-Methyl-N-benzyl-3,4-dihydroxyphenylpropionamide by carrying out the same procedures as described in Example 1.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:22](=[O:24])[CH3:23])[C:14]4[C:19]([C:20]=3[CH:21]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)O1.[Br:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29](Br)[CH:28]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.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>[Br:26][C:27]1[CH:28]=[C:29]([C:9]2[CH:21]=[CH:20][C:12]3[N:13]([C:22](=[O:24])[CH3:23])[C:14]4[C:19]([C:11]=3[CH:10]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:30]=[CH:31][CH:32]=1
Reactant: Brc1cccc(Br)c1
Reactant: CC(=O)n1c2ccccc2c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
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: O
Solvent: Cc1ccccc1
Product: CC(=O)n1c2ccccc2c2cc(-c3cccc(Br)c3)ccc21
Temperature: 25 °C
Yield: 23 %

Procedure:
A mixture solution of 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazol-9-yl)ethanone (10.00 g, 29.8 mmol), 1,3-dibromobenzene (17.59 g, 74.6 mmol), Pd(PPh3)4 (0.689 g, 0.597 mmol) and K2CO3 (12.37 g, 89 mmol) in toluene (100 mL) and water (20 mL) was refluxed under N2 overnight. After cooling to room temperature, the organic phase was isolated and the solvent was evaporated. The residue was purified by column chromatography on silica gel with hexane/DCM (1/1, v/v) as eluent to yield 1-(3-(3-bromophenyl)-9H-carbazol-9-yl)ethanone (2.5 g, 23%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:38]2[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]2)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11]
Reactant: CN1CCNCC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cccc(Cl)c4Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cccc(Cl)c4Cl)cc32)c(C)c1C(=O)N1CCN(C)CC1

Procedure:
5-[5-(2,3-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.2 mmol), was coupled with 1-methyl-piperazine (31 mg, 1.2 eq.) using HOBt (1.2 eq.), EDAC.HCl (1.2 eq.) and TEA (3 eq.) to give the titled compound.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([NH2:20])=[O:19])=[O:15])[CH2:10][CH2:11][CH2:12][CH3:13])=O)(C)(C)C.[ClH:24].O1CCOCC1>>[ClH:24].[NH2:8][C@H:9]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([NH2:20])=[O:19])=[O:15])[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(N)=O
Agent: Cl
Solvent: C1COCCO1
Product: CCCC[C@H](N)C(=O)N1CCC[C@H]1C(N)=O
Reaction time: 1 h

Procedure:
The N-tert-butyloxycarbonyl-L-norleucyl-proline amide (1 g, 3.05 mmol) was placed in a round bottom flask to which freshly prepared 4N HCl/dioxane (25 ml) was added. The solution was stirred for 1 hour. Evaporation of solvent in vacuo and then crystallization of an oily residue from methanol/ethyl ether gave the title compound as a crystal-line product (0.76 g, 95%); oil, [α]D -17.7° (C=1; DMF); Rf 0.31 (1-butanol/acetic acid/water 4:1:1), Rf 0.42 (1 butanol/acetic acid/water, 4:1:5, upper phase).
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][O:5][CH2:6][C:7](=O)[CH2:8][C:9]#[N:10]>C(O)C>[CH3:4][O:5][CH2:6][C:7]1[CH:8]=[C:9]([NH2:10])[NH:2][N:3]=1
Reactant: COCC(=O)CC#N
Reactant: NN
Solvent: CCO
Solvent: O
Product: COCc1cc(N)[nH]n1
Temperature: 25 °C
Yield: 53 %

Procedure:
Hydrazine monohydrate (0.49 ml) was added to a solution of the thus obtained 4-methoxy-3-oxobutyronitrile (1.14 g) in ethanol (50 ml), and refluxed for 17 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (eluting solvent; dichloromethane:methanol 50:1) to give 5-methoxymethyl-2H-pyrazol-3-ylamine (684 mg, Y.:53%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][NH:9][C:10](=O)OC)[CH:2]=1.[OH-].[Na+].N[C:17]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[CH:21][C:18]=1C=O>OS(O)(=O)=O>[CH3:26][O:25][C:23]1[CH:24]=[C:17]2[C:10](=[CH:21][C:22]=1[O:27][CH3:28])[N:9]=[CH:8][C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[CH:18]2
Reactant: COC(=O)NC=Cc1cccnc1
Reactant: COc1cc(N)c(C=O)cc1OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2cc(-c3cccnc3)cnc2cc1OC
Temperature: 22 °C

Procedure:
A solution of 600 mg (3.37 mmol) of methyl N-2-(pyrid-3-yl)vinylcarbamate in 10 mL of 6N H2SO4 is refluxed for 10 minutes, cooled to 0° C. and basified to pH 11 with 50% NaOH. A solution of 400 mg (2.03 mmol) of 2-amino-4,5-dimethoxybenzaldehyde is immediately added and the mixture refluxed for 2.5 hours, cooled to 22° C. and partitioned between ether (150 mL) and water (100 mL). The aqueous layer is back extracted with chloroform and the combined organics are dried (MgSO4) and evaporated to obtain an oil which is recrystallized from hexane/ethyl acetate twice to give 3-(6,7-dimethoxyquinolin-3-yl)pyridine m.p. 131-132° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]1.Br[CH2:17][C:18]([C:20]([F:23])([F:22])[F:21])=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:21][C:20]([F:23])([F:22])[C:18]1[C:11]2[C:12](=[O:14])[CH2:13][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:9][C:10]=2[O:15][CH:17]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: Cc1ccccc1C1CC(=O)CC(=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccccc1C1CC(=O)c2c(C(F)(F)F)coc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.9 %

Procedure:
A mixture of 5-(2-methylphenyl)cyclohexane-1,3-dione (2.0 g), 1-bromo-3,3,3-trifluoroacetone (1.9 g), potassium carbonate (2.7 g) and dimethylformamide (30 ml) was stirred at room temperature for 2 hours, and then at 150° C. for 12 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added ethyl acetate. The mixture was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane). The resulting crystals were recrystallized from isopropylether and hexane to give colorless crystals of 3-trifluoromethyl-6-(2-methylphenyl)-4,5,6,7-tetrahydrobenzofuran-4-one (0.26 g).