Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N+:13]([O-:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].I[CH2:17][CH2:18][C:19](=[O:29])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([N+:13]([O-:15])=[O:14])[CH2:17][CH2:18][C:19](=[O:29])[CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(CCI)CCc1ccc(Cl)cc1
Reactant: COc1ccc(CC[N+](=O)[O-])cc1OC
Solvent: C1CCOC1
Product: COc1ccc(CC(CCC(=O)CCc2ccc(Cl)cc2)[N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.6 %

Procedure:
To a solution of 48.5 g (0.23 mole) of 2-(3,4-dimethoxyphenyl)-1-nitroethane in 400 ml of dry tetrahydrofuran was added 96.0 g (0.23 mole) of 40% Triton B. The solution was stirred at room temperature for 10 min. 70.3 g (0.23 mole) of 5-iodo-1-(4'-chlorophenyl)-3-pentanone in a minimum amount of dry tetrahydrofuran was added dropwise. The mixture was heated at 50° C. for 3 hr., then allowed to stir at room temperature overnight. Solvent was removed in vacuo and the residue taken up in ether and extracted twice with water. The organic layer was dried over anh MgSO4, filtered and concentrated at reduced pressure. The crude concentrate was passed through HPLC to give 65 g of purified material.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[S:13]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14]1>>[Cl:1][C:2]1[N:3]([C:15]2[CH:16]=[CH:17][S:13][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: OB(O)c1ccsc1
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Product: O=Cc1c(Cl)n(-c2ccsc2)c2ccccc12

Procedure:
The title compound was prepared analogously as described in example 9, step 2, using 2-chloro-1H-indole-3-carbaldehyde (300 mg, 1.67 mmol) and thiophene-3-boronic acid. Yield: 123 mg.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])[CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40]([OH:42])=[O:41])=[CH:35][CH:34]=1>C1COCC1>[CH2:29]([N:24]1[C:23]([C:21]([NH:20][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[C:12]([C:9]2[CH:8]=[C:7]3[C:6](=[CH:11][CH:10]=2)[NH:5][C:4](=[O:31])[C:3]3=[CH:2][NH:32][C:33]2[CH:34]=[CH:35][C:36]([CH2:39][C:40]([OH:42])=[O:41])=[CH:37][CH:38]=2)=[O:13])=[O:22])=[CH:27][C:26]([CH3:28])=[N:25]1)[CH3:30]
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)C(=CO)C(=O)N3)c1
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)C(=CNc2ccc(CC(=O)O)cc2)C(=O)N3)c1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-amide (as prepared in Example 1, 30 mg, 0.072 mmol) and THF (1 mL). To the resulting solution was added 4-aminophenylacetic acid (16.4 mg, 0.1082 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of ice cold THF yielding 42% (16.7 mg, 0.030 mmol) of the title compound.
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[O:7].[OH:8][C:9]1C(=O)N(CC2C=CC(OC)=CC=2)CCC=1C(=O)CC.COS(OC)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:9][O:8][C:3]1[C:2](=[O:7])[NH:1][CH:6]=[CH:5][CH:4]=1
Reactant: CCC(=O)C1=C(O)C(=O)N(Cc2ccc(OC)cc2)CC1
Reactant: O=c1cccc[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COc1ccc[nH]c1=O
Reaction time: 16 h

Procedure:
said pyridinone compound of Formula (6.0.0) by methylation with dimethylsulfate; wherein a reaction mixture is established with dimethylformamide (DMF) solvent in the presence of cesium carbonate, Cs2CO3, with gradual addition of said dimethylsulfate over a period of 30 minutes, while said reaction mixture temperature is kept at from 20° to 25° C.; and thereafter, said reaction mixture is maintained at said temperature and stirred for 16 hours; whereby there is produced a 3-methoxy-pyridinone compound N-protected by p-methoxybenzyl, of Formula (7.0.0):
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)=O>CC(C)=O>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=3[CH3:8])[S:13][CH:15]=2)=[CH:19][CH:20]=1
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Solvent: CC(C)=O
Product: COC(=S)c1cc(-c2nc(-c3ccc(C)cc3)cs2)c(C)s1
Yield: 72.4 %

Procedure:
103 mg (0.416 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 5 mL of reagent grade acetone. 2-Bromo-4′-methyl acetophenone (0.416 mmol; 89 mg) was added and the solution was allowed to reflux for 3 h. The solution was allowed to cool and crude product was filtered and washed two times with acetone and purified on a 1 mm silica plate eluting with 20% ethyl acetate/hexane to afford 104 mg (69% yield) of methyl 4-[4-(4-methylphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: [OH:1][C:2]1([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])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:34][N:35]([CH3:41])[CH:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[OH:1][C:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:38]4[CH2:39][CH2:40][CH:36]([N:35]([CH3:41])[CH3:34])[CH2:37]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH2:3]1
Reactant: CN(C)C1CCNC1
Reactant: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(N4CCC(N(C)C)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and N,N-dimethylpyrrolidin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.16 (s, 1H), 4.00 (t, 2H), 3.80 (t, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.22 (s, 6H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27 (t, 1H), 1.07 (t, 1H), 0.83 (d, 3H). m/z: 446 [M+H]
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:33])[C@@H:8]([N:15]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-])=O)[CH:25]=2)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[CH:1]1([O:6][C:7](=[O:33])[C@@H:8]([N:15]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=2)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1cccc([N+](=O)[O-])c1)[C@H](C(=O)OC1CCCC1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(Cc1cccc(N)c1)[C@H](C(=O)OC1CCCC1)c1ccccc1
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of (S)-[(3-nitro-benzyl)-tert-butoxycarbonyl-amino]-phenyl-acetic acid cyclopentyl ester (1.509 g, 3.32 mmol) in ethanol (10 ml) was added palladium on carbon (10%, 0.38 g, 0.36 mmol). The flask was evacuated and back-filled with hydrogen gas. The mixture was stirred overnight, then filtered through Celite, washed with ethanol (150 ml) and then concentrated to yield the desire product as a colourless oil (1.351 g, 96% yield). 1H NMR (300 MHz, CDCl3), δ:7.19-7.42 (5H, m), 6.97 (1H, t, J=7.5 Hz), 6.46 (2H, dd, J=8.1, 16.5 Hz), 6.29 (1H, br s), 5.58 (1H, br s), 5.29 (1H, br s), 4.69 (1H, br s), 4.00 (1H, d, J=15.9 Hz), 3.74 (1H, q, J=6.9 Hz), 3.51 (2H, br s), 1.20-2.00 (17H, m)
Reaction SMILES: [C:1]1([N:7]([CH2:40][CH2:41][CH2:42][O:43]CC2C=CC=CC=2)[C:8]([C:10]2[CH:39]=[CH:38][C:13]3[N:14]([CH3:37])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:36])[NH:26][C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:28])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>ClCCl.C(O)C>[C:1]1([N:7]([CH2:40][CH2:41][CH2:42][OH:43])[C:8]([C:10]2[CH:39]=[CH:38][C:13]3[N:14]([CH3:37])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:36])[NH:26][C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:28])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCCOCc4ccccc4)c4ccccc4)ccc3n2C)cc1
Solvent: CCO
Solvent: ClCCl
Product: CCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCCO)c4ccccc4)ccc3n2C)cc1
Yield: 26 %

Procedure:
Prepared analogously to Example 165 from 1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy-n-propyl)amide by catalytic debenzylation. Yield: 26% of theory, C33H40N6O4 (584.7); Rf value: 0.39 (silica gel; dichloromethane/ethanol=9:1); EKA mass spectrum: (M+H)+=585; (M+H+Na)++=304; (M+Na)+=607.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][CH2:16][NH:17][C:18](=[O:30])[CH2:19][O:20][C:21]1[C:26]([CH3:27])=[N:25][C:24]([CH3:28])=[C:23]([CH3:29])[N:22]=1>CN(C)C=O>[C:1]1([S:7][CH2:15][CH2:16][NH:17][C:18](=[O:30])[CH2:19][O:20][C:21]2[C:26]([CH3:27])=[N:25][C:24]([CH3:28])=[C:23]([CH3:29])[N:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1nc(C)c(OCC(=O)NCCBr)nc1C
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(C)c(OCC(=O)NCCSc2ccccc2)nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.1 %

Procedure:
Thiophenol (0.60 g, 5.4 mM) and potassium carbonate (0.75 g, 5.4 mM) were added to compound 648 (0.91 g, 3.0 mM) dissolved in dimethylformamide (10 ml) and the mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated in vacuo, the residue was dissolved in chloroform and washed with dilute aqueous potassium carbonate. The aqueous layer was further extracted with chloroform. The combined organic layer was chromatographed by eluting successively with benzene and benzene-ethyl acetate (10:1) to obtain the product (0.35 g, yield: 35.2%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:22])[C:9](=[O:21])[C:10]([C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)([CH3:12])[CH3:11])=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[CH:3]=1.CN(C)C=O.Cl[C:36]([F:43])([F:42])C(OCC)=O>O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:22])[C:9](=[O:21])[C:10]([C:13]2[CH:18]=[C:17]([O:19][CH:36]([F:43])[F:42])[CH:16]=[C:15]([Cl:20])[CH:14]=2)([CH3:11])[CH3:12])=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[CH:3]=1
Reactant: CN(C(=O)C(C)(C)c1cc(O)cc(Cl)c1)c1cnc(Cl)cc1-c1ccccc1Cl
Reactant: CCOC(=O)C(F)(F)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)C(C)(C)c1cc(Cl)cc(OC(F)F)c1)c1cnc(Cl)cc1-c1ccccc1Cl
Temperature: 65 °C
Yield: 48.7 %

Procedure:
To a solution of 0.700 g (1.56 mmol) N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3-chloro-5-hydroxy-phenyl)-N-methyl-isobutyramide in 10 ml N,N-Dimethylformamide 0.215 g (1.56 mmol) K2CO3 and 0.2 ml (1.56 mmol) ethyl chlordifluoroacetate was added and the resulting suspension heated at 65° C. for 15 h. After cooling to ambient temperature, the reaction mixture was poured into 75 ml water and extracted three times with 80 ml CH2Cl2. The combined organic solvents were dried (Na2SO4), filtered and evaporated. The residue was purified by flash-chromatography (SiO2, CH2Cl2/ethyl acetate 4:1) to give 0.38 g (49%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=3)[CH:9]=2)[C:4](=[O:20])[CH2:3]1.C([O-])([O-])=[O:23].[K+].[K+].CS(C)=O>O>[CH3:1][C:2]1([CH3:21])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[CH:19]=[CH:18][C:15]([C:16]([NH2:17])=[O:23])=[CH:14][N:13]=3)[CH:9]=2)[C:4](=[O:20])[CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)CC(=O)c2ccc(Oc3ccc(C#N)cn3)cc21
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)CC(=O)c2ccc(Oc3ccc(C(N)=O)cn3)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 188.3 %

Procedure:
Add 30% aqueous H2O3 (3.15 ml) to a suspension of 6-(3,3-Dimethyl-1-oxo-indan-5-yloxy)nicotinonitrile (877 mg, 3.15 mmol), K2CO3 (218 mg, 1.57 mmol) and DMSO (10 ml) stirring under nitrogen at ambient temperature. After four hours, dilute the reaction mixture with water (100 ml) and extract with EtOAc (2×). Wash the extract with water and brine, dry (MgSO4) and concentrate on rotary evaporator to yield 876 mg of the title compound as an off-white solid. Mass spectrum (ion spray): m/z=297 (M+1); 1HNMR (CDCl3): 8.62 (s, 1H), 8.24 (d, 1H), 7.75 (d, 1H), 7.24 (s, 1H), 7.14 (d, 1H), 7.07 (d, 1H), 5.91 (broad, 2H), 2.63 (s, 2H), 1.43 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](OCC)=[O:9])=[C:6]([N:13]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]=[C:4]([S:27][CH3:28])[N:3]=1.[Li+].CC([N-]C(C)C)C.O>O1CCCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:9])[CH:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][N:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[N:5]=[C:4]([S:27][CH3:28])[N:3]=1
Reactant: CCOC(=O)CCN(c1ccccc1)c1nc(SC)nc(Cl)c1C(=O)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1CN(c2ccccc2)c2nc(SC)nc(Cl)c2C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 102.4 %

Procedure:
To an ice-cooled solution of ethyl 4-chloro-6-((3-ethoxy-3-oxopropyl)(phenyl)amino)-2-(methylthio)pyrimidine-5-carboxylate (23.0 g, 54.25 mmol) in tetrahydrofuran (400 mL), LDA [generated at 0° C. using diisopropylamine (25.37 mL, 179.4 mmol) and n-BuLi (74.2 mL, 173.9 mmol) in tetrahydrofuran (300 mL)] was added dropwise. The reaction mixture was further stirred for additional 1 h and water (500 mL) was added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted using EtOAc (200 mL×2). The combined organic layer was washed with water (500 mL) and brine (500 mL); dried over anhydrous sodium sulphate and concentrated under reduced pressure to give crude product. Crude product from two batches of the same size were combined and purified by silica gel column chromatography (polarity) to provide ethyl 4-chloro-2-(methylthio)-5-oxo-8-phenyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carboxylate (21 g, 51.2% yield). 1H NMR (400 MHz, CDCl3): δ 7.48-7.43 (m, 2H), 7.37-7.28 (m, 3H), 4.37 (dd, J=7.2, 13.6 Hz, 1H), 4.27 (q, J=7.2 Hz, 2H), 4.11 (dd, J=4.8, 13.6 Hz, 1H), 3.75 (dd, J=4.8, 7.2 Hz, 1H), 2.17 (s, 3H), 1.29 (t, J=7.2 Hz, 3H). LCMS [M+H]: 378
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]([CH2:15][C:16]([O:18]CC)=O)[NH:12][CH2:13][CH2:14][C:5]2=1.C1CCCCC1.[CH3:27][N:28]=[C:29]=[O:30].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]3[CH2:15][C:16](=[O:18])[N:28]([CH3:27])[C:29](=[O:30])[N:12]3[CH2:13][CH2:14][C:5]2=1
Reactant: CCOC(=O)CC1NCCc2c1[nH]c1ccc(Cl)cc21
Reactant: CN=C=O
Agent: Cl
Solvent: CCO
Solvent: C1CCCCC1
Product: CN1C(=O)CC2c3[nH]c4ccc(Cl)cc4c3CCN2C1=O

Procedure:
10 g of ethyl 6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-acetate (prepared according to the patent entitled Pyridoindoles, filed by the Applicant Company on this same day) are placed in a round-bottomed flask and 150 ml of cyclohexane and 2.5 ml (1.9 g) of methyl isocyanate are added. The mixture is heated at the reflux temperature for 1 hour. It is cooled in an ice bath and filtered. This yields a white solid which is taken up in 150 ml of ethanol. The mixture is stirred and ethanol saturated with hydrogen chloride (30 ml) is added. The mixture is heated under reflux for 1 hour. It is allowed to cool and filtered. The solid is recrystallised from ethanol.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH3:28])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pt]=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH3:28])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)(=[O:11])=[O:12])=[CH:6][CH:5]=1
Reactant: CCCOc1ccc(N2CCN(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)CC2)cc1
Reactant: [H][H]
Agent: O=[Pt]
Product: CCCOc1ccc(N2CCN(S(=O)(=O)c3ccc(N)cc3)CC2)cc1

Procedure:
In the manner given in Example 1B, 1[(p-nitrophenyl)sulfonyl] -4-(p-propoxyphenyl)piperazine is reduced with hydrogen over platinum oxide catalyst (PtO2) to give 1-[(p-aminophenyl)sulfonyl]-4-(p-propoxyphenyl)piperazine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH:13]([CH3:15])[CH3:14])[CH:6]=[C:5]2[C:16]([F:19])([F:18])[F:17].[C:20]([O:23]CC)(=[O:22])C.O>>[CH:13]([O:12][C:7]1[CH:6]=[C:5]([C:16]([F:19])([F:18])[F:17])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:20]([OH:23])=[O:22])[CH:3]=2)[N:8]=1)([CH3:15])[CH3:14]
Reactant: CCOC(C)=O
Reactant: CC(C)Oc1cc(C(F)(F)F)c2cc(Br)ccc2n1
Solvent: O
Product: CC(C)Oc1cc(C(F)(F)F)c2cc(C(=O)O)ccc2n1

Procedure:
The title compound was synthesized by carbonylation of 6-bromo-2-isopropoxy-4-trifluoromethyl-quinoline (CAS [328955-63-1]) in ethyl acetate/water using 50 bar CO, PdCl2 dppf CH2Cl2, 80° C. for 20 h. Light grey solid. MS (m/e, ISP neg. ion)=298.3 [M−H+].
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=1.CN([CH:28]=[O:29])C.Cl>O1CCCC1.O>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[C:18]=1[CH:28]=[O:29]
Reactant: Fc1ccc(Br)cc1F
Reactant: CN(C)C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1c(Br)ccc(F)c1F
Yield: 56.2 %

Procedure:
A solution of 152 mmol of 2,2,6,6-tetramethylpiperidine and 152 mmol of n-butyllithium (1.6 M solution in n-hexane) in 280 ml of dry tetrahydrofuran is admixed with 145 mmol of 1-bromo-3,4-difluorobenzene at −75° C. This temperature is maintained for 4 hours, and then 174 mmol of DMF are added dropwise. The reaction mixture is then slowly thawed, hydrolyzed with water at −20° C., acidified using hydrochloric acid and extracted with tert-butyl methyl ether. The combined organic extracts are washed with saturated sodium chloride solution and dried using sodium sulfate. The solvent is removed under reduced pressure, and the raw product is purified by chromatography over silica gel (eluent: dichloromethane/n-heptane 1:1) and recrystallization from n-heptane, yielding 18 g (56%) of 2-bromo-5,6-difluorobenzaldehyde in the form of slightly yellow crystals.—M.p.: 40-43.5° C.—1H-NMR (400 MHz, CDCl3/TMS): δ=10.31 (dd, 4J(HF)=2 Hz, 5J(HF)=1.5 Hz, 1 H, CHO), 7.45 (ddd, 3J(HH)=9 Hz, 4J(HF)=4 Hz, 5J(HF)=2 Hz, 1 H, Har), 7.28 (ddd, 3J(HH)=9 Hz, 3J(HF)=9 Hz, 4J(HF)=8 Hz, 1 H, Har).—19F-NMR (376.5 MHz, 1H broad-band decoupled, CDCl3/CFCl3): δ=−136.4 (d, 3J=19.2 Hz), −139.2 (d, 3J=19.2 Hz).
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@H:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:31]([O:33][CH2:34][C:35]#[C:36][CH3:37])=[O:32]>O.ClCCl>[O:23]=[C:15]1[N:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:2]3([CH3:1])[CH2:7][CH2:6][N:5]([C:31]([O:33][CH2:34][C:35]#[C:36][CH3:37])=[O:32])[CH2:4][CH2:3]3)[CH2:9][CH2:10]2)[C@H:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]2[NH:16]1
Reactant: CC#CCOC(=O)Cl
Reactant: CC1(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC#CCOC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.5 %

Procedure:
To a solution of (3aS,7aS)-3-[1-(4-methyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-one (HCl salt, 0.4105 g, 1.15 mmol) and potassium carbonate (0.170 g, 1.23 mmol) in water (3.00 mL) was added a solution of but-2-ynyl chloroformate (0.156 mL, 1.38 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at room temperature overnight. The mixture was poured into hydrometrix varian column chem elut catridge column and rinsed with dichloromethane (3 Column volumes). Concentrated in vacuo and the residue was purified by flash chromatography (0 to 50% MeOH/Ethyl acetate) and followed by preparative LC/MS (high pH) to give the title compound (0.036 g, 7.59%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1H NMR (400 MHz, CDCl3) δ ppm 1.30-1.47 (m, 6H), 1.49 (s, 2H), 1.62-1.76 (m, 1H), 1.76-2.00 (m, 9H), 2.34 (s, 2H), 2.72-2.98 (m, 6H), 2.99-3.09 (m, 2H), 3.49-3.85 (m, 2H), 4.11 (s, 1H), 4.27 (s, 2H), 4.49 (s, 1H), 4.61-4.72 (m, 2H) MS (M+1): 417.3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[NH:19]1[C:27]2[C:22](=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20]1>>[NH:19]1[C:27]2[C:22](=[C:23]([C:2]3[CH:3]=[C:4]([N:8]4[CH2:16][CH:15]5[CH2:17][N:11]6[CH2:12][CH:13]([CH2:18][CH:9]4[CH2:10]6)[CH2:14]5)[CH:5]=[N:6][CH:7]=3)[CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20]1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Reactant: OB(O)c1cccc2[nH]ccc12
Product: c1cc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)c2cc[nH]c2c1

Procedure:
The title compound was prepared from the product of Example 65A and 1H-indol-4-ylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 344.0 (M+H)+, retention time 1.27 minutes.
Reaction SMILES: COC1C=CC(C[N:8]2[C:16]([CH3:18])([CH3:17])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:19]#[N:20])[CH:14]=3)[C:9]2=[O:21])=CC=1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>CC#N.O>[CH3:17][C:16]1([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:19]#[N:20])[CH:14]=2)[C:9](=[O:21])[NH:8]1
Reactant: COc1ccc(CN2C(=O)c3ccc(C#N)cc3C2(C)C)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CC1(C)NC(=O)c2ccc(C#N)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
To a solution of 2-(4-methoxy-benzyl)-3,3-dimethyl-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile (3.5 g, 11.42 mmol) in MeCN (70 mL) was added CAN (18.79 g, 34.27 mmol) in 30 mL of water at 0° C. The resulting reaction mixture was stirred at 0° C. for 1 hour until all the starting material was consumed. The reaction mixture was extracted between water and EtOAc and the combined organic layers were dried over anhy. MgSO4, filtered, and concentrated under reduced pressure to give a crude product which was purified by column chromatography to afford the title compound (1.06 g, 49.8%) as a solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=1.CN(C)[CH:23]=[O:24].[Cl-].[NH4+]>O1CCCC1>[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[C:19]=1[CH:23]=[O:24]
Reactant: CN(C)C=O
Reactant: Clc1cncc(Cl)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1c(Cl)cncc1Cl
Reaction time: 0.33 h
Yield: 77.3 %

Procedure:
Under an argon atmosphere, to a solution of diisopropylamine (33.6 ml, 0.24 mol) in tetrahydrofuran (400 ml) at -65° C. was added a 1.6 M solution of n-butyl lithium in hexanes (156 ml). After 20 minutes later, a solution of 3,5-dichloropyridine (29.6 g, 0.20 mol) in tetrahydrofuran (150 ml) was added dropwise, and the mixture was stirred for 30 minutes. Subsequently, the mixture was treated with dimethylformamide (23.2 ml, 0.30 mol) in tetrahydrofuran (50 ml), and then stirred for one hour under the same conditions. The reaction mixture was poured into a 5% aqueous ammonium chloride solution (1,000 ml) and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried, and then concentrated under reduced pressure. The residue was chromatographed on silica gel, to thereby obtain the title compound (27.2 g, yield 77%).