Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][C:10]1[C:18]([CH3:19])=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][C:11]=1[CH2:20][CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=[N:28]C=2C=1.CCN=C=NCCCN(C)C.Cl.N>C(O)(C)C.C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[CH2:8][CH2:9][C:10]1[C:18]([CH3:19])=[CH:17][C:13]([C:14](=[O:15])[NH2:28])=[CH:12][C:11]=1[CH2:20][CH3:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CCc1cc(C(=O)O)cc(C)c1CCC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: CC(C)O
Product: CCc1cc(C(N)=O)cc(C)c1CCC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of 4-(2-tert-butoxycarbonyl-ethyl)-3-ethyl-5-methyl-benzoic acid (36.0 g, 123 mmol) in isopropanol (400 mL), HOBT (18.3 g, 135 mmol) followed by EDC HCl (27.1 g, 142 mmol) is added. The mixture is stirred at rt for 1 h before aq. ammonia (69 mL of 25% solution) is added. Stirring is continued for 1 h before the mixture is diluted with DCM (500 mL) and washed with half sat. aq. NaHCO3 solution (3×400 mL), followed by water (400 mL). The org. extract is dried over MgSO4, filtered and concentrated. The crude product is trituated with TBME 8250 mL). The solid material is collected, washed with additional TBME (50 mL) and dried under high vacuum to give 3-(4-carbamoyl-2-ethyl-6-methyl-phenyl)-propionic acid tert-butyl ester (31.91 g) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[CH:9]([C:11]1([C:16]([O:18][CH3:19])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1)=O.C(C1(C(OC)=O)CCC1)=O>>[OH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([CH2:9][C:11]2([C:16]([O:18][CH3:19])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:2][CH2:3]1
Reactant: OCC1CCNCC1
Reactant: COC(=O)C1(C=O)CCCC1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)C1(CN2CCC(CO)CC2)CCCC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using piperidin-4-ylmethanol and methyl 1-formylcyclopentanecarboxylate (Synthesis, 1997, 32) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutanecarboxylate.
Reaction SMILES: [CH:1]1([C:6]2[N:10]3[C:11]([CH3:21])=[N:12][N:13]=[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:9]3=[N:8][C:7]=2[OH:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl[CH2:25][C:26]1[N:27]([CH2:31][CH3:32])[N:28]=[CH:29][N:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]1([C:6]2[N:10]3[C:11]([CH3:21])=[N:12][N:13]=[C:14]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:9]3=[N:8][C:7]=2[O:22][CH2:25][C:26]2[N:27]([CH2:31][CH3:32])[N:28]=[CH:29][N:30]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCn1ncnc1CCl
Reactant: Cc1nnc(-c2ccccc2)c2nc(O)c(C3CCCC3)n12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1ncnc1COc1nc2c(-c3ccccc3)nnc(C)n2c1C1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.9 %

Procedure:
To a solution of 3-cyclopentyl-5-methyl-8-phenylimidazo[1,2-d][1,2,4]triazin-2-ol (175 mg, 0.59 mmol) and 3-chloromethyl-2-ethyl-2H-[1,2,4]triazole hydrochloride (130 mg, 0.71 mmol) in anhydrous N,N-dimethylformamide under an atmosphere of nitrogen was added potassium carbonate (329 mg, 2.37 mmol). The reaction mixture was stirred at room temperature for 3 h, then evaporated in vacuo. The residue was purified by flash chromatography (SiO2; 2% MeOH in CH2Cl2), and the product recrystallised from ethyl acetate/isohexane to afford the title compound (45 mg) as a white solid, m.p. 94-96° C.; δH (400 MHz; CDCl3) 1.44 (3H, t, J 7.2), 1.65-2.04 (8H, m), 3.01 (3H, s), 3.70 (1H, m), 4.29 (2H, q, J 7.2), 5.65 (2H, s), 7.52-7.60 (3H, m), 7.91 (1H, s), 8.10 (2H, m); m/z (ES+) 404 (M++H, 100%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([C:8]([OH:10])=[O:9])[CH2:3]1.C(N(CC)CC)C.[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.Cl>ClCCl>[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([N:2]2[CH2:7][CH2:6][CH2:5][C@H:4]([C:8]([OH:10])=[O:9])[CH2:3]2)=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: O=C(O)[C@H]1CCCNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)[C@H]1CCCN(C(=O)c2ccc(F)cc2)C1
Reaction time: 8 h
Yield: 92.3 %

Procedure:
To a suspension of (S)-piperidine-3-carboxylic acid hydrochloride (0.75 g, 4.53 mmol) in dry dichloromethane (30 mL), triethylamine (1.97 mL, 14.0 mmol) and 4-fluorobenzoyl chloride (543 mL, 4.53 mmol) were added dropwise at 0° C. The resulting solution was kept under stiffing overnight at room temperature, under nitrogen atmosphere, then HCl 1N (30 mL) was added and the phases were separated. The organic layer was washed with HCl 1N (30 mL), with water (30 mL), dried over Na2SO4 and evaporated under reduced pressure to provide 1.05 g of 1-(4-fluoro-benzoyl)-(S)-piperidine-3-carboxylic acid as a yellow oil, used for the next step without further purification.
Reaction SMILES: [N:1]1([CH2:6][C@H:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:8][C:9]2[C:10]([CH2:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:36]=[O:37].CS(C)=O>C(O)C>[OH:37][CH2:36][C:2]1[N:1]([CH2:6][C@H:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:8][C:9]2[C:10]([CH2:20][S:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)(=[O:23])=[O:22])=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=1
Reactant: C=O
Reactant: O=C1CCCc2c1ccc(O[C@H](Cn1ccnc1)c1ccccc1)c2CS(=O)(=O)c1ccccc1
Solvent: CCO
Solvent: CS(C)=O
Product: O=C1CCCc2c1ccc(O[C@H](Cn1ccnc1CO)c1ccccc1)c2CS(=O)(=O)c1ccccc1
Temperature: 130 °C
Reaction time: 24 h
Yield: 61 %

Procedure:
A mixture of (S)-6-[2-(1H-imidazol-1-yl)-1-phenylethoxy]-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone (see example 3, 250 mg, 0.51 mmol), paraformaldehyde (1.5 g) and dimethylsulfoxide (6 mL) was stirred at 130° C. for 24 h. The mixture was diluted with ethanol (10 mL), filtered, concentrated, diluted with water (50 mL) and extracted with ethyl acetate (4×10 mL). The combined extracts were washed with water (3×10 mL), dried (brine, Na2SO4), and concentrated. The residue was purified by dry-flash column chromatography (SiO2, 2.5-22.5% 2-propanol-dichloromethane) to give (S)-6-{2-[2-(hydroxymethyl)-1H-imidazol-1-yl]-1-phenylethoxy}-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone as a white solid, 161 mg, 61% yield. NMR spectrum was consistent with structure. MS EI: M+* 517.1816 (M+* 517.1797).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][CH2:21][CH3:22].[CH:23]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:27][CH:26]=1)=O.[BH4-].[Na+]>C1COCC1.CO>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][CH2:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:23][C:25]3[CH:26]=[CH:27][C:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:29][CH:30]=3)[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: COC(=O)Cc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNCc1ccc(CC(=O)OC)cc1
Reaction time: 1 h

Procedure:
The product from step (vii) (55 mg) was combined with methyl (4-formylphenyl)acetate (0.0329 g) and stirred in THF (15 mL) for 16 h. Sodium borohydride (0.015 g) was added followed by MeOH (3 drops) and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with MeOH and purified via RPHPLC to give the title compound. Yield 17 mg.
Reaction SMILES: Cl[C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[CH2:35][CH2:34][CH2:33][C:32](=[O:36])[CH:31]=1)CCC>CN(C=O)C.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:11][C:10]1[C:2]([C:30]2[CH2:35][CH2:34][CH2:33][C:32](=[O:36])[CH:31]=2)=[N:3][C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[C:5]([CH:9]=1)[C:6]([NH2:8])=[O:7]
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CC(=O)CCC1
Reactant: NC(=O)c1cc(F)c(Cl)nc1Nc1ccc(N2CCOCC2)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)c1cc(F)c(C2=CC(=O)CCC2)nc1Nc1ccc(N2CCOCC2)cc1
Yield: 23.5 %

Procedure:
A solution of 6-chloro-5-fluoro-2-(4-morpholinophenylamino)nicotinamide (80 mg, 0.228 mmol), 3-(tributylstannyl)cyclohex-2-enone (105 mg, 0.274 mmol) (synthesized according to literature procedure: Tet. Lett., 31:1837-1840 (1990)), and dichloro bis(triphenylphosphine)palladium (II) (16.05 mg, 0.023 mmol) in DMF (2 mL) was microwaved at 160° C. for 1 h. The reaction mixture was diluted with methylene chloride, washed with satd. NaHCO3, water, and concentrated. The residue was purified prep-HPLC. The product containing fractions were collected, basified with 1N NaOH, and extracted with methylene chloride twice. The combined organic fractions were washed with water, concentrated, and further purified by MPLC (ISCO, 5% ammonia/methanol/methylene chloride, 40 g silica gel column) to give 22 mg brown solid. LC-MS: (M+H)+=411.25. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.76-10.84 (1H, m), 8.28-8.39 (1H, m), 8.13-8.21 (1H, m), 7.83-7.91 (1H, m), 7.45-7.53 (2H, m), 6.88-6.96 (2H, m), 6.52-6.57 (1H, m), 3.67-3.77 (4H, m), 3.04 (4H, d, J=4.95 Hz), 2.76-2.85 (2H, m), 2.39-2.46 (2H, m), 2.01-2.09 (2H, m).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[F:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH:18]=CN(C)C)[N:12]([C:23]1[C:24]([CH3:29])=[N:25][CH:26]=[CH:27][CH:28]=1)[C:11]2=[O:30]>O1CCCC1>[F:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH:18]=[O:2])[N:12]([C:23]1[C:24]([CH3:29])=[N:25][CH:26]=[CH:27][CH:28]=1)[C:11]2=[O:30]
Reactant: Cc1ncccc1-n1c(C=CN(C)C)nc2ccc(F)cc2c1=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ncccc1-n1c(C=O)nc2ccc(F)cc2c1=O
Yield: 83.3 %

Procedure:
To a well stirred mixture of sodium periodate (1.76 g, 8.26 mmol) in pH 7 buffer (10 mL) and tetrahydrofuran (15 mL) was added 6-fluoro-2-(2-dimethylamino-vinyl)-3,4-dihydro-3-(2-methyl-pyridin-3-yl)-quinazolin-4-one (0.69 g, 2.12 mmol) all at once. The mixture warmed slightly to the touch and was stirred for 1 hour at ambient temperature. The reaction was concentrated at reduced pressure and the residue treated with a 1:2 mixture of water and chloroform. The tan solid was collected, washed well with water and chloroform and dried under a stream of nitrogen to afford 0.50 g (80%) of 6-fluoro-3,4-dihydro-3-(2-methyl-pyridin-3-yl)-quinazolin-4-one-2-carboxaldehyde as a 1:1 mixture of free aldehyde and hydrate which had: mp 175-177° C.; 1H NMR δ 9.46 (s, 0.5H) [CHO], 8.53 (br s, 1H), 8.10-8.07 (s, 0.5H), 7.94-7.70 (m, 3.5H), 7.39-7.32 (m, 1H), 6.59 (br s, 0.5H) [hydrate OH], 6.47 (br s, 0.5H) [hydrate OH], 5.17 (s, 0.5H) [hydrate methine CH], 2.20 (s, 3H); APCI MS m/z=284.1 (P+1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][S:12][C:13]1[CH:29]=[CH:28][C:16]([CH:17]=[CH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.ClC1C=CC=C(C(OO)=[O:38])C=1.C(=O)([O-])O.[K+]>ClC=CCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][S:12]([C:13]1[CH:29]=[CH:28][C:16]([CH:17]=[CH:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=2)=[CH:15][CH:14]=1)=[O:38]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(O)c1ccc(C=Cc2ccc(SCc3ccc4ccccc4n3)cc2)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClC=CCl
Product: O=C(O)c1ccc(C=Cc2ccc(S(=O)Cc3ccc4ccccc4n3)cc2)cc1

Procedure:
4-(4-(2-quinolinylmethylthio)styryl)benzoic acid (4 mmol) in dichloroethene (50 ml) is stirred with m-chloroperbenzoic acid (4 mmol) and solid potassium hydrogen carbonate (1.0 g). The reaction is assayed by TLC and upon consumption of the starting thio compound, the mixture is filtered, washed with dilute aqueous sodium bisulfite, dried and evaporated to give 4-(4-(2-quinolinylmethylsulfinyl)styryl)benzoic acid.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]1[C:25]2[CH2:24][CH2:23][N:22]([C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH2:21][CH2:20][C:19]=2[CH:18]=[CH:17][C:16]=1[Cl:32]>C(Cl)Cl>[Cl:32][C:16]1[CH:17]=[CH:18][C:19]2[CH2:20][CH2:21][N:22]([C:26](=[O:31])[C:27]([F:29])([F:28])[F:30])[CH2:23][CH2:24][C:25]=2[C:15]=1[NH:14][CH2:13][CH2:12][CH2:11][NH:10][C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:9]
Reactant: O=C=Nc1ccccc1
Reactant: NCCCNc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Solvent: ClCCl
Product: O=C(NCCCNc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)Nc1ccccc1
Yield: 28 %

Procedure:
Combine phenyl isocyanate (15 μL, 0.137 mmol) and 6-(3-amino-propylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (48 mg, 0.137 mmol) in DCM and stir for 16 h. Concentrate, add DCM, filter and collect the solid to obtain 7-chloro-6-[3-(3-phenyl-ureido)-propylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (18 mg, 28%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([OH:8])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:25][C:24]=1[NH2:35]>CN(C=O)C>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)=[CH:25][C:24]=1[NH:35][C:6]([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)=[O:8]
Reactant: O=C(O)c1ncc[nH]1
Reactant: COc1ccc(N2CCOCC2)cc1N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COc1ccc(N2CCOCC2)cc1NC(=O)c1ncc[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.3 %

Procedure:
To a suspension of 1.0 g of imidazole-2-carboxylic acid (8.9 mmol) in 15 ml DMF was added 1.6 g of CDI (9.8 mmol) and stirred at ambient temperature for 1 h. Then the mixture was refluxed for 30 min. After cooling to ambient temperature, 2.0 g of 2-methoxy-5-morpholin-4-yl-phenylamine (9.8 mmol) were added and the reaction mixture was heated to reflux for 16 h. The mixture was evaporated and the residue taken up in water (40 ml) and extracted 3 times with ethyl acetate. The combined organic phases were dried on sodium carbonate, evaporated and the residue subjected to column chromatography (silica gel, ethyl acetate/hexanes 2:1). 0.25 g 1H-imidazole-2-carboxylic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (9%) were obtained as a white solid; M.p.: 227–230° C. 0.2 g of 1H-Imidazole-2-carboxylic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (0.66 mmol) were taken up in toluene (8.0 ml) and treated with 0.8 g of Lawesson reagent (2.0 mmol). The reaction mixture was heated to reflux for 22 h. After cooling to ambient temperature, water (25 ml) was added and the mixture was extracted 3 times with ethyl acetate. The combined organic phases were dried on sodium carbonate, evaporated and the residue subjected to column chromatography (silica gel, ethyl acetate/hexanes 1:1). 0.125 g of 1H-imidazole-2-carbothioic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (59%) was obtained as a yellow foam; MS (ISP): m/e=319 (M+H+).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:34]=[CH:33][C:9]([CH2:10][O:11][C:12](=[O:32])[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([O:29][CH2:30][CH3:31])[C:21]([O:23]CC(Cl)(Cl)Cl)=[O:22])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].C(O)(=O)C>C(Cl)Cl.[Zn]>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][O:11][C:12](=[O:32])[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([C:21]([OH:23])=[O:22])[O:29][CH2:30][CH3:31])=[CH:15][CH:14]=2)=[CH:33][CH:34]=1)(=[O:4])=[O:3]
Reactant: CCOC(Cc1ccc(C(=O)OCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(Cc1ccc(C(=O)OCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)O
Reaction time: 17 h

Procedure:
To a solution of 4-[2-ethoxy-2-(2,2,2-trichloro-ethoxycarbonyl)-ethyl]-benzoic acid 4-methane sulfonyloxy-benzyl ester (0.02 g, 0.036 mmol) in dry DCM (2 mL) was first added zinc dust (0.047 g, 0.722 mmol), then acetic acid (1.08 mL, 18.06 mmol) at 0° C. The resulting inhomogeneous mixture was stirred for 17 h without removing the ice bath. The zinc was filtered off and washed with DCM and MeOH and the remaining filtrates were combined and evaporated under reduced pressure. The crude product was purified by column chromatography using DCM/MeOH (92:8) as the eluent. The title compound was obtained as an oil (0.005 g, 36%). 1H NMR (400 MHz, CDCl3): δ 7.91-7.93 (d, 2H), 7.42-7.44 (d, 2H, 7.19-7.24 (m, 4H), 5.27 (s, 2H), 4.03 (m, 1H), 3.52 (m, 1H), 3.37 (m, 1H), 2.99-3.14 (m, 2H), 3.08 (s, 3H), 2.63 (t, 3H). Mass Spectrum: M−H+ 421.23.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:22])[CH:4]=[C:5]([CH2:10][NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)(=[O:14])=[O:13])[O:6][C:7]=1[CH2:8][OH:9].[CH2:23](OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1CO)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:1][C:2]1[C:3](=[O:22])[CH:4]=[C:5]([CH2:10][NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)(=[O:14])=[O:13])[O:6][C:7]=1[CH2:8][OH:9])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=c1cc(CNS(=O)(=O)c2ccccc2)oc(CO)c1OCc1ccccc1
Reactant: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(O)c(CO)o2)c1
Product: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(CO)o2)c1
Yield: 27.12 %

Procedure:
N-(5-Benzyloxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-3-methyl-benzenesulfonamide (10-04) (2.6 g, 27.12%) was synthesized as a white solid from N-(5-hydroxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-3-methyl-benzenesulfonamide (9-04) (7.5 g, 23.07 mmol) following the procedure described for N-(5-benzyloxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (10-01).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH:18]([N:21]([CH:36]([CH3:38])[CH3:37])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][C:28]=1[CH3:35])=[O:26])([CH3:20])[CH3:19]>C(O)C.N1CCCCC1>[CH:36]([N:21]([CH:18]([CH3:20])[CH3:19])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[NH:12][C:11]2=[O:17])[NH:29][C:28]=1[CH3:35])=[O:26])([CH3:37])[CH3:38]
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN(C(C)C)C(C)C
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Br)c4)c32)c(C)c1C(=O)NCCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 30.5 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diisopropylamino-ethyl)-amide (73 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diisopropylamino-ethyl)-amide as a yellow solid (43 mg, 30%).
Reaction SMILES: [C:1]([O:4][CH:5]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[CH:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16](C(=O)C)[C:15]2=[O:26])[CH2:10][CH2:9]1)[CH3:7])(=[O:3])[CH3:2].Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O.O>C(Cl)(Cl)Cl.CO>[C:1]([O:4][CH:5]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[CH:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[NH:16][C:15]2=[O:26])[CH2:10][CH2:9]1)[CH3:7])(=[O:3])[CH3:2]
Reactant: COc1ccc(C(OC(C)=O)C(C)N2CCC(n3c(=O)n(C(C)=O)c4ccccc43)CC2)cc1OC
Agent: [Mg+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: COc1ccc(C(OC(C)=O)C(C)N2CCC(n3c(=O)[nH]c4ccccc43)CC2)cc1OC
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 85.9 %

Procedure:
In this Example, 0.7 g of 1-[3-acetoxy-3-(3,4-dimethoxyphenyl)-2-propyl]-4-(3-acetyl-2-keto-1-benzimidazolinyl)-piperidine is dissolved in a mixture of 2 ml of chloroform and 1 ml of methanol. To the solution is added 0.7 g of magnesium perchlorate and the mixture is stirred at room temperature for 2 minutes. Water is added to the reaction solution and the mixture is stirred. The chloroform layer is recovered and washed 2 times with water. The washed solution is dried and chloroform is distilled away. The resulting residue is recrystallized from dioxane to obtain 550 mg of 1-[3-acetoxy-3-(3,4-dimethoxyphenyl)-2-propyl]-4-(2-keto-1-benzimidazolinyl)-piperidine.
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.OS(O)(=O)=O>O>[O:15]=[C:14]1[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:4]2[N:3]=[C:2]([OH:1])[CH:11]=[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]1[C:5]=23
Reactant: O=C(O)c1ccccc1-c1nc(O)cc2ccccc12
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1c2ccccc2-c2nc(O)cc3cccc1c23
Temperature: 130 °C
Reaction time: 1 h

Procedure:
103 g. of o-(3-hydroxy-1-isoquinolinyl)-benzoic acid were dispersed in 310 ml. of 96% H2SO4. This dispersion was then heated to 130° C. and kept under stirring at that temperature for one hour. The reaction mass was then cooled to about 90° C. and was then carefully poured into about 20 liters of hot water at 90°-95° C. The reaction mass was then stirred for 1 hour while leaving it to cool down.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8].[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[O:26]=[C:25]([NH:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:8])[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:24]([NH:23][C:21](=[O:22])[O:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:28]
Reactant: Nn1cccc1C(=O)Nc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1cccc1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
2.00 g (9.94 mmol) of 1-amino-N-phenyl-1H-pyrrole-2-carboxamide were dissolved in 50 mL of DMF. To this solution, 2.07 g (10.94 mmol) of (S)-2-(tert-butoxycarbonylamino)propanoic acid (purchased from Aldrich®, cat. no. 13, 451-1) and 2.10 g (10.95 mmol) of EDC.HCl were added and the resulting reaction mixture was stirred at room temperature overnight. The solvent was then evaporated under vacuum, the residue was taken up in ethyl acetate and the organic solution was washed with an aqueous solution of sodium bicarbonate and brine, it was dried over magnesium sulphate, filtered and the solvent was evaporated. The product was purified by flash chromatography (0-5% methanol in dichloromethane). 2.21 g (60% yield) of the final product were obtained as a white solid.