Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[C:9]([O:13][C:14](=[O:44])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[C:19]([C:28]2[CH:37]=[C:36]3[C:31]([C:32]([CH3:42])([CH3:41])[CH2:33][C:34](=[O:40])[N:35]3[CH2:38][CH3:39])=[CH:30][C:29]=2[CH3:43])[CH:18]=1)([CH3:12])([CH3:11])[CH3:10]>CS(C)=O>[C:9]([O:13][C:14]([CH:15]1[CH2:2][CH:16]1[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[C:19]([C:28]2[CH:37]=[C:36]3[C:31]([C:32]([CH3:42])([CH3:41])[CH2:33][C:34](=[O:40])[N:35]3[CH2:38][CH3:39])=[CH:30][C:29]=2[CH3:43])[CH:18]=1)=[O:44])([CH3:11])([CH3:10])[CH3:12]
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C=CC(=O)OC(C)(C)C)ccc3OC(F)(F)F)cc21
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C4CC4C(=O)OC(C)(C)C)ccc3OC(F)(F)F)cc21
Temperature: -10 °C
Reaction time: 0.58 h

Procedure:
To a round bottom flask was added trimethylsulfoxonium iodide (2.8 mmol, 0.37 g) and 60% NaH (2.8 mmol, 0.07 g) and the flask was cooled to −10° C. with an ice-water bath. DMSO 92 ML) was then added dropwise. Initially some foamy suspension was observed. The cooling bath was removed and the reaction mixture was allowed to stir at r.t. for 30-40 min till the reaction mixture became a turbid solution. Compound 2B (0.17mmol, 0.085 g) was then dissolved in 1.5 mL DMSO and was added to the reaction mixture. The golden yellow solution was stirred at 50° C. (oil bath) for 2 h. After cooling to r.t., the reaction mixture was poured into 5 mL of ice-water. It was extracted with EtOAc (3×15 mL). The organic layer was washed with water followed by brine and was then dried over Na2SO4. The solvent was filtered and evaporated in vacuo to obtain 2-[3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-phenyl]-cyclopropanecarboxylic acid tert-butyl ester as a colorless oil. It was purified by preparative TLC with 3.5:1 hexanes-EtOAc as the eluting system to obtain 0.04 g of the product as a white foam. The product has the same Rf as the starting material. However, the product does not stain with KMnO4 stain indicating the disappearance of the double bond while the starting material does.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[S:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.[CH2:38](P(=O)(OCC)OCC)[P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42].CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[S:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:38]/[P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])=[CH:11][N:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(N2CCCCC2)sc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(N3CCCCC3)sc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 58.3 %

Procedure:
To a mixture of 3-[(3-methoxy-4-{[5-methyl-2-(piperidin-1-yl)-1,3-thiazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.15 g), tetraethyl methylenediphosphonate (0.09 g) and N,N-dimethylformamide (5 mL) was added sodium hydride (60% in oil, 0.015 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-{3-[(3-methoxy-4-{[5-methyl-2-(piperidin-1-yl)-1,3-thiazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as colorless crystals (0.11 g, yield 58%) from a fraction eluted with ethyl acetate-hexane (4:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 95-96° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:17])[C:15]=1[F:16])[CH:5]=[C:6]([C:10](=O)[CH3:11])[C:7](=[O:9])[CH3:8].S(O)(O)(=O)=O.[CH3:23][O:24][C:25](=[NH:27])[NH2:26].C([O-])(O)=O.[Na+]>CCO>[CH3:23][O:24][C:25]1[NH:27][CH:5]([C:4]2[CH:13]=[C:14]([F:17])[C:15]([F:16])=[C:2]([F:1])[CH:3]=2)[C:6]([C:7](=[O:9])[CH3:8])=[C:10]([CH3:11])[N:26]=1
Reactant: COC(=N)N
Reactant: CC(=O)C(=Cc1cc(F)c(F)c(F)c1)C(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: COC1=NC(C)=C(C(C)=O)C(c2cc(F)c(F)c(F)c2)N1
Temperature: 97.5 °C
Yield: 35.8 %

Procedure:
A mixture 3-(3,4,5-trifluorobenzylidene)-2,4-pentanedione (26.2 mmol), O-methylisourea hydrogen sulfate (3.22 g, 39.3 mmol), and NaHCO3 (6.6 g, 78.6 mmol) in EtOH (400 mL) was stirred and heated at 95-100° C. for 6 h. The mixture was filtered and the solid filter cake was washed with ethanol (100 mL). The solvent was evaporated from the combined filtrates and the crude product was purified by flash column chromatography (EtOAc/hexane, 1/9 to 1/4), to afford the desired product as an oil (2.80 g, 36%).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C)(=O)=O)=[CH:13][CH:12]=[N:11][C:10]=2[O:21][CH2:22][CH3:23])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:24][C:25]1[C:26]([CH3:31])=[CH:27][CH:28]=[CH:29][CH:30]=1>C(#N)C>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31])=[CH:13][CH:12]=[N:11][C:10]=2[O:21][CH2:22][CH3:23])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OCC)nccc2c1OS(C)(=O)=O
Reactant: Cc1ccccc1N
Solvent: CC#N
Product: CCCC(=O)c1cnc2c(OCC)nccc2c1Nc1ccccc1C
Yield: 86 %

Procedure:
3-Butyryl-8-ethoxy-4-methanesulfonyloxy-1,7-naphthyridine (338 mg) and o-toluidine (214 mg) were dissolved into 7 ml of acetonitrile, and the solution was heated to reflux for 30 minutes and concentrated to evaporate solvent under reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform, and the organic phase was washed with water and then saturated sodium bicarbonate. After dying, and concentration under reduced pressure, the resulting residue was subjected to silica gel column chromatography using a mixture of hexane:ethyl acetate (2:1) as an eluant to give yellow titled compound (300 mg, 86%)
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:10]=2)[N:5]=[C:4]([CH3:17])[C:3]=1[CH3:18].[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:10]=2)[N:5]=[C:4]([CH3:17])[C:3]=1[CH3:18])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCc1ccc2nc(C)c(C)c(O)c2c1
Product: CCCCCc1ccc2nc(C)c(C)c(OC(C)=O)c2c1
Yield: 74 %

Procedure:
100 Milligrams of 4-hydroxy-2,3-dimethyl-6-n-pentyl-quinoline (Compound No. 97) was stirred in 2 ml of acetic anhydride at 120° C. for 4 hours. After the solvent was evaporated, 20 ml of ethyl acetate was added and the reaction mixture was washed with an aqueous saturated sodium hydrogencarbonate solution and a saturated brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the resultant crude product was purified by column chromatography on silica gel (WAKOGEL® C-100) eluting with n-hexane/ethyl acetate (5:1) to obtain 87.4 mg of 4-acetoxy-2,3-dimethyl-6-n-pentyl-quinoline (yield 74%). Its NMR spectral data are shown in the following Table 2.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C@@H:9](OS(C)(=O)=O)[CH3:10])(=O)=O.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>C(OCC)(=O)C>[CH2:16]([N:23]1[CH2:10][CH2:9][CH2:8][C@H:7]1[CH3:6])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: C[C@@H](CCCOS(C)(=O)=O)OS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: C[C@@H]1CCCN1Cc1ccccc1
Yield: 100 %

Procedure:
First, 2.49 g (9.6 mmol) of (S)-1,4-bis(methanesulfonyloxy)pentane produced in Example 5 and 5.13 g (47.9 mmol) of benzylamine were stirred at 70° C. for three hours. Subsequently, 30 mL of ethyl acetate and 4.0 g of a 20 weight percent aqueous solution of sodium hydroxide were added to the mixture to perform an extraction. The organic layer was concentrated under a reduced pressure to obtain a yellow oily substance. This product was purified by silica gel column chromatography. Thus, (R)-1-benzyl-2-methylpyrrolidine was obtained as a light yellow oily substance (1.83 g, yield: 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:18]([F:21])([F:20])[F:19])=[C:15]([CH:17]=3)[NH2:16])=[CH:10][N:4]2[N:3]=1.C(#N)C.[CH3:25][C:26]([CH3:31])([CH3:30])[C:27](Cl)=[O:28]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:4]([CH:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:18]([F:19])([F:20])[F:21])=[C:15]([NH:16][C:27](=[O:28])[C:26]([CH3:31])([CH3:30])[CH3:25])[CH:17]=3)[N:8]=2)[N:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cc(-c2cn3nc(Cl)ccc3n2)ccc1C(F)(F)F
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)(C)C(=O)Nc1cc(-c2cn3nc(Cl)ccc3n2)ccc1C(F)(F)F
Temperature: 80 °C
Yield: 93.4 %

Procedure:
A 40 mL vial is charged with 5-(6-chloroimidazo[2,1-f]pyridazin-2-yl)-2-(trifluoromethyl)aniline (0.531 g, 1.7 mmol), acetonitrile (14 mL), and pyridine (0.275 mL). The stirred mixture is added trimethylacetyl chloride (0.419 mL, 3.4 mmol) and heated for 20 min at 80° C. The reaction is concentrated, taken into EtOAc (25 mL), washed once with HCl (15 mL, 1M) then NaOH (15 mL, 1M). Organic is dried, concentrated and purified by silica gel chromatography (0-100% EtOAc in Hexanes) to give the title compound (630 mg, 93% yield). LCMS (m/z)=397.4, 399.3 [M+H]+, tR=2.87 min. (compound same as Example 126)
Reaction SMILES: C(OC(N1CCN([C:12]2[N:21]=[C:20]3[C:15]([C:16](=[O:27])[C:17]([C:24]([OH:26])=[O:25])=[CH:18][N:19]3[CH:22]=[CH2:23])=[CH:14][C:13]=2[F:28])CC1)=O)C.[OH-:29].[Na+]>>[F:28][C:13]1[CH:14]=[C:15]2[C:20](=[N:21][C:12]=1[OH:29])[N:19]([CH:22]=[CH2:23])[CH:18]=[C:17]([C:24]([OH:26])=[O:25])[C:16]2=[O:27]
Reactant: [OH-]
Reactant: C=Cn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C(=O)OCC)CC3)nc21
Agent: [Na+]
Product: C=Cn1cc(C(=O)O)c(=O)c2cc(F)c(O)nc21
Temperature: 90 °C
Reaction time: 24 h

Procedure:
A mixture of 7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-1-vinyl-1,8-naphthyridine-3-carboxylic acid (78 g) and aqueous 20% sodium hydroxide (1,100 ml) was refluxed with stirring for 24 hours. After cooling, the resulting crystals were collected by filtration and washed with aqueous 10% sodium hydroxide (50 ml). The crystals were added to water (600 ml) and the mixture was heated at 90° C. and the acetic acid (50 ml) was added. After treatment with charcoal, the solution was acidified with concentrated hydrochloric acid (100 ml), and cooled in an ice-bath. The resulting crystals were collected by filtration, washed with water, and recrystallized from ethanol-chloroform to give 42.5 g of 6-fluoro-1,4-dihydro-7-hydroxy-4-oxo-1-vinyl-1,8-naphthyridine-3-carboxylic acid, m.p. 256°-259° C.
Reaction SMILES: [C:1]1([CH:7]([NH2:18])[C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]1([CH2:25][CH2:26][C:27]([NH:29][CH2:30][C:31](O)=[O:32])=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([CH2:25][CH2:26][C:27]([NH:29][CH2:30][C:31](=[O:32])[NH:18][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:17])[F:15])=[CH:10][CH:9]=2)=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)CNC(=O)CCc1ccccc1
Reactant: NC(c1ccccc1)c1ccc(C(F)(F)F)cc1
Product: O=C(CCc1ccccc1)NCC(=O)NC(c1ccccc1)c1ccc(C(F)(F)F)cc1

Procedure:
Prepared in analogy to example 1.1 from rac-C-phenyl-C-(4-trifluoromethyl-phenyl)-methylamine (CA [154238-38-2]) and (3-phenyl-propionylamino)-acetic acid (CA [56613-60-6]).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:8])[NH:5][C:6]=1[Cl:7].[H-].[Na+].Br[CH2:12][C:13]1[S:28][C:16]2[N:17]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:18](=[O:23])[N:19]([CH3:22])[C:20](=[O:21])[C:15]=2[C:14]=1[C:29]([O:31][CH3:32])=[O:30].O>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH3:8])[N:5]([CH2:12][C:13]2[S:28][C:16]3[N:17]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:18](=[O:23])[N:19]([CH3:22])[C:20](=[O:21])[C:15]=3[C:14]=2[C:29]([O:31][CH3:32])=[O:30])[C:6]=1[Cl:7]
Reactant: Cc1nc(Cl)c(Cl)[nH]1
Reactant: COC(=O)c1c(CBr)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(Cn2c(C)nc(Cl)c2Cl)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4,5-Dichloro-2-methylimidazole (1.3 g) in dry tetrahydrofuran (20 ml) was added dropwise to a suspension of sodium hydride (0.34 g, 60%) in dry tetrahydrofuran (20 ml) at room temperature under nitrogen. After 15 min, a solution of the product of step b) (3.35 g) in dry tetrahydrofuran (20 ml) was added dropwise and the reaction was stirred for 3 h at room temperature. The solution was poured into water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash silica chromatography eluting with a gradient 50-100% ethyl acetate in isohexane to give the sub-title compound as a white solid (2.28 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH2:16][CH2:15]3)[C:7](=[O:14])[N:8]2[CH:11]2[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:17](O)(=[O:24])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>>[CH:11]1([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[CH:10]=3)[C:6]3([CH2:16][CH2:15]3)[C:7]2=[O:14])[CH2:12][CH2:13]1
Reactant: O=C(O)c1ccncc1
Reactant: Nc1ccc2c(c1)N(C1CC1)C(=O)C21CC1
Product: O=C(Nc1ccc2c(c1)N(C1CC1)C(=O)C21CC1)c1ccncc1

Procedure:
Prepared in analogy to example 26 from 6′-amino-1′-cyclopropylspiro[cyclopropane-1,3′-indolin]-2′-one and isonicotinic acid. The title compound was obtained as light yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:27][CH2:28][CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)[C:9]2[CH:10]=[CH:11][C:12]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[C:13]([CH:18]=2)[C:14]([O:16]C)=[O:15])=[CH:4][CH:3]=1.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:27][CH2:28][CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)[C:9]2[CH:10]=[CH:11][C:12]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[C:13]([CH:18]=2)[C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(C(NCCn2ccnc2)c2ccc(F)cc2)ccc1Cc1ccc(F)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(C(NCCn2ccnc2)c2ccc(F)cc2)ccc1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
A mixture of methyl 5-[1-(4-fluorophenyl)-2-(imidazol-1-yl)ethylaminomethyl]-2-(4-fluorobenzyl)benzoate (1.5 g) sodium hydroxide (0.65 g), water (10 ml) and methanol (50 ml) was stirred under an inert atmosphere at ambient temperature for 2 hours. It was then acidified to pH 4-5 with 1M citric acid and evaporated to dryness. The residue was partitioned between ethyl acetate and water, the organic layer separated, treated with saturated brine, dried and evaporated to dryness to give 5-[1-(4-fluorophenyl)-2-(imidazol-1-yl)ethylaminomethyl]-2-(4-fluorobenzyl)benzoic acid as a white foam (1.0 g).
Reaction SMILES: CO[C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)Cc1ccc(O)cc1
Product: O=C(Cc1ccc(O)cc1)NCc1ccccc1
Reaction time: 8 h

Procedure:
A mixture of 80 g of 4-hydroxyphenylacetic acid methyl ester and 51.6 g of benzylamine is brought to 180° C. for 8 hours. The mixture is allowed to return to room temperature and the crystals are filtered off and washed with ethanol and then ethyl ether.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[CH2:8][C:9]3[C:21]4[NH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13]=4[C:12]4[C:22](=[O:25])[NH:23][CH2:24][C:11]=4[C:10]=3[C:4]=2[CH:3]=1.[CH:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)=[CH2:27].C(N(CC)CC)C>CN(C=O)C.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>[N:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH:26]=[CH:27][C:2]1[CH:7]=[CH:6][C:5]2[CH2:8][C:9]3[C:21]4[NH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13]=4[C:12]4[C:22](=[O:25])[NH:23][CH2:24][C:11]=4[C:10]=3[C:4]=2[CH:3]=1
Reactant: O=C1NCc2c3c(c4[nH]c5ccccc5c4c21)Cc1ccc(Br)cc1-3
Reactant: C=Cc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1NCc2c3c(c4[nH]c5ccccc5c4c21)Cc1ccc(C=Cc2ccccn2)cc1-3
Temperature: 25 °C
Yield: 83.7 %

Procedure:
To a solution of 3-bromo-5H,6H,12H,13H-indeno[2,3-a]pyrrolo[3,4-c]carbazole-7(7H)one (Compound I-9) (100 mg, 0.26 mmol), 2-vinylpyridine (54 mg, 0.6 mL, 0.51 mmol) and triethylamine (0.5 mL) in DMF (4 mL) was added tetrakis(triphenylphosphine)palladium(0) (30 mg). The solution was heated in a sealed reaction tube at 100°-110° C. for 48 h. The mixture was cooled to ambient temperature, filtered through a pad of Celite®, then the solvent was concentrated at reduced pressure. The product was triturated with MeOH to give 90 mg (84%) of Compound I-31 as a yellow solid, purification by column chromatography (silica gel, EtOAc:MeOH, 9:1), mp>320° C. 1H NMR (DMSO-d6, 300 MHz): δ4.2 (s, 2H), 5.0 (s, 2H), 7.2-7.42 (m, 4H), 7.58-7.7 (m, 4H), 7.8-7.95 (m, 2H), 8.3 (s, 1H), 8.6 (d, 1H, J=6 Hz), 8.63 (s, 1H), 9.4 (d, 1H, J=9 Hz), 12.1 (s, 1H). MS(FAB): m/e 414 (m+1)+.
Reaction SMILES: [C:1]([Si:5]([CH3:42])([CH3:41])[O:6][CH2:7][CH2:8][N:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]2[CH:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[C:38](O)=[O:39])=[CH:32]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1)[CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl.[O:62]1[CH2:67][CH2:66][CH2:65][CH2:64][CH:63]1[O:68][NH2:69]>CN(C=O)C>[C:1]([Si:5]([CH3:42])([CH3:41])[O:6][CH2:7][CH2:8][N:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]2[CH:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[C:38]([NH:69][O:68][CH:63]3[CH2:64][CH2:65][CH2:66][CH2:67][O:62]3)=[O:39])=[CH:32]2)(=[O:29])=[O:30])=[CH:24][CH:23]=1)[CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: NOC1CCCCO1
Reactant: CC(C)(C)[Si](C)(C)OCCN(CCc1c[nH]c2ccccc12)Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)O)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCN(CCc1c[nH]c2ccccc12)Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NOC3CCCCO3)c2)cc1
Reaction time: 1.5 h

Procedure:
(E)-3-{1-[4-({[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylic acid (compound C15) (1.15 g, 1.16 mmol), HOBtH2O (171 mg, 1.16 mmol) and triethylamine (2 ml) is dissolved in DMF (100 ml) at room temperature. After addition of EDC.HCl (786 mg, 3.48 mmol) the mixture is stirred for 1.5 hours. Then it is added O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine (136 mg, 1.16 mmol) and stirred for 17 hours. After evaporation and addition of 200 ml water the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate. Then it is filtrated and evaporated. The crude product is purified by a silica gel flash chromatography using dichloromethane-methanol eluent.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:21](Cl)(=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37]>C(Cl)Cl.C(O)C>[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37].[C:21]([O:18][CH2:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([C:6]2[C:5]3[CH:19]=[CH:20][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:10][CH2:11]1)(=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: CCCCCCCCCC(=O)Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: ClCCl
Solvent: CCO
Product: CCCCCCCCCC(=O)OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 0.33 h

Procedure:
To a solution 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl)propanol (1.81 gm, 6.5 mmol) triethylamine (0.9 gm, 9.0 mmol) in DCM (45 ml) was added decanoyl chloride (1.5 gm, 7.8 mmol) dropwise at room temperature. The mixture was stirred for 20 minutes, then concentrated down to a crude solid. The solid was extracted into EtOAc (20 ml), and the insoluble salts were filtered. The EtOAc was removed. The crude oil was purified by flash chromatography (Sorbsil C-30, 30 gm; eluted with MeOH:DCM). The oil thus obtained (2.54 gm, 90%) was converted to a fumarate salt with fumaric acid (670 mg) in ethanol. The crystals collected weighed 1.61 gm, m.p.=100°-102° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]=[C:14]=S)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[NH2:16][C:17]1[CH:18]=[C:19]([CH:31]=[CH:32][C:33]=1[NH:34][CH2:35][CH2:36][CH2:37][N:38]([CH3:47])[CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1)[C:20]([N:22]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21].N.[ClH:49]>O1CCCC1.C(OCC)C>[ClH:49].[CH2:27]([N:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([C:19]1[CH:31]=[CH:32][C:33]2[N:34]([CH2:35][CH2:36][CH2:37][N:38]([CH3:47])[CH2:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=3)[C:14]([NH:13][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)=[N:16][C:17]=2[CH:18]=1)=[O:21])[CH:28]([CH3:29])[CH3:30]
Reactant: CC(C)CN(CC(C)C)C(=O)c1ccc(NCCCN(C)CCc2ccccn2)c(N)c1
Reactant: COc1cc(N=C=S)cc(OC)c1OC
Agent: Cl
Agent: N
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(Nc2nc3cc(C(=O)N(CC(C)C)CC(C)C)ccc3n2CCCN(C)CCc2ccccn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3,4,5 trimethoxyphenylisothiocyanate (27 mg, 1.2 eq) and N-methylcyclohexylcarbodiimide-N-methyl-polystyrene resin (acquired from Novabiochem; load 1.69 mmol/g, 236 mg, 4 eq) are added successively to a solution of 3-amino-N,N-diisobutyl-4-({3-[methyl(2-pyridin-2-ylethyl)amino]propyl}amino)benzamide (48 mg, 1 eq) in tetrahydrofuran (2 ml). The mixture is heated under reflux for 18 hours then cooled down to ambient temperature and aminomethyl polystyrene resin (acquired from Novabiochem, 2 eq) is added. After stirring for 4 hours at ambient temperature, the mixture is filtered on frit and the filtrate is concentrated under reduced pressure at 40° C. The residue obtained is dissolved in ethyl ether and a solution of 1N HCl in ethyl ether is added dropwise in order to produce the expected compound in the form of the hydrochloride salt (80 mg, 89% yield).