Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[C:11](\[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)/[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[NH:26]([C:42]([O:44]CC1C2C(=CC=CC=2)C2C1=CC=CC=2)=[O:43])[C@H:27]([C:39](O)=[O:40])[CH2:28][C:29](=[O:38])[O:30]CC1C=CC=CC=1.C[N:60]([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(=O)([O-])O.[Na+]>C(#N)C.O.C(N(CC)CC)C>[NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[C:11](\[C:14]2[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=2)/[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:42]([NH:26][C@H:27]([C:39]([NH-:60])=[O:40])[CH2:28][C:29](=[O:38])[OH:30])([O:44][CH2:15][CH:16]1[C:3]2[C:4](=[CH:5][CH:6]=[CH:7][CH:2]=2)[C:10]2[C:17]1=[CH:18][CH:19]=[CH:14][CH:11]=2)=[O:43]
Reactant: O=C(C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OCc1ccccc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: COc1ccc(/C=C(/C#N)c2cc(OC)c(OC)c(OC)c2)cc1N
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: [NH-]C(=O)[C@H](CC(=O)O)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 135.8 %

Procedure:
Nine-hundred milligrams (2.65 mmols) of (E)-3-(3-amino-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-prop-2-enenitrile, 1,400 mg of Fmoc-L-Asp(OBn), 1,300 mg of a BOP reagent and 660 mg of HOBt.H2O were dissolved in 50 ml of acetonitrile, and 0.5 ml of triethylamine were added thereto. The mixture was reacted at room temperature for 86 hours. One-hundred milliliters of water and a small amount of sodium hydrogencarbonate were added thereto, and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was purified using a silica-gel column (eluent, mixture of ethyl acetate and dichloromethane at a ratio by volume of 1:10), and then concentrated to give 1,319 mg (1.80 mmols) of the final product in a yield of 68%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:9]1[C:10]([C:16]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:19]3[CH:28]=[C:29]([CH3:32])[CH:30]=[CH:31][C:18]=3[N:17]=2)=[N:11][C:12](Br)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:47]([NH2:50])[C:48]#[CH:49]>CN(C=O)C.C(OCC)(=O)C.I[Cu].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>[NH2:50][CH2:47][C:48]#[C:49][C:12]1[N:11]=[C:10]([C:16]2[N:20]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[C:19]3[CH:28]=[C:29]([CH3:32])[CH:30]=[CH:31][C:18]=3[N:17]=2)[C:9]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])=[N:14][CH:13]=1
Reactant: C#CCN
Reactant: Cc1ccc2nc(-c3nc(Br)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n(C(=O)OC(C)(C)C)c2c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc2nc(-c3nc(C#CCN)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n(C(=O)OC(C)(C)C)c2c1

Procedure:
tert-Butyl 2-[3-[bis(tert-butoxycarbonyl)amino]-6-bromo-pyrazin-2-yl]-6-methyl-benzimidazole-1-carboxylate (1000 mg, 1.654 mmol), iodocopper (31.50 mg, 0.1654 mmol), Pd(PPh3)4 (191.1 mg, 0.1654 mmol), triethylamine (836.8 mg, 1.153 mL, 8.270 mmol) and prop-2-yn-1-amine (182.2 mg, 3.308 mmol) were stirred in DMF (5 mL) at ambient temperature for 2 hours. The reaction mixture was diluted with ethyl acetate the organic layer washed with water, brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by column chromatography eluting with 25/75 ethyl acetate/petroleum ether to give the sub-title compound as an off-white solid which was used directly in the next step with out further purification.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:29])[NH:12][CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[O:17])[N:10]=2)[CH2:3]1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>C(Cl)Cl.N1C=CC=CC=1>[CH3:30][S:31]([O:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:29])[NH:12][CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[O:17])[N:10]=2)[CH2:3]1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NCCNC(=O)c1csc(N2CC(O)C2)n1)OCc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)NCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.9 %

Procedure:
To a solution of 3-hydroxy-1-{4-[2-(p-nitrobenzyloxycarbonylamino)ethylcarbamoyl]-1,3-thiazol-2-yl}azetidine (658.4 mg, 1.56 mmol) (obtained as described in Reference Example 56(5)) in a mixture of methylene chloride (33 ml) and pyridine (5 ml) were added methanesulfonyl chloride (0.31 ml, 4.00 mmol) and triethylamine (0.57 ml, 4.09 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the resulting mixture was stirred at room temperature for 4 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed successively with 0.5M aqueous hydrochloric acid solution, saturated aqueous sodium hydrogencarbonate solution, and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:acetonitrile (1:2) as the eluant to afford 3-methanesulfonyloxy-1-{4-[2-(p-nitrobenzyloxycarbonylamino)-ethylcarbamoyl]-1,3-thiazol-2-yl}azetidine (607.3 mg, yield 78%) as a pale yellow solid.
Reaction SMILES: [CH:1]1([NH:9][C:10](=[O:31])[C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16](=[O:30])[C@H:17]([CH3:29])[NH:18][C:19]([O:21]CC2C=CC=CC=2)=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:32](OC(=O)CC)(=O)[CH2:33]C>Br.C(O)(=O)C.C(Cl)(Cl)Cl.CCOCC>[CH:1]1([NH:9][C:10](=[O:31])[C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16](=[O:30])[C@H:17]([CH3:29])[NH:18][C:19](=[O:21])[CH2:32][CH3:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NC1CCCCCCC1
Reactant: CCC(=O)OC(=O)CC
Agent: Br
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)NC1CCCCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
2 g (0.0047 mol) of N-benzyloxycarbonyl-L-alanyl-L-proline cyclooctylamide were dissolved in 10 ml of 4-N hydrogen bromide in acetic acid and the solution was stirred at room temperature for 1 hour. 100 ml of anhydrous ether were added and an oil precipitated out of the solution. The ether layer was decanted off and the oil washed with 100 ml of anhydrous ether. The ether layer was again decanted off and the oil dissolved in 30 ml of dry pyridine. 1.2 g (0.0094 mol) of propionic anhydride were added and the solution was stirred at room temperature for 2 hours. The pyridine was removed by evaporation, 50 ml of toluene were added to the residue and the mixture was again evaporated in order to azeotropically remove any residual pyridine. The solid obtained was taken up in 100 ml of chloroform, the solution was washed with sodium chloride solution and dried over magnesium sulphate. The solution was then evaporated to yield an oil. This oil was dissolved in the minimum volume of ether and petroleum ether was added, whereby a white solid crystallised out of the solution. There was obtained 0.900 g (56.3%) of N-propionyl-L-alanyl-L-proline cyclooctylamide of melting point 142°-143° C.; [α]D20 =-120.3° (c=0.82% in methanol).
Reaction SMILES: F[C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:7]=1[CH3:8].[NH4+:15].[OH-]>>[NH2:15][C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(-c2ccccc2)nnc1F
Reactant: [NH4+]
Agent: [OH-]
Product: Cc1cc(-c2ccccc2)nnc1N

Procedure:
A mixture of 3-fluoro-4-methyl-6-phenylpyridazine (1.0 g) and 50 mL of 28% aqueous NH4OH is heated in a pressure bottle to 95°-100° C. The reaction mixture is cooled and thereafter extracted with CH2Cl2. The organic materials are then extracted with 10% aqueous HCl. The acid phase is washed with CH2Cl2, cooled and basified with caustic. The resulting mixture is extracted several times with CH2Cl2. The organic extracts are then combined and dried with MgSO4 and the remaining liquid is concentrated to give 550 mg (56%) crude product as a yellow solid. Recrystallization from EtOH gives an analytically pure material melting at 132°-134° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][CH:31]=3)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24]
Reactant: CN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Reactant: CCOC(=O)Cc1ccc(N)cc1
Product: CCOC(=O)Cc1ccc(Nc2ncc3c(n2)N(C)C(=O)N(c2c(Cl)cccc2Cl)C3)cc1
Temperature: 185 °C
Yield: 37.6 %

Procedure:
A mixture of 200 mg (0.52 mmol) of 3-(2,6-dichlorophenyl)-3,4-dihydro-7-methanesulfonyl-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 800 mg (4.47 mmol) of ethyl 4-aminophenylacetate was heated at 185° C. for 45 minutes. The residue was partitioned between 10 ml of ethyl acetate and 10 ml of 2M hydrochloric acid and the insoluble cream colored solid was collected by filtration and washed with 20 ml of water and 20 ml of ethyl acetate and then dried under a high vacuum. 95 mg (38%) of ethyl 2-[4-[[3-(2,6-dichlorophenyl)-1,2,3,4-tetrahydro-1-methyl-2-oxopyrimido[4,5-d]pyrimidin-7-yl]amino]phenyl]acetate of melting point 211-212° C. were isolated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15]Br)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2
Reactant: Nc1ncnn2c(CCCCBr)cc(Br)c12
Reactant: C1CCNC1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncnn2c(CCCCN3CCCC3)cc(Br)c12
Temperature: 55 °C
Yield: 80.3 %

Procedure:
To a solution of 5-bromo-7-(4-bromobutyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (597 mg, 1.72 mmol) in DMF (10 mL) was added pyrrolidine (158 μL, 1.89 mmol), triethylamine (717 μL, 5.15 mmol), and sodium iodide (26 mg, 0.17 mmol). The reaction was heated (55° C.) for 22 h and then cooled to rt. The mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The layers were separated and the aqueous phase was further extracted with ethyl acetate (3×50 mL). The combined organics were washed with water (1×50 mL), brine, dried (Na2SO4) and evaporated to afford 467 mg (80%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 7.81 (s, 1 H), 6.60 (s, 1 H), 2.81 (t, 2 H), 2.40-2.31 (m, 6 H), 1.70-1.59 (m, 6 H), 1.50-1.40 (m, 2 H); ES-MS m/z 338.1 [M+H]+, HPLC RT (min) 1.12.
Reaction SMILES: C1(C[N:8]2[CH2:14][CH2:13][C:12]3=[CH:15][NH:16][N:17]=[C:11]3[CH2:10][CH2:9]2)C=CC=CC=1.[ClH:18]>C(O)C.[Pd]>[ClH:18].[N:17]1[NH:16][CH:15]=[C:12]2[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=12
Reactant: c1ccc(CN2CCc3c[nH]nc3CC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1[nH]nc2c1CCNCC2
Reaction time: 18 h

Procedure:
6-(Phenylmethyl)-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine (may be prepared as described in Description 5) (5.52 g, 24.29 mmol) was dissolved in ethanol (70 ml) under argon and 2M hydrochloric acid (12.2 ml, 24.4 mmol) added, followed by 50% wet 10% palladium on carbon catalyst (1 g). The mixture was stirred under an atmosphere of hydrogen for 18 hours. The catalyst was filtered and the filtrate evaporated to give the title compound (D6). MS (ES+) m/e [M+H]+
Reaction SMILES: C(OC(N1CC[N:11]([CH2:14][C:15]2[C:16](=[O:36])[N:17]([CH2:30][CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([F:29])[CH:22]=3)[CH:20]=2)CC1)=O)(C)(C)C.C1(CN2C(=O)C(COS(C)(=O)=O)=CC(C3C=CC(OC)=C(F)C=3)=N2)CCCC1>>[NH2:11][CH2:14][C:15]1[C:16](=[O:36])[N:17]([CH2:30][CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([F:29])[CH:22]=2)[CH:20]=1
Reactant: COc1ccc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(CC3CCCC3)n2)cc1F
Agent: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CCCC3)n2)cc1F
Product: COc1ccc(-c2cc(CN)c(=O)n(CC3CCCC3)n2)cc1F
Yield: 53.7 %

Procedure:
Following the procedure of Example 24 (1), 2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one was reacted to yield a crude product. Without purification, the crude product was reacted further in accordance with the procedure of Example 24 (2) to yield the title compound as a yellow oil (yield: 53.7%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]=[C:6]2[NH:16][N:17]=[C:18]([I:19])[C:5]=12.[CH3:20]I.[Li+].[Cl-]>CN(C=O)C.C(OCC)(=O)C>[Cl:3][C:4]1[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:8][N:7]=[C:6]2[N:16]([CH3:20])[N:17]=[C:18]([I:19])[C:5]=12
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(I)c12
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1nc(I)c2c(Cl)c(-c3ccccc3)nnc21
Reaction time: 2 h
Yield: 48.5 %

Procedure:
Sodium hydride (60% in mineral oil, 674 mg, 16.9 mmol) was added to a suspension of 4-chloro-3-iodo-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (3 g, 8.4 mmol) in dry DMF (42 mL) then methyl iodide (1.05 mL, 16.9 mmol) was added. The reaction mixture was stirred for 2 h. LiCl solution (4% in water) and ethyl acetate were added and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (silica gel, ethyl acetate/isohexane 0:1 to 1:1) yielding the intermediate as a solid (1.51 g).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:5]2[CH2:6][CH2:7][C:4]=12.CC1C=CC=CC=1[CH2:14][Cl:15]>>[Cl:15][CH2:14][C:4]12[CH:3]=[CH:10][CH:9]=[CH:8][CH:5]1[CH2:6][CH2:7]2.[Cl:1][CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:5]2[CH2:6][CH2:7][C:4]=12
Reactant: Cc1ccccc1CCl
Agent: ClCc1cccc2c1CC2
Product: ClCC12C=CC=CC1CC2

Procedure:
Preparation of 4-chloromethylbenzocyclobutene was also effected by a similar procedure beginning with o-methylbenzyl chloride, however, the procedure yielded about a 1:2 mixture of 3-chloromethylbenzocyclobutene and 4-chloromethylbenzocyclobutene.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]([C:5]1[CH:16]=[C:15]([O:17]CC2C=CC=CC=2)[C:8]2[N:9]=[C:10]([CH2:13][CH3:14])[N:11]([CH3:12])[C:7]=2[CH:6]=1)=[O:4].C(O)(=O)C>C(O)C.[Pd]>[CH3:25][N:2]([CH3:1])[C:3]([C:5]1[CH:16]=[C:15]([OH:17])[C:8]2[N:9]=[C:10]([CH2:13][CH3:14])[N:11]([CH3:12])[C:7]=2[CH:6]=1)=[O:4]
Reactant: CCc1nc2c(OCc3ccccc3)cc(C(=O)N(C)C)cc2n1C
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1nc2c(O)cc(C(=O)N(C)C)cc2n1C
Yield: 106.4 %

Procedure:
A solution of 10.9 g (26.6 mmol) 7-benzyloxy-2-ethyl-3-methyl-3H-benzimidazole-5-carboxylic acid dimethylamide and 1.8 ml acetic acid in 160 ml ethanol was hydrogenated over 1.7 g 10% Pd/C in autoclave (5 bar H2) at 50° C. for 18 h. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was crystallized from acetone to afford 7 g (91%) of the title compound as a white solid. m.p. 193°-199° C.
Reaction SMILES: [CH2:1]([C:6]1[CH:38]=[CH:37][C:9]([O:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20](=[O:36])[C:21]3[CH:26]=[CH:25][C:24]([O:27]CC4C=CC=CC=4)=[CH:23][C:22]=3[Cl:35])=[CH:15][CH:14]=2)=[O:12])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C1CCCCC1>[OH-].[OH-].[Pd+2].C(O)C>[CH2:1]([C:6]1[CH:38]=[CH:37][C:9]([O:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20](=[O:36])[C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=3[Cl:35])=[CH:15][CH:14]=2)=[O:12])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(OC(=O)c2ccc(OC(=O)c3ccc(OCc4ccccc4)cc3Cl)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCCCC1
Solvent: CCO
Product: CCCCCc1ccc(OC(=O)c2ccc(OC(=O)c3ccc(O)cc3Cl)cc2)cc1
Yield: 80 %

Procedure:
2.5 g (4.7 mmol) of 4-benzyloxy-2-chloro-benzoic acid 4-(4-pentyl-phenoxycarbonyl)-phenyl ester, 20 mL of cyclohexane and 0.13 g of palladium hydroxide/carbon were added to 25 mL of dehydrated ethanol and refluxed for 12 hours in the presence of argon. The resulting reaction mixture was filtered and the filtrate was concentrated. The residue was recrystallized from hexane/ethyl acetate to obtain 1.65 g of a white solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH2:9])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18].[OH-].[Na+]>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:9][C:17](=[O:19])[CH3:18])[CH:5]=[CH:4][CH:3]=1
Reactant: NCc1cccc(Br)n1
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1cccc(Br)n1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of C-(6-Bromo-pyridin-2-yl)-methylamine (5440 mg, 29.08 mmol) in dichloromethane (100 mL) at room temperature was added triethylamine (5886 mg, 58.17 mmol) and acetyl chloride (2511 mg, 31.99 mmol). The reaction mixture was heated at 40° C. for 3 h and cooled down to room temperature. A solution of sodium hydroxide (1N) was added and the reaction was stirred for 1 h at room temperature. The layers were separated and the organic phase was concentrated under reduced pressure. The crude mixture was dissolved in EtOH (50 mL) and concentrated hydrochloric acid (10 mL) was added. The mixture was stirred for 30 min and benzene was added followed by sodium hydroxide pellets until pH 10 was reached. The phases were separated and the organic layer was washed with an aqueous solution of ammonium chloride and the volatiles were removed in vacuo. The crude material was purified by column chromatography with a gradient of 0 to 5% methanol/dichloromethane to give N-(6-Bromo-pyridin-2-ylmethyl)-acetamide as viscous orange oil. MS ES (MH+ 229.1/231.0).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:23]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:16]4[N:17]=[CH:18][CH:19]=[C:20]([CH:21]=O)[C:15]=4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:34][CH3:35].[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:43]2[CH:50]=[CH:49][C:46]([CH2:47][NH2:48])=[CH:45][CH:44]=2)[CH2:39][CH2:38]1>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:23]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:48][CH2:47][C:46]5[CH:45]=[CH:44][C:43]([N:40]6[CH2:39][CH2:38][N:37]([CH3:36])[CH2:42][CH2:41]6)=[CH:50][CH:49]=5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:34][CH3:35]
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(C=O)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Reactant: CN1CCN(c2ccc(CN)cc2)CC1
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNCc4ccc(N5CCN(C)CC5)cc4)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C

Procedure:
The product is prepared by following the procedure described in example 34, stage (j), starting with 0.1 g of 2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-carbaldehyde and 0.209 cm3 of 4-(4-methylpiperazino)benzylamine instead of the cyclopropylamine used in example 34, stage (j). After purification by flash-pack chromatography (SiO2, dichloromethane/methanol 90/10 by volume as eluents), 0.083 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]-[4-(4-methylpiperazin-1-yl)-benzyl]amine is obtained with the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[CH2:16]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[CH3:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH2:16]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:11]([C:6]2[C:5]([Cl:13])=[C:4]([Cl:14])[C:3]([Cl:15])=[C:2]([Cl:1])[C:7]=2[C:8]([OH:10])=[O:9])=[O:12])=[C:25]1[CH3:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: CCCCCCCCn1c(C)cc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCCCCCn1c(C)c(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c2ccccc21

Procedure:
Proceeding in the same manner as that described in part A of Example 6 above, 14.3 g (0.05 mole) of tetrachlorophthalic anhydride, 16.0 g (0.052 mole) of 76.5 percent active 1-n-octyl-2-methylindole and 13.3 g (0.10 mole) of aluminum chloride were interacted to obtain 2-[(1-n-octyl-2-methyl-3-indolyl)carbonyl]-3,4,5,6-tetrachlorobenzoic acid (Formula VIII: R°=R1 =R2 =R3 =Cl; R5 =CH3 ; R6 =(CH2)7CH3 ; Y1 =H), a pale orange solid melting at 132°-134° C. The infrared spectrum, showing a maximum at 1745 cm-1 (C=O; s) and the nuclear magnetic resonance spectrum was in accord with the structure.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[C:7]([NH:22][C:23]([NH:25][C:26]2[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=2[CH:35]([CH3:37])[CH3:36])=[O:24])[C:6]1=[O:38])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl.[CH3:48][N:49]([CH3:54])[CH2:50][CH2:51][CH2:52]Cl>CN(C=O)C.O>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:52][CH2:51][CH2:50][N:49]([CH3:54])[CH3:48])[CH:16]=2)=[C:7]([NH:22][C:23]([NH:25][C:26]2[C:27]([CH:35]([CH3:37])[CH3:36])=[CH:28][CH:29]=[CH:30][C:31]=2[CH:32]([CH3:33])[CH3:34])=[O:24])[C:6]1=[O:38])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(O)c2)c2cccnc21
Reactant: CN(C)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCCCN(C)C)c2)c2cccnc21
Reaction time: 10 h
Yield: 37.6 %

Procedure:
To a suspension of N-{ 1-butyl-4-(3-hydroxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl}-N'-(2,6-diisopropylphenyl)urea (200 mg, 0.4 mmol), potassium carbonate (166 mg, 1.2 mmol), and sodium iodide (5 mg) in DMF (10 ml) was added 3-dimethylaminopropyl chloride hydrochloride (63 mg) at room temperature, and the mixture was stirred at 60°-70° C. for 10 hours. After allowed to stand for cooling, the mixture was poured into water, extracted with ethyl acetate, washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure, and purified by silica gel column chromatography (10% methanol in chloroform) to give the title compound (88 mg, 0.15 mmol).