Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:5]([C:8]1[C:9]([F:14])=[N:10][CH:11]=[CH:12][CH:13]=1)[CH2:6][CH3:7])(=O)C.[H][H]>C(O)C.[Pd]>[CH2:5]([C:8]1[C:9]([F:14])=[N:10][CH:11]=[CH:12][CH:13]=1)[CH2:6][CH3:7]
Reactant: [H][H]
Reactant: CCC(OC(C)=O)c1cccnc1F
Agent: [Pd]
Solvent: CCO
Product: CCCc1cccnc1F

Procedure:
3.50 g (17.7 mmol) of the product from example 49A are dissolved in 30 ml of ethanol and admixed with 2.00 g of 10% palladium on activated carbon. Hydrogenation is effected overnight in a hydrogen atmosphere under standard pressure. The mixture is filtered with suction, washed with ethanol and concentrated cautiously under reduced pressure. This affords 1.9 g of approx. 89% pure product (69% of theory), which is converted further without purification.
Reaction SMILES: C(O[C:9]([N:11]([CH2:13][C:14]1[N:15]([CH2:23][CH3:24])[C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)C)=O)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[CH2:23]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[C:14]1[CH2:13][NH:11][CH3:9])[CH3:24]
Reactant: CCn1c(CN(C)C(=O)OCc2ccccc2)cc2ccccc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCn1c(CNC)cc2ccccc21
Reaction time: 8 h
Yield: 99.6 %

Procedure:
2-[N-(Benzyloxycarbonyl)-N-methylaminomethyl]-1-ethyl-1H-indole (1.30 g, 4.0 mmole) was added to a suspension of Peariman's catalyst (about 0.30 g) in MeOH at RT in a Parr flask. The reaction was placed under 50 p.s.i. of H2 and shaken for 8 hr. The mixture was filtered through celite(D and the filter pad was washed with MeOH. The filtrate was concentrated to afford the title compound (0.75 g, 100%) as a light yellow solid: MS (ES) m/e 189 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=S)=[CH:5][CH:4]=1.O.[NH2:22][NH2:23]>C(O)C>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7](=[N:22][NH2:23])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=S)Nc2ccc([N+](=O)[O-])cc2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=NN)Nc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
A mixture of 10 g of 4-methoxy-4'-nitrothiobenzanilide [prepared by process of Ann. Chem., Vol. 716 (1968), p. 209-211], 100 ml of ethanol and 15 ml of hydrazine hydrate was heated to reflux and then was allowed to return to room temperature and was filtered. The product was washed with ethanol and dried at 80° C. under reduced pressure to obtain 7.9 g of 4-methoxy-N-(4-nitrophenyl)-benzene-carbohydrazonamide melting at 104° C.
Reaction SMILES: [Cl:1][SiH2:2][Cl:3].[CH2:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[CH2:21]([SiH:2]([Cl:3])[Cl:1])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH3:4]
Reactant: C=CCCCCCCCCCCCCCCCC
Reactant: Cl[SiH2]Cl
Product: CCCCCCCCCCCCCCCCCC[SiH](Cl)Cl
Reaction time: 30 h

Procedure:
Dichlorosilane in an amount of 60.6 g (0.6 mol), 176.4 g of 1-octadecene (0.7 mol) and 0.07 mol % of RhCl(PPh)3 (relative to dichlorosilane) were charged in a 500 ml pressure-proof stainless steel reactor. After sealing, reaction was carried out at 130° C. for 30 hours. The reacted liquid was distilled in vacuo to give n-octadecyldichlorosilane (n--C18H37SiHCl2).
Reaction SMILES: [H-].[Na+].CS(C)=O.[I-].[CH3:8][S+](C)(C)=O.[CH2:13]([C@@:15]12[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][C@H:16]1[CH2:17][CH2:18][CH2:19][C:20]1[C:21]2=[CH:22][C:23]2[CH:24]=[N:25][N:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:27]=2[CH:28]=1)[CH3:14]>C1COCC1>[CH2:13]([C@@:15]12[CH2:39][CH2:38][C@@:37]3([CH2:8][O:40]3)[CH2:36][C@H:16]1[CH2:17][CH2:18][CH2:19][C:20]1[C:21]2=[CH:22][C:23]2[CH:24]=[N:25][N:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:27]=2[CH:28]=1)[CH3:14]
Reactant: C[S+](C)(C)=O
Reactant: CC[C@@]12CCC(=O)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC[C@@]12CC[C@@]3(CO3)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 65 °C

Procedure:
Sodium hydride (60 wt % in oil, 0.023 g, 0.967 mmol) was added carefully to a flask containing about 3 mL DMSO then heated to about 65° C. for about 30 min. The reaction was cooled to rt then diluted with 2 mL THF. The reaction was further cooled in an ice water bath and trimethylsulfoxonium iodide (0.213 g, 0.967 mmol) was added in one portion and stirred about 15 min. (4aR,12bR)-12b-ethyl-9-(4-fluorophenyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3 (2H)-one (9, R1=4-Fluorophenyl, R2=Ethyl) (0.182, 0.483 mmol) in 2 mL THF was introduced via syringe and allowed to warm to rt over about 18 hrs. THF was removed in vacuo and the residue was diluted with 15 mL water and extracted with EtOAc (15 mL×3). The combined organics were washed with sat. aq. NaCl. The organic layer was dried over MgSO4 filtered and concentrated to a crude viscous oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH3:21])[CH:10]([C:22]([OH:24])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH3:21])[CH:10]([C:22]([N:36]2[CH2:37][CH2:38][N:33]([C:27]3[CH:28]=[C:29]([CH3:32])[CH:30]=[CH:31][C:26]=3[CH3:25])[CH2:34][CH2:35]2)=[O:24])[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1ccc(C)c(N2CCNCC2)c1
Reactant: Cc1cc(F)ccc1N1CCN(C(=O)OC(C)(C)C)CC1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(C(=O)OC(C)(C)C)CCN3c3ccc(F)cc3C)CC2)c1

Procedure:
4-(4-fluoro-2-methyl-phenyl)-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester (CAS Reg. No.: [499780-10-8]) (100 mg) in DMF (2.5 mL) was treated with 1-(2,5-dimethylphenyl)piperazine (62 mg), 2-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium hexafluoro phosphate (HBTU) (123 mg) and triethylamine (124 μL) at ambient temperature for 5 h. Water was added, the phases were separated and the inorganic phase was extracted with tert-butyl-methyl ether (TBME). The combined organic phases were washed with water and brine, dried (Na2SO4), filtered and evaporated. Purification by chromatography (SiO2, n-heptane/ethyl acetate 2:1) gave 3-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-4-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester as a white solid (143 mg), MS: 511.5 ([M+H]+).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][C:31]=1[C:32]([F:35])([F:34])[F:33])[O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([C:24](=[O:28])[C:25]([NH2:27])=[O:26])=[CH:16]2)=[CH:11][CH:10]=1)#[N:4]>CCO.C1COCC1>[C:3]([C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][C:31]=1[C:32]([F:35])([F:33])[F:34])[O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]([OH:28])[C:25]([NH2:27])=[O:26])=[CH:16]2)=[CH:13][CH:14]=1)#[N:4]
Reactant: N#Cc1cc(Oc2ccc(-n3cc(C(=O)C(N)=O)c4ccccc43)cc2)ccc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1cc(Oc2ccc(-n3cc(C(O)C(N)=O)c4ccccc43)cc2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
NaBH4 (40 mg) was added to a solution of compound 59 in EtOH/THF (2 mL/2 mL) at room temperature, and the mixture was shaken at room temperature for 3 hours. The reaction was quenched with water, extracted with EtOAc (30 mL), concentrated, and purified by column (CHCl3/MeOH 7/1) to give compound 60 as a white solid (70 mg, 70%): 1H-NMR (400 MHz, CD3OD): δ 7.92 (d, 1H, 8.8 Hz), 7.87 (d, 1H, 7.9 Hz), 7.66-7.69 (m, 3H), 7.53-7.56 (m, 2H), 7.45-7.48 (m, 1H), 7.35-7.38 (m, 1H), 7.15-7.25 (m, 2H), 5.41 (br, 1H); LC/MS: m/z=474.3 [M+Na]+ (Calc: 451.4).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH2:10][C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1.I[CH3:19]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH:10]([C:11]1[N:12]=[CH:13][CH:14]=[CH:15][N:16]=1)[CH3:19]
Reactant: CI
Reactant: O=C(Cc1ncccn1)c1ccc(F)cc1F
Product: CC(C(=O)c1ccc(F)cc1F)c1ncccn1
Yield: 89 %

Procedure:
Methylation of the product of part (i) (3.50 g) with iodomethane (5.32 g) according to the method of Example 11(ii) gave the title compound (3.30 g), m.p. 118°-119°.
Reaction SMILES: [CH3:1][Mg+].[Br-].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[N:14]=[C:13]([CH2:24][CH2:25][C:26](=[O:28])[CH3:27])[CH:12]=2)=[CH:7][CH:6]=1>C1COCC1>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[N:14]=[C:13]([CH2:24][CH2:25][C:26]([OH:28])([CH3:1])[CH3:27])[CH:12]=2)=[CH:9][CH:10]=1
Reactant: C[Mg+]
Reactant: COc1ccc(-n2nc(CCC(C)=O)cc2-c2ccc(Cl)cc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(CCC(C)(C)O)cc2-c2ccc(Cl)cc2)cc1
Reaction time: 1 h

Procedure:
To a solution of MeMgBr (1.32 ml of 3.2M, 4.23 mM) in THF (15 ml) at 0° C., was added a solution of the ketone 23, (1.00 g, 2.82 mM) in THF (25 ml) dropwise over a 20 minute period. After stirring for 1 hour, the reaction mixture was quenched with a saturated NH4Cl solution, diluted to a 100 ml volume with Et2O, washed with H2O, dried (Na2SO4), filtered, and concentrated in vacuo. Chromatography of the residue (Baker silica gel, 45 g) with Et2O as eluent, afforded 27, (0.68 g, 80% corrected for recovered starting material) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][O:8][C:9]2[C:14](=[O:15])[CH:13]=[CH:12][NH:11][CH:10]=2)=[CH:5][CH:4]=1.[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](Br)[N:20]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Br:18][C:19]1[N:20]=[C:21]([N:11]2[CH:12]=[CH:13][C:14](=[O:15])[C:9]([O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=3)=[CH:10]2)[CH:22]=[CH:23][CH:24]=1
Reactant: Brc1cccc(Br)n1
Reactant: COc1ccc(COc2c[nH]ccc2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(COc2cn(-c3cccc(Br)n3)ccc2=O)cc1
Temperature: 120 °C

Procedure:
A mixture of 3-[(4-methoxybenzyl)oxy]pyridin-4(1H)-one (2.31 g, 10 mmol), 2,6-dibromopyridine (4.74 g, 20 mmol), and K2CO3 (3.45 g, 25 mmol) in DMSO was heated at 120° C. overnight. After cooling to rt, the solid was removed by filtration and the DMSO solution was purified by flash chromatography to give 6′-bromo-3-[(4-methoxybenzyl)oxy]-4H-1,2′-bipyridin-4-one. 1H NMR (600 MHz, DMSO): δ 8.42 (dd, J=7.7, 2.4 Hz, 1 H); 8.22 (d, J=2.4 Hz, 1 H); 8.03-7.96 (m, 1 H); 7.96-7.89 (m, 1 H); 7.71 (t, J=7.7 Hz, 1 H); 7.40 (d, J=8.4 Hz, 2 H); 6.96 (d, J=8.4 Hz, 2 H); 6.42 (d, J=7.7 Hz, 1 H); 5.03 (s, 2 H); 3.76 (s, 3 H); 264.1; MS (M+H)+ 387.
Reaction SMILES: [BH4-].[Li+].[C:3]([C:5]([C:28]1[CH:33]=[CH:32][C:31]([C:34](OC)=[O:35])=[CH:30][CH:29]=1)([CH:25]([CH3:27])[CH3:26])[CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:11][CH2:10]1)#[N:4].Cl>O1CCCC1>[C:3]([C:5]([C:28]1[CH:29]=[CH:30][C:31]([CH2:34][OH:35])=[CH:32][CH:33]=1)([CH:25]([CH3:27])[CH3:26])[CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:11][CH2:10]1)#[N:4]
Reactant: COC(=O)c1ccc(C(C#N)(CCCN2CCN(CCOc3ccc(F)cc3)CC2)C(C)C)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)C(C#N)(CCCN1CCN(CCOc2ccc(F)cc2)CC1)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.6 %

Procedure:
Lithium borohydride (3 mg) was added to a tetrahydrofuran solution (2 ml) containing the 1-[4-cyano-5-methyl-4-(4-carbomethoxyphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine (64 mg) obtained in Example 12, and the mixture was heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, then 1 N hydrochloric acid (1 ml) was added thereto, and the mixture was stirred at room temperature for 10 minutes. The organic layer was partitioned by adding aqueous saturated sodium bicarbonate and ethyl acetate, washed with water, and dried over sodium sulfate anhydrous. The residue obtained by evaporation was purified by Cromatorex NH silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (57 mg, 95%) as a colorless oil. 4 N hydrogen chloride/ethyl acetate solution was added at room temperature to a solution of this free compound (27 mg) in methanol. The solution was stirred for 10 minutes, and then the solvent was evaporated, whereby the hydrochloride (31 mg) of the title compound was obtained.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:23])[CH2:16][C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][CH:10]=1)C1C=CC=CC=1.[N+:24]([C:27]1[CH:32]=[CH:31][C:30](ON)=[CH:29][CH:28]=1)([O-:26])=[O:25]>Br.C(O)(=O)C>[CH2:18]([C:17]1[O:22][C:30]2[CH:31]=[CH:32][C:27]([N+:24]([O-:26])=[O:25])=[CH:28][C:29]=2[C:16]=1[C:15](=[O:23])[C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCC(=O)CC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: NOc1ccc([N+](=O)[O-])cc1
Agent: Br
Solvent: CC(=O)O
Product: CCCCc1oc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59 %

Procedure:
1-(4-Benzyloxyphenyl)-heptane-1,3-dione (191 mg; see Example 1 (a)), was suspended in 1 ml HBr/acetic acid and O-4-nitrophenylhydroxylamine, 100 mg, was added. The mixture was stirred at room temperature for 6 h. After quenching with water and extraction to EtOAc followed by evaporation of the solvent, a crude material containing approximately 125 mg of the title compound was obtained. Yield ca. 59%.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:35]([NH:37][CH3:38])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:35]([NH:37][CH3:38])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCN(C(=O)NC)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCN(C(=O)NC)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2c1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-methylaminocarbonyl-n-pentylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: COC1C=C(NC2C3C(=C(C)C=C(S(C4C=CC=C(C(=O)NCCCCCCCC=O)C=4)(=O)=O)C=3)N=CC=2C(N)=O)C=CC=1.[OH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][O:52][CH:53]1[CH2:58][CH2:57][N:56]([C:59]([C:61]2[CH:62]=[C:63]([S:67]([C:70]3[CH:71]=[C:72]4[C:77](=[C:78]([CH3:80])[CH:79]=3)[N:76]=[CH:75][C:74]([C:81]([NH2:83])=[O:82])=[C:73]4[NH:84][C:85]3[CH:90]=[CH:89][CH:88]=[C:87]([O:91][CH3:92])[CH:86]=3)(=[O:69])=[O:68])[CH:64]=[CH:65][CH:66]=2)=[O:60])[CH2:55][CH2:54]1>>[CH3:92][O:91][C:87]1[CH:86]=[C:85]([NH:84][C:73]2[C:72]3[C:77](=[C:78]([CH3:80])[CH:79]=[C:70]([S:67]([C:63]4[CH:64]=[CH:65][CH:66]=[C:61]([C:59]([N:56]5[CH2:55][CH2:54][CH:53]([O:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH:46]=[O:45])[CH2:58][CH2:57]5)=[O:60])[CH:62]=4)(=[O:69])=[O:68])[CH:71]=3)[N:76]=[CH:75][C:74]=2[C:81]([NH2:83])=[O:82])[CH:90]=[CH:89][CH:88]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N5CCC(OCCCCCCO)CC5)c4)cc23)c1
Agent: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCC=O)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N5CCC(OCCCCCC=O)CC5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 112, using Intermediate 88 as a substrate. ES/MS calcd. for C36H41N4O7S+ 673.3. Found m/z=673.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)=[O:19])=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+].[Br:37]Br.O>C(O)(=O)C>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:30])([F:31])[F:29])[CH:22]=2)=[O:19])=[C:15]([Br:37])[CH:16]=1
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)c(Br)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
In 30 mL of acetic acid, 1 g (2.23 mmol) of 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea and 0.8 g (9.75 mmol) of sodium acetate were dissolved and to the solution, 0.7 g (4.38 mmol) of bromine was added dropwise and the mixture solution was stirred at 50° C. for one hour. To the reaction solution, 40 mL of water was added, and the deposited product was collected by filtration, and recrystallized from ethanol to obtain 1.095 g (93%) of a target product as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([Cl:18])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc2cc(Br)ccc2c1
Reaction time: 8 h
Yield: 100.1 %

Procedure:
6-bromo-2-naphthoic acid (72.3 g, 282 mmol, 1.0 equiv.) was suspended in dichloromethane (600 mL) and DMF (catalytic, 5 drops) was added. Oxalylchloride (71.6 g, 564 mmol, 2.0 equiv.) was added portion wise during 1 hour. The reaction mixture was stirred overnight with a CaCl2 drying tube mouthed on the flask. Complete dissolution occurred. The reaction mixture was concentrated, dichloromethane (100 mL) was added and the solvent was evaporated again, yielding 6-bromo-2-naphthoyl chloride (76.1 g, 100%) as an oil which was used as such in next step.
Reaction SMILES: [CH:1]1([O:6][C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[CH:16][N:15]([CH2:18][C:19]4[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][C:20]=4[O:29][CH3:30])[C:14]=3[CH:31]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.O.[OH-].[Li+].Cl>O.CO>[CH:1]1([O:6][C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[CH:16][N:15]([CH2:18][C:19]4[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=4[O:29][CH3:30])[C:14]=3[CH:31]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(Cn2cnc3ccc(NC(=O)OC4CCCC4)cc32)c(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1Cn1cnc2ccc(NC(=O)OC3CCCC3)cc21
Reaction time: 4 h
Yield: 78 %

Procedure:
A stirred solution of methyl 4-[6-(cyclopentyloxycarbonyl)aminobenzimidazol-1-ylmethyl]-3-methoxybenzoate in 1:1 v/v tetrahydrofuran:methanol (7 ml.) was treated with water (1.4 ml.) and lithium hydroxide monohydrate (0.3 g.). Stirring was continued at ambient temperature for 4 hours. The solvent was then evaporated. The resultant residue was dissolved in water. The solution obtained was acidified with 10% v/v hydrochloric acid. The resultant precipitate was collected by filtration to give the title compound (0.43 g., 78%). An analytical sample was obtained as a white powder by recrystallization from aqueous ethanol; m.p. 241°-242° C.
Reaction SMILES: [BH4-].[Na+].[CH:3]1([CH2:6][O:7][C:8]2[CH:9]=[C:10]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH:25]=[O:26])[CH:21]=4)[N:16]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=4)[C:15]=3[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:11]=[CH:12][CH:13]=2)[CH2:5][CH2:4]1>CO>[CH:3]1([CH2:6][O:7][C:8]2[CH:9]=[C:10]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][OH:26])[CH:21]=4)[N:16]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=4)[C:15]=3[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:11]=[CH:12][CH:13]=2)[CH2:5][CH2:4]1
Reactant: CCOC(=O)c1c(-c2cccc(OCC3CC3)c2)c2cc(OCC=O)ccc2n1Cc1cccc(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1c(-c2cccc(OCC3CC3)c2)c2cc(OCCO)ccc2n1Cc1cccc(OC)c1
Reaction time: 2 h
Yield: 95.1 %

Procedure:
Sodium borohydride (38 mg, 1.0 mmol) was added to a stirred solution of ethyl 3-[3-(cyclopropylmethoxy)phenyl]-1-(3-methoxybenzyl)-5-(2-oxoethoxy)-1H-indole-2-carboxylate (Example 136, 380 mg, 0.74 mmol) in methanol (10 mL). The reaction was stirred for 2 h and then the reaction was quenched with water (100 mL). The product was extracted with ethyl acetate (3×40 mL) and then the combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to leave 363 mg (95%) of product containing some impurities. The material was used in the next reaction without further purification. The product had: 1H NMR (300 MHz, acetone-D6) δ 7.34-7.46 (m, 3 H), 7.16 (dd, 1 H), 6.93-7.02 (m, 4 H), 6.65-6.81 (m, 3 H), 5.78 (s, 2 H), 3.82-4.23 (m, 9 H), 3.69 (s, 3 H), 1.24-1.34 (m, 1 H), 1.02 (t, 3 H), 0.60-0.70 (m, 2 H), 0.34-0.44 (m, 2 H).
Reaction SMILES: [CH2:1]([N:3]([C:13]1[CH:18]=[C:17]([O:19]C)[CH:16]=[CH:15][C:14]=1[CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:31]C)[CH:27]=2)[CH2:22]1)[C:4](=O)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:2].C(N(C1C=C(OC)C=CC=1C1CCC2C(=CC=C(OC)C=2)C1)CCN1CCCCC1)C>>[CH2:1]([N:3]([CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[C:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=1[CH:21]1[CH2:30][CH2:29][C:28]2[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:23]=2[CH2:22]1)[CH3:2]
Reactant: CCN(C(=O)CN1CCCCC1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: CCN(CCN1CCCCC1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Product: CCN(CCN1CCCCC1)c1cc(O)ccc1C1CCc2cc(O)ccc2C1

Procedure:
Synthesized from N-ethyl-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]-2-piperidin-1-ylacetamide according to an analogous synthetic method to Example 337 described below, the total amount of ethyl [5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl](2-piperidin-1-ylethyl)amine (108 mg) was used according to an analogous synthetic method to Example 111 described below to provide the title compound (84 mg).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[C:14](Br)[CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2)(=[O:4])=[O:3].[N+:17]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18]>>[CH3:1][S:2]([CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:17]([O-:19])=[O:18])[CH:25]=3)[CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2)(=[O:4])=[O:3]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CS(=O)(=O)Cc1cc(Br)c2ncccc2c1
Product: CS(=O)(=O)Cc1cc(-c2cccc([N+](=O)[O-])c2)c2ncccc2c1

Procedure:
6-(methylsulfonylmethyl)-8-bromoquinoline and 3-nitrobenzene boronic acid can be combined to form 6-(methylsulfonylmethyl)-8-(3-nitrophenyl)quinoline.