Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16](O)=[O:17].CO>C1COCC1>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[CH2:16][OH:17]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.9 %

Procedure:
LiAlH4 (1.0 m in THF, 5.0 mL, 5.0 mmol) was slowly added to a solution of indole-2-carboxylic acid (403 mg, 2.5 mmol) in dry THF (18 mL) at 0° C. The resultant yellow solution was warmed to room temperature and stirred for 18 hours. MeOH (0.5 mL) was added and the solution concentrated under reduced pressure (3×). The resultant orange syrup was partially dissolved in CHCl3 (150 mL) and washed consecutively with H2O (10 mL) and NH4Cl (10 mL). The aqueous layer was extracted with CHCl3 (2×25 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. Purification by column chromatography on silica gel (100% CH2Cl2) afforded the desired alcohol (250 mg, 68%) as a yellow solid. 1H NMR (CDCl3) δ 4.84 (s, 2H), 6.42 (d, 1H, J=0.9 Hz), 7.11-7.20 (m, 2H), 7.36 (d, 1H, J=7.5 Hz), 7.59 (d, 1H, J=7.5 Hz), 8.31 (br s, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[S:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:13](I)[C:12]=2[C:22]#[N:23])[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].[Cl-].[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][Zn+])=[CH:28][CH:27]=1>O1CCCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[S:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:13]([CH2:30][C:29]3[CH:32]=[CH:33][C:26]([Cl:25])=[CH:27][CH:28]=3)[C:12]=2[C:22]#[N:23])[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1sc(-c2ccnc(NC(C)=O)c2)c(C#N)c1I
Reactant: Clc1ccc(C[Zn+])cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(-c2ccnc(NC(C)=O)c2)c(C#N)c1Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
To a solution of ethyl 5-[2-(acetylamino)pyridin-4-yl]-4-cyano-3-iodothiophene-2-carboxylate (0.209 g, 0.474 mmol) in tetrahydrofuran (3.3 mL) was added 4-chlorobenzylzinc chloride (0.50M solution in tetrahydrofuran, 1.89 mL, 0.947 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.0182 g, 0.0355 mmol) under argon. The solution was stirred at 60° C. for 3 hours. The reaction was allowed to cool to room temperature and then the solvent was evaporated in vacuo. Column chromatography was performed to yield the title compound (0.159 g, 76%). LCMS: (FA) ES+, 440. 1H NMR (400 MHz, CDCl3) δ: 8.66 (br s, 1H), 8.60 (br s, 1H), 8.38 (d, J=5.27 Hz, 1H), 7.51-7.47 (m, 1H), 7.33-7.23 (m, 4H), 4.51 (s, 2H), 4.39 (q, J=7.03 Hz, 2H), 2.24 (s, 3H), 1.39 (t, J=7.03 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[C:8]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:9]=3[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:35]([C:37]1[N:38]=[CH:39][N:40](C(OC(C)(C)C)=O)[CH:41]=1)=[CH2:36]>CN(C=O)C>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:8]2[C:7]([O:6][C:5]3[CH:26]=[CH:27][C:2](/[CH:36]=[CH:35]/[C:37]4[N:38]=[CH:39][NH:40][CH:41]=4)=[CH:3][CH:4]=3)=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[S:10][C:9]=2[CH:20]=1
Reactant: C=Cc1cn(C(=O)OC(C)(C)C)cn1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(Br)cc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/c3c[nH]cn3)cc2)cc1
Temperature: 150 °C
Yield: 79.6 %

Procedure:
To a microwave vial, 3-(4-bromophenoxy)-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (50 mg, 0.113 mmol) was dissolved in DMF (2 mL) and triethyl amine (0.474 mL, 3.40 mmol). To the solution was added tert-butyl 4-vinyl-1H-imidazole-1-carboxylate (66.0 mg, 0.340 mmol) and Pd(PPh3)2C12 (7.95 mg, 0.011 mmol). The system was flushed with nitrogen and heated at 150° C. for 1 h under microwave radiation. The mixture was cooled to room temperature and diluted with DCM and sat. NH4Cl. The organic layer was collected (phase separator) and concentrated onto silica gel and the material was purified by column chromatography (SiO2, 0-30% DCM/MeOH) to afford (E)-4-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-1H-imidazole (41 mg, 0.090 mmol, 80% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.78 (d, J=1.52 Hz, 1H), 7.51-7.62 (m, 2H), 7.46-7.51 (m, 1H), 7.39 (d, J=9.09 Hz, 2H), 7.32 (d, J=2.53 Hz, 1H), 7.15 (d, J=9.09 Hz, 1H), 7.08 (d, J=16.67 Hz, 1H), 6.76-6.95 (m, 6H), 3.77 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15](=[O:26])[CH:16]([NH2:25])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH3:13][O:14][C:15](=[O:26])[CH:16]([NH:25][C:10](=[O:11])[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1
Reactant: COC(=O)C(N)Cc1ccc(O)cc1
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(=O)C(Cc1ccc(O)cc1)NC(=O)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 3(4-hydroxy phenyl) propionic acid (10 grams, 60.17 mmol) and Example 1 (11.7 grams, 60.00 mmol) in anhydrous dichloro methane (100 mL) under a nitrogen atmosphere at 0° C. is added dropwise to a solution of 1,3-dicyclohexyl carbodiimide(31 grams, 150.24 mmol) in dichloro methane (75 mL). The mixture is stirred at room temperature for 6 hours. The resulting solids are filtered off. The organic phase is washed with 5% sodium bicarbonate (2×25 mL) and water (2×25 mL), dried over sodium sulphate, and distilled to give crude 23, which can be purified in appropriate solvent.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:23](O)[CH2:24][OH:25].N>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1([O:25][CH2:24][CH2:23][O:11]1)[CH2:6][CH2:5]2
Reactant: OCCO
Reactant: O=C1CCc2cc(Br)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: c1ccccc1
Product: Brc1ccc2c(c1)CCC21OCCO1

Procedure:
A mixture of 5-bromo-1-indanone (13.0 g, 61.8 mmol), p-toluenesulfonic acid (23 mg, 0.12 mmol) and ethylene glycol (27.6 mL, 494.6 mmol) in benzene (140 mL) was refluxed for about 24 hours, using a Dean-Stark trap to remove water. The mixture was cooled, poured into excess 5% aqueous sodium bicarbonate and was extracted with toluene. The combined organic extracts were washed with brine, dried with MgSO4, filtered, and evaporated in vacuum. The residue was purified by flash column chromatography using dichloromethane as the mobile phase to give the above intermediate. MS (DCI/NH3): m/z 254, 256 (M)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1)[N:30]=[C:29]2[C:41]([OH:43])=O.C(N(C(C)C)CC)(C)C.[NH2:53][C:54]1[CH:55]=[CH:56][C:57]([C:60]([F:63])([F:62])[F:61])=[N:58][CH:59]=1>CN(C=O)C>[Br:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1)[N:30]=[C:29]2[C:41]([NH:53][C:54]1[CH:59]=[N:58][C:57]([C:60]([F:63])([F:61])[F:62])=[CH:56][CH:55]=1)=[O:43]
Reactant: O=C(O)c1nn(C2CCCCO2)c2ccc(Br)cc12
Reactant: Nc1ccc(C(F)(F)F)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C(F)(F)F)nc1)c1nn(C2CCCCO2)c2ccc(Br)cc12
Temperature: 25 °C
Yield: 92.9 %

Procedure:
HATU (1.125 g, 2.96 mmol) was added to a solution of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (CXVIII) (0.876 g, 2.69 mmol) and diisopropylethylamine (1.03 mL, 5.92 mmol) in DMF stirred at room temperature under argon. After stirring 5 min, the solution was added with 5-amino-2-trifluoromethylpyridine (CXXVII) (0.479 g, 2.96 mmol). The solution was stirred 24 h at room temperature under argon. The DMF was removed under reduced pressure, and the residue was treated with water, sonicated briefly and filtered. The solids were washed with cold water and dried at room temperature. The product was purified by silica gel column chromatography (100% hexanes→7:93 EtOAc:hexanes) to afford 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1H-indazole-3-carboxamide (CXXVIII) as a white solid (1.17 g, 2.50 mmol, 93% yield). 1H NMR (DMSO-d6) δ ppm 10.93 (s, 1H), 9.23 (d, J=1.9 Hz, 1H), 8.60 (dd, J=6.8, 1.4 Hz, 1H), 8.38 (d, J=4.4 Hz, 1H), 7.95 (m, 2H), 7.70 (dd, J=7.1, 1.5 Hz, 1H),), 6.04 (dd, J=8.1, 1.9 Hz, 1H), 3.98 (m, 1H), 3.82 (m, 1H), 2.59-2.54 (m, 1H), 2.08-2.03 (m, 2H), 1.81-1.77 (m, 1H). 1.66-1.61 (m, 2H); ESIMS found for C19H16BrF3N4O2 m/z 470.0 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[NH:5][CH:4]=1)[CH3:2].S(Cl)([Cl:19])(=O)=O>ClCCl>[Cl:19][C:4]1[NH:5][C:6]2[C:11]([C:3]=1[CH2:1][CH3:2])=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=2
Reactant: O=S(=O)(Cl)Cl
Reactant: CCc1c[nH]c2cc(C(=O)OC)ccc12
Solvent: ClCCl
Product: CCc1c(Cl)[nH]c2cc(C(=O)OC)ccc12
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 3-ethylindole-6-carboxylate (138 mg) in dichloromethane (5 ml) was added sulfuryl chloride (0.066 ml), and the mixture was stirred at 20° C. for 1 hour. The resulting mixture was poured into ice and extracted with ethyl acetate. The combined organic phase was washed with aqueous sodium bicarbonate and brine, then dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate (4:1) to give methyl 2-chloro-3-ethylindole-6-carboxylate (58.2 mg) as a solid.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C([O-])(=O)C.[Na+].Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:23][CH2:22]1.O>CS(C)=O>[O:7]=[C:6]1[C:5]2[C:4](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3](=[O:12])[N:2]1[O:1][CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:25][CH2:26]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: COc1ccccc1N1CCN(CCCl)CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1N1CCN(CCON2C(=O)c3ccccc3C2=O)CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 50.6 %

Procedure:
A mixture of 6.73 g of N-hydroxyphthalimide, 3.73 g of sodium acetate and 10 g of 1-(2-chloroethyl)-4-(2-methoxyphenyl)piperazine in 100 ml of anhydrous dimethylsulfoxide was stirred at 100° C. for 4 hours. The reaction mixture was then cooled to room temperature, poured into water and extracted with ethyl acetate. The collected organic layers were washed with 1N sodium hydroxide, dried on anhydrous sodium sulfate and evaporated to dryness in vacuo to give 7.58 g of the title compound. A sample was crystallized from cyclohexane, m.p. (76) 80°-83° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)CCC>[C:19]1([N:25]2[C:8](=[O:10])[C:7]3=[CH:6][NH:5][CH:4]=[C:3]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:2]3=[N:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)c1cncc(-c2ccccc2)c1Cl
Solvent: CCCCO
Product: O=c1c2c[nH]cc(-c3ccccc3)c-2nn1-c1ccccc1
Yield: 9.4 %

Procedure:
A mixture of ethyl 4-chloro-3-phenyl-5-pyridinecarboxylate (0.300 g, 1.15 mmol) and phenylhydrazine (0.125 ml, 1.27 mmol) in 1-butanol (25 ml) was stirred at reflux under nitrogen for 24 h. More phenylhydrazine (0.125 ml, 1.27 mmol) was added and the mixture was stirred at reflux for a further 3 days. The solvent was removed in vacuo and dichloromethane, followed by hydrogen chloride in diethyl ether, was added. The solution was filtered, and the filtrate was washed with aqueous NaHCO3 and evaporated in vacuo to give 31 mg (9%) of the title compound as a yellow solid; mp 280-285° C.; 1H NMR (250 MHz, DMSO-d6) δ7.18 (1H, t, J 7.4 Hz), 7.41-7.56 (5H, m), 7.91 (1H, s), 8.17 (2H, d, J 7.1 Hz), 8.22 (2H, d, J 7.5 Hz), 8.58 (1H, s), 12.60 (1H, br s); MS (ES+) m/z 288 [MH]+. Anal. found: C, 70.03; H, 5.00; N, 13.41. C18H12N3O.1.3H2O requires: C, 69.80; H, 4.75; N, 13.56%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:21])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14](F)=[C:13]([N+:18]([O-])=O)[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CCOC(C)=O>[Cl:1][C:2]1[C:3]([CH3:21])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)=[C:13]([NH2:18])[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: Cc1c(Cl)cnc2[nH]c(-c3ccc(F)c([N+](=O)[O-])c3)nc12
Solvent: CCOC(C)=O
Product: Cc1c(Cl)cnc2[nH]c(-c3ccc(N4CCN(C)CC4)c(N)c3)nc12
Reaction time: 0.25 h

Procedure:
Crude 6-chloro-2-(4-fluoro-3-nitrophenyl)-7-methyl-3H-imidazo[4,5-b]pyridine (Example 252) (333 mg) and 1-methylpiperazine (1.0 ml) were mixed and left at room temperature for 15 min, whereupon it was diluted with EtOAc (50 ml) and washed with water (100 ml). The aqueous phase was extracted with EtOAc (50 ml) and the combined organic phase was evaporated in vacuo. The yellow oily residue was dissolved in methanol (100 ml) and hydrogenated in a Parr apparatus (Raney nickel, 60 psi, 5 h). The catalyst was removed by filtration and the solvent removed in vacuo. The residue was purified by semi-preparative HPLC-C18 affording the product as a trifluoroacetate. The salt was dissolved in EtOAc (10 ml) and washed with aqueous 10% NaHCO3 solution (5 ml), brine (5 ml) and dried (MgSO4). Evaporation of the solvent yielded the product as an off-white powder (67 mg, 25%).
Reaction SMILES: [CH3:1][C:2]([C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][N:19]=2)=[C:8]([C:10]2[C:11]([F:17])=[C:12]([CH:14]=[CH:15][CH:16]=2)[NH2:13])[N:9]=1)([CH3:4])[CH3:3].[F:24][C:25]1[CH:26]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>>[CH3:4][C:2]([C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][N:19]=2)=[C:8]([C:10]2[C:11]([F:17])=[C:12]([NH:13][S:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[CH:26]=3)(=[O:33])=[O:32])[CH:14]=[CH:15][CH:16]=2)[N:9]=1)([CH3:1])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccncn2)s1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2F)c(-c2ccncn2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluoroaniline (70 mg, 0.213 mmol) and 3-fluorobenzenesulfonyl chloride (124 mg, 0.639 mmol), the title compound was obtained as a solid (76 mg, 73% yield). MS (ESI): 488 [M+H]+.
Reaction SMILES: C([O:3][C:4]([CH2:6][S:7][CH2:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=1)=[O:5])C.[ClH:26]>CO.[OH-].[Na+].CC(C)=O>[ClH:26].[C:4]([CH2:6][S:7][CH2:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)CSCCCc1cn(-c2cccnc2)c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CO
Product: O=C(O)CSCCCc1cn(-c2cccnc2)c2ccccc12

Procedure:
A solution of 90 mg of 3-[3-(ethoxycarbonylmethylthio)propyl]-N-(3-pyridyl)indole in 5 ml of methanol and 1 ml of 1N sodium hydroxide is refluxed for 10 hours, cooled and evaporated. The resulting oil is partitioned between ether and water. The aqueous phase is brought to pH=6 with concentrated sulfuric acid, is extracted with chloroform and the chloroform extract is dried over sodium sulfate. Filtration and evaporation gives an oil which is redissolved in 2 ml of acetone and is treated with 0.07 ml of 3N ethereal hydrogen chloride. Evaporation and crystallization from acetone-ether yields 3-[3-(carboxymethylthio)propyl]-N-(3-pyridyl)indole hydrochloride, m.p. 106°-110°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21]C)[CH:17]=2)[CH:12]=1.B(Br)(Br)Br>>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([OH:21])[CH:15]=[CH:14]2
Reactant: COc1cc(F)c(-c2ccc3cc(OC)ccc3c2)c(F)c1
Agent: BrB(Br)Br
Product: Oc1cc(F)c(-c2ccc3cc(O)ccc3c2)c(F)c1

Procedure:
The title compound was prepared by reacting 2-(2,6-difluoro-4-methoxyphenyl)-6-methoxynaphthalene (1.5 g, 5.0 mmol) with boron tribromide (25 mL of 1.0 M solution in CH2Cl2, 25 mmol) according to method D to yield 1.35 g (99%) of a yellowish solid: mp>240° C.; 1H NMR (DMSO-d6): δ 6.55-6.63 (2H, m), 7.11 (1H, dd, J=8.76 Hz, J=2.34 Hz), 7.15 (1 h, d, J=2.05 Hz), 7.36 (1H, dd, J=8.58 Hz, J=1.34 Hz), 7.39 (1H, d, J=8.83 Hz), 7.79 (1H, s), 7.80 (1H, d, J=8.74 Hz), 9.85 (1H, s), 10.48 (1H, s); MS (ESI) m/z271 (M−H)−; MS (ESI) m/z543 (2M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[CH3:19][C@H:20]1[NH:25][C@@H:24]([CH3:26])[CH2:23][N:22]([C:27]([C:29]2[C:30]([CH3:37])=[C:31]([CH:35]=O)[NH:32][C:33]=2[CH3:34])=[O:28])[CH2:21]1>C(O)C.N1CCCCC1>[CH3:19][C@H:20]1[NH:25][C@@H:24]([CH3:26])[CH2:23][N:22]([C:27]([C:29]2[C:30]([CH3:37])=[C:31]([CH:35]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[NH:13][C:12]3=[O:18])[NH:32][C:33]=2[CH3:34])=[O:28])[CH2:21]1
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1C[C@@H](C)N[C@@H](C)C1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]c(C)c(C(=O)N4C[C@@H](C)N[C@@H](C)C4)c2C)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.6 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (68.5 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 3-[4-[(cis)-3,5-Dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (88 mg, 73%).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13]([C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=3)[C:10]([CH3:21])([CH3:20])[CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:22]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)=O.[OH-].[Na+].Cl>CCO.C1COCC1>[O:19]=[C:17]([C:13]1[CH:14]=[CH:15][C:16]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH2:9][C:10]([CH3:21])([CH3:20])[C:11]=2[CH:12]=1)[CH:18]=[CH:22][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CC=C2c1ccccc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC=C(c2ccccc2)c2ccc(C(=O)C=Cc3ccc(C(=O)O)cc3)cc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 115.0 mg (0.42 mmol) of 3,4-dihydro-1-phenyl-4,4-dimethyl-6-acetylnaphthalene (Compound 100H) and 65.0 mg (0.43 mmol) of 4-formyl-benzoic acid in 5.0 ml EtOH and 1.0 ml THF, was added 120.0 mg (3.00 mmol; 3.0 ml of a 1M aqueous solution) of NaOH. The resulting yellow solution was stirred at room temperature for 12 hours. The solution was acidified with 6% aqueous HCl and extracted with EtOAc. The combined organic layers were dried (MgSO4), concentrated under reduced pressure, and the title compounds was isolated by column chromatography (50% EtOAc--hexanes) as a pale yellow solid. 1H NMR (CDCl3): δ 8.13 (2H, d, J=7.7 Hz), 8.04 (1H, s), 7.81 (1H, d, J=15.5 Hz), 7.75 (3H, m), 7.60 (1H, d, J=15.5 Hz), 7.35 (5H, m), 7.14 (1H, d, J=8.1 Hz), 6.15 (1H, t, J=4.2 Hz), 2.41 (2H, d, J=4.2 Hz), 1.41 (6H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.O.NN>C(O)C.[Ni]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([NH2:9])[CH:3]=1
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1ccc(Br)cc1N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.4 %

Procedure:
To a stirred solution of 4-bromo-2-nitrotoluene (2.04 g, 9.44 mmol) (Aldrich Chemical Company) in ethanol (25 mL) was added hydrazine hydrate (1.14 mL, 23.60 mmol) drop-wise. After being stirred for 5 min, a suspension of Raney nickel (˜100 mg) in ethanol (5 mL) was added slowly and carefully. Gas evolution was observed. After gas evolution subsided, the reaction mixture was heated to reflux for 1 h. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated on a rotary evaporator, diluted with water (25 mL) and extracted with chloroform (3×100 mL). The combined chloroform extracts were dried over sodium sulfate, filtered and concentrated to produce 1.57 g (89.4%) of a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH:8]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[CH2:9][O:10][C:6]=2[C:5]([CH3:18])=[C:4]([CH3:19])[C:3]=1[NH2:20].C([O:24][CH2:25][CH3:26])(=O)C>>[CH3:1][C:2]([CH3:7])([CH3:3])[CH2:26][C:25]([NH:20][C:3]1[C:4]([CH3:19])=[C:5]([CH3:18])[C:6]2[O:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[C:7]=2[C:2]=1[CH3:1])=[O:24]
Reactant: CCOC(C)=O
Reactant: Cc1ccc(C2COc3c(C)c(C)c(N)c(C)c32)cc1
Product: Cc1ccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)cc1
Yield: 80 %

Procedure:
Using 4,6,7-trimethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 307, the title compound was synthesized in the same manner as in Example 1. Yield: 80%. Melting point: 176-177° C. (ethyl acetate).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[I:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:22]([CH3:23])=[CH:21][C:20](=[O:24])[C:19]([C:25]([OH:27])=[O:26])=[N:18]2)=[CH:13][CH:12]=1>CCCCCC>[I:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:22]([CH3:23])=[CH:21][C:20](=[O:24])[C:19]([C:25]([O:27][CH2:1][CH2:2][CH2:3][CH3:4])=[O:26])=[N:18]2)=[CH:13][CH:12]=1
Reactant: Cc1cc(=O)c(C(=O)O)nn1-c1ccc(I)cc1
Reactant: CCCCO
Solvent: O=S(Cl)Cl
Solvent: CCCCCC
Product: CCCCOC(=O)c1nn(-c2ccc(I)cc2)c(C)cc1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 52 %

Procedure:
To 50 ml of n-butanol, cooled to -5° C., there is added dropwise 2.62 g (0.022 mol) of thionyl chloride. The solution is stirred at 0° C. for 15 minutes and to it there is added 7.12 g (0.02 mol) of 1-(4-iodophenyl)-1,4-dihydro-4-oxo-6-methylpyridazine-3-carboxylic acid. (See Example 3). The suspension formed is stirred at room temperature for 3 days and to it there is added 150 ml of hexane. The suspension is stirred at room temperature for 2 days and is vacuum filtered. The filter cake (HCl salt of the desired product) is air dried and slurried in 150 ml of water for 3 hrs. The suspension is vacuum filtered to afford 4.25 g (52% yield) of product, mp 134°-137° C.