Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C@@H:7]2[C@@H:2]1[C:3]([CH3:18])([CH3:17])[O:4][C:5]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([O:15][CH3:16])=[CH:8][C:6]=12.Cl([O-])(=O)(=O)=O.[Li+].[Cl-].[NH4+:26]>O1CCOCC1>[CH3:16][O:15][C:9]1[C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:5]2[O:4][C:3]([CH3:18])([CH3:17])[C@H:2]([OH:1])[C@@H:7]([NH:26][CH2:2][CH2:7][C:6]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:5]=3)[C:6]=2[CH:8]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])OC(C)(C)[C@@H]1O[C@@H]21
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc2c(cc1[N+](=O)[O-])OC(C)(C)[C@H](O)[C@H]2NCCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of (3R*,4S*)-3,4-epoxy-6-methoxy-2,2-dimethyl-7-nitro-3,4-dihydro-2H-1-benzopyran (2.50 g, 9.95 mmol) in 1,4-dioxane(5.0 mL), lithium perchlorate (1.06 g, 9.95 mmol) and 4-(phenylethyl)amine (1.50 mL, 11.9 mmol) were added at room temperature and the mixture was stirred at 80° C. for 1 hour. Upon the completion of the reaction, an aqeuous solution of saturated ammonium chloride was added to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by column chromatography (hexane/ethyl acetate=6/4) and the aimed product was obtained as yellow amorphous substance (quantitative yield).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[H-].[CH2:6]([Al+]CC(C)C)C(C)C.[Nd].C(Br)C=C.[CH2:20](O)[CH2:21][CH2:22][CH3:23].[H-].C([Al+]CC(C)C)C(C)C>[Nd].CCCCCC>[CH2:1]=[CH:2][C:3](=[CH2:6])[CH3:4].[CH2:20]=[CH:21][CH:22]=[CH2:23]
Reactant: CCCCO
Reactant: CC(C)C[Al+]CC(C)C
Agent: C=CC=C
Agent: [H-]
Agent: [Nd]
Solvent: CCCCCC
Solvent: C=CCBr
Product: C=CC(=C)C
Temperature: 20 °C
Yield: 87 %

Procedure:
In this experiment, an isoprene-butadiene copolymer rubber was prepared using an alcohol modified neodymium catalyst system. In this procedure, a one gallon (3.78 liter) reactor was charged with 1,214 grams of hexane containing 81.3 grams of butadiene and 558.43 grams of 1.23 molar diisobutylaluminum hydride (DIBAH) in hexane, (i.e., 25% weight percent DIBAH). The reactor was maintained at 20° C. by cooling. N-butanol (11.16 grams) was added with stirring. After stirring for thirty minutes, 107.5 grams of 10.1% neodymium solution (neodymium neodecanoate) diluted with 160 grams of dry hexane, was charged to the reactor. The-solution was stirred for another thirty minutes after which time 18.2 grams of allyl bromide was added. The cooling was stopped and the solution was allowed to warm up. A delayed exothermic reaction was noted. After twenty minutes, bring the solution temperatures to about 10° C. above ambient temperature. When the temperature ultimately dropped, the catalyst solution was aged by heating at 65° C. for ninety minutes. The catalyst prepared had a butanol-DIBAH!Nd-allyl bromide-butadiene molar ratio of 2-13!-1-2-20, respectively, and a concentration of 0.025 molarity with respect to the neodymium.
Reaction SMILES: CS(C)=O.F[C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=O.C(N(CC)CC)C.[C:21]([O:25][CH3:26])(=[O:24])[CH2:22][SH:23]>ClCCl.CCCCCC>[S:23]1[C:22]([C:21]([O:25][CH3:26])=[O:24])=[CH:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]1=2
Reactant: COC(=O)CS
Reactant: O=Cc1ccccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84.7 %

Procedure:
A 100 ml 3-necked round-bottomed flask, reflux condenser, thermometer adapter, gas inlet, and Teflon stirrer were oven-dried for 12 hours at 160° C. The apparatus was rapidly assembled, fitted with a thermometer, flushed with dry nitrogen gas, sealed with rubber septa and allowed to cool to room temperature. The cooled reaction flask was charged with anhydrous dimethyl sulfoxide (40 ml), 2-fluorobenzaldehyde (4.44 g, 31.53 mmole), anhydrous triethylamine (2.5 equivalents, 78.83 mmole, 7.976 g, 11 ml) and methyl thioglycolate (1.1 equivalents, 3.681 g, 3.10 ml, 34.68 mmole) and heated to 75° C. with rapid stirring. The progress of the reaction was monitored by TLC (silica, 10% dichloromethane-hexane, UV visualization). After 18 hours the reaction mixture was cooled to room temperature and poured onto an ice/water bath (250 ml). The resulting slurry was stirred for 20 minutes, filtered, washed with cold water (2×100 ml) and dried in vacuo to give 5.136 g (85%) of methyl benzo[b]thiophene-2-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.[Cl:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C>[Cl:12][CH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2
Reactant: Cc1ccc2nccnc2c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Product: ClCc1ccc2nccnc2c1
Reaction time: 6 h

Procedure:
In a 500 ml flask, 6-methyl-quinoxaline (10 g, 69.4 mmol) was dissolved together with N-chlorosuccinimide (14 g, 105.3 mmol) and benzoyl peroxide (BP, 0.4 g, 1.65 mmol) in 240 g of acetonitrile. The flask was connected to a reflux-condenser and the solution was refluxed for 6 hours followed by another addition of 0.1 g of benzoyl peroxide. Reflux was then continued for another 6 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:10]([OH:20])=[C:9]([OH:21])[C:8]=2[C:7]1=[O:22].[CH3:27][O-].C[O-].[Mg+2].IC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:21])[C:10](=[O:20])[N:11]([CH3:27])[C:12]=2[C:16]([O:18][CH3:19])=[O:17])[C:7]1=[O:22]
Reactant: C[O-]
Reactant: COC(=O)c1nc(O)c(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: [Mg+2]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1c2c(c(O)c(=O)n1C)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 6-(3-chloro-4-fluorobenzyl)-3,4-dihydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate (18.00 g, 47 mmol) in DMF (200 mL) was added magnesium methylate (96.08 mL, 95 mmol), and the reaction was warmed for 1 hour and cooled. The reaction was treated with iodomethane (17.66 mL, 283 mmol) and stirred at 45° C. overnight. At this time, LCMS showed the reaction incomplete, and an additional equivalent of iodomethane (2.95 mL, 48 mmol) was added. The reaction was again stirred for 4 hours. The solvent was removed in vacuo, and the resulting oil was partitioned between chloroform and 1N HCl. The aqueous layer was washed twice more with chloroform. The organic fractions were extracted with 10% sodium bisulfite, and the bisulfite layer was washed twice with chloroform. The combined organic layers were washed with 5% aqueous HCl and brine, dried over sodium sulfate and concentrated in vacuo to afford the product as a black oil. This material appears quite clean by NMR and HPLC, but is highly colored.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:22][CH:21]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:24][CH:25]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCc1ccc(OCc2nc(-c3ccccc3)c(-c3ccccc3)o2)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCc1ccc(OCc2nc(-c3ccccc3)c(-c3ccccc3)o2)cc1

Procedure:
Methyl 3-[4-[(4,5-diphenyl-2-oxazolyl)methoxy]phenyl]propanoate was hydrolyzed with aqueous sodium hydroxide according to the procedure of Example 18 to provide the title compound, m.p. 124°-127° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[NH2:21])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:21][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[NH:14][CH2:13][CH:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)=[O:29])=[CH:26][CH:25]=1
Reactant: Nc1cnccc1NCC1CCN(c2ccncc2)CC1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)Nc2cnccc2NCC2CCN(c3ccncc3)CC2)cc1
Yield: 6.2 %

Procedure:
Using a similar procedure to that described in Example 2, Part D, N4-[1-(4-pyridyl)piperidin-4-ylmethyl]-3,4-pyridinediamine (110 mg, 0.388 mmol) and 4-methoxybenzoyl chloride (0.66 mL, 0.388 mmol) yielded 10 mg (6%) of the title compound as a hydrochloride salt.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][OH:12].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[N:7]=1
Reactant: OCCO
Reactant: O=Cc1cccc(Br)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Brc1cccc(C2OCCO2)n1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
A mixture of 6-bromo-pyridine-2-carbaldehyde (2.0 g, 10.75 mmol), ethylene glycol (3 mL, 53.75 mmol), and a catalytic amount of TsOH in toluene (50 mL) was heated to reflux with a Dean-Stark trap for 1.5 hours and cooled down to room temperature and concentrated in vacuo. The residue was purified on silica gel column with 2% EtOAc in CH2Cl2 to yield 2-bromo-6-[1,3]dioxolan-2-yl-pyridine as a colorless liquid (1.97 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][CH2:22][CH2:23][C:24]2[CH:25]=[C:26]([CH2:30][C:31]([O:33]CC3C=CC(OC)=CC=3)=[O:32])[CH:27]=[CH:28][CH:29]=2)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:43])[N:10]1[CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH:45]1[OH:50].FC(F)(F)C(O)=O>C(Cl)CCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][CH2:22][CH2:23][C:24]2[CH:25]=[C:26]([CH2:30][C:31]([OH:33])=[O:32])[CH:27]=[CH:28][CH:29]=2)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:43])[N:10]1[CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH:45]1[OH:50]
Reactant: COc1ccc(COC(=O)Cc2cccc(CCNC(=O)C3c4ccccc4C(=O)N(C4CCCCC4O)C3c3ccc(Cl)cc3Cl)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: O=C(O)Cc1cccc(CCNC(=O)C2c3ccccc3C(=O)N(C3CCCCC3O)C2c2ccc(Cl)cc2Cl)c1
Reaction time: 4 h
Yield: 41.2 %

Procedure:
To a mixture of 990 mg of 4-methoxybenzyl (3-{2-[({(3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl}carbonyl)amino]ethyl}phenyl)acetate and 10 ml of ethylene chloride was added 10 ml of trifluoroacetic acid at room temperature, followed by stirring for 4 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in 20 mL of methanol, and 20 mL of a saturated aqueous sodium hydrogen carbonate solution was added thereto at room temperature, followed by stirring for 30 minutes. The organic solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate and neutralized with 1 M hydrochloric acid. The product was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 339 mg of (3-{2-[({(3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl}carbonyl)amino]ethyl}phenyl)acetic acid as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][C:12](=[O:14])[CH2:11][CH2:10][N:9]2[C:15]([N:17]2[CH2:23][C:22]3[CH:24]=[C:25]([C:28]4[CH:29]=[C:30]5[NH:36][C:35]([NH:37]C(=O)OCC6C=CC=CC=6)=[N:34][C:31]5=[N:32][CH:33]=4)[CH:26]=[CH:27][C:21]=3[O:20][CH2:19][CH2:18]2)=[O:16])[CH:5]=[CH:6][CH:7]=1>C(O)(=O)C.[Pd]>[NH2:37][C:35]1[NH:36][C:30]2[C:31]([N:34]=1)=[N:32][CH:33]=[C:28]([C:25]1[CH:26]=[CH:27][C:21]3[O:20][CH2:19][CH2:18][N:17]([C:15]([N:9]4[CH2:10][CH2:11][C:12](=[O:14])[CH2:13][CH:8]4[C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[O:16])[CH2:23][C:22]=3[CH:24]=1)[CH:29]=2
Reactant: O=C1CCN(C(=O)N2CCOc3ccc(-c4cnc5nc(NC(=O)OCc6ccccc6)[nH]c5c4)cc3C2)C(c2cccc(F)c2)C1
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1nc2ncc(-c3ccc4c(c3)CN(C(=O)N3CCC(=O)CC3c3cccc(F)c3)CCO4)cc2[nH]1
Yield: 38.3 %

Procedure:
A solution of phenylmethyl [6-(4-{[2-(3-fluorophenyl)-4-oxopiperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridin-2-yl]carbamate (0.15 g, 0.24 mmol) in acetic acid (5 mL) was hydrogenated at 1 atm over 10% palladium on carbon (0.15 g) for 18 h. The catalyst was removed by filtration and the filtrate was concentrated. The resulting brown residue was dissolved in methanol and purified by preparative reverse phase HPLC to afford 1-{[7-(2-amino-1H-imidazo[4,5-b]pyridin-6-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}-2-(3-fluorophenyl)piperidin-4-one (46 mg, 39% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): 11.44 (bs, 1H), 8.17 (s, 1H), 6.97-7.60 (m, 7H), 6.75 (s, 1H), 5.18 (t, 1H), 4.51-4.66 (m, 2H), 4.13-4.30 (m, 2H), 3.56-3.78 (m, 3H), 3.21-3.31 (m, 1H), 2.79-2.99 (m, 2H), 2.51-2.61 (m, 1H), 2.32 (d, 1H); MS (EI) for C27H25FN6O3: 501 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[C:6]=1[CH2:21]Br)=[O:4].[CH3:23][O:24][C:25](=[O:38])[CH2:26][NH:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[C:6]=1[CH2:21][N:27]([CH2:26][C:25]([O:24][CH3:23])=[O:38])[S:28]([C:31]1[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=1)(=[O:30])=[O:29])=[O:4]
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)c1cc(Br)c(=O)n([C@@H](C)c2ccccc2)c1CBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN(Cc1c(C(=O)OC)cc(Br)c(=O)n1[C@@H](C)c1ccccc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.7 %

Procedure:
A mixture of (S)-5-bromo-2-bromomethyl-6-oxo-1-(1-phenyl-ethyl)-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (2.67 g, 6.22 mmol), (toluene-4-sulfonylamino)-acetic acid methyl ester (1.44 g, 5.91 mmol), sodium iodide (1.87 g, 12.4 mmol) and potassium carbonate (1.72 g, 12.4 mmol) in DMF (60 mL) was stirred at r.t. for 16 h. Brine (100 mL) was added, and the resulting suspension was extracted with EtOAc. The organic layer was washed with water and brine, and dried over MgSO4. After the solvent was evaporated in vacuo, the crude product was chromatographed (0-50% EtOAc/hexanes) to give 2.26 g of the title compound as a viscous oil. MS: (+) m/z 613, 615 (M+Na, 79/81Br).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]([O:10][CH3:11])=[CH:8][C:6]([NH2:7])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.[CH3:15][C:16](=O)[CH:17]=[CH:18][CH3:19]>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:11][O:10][C:9]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]2[C:8]=1[C:16]([CH3:15])=[CH:17][C:18]([CH3:19])=[N:7]2
Reactant: CC=CC(C)=O
Reactant: COc1cc(N)c([N+](=O)[O-])cc1OC
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COc1cc([N+](=O)[O-])c2nc(C)cc(C)c2c1OC
Yield: 14 %

Procedure:
4,5-Dimethoxy-2-nitroaniline and 3-penten-2-one were subjected to a Skraup reaction. A black, tarry substance was obtained, from which an orange solid could be isolated by chromatography over silica gel using benzene-ethyl acetate (19:1) to elute the product. That material was thrice crystallized from 2-propanol, re-chromatographed, and again crystallized to afford 14% yield of golden 5,6-dimethoxy-2,4-dimethyl-8-nitroquinoline. Although it melted 85°-108°, it showed a single spot on two tlc systems.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[C:22]4[C:17](=[CH:18][C:19]([CH:23]=O)=[CH:20][CH:21]=4)[NH:16][N:15]=3)=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31](=[O:36])[CH2:30]2.N1CCCCC1>CO>[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31](=[O:36])/[C:30]/2=[CH:23]/[C:19]1[CH:18]=[C:17]2[C:22]([C:14]([C:11]3[CH:12]=[N:13][C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[N:9][CH:10]=3)=[N:15][NH:16]2)=[CH:21][CH:20]=1
Reactant: CN1CCN(c2ncc(-c3n[nH]c4cc(C=O)ccc34)cn2)CC1
Reactant: COc1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1)/C(=C\c1ccc3c(-c4cnc(N5CCN(C)CC5)nc4)n[nH]c3c1)C(=O)N2
Temperature: 60 °C
Yield: 2.6 %

Procedure:
A round bottom flask was charged with 3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-indazole-6-carbaldehyde (26 mg, 0.80 mmol), 5-methoxyoxindole (13 mg, 0.80 mmol), piperidine (0.8 uL, 0.008 mmol) and MeOH (2 mL). The reaction was then heated to 60° C. for 4 hrs. An orange precipitate formed which was further precipitated by cooling to room temperature. The orange solid was then filtered and washed with MeOH (5 mL) giving 9.8 mg, 26% of the title compound. 1H NMR (400 MHz, d6-DMSO) δ 13.46 (s, 1H), 10.44 (s, 1H), 8.97 (s, 2H), 8.18 (d, J=8.5 Hz, 1H), 7.94 (s, 1H), 7.78 (s, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.20 (s, 1H), 6.85 (d, J=10.6 Hz, 1H), 6.80 (d, J=9.0 Hz, 1H), 3.82 (br t, 4H), 3.59 (s, 3H), 2.39 (br t, 4H), 2.23 (s, 3H); MS ESI 468.3 [M+H]+, calcd for [C26H25N7O2+H]+ 468.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:18]O>>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:18])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1O
Reactant: CO
Product: COc1ccc(C(=O)Cc2ccccc2)c(O)c1
Yield: 87.9 %

Procedure:
Using the previous procedure and starting from 1-(2,4-dihydroxyphenyl)-2-phenylethanone (7.08 g, 31.0 mmol) and methanol (1.32 mL, 32.55 mmol), 6.60 g (88%) of the title compound was obtained as a white solid: mp 87-88° C. (lit. 92° C.); IR (KBr) 1635, 1620, 1589, 1437, 1350, 1291, 1230, 1206, 1127, 1021, 958, 802, 739, 729, 551 cm−1; 1H NMR (400 MHz, CDCl3) δ 12.71 (br s, 1H), 7.74 (d, J=8.7 Hz, 1H), 7.31-7.34 (m, 2H), 7.23-7.26 (m, 3H), 6.40-6.44 (m, 2H), 4.20 (s, 2H), 3.81 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 202.38, 166.61. 166.30, 134.82, 132.47, 129.76, 129.16, 127.50, 113.58, 108,27, 101.44, 56.00, 45.27.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH2:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([BH3-])#N.[Na+].C=O.C(O)(=O)C>CO>[CH3:23][N:18]1[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]1[CH2:16][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [BH3-]C#N
Reactant: c1ccc(-c2[nH]c3ccccc3c2C[C@H]2CCCCN2)cc1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCCC[C@@H]1Cc1c(-c2ccccc2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.4 %

Procedure:
To a solution of 1.1 g (3.8 mmol) of 2-phenyl-3-(piperidin-2(R)-ylmethyl)-1H-indole and 238 mg (3.8 mmol) of sodium cyanoborohydride in methanol (20 ml) at 0° C. was added a solution of formaldehyde (527 mg of a 37% w/w aqueous solution) and glacial acetic acid (0.5 ml, 8.7 mmol) in methanol (10 ml). After stirring at room temperature for 3 hr the reaction was evaporated in vacuo. The residue was partitioned between saturated potassium carbonate (20 ml) and EtOAc (20 ml), the organic layer separated, and the aqueous layer extracted with EtOAc (2×20 ml). The combined EtOAc layers were washed with water (50 ml), saturated sodium chloride (50 ml), dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography (SiO2; 5% MeOH in CH2Cl2+0.5% NH3) and the product recrystallised from Et2O/hexanes to afford 210 mg (0.7 mmol; 18%) of 3-(1-methylpiperidin-2(R)-ylmethyl)-2-phenyl-1H-indole as a white solid. (Found: C, 81.50; H, 7.98; N, 9.14; C21H24N2.0.25H2O requires C, 81.64; H, 7.99; N, 9.07%); mp 150° C. (from Et2O/hexane); [α]D23+80.0 (c 1.0 in CHCl3); δH (360 MHz; CDCl3) 0.96-1.14 (2H, m, aliphatics), 1.44-1.58 (4H, m, aliphatics), 2.06-2.16 (1H, m, aliphatic), 2.21-2.32 (1H, m, aliphatic), 2.46 (3H, s, CH3), 2.76-2.89 (2H, m, aliphatics), 3.47 (1H, dd, J 13.8 and 3.8, indole CHAHB), 7.14 (1H, m, indole H5), 7.20 (1H, m, indole H6), 7.33-7.38 (2H, m, aromatics), 7.43-7.47 (2H, m, aromatics), 7.57 (2H, d, J 7.1, aromatics), 7.65 (1H, d, J 7.8, aromatic), 8.05 (1H, br s, NH); m/z (ES+) 305 (M++H, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Br:11])[CH:5]=1.Br[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[H-].[Na+].O>CN(C=O)C>[C:18]([O:17][C:15](=[O:16])[CH2:14][O:10][C:8]1[CH:7]=[C:6]([Br:11])[CH:5]=[C:4]([C:3]([O:2][CH3:1])=[O:12])[CH:9]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)c1cc(O)cc(Br)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Br)cc(OCC(=O)OC(C)(C)C)c1

Procedure:
To a stirred solution of 3-bromo-5-hydroxybenzoic acid methyl ester (10.2 g) and tert-butyl bromoacetate (9.7 ml) in anhydrous DMF was added sodium hydride (60% dispersion in mineral oil, 2.69). After 30 min water (10 ml) aws added. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was removed and the organic phase washed with further water, 1M sodium hydroxide solution and dried with brine and over sodium sulphate. Concentration under reduced pressure gave the title compound as dark yellow gum (12.8 g).
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[N:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]=[O:21].C(N(CC)CC)C.O1CCCC1>O>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:20]([NH:19][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:21])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: CCOC(=O)CN=C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CNC(=O)N1CCN(c2ccccc2C(C)(C)C)CC1
Temperature: 25 °C
Yield: 90 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (400 mg), ethyl isocyanatoacetate (258 mg), triethylamine (0.418 mL), and tetrahydrofuran (20 mL) was stirred at room temperature for over-night. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (430 mg, 90%) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=O)=[CH:4][C:3]=1[CH2:12][O:13]C.O[N:16]=[C:17]([C:19]1[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)[NH2:18]>>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:18]=[C:12]([C:3]3[CH:2]=[CH:11][C:10]([C:2]4[CH:11]=[CH:10][CH:5]=[CH:4][C:3]=4[CH3:12])=[C:5]([CH2:6][O:8][CH3:9])[CH:4]=3)[O:13][N:16]=2)=[CH:20][N:21]=1
Reactant: COc1ccc(C(N)=NO)cn1
Reactant: COCc1cc(C(=O)OC)ccc1Br
Product: COCc1cc(-c2nc(-c3ccc(OC)nc3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described in Method B starting from Intermediate A1 and N′-hydroxy-6-methoxypyridine-3-carboximidamide (UkrOrgSynthesis BBV-066226). After purification by precipitation from MeOH, the title compound was obtained as a white powder. HPLC (Method A), Rt: 5.8 min (purity: 99.8%). UPLC/MS, M+(ESI): 388.3. 1H NMR (DMSO-d6, 300 MHz) δ 8.91 (d, J=2.2 Hz, 1H), 8.34 (dd, J=8.7, 2.2 Hz, 1H), 8.31 (d, J=1.4 Hz, 1H), 8.16 (dd, J=7.9, 1.4 Hz, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.36-7.26 (m, 3H), 7.14 (d, J=7.1 Hz, 1H), 7.06 (d, J=8.7 Hz, 1H), 4.22 (d, J=12.8 Hz, 1H), 4.16 (d, J=12.8 Hz, 1H), 3.96 (s, 3H), 3.24 (s, 3H), 2.03 (s, 3H).