Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][N:7]=[C:8]3[C:13]=2[C:12]=1[C:11](=[O:14])[C:10]1[CH:15]=[CH:16][CH:17]=[CH:18][C:9]3=1.ClC1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C(Cl)=CC=1.[N-:37]=[N+]=[N-].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][N:7]=[C:8]3[C:9]4[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=4[C:11](=[O:14])[NH:37][C:12]=1[C:13]=23
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1c2ccccc2-c2n[nH]c3ccc(Cl)c1c23
Agent: O=C1c2ccccc2C(=O)c2c(Cl)ccc(Cl)c21
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C1Nc2c(Cl)ccc3[nH]nc(c23)-c2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.9 %

Procedure:
To a solution of 1.02 g of 5-chloro-2,6-dihydrodibenzo[cd,g]indazol-6-one [synthesized from 1,4-dichloroanthraquinone [CAS No. 602-25-5] as a starting material according to the method described in Patent No. WO-0112609] in 5 ml concentrated sulfuric acid was added 0.78 g of sodium azide [CAS No. 26628-22-8], followed by stirring at room temperature for 2 days. The reaction mixture was poured onto 50 ml of ice-water, the precipitated powder was collected by filtration and dried in vacuo. The powder was dissolved in 10 ml of dimethylformamide and 5 ml of ethyl acetate was added. To the suspension was added saturated aqueous sodium hydrogencarbonate solution, and stirred. The crystals were collected by filtration, sequentially washed with hydrous dimethylformamide and water and dried in vacuo, to give 647 mg of the title compound as green crystals.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[OH-].[Na+].Cl>CCO>[CH3:17][N:14]1[CH2:15][CH2:16][CH:11]([CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:18])=[O:2])[CH2:12][CH2:13]1
Reactant: COC(=O)c1ccccc1CC1CCN(C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCC(Cc2ccccc2C(=O)O)CC1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of 2-(1-methyl-piperidin-4-ylmethyl)-benzoic acid methyl ester (97 mg; 0.39 mmol; 1 eq.) and 5M NaOH (2 mL) in EtOH (3 mL) was stirred at 60° C. for 4 hours. After cooling down, the solution was neutralised with 1M HCl and freeze dried to afford the title compound as a white solid which was used without further purification. HPLC (max plot) 99.8% Rt 1.77 min. UPLC/MS: (MS+) 248.2 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([CH3:15])=[N:8]1)([CH3:6])[C:3]([OH:5])=O.[C:16]([NH:19][NH2:20])(=[O:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:16]([NH:19][NH:20][C:3](=[O:5])[C:2]([CH3:1])([N:7]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([CH3:15])=[N:8]1)[CH3:6])(=[O:18])[CH3:17]
Reactant: Cc1nn(C(C)(C)C(=O)O)cc1[N+](=O)[O-]
Reactant: CC(=O)NN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NNC(=O)C(C)(C)n1cc([N+](=O)[O-])c(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
To a mixture of 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanoic acid (500 mg, 2.38 mmol) in DCM (20 ml) was added acetohydrazide (211 mg, 2.86 mmol), HATU (1.8 g, 4.76 mmol), and DIPEA (618 mg, 4.76 mmol). The mixture was stirred at room temperature for 1 h. After concentration, the residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (1/3) to give the title product (600 mg, 95%) as light yellow oil. LC-MS (ESI): m/z=270.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:21]4[CH:20]=[CH:19][C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc5ccccc5c4)cc3CC[C@@H]12
Yield: 54.5 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 2-naphthylboronic acid (168 mg, 0.98 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80° for 16 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatagraphy (ethyl acetate eluent) to give 126 mg (55%) of the title compound as a white solid. mp 221°-223°. FDMS: m/e=355. α[D]589 =+73.58 (C=1.06, chloroform).
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].CS(C)=O.OO.[C:13]([C:15]1[C:16]([NH:21][C:22](=O)[CH2:23][O:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:17][CH:18]=[CH:19][CH:20]=1)#[N:14]>O.CO.C(OCC)(=O)C>[CH2:25]([O:24][CH2:23][C:22]1[NH:14][C:13](=[O:2])[C:15]2[CH:20]=[CH:19][CH:18]=[N:17][C:16]=2[N:21]=1)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cccnc1NC(=O)COCCc1ccccc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1[nH]c(COCCc2ccccc2)nc2ncccc12
Reaction time: 3 h

Procedure:
Potassium carbonate (1.22 g, 8.82 mmol), DMSO (0.44 ml), and hydrogen peroxide (0.9 ml of a 30% solution in H2O) were added to a suspension of N-(3-cyano-pyridin-2-yl)-2-phenethyloxy-acetamide (400 mg, 1.42 mmol) in methanol (6 ml). After 3 h at r.t., the mixture was taken up in ethyl acetate, and washed with salt. NH4Cl. The solution was dried (Na2SO4) and the solvent was evaporated. The residue was triturated with tert-butyl methyl ether to give the title compound. MS: m/e=280.4 [M−H−], 1H NMR (d6-DMSO): 2.91 (t, 2H), 3.78 (t, 2H), 4.45 (s, 2H), 7.17-7.22 (m, 5H), 7.53 (dd, 1H), 8.49 (d, 1H), 8.93 (d, 1H), 12.44 (bs, 1H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:10][CH2:9][CH2:8][CH2:7][NH:6][C:4]1=[O:5].C(N(CC)CC)C.Cl[C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[C:20]1([C:19]([NH:2][C@@H:3]2[CH2:10][CH2:9][CH2:8][CH2:7][NH:6][C:4]2=[O:5])([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N[C@@H]1CCCCNC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1NCCCC[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a stirred suspension of 173 g of (R)-α-amino-ε-caprolactam hydrochloride, 266 g of triethylamine and 1,700 ml of chloroform, 293 g of chlorotriphenylmethane was added portionwise under ice-cooling. The resulting mixture was stirred for an hour under the same conditions, and then for two hours at room temperature. The reaction mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and to the resultant oily residue 600 ml of n-hexane-ethyl acetate (2:1) mixture was added under heating and stirring. The crystalline precipitates obtained were collected by filtration, washed with 1,000 ml of n-hexane-ethyl acetate (10:1) mixture and dried to provide 290 g of (R)-α-triphenylmethylamino-ε-caprolactam, m.p. 189° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:12])=[CH:5][C:6]=1[C:7]([O:9]CC)=O.[C:13]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)#[N:14].Cl>O1CCOCC1>[O:9]=[C:7]1[NH:14][C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:1][C:2]2[S:3][C:4]([CH3:12])=[CH:5][C:6]1=2
Reactant: N#Cc1cccnc1
Reactant: CCOC(=O)c1cc(C)sc1N
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc2c(=O)[nH]c(-c3cccnc3)nc2s1
Yield: 95.1 %

Procedure:
5 g of 2-amino-5-methyl-3-ethoxycarbonylthiophene together with 2.7 g of 3-cyanopyridine are dissolved in 40 ml of dioxane. Then, gaseous HCl is passed through the solution for 5 hours. After customary workup, 6 g of 3,4-dihydro-4-oxo-2-(pyridin-3-yl)-6-methylthieno[2,3-d]pyrimidine are obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:25]=[C:26]2[CH:32]=[CH:31][NH:30][C:27]2=[N:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CN(C=O)C.ClCCl.CO>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:25]=[C:26]2[CH:32]=[CH:31][NH:30][C:27]2=[N:28][CH:29]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Reactant: Oc1cnc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(Oc3cnc4[nH]ccc4c3)ncnc2cc1OCCCN1CCCC1
Temperature: 95 °C
Reaction time: 6 h
Yield: 17.5 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (218 mg, 0.68 mmol), (prepared as described for the starting material in Example 9), 5-hydroxy-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.75 mmol) and potassium carbonate (280 mg, 2.0 mmol) in DMF (4 ml) was stirred at 95° C. for 6 hours and allowed to cool to ambient temperature. The reaction mixture was treated with 1.0 N aqueous sodium hydroxide solution and allowed to stir at ambient temperature for a few minutes. The resulting precipitate was filtered off, washed with water and air dried to give a crude product which was purified by column chromatography, eluting with dichloromethane/methanol/880 ammonia (100/8/1). The relevant fractions were combined and evaporated ‘in vacuo’ to give a white solid. This was recolumned using dichloromethane/methanol (4/1) solvent to give a white solid which was triturated with acetone, filtered and dried to give 6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-4-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)quinazoline (50 mg, 18%).
Reaction SMILES: Cl[C:2]1[C:11](=[O:12])[N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[C:3]=1Cl.[C:15](/[C:17](/[S-:22])=[C:18](\[C:20]#[N:21])/[S-:19])#[N:16].[Na+].[Na+].O>O1CCCC1>[O:12]=[C:11]1[C:2]2[S:19][C:18]([C:20]#[N:21])=[C:17]([C:15]#[N:16])[S:22][C:3]=2[C:4](=[O:13])[N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][N:6]12
Reactant: O=c1c(Cl)c(Cl)c(=O)n2n1CCCC2
Reactant: N#C/C([S-])=C(/[S-])C#N
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC1=C(C#N)Sc2c(c(=O)n3n(c2=O)CCCC3)S1
Temperature: 40 °C
Reaction time: 18 h
Yield: 38.6 %

Procedure:
An amount of 1 g (4.254 mmol) of 2,3-dichloro-6,7,8,9-tetrahydropyridazino[1,2-a]pyridazine-1,4-dione (II-1) is introduced in 20 ml of absolute tetrahydrofuran. Subsequently 0.869 g (4.254 mmol) of disodium (Z)-1,2-dicyanoethene-1,2-bis(thiolate) and 2 ml of water are added and the mixture is stirred at 40° C. for 18 hours. It is filtered with suction and extracted with methylene chloride and water, and the extract is dried and concentrated. Chromatography on silica gel (cyclohexane/ethyl acetate 0-100%) gives 0.5 g (99% purity, 38.3% of theory) of 5,12-dioxo-5,7,8,9,10,12-hexahydro[1,4]dithiino[2,3-d]pyridazino[1,2-a]pyridazine-2,3-dicarbonitrile.
Reaction SMILES: C([O:4][C@@H:5]1[CH2:9][C:8](=[O:10])[C:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[CH:6]1)(=O)C.[OH-].[K+].CO>CO>[OH:4][C@@H:5]1[CH2:9][C:8](=[O:10])[C:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[CH:6]1
Reactant: COc1cccc(CC2=C[C@H](OC(C)=O)CC2=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc(CC2=C[C@H](O)CC2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
(R)-3-(3-Methoxybenzyl)-4-oxocyclopent-2-enyl acetate (0.5 g, 1.48 mmol), was dissolved in MeOH (5 ml), 7% KOH/CH3OH (5 ml) was added to the solution, and the mixture was stirred at room temperature overnight. The mixture was evaporated and the resulting residue was neutralized by HCl to pH=6.5, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and evaporated. The resulting residue was purified by chromatography on a silica gel column using hexane-EtOAc as eluent to give (R)-4-hydroxy-2-(3-methoxybenzyl)cyclopent-2-enone as yellow oil: 0.4 g, (yield: 92%) [α]D20=+3.5˜5.7°
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH:14]=[O:15].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][Cl:22]>CS(C)=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][Cl:22])[CH:9]=[C:8]2[CH:14]=[O:15]
Reactant: COc1ccc2[nH]cc(C=O)c2c1
Reactant: ClCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccc2c(c1)c(C=O)cn2CCCCCCl
Reaction time: 0.5 h

Procedure:
To a stirred mixture of powdered potassium hydroxide in methyl sulfoxide is added dropwise a solution of 5-methoxyindole-3-carboxaldehyde in methyl sulfoxide. The mixture is stirred for 30 min and 1-bromo-5-chloropentane is added dropwise. The mixture is stirred for 1 h and partitioned between ethyl acetate and water. The combined organic extracts are washed (water, brine), dried (sodium sulfate) and concentrated in vacuo to give the product.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH:13]([C:18]2([F:31])[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[C:14]([F:17])([F:16])[F:15])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl>CO>[ClH:1].[Cl:1][C:2]1[C:11]([O:12][CH:13]([C:18]2([F:31])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:14]([F:15])([F:16])[F:17])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(C(Oc2nc3ccccc3nc2Cl)C(F)(F)F)CC1
Agent: Cl
Solvent: CO
Product: FC(F)(F)C(Oc1nc2ccccc2nc1Cl)C1(F)CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 209.4 %

Procedure:
2-Chloro-3-[2,2,2-trifluoro-1-(1-tert-butoxycarbonyl-4-fluoropiperidin-4-yl)ethoxy]quinoxaline (367 mg, 0.797 mmol) was dissolved in methanol (4.0 mL). To this, a 10% solution of hydrogen chloride in methanol (4.0 mL) was added and the mixture was stirred at room temperature for 1 hour. The mixture was further stirred at 50° C. for 1 hour and the solvent was evaporated off under reduced pressure. Thus, 2-chloro-3-[2,2,2-trifluoro-1-(4-fluoropiperidin-4-yl)-ethoxy]quinoxaline hydrochloride (334 mg, yield: 100%) was obtained.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[N:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=4)[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][N:26]=[C:27]=[S:28]>C(O)C>[CH3:25][NH:26][C:27]([NH:24][C:21]1[CH:22]=[N:23][C:18]([O:17][C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[O:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:16][CH2:15]3)=[CH:19][CH:20]=1)=[S:28]
Reactant: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: CN=C=S
Solvent: CCO
Product: CNC(=S)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1

Procedure:
Solution of 6-(2-phenylchroman-6-yloxy)pyridin-3-ylamine (150 mg) and methyl isothiocyanate (94 μl) in ethanol was refluxed for 10 hours. After cooling solvents were evaporated. Crude product of 1-methyl-3-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]thiourea was purified by column chromatography (5% methanol in dichloromethane). 1H NMR (400 MHz, d6-DMSO) δ: 9.45 (bs, 1H), 8.02 (d, 1H, J 2.7 Hz), 7.81 (dd, 1H, J 2.7, 8.8 Hz), 7.70 (bs, 1H), 7.47-7.38 (m, 4H), 7.36-7.32 (m, 1H), 6.94-6.86 (m, 4H), 5.12 (dd, 1H J 2.3, 10.1 Hz), 2.98-2.93 (m, 1H), 2.90 (d, 3H, J 4.3 Hz), 2.76-2.71 (m, 1H), 2.19-2.15 (m, 1H), 2.15-1.99 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:13])[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].O.Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(#N)C>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][O:13][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:11][CH2:12][CH:3]([CH2:2][OH:1])[CH2:4]2)[CH3:27]
Reactant: OCC1CCc2c(O)cccc2C1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)COc1cccc2c1CCC(CO)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 2-hydroxymethyl-5-hydroxy-1,2,3,4-tetrahydronaphthalene (2.72 g,) and potassium carbonate (3.17 g) in acetonitrile, ethyl bromoacetate (2 ml) was added at room temperature. After stirring overnight at room temperature, the reaction mixture was poured into water and extracted with ether. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The residue was purified by silica gel chromatography (hexane:ethyl acetate=6:4) to give the title compound (4.10 g) having the following physical data.
Reaction SMILES: CI.[CH3:3][C:4]([CH3:48])=[CH:5][CH2:6][CH2:7][C@@:8]1([CH3:47])[O:17][C:16]2[C:15]([CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[C:14]3[O:23][C@@:24]45[C@@:34]6([CH2:39]/[CH:40]=[C:41](\[C:43]([OH:45])=[O:44])/[CH3:42])[O:35][C:36]([CH3:38])([CH3:37])[C@@H:25]4[CH2:26][C@H:27]([C:32]6=[O:33])[CH:28]=[C:29]5[C:30](=[O:31])[C:13]3=[C:12]([OH:46])[C:11]=2[CH:10]=[CH:9]1.N12CCCN=C1CCCC[CH2:50]2>CN(C)C=O.[Cl-].[Na+].O>[CH3:3][C:4]([CH3:48])=[CH:5][CH2:6][CH2:7][C@@:8]1([CH3:47])[O:17][C:16]2[C:11](=[C:12]([OH:46])[C:13]3[C:30](=[O:31])[C:29]4[C@@:24]5([C@@:34]6([CH2:39]/[CH:40]=[C:41](\[C:43]([O:45][CH3:50])=[O:44])/[CH3:42])[O:35][C:36]([CH3:37])([CH3:38])[C@@H:25]5[CH2:26][C@H:27]([C:32]6=[O:33])[CH:28]=4)[O:23][C:14]=3[C:15]=2[CH2:18][CH:19]=[C:20]([CH3:21])[CH3:22])[CH:10]=[CH:9]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(C)=CCC[C@]1(C)C=Cc2c(O)c3c(c(CC=C(C)C)c2O1)O[C@]12C(=C[C@@H]4C[C@H]1C(C)(C)O[C@@]2(C/C=C(/C)C(=O)O)C4=O)C3=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)/C(C)=C\C[C@@]12OC(C)(C)[C@@H]3C[C@@H](C=C4C(=O)c5c(O)c6c(c(CC=C(C)C)c5O[C@]431)O[C@](C)(CCC=C(C)C)C=C6)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.5 %

Procedure:
A solution of methyl iodide (29 μL, 0.477 mmol) in 1.0 mL of N,N-dimethylformamide was added to a solution of gambogic acid (0.200 g, 0.318 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (47.6 μL, 0.318 mmol) in 0.2 mL of N,N-dimethylformamide and the mixture was stirred at room temperature for 3 h. The reaction mixture was poured into brine (30 mL) and was extracted with methylene chloride. The organic layer was wash with brine (2×30 mL) and the combined organic extracts were dried over MgSO4 and concentrated in vacuo to give the crude product. It was purified by column chromatography (18×2 cm column, SiO2, EtOAc/Hexane 1:5) to afford the methyl gambogate as an orange solid (0.14 g, 69 %). 1H NMR (CDCl3): 12.85 (s, 1H), 7.54 (d, J=6.9 Hz, 1H), 6.67 (d, J=10.5 Hz, 1H), 5.94 (t, J=6 Hz, 1H), 5.43 (d, J=10.2 Hz, 1H), 5.05 (m, 2H), 3.49 (m, 1H), 3.43 (s, 3H), 3.35-3.10 (s, 2H), 3.00 (t, J=7.2 Hz, 1H), 2.52 (d, J=10.2 Hz, 1H), 2.32 (quar, J=4.8 Hz, 1H), 2.02 (m, 1H), 1.74 (s, 3H), 1.69 (s, 3H), 1.67-1.64 (m, 9H), 1.55 (s, 3H), 1.44 (s, 3H), 1.29 (s, 3H).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[OH-].[Na+].C(N(C(C)C)CC)(C)C.Cl[C:29]1[CH:45]=[CH:44][C:32]([C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[C:38]([I:43])[CH:37]=2)=[O:34])=[CH:31][N:30]=1.Cl.COC1C=CC(N2CCNCC2)=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[I:43][C:38]1[CH:37]=[C:36]([NH:35][C:33](=[O:34])[C:32]2[CH:44]=[CH:45][C:29]([N:14]3[CH2:15][CH2:16][N:11]([C:8]4[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:10][CH:9]=4)[CH2:12][CH2:13]3)=[N:30][CH:31]=2)[CH:41]=[CH:40][C:39]=1[CH3:42]
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1I
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCN(c3ccc(C(=O)Nc4ccc(C)c(I)c4)cn3)CC2)cc1
Temperature: 120 °C

Procedure:
4-methoxyphenyl piperazine dihydrochloride (110 mg, 0.41 mmol) was partitioned between CH2Cl2 and 2N aq. NaOH. The aqueous layer was extracted twice more with CH2Cl2 and the combined organic layer was dried and concentrated. The residue was dissolved in dioxane (6 mL). The solution was then treated with diisopropyl ethylamine (0.07 mL, 0.41 mmol), a catalytic amount of DMAP and 6-chloro-N-(3-iodo-4-methyl-phenyl)-nicotinamide (50 mg, 0.13 mmol). The mixture was heated in a sealed tube at 120° C. for 22 hr. The mixture was then cooled, followed addition of another portion of 4-methoxyphenyl piperazine hydrochloride (110 mg, 0.41 mmol) and diisopropyl ethyl amine (0.14 mL, 0.82 mmol). The mixture was stirred at 120° C. for 3 more days then cooled and partitioned between EtOAc and aq. saturated Na2CO3. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was chromatographed on a silica gel column with 20-40% EtOAc in hexanes to afford the product. HRMS m/z calcd for C24H25N4O2I [M+H]+: 529.1095. Found: 529.1098.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[CH3:13][N:14]1[CH:18]2[CH2:19][C:20]([CH2:22][CH:15]1[CH2:16][CH2:17]2)=O.OP(O)(O)=O>C(O)(=O)C>[CH3:13][N:14]1[CH:15]2[CH2:16][CH2:17][CH:18]1[CH2:19][C:20]([C:7]1[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[NH:9][CH:8]=1)=[CH:22]2
Reactant: CN1C2CCC1CC(=O)C2
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Product: CN1C2C=C(c3c[nH]c4ccc([N+](=O)[O-])cc34)CC1CC2
Temperature: 0 °C
Reaction time: 24 h
Yield: 30.9 %

Procedure:
A solution of 5-nitroindole (38) (0.5 g, 3.083 mmol) in glacial acetic acid (10 mL) was treated with tropinone (0.85 g, 6.617 mmol), followed by 2 M H3PO4 in glacial acetic acid (5 mL) at 100° C. and the resulting solution was stirred at same temperature for 24 h. The reaction was brought to room temperature, poured in to ice-cold 10% NH4OH solution (50 mL) and product was extracted into CH2Cl2 (2 25 mL). The combined CH2Cl2 layer was washed with brine (15 mL) and dried (Na2SO4). The solvent was evaporated and crude material was purified by column chromatography on silica gel (2 M NH3 in methanol: CH2Cl2, 1:9) to obtain compound 89 (0.27 g, 31%) as a solid. mp 234-236° C.; 1H NMR (DMSO-d6) δ 1.51-1.60 (m, 1H), 1.79-1.86 (m, 1H), 1.95-2.14 (m, 4H), 2.32 (s, 3H), 2.76-2.83 (m, 1H), 3.43 (t, 1H, J=5.4 Hz), 6.31 (d, 1H, J=5.1 Hz), 7.54 (d, 1H, J=8.7 Hz), 7.61 (s, 1H), 8.01 (dd, 1H, J=2.1, 9.0 Hz), 8.68 (d, 1H, J=2.4 Hz), 11.86 (s, 1H); ESI-MS m/z (%): 284 (MH+, 100). N-(3-(8-Methyl-8-azabicyclo[3.2.1]oct-3-en-3-yl)-1H-indol-5-yl)thiophene-2-carboximidamide (90): A solution of compound 89 (0.25 g, 0.882 mmol) in dry ethanol (10 mL) was treated with Pd—C (0.025 g) and purged with hydrogen gas. The reaction was stirred under hydrogen atm. (balloon pressure) for overnight (14 h). The solid was filtered off using celite bed and washed with ethanol (2 5 mL). The combine d ethanol layer was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.5 g, 1.764 mmol) at room temperature and stirred for 24 h. Ethanol was evaporated and crude material was basified with sat. NaHCO3 solution (20 mL) and product was extracted into CH2Cl2 (2 25 mL). The combined CH2Cl2 layer was washed with brine (15 mL) and dried (Na2SO4). The solvent was evaporated and crude was purified by column chromatography on silica gel (2 M NH3 in methanol: CH2Cl2, 1:9) to obtain compound 90 (0.14 g, 44%) as a solid. mp 93-95° C.; 1H NMR (DMSO-d6) δ 1.60-1.65 (m, 1H), 1.84-1.90 (m, 1H), 2.02-2.26 (m, 4H), 2.41 (s, 3H), 2.83-2.89 (m, 1H), 3.46-3.55 (m, 1H), 6.20 (brs, 2H), 6.67 (d, 1H, J=7.8 Hz), 7.10 (s, 1H), 7.23-7.31 (m, 3H), 7.60-7.72 (m, 2H), 10.99 (s, 1H); ESI-MS m/z (%): 363 (MH+, 65), 182 (100), 119 (48); ESI-HRMS calculated for C21H23N4S (MH+), Calculated: 363.1633; Observed: 363.1637.