Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([NH:20][CH:21]2[C:32](=[O:33])[N:23]3[CH:24]([C:29](=O)[NH2:30])[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.C(Cl)(Cl)=O>C(Cl)(Cl)Cl>[C:1]1([C:7]([NH:20][CH:21]2[C:32](=[O:33])[N:23]3[CH:24]([C:29]#[N:30])[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1C(N)=O
Agent: O=C(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1C#N
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 67.3 %

Procedure:
A mixture of 6-triphenylmethylamino-2,2-dimethyl-3-carbamylpenam (11.01g., 0.024 mole), dry pyridine (4.9g., 0.062 mole) and dry chloroform (250 ml.)is stirred for five minutes and the resulting solution cooled to 0° C. in a wet ice/acetone bath. Phosgene (8.8 ml. of 3.41 molar solution in chloroform) is added by means of a syringe. The reaction mixture is stirred at 5° C. for ten minutes after which the cooling bath is removed and the reaction mixture allowed to warm to room temperature. It is stirred for 30 minutes and then washed successively with water (300 ml.), 1N hydrochloric acid (300 ml.), and water (300 ml.). The chloroform solution is dried (MgSO4), treated with activated charcoal, and filtered through diatomaceous earth. The filtrate is concentrated to reduced pressure and the residue taken up in methylene chloride (450 ml.).The methylene chloride solution is washed successively with 1N hydrochloricacid (150 ml.) and water (300 ml.) and then dried using anhydrous sodium sulfate. The dried solution is then filtered and concentrated under reduced pressure to give the product as a golden foam (7.1 g., 67.3%).
Reaction SMILES: O.[OH-].[Li+].C([O:7][CH2:8][CH2:9][CH:10]([N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][C:20]([Br:25])=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:14]=[C:13]1[CH2:26][O:27]C(=O)C)[CH3:11])(=O)C>CO>[Br:25][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:12]([CH:10]([CH3:11])[CH2:9][CH2:8][OH:7])[C:13]([CH2:26][OH:27])=[N:14][C:15]=3[CH:16]=[N:17][C:18]=2[CH:19]=1
Reactant: CC(=O)OCCC(C)n1c(COC(C)=O)nc2cnc3cc(Br)ccc3c21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(CCO)n1c(CO)nc2cnc3cc(Br)ccc3c21
Temperature: 25 °C
Reaction time: 48 h
Yield: 29 %

Procedure:
Lithium hydroxide hydrate (5.3 g, 126 mmol) was added to a solution of 3-{2-[(acetyloxy)methyl]-7-bromo-1H-imidazo[4,5-c]quinolin-1-yl}butyl acetate (9.14 g, 21.0 mmol) in methanol (150 mL). The resulting mixture was stirred for two days at room temperature and filtered. The methanol was removed from the filtrate under reduced pressure. The crude product mixture was partitioned between dichloromethane and 10% aqueous sodium carbonate. The aqueous fraction was extracted with dichloromethane, and the combined organic fractions were concentrated under reduced pressure. The resulting solid was triturated with acetonitrile, isolated by filtration, and washed with cold acetonitrile to provide 2.13 g of 3-[7-bromo-2-(hydroxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butan-1-ol. A portion of this material was mixed with material from a separate run.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([CH2:16]O)[C:13]([F:18])=[CH:12][C:10]=3[N:11]=2)=[C:5]([CH3:19])[NH:4][N:3]=1.[Br-].[CH3:21][NH:22][CH3:23]>>[CH3:21][N:22]([CH2:16][C:14]1[C:13]([F:18])=[CH:12][C:10]2[N:11]=[C:7]([C:6]3[C:2]([NH2:1])=[N:3][NH:4][C:5]=3[CH3:19])[S:8][C:9]=2[CH:15]=1)[CH3:23]
Reactant: Cc1[nH]nc(N)c1-c1nc2cc(F)c(CO)cc2s1
Reactant: CNC
Agent: [Br-]
Product: Cc1[nH]nc(N)c1-c1nc2cc(F)c(CN(C)C)cc2s1

Procedure:
The title compound (28 mg) was prepared in two steps starting from 30 mg (0.1 mmol) of [2-(3-amino-5-methyl-1H-pyrazol-4-yl)-5-fluorobenzothiazol-6-yl]methanol. The reaction of the bromide was carried out with excess dimethylamine. MS (m/z, ES+): 306.1 (M+1, 43%), 261.1 (60%), 153.5 (100%).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12]>C(O)(C)(C)C>[CH3:15][O:14][C:10](=[O:13])[CH2:11][CH2:12][C:7]([C:8]#[N:9])([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:12][CH2:11][C:10]([O:14][CH3:15])=[O:13]
Reactant: C=CC(=O)OC
Reactant: N#CCc1ccccc1
Solvent: CC(C)(C)O
Product: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccccc1
Temperature: 25 °C

Procedure:
Phenylacetonitrile (11.7 g, 0.1 mole) and methyl acrylate (47 ml, 0.5 mole) were added to tert-butanol (60 ml) and heated to boiling point. The source of heat was then removed. Triton B (benzyltrimethylammonium hydroxide, 40% in methanol, 15.2 ml) dissolved in tert-butanol (23 ml) was added dropwise, first of all slowly and then at a faster rate. After the dropwise addition the reaction mixture was boiled under reflux for 4 hours. The reaction mixture was cooled to room temperature overnight. The reaction mixture was worked up by adding toluene (100 ml) and water (70 ml). The organic phase was separated and washed with water (1×70 ml) and saturated sodium chloride solution (1×50 ml). After drying over Na2SO4, the solvent was distilled off in a fume cupboard on account of the strong smell. Purification was carried out by bulb tube distillation at a pressure of 7.8×10−2 mbar and at a temperature of 235° C. The desired 4-cyano-4-phenylheptanedioic acid dimethyl ester was obtained in a yield of 21.45 g (72%) as a colourless viscous substance.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH2:8][CH2:7]1)[CH2:3]O.C(N(CC)CC)C.C1(C)C=CC(S([Cl:41])(=O)=O)=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:41][CH2:3][C:2]([CH3:1])([CH3:24])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH2:8][CH2:7]1
Reactant: CC(C)(CO)CN1CCN(c2ccccc2OCC(F)(F)F)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CCl)CN1CCN(c2ccccc2OCC(F)(F)F)CC1
Reaction time: 8 h
Yield: 19705.9 %

Procedure:
A mixture of 2,2-dimethyl-3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}-1-propanol (991 mg, 2.9 mol), triethylamine (0.4 mL, 2.9 mmol), p-toluenesulfonyl chloride (678 mg, 3.4 mmol), 4-dimethylaminopyridine (35 mg, 0.29 mmol) and methylene chloride (15 mL) was stirred 8 hours at 20° to 25° C. The reaction mixture then was filtered and concentrated and the residue was purified by chromatography on silica gel eluting with hexanes/ethyl acetate (95:5) to give 1-chloro-2,2-dimethyl-3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propane (238 mg, 0.67 mol).
Reaction SMILES: [C:1]1([CH3:9])[C:2]([CH:7]=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.C([O-])(=O)C.[NH4+].[N+:15]([CH3:18])([O-:17])=[O:16]>C(O)(=O)C.O>[CH3:9][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:18][N+:15]([O-:17])=[O:16]
Reactant: C[N+](=O)[O-]
Reactant: Cc1ccccc1C=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccccc1C=C[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
Ortho-tolualdehyde (10.00 g, 83.23 mmol) was dissolved in acetic acid (50 ml), ammonium acetate (6.93 g, 89.89 mmol) and nitromethane (7 ml, 129 mmol) were added, and the mixture was stirred at 110° C. for 8 hr and stood at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound (12.71 g, yield 94%) as a bistered oil.
Reaction SMILES: [CH:1]1([N:5]2[C:9](=[O:10])[C:8]([NH:11]C(=O)OC(C)(C)C)=[C:7]([CH3:19])[N:6]2[CH3:20])[CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O>C(Cl)Cl.O>[NH2:11][C:8]1[C:9](=[O:10])[N:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)[N:6]([CH3:20])[C:7]=1[CH3:19]
Reactant: Cc1c(NC(=O)OC(C)(C)C)c(=O)n(C2CCC2)n1C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: Cc1c(N)c(=O)n(C2CCC2)n1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (2-cyclobutyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)carbamate in DCM (5 mL) was added sulfuric acid (0.034 mL, 0.634 mmol). The reaction mixture was stirred at room temperature overnight. Further sulfuric acid (0.068 mL, 1.268 mmol) was added to the reaction mixture and it was stirred for 2 hours. The resulting mixture was diluted with DCM and water and the layers separated. The aqueous layer was made basic by the dropwise addition of 2M NaOH (aq). The aqueous layer was extracted with DCM (×3) and the combined organic extracts were passed through a phase separating cartridge. The eluent was concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(N(CC)CC)C.Br[CH2:18][C:19]1[S:20][C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[C:23]=1[Cl:24]>C(O)C>[Cl:24][C:23]1[C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[S:20][C:19]=1[CH2:18][S:8][C:6]1[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Clc1c(CBr)sc2ccccc12
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2sc3ccccc3c2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (148 mg, 1.0 mmol) was dissolved in absolute ethanol (8 mL), then triethylamine (180 μL, 1.3 mmol) and 2-(bromomethyl)-3-chloro-1-benzothiophene (300 mg, 1.2 mmol) were added. The mixture was stirred overnight at room temperature. The precipitate was filtered, washed with ethanol and water and then diethyl ether, and dried in vacuo to afford to 2-{[(3-chloro-1-benzothiophen-2-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (195 mg, 58% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.27 (s, 3H), 4.72 (s, 2H), 5.69 (s, 1H), 6.07 (bs, 1H), 7.43-7.53 (m, 2H), 7.73-7.76 (m, 1H), 7.97-8.00 (m, 114), 12.29 (bs, 1H); LRMS (ES+) m/z 323 (100%, M+1), 325 (35%, M+3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[C:11]([O:15][C:16](=[O:38])[CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][C:25]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:35][CH2:36][CH3:37])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:11]([O:15][C:16](=[O:38])[CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][C:25]([N:27]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:5](=[O:6])[C:4]3[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:35][CH2:36][CH3:37])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3cccc(F)c3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Fluoro-benzoyl chloride (42 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C30H32FN3O3+H: 502, observed: 502.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4](F)[CH:3]=1.[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(OCC)(=O)C.Cl>O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:18][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: NC1CCCCC1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(Br)cc1NC1CCCCC1

Procedure:
A mixture of 4-bromo-2-fluorobenzoic acid (1.0 g) and cyclohexylamine (10 ml) was stirred under reflux for 5 hours. The mixture was poured into ethyl acetate (50 ml) and water (50 ml), acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to give 4-bromo-2-(cyclohexylamino)benzoic acid (1.32 g).
Reaction SMILES: [C:1]([CH2:3][CH2:4][C@H:5]([CH2:9][C:10]([OH:12])=[O:11])[C:6]([OH:8])=[O:7])#[N:2].[CH3:13][N:14]1[C@H:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17][O:16][C:15]1=[O:26].CO>O=[Pt]=O.C(Cl)(Cl)Cl>[CH3:13][N:14]1[C@H:18]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:17][O:16][C:15]1=[O:26].[NH2:2][CH2:1][CH2:3][CH2:4][C@H:5]([CH2:9][C:10]([O-:12])=[O:11])[C:6]([O-:8])=[O:7]
Reactant: N#CCC[C@H](CC(=O)O)C(=O)O
Agent: O=[Pt]=O
Agent: CN1C(=O)OC[C@H]1Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: NCCC[C@H](CC(=O)[O-])C(=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 71 (2.0 g, 5.8 mmol), PtO2 (0.8 g), CH3OH (50 mL), and CHCl3 (5 mL) were shaken on the Parr apparatus under a hydrogen atmosphere (60 PSI) at ambient temperature for 3 hours. The reaction mixture was filtered through a celite pad and then concentrated to furnish the crude amine.HCl 72 as a yellow oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([O:13][P:14]([O:18]CC)[O:15][CH2:16][CH3:17])[CH3:12]>CCO.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:11]([O:13][P:14]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])(=[O:18])[O:15][CH2:16][CH3:17])[CH3:12]
Reactant: CCOP(OCC)OCC
Reactant: O=[N+]([O-])c1ccccc1I
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCO
Product: CCOP(=O)(OCC)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
3.9 g of Cu(II) acetate are added to a solution of 5 g 1-iodo-2-nitrobenzene and 5 g of triethylphosphite in 20 ml of EtOH, the mixture obtained is refluxed for 24 hours, cooled to rt and partitioned between EtOAc and half-saturated aqueous NaCl-solution. The organic layer obtained is dried, solvent is evaporeated and the evaporation residue is subjected to column chromatography (silicagel, toluene:acetonitrile=3:1). (2-Nitro-phenyl)-phosphonic acid diethyl ester is obtained in the form of an orange oil. MS: MNa+ 282
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:9][C:10]([CH3:12])=O.C(O)(=O)C>>[NH:1]([C:10]([CH3:12])=[CH:9][C:8]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C=C(C)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound is commercially available. A mixture of aniline (9.785 mL, 107.4 mmol), ethyl acetoacetate (13.69 mL, 107.4 mmol), and acetic acid (0.6 mL, 10 mmol) was stirred at ambient temperature overnight. It was partitioned between heptane (50 mL) and sat. aq. NaHCO3 solution (50 mL). The organic layer was dried and evaporated to give the title compound of >90% purity that was used in the next steps without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.Br[CH2:15][CH2:16][CH:17]=[CH2:18]>>[CH2:18]([CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13])[CH2:17][CH:16]=[CH2:15]
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: C=CCCBr
Product: C=CCCC1CCc2cc(OC)ccc2C1=O

Procedure:
The title compound 75 is prepared according to the procedure reported in step A of Example 17 with 6-methoxy-1-tetralone (0.88 g, 5.0 mmol) and 4-bromo-but-1-ene (5.0 mmol, 1 equiv) as reactants.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Nc1ccc(C(=O)O)cc1
Product: Nc1ccc(C(=O)Cl)cc1
Yield: 100 %

Procedure:
Thionyl chloride (10 ml) was added to 4-aminobenzoic acid (1.0 g, 7.29 mmol) and the solution was heated to reflux for 16 hr. Thionyl chloride was removed under vacuum to yield 4-amino-benzoyl chloride (1.13 g, 100%).
Reaction SMILES: CN1[C@@H]([C@H:12]2[O:21][C:19](=[O:20])[C:18]3[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=[CH:14][C:13]2=3)C2C(OC)=C3OCOC3=CC=2CC1.N1C=CC=CC=1.ICl.N>C(#N)C>[CH3:25][O:24][C:16]1[C:17]([O:22][CH3:23])=[C:18]2[C:13]([CH2:12][O:21][C:19]2=[O:20])=[CH:14][CH:15]=1
Reactant: COc1ccc2c(c1OC)C(=O)O[C@@H]2[C@H]1c2c(cc3c(c2OC)OCO3)CCN1C
Agent: ClI
Agent: N
Solvent: CC#N
Solvent: c1ccncc1
Product: COc1ccc2c(c1OC)C(=O)OC2
Reaction time: 6 h
Yield: 76 %

Procedure:
Iodination of noscapine was now carried out by addition of pyridine-iodine chloride (1.46 g, 6 mmol) to a solution of noscapine (1 g, 2.42 mmol) in acetonitrile (20 ml) and the resultant mixture was stirred at room temperature for 6 hours and then at 100° C. for 6 hours. After cooling, excess ammonia was added and filtered through celite pad to remove the black nitrogen triiodide. The filtrate was made acidic with 1 M HCl and filtered to collect the yellow solid, washed with water and air-dried to afford (S)-3-(R)-9-iodo-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-6,7-dimethoxyisobenzofuran-1 (3H)-one (5). Yield: 76%, mp 172.3-172.6° C.; 1H NMR (CDCl3, 400 MHz): δ 7.15 (d, 1H, J=8.1 Hz), 7.01 (d, 1H, J=8.1 Hz), 6.11 (s, 2H), 5.36 (d, 1H, J=4.8 Hz), 4.25 (d, 1H, J=4.8 Hz), 3.85 (s, 3H), 3.74 (s, 3H), 3.72 (s, 3H), 2.78-2.72 (m, 2H), 2.55-2.50 (m, 2H), 2.32 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 168.2, 155.1, 151.5, 148.3, 146.5, 143.1, 140.3, 120.4, 119.5, 113.3, 101.5, 85.9, 82.2, 61.8, 56.6, 55.7, 54.5, 54.1, 51.2, 39.8, 30.1, 18.8; HRMS (ESI): m/z Calcd. for C22H23INO7 (M+1), 540.3209. Found, 540.3227 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1COCC1>[CH2:18]([N:6]1[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([Br:15])[CH:11]=2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Brc1ccc2c(c1)c1cc(Br)ccc1n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Under a nitrogen atmosphere, 3,6-dibromocarbazole (9.75 g, 30 mmol) was slowly added to a suspension of sodium hydride (45 mmol) in dried THF (100 mL), and then stirred for 30 minutes at room temperature. Benzylbromide (6.72 g, 40 mmol) was dropped into the reaction mixture to be stirred for 20 hours. After addition of water (about 100 mL), a precipitated solid was filtrated, and the filtrate (residuum of the filtration) was washed with an aqueous sodium hydrogencarbonate solution, and then was dissolved in ethanol. The solution was dried by magnesium sulfate, filtrated and concentrated. The residuum was recrystallized with ethanol to give N-benzyl-3,6-dibromocarbazole as a white solid. The yield was 61%.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)=O.[NH2:16][C:17]1[NH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>C(O)(=O)C>[C:11]([C:10]1[CH:13]=[CH:14][C:7]([C:5]2[CH:4]=[CH:3][N:21]3[C:17](=[N:18][C:19]4[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=43)[N:16]=2)=[CH:8][CH:9]=1)#[N:12]
Reactant: CN(C)/C=C/C(=O)c1ccc(C#N)cc1
Reactant: Nc1nc2ccccc2[nH]1
Solvent: CC(=O)O
Product: N#Cc1ccc(-c2ccn3c(n2)nc2ccccc23)cc1

Procedure:
To a solution of (E)-4-(3-(dimethylamino)acryloyl)benzonitrile (2.0 g, 10.0 mmol) and 2-aminobenzimidazole (1.33 g, 10 mmol) in acetic acid (15 mL) was heated at 120° C. for 16 hours. The mixture was concentrated to a residue and treated with sodium bicarbonate solution to neutralize the residual acetic acid. The resulting suspension was added EtOAc, sonicated, and filtered. The solid collected was washed with water, ether, and dried under high vacuum to give 630 mg (23%) of T709 as yellow solid. A small amount was purified by HPLC (acetonitrile/H2O) for NMR and bioassay. 1H NMR (CD3OD): δ 9.83 (1H, d, J=8.4 Hz), 8.59 (2H, m), 8.46 (1H, d, J=8.4 Hz), 8.36 (1H, d, J=6.8 Hz), 8.01 (2H, m), 7.93 (1H, m), 7.87 (1H, m), 7.74 (1H, m); MS: 271 (M+H+).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:30](=[O:31])[O:29]1>C(Cl)(Cl)Cl>[C:1]([C:9]1[CH:10]=[C:11]([CH:15]([CH3:19])[C:16]([O:18][CH:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:30](=[O:31])[O:29]2)=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC(Br)c2ccccc21
Reactant: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C(=O)OC1OC(=O)c2ccccc21)c1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 25 h
Yield: 79 %

Procedure:
To a solution of 7.6 g of 2-(3-benzoylphenyl)propionic acid in 30 ml of chloroform and 3.4 g of triethylamine is added a solution of 6.2 g of 3-bromophthalide in 20 ml of chloroform. The solution thus obtained is stirred 25 hours at room temperature, the organic phase is washed with an aqueous solution of sodium bicarbonate, then with water and finally dried on anhydrous sodium sulfate and evaporated to dryness to give the phthalidyl 2-(3-benzoylphenyl)propionate; yield 79%.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH:9]2[CH2:10][CH2:11][CH:5]1[CH2:6][CH:7]([C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=1)[CH2:8]2.[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[SH:32])[CH:25]=[CH:24][CH:23]=1>>[CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[CH:7]1[CH2:6][CH:5]2[N:4]([CH2:3][CH2:2][S:32][C:30]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:31]=3[N:22]=[CH:23][CH:24]=[CH:25]4)[CH:9]([CH2:10][CH2:11]2)[CH2:8]1
Reactant: ClCCN1C2CCC1CC(c1ccc3ccccc3c1)C2
Reactant: Sc1cccc2cccnc12
Product: c1ccc2cc(C3CC4CCC(C3)N4CCSc3cccc4cccnc34)ccc2c1

Procedure:
The title compound was prepared by the procedure described in Example 8, Step 5, except that 8-(2-chloroethyl)-3-(2-naphthyl)-8-azabicyclo[3.2.1]octane was used in place of 8-(2-chloroethyl)-3-(2-naphthyl)-8-azabicyclo[3.2.1]oct-2-ene, and 8-quinolinethiol was used in place of 6-methoxyquinolin-8-ol. Yield: 36% of a tan solid. The corresponding oxalate salt was prepared by combining the title compound with 1 equiv. of oxalic acid in CH2Cl2/MeOH to precipitate a white solid. Yield: 71%; mp: 200-203° C.; MS (ES) m/z: 425.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][NH:26][CH3:27]>>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][N:26]([CH3:27])[S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CNCc1ccco1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)N(C)Cc3ccco3)s2)c(C)[nH]c1=O
Yield: 78 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with furan-2-ylmethyl-methyl-amine as described in Step 5, Example 24 to give the title compound as a cream solid (78% yield). LC/MS: RT 3.03 min, n/e 393 (M+H); 1H NMR (δ, ppm): 11.85 (1H, s), 7.62 (2H, m), 7.35 (1H, s), 7.23 (1H, d), 6.40 (2H, dd), 4.27 (2H, s), 2.70 (3H, s), 2.41 (2H, q), 2.32 (3H, s), 1.10 (3H, t).