Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[I:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH:5]=1.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:18]=1[C:19](Cl)=[O:20].Cl>CC(C)=O.O>[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:18]=1[C:19]([NH:10][C@H:9]([C:11]([OH:13])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([I:3])=[CH:15][CH:14]=1)=[O:20]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: N[C@@H](Cc1ccc(I)cc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(N[C@@H](Cc1ccc(I)cc1)C(=O)O)c1c(Cl)cccc1Cl
Temperature: 10 °C

Procedure:
Water (21 mL), acetone (9.80 mL) and a 6M sodium hydroxide aqueous solution (5.20 mL) were added to 7.50 g of 4-iodo-L-phenylalanine and the resulting mixture was stirred at 10° C. to thus give a uniform solution. To this solution, there were alternatively added 4.05 mL of 2,6-dichlorobenzoyl chloride and 4.50 mL of a 6M sodium hydroxide aqueous solution while taking care to maintain the pH value of not less than 13 and the temperature of not higher than 15° C. After confirming the completion of the reaction, 6.50 mL of a 6M hydrochloric acid aqueous solution was added to the reaction system to thus precipitate the desired product. The solid thus separated was isolated through filtration under reduced pressure, washed with 15 mL of water and dried at 70° C. for 4 hours under reduced pressure to thus give 12.42 g of the intended product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:16]1(=O)[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH:16]1[CH:21]=[CH:20][C:19]([N:8]([C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:18][CH:17]=1
Reactant: Brc1ccc(Nc2ccc(Br)cc2)cc1
Reactant: O=C1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc(N(c2ccccc2)c2ccc(Br)cc2)cc1
Yield: 91 %

Procedure:
The preparation was carried out analogously to K. Haga et al, Bull. Chem. Soc. Jpn., 1986, 59, 803-7: 3.10 g (10.4 mmol) of bis(4-bromophenyl)amine (J. Berthelot et al, Can. J. Chem., 1989, 67, 2061), 1.28 g of cyclohexane-1,4-dione (11.4 mmol) and 2.17g (11.4 mmol) of p-toluenesulfonic acid hydrate were heated in 50 ml of toluene on a water separator. After a reaction time of 12 hours, the solvent was removed and the product was purified by column chromatography (hexane/ethyl acetate 4:1). 3.82 g (9.46 mmol, 91%) of 4,4′-dibromotriphenylamine were obtained as a viscous oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][C:22]=2[CH2:31][NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])[N:16]=1)([CH3:3])[CH3:2].CO.[BH3-]C#N.[Na+]>C(O)=O.O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][C:22]=2[CH2:31][NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])[N:16]=1)([CH3:2])[CH3:3]
Reactant: Cc1ccccc1NCc1ccc2ccccc2c1-c1cccc(C=Nc2c(C(C)C)cccc2C(C)C)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: O=CO
Product: Cc1ccccc1NCc1ccc2ccccc2c1-c1cccc(CNc2c(C(C)C)cccc2C(C)C)n1

Procedure:
To a solution of 1.50 g (2.90 mmol) of (2,6-diisopropylphenyl){[6-(2-{[(2-methylphenyl)amino]methyl}-1-naphthyl)pyridin-2-yl]methylene}amine in 20 ml of methanol 0.30 g (4.70 mmol) of NaBH3CN was added in one portion followed by addition of three drops of 88% formic acid. The reaction mixture was refluxed for 1 h and then poured into 50 ml of water. The crude product was extracted with 2×20 ml of ether. The organic extract was washed by water, dried over K2CO3, and then evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um; eluent: hexanes-ethyl acetate=5:1, vol.). Yield 1.00 g (67%) of yellow oil which crystallized at room temperature. Anal. calc. for C36H39N3: C, 84.17; H, 7.65; N, 8.18. Found: C, 84.25; H, 7.78; N, 8.00. 1H NMR (CDCl3): 7.91 (d, J=8.4 Hz, 1H, 4-H in naphthyl), 7.89 (m, 1H, 8-H in naphthyl), 7.79 (m, 1H, 4-H in Py), 7.66 (d, J=8.4 Hz, 1H, 3-H in naphthyl), 7.47 (m, 1H, 7-H in naphthyl), 7.36-7.42 (m, 4H, 3,5-H in Py and 5,6-H in naphthyl), 7.04-7.10 (m, 3H, 3,5-H in ortho-tolyl and 4-H in 2,6-diisopropylphenyl), 7.01 (m, 2H, 3,5-H in 2,6-diisopropylphenyl), 6.61 (m, 1H, 4-H in ortho-tolyl), 6.52 (m, 1H, 6-H in ortho-tolyl), 4.22-4.35 (m, 4H, CH2N), 4.02 (br. s, 1H, NH), 3.93 (br. s, 1H, NH), 3.28 (sept, J=6.8 Hz, 2H, CHMe2), 2.09 (s, 3H, Me in ortho-tolyl), 1.16 (d, J=6.8 Hz, 6H, CHMeMe′), 1.14 (d, J=6.8 Hz, 6H, CHMeMe′).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]2[CH:17]=[C:16]([CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH:15]=[CH:14][C:13]=2[NH2:26])=[N:8][C:7]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:5])[CH3:2].[CH:33](OCC)(OCC)OCC>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:12]3[CH:17]=[C:16]([CH2:18][N:19]4[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]4)[CH:15]=[CH:14][C:13]=3[N:26]=[CH:33]2)=[N:8][C:7]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:5])[CH3:2]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)c1sc(Nc2cc(CN3CCN(C)CC3)ccc2N)nc1-c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1sc(-n2cnc3ccc(CN4CCN(C)CC4)cc32)nc1-c1ccccc1

Procedure:
To a mixture of 2-[2-amino-5-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-4-phenyl-thiazole-5-carboxylic acid ethyl ester (VII.1a) from previous step and 0.2 mL of acetic acid was added 0.2 mL of triethyl orthoformate. The reaction mixture was heated to 60 degrees for 1 hour, and then concentrated under reduced pressure. The residue was diluted with 10 mL of water and 2 mL of saturated sodium bicarbonate and then extracted three times with 5 mL of dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol-dichloromethane (gradient 0:100-10:90) to give 0.041 g of 2-[6-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-4-phenyl-thiazole-5-carboxylic acid ethyl ester (I.1a) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=[O:4].C(OC([C:11]1[N:12]=[CH:13][C:14]2[NH:15][C:16]3[C:21]([C:22]=2[CH:23]=1)=[CH:20][C:19](Br)=[CH:18][CH:17]=3)=O)C.[Na].[CH3:26][OH:27]>[Cu]I>[CH3:1][N:2]([CH3:5])[C:3]([C:11]1[N:12]=[CH:13][C:14]2[NH:15][C:16]3[C:21]([C:22]=2[CH:23]=1)=[CH:20][C:19]([O:27][CH3:26])=[CH:18][CH:17]=3)=[O:4]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(Br)cc12
Reactant: CO
Agent: [Cu]I
Agent: [Na]
Product: COc1ccc2[nH]c3cnc(C(=O)N(C)C)cc3c2c1
Temperature: 145 °C

Procedure:
4 ml of dimethylformamide, 250 mg of copper (I) iodide and 160 mg of 6-bromo-β-carbolin-3-carboxylic acid ethyl ester are added to a solution, prepared under argon, of 230 mg of sodium in 3 ml of absolute methanol, and the whole is heated for 6 hours at 145° C. The solution is then concentrated in vacuo, the residue is washed with water, dried and chromatographed on silica gel with chloroform-methanol (8:2). 67 mg of 6-methoxy-β-carbolin-3-carboxylic acid dimethylamide of melting point 195° C. (decomposition) is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[N:9]([CH3:10])[C:8]([NH2:11])=[N:7][CH:6]=1.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28](O)=[O:29])[CH2:27][CH2:26]3)=[CH:24][C:19]=2[O:18][CH2:17]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[N:9]([CH3:10])[C:8]([NH:11][C:28]([C:25]2([C:23]3[CH:22]=[CH:21][C:20]4[O:16][CH2:17][O:18][C:19]=4[CH:24]=3)[CH2:27][CH2:26]2)=[O:29])=[N:7][CH:6]=1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: Cn1c(Cc2ccccc2Cl)cnc1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1c(Cc2ccccc2Cl)cnc1NC(=O)C1(c2ccc3c(c2)OCO3)CC1
Reaction time: 16 h
Yield: 22 %

Procedure:
5-(2-Chloro-benzyl)-1-methyl-1H-imidazol-2-ylamine (21 mg, 0.10 mmol) and 1-benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (22 mg, 0.10 mmol) were dissolved in acetonitrile (1.5 mL) containing triethylamine (42 L, 0.30 mmol). Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 49 mg, 0.11 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography to yield the pure product as a trifluoroacetic acid salt (11 mg, 0.022 mmol, 22%). ESI-MS m/z calc. 409.1. found; 410.1 (M+1)+ Retention time 2.40 minutes.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:36][CH:37]([F:39])[F:38])=[C:13]([C:15]2[C:19]([NH:20][C:21]([C:23]3[CH:24]=[N:25][N:26]4[CH:31]=[CH:30][CH:29]=[N:28][C:27]=34)=[O:22])=[CH:18][N:17]([CH2:32][C:33](O)=[O:34])[N:16]=2)[CH:14]=1.Cl.[N:41]1([CH:47]2[CH2:52][CH2:51][O:50][C:49](=[O:53])[CH2:48]2)[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:36][CH:37]([F:39])[F:38])=[C:13]([C:15]2[C:19]([NH:20][C:21]([C:23]3[CH:24]=[N:25][N:26]4[CH:31]=[CH:30][CH:29]=[N:28][C:27]=34)=[O:22])=[CH:18][N:17]([CH2:32][C:33](=[O:34])[N:44]3[CH2:43][CH2:42][N:41]([CH:47]4[CH2:52][CH2:51][O:50][C:49](=[O:53])[CH2:48]4)[CH2:46][CH2:45]3)[N:16]=2)[CH:14]=1
Reactant: O=C1CC(N2CCNCC2)CCO1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C1CC(N2CCN(C(=O)Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)CC2)CCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid trifluoroacetate (100 mg, 0.17 mmol) in DMF (3 mL) was added 4-(piperazin-1-yl)oxan-2-one hydrochloride (76 mg, 0.34 mmol), DIEA (67.2 mg, 0.52 mmol), HATU (79.2 mg, 0.21 mmol). The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (35.0% up to 39.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 35.0% in 2 min); Detector, UV 254/220 nm. This resulted in 14.5 mg (13%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-[4-(2-oxooxan-4-yl)piperazin-1-yl]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. LCMS (Method 28) [M+H]+=629.1, RT=1.44 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=2.0, 7.2 Hz), 8.69-8.68 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 7.2 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.24 (s, 2H), 4.35-4.29 (m, 1H), 4.19-4.16 (m, 1H), 3.50-3.32 (m, 6H), 3.02-2.99 (m, 1H), 2.69-2.51 (m, 4H), 2.08-1.98 (m, 1H), 1.77-1.75 (m, 1H).
Reaction SMILES: [CH3:1][S:2]([N:5]([CH3:11])[NH:6][S:7]([CH3:10])(=[O:9])=[O:8])(=[O:4])=[O:3].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:19]([O:21][CH3:22])=[O:20]>CC(C)=O>[CH3:1][S:2]([N:5]([CH3:11])[N:6]([S:7]([CH3:10])(=[O:8])=[O:9])[C:19]([O:21][CH3:22])=[O:20])(=[O:3])=[O:4]
Reactant: CN(NS(C)(=O)=O)S(C)(=O)=O
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)N(N(C)S(C)(=O)=O)S(C)(=O)=O

Procedure:
1,2-Bis(methylsulfonyl)-2-(methoxycarbonyl)-1-methylhydrazine (compound 6) was synthesized as follows: A mixture of 1,2-bis(methylsulfonyl)-1-methylhydrazine (Shyam et al., J. Med. Chem. 30 2157-2161 (1987)) (1.00 g, 0.005 mol), anhydrous sodium carbonate (1.9 g, 0.018 mol), methyl chloroformate (1.23 g, 0.013 mol) and acetone (30 ml) was heated under reflux for 18 hr. The reaction mixture was filtered and the filtrate evaporated to dryness in vacuo. The residue, a thick oil, was stirred with methanol (5 ml) and cooled in ice. The solid that separated was filtered and recrystallized from ethanol-petroleum ether (0.63 g, 48.9%). The melting point (Mp) of this compound was found to be approximately 88-89° C. Analysis of the compound by 1H NMR (CDCl3) showed the following results: δ 0 4.0(3H, s, OCH3), 3.5, 3.4, 3.1 (9H, 3s, 2 CH3SO2 and NCH3).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([C:21]([OH:23])=[O:22])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:30])[CH:17]=4)[C:12]3=[O:31])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:32](O)[CH2:33][CH3:34]>>[CH2:32]([O:22][C:21]([C:20]1[N:11]([CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:17][C:16]([Br:30])=[CH:15][CH:14]=2)=[O:23])[CH2:33][CH3:34]
Reactant: CCCO
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Product: CCCOC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2

Procedure:
The present compound was synthesized by a method similar to that in Example 200 and using 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (300 mg) and propanol. Colorless crystals (190 mg).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]([C:17](=[O:25])[CH2:18][N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:6]=12.[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]Br.C(N(CC)CC)C.N>CO.C(Cl)(Cl)Cl>[CH3:1][C:2]1[S:3][CH:4]=[C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]([C:17](=[O:25])[CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][Br:26])[CH2:21][CH2:20]3)[C:6]=12
Reactant: BrCCCCCCCCCCBr
Reactant: Cc1scc2c1N(C(=O)CN1CCNCC1)c1ccccc1NC2=O
Agent: N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1scc2c1N(C(=O)CN1CCN(CCCCCCCCCCBr)CC1)c1ccccc1NC2=O

Procedure:
A solution of 38 (20 mg, 57 μmol), 1,10-dibromodecane (0.22 g. 0.73 mmol), and triethylamine (0.2 mL) was stirred in MeOH (0.5 mL) at 25° C. for 3 days. The reaction was judged complete by TLC (Rf of product on silica, with chloroform:methanol:ammonia, 90:10:1, by volume was 0.66), and all volatile materials were removed in vacuo. The remaining residue was dissolved in 0.5N HCl. The acidic aqueous layer was washed with ether (2×), and then made basic (=pH 9) by addition of 10% sodium carbonate. The product was extracted into CHCl3 (3×), and the combined organic layers were dried over Na2SO4, filtered and evaporated in vacuo to give the crude product as a glass. Yield 20 mg (61%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11].[F:12][C:13]([F:27])([F:26])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38]>C(O)CCC.C(O)C>[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38].[F:26][C:13]([F:12])([F:27])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([N:20]2[CH2:21][CH2:22][N:23]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[CH2:10][CH2:9][CH2:8][C:7]3=[O:11])[CH2:24][CH2:25]2)[CH:15]=1
Reactant: FC(F)(F)c1ccnc(N2CCNCC2)c1
Reactant: O=C1CCCN1CCCCBr
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Solvent: CCO
Product: O=C1CCCN1CCCCN1CCN(c2cc(C(F)(F)F)ccn2)CC1
Yield: 52 %

Procedure:
2 7 g of 1-(4-bromobutyl)-2-pyrrolidinone were mixed with 2.2 g of 1-[4-(trifluoromethyl)-2-pyridinyl]piperazine dissolved in 30 ml of butanol, after which 1.3 g of sodium carbonate were added. The mixture was refluxed for 2 hours, after which the precipitate was filtered and washed with butanol. The solvent was evaporated and the residue was dissolved in dichloromethane, washed with water, and dried over anhydrous magnesium sulfate. After evaporation of the solvent 3.4 g of 1-[4-[4-[4-(trifluoromethyl)-2-pyridinyl]-1-piperazinyl]butyl]-2-pyrrolidinone were obtained. To make the monofumarate, 1 g of fumaric acid dissolved in absolute ethanol was mixed with the free base. The resulting compound was recrystallized twice from acetonitrile, after which 2.4 g (52% yield) of 1-[4-[4-[4-(trifluoromethyl)-2-pyridinyl]-1-piperazinyl]butyl]-2pyrrolidinone (E)-2-butenedioate (1:1) salt were obtained with a melting point of 140° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:12].[C:13]1(=O)[O:18][C:16](=[O:17])[CH:15]2[CH2:19][CH2:20][CH:21]=[CH:22][CH:14]12.C(OCC)(=O)C.C(Cl)Cl>C(O)(=O)C>[F:12][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[N:1]1[C:13](=[O:18])[C:14]3[CH2:22][CH2:21][CH2:20][CH2:19][C:15]=3[C:16]1=[O:17])[NH:8][C:7](=[O:11])[CH2:6]2
Reactant: Nc1cc2c(cc1F)CC(=O)N2
Reactant: O=C1OC(=O)C2CCC=CC12
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1Cc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc2N1
Yield: 77.4 %

Procedure:
A mixture of 6-amino-5-fluoro-2-indolinone (10.5 g, 63.25 mmol) and tetrahydrophthalic anhydride (10.95 g, 66.42 mmol) in acetic acid (30 mL) is heated at reflux for 2 hours, cooled and concentrated in vacuo to obtain a residue. Chromatography of the residue using silica gel and a 3:7 ethyl acetate/methylene chloride solution gives the title product as a light violet solid (14.7 g, mp 234°-236° C.). Following the procedure of Example 3, but substituting 6-amino-2-indolinone for 6-amino-5-fluoro-2-indolinone gives N-(2-oxo-6-indolinyl)-1-cyclohexene-1,2-dicarboximide as a green solid, mp 225°-226° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1CCC1=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClS(N=C=O)(=O)=O>C(OC(=O)C)C>[C:9](=[O:10])([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[NH2:11]
Reactant: O=C1CCN1C(=O)OCc1ccccc1
Agent: O=C=NS(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: NC(=O)OCc1ccccc1

Procedure:
Solution A 1.99 g benzyloxycarbonyl-azetidinon and 1.29 g chlorosulfonyl isocyanate were stirred for 1 hour in 50 ml ethylacetate at 5° C. A solution of (S)-[1-[[chlorosulfonyl)amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][CH:16]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:14]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:19]([C:15]2[CH:14]=[C:13]([CH3:23])[CH:18]=[CH:17][CH:16]=2)(=[O:21])=[O:20])=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2CCCN2)cc1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Product: Cc1cccc(S(=O)(=O)N2CCCC2c2ccc(F)cc2)c1

Procedure:
The title compound, light brown solid, m.p. 102° C. and MS: m/e=319 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and toluene-3-sulfonyl chloride.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10][C:9]([C:17]2[N:18]=[CH:19][C:20]3[C:25]([CH:26]=2)=[C:24]([OH:27])[CH:23]=[CH:22][CH:21]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:31]>CN(C)C=O.[Cl-].[Na+].O>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10][C:9]([C:17]2[N:18]=[CH:19][C:20]3[C:25]([CH:26]=2)=[C:24]([O:27][CH3:31])[CH:23]=[CH:22][CH:21]=3)=[CH:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)ON=c1cc(-c2cc3c(O)cccc3cn2)oc2ccccc12
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2cnc(-c3cc(=NOC(C)(C)C)c4ccccc4o3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a ice-water bath cooled solution of 2-(5-hydroxy-isoquinolin-3-yl)-chromen-4-one O-tert-butyl oxime (80 mg, 0.22 mmol) in dimethylformamide (2.5 ml) was added sodium hydride (60% in mineral oil, 13 mg, 0.33 mmol) under argon and the mixture was stirred at room temperature for 1 hour. The solution was cooled to 0° C. and iodomethane (15 μl, 0.24 mmol) was added. The resulting solution was stirred at room temperature for 20 hours and then hydrolyzed with brine. The mixture was extracted with ethyl acetate, washed with brine, dried over sodium sulfate and then purified by flash chromatography over silica gel (cyclohexane/ethyl acetate: 80/20) to yield 2-(5-methoxy-isoquinolin-3-yl)-chromen-4-one O-tert-butyl oxime (65 mg, 79%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[CH3:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:27]4[CH:26]=[N:25][C:24]([CH3:23])=[CH:29][CH:28]=4)[CH:3]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3ccc(C)nc3)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (124 mg, 0.564 mmol) and K2CO3 (116 mg, 0.845 mmol) in DME-water (2:1) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(3-(6-methylpyridin-3-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) d (ppm): 8.84 (s, 1H), 8.56 (d, 1H), 7.83 (d, 1H), 7.75-7.8 (m, 3H), 7.57 (d, 1H), 7.38 (s, 1H), 7.18 (d, 1H), 7.04 (d, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 3.8 (m, 1H), 3.6 (m, 1H), 3.0-3.22 (m, 5H), 2.77 (s, 3H), 2.4 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][CH2:19][CH2:20][NH2:21])[C:10]3[N:22]=[CH:23][CH:24]=[CH:25][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([O:28][CH:29](OCC)OCC)[CH3:27]>>[CH2:26]([O:28][CH:29]=[N:21][CH2:20][CH2:19][CH2:18][N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:9]2[CH:25]=[CH:24][CH:23]=[N:22][C:10]1=2)[CH3:27]
Reactant: NCCCN1c2ccccc2C(c2ccccc2)=Nc2cccnc21
Reactant: CCOC(OCC)OCC
Product: CCOC=NCCCN1c2ccccc2C(c2ccccc2)=Nc2cccnc21
Reaction time: 8 h

Procedure:
A solution of 8.8 g (0.021 mole) of 6-phenyl-11H-pyrido [2,3-b][1,4]bezodiazepine-11-propanamine in 150 ml of triethylorthoformate was heated at refux for 41/2 hr and allowed to stand overnight. The mixture was concentrated in vacuo, the residue was washed with pet-ether (30°-60° C.). Chemical ionization mass spec indicated the product was a mixture containing the title compound.