Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[NH:25]([C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[C:26]1([NH:25][C:32](=[O:33])[C:34]2[CH:39]=[CH:38][C:37]([C:2]3[C:10]4[C:5](=[N:6][CH:7]=[N:8][C:9]=4[NH2:11])[N:4]([C@H:12]4[CH2:17][CH2:16][C@@H:15]([N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)[CH2:14][CH2:13]4)[N:3]=3)=[CH:36][CH:35]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(Nc1ccccc1)c1ccc(B(O)O)cc1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(C(=O)Nc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Yield: 27.7 %

Procedure:
cis-3-Iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.226 mmol), 4-(anilinocarbonyl)phenylboronic acid (60 mg, 0.249 mmol), palladium tetrakistriphenyphosphine(16 mg, 0.014 mmol) and sodium carbonate (58 mg, 0.544 mmol) were mixed with ethylene glycol dimethyl ether (3 mL) and water (1.5 mL). The reaction mixture was heated at reflux overnight. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was by preparative thin layer column chromatography using dichloromethane/methanol/ammonium hydroxide (95:5:05) as mobile phase to give cis-N1-phenyl-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}benzamide (32 mg, 27%). 1H NMR (DMSO-d6) δ 1.60 (m, 4H), 1.73 (m, 2H), 2.08 (m, 2H), 2.19 (s, 3H), 2.28 (m, 11H), 4.84 (m, 1H), 7.12 (m, 1H), 7.38 (m, 2H), 7.81 (m, 4H), 8.16 (d, J=8.30 Hz, 2H), 8.27 (s, 1H), 10.34 (s, 1H). LC/MS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.5 mL/min.): MH+ =511.2, Rt=2.41 min.
Reaction SMILES: [CH:1]([O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:21]([O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH:32]=[O:33])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:21]([O:28][C:29]1[CH:30]=[C:31]([CH:32]([OH:33])[CH:5]([O:4][CH:1]([CH3:3])[CH3:2])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:34]=[CH:35][CH:36]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Reactant: CCOC(=O)COC(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(OC(C)C)C(O)c1cccc(OCc2ccccc2)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 46.4 %

Procedure:
9.5 g of Ethyl 2-isopropoxyacetate was dissolved in 200 ml of tetrahydrofuran anhydride, and the mixture was cooled to −78° C. under nitrogen atmosphere. After adding 6.5 ml of lithium bis(trimethylsilyl)amide (1M solution in tetrahydrofuran), 15 g of 3-benzyloxybenzaldehyde in tetrahydrofuran (50 ml) was added via a cannula. The temperature of the solution was elevated to room temperature, and the mixture was stirred for 3 hours. The reaction solution was treated with saturated aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was distilled off. The residue was purified by silica gel column chromatography, to give 10.8 g of ethyl 3-[3-(benzyloxy)phenyl]-3-hydroxy-2-isopropoxypropanoate as a mixture of erythro and threo in the 3:1 hexane-ethyl acetate fraction. This product was dissolved in 50 ml of pyridine and 3.5 ml of methanesulfonyl chloride was added under ice-cooling. After stirring overnight at room temperature, the reaction mixture was diluted with ethyl acetate, and washed with 1N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was distilled off, to give 13.7 g of ethyl 3-[3-(benzyloxy)phenyl]-2-isopropoxy-3-[(methylsulfonyl) oxy]propanoate. This product was dissolved in 450 ml of ethanol, 3.9 g of 10% palladium carbon was added, and the mixture was stirred overnight at room temperature under hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated, to give 7.5 g of the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH3:11][C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([C:21]#[N:22])=[CH:16][CH:15]=2.C(=O)([O-])[O-].[K+].[K+]>O>[CH:8]([C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:21]#[N:22])[CH:18]=2)[NH:13][C:12]=1[CH3:11])=[O:9]
Reactant: CN(C)C=O
Reactant: Cc1cc2cc(C#N)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1[nH]c2ccc(C#N)cc2c1C=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under ice-cooling, 1.3 ml of phosphorus oxychloride was added to 7 ml of N,N-dimethylformamide at an inner temperature of from 10 to 20° C., followed by stirring at room temperature for 15 minutes. Under ice-cooling, 9 ml of an N,N-dimethylformamide solution of 2-methyl-1H-indole-5-carbonitrile was added to this solution at an inner temperature of from 10 to 20° C., followed by overnight stirring at room temperature. A 64 ml portion of water was added thereto at 0° C. and the pH was adjusted to 8 with potassium carbonate, followed by 2.5 hours of stirring at room temperature. The thus precipitated solid was collected by filtration, washed with water and then dried at 80° C. under a reduced pressure to obtain 1.73 g of 3-formyl-2-methyl-1H-indole-5-carbonitrile as a pale yellow solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=3[CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[NH:10][C:9]=2[C:8]([O:29][CH3:30])=[CH:7][CH:6]=1)=O.[Cl:31][C:32]1[N:33]=[CH:34][N:35]([CH2:38][CH2:39][CH2:40][NH2:41])[C:36]=1[Cl:37].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1.O.CN(C1C=CN=CC=1)C>[Cl:31][C:32]1[N:33]=[CH:34][N:35]([CH2:38][CH2:39][CH2:40][NH:41][C:3]([C:5]2[C:13]3[N:12]=[C:11]([C:14]4[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=4[CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[NH:10][C:9]=3[C:8]([O:29][CH3:30])=[CH:7][CH:6]=2)=[O:2])[C:36]=1[Cl:37]
Reactant: NCCCn1cnc(Cl)c1Cl
Reactant: COC(=O)c1ccc(OC)c2[nH]c(-c3ccc(N)cc3CCN3CCOCC3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)NCCCn2cnc(Cl)c2Cl)c2nc(-c3ccc(N)cc3CCN3CCOCC3)[nH]c12
Temperature: 25 °C
Yield: 60 %

Procedure:
2-[(2-morpholinoethyl)-4-amino-phenyl]-7-methoxy-1H-benzoimidazole-4-carboxylic acid methyl ester (22 mg, 0.05 mmol) was dissolved in THF/H2O, LiOHH2O (6.7 mg, 0.16 mmol) was added thereto and stirred at room temperature. The resulting solution was filtered to remove residual LiOHH2O, and the solvent was removed. The residue was dried and dissolved in DMF. Added thereto were 4,5-dichloro-1-(3-aminopropyl)imidazole (12.5 mg, 0.06 mmol), EDCI (30.9 mg, 0.16 mmol), DMAP (65.6 mg, 0.54 mmol) and HOBt (21.8 mg, 0.16 mmol), followed by stirring at room temperature. The resulting solution was extracted with ethyl acetate and concentrated under a reduced pressure. The resulting residue was purified by silica gel chromatography to obtain the title compound (19 mg, 0.03 mmol) in a yield of 63%.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Cl[CH2:21][C:22]1[C:23]2[C:28]([CH:29]=[C:30]3[C:35]=1[CH:34]=[CH:33][CH:32]=[CH:31]3)=[CH:27][CH:26]=[CH:25][CH:24]=2>>[CH:24]1[C:23]2[C:28](=[CH:29][C:30]3[C:35]([C:22]=2[CH2:21][N:7]2[C:8]([S:9][C:10]4[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=4)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:27]=[CH:26][CH:25]=1
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: ClCc1c2ccccc2cc2ccccc12
Product: CCc1c(Sc2cc(C)cc(C)c2)n(Cc2c3ccccc3cc3ccccc23)c(=O)[nH]c1=O
Yield: 41.8 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 9-chloromethyl anthracene were reacted by the same way with the example 1 to obtain the titled compound (195 mg, yield: 41.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:23]([O-])=O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[CH:11][CH:10]=1>CO.[Pt]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[CH:13][CH:14]=1)[NH2:23]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(CCCn3ccnc3)cc2)c(Cl)c1
Agent: [Pt]
Solvent: CO
Product: Nc1ccc(Oc2ccc(CCCn3ccnc3)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.2 %

Procedure:
To a solution of 3-chloro-4-{4-[3-(1H-imidazol-1-yl)propyl]phenoxy}nitrobenzene (669 mg) in methanol (7 mL) was added 5% Pt/C (140 mg), and the mixture was stirred under hydrogen atmosphere at room temperature for 16 hrs. 5% Pt/C was filtered off and the filtrate was concentrated. The residue was purified by basic silica gel column chromatography (eluent, ethyl acetate:hexane=80:20→100:0) and further washed with diethyl ether and hexane to give the title compound (277 mg) as a powder.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([NH2:15])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>CC#N>[CH:12]1([NH:15][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(F)cc1NC1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of 2,4-difluoro-1-nitrobenzene (0.7 mL, 6.3 mmol) in anhydrous CH3CN (10 mL) were added cyclopropylamine (0.4 mL, 6.3 mmol) and DIPEA (1.1 mL, 6.3 mmol). The reaction mixture was stirred at RT for 18 h then evaporated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% EtOAc in cyclohexane) to afford the title compound as a yellow solid (6.3 mmol, quantitative). 1H NMR (CDCl3, 300 MHz): δ 8.26-8.09 (2H, m), 6.95 (1H, dd, J=11.43, 2.68 Hz), 6.46-6.35 (1H, m), 2.60-2.50 (1H, m), 0.98-0.89 (2H, m), 0.71-0.63 (2H, m).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH3:13][C:14]1[CH:15]=[C:16]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[CH:17]=[C:18]2[C:23]=1[NH:22][C:21](=[O:24])[CH:20]=[CH:19]2.O[CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:13][C:14]1[CH:15]=[C:16]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:33][C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)=[CH:27][CH:26]=2)[CH:17]=[C:18]2[C:23]=1[NH:22][C:21](=[O:24])[CH:20]=[CH:19]2
Reactant: OCc1ccncc1
Reactant: Cc1cc(-c2ccc(O)cc2)cc2ccc(=O)[nH]c12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(OCc3ccncc3)cc2)cc2ccc(=O)[nH]c12
Yield: 70.5 %

Procedure:
A solution of diethylazodicarboxylate (0.189 cm3) in THF (5 cm3) was added at room temperature to a stirred suspension of 8-methyl-6-[4-hydroxyphenyl]-2-(1H)-quinolone (0.25 g), 4-hydroxymethylpyridine (0.109 g) and triphenylphosphine (0.315 g) in THF (10 cm3) under nitrogen. The mixture was heated under reflux for 18 hours, silica (10 g) (Merck "MK 60.9385" [Trade Mark]) was added and voltatile material was removed in vacuo. The residue was placed on top of a silica column (Merck "MK 60.9385" [Trade Mark]) and eluted with ethyl acetate:methanol, 9:1. Combination and evaporation of the appropriate fractions in vacuo gave a solid (0.24 g) which was recrystallised from ethyl acetate-methanol to afford the title compound, m.p. 270.5°-273.5°, (0.08 g).
Reaction SMILES: [CH:1]([N:4]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH:6]=[N:5]1)([CH3:3])[CH3:2]>Br>[OH:28][C:25]1[CH:26]=[CH:27][C:22]([N:19]2[CH2:18][CH2:17][N:16]([C:13]3[CH:12]=[CH:11][C:10]([N:7]4[C:8](=[O:9])[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6]4)=[CH:15][CH:14]=3)[CH2:21][CH2:20]2)=[CH:23][CH:24]=1
Reactant: COc1ccc(N2CCN(c3ccc(-n4cnn(C(C)C)c4=O)cc3)CC2)cc1
Agent: Br
Product: CC(C)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Yield: 96 %

Procedure:
This compound was synthesized as a white amorphous solid from 4d (31.6 mg, 0.080 mmol) in 48% aqueous HBr (1.0 mL) in 96% yield by following general procedure 1.4: MALDI-MS: 380.2 (M+H+), 402.2 (M+Na+).
Reaction SMILES: [CH2:1]([C@H:8]([NH:41]C(=O)OC(C)(C)C)[C@@H:9]([OH:40])[CH2:10][C@@H:11]([NH:19][C:20](=[O:39])[C@@H:21]([N:26]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[N:33]=[C:34]([CH3:37])[S:35][CH:36]=2)[C:27]1=[O:38])[C@@H:22]([CH3:25])[CH2:23][CH3:24])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1>[NH2:41][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]([OH:40])[CH2:10][C@@H:11]([NH:19][C:20](=[O:39])[C@@H:21]([N:26]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[N:33]=[C:34]([CH3:37])[S:35][CH:36]=2)[C:27]1=[O:38])[C@@H:22]([CH3:25])[CH2:23][CH3:24])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC[C@H](C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)N1CCN(Cc2csc(C)n2)C1=O
Agent: Cl
Solvent: C1CCOC1
Product: CC[C@H](C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1)N1CCN(Cc2csc(C)n2)C1=O
Temperature: 60 °C

Procedure:
A solution containing the product from Example 11E (0.27 g, 0.4 mmol) in THF (4 mL) was treated with an HCl solution (0.70 mL, 4 N in dioxane), heated at 60° C. for 3 hours, cooled to 25° C., and concentrated to give the title compound as the hydrochloride salt.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[N:16]([CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([O:32][CH2:33][C:34]([F:37])([F:36])[F:35])[C:29](O)=[O:30])=[CH:23][CH:22]=1)[CH3:17]>C1C=CC=CC=1>[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[N:16]([CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([O:32][CH2:33][C:34]([F:37])([F:36])[F:35])[C:29]([Cl:4])=[O:30])=[CH:23][CH:22]=1)[CH3:17]
Reactant: CN(CCOc1ccc(CC(OCC(F)(F)F)C(=O)O)cc1)c1nc2ccccc2o1
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: CN(CCOc1ccc(CC(OCC(F)(F)F)C(=O)Cl)cc1)c1nc2ccccc2o1

Procedure:
Oxalyl chloride (1.1 mL) was added to a solution of (±)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2,2,2-trifluoroethoxy)propanoic acid (1.72 g) in dry benzene (30 mL). The mixture was heated at reflux for 2 hours, cooled and evaporated to dryness to give the title compound as a gum which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=4)=[O:19])=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:28](O)=[O:29])=[CH:4][N:3]=1.[CH2:31]([N:33]([CH2:38][CH3:39])[CH2:34][CH2:35][CH2:36][NH2:37])[CH3:32].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.CO.C(OCC)(=O)C.O>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:19])[NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=4)=[CH:15][CH:16]=3)=[CH:9][S:10][C:6]=2[C:5]([C:28]([NH:37][CH2:36][CH2:35][CH2:34][N:33]([CH2:38][CH3:39])[CH2:31][CH3:32])=[O:29])=[CH:4][N:3]=1
Reactant: Nc1ncc(C(=O)O)c2scc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)c12
Reactant: CCN(CC)CCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCOCC1
Product: CCN(CC)CCCNC(=O)c1cnc(N)c2c(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)csc12

Procedure:
A solution of example 1C (7.41 g, 17.55 mmol), N,N-diethyl-1,3-propanediamine (3.32 ml, 21.06 mmol), 1-hydroxybenzotriazole hydrate (2.96 g, 19.31 mmol) and N-methylmorpholine (4.82 ml, 43.9 mmol) in N,N-dimethylformamide (88 ml) at room temperature was treated with 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (6.06 g, 31.6 mmol). The mixture was added to a well stirred solution of water (800 ml) and ethyl acetate (150 ml) using methanol to rinse the syringe and filter. The resulting suspension was stirred under a stream of nitrogen for several minutes to remove some of the methanol, and filtered with water and diethyl ether rinses to give, after drying, the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.96 (t, J=7.14 Hz, 6H), 1.61-1.73 (m, 2H), 2.40-2.47 (m, 4H), 3.23-3.38 (m, 4H), 5.89 (bs, 2H), 6.80 (td, J=8.33, 2.78, 1H), 7.14 (bd, J=9.12, 1H), 7.27-7.34 (m, 1H), 7.37 (d, J=8 Hz, 2H), 7.47 (s, 1H) 7.51 (dt, J=11.92, 2.38 Hz, 1H), 7.60 (d, J=8 Hz, 2H), 8.45-8.53 (m, 2H) 8.94 (s, 1H) 8.98 (s, 1H). MS (ESI(+)) m/e 535.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([CH:13]=1)[CH2:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.C([Li])CCC.[CH3:20][N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([CH:7]([N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)[C:24]2([OH:27])[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)[CH:13]=1
Reactant: CN1CCC(=O)CC1
Reactant: Fc1ccc(Cl)cc1Cn1cccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC(O)(C(c2cc(Cl)ccc2F)n2cccc2)CC1
Temperature: -80 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(5-chloro-2-fluorobenzyl)pyrrole of Example XVIIIa (15 g, 72 mmole) in 100 ml THF, cooled to -80° C., is added a solution of n-butyllithium (2.5 M in hexane 75 mmole, 30 ml) over a period of ten minutes. The mixture is stirred at -80° C. for one hour, then at -50° C. for 15 minutes. The mixture is again cooled to -80° C., then a solution of 1-methyl-4-piperidone (8.1 g, 72 mmole) in 50 ml THF is added. After stirring at ambient temperature for two hours, the mixture is poured over 500 ml ice water and is extracted with ether. The organic layer is extracted with diluted HCl. The aqueous acidic extract is then basified with sodium carbonate and extracted with ether. The organic extracts are washed twice with water and dried (saturated NaCl, anhydrous MgSO4). The solution is filtered and concentrated to a solid (21 g, 90%, m.p. 110°-115° C.) of which 4 g is recrystallized from hexanes to yield crystals, m.p. 124°-125° C. of 4-[(5-chloro-2-fluorophenyl)-(1-pyrryl)methyl]-1-methyl-4-piperidinol.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]([CH2:19][CH2:20][CH2:21][Cl:22])[C@H:9]1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(O)=[O:6].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[Cl:22][CH2:21][CH2:20][CH2:19][N:10]1[C:9]2[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[C:5](=[O:6])[C:8]=2[C:17]2[CH2:16][CH2:15][CH:14]=[CH:13][C:12]=2[C:11]1=[O:18]
Reactant: COc1ccc([C@H]2[C@@H](C(=O)O)c3ccccc3C(=O)N2CCCCl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccc2c(c1)C(=O)c1c3c(c(=O)n(CCCCl)c1-2)C=CCC3
Temperature: 25 °C
Yield: 16.9 %

Procedure:
Thionyl chloride (2 mL) was added to a solution of cis-4-carboxy-N-(3-chloropropyl)-3,4-dihydro-3-(4-methoxyphenyl)-1(2H)isoquinolone (8a) (0.510 g, 1.364 mmol) in benzene (40 mL). The reaction mixture was heated at reflux for 30 min, allowed to cool to room temperature, and concentrated. The residue was diluted with nitrobenzene (20 mL), chilled in an ice bath, and aluminum chloride (0.364 g, 2.728 mmol) was added. The reaction mixture was removed from the bath and heated at 100° C. for 1.5 h. Ice water (100 mL) was added and the solution was extracted with CHCl3 (3×50 mL). The combined organic layer was washed with sat NaHCO3 (3×50 mL), sat NaCl (50 mL), and dried over sodium sulfate. The solution was concentrated, hexanes (250 mL) were added, and liquid was decanted. The obtained solid was washed with hexanes (100 mL) and the liquid was again decanted. The solid was purified by flash column chromatography (SiO2), eluting with chloroform, to provide a purple-red solid (0.082 g, 17%) that was precipitated from EtOAc/hexanes: mp 195-198° C. IR (KBr) 1662, 1611, 1505, 1481, 1432, and 1299 cm−1; 1H NMR (CDCl3) δ 8.67 (d, J=8.1 Hz, 1H), 8.31 (dd, J=8.2 Hz and 0.7 Hz, 1H), 7.73 (m, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.45 (m, 1H), 7.22 (d, J=2.6 Hz, 1H), 6.86 (dd, J=8.4 Hz and 2.6 Hz, 1H), 4.67 (m, 2H), 3.89 (s, 3H), 3.83 (m, 2H), 2.43 (m, 2H); CIMS m/z (rel intensity) 354/356 (MH+, 100/30). Anal. (C20H16ClNO3) C, H, N.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][OH:13])=[CH:2]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>>[CH3:14][S:15]([O:13][CH2:12][CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCc1c[nH]c2ccccc12
Product: CS(=O)(=O)OCCCc1c[nH]c2ccccc12

Procedure:
3-(3-Indolyl)-1-propyl methanesulfonate was prepared by following the general procedure of Example 43 for mesylation as a colorless oil (170 mg, 81%) from 3-(3-indolyl)-1-propanol (145 mg, 0.83 mmol) and methanesulfonyl chloride (142 mg, 1.24 mmol). 1H NMR (CDCl3, 300 MHz) δ2.17 (qu, 2H, J=7.3 Hz), 2.92 (t, 2H, J=7.0 Hz), 2.99 (s, 3H), 4.27 (t, 2H, J=6.4 Hz), 7.04 (d, 1H, J=2.2 Hz), 7.12 (dt, 1H, J=1.1, 7.0 Hz), 7.21 (dt, 1H, J=1.1, 7.0 Hz), 7.38 (d, 1H, J=8.1 Hz), 7.59 (d, 1H, J=7.3 Hz), 8.00 (br, 1H) ppm.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][N:6]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2[NH:14][C:15]([CH:18]=O)=[C:16]([CH3:17])[C:8]=2[C:7]1=[O:20])[CH3:2].[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27]2.N1CCCCC1>C(O)C>[CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][N:6]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2[NH:14][C:15](/[CH:18]=[C:27]3\[C:28](=[O:33])[NH:29][C:30]4[C:26]\3=[CH:25][C:24]([F:23])=[CH:32][CH:31]=4)=[C:16]([CH3:17])[C:8]=2[C:7]1=[O:20])[CH3:2]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCN(CC)CCN1CCCCc2[nH]c(C=O)c(C)c2C1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCN1CCCCc2[nH]c(/C=C3\C(=O)Nc4ccc(F)cc43)c(C)c2C1=O
Temperature: 25 °C
Yield: 48.4 %

Procedure:
5-(2-Diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7,8,9-hexahydro-1H-1,5-diaz a-cyclopentacyclooctene-2-carbaldehyde 60e (20 mg, 0.066 mmol) was dissolved in 1 ml of ethanol under stirring, and added with 5-fluoro-1,3-dihydro-indol-2-one (9.9 mg, 0.066 mmol) to the solution at room temperature. The reaction mixture was stirred in dark until dissolved, added with 0.1 ml of piperidine, and heated to reflux for 2 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled down to room temperature, filtered to obtain the title compound (Z)-5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-6,7,8,9-tetrahydro-1H,5H-1,5-diaza-cyclopentacycloocten-4-one 60 (14 mg, yield 48.8%) as a yellow solid.