Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:35])[N:8]([CH2:31][C:32](O)=[O:33])[C:9](=[O:30])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[NH:28][C:27](=[O:29])[O:26][N:25]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[C:36]([NH2:40])([CH3:39])([CH3:38])[CH3:37].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(OCC)(=O)C.CN(C)C=O>[C:36]([NH:40][C:32](=[O:33])[CH2:31][N:8]1[C:9](=[O:30])[C:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][C:27](=[O:29])[O:26][N:25]=3)=[CH:16][CH:17]=2)=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=[C:7]1[CH3:35])([CH3:39])([CH3:38])[CH3:37]
Reactant: CCCCc1nc(C)n(CC(=O)O)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(CC(=O)NC(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.3 %

Procedure:
A mixture of [4-butyl-2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-1(6H)-yl]acetic acid (0.10 g), tert-butylamine (0.02 g), 1-hydroxybenzotriazole (0.03 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.044 g) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with diluted hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.074 g, 66%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15]Br)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[F:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:23][N:24]2[CH3:27])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.C1(C)C=CC=CC=1>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15][N:31]3[CH2:30][CH2:29][CH:28]([C:22]4[C:21]5[C:25](=[CH:26][C:18]([F:17])=[CH:19][CH:20]=5)[N:24]([CH3:27])[N:23]=4)[CH2:33][CH2:32]3)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(sc(C)c2CCBr)C1
Reactant: Cn1nc(C2CCNCC2)c2ccc(F)cc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(=O)N1CCc2c(sc(C)c2CCN2CCC(c3nn(C)c4cc(F)ccc34)CC2)C1
Temperature: 90 °C
Reaction time: 22 h
Yield: 60.8 %

Procedure:
A mixture of 590 mg of 6-acetyl-3-(2-bromoethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine, 580 mg of 4-(6-fluoro-1-methyl- 1H-indazol-3-yl) piperidine, 780 mg of potassium carbonate and 415 mg of potassium iodide in 10 ml of dimethylformamide and 10 ml of toluene was stirred at 90° C. for 22 hours and concentrated in vacuo. To the residue were added ethyl acetate and water, and separated. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on a silica gel to give 540 mg of 6-acetyl-3-(2-(4-(6-fluoro-1-methyl-1H-indazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 213°-216° C. as oxalate thereof.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:4][CH:5]=[CH:6][CH:7]=1.[N+](N[C:17]1[NH:22][C:21](=[O:23])[C:20]([CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[C:29]([CH2:31][N:32]([CH3:34])[CH3:33])[CH:30]=2)=[CH:19][N:18]=1)([O-])=O>>[CH3:1][C:2]1[C:3]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:17]2[NH:22][C:21](=[O:23])[C:20]([CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[C:29]([CH2:31][N:32]([CH3:33])[CH3:34])[CH:30]=3)=[CH:19][N:18]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1CCCCN
Reactant: CN(C)Cc1cncc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)c1
Product: Cc1cccnc1CCCCNc1ncc(Cc2cncc(CN(C)C)c2)c(=O)[nH]1

Procedure:
Reaction 4-(3-methylpyridyl)butylamine with 2-nitroamino-5-(5-dimethylaminomethyl-3-pyridylmethyl)-4-pyrimidone gives 2-[4-(3-methylpyridyl)butylamino]-5-(5-dimethylaminomethyl-3-pyridylmethyl)-4-pyrimidone.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[NH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[N:25]1([NH:24][C:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:20][N:19]=2)=[O:23])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: NN1CCOCC1
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)NN2CCOCC2)nc1
Yield: 82 %

Procedure:
As described for example 7, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (81.6 mg, 0.26 mmol) was converted, using N-aminomorpholine instead of isopropylamine, to the title compound (85 mg, 82%), which was obtained as a white solid. MS: m/e=396.2 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:35])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([N:19]2[CH2:27][C:26]3[C:21](=[C:22]([NH:28][C:29]([CH:31]4[CH2:33][CH2:32]4)=[O:30])[CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:34])[CH2:15][C:16](O)=[O:17])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].C(N1C=CN=C1)([N:38]1C=CN=C1)=O.[OH-].[NH4+].O>O1CCCC1>[F:1][CH:2]([F:35])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([N:19]2[C:20](=[O:34])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][C:22]=3[NH:28][C:29]([CH:31]3[CH2:33][CH2:32]3)=[O:30])[CH2:27]2)[CH2:15][C:16](=[O:17])[NH2:38])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CC(c1ccc(OC(F)F)c(OC(F)F)c1)N1Cc2cccc(NC(=O)C3CC3)c2C1=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)CC(c1ccc(OC(F)F)c(OC(F)F)c1)N1Cc2cccc(NC(=O)C3CC3)c2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
To a solution of 3-(3,4-bis-difluoromethoxy-phenyl)-3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionic acid (400 mg, 0.81 mmol) in tetrahydrofurane was added carbonyldiimidazole (200 mg, 1.21 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added ammonium hydroxide (0.12 ml, 1.6 mmol). The resulted mixture was stirred at room temperature for 2 hours. Water (5 ml) was added to the reaction mixture. THF was removed in vacuo and the resulted mixture was taken up in ethyl acetate (20 ml). The organic layer was washed with saturated sodium bicarbonate solution (3×10 ml), water (10 ml), brine (10 ml) and was dried over magnesium sulfate. The solvent was removed in vacuo. The resulted oil was purified by HPLC (acetonitrile:water=45:55) to give cyclopropanecarboxylic acid {2-[1-(3,4-bis-difluoromethoxy-phenyl)-2-carbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (230 mg, 46%): mp, 198-200° C.; 1HNMR (DMSO-d6): δ 0.87 (d, J=5 Hz, 4H, cyclopropyl ring CH2CH2), 1.74-1.79 (m, 1H, cyclopropyl ring CH), 2.99 (d, J=7.5 Hz, 2H, CH2CONH2), 4.29 (d, J=18 Hz, 1H, CHHN), 4.61 (d, J=18 Hz, 1H, CHHN), 5.69-5.75 (m, 1H, CHN), 6.97 (broad, 1H, NHH), 7.19 (t, JH-F=75 Hz, 1H, OCF2H), 7.22 (t, JH-F=75 Hz, 1H, OCF2H), 7.34-7.37 (m, 3H, Ar), 7.47-7.58 (m, 2H, NHH+1 Ar), 8.23 (d, J=8 Hz, 1H, Ar), 10.51 (s, 1H, NHCO); 13C NMR (CDCl3): 8.26, 15.95, 38.10, 47.37, 51.89, 112.77, 112.90, 116.90, 117.03, 117.40, 117.70, 117.99, 120.57, 121.03, 121.16, 121.74, 125.72, 133.38, 137.51, 138.81, 141.60, 141.65, 141.70, 142.15, 142.20, 142.25, 142.79, 168.74, 171.37, 172.24; Anal. Calcd. for C23H21F4N3O5: C, 55.76; H, 4.27; N, 8.48. Found: C, 55.98; H, 4.00; N, 8.46.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C:10](O)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CCCC1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCCCCC1CCCCC1

Procedure:
4-cyclohexylbutyric acid (Aldrich) is reduced with excess lithium aluminum hydride in ether to yield 4-cyclohexyl-1-butanol (D. S. Hiers and R. Adams, J. Am. Chem. Soc., 48 2385 (1926)) which is chloro-methylated with hydrogen chloride and formaldehyde to yield the desired compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][C@H:14]2[C@H:10]([CH:11]=[CH:12][C:13]2=[O:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Rh]>[CH2:1]([N:8]1[CH2:15][C@H:14]2[C@H:10]([CH2:11][CH2:12][C:13]2=[O:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C1C=C[C@@H]2CN(Cc3ccccc3)C[C@H]12
Agent: [Rh]
Solvent: CCOC(C)=O
Product: O=C1CC[C@@H]2CN(Cc3ccccc3)C[C@H]12
Yield: 83.1 %

Procedure:
5% Rhodium-on-alumina (700 mg) was added to a solution of (1R,5S)-7-benzyl-2-oxo-7-azabicyclo[3.3.0]oct-3-ene (1.57 g, 7.34 mmol) in ethyl acetate (50 ml), and the mixture was vigorously stirred in a hydrogen atmosphere for 3.5 hours. The insoluble matter was removed by Celite filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give 1.31 g (6.10 mmol, 83%) of the title compound as a colorless oily substance.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH:15]1[C:27]([NH2:29])=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH:15]1[CH2:27][NH2:29])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Yield: 99 %

Procedure:
To a stirred suspension of LAH (0.9 g, 25.9 mmol) in dry THF (150 mL) was added 1,4-dibenzyl-piperazine-2-carboxylic acid amide (4.0 g, 12.93 mmol) and the mixture was stirred under reflux for 20 h (monitored by TLC). The stirred mixture was cooled with an ice-bath and quenched with Rochelle's salt (6 mL), warmed to room temperature, and the suspension was poured over a pad of silica gel (20 mm). The celite was washed with 15% MeOH in CH2Cl2 with 1% NH4OH (3×50 mL) and eluted through pad of silica gel. The eluent was concentrated under reduced pressure to give the desired product in 99% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Cl)=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)=[O:5])[CH3:2].CC(C)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:26]=[N+:27]=[N-:28])=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)=[O:5])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1sc(Cl)nc1-c1cccc(C(F)(F)F)c1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1sc(N=[N+]=[N-])nc1-c1cccc(C(F)(F)F)c1
Yield: 97.5 %

Procedure:
To a stirred solution of 2.99 g (8.90 mmole) of 2-chloro-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester, 27 mL of acetone and 27 mL of water was added 2.97 g (45.15 mmole) of sodium azide. The mixture was heated at 70 degrees for 11 hours. The mixture was partitioned between 200 mL of ethyl acetate and 75 mL of water. The aqueous layer was extracted twice with 60 mL of ethyl acetate. The combined ethyl acetate layers were washed with 50 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2.97 g of 2-azido-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester as a dark brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([Br:17])[C:14]=1[O:15][CH3:16])[CH:6]=[C:7]([C:10]#[N:11])[C:8]#[N:9].[C:18]1([OH:28])[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[CH:21]=[CH:20][CH:19]=1.N1CCCCC1>C(O)C>[NH2:9][C:8]1[O:28][C:18]2[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[CH:21]=[CH:20][C:19]=2[CH:6]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:14]([O:15][CH3:16])=[C:13]([Br:17])[CH:12]=2)[C:7]=1[C:10]#[N:11]
Reactant: Oc1cccc2c1CCCC2
Reactant: COc1cc(C=C(C#N)C#N)cc(Br)c1OC
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2c3CCCC2)cc(Br)c1OC
Yield: 1.4 %

Procedure:
To a stirred suspension of 3,4-dimethoxy-5-bromobenzylidenemalononitrile (293 mg, 1 mmol) and 5,6,7,8-Tetrahydro-1-naphthol (148 mg, 1 mmol) in ethanol (4 ml) was added piperidine (0.1 ml, 1 mmol), and the mixture was refluxed for 2 h. The solvent was evaporated and the residue was purified by column chromatography (EtOAc/Hexane, 1:2), yielding the title compound (6 mg, 1.4%). 1H NMR (CDCl3): 7.89 (d, J=2.0, 1H), 6.80-6.69 (m, 3H), 4.63 (s, 3H), 3.86 (s, 3H), 3.83 (s, 3H), 2.72 (m, 4H), 1.8 (m, 4H).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:8]=[C:9]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]2([C:23](=[O:24])[NH:22][C:21](=[O:25])[NH:20]2)[C:12]1=[O:26].O>C(O)(=O)C>[Cl:4][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:11]([CH2:10][C:9]1[CH:27]=[CH:28][C:29]([Cl:30])=[C:7]([Cl:6])[CH:8]=1)[C:12](=[O:26])[C:13]12[C:23](=[O:24])[NH:22][C:21](=[O:25])[NH:20]1
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C1NC(=O)C2(N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=O)C2(N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc12
Reaction time: 0.67 h

Procedure:
Sulphuryl chloride (16.0 ml.) was added during 10 minutes to a stirred mixture of 1'-(3,4-dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (28.2 g.) in acetic acid (400 ml.). The mixture obtained was then stirred at 60°-65° C. for 40 minutes. The clear solution which formed was poured into water (3 l.). The solid which was precipitated was collected by filtration, washed with water and air-dried. Recrystallisation of the crude solid thus obtained from aqueous propan-2-ol gave 5'-chloro-1'-(3,4-dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (15.4 g.), m.p. 257°-259° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.F[C:25]1[C:30]([CH:31]2[CH2:35][N:34]([CH3:36])[C:33](=[O:37])[CH2:32]2)=[CH:29][CH:28]=[CH:27][N:26]=1>CN1C(=O)CCC1>[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:25]2[C:30]([CH:31]3[CH2:35][N:34]([CH3:36])[C:33](=[O:37])[CH2:32]3)=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:19][CH:18]=1
Reactant: CN1CC(c2cccnc2F)CC1=O
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CN1CC(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CC1=O
Temperature: 100 °C
Yield: 73.1 %

Procedure:
To a mixture of cesium carbonate (0.625 g, 1.92 mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (0.445 g, 1.84 mmol), and 4-(2-fluoropyridin-3-yl)-1-methylpyrrolidin-2-one (0.111 g, 0.572 mmol) was added NMP (2 mL). The reaction mixture was degassed and heated to 100° C. for 30 min, heated to 120° C. for 3.5 h, and diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (3×), and the combined organic extracts were washed with 1 M NaOH (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (20% to 80% EtOAc (10% MeOH) in hexanes) gave 4-(2-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyridin-3-yl)-1-methylpyrrolidin-2-one (0.174 g, 0.418 mmol, 73% yield) as a white solid and a 1:1 mixture of enantiomers. MS (ESI, pos. ion) m/z: 417.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[N:8]=[CH:7][N:6]=1>C(O)C>[NH:2]([C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[N:8]=[CH:7][N:6]=1)[NH2:3]
Reactant: Clc1cc(N2CCCCC2)ncn1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1cc(N2CCCCC2)ncn1

Procedure:
17.7 ml (18.2 g, 364.2 mmol) hydrazine hydrate are added dropwise to a solution of 6.0 g (30.4 mmol) 4-chloro-6-piperidin-1-ylpyrimidine in 50 ml ethanol at RT, while stirring. The reaction solution is subsequently stirred at 80° C. for 16 h. For working up, the mixture is concentrated in vacuo, the residue is stirred in water, the solid which has precipitated out is filtered off, the residue on the filter is washed twice with 150 ml water each time and twice with 100 ml diethyl ether each time and the product is dried in vacuo.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH:5]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([Br:17])[CH:12]=1)C(OCC)=O)C.C([O-])([O-])=O.[K+].[K+]>O>[Br:17][C:13]1[CH:12]=[C:11]([CH2:5][C:4]([OH:18])=[O:3])[CH:16]=[CH:15][N:14]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccnc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)Cc1ccnc(Br)c1
Temperature: 100 °C

Procedure:
A suspension of 2-(2-bromo-pyridin-4-yl)-malonic acid diethyl ester (115 g, 316 mmol) and K2CO3 (125.23 g, 907.5 mmol) in water (500 ml) was heated at 100° C. for 8 h under constant stirring. Reaction mixture was cooled to rt and concentrated under reduced pressure to remove solvent completely. The solid residue was dissolved in minimum quantity of water (25 ml) and washed with 20% ethyl acetate in hexane to remove non polar impurities. The aqueous layer was separated and cooled to 0° C. followed by adjusting pH 6 to 7 using aq. 6 N HCl. The precipitated solid was filtered using Buchner funnel, washed with ice cold water and dried under vacuum to furnish title compound as an off white solid. with sufficient purity. Yield: 60.0 g (76.3%). TLC (70% ethyl acetate in hexane) Rf=0.05; LCMS: RtH8=0.193; [M+1]+=215.9 and 217.9; HPLC RtH9=3.025 min (98%); 1H NMR (400 MHz, CDCl3): δ 12.71 (s, 1H), 8.33 (d, 1H), 7.61 (s, 1H), 7.37 (d, 1H), 3.71 (s, 3H).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:18]=[CH:17][C:16]3[N:15]([CH3:19])[C:14]4[CH2:20][CH:21]5[NH:25][CH:24]([C:13]=4[C:12]=3[C:11]=2C(OC(C)(C)C)=O)[CH2:23][CH2:22]5)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:33]CCl.Cl>CO.C(OCC)C>[ClH:33].[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14]2[CH2:20][CH:21]4[NH:25][CH:24]([C:13]3=2)[CH2:23][CH2:22]4)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccccc4)ccc31)C1CCC(C2)N1
Reactant: ClCCl
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cn1c2c(c3cc(S(=O)(=O)c4ccccc4)ccc31)C1CCC(C2)N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86 %

Procedure:
The product from step C (1.22 g, 2.7 mmol) was dissolved in methanol (7 mL) and dichloromethane (5 mL) and 2N HCl in diethylether (70 mL) was added. The reaction was stirred at room temperature for 12 h, after which a precipitate formed. The mixture was diluted with diethylether and filtered providing 2-phenylsulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole hydrochloride (900 mg, 86%) as an off-white solid: Mpt 238-244° C. (dec.); 1H NMR (300 MHz, d6-DMSO) δ 9.69 (brs, 1H), 9.15 (brs, 1H), 8.38 (s, 1H), 7.92 (dd, J=8.0, 1.7 Hz, 2H), 7.60 (m, 5H), 5.36 (d, J=4.8 Hz, 1H), 4.47 (brs, 1H), 3.68 (s, 3H), 3.34 (dd, 1H, partially masked by solvent), 3.00 (d, J=17.2 Hz, 1H), 2.25 (m, 2H), 2.08 (t, J=9.6 Hz, 1H), 1.80 (m, 1H); ESI MS m/z 353 [M+H]+; HPLC (Method A)>99% (AUC), tR=12.02 min.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]([CH2:9][CH3:10])[N:6]=[CH:7][N:8]=1.[C:11]1([N:17]2[C:21]3[NH:22][C:23](=[O:30])[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=4[C:20]=3[CH:19]=[N:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:9]([N:5]1[C:4]([CH2:3][O:30][C:23]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[C:20]3[CH:19]=[N:18][N:17]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:21]=3[N:22]=2)=[N:8][CH:7]=[N:6]1)[CH3:10]
Reactant: CCn1ncnc1CCl
Reactant: O=c1[nH]c2c(cnn2-c2ccccc2)c2ccccc12
Agent: Cl
Product: CCn1ncnc1COc1nc2c(cnn2-c2ccccc2)c2ccccc12
Yield: 76.5 %

Procedure:
Prepared as for Example 1, step c), using 3-chloromethyl-2 -ethyl-2H-[1,2,4]triazole hydrochloride (0.10 g, 0.55 mmol) and 3,4-dihydro-3-phenyl-5H-pyrazolo[3,4-c]isoquinolin-5-one (0.095 g, 0.36 mmol) to give the title compound (0.102 g, 76%) as an off-white powder, m.p. 147-148° C. Found: C, 66.49; H, 4.83; N, 22.16. C21H18N6O.0.5(H2O) requires C, 66.48; H, 5.05; N, 22.15%. δH (400 MHz; CDCl3) 1.47 (3H, t, J=7), 4.30 (2H, q, J=7), 5.82 (2H, s), 7.36 (1H, dd, J=8 and 7), 7.51-7.58 (3H, m), 7.83 (1H, dd, J=8 and 7), 7.96 (1H, s), 8.16 (1H, d, J=8), 8.22 (2H, d, J=8), 8.30 (1H, d, J=8), 8.42 (1H, s); m/z (ES+) 371 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(=O)C)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].C1(O)C=CC=CC=1.[CH3:26][O:27][CH2:28][CH2:29]Br>CN(C=O)C>[CH3:26][O:27][CH2:28][CH2:29][O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CC(=O)N1CCN(c2ccc(O)cc2)CC1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: Oc1ccccc1
Solvent: CN(C)C=O
Product: COCCOc1ccc(N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(4-(2-Methoxyethoxy)phenyl)piperazine is prepared from 4-(4-hydroxy-phenyl)-1-acetylpiperazine. To NaH (60% in mineral oil, 0.79 g, 20 mmol) in DMF (25 ml) add the phenol (3.0 g, 13.6 mmol), followed by 2-bromoethyl methyl ether (2.27 g, 16.3 mmol). Stir at RT 18 h, concentrate, and partition between EtOAc and 5% citric acid. Wash the organic with 1N NaOH, then brine. Dry over MgSO4, and concentrate to obtain the alkylated product as a white solid. Heat this material (2.2 g, 7.9 mmol) in 6N HCl (30 ml) at reflux for 1 h. Allow to cool and basify to pH=10 with NaOH. Extract with CH2Cl2 and wash with water and then brine. Dry the organic with MgSO4 and concentrate to give the piperazine as a yellow oil.
Reaction SMILES: [CH:1]([N:4]([CH:19]([CH3:21])[CH3:20])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[C:10](=O)[C:8]1=[O:9])([CH3:3])[CH3:2].Cl.[NH2:23][NH:24][C:25]([NH2:27])=[O:26]>>[CH:1]([N:4]([CH:19]([CH3:21])[CH3:20])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)/[C:10](=[N:23]\[NH:24][C:25]([NH2:27])=[O:26])/[C:8]1=[O:9])([CH3:3])[CH3:2]
Reactant: NNC(N)=O
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2CCN(C(C)C)C(C)C
Agent: Cl
Product: Cc1ccc2c(c1)/C(=N\NC(N)=O)C(=O)N2CCN(C(C)C)C(C)C
Yield: 53.9 %

Procedure:
By using 1-(2-diisopropylaminoethyl)-5-methylisatin and semicarbazide hydrochloride, a method analogous to that described in Example 4 was carried out to obtain (E)-1-(2-diisopropylaminoethyl)-5-methylisatin 3-semicarbazone having a melting point of 159°-161° C. (yield: 53.9%, recrystallizing solvent: chloroform-hexane).