Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([CH2:9][OH:10])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[C:17](OC(=O)C)(=[O:19])[CH3:18].[OH-].[Na+]>CO>[C:17]([NH:1][C:2]1([CH2:9][OH:10])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1)(=[O:19])[CH3:18]
Reactant: CN1CCC(N)(CO)CC1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: CC(=O)NC1(CO)CCN(C)CC1
Yield: 45 %

Procedure:
4-amino-4-hydroxymethyl-1-methylpiperidine (2.95 g, 0.02 mole), potassium carbonate (6.5 g, 0.047 mole) and acetic anhydride (8.5 g, 0.08 mole) in methanol were mixed at room temperature for two hours. Sodium hydroxide was added for neutralization and the solution extracted with chloroform. After evaporation the white solid obtained was crystallized with warm acetone affording 4-acetamido-4-hydroxymethyl-1-methylpiperidine (1.67 g, 0.009 mole, 45% yield).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:6])[CH2:4][C:3]1=[O:7].[CH3:14][C:15]1[C:16]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:17]=2[S:18][C:19]=1[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)O>>[CH3:14][C:15]1[C:16]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:17]=2[S:18][C:19]=1[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:4]1[C:3](=[O:7])[C:2]([CH3:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]=1[OH:6]
Reactant: Cc1ccc2sc(C(O)c3ccccc3)c(C)c2c1
Reactant: CC1(c2ccccc2)C(=O)CC1=O
Product: Cc1ccc2sc(C(C3=C(O)C(C)(c4ccccc4)C3=O)c3ccccc3)c(C)c2c1

Procedure:
23.2 Using general procedure D, 2-methyl-2-phenyl-cyclobutane-1,3-dione (Lit. 1) was reacted with (3,5-dimethyl-benzo[b]thiophen-2-yl)-phenyl-methanol to give the title compound as a colorless solid. MS: 423.5 ([M−H]−).
Reaction SMILES: [N:1]1[C:2]([CH2:13][OH:14])=[CH:3][N:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[S:6][C:5]=12>C(Cl)Cl.O=[Mn]=O>[CH:13]([C:2]1[N:1]=[C:5]2[N:4]([CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[S:6]2)=[O:14]
Reactant: OCc1cn2c(n1)sc1ccccc12
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1cn2c(n1)sc1ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of imidazo[2,1-b]-benzthiazole-2-methanol (2.04 g, 10 mmol) in methylene chloride (200 ml), activated MnO2 (15 g, excess) was added. The reaction mixture was stirred at room temperature for 24 h and filtered through a pad of celite. The reaction mixture was concentrated and the product was purified by silica gel column chromatography by eluting it with 75% ethyl acetate; hexane. Brown solid; Yield: 800 mg, 40%; M+H 203.
Reaction SMILES: [NH2:1][C:2]1[N:12]2[C:13]3[N:8]([C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)=[CH:10][CH2:11]2)[N:7]=[CH:6][C:5]=3[C:4](=[O:24])[N:3]=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.[Cl:41][CH2:42][C:43](Cl)=[O:44].O>O1CCCC1>[Cl:41][CH2:42][C:43]([NH:1][C:2]1[N:12]2[C:13]3[N:8]([C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)=[CH:10][CH2:11]2)[N:7]=[CH:6][C:5]=3[C:4](=[O:24])[N:3]=1)=[O:44]
Reactant: O=C(Cl)CCl
Reactant: Nc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCl)Nc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A 500 mg amount of 5-amino-8-[3-(trifuoromethyl)phenyl]-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one (prepared as described in Example 29) was suspended and stirred in 30 ml of dry tetrahydrofuran, then 1 equivalent (0.322 g) of [1,8-bis(dimethylamino)-naphthalene,N,N,N',N'-tetramethyl-1,8-naphthalenediamine] (Proton Sponge® was added followed by 1.1 equivalents (0.187 g) of chloroacetyl chloride. The reaction mixture was heated at reflux for 16 hours, then allowed to cool to room temperature. The mixture was poured into 200 ml of water and the resulting precipitate was collected by filtration to give 423 mg of the product of the example as a brown solid, m.p. 189°-192° C. (dec).
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:4]=[C:5]2[C:10]=1[CH:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:7]=[C:6]2[CH:15]([OH:17])[CH3:16].N12CCCN=C1CCCCC2.[Cl:37][C:38]([Cl:42])([Cl:41])[C:39]#[N:40]>C(OCC)C>[Cl:37][C:38]([Cl:42])([Cl:41])[C:39](=[NH:40])[O:17][CH:15]([C:6]1[C:5]2[C:10](=[C:2]([Br:1])[N:3]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:24])([CH3:23])[CH3:25])[N:4]=2)[CH:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:7]=1)[CH3:16]
Reactant: CC(O)c1cc(C(F)(F)F)cc2c(Br)n(COCC[Si](C)(C)C)nc12
Reactant: N#CC(Cl)(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc2c(Br)n(COCC[Si](C)(C)C)nc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(±)-1-(3-Bromo-5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethanol (1.07 g, 2.44 mmol) was dissolved in diethyl ether (10 mL), cooled to 0° C. and treated with 1,8-diazabicyclo(5.4.0)undec-7-ene (70 μL, 0.49 mmol). The reaction was stirred for 10 min and treated with trichloroacetonitrile (370 μL, 3.65 mmol) dropwise over 10 min. The reaction was allowed to warm to room temperature overnight and concentrated. Flash chromatography on silica gel (5% ethyl acetate/hexanes) gave 1.29 g (91%) as an oil. 1H-NMR (CDCl3, 300 MHz) δ 8.25 (s, 1H), 7.86 (s, 1H), 6.66 (q, J=6.6 Hz, 1H), 6.27 (d, J=11.7 Hz, 1H), 5.68 (d, J=11.7 Hz, 1H), 3.52-3.59 (m, 2H), 1.77 (d, J=6.6 Hz, 3H), 0.82-0.87 (m, 2H), 0.05 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:27][CH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33](Cl)[CH:32]=1)[OH:30]>>[OH:30][C@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:28][NH:27][CH:22]1[CH2:23][CH2:24][N:19]([C:16]2[CH:17]=[CH:18][C:13]([NH:12][S:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)(=[O:10])=[O:11])=[CH:14][CH:15]=2)[CH2:20][CH2:21]1
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: NC[C@H](O)c1cccc(Cl)c1
Agent: Cl
Product: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)c4ccccc4)CC3)cc2)cc1

Procedure:
The title compound was prepared from 4-methoxy-N-[4-(4-oxo-piperidine-1-yl)-phenyl]-benzenesulfonamide (which was obtained in Example 218) and (1R)-2-amino-1-(3-chloro-phenyl)-ethanol hydrochloride (which was obtained in Example 1) according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.55-1.75 (m, 2H), 2.05-2.15 (m, 2H), 2.50-3.10 (m, 5H), 3.50-3.70 (m, 2H), 3.79 (s, 3H), 4.90-5.05 (m, 1H), 6.10-6.20 (m, 1H), 6.79 (d, J=9.0 Hz, 2H), 6.89 (d, J=9.0 Hz, 2H), 7.05 (d, J=11.8 Hz, 2H), 7.25-7.50 (m, 5H), 7.60 (d, J=11.8 Hz, 2H), 9.70 (brs, 1H); MS (ES) m/z: 482.2 (MH+); HRMS Calcd. for C26H32N3O4S(MH+): 482.2114. Found: 482.2120.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:10]2[CH2:21][C@@H:7]1[CH2:8][CH2:9]2)=O)C.[Na].[Br:23][C:24]1[CH:39]=[N:38][C:27]2[NH:28][C:29]([CH2:34][C:35]([O-])=[O:36])=[N:30][S:31](=[O:33])(=[O:32])[C:26]=2[CH:25]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[Br:23][C:24]1[CH:39]=[N:38][C:27]2[NH:28][C:29]([C:34]3[C:35](=[O:36])[N:12]([CH2:13][C:14]4[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=4)[C@@H:11]4[C@H:6]([C:4]=3[OH:3])[C@@H:7]3[CH2:21][C@H:10]4[CH2:9][CH2:8]3)=[N:30][S:31](=[O:33])(=[O:32])[C:26]=2[CH:25]=1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)cc1
Reactant: O=C([O-])CC1=NS(=O)(=O)c2cc(Br)cnc2N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1C(C2=NS(=O)(=O)c3cc(Br)cnc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Reaction time: 0.02 h
Yield: 60.3 %

Procedure:
(1 S,2R,3S,4R)-3-(4-Fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 61, 0.213 g, 0.73 mmol), sodium-(7-bromo-1,1-dioxo-1,4-dihydro-1λ6-pyrido[2,3-e][1,2,4]thiadiazin-3-yl)-acetate (0.25 g, 0.73 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.305 g, 0.803 mmol) were combined and dissolved in N,N-dimethylformamide (1.5 mL). The mixture was shaken vigorously for about 1 min until everything dissolved. The solution continued to stir for 1 h. Triethylamine (0.5 mL, 3.65 mmol) was added and the mixture was stirred at 50° C. for 16 h. The mixture was concentrated in vacuo to a volume of ˜5 mL. Water (˜20 mL) was added and the product precipitated. The solid was collected by vacuum filtration and purified by flash column chromatography (Merck silical gel 60, 40-63 μm; 35% ethyl acetate in hexanes) to afford the desired product, (0.24 g, 0.44 mmol, 60%) as a white, brittle foam. A portion of the product (0.07 g, 0.128 mmol) was recrystallized from n-propanol (0.5 mL) to afford the pure desired product, 5-(7-bromo-1,1-dioxo-1,4-dihydro-1λ6-pyrido[2,3-e][1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.044 g, 0.081 mmol, 63%), as a yellow powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.13-1.23 (2H, m), 1.38-1.60 (4H, m), 2.51 (1H, s), 2.63 (1H, s), 3.00 (1H, d, J=8.4 Hz), 3.55 (1H, d, J=9.4 Hz), 4.41 (1H, d, J=14.7 Hz), 4.95 (1H, d, J=15.4 Hz), 7.14 (2H, t, J=9.0 Hz), 7.33 (2H, dd, J1=8.6 Hz, J2=5.5 Hz), 8.66 (1H, s), 8.82 (1H, s). LC-MS (ESI) calcd for C23H20BrFN4O4S 546.04, found 547.2 [M+H+].
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[Br:11][C:12]1[N:17]=[C:16]([CH2:18][NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[O:29][CH3:30])[CH:15]=[CH:14][CH:13]=1>O1CCCC1>[Br:11][C:12]1[N:17]=[C:16]([CH2:18][N:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[O:29][CH3:30])[CH:1]=[O:3])[CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CNCc2cccc(Br)n2)c(OC)c1
Solvent: O=CO
Solvent: C1CCOC1
Product: COc1ccc(CN(C=O)Cc2cccc(Br)n2)c(OC)c1
Temperature: 55 °C
Reaction time: 0.75 h

Procedure:
To acetic anhydride (0.703 mL) was added dropwise formic acid (0.349 mL) under ice-cooling, and the mixture was stirred at 55° C. for 45 min. The mixture was allowed to be cooled to room temperature, and tetrahydrofuran (10 mL) was added thereto. A solution of 1-(6-bromopyridin-2-yl)-N-(2,4-dimethoxybenzyl)methanamine obtained in Reference Example 19 (930 mg) in tetrahydrofuran (10 mL) was added dropwise thereto over 3 min under ice-cooling, and the reaction mixture was stirred at room temperature for 30 min. The reaction solution was concentrated under reduced pressure, the obtained colorless oil was subjected to azeotropy with toluene, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (932 mg).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1.Cl.Cl[CH2:17][C:18]1[S:22][CH:21]=[N:20][CH:19]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[S:22]1[C:18]([CH2:17][O:3][CH:4]2[CH2:5][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7]2)=[CH:19][N:20]=[CH:21]1
Reactant: ClCc1cncs1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(OCc2cncs2)C1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in oil, 292 mg, 7.30 mmol) was added to a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (602 mg, 3.47 mmol) in dimethylformamide (8 mL) at room temperature. The reaction mixture was stirred for 30 minutes prior to the addition of a solution of 5-(chloromethyl)thiazole hydrochloride (1.18 g, 6.85 mmol) and diisopropylethylamine (2.42 mL, 13.89 mmol) in dimethylformamide (3 mL) at 0° C. The reaction mixture was then heated up to 80° C. and stirred overnight. Since the LCMS monitoring still indicated the presence of starting material, an additional portion of sodium hydride (60% in oil, 139 mg, 3.47 mmol) was added. The reaction mixture was then stirred again at 80° C. After 17 hours stirring at 80° C., the reaction mixture was partitioned between ethyl acetate (20 mL) and water (20 mL). The aqueous phase was separated and extracted with ethyl acetate (2×40 mL). The combined organic phases were washed with a solution of sodium hydroxide (5×50 mL) and with brine (3×100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel, using petroleum ether/dichloromethane/ethyl acetate (7/0/3 to 2/0/8, then 0:5:5 to 0/2/8) as eluent. A second purification was performed on silica gel, using petroleum dichloromethane/acetone (9/1 to 8/2) as eluent. The title product was obtained as a yellow oil (150 mg, 16%).
Reaction SMILES: [C:1]1(=[O:14])[C:6]2[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[S:9][C:5]=2[CH2:4][CH2:3][NH:2]1.I[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[CH3:22].N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:22][C:21]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N:2]1[CH2:3][CH2:4][C:5]2[S:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[C:6]=2[C:1]1=[O:14]
Reactant: O=C1NCCc2sc3ccccc3c21
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2sc3ccccc3c2C1=O
Yield: 43.7 %

Procedure:
Using analogous reaction conditions as described in Example 1, 3,4-dihydro-2H-benzo[4,5]thieno[3,2-c]pyridin-1-one (I-9d: 0.15 g, 0.0007 mol) was reacted with 3-iodo-4-methyl-pyridine (0.178 g, 0.0008 mol), 1,4-dioxane (50 mL), copper iodide (0.014 g, 0.00007 mol), trans-1,2-diamino cyclohexane (0.03 g, 0.0002 mol) and potassium phosphate (0.39 g, 0.0018 mol) to afford the crude product. Purification by column chromatography on silica gel (1.5% methanol in CHCl3) afforded 90 mg of the product (39.13% yield).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.[S:14](=O)(=[O:17])([OH:16])[OH:15]>>[Br:1][CH2:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:6][CH:5]=1
Reactant: BrCCc1cccc2ccccc12
Reactant: O=S(=O)(O)O
Product: O=S(=O)(O)c1ccc(CCBr)c2ccccc12
Temperature: 0 °C
Reaction time: 24 h

Procedure:
1-(2-bromoethyl)naphthalene (120 g) was stirred in an ice bath while fuming sulfuric acid (50 g) was slowly added dropwise. After the dropwise addition, the mixture was stirred at 0° C. for 24 hours, whereby 4-(2-bromoethyl)naphthalenesulfonic acid was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7][OH:8].N1C=CC=CC=1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C(Cl)(Cl)Cl>[C:17]([O:8][CH2:7][C:6]1[CH:9]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[Cl:10])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1cc(Br)ccc1Cl
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(OCc1cc(Br)ccc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-2-chlorobenzylalcohol (1.0 g) and pyridine (0.44 mL) in chloroform (40 mL) was added benzoyl chloride (0.58 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1N HCl under ice-cooling, and the mixture was extracted with chloroform. The organic layer was washed successively with water, an aqueous saturated sodium hydrogencarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. The resultant residue was triturated with diisopropylether to give 5-bromo-2-chlorobenzyl benzoate (753 mg) as a colorless powder.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H-].[Na+].Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:22][C:23]2[C:28]([Cl:29])=[CH:27][N:26]=[CH:25][C:24]=2[Cl:30])=[N:12][N:11]=1.O>CN(C=O)C>[Cl:30][C:24]1[CH:25]=[N:26][CH:27]=[C:28]([Cl:29])[C:23]=1[CH2:22][C:13]1[C:14]2[C:19](=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:10]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])[NH:11][N:12]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)C(N1CCCC1=O)NN=C2Cc1c(Cl)cncc1Cl
Temperature: 40 °C
Yield: 53.5 %

Procedure:
A solution of 2-pyrrolidinone (0.14 ml, 1.83 mmoles) in dry DMF (10 ml) under N2 was added with NaH (0.068 g, 1.7 mmoles; 60% in oil) and the mixture was heated to 40° C. for 1 hour, cooled and added with 4-chloro-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (0.5 g, 1.41 mmoles), prepared as described in example 45. The mixture was heated to 80° C. overnight, then poured into water (10 volumes) and extracted three times with ethyl acetate. The organic phase was discoloured with charcoal, anhydrified and concentrated to give a solid which was flash chromatographed (eluent: ethyl acetate/petrolatum 9:1). The resultant solid was triturated in ethyl ether and 0.306 g of the title compound were yielded (yield: 53%). m.p.: 223-225° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.Cl.[O:12]([NH2:14])[CH3:13]>>[CH3:13][O:12][N:14]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:9]
Reactant: CON
Reactant: CC(=O)c1ccc(F)cc1
Agent: Cl
Product: CON=C(C)c1ccc(F)cc1
Yield: 92 %

Procedure:
Reaction of 4′-fluoroacetophenone with methoxylamine hydrochloride as described in the preparation of compound 1-A gave the title oxime ether as a clear oil (92% yield). 1HNMR indicated a 87:13 mixture of E and Z isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 2.21 (3H, s, CH3), 3.99 (3H, s, OCH3), 7.04 (2H, m, aromatics), 7.63 (2H, m, aromatics).
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:18]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:17]3[CH:27]=[CH:28][CH:29]=[CH:30][C:16]=3[N:15]=2)[CH2:9][CH2:8]1>O1CCCC1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:18]2[C:17]3[CH:27]=[CH:28][CH:29]=[CH:30][C:16]=3[N:15]=[C:14]2[NH:13][CH:10]2[CH2:11][CH2:12][N:7]([CH2:6][CH2:5][N:4]=[C:1]=[S:3])[CH2:8][CH2:9]2)=[CH:21][CH:22]=1
Reactant: S=C=S
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Solvent: C1CCOC1
Product: Fc1ccc(Cn2c(NC3CCN(CCN=C=S)CC3)nc3ccccc32)cc1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred and cooled (below 10° C.) mixture of 5.04 parts of carbon disulfide, 2.06 parts of N,N'-methanetetraylbis[cyclohexanamine] and 45 parts of tetrahydrofuran was added dropwise a solution of 3.7 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-(4-fluorophenylmethyl)-1H-benzimidazol-2-amine in tetrahydrofuran. Upon completion, stirring was continued overnight while the mixture was allowed to reach room temperature. The reaction mixture was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 4 parts (100%) of 1-(4-fluorophenylmethyl)-N-[1-(2-isothiocyanatoethyl)-4-piperidinyl]-1H-benzimidazol-2-amine as a residue (intermediate 141).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[CH2:24]([NH2:27])[CH2:25][CH3:26].C(O)(=O)C.O>CCO>[CH2:24]([NH:27][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4])[CH2:25][CH3:26]
Reactant: CCCN
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 80 °C
Yield: 51.2 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (35 mg, 0.11 mmol) and n-propylamine (0.1 mL, 1.1 mmol) in 2 mL of EtOH was heated in a sealed tube at 80° C. for 4 h. After cooling to r.t., acetic acid (0.1 mL) and water (3 mL) were added. The mixture was extracted several times with EtOAc. The combined organic layer was dried over MgSO4 and concentrated. The crude product was chromatographed (5-35% EtOAc/hexanes) to give 19 mg of the title compound. MS: (+) m/z 338.02 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])(C)C.FC(F)(F)C(O)=O.C(=O)([O-])ON1C(=O)CC(C[C:34]2[C:46]3C[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:38]=3[CH:37]=[CH:36][CH:35]=2)C1=O>ClCCl>[CH:43]1[C:44]2[CH:4]([CH2:1][O:5][C:6]([NH:8][C:9]([CH3:16])([CH3:17])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[O:7])[C:46]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:39]=2[CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: O=C([O-])ON1C(=O)CC(Cc2cccc3c2Cc2ccccc2-3)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C/C=C/C(=O)O)NC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 1 h
Yield: 36.5 %

Procedure:
To a solution of (2E)-5-(tert-butyloxycarbonylamino)-5-methylhex-2-enoic acid (0.5 g, 2.1 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (5 ml) and stirred for 60 min and concentrated in vacuo. Then a 10% aqueous solution of sodium carbonate (30 ml) and dioxane (30 ml) were added followed by 9H-fluorenylmethyl-succinimidyl carbonate (0.67 g, 2.1 mmol) and stirred overnight. The mixture was washed with petrol ether (2×20 ml) and the aqueous layer was acidified with 4N sulphoric acid (pH~3) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with 1N sulfuric acid, water (4×20 ml), brine (20 ml), dried (Magnesiumsulfate) and concentrated in vacuo. The obtained product was precipitated from dichloromethane/ether and filtered to give 280 mg of (2E)-5-(((9H-flouren-9-yl)methoxy)carbonylamino)-5-methyl-hex-2-enoic acid, which was used without further purification.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=O)=O)=[CH:3][CH:2]=1.[I-].[Na+].[I-].S(=O)(O)[O-].[Na+].II.[OH-].[Na+]>C(O)(=O)C.O>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7][S:7][C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: II
Agent: O=S([O-])O
Agent: [I-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(SSc2ccc(C)cc2)cc1
Temperature: 60 °C
Yield: 96.6 %

Procedure:
19 g (0.1 mole) of p-toluene sulfonyl chloride are dissolved in 100 ml acetic acid whereupon 1.5 g (0.01 mole) of sodium iodide are added and the reaction mixture is stirred until the iodide is completely dissolved (5 minutes). The reaction mixture becomes dark brown. A 30% sodium bisulfite solution is slowly added dropwise at a rate that on addition the iodine color of the mixture should just disappear. During the dropwise addition the temperature of the mixture is raised to 60° C. (within about 30 minutes). The reaction is continued at this temperature until the color of iodine does not appear any more. At the end of the reaction the reaction mixture is diluted with 50 ml of water and the pH is adjusted to the value of 4 by adding a 20% sodium hydroxide solution. The reaction mixture is extracted three times with 80 ml of n-hexane each, the hexane phases are combined, dried over anhydrous sodium sulfate and evaporated under atmospheric pressure. From the distillation residue the traces of solvent are removed at 70° C. in vacuo and the product is crystallized at 20° C. Thus 11.9 g of p-tolyl-disulfide are obtained, yield 97%. Mp.: 43°-45° C.