Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C@@:4]1([C:30]([O:32]C)=O)[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15]CC3C=CC=CC=3)=[CH:11][CH:10]=2)[N:5]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])#[N:2]>CO.[Ni]>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([C@H:6]2[CH2:7][CH2:8][C@:4]3([CH2:3][CH2:1][NH:2][C:30]3=[O:32])[N:5]2[C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])=[CH:10][CH:11]=1
Reactant: COC(=O)[C@]1(CC#N)CC[C@H](c2ccc(OCc3ccccc3)cc2)N1C(=O)OC(C)(C)C
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(O)cc2)CC[C@]12CCNC2=O
Reaction time: 14 h
Yield: 67.8 %

Procedure:
To a solution of 1-(1,1-dimethylethyl) 2-methyl (2R,5R)-2-(cyanomethyl)-5-{4-[(phenylmethyl)oxy]phenyl}-1,2-pyrrolidinedicarboxylate (D24, 2.7 g, 5.99 mmol): in methanol (50 ml) was added Raney Nickel (slurry in water) and the mixture was stirred under a hydrogen atmosphere (7 atmospheres) for 14 hours. The catalyst was filtered off, the solvent removed under reduced pressure, and the solid residue was treated with toluene (3×20 ml) and dried under vacuum. The dry white solid obtained was refluxed in methanol (40 ml) for five hours until cyclization was complete. The solvent was removed under reduced pressure and the crude material purified by chromatography on silica gel using dichloromethane/methanol (95:5 to 90:10) to afford the title compound as a white solid (1.35 g, 68%); Rt (HPLC): 3.91 min; Rf (dichloromethane:methanol=9:1): 0.41; MS: (ES/+) m/z: 665 [M+Na+], 355 [M+Na+]; C18H24N2O4 requires 332; 1H NMR (400 MHz, DMSO-d6) δ(ppm): 9.11 (s, 1H); 7.76 and 7.66 (s, s, 1H); 7.43 (dd, 2H); 6.66 (dd, 2H); 4.81-4.70 (m, 1H); 3.29-3.20 (m, 1H); 3.19-3.09 (m, 1H); 2.47-2.20 (m, 2H); 2.08-1.85 (m, 2H); 1.84-1.74 (m, 1H); 1.68-1.52 (m, 1H); 1.33 and 1.08 (s, s, 9H).
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[CH:3]=1.[NH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][NH:25][S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]2[C:44]3[C:39](=[C:40]([Cl:46])[CH:41]=[C:42]([Cl:45])[CH:43]=3)[CH2:38][N:37]([CH3:47])[CH2:36]2)[CH:30]=1)(=[O:28])=[O:27]>>[Cl:45][C:42]1[CH:43]=[C:44]2[C:39](=[C:40]([Cl:46])[CH:41]=1)[CH2:38][N:37]([CH3:47])[CH2:36][CH:35]2[C:31]1[CH:30]=[C:29]([S:26]([NH:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][NH:13][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([C:1]([NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][NH:25][S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]4[C:44]5[C:39](=[C:40]([Cl:46])[CH:41]=[C:42]([Cl:45])[CH:43]=5)[CH2:38][N:37]([CH3:47])[CH2:36]4)[CH:30]=3)(=[O:28])=[O:27])=[O:12])[CH:3]=2)(=[O:28])=[O:27])[CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)c1cccc(C(=O)O)c1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN)c2)C1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)c3cccc(C(=O)NCCOCCOCCOCCNS(=O)(=O)c4cccc(C5CN(C)Cc6c(Cl)cc(Cl)cc65)c4)c3)c2)C1
Yield: 77 %

Procedure:
Compound 228 was prepared following the procedure outlined in Example 215 using isophthalic acid (8.0 mg, 0.0484 mmol) and N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (Compound 28, 75 mg, 0.0968 mmol). Purification by preparative HPLC gave the title compound (45.6 mg) as a TFA salt. 1H-NMR (400 MHz, CD3OD): δ 8.25 (s, 1H), 7.92 (d, 2H), 7.85 (d, 2H), 7.73 (s, 2H), 7.58 (t, 2H), 7.49 (m, 5H), 6.81 (s, 2H), 4.83-4.71 (m, 4H), 4.49 (d, 2H), 3.87 (m, 2H), 3.67-3.54 (m, 28H), 3.45 (t, 5H), 3.44 (q, 5H), 3.14 (s, 7H), 2.99 (t, 4H). MS (m/z): 1223.19 [M+H]+.
Reaction SMILES: [C:1]1([C@@H:7]2[C:12]3=[CH:13][C:14]([NH2:26])=[N:15][C:16]4[C@@H:17]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH2:18][CH2:19][N:10]([C:11]=43)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:35]([O:37][CH3:38])=[O:36]>ClCCl>[C:1]1([C@@H:7]2[C:12]3=[CH:13][C:14]([NH:26][C:35](=[O:36])[O:37][CH3:38])=[N:15][C:16]4[C@@H:17]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH2:18][CH2:19][N:10]([C:11]=43)[CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cc2c3c(n1)[C@@H](c1ccccc1)CCN3CC[C@@H]2c1ccccc1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Nc1cc2c3c(n1)[C@@H](c1ccccc1)CCN3CC[C@@H]2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.5 %

Procedure:
To a solution (4R,10R)-4,10-diphenyl-4,5,6,8,9,10-hexahydropyrido[3,2,1-de][1,5]naphthyridin-2-amine (Intermediate 4), (110 mg, 0.322 mmol) in dichloromethane (10 mL) was added two equivalent of triethyl amine (0.090 mL, 0.644 mmol), followed by methyl chloroformate (0.037 mL, 0.483 mmol) under argon at 0° C. The reaction mixture was then stirred at room temperature for overnight. The mixture was quenched with water (30 mL). The residue was isolated in a typical aqueous workup and purified by MPLC (medium pressure liquid chromatography) using silica gel column with 10 to 15% EtOAc:Hexane to give methyl (4R,10R)-4,10-diphenyl-4,5,6,8,9,10-hexahydropyrido[3,2,1-de][1,5]naphthyridin-2-ylcarbamate, (179), (20 mg). 1H NMR (300 MHz, CDCl3) δ ppm 2.00-2.18 (m, 2H) 2.22-2.39 (m, 2H) 3.03-3.22 (m, 4H) 3.50-3.64 (m, 3H) 3.54-3.65 (m, 3H) 4.05-4.23 (m, 2H) 6.61 (br. s., 2H) 7.08-7.38 (m, 10H)
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]([O:25][C:26](=[O:36])[C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1)[CH3:24]>C1(C)C=CC=CC=1>[CH2:23]([O:25][C:26](=[O:36])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]2[N:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)=[O:35])=[CH:29][CH:28]=1)[CH3:24]
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: c1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccccc2)C2CCCCC2)cc1

Procedure:
In analogy to the procedure described in example 1.2, cyclohexyl-(2-phenyl-2H-indazol-3-yl)-amine (example 1.1) was reacted with 4-isocyanato-benzoic acid ethyl ester ([30806-83-8]) in toluene to give the title compound as yellow solid. MS: m/e=483.3 [M+H+].
Reaction SMILES: [ClH:1].F[C:3]1[CH:4]=[C:5]([C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25](F)[CH:24]=2)=[CH:10][O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]=[C:16]([C:20]([OH:22])=[O:21])[CH2:15]2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].O.Cl>C(O)C>[ClH:1].[C:23]1([C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:3][CH:4]=2)=[CH:10][O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]=[C:16]([C:20]([OH:22])=[O:21])[CH2:15]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)C1=CCCN(CCOC=C(c2cccc(F)c2)c2cccc(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1=CCCN(CCOC=C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95.8 %

Procedure:
1-[2-[[2,2-Diphenylethenyl]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridine carboxylic acid methyl ester (4.33 g, 0.01147 mol) (prepared as described in Method D) was dissolved in ethanol (50 ml) and 10 N sodium hydroxide solution (11.5 ml) was introduced, followed by water (5 ml). The solution was stirred at room temperature for 2.5 h and stored at 4° C. for 18 h. 2 N hydrochloric acid solution was added until the pH reached ca. 2, and the mixture was extracted with dichloromethane (3 × 60 ml). The combined extracts were dried (MgSO4) and evaporated to give a foam (4.24 g) which was crystallized from 2-propanol to provide the title compound (2.32 g, 52%) as a white solid, m.p. 173°-176°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([OH:11])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:20][CH2:21][CH2:22][O:23][CH3:24]>C(#N)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([O:11][CH2:20][CH2:21][CH2:22][O:23][CH3:24])[CH:5]=1
Reactant: COCCCI
Reactant: COC(=O)c1ccc(Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCCOc1cc(C(=O)OC)ccc1Br

Procedure:
A solution of 4-bromo-3-hydroxy-benzoic acid methyl ester (12 g, 51.9 mmol), potassium carbonate (10.77 g, 77.9 mmol) and 1-iodo-3-methoxy propane (11.42 g, 57.1 mmol) in acetonitrile (250 mL) is stirred at reflux for 16 h. The solvent is concentrated under reduced pressure, H2O (100 mL) is added, and the aqueous layer extracted with ether (50 mL×4). The combined organic extracts are washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title which was used without further purification in the next step. TLC, Rf (hexane/AcOEt 2:1)=0.65. 1H-NMR (CDCl3, 300 MHz): δ=2.12 (p, 2H), 3.38 (s, 3H), 3.63 (t, 2H), 3.9 (s, 3H), 4.2 (t, 2H), 7.5 (d, 1H), 7.55 (m, 1H), 7.6 (d, 1H) ppm.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)=[CH2:7])[N:3]=[CH:2]1.[H][H]>FC(F)(F)C(O)=O.[Pd]>[NH:1]1[CH:5]=[C:4]([CH:6]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH3:7])[N:3]=[CH:2]1
Reactant: [H][H]
Reactant: C=C(c1c[nH]cn1)c1cccc2cccnc12
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: CC(c1c[nH]cn1)c1cccc2cccnc12
Yield: 86.2 %

Procedure:
The vinyl compound, 8-[1-(1H-imidazol-4-yl)-vinyl]-quinoline (0.23 g) in trifluoroacetic acid:TFA (15 mL) was reduced by the action of 10% Pd/C (58 mg) under 50 psi of hydrogen for 18 h at rt. The mixture was filtered through Celite and basified with NH3-MeOH. The solvent was removed under vacuum. The residue was purified by chromatography on silica gel with 4% NH3-MeOH:CH2Cl2 to give 8-[1-(1H-imidazol-4-yl)-ethyl]-quinoline (Intermediate C2) 0.2 g.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]([C:9]1[O:18][C:12]2[NH:13][CH:14]=[CH:15][C:16](=O)[C:11]=2[CH:10]=1)=[O:8]>CN(C)C=O>[CH3:5][O:6][C:7]([C:9]1[O:18][C:12]2=[N:13][CH:14]=[CH:15][C:16]([Cl:3])=[C:11]2[CH:10]=1)=[O:8]
Reactant: COC(=O)c1cc2c(=O)cc[nH]c2o1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(Cl)ccnc2o1

Procedure:
After adding thionyl chloride (8.0 ml) and dimethylformamide (0.08 ml) to 4-oxo-4,7-dihydro-furo[2,3-b]pyridine-2-carboxylic acid methyl ester (2.0 g), the mixture was heated to reflux for 1 hour. After cooling, the mixture was concentrated under reduced pressure and the precipitated crystals were filtered out and washed with tetrahydrofuran and ethyl acetate to obtain the title compound (2.1 g).
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[C:19]3[C:18]([O:20][CH3:21])=[CH:17][CH:16]=[C:15]([C:22]([O:24]C4C=CC([N+]([O-])=O)=CC=4)=O)[C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=1.[Cl:36][C:37]1[CH:38]=[N:39][CH:40]=[C:41]([Cl:44])[C:42]=1[NH2:43].[H-].[Na+].Cl>CN(C=O)C.O>[Cl:36][C:37]1[CH:38]=[N:39][CH:40]=[C:41]([Cl:44])[C:42]=1[NH:43][C:22]([C:15]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:6][C:5]3[CH:34]=[CH:35][C:2]([F:1])=[CH:3][CH:4]=3)[C:19]=2[C:18]([O:20][CH3:21])=[CH:17][CH:16]=1)=[O:24]
Reactant: Nc1c(Cl)cncc1Cl
Reactant: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2c3ccccc3n(Cc3ccc(F)cc3)c12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c3ccccc3n(Cc3ccc(F)cc3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
To a solution of 4-Nitrophenyl 9-(4-fluoro benzyl)-1-methoxy-9H-4-carbazole carboxylate (50 mg, 0.106 mmoles) in dry DMF (4 ml) under nitrogen atmosphere, 3,5dichloro-4-amino pyridine (17.34 mg, 0.106 mmoles) was added followed by sodium hydride (60% suspension, 8.5 mg, 0.212 mmoles) and the reaction mixture was stirred at room temperature for two hours. Ice pieces were added to the reaction mixture, diluted with water (15 ml) and neutralized with 1N HCl. The precipitated product was filtered, washed with water and dried under vacuum to give 15 mg of the title compound as an off white solid, m.p: 222-225° C.
Reaction SMILES: [Mg].Cl[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C[Mg]Br.[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:28][CH2:29][CH2:30][CH2:31][CH:32]=[O:33]>C(OCC)C.C(Br)C>[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:28][CH2:29][CH2:30][CH2:31][CH:32]([OH:33])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH3:3]
Reactant: CCCCCCCCCCCCCCCCCl
Reactant: O=CCCCOC1CCCCO1
Agent: C[Mg]Br
Agent: [Mg]
Solvent: CCOCC
Solvent: CCBr
Product: CCCCCCCCCCCCCCCCC(O)CCCOC1CCCCO1
Yield: 70 %

Procedure:
To a refluxing mixture of 1.26 g of magnesium turnings, 15.5 ml of 1-chlorohexadecane, and 100 ml of anhydrous diethyl ether were added 0.5 ml of a 3.2 M solution of methylmagnesium bromide in diethyl ether and 0.05 ml of ethyl bromide. The reaction mixture was refluxed for a period of 6 hours. A solution of 3.0 g of 4-[(tetrahydro-2H-pyran-2-yl)oxy]butanal in 10 ml of diethyl ether was added, and the reaction mixture refluxed for an additional hour. The reaction mixture was poured into a mixture of ice and a saturated aqueous solution of ammonium chloride, and filtered. Upon standing the filtrate separated into organic and inorganic phases. The organic phase was dried over anhydrous sodium sulfate and concentrated to an oil. Flash chromatography of the oil utilizing 25% diethyl ether/petroleum ether yielded 4.8 g (70%) of 1-[(tetrahydro-2H-pyran-2-yl)oxy]eicosan-4-ol as a solid, mp 39-43°.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]=[N:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([OH:19])=[C:11]([C:20]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[S:22](=[O:31])(=[O:30])[N:21]=3)[C:10]2=[O:32])=[CH:4][CH:3]=1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[Cl:1][C:2]1[S:6][C:5]([CH2:7][NH:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([OH:19])=[C:11]([C:20]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[S:22](=[O:30])(=[O:31])[N:21]=3)[C:10]2=[O:32])=[CH:4][CH:3]=1
Reactant: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1N=Cc1ccc(Cl)s1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1NCc1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 261A (0.048 g, 0.099 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.008 mL, 0.198 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.074 mL, 0.149 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water (6.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with dichloromethane/diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 4.10 (s, 2 H) 6.24 (t, J=6.43 Hz, 1 H) 7.19 (m, 1 H) 7.30 (m, 3 H) 7.43 (d, J=8.46 Hz, 1 H) 7.56 (m, 3 H) 7.67 (d, J=8.09 Hz, 1 H) 8.12 (d, J=7.72 Hz, 1 H) 15.95 (s, 1 H). MS (ESI−) m/z 485 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][C:8](=[O:10])[CH3:9])=[CH:5][N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.[CH3:17][C:18](C)([O-])C.[Na+].C(Br)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[Cl:1][C:2]1[C:6]([N:7]([CH2:17][CH3:18])[C:8](=[O:10])[CH3:9])=[CH:5][N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)Nc1cn(-c2cccnc2)nc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CCBr
Solvent: C1CCOC1
Product: CCN(C(C)=O)c1cn(-c2cccnc2)nc1Cl
Temperature: 38 °C
Reaction time: 0.08 h

Procedure:
In a 125 mL 3-neck round-bottomed flask was added N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (2.57 g, 9.44 mmol), tetrahydrofuran (55 mL), and sodium tert-butoxide (1.81 g, 18.9 mmol). The suspension was stirred for 5 minutes then ethyl bromide (1.41 mL, 18.9 mmol), and tetrabutylammonium iodide (67 mg, 0.2 mmol) were added. The resulting gray colored suspension was then heated to 38° C. The reaction was analyzed after 3 hours and found to have gone to 81% completion, after 24 hours the reaction was found to have gone to completion. The reaction mixture was allowed to cool to ambient temperature and quenched with ammonium hydroxide/formic acid (HCO2H) buffer (10 mL). The mixture was then diluted with tetrahydrofuran (40 mL), ethyl acetate (120 mL), and saturated sodium bicarbonate (30 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×30 mL). The organic layers were combined and silica gel (37 g) was added. The solvent was removed in vacuo to give a solid that was purified using semi-automated silica gel chromatography (RediSep Silica 220 g column; hexanes (0.2% triethylamine)/ethyl acetate, 40/60 to 0/100 gradient elution system, flow rate 150 mL/minutes) to give, after concentration, an orange solid weighing (2.19 g, 88%)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:19]([C:6]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:7]1=[O:11])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C1Nc2cc(Cl)ccc2C1c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1ccccc1)c1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
A mixture of rac-6-chloro-3-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (0.17 g, 0.6 mmol) (from Example 7b supra), benzyl bromide (0.12 g, 0.7 mmol) (Aldrich), potassium iodide (0.12 g, 0.71 mmol) and potassium carbonate (0.18 g, 1.3 mmol) in acetone (5 mL) was heated at 60° C. for 5 hours in a capped pressure tube. Mixture was then stirred at room temperature over night and then diluted with ethyl acetate (50 mL) and extracted with water (2×50 mL) and brine (50 mL). Aqueous layers were back washed with ethyl acetate (50 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (Biotage 40S, dichloromethane, then 5% ethyl acetate in dichloromethane as solvent) to give two products. Lower Rf sample was recrystallized from ethyl acetate-hexanes to give rac-3-benzyl-6-chloro-3-(4-chloro-phenyl)-1,3-dihydro-indol-2-one as white plates. (Yield 0.16 g, 72.4%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([N:21]=[CH:22]OCC)#[N:20].[ClH:26].C(O)C>C(O)C.C(OCC)C>[ClH:26].[C:19]([NH:21][CH:22]=[N:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:16]=[CH:17][CH:18]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)#[N:20]
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CCOC=NC#N
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: N#CNC=NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C

Procedure:
To a solution of 2.48 g of 3-[3-(1-piperidinylmethyl)phenoxy]-1-propanamine (prepared according to British Pat. No. 2,023,123 which is hereby incorporated by reference) in 25 ml of absolute ethanol, are added dropwise 0.98 g of ethyl N-cyano-formimidate in 15 ml of ethanol, under stirring and at room temperature. Stirring is maintained for 30 minutes, and then the ethanol is removed by underpressure distillation. An oil residue is formed, which is then dissolved in 250 ml of ethyl ether, after which 0.95 ml of 10N HCl/ethanol are added, yielding 1.4 g of N-cyano-N'-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]formamidine hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]([O:15][CH3:16])=[O:14].C(O)(C)(C)C.N.[K].[CH2:24](I)[CH2:25][CH2:26][CH3:27]>O1CCCC1>[CH2:24]([C:4]1([C:13]([O:15][CH3:16])=[O:14])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][CH:12]=[C:3]1[O:2][CH3:1])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCI
Reactant: COC(=O)c1c(OC)ccc2ccccc12
Agent: N
Agent: [K]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CCCCC1(C(=O)OC)C(OC)=CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of methyl 2-methoxynaphthoate (3.25 g, 15 mmol) and tert-butyl alcohol (1.48 ml, 15 mmol) in tetrahydrofuran (10 mL) at −78° C. was added liquid ammonia (60 mL). Potassium metal (2.9 g, 75 mmol) was added in small pieces until the solution stayed dark blue for 30 min. Butyl iodide (5.47 mL, 48 mmol) was added dropwise (the blue coloration disappeared about half-way through addition) and stirring was continued for 1 hour at −78° C. The solution was allowed to warm to room temperature and purged with nitrogen to remove excess ammonia. To the resulting slurry a solution of saturated sodium bicarbonate (100 mL) was added, and the solution was extracted with ether (3×50 mL). The combined organic phases were washed with 10% Na2S2O3 (aq), dried (Na2SO4), and concentrated in vacuo. Column chromatography on silica (20% ethyl acetate/hexane) gave the title compound as a light yellow oil. This oil was triturated with hexane to afford a white solid (3.2 g, 77.6%).
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[CH:14][C:15]([I:17])=[CH:16][C:4]=2[CH2:3]1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>[OH-].[Na+]>[I:17][C:15]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH:2]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:3][C:4]=2[CH:16]=1
Reactant: C1CNCCN1
Reactant: ClC1Cc2cc(I)ccc2Sc2ccccc21
Agent: [Na+]
Agent: [OH-]
Product: Ic1ccc2c(c1)CC(N1CCNCC1)c1ccccc1S2

Procedure:
10.1 g of 10-chloro-10,11-dihydro-2-iodo-dibenzo[b,f]thiepin and 23.3 g of piperazine are held at 120°-130° C for 1 hour. The mixture is cooled, diluted with 2-N sodium hydroxide and extracted with ether. The organic phase is washed with water until neutral and extracted with 500 ml of 2-N hydrochloric acid. The aqueous phase is made alkaline and extracted with chloroform. The organic phase is dried over magnesium sulphate and concentrated under reduced pressure. There is obtained 1-(10,11-dihydro-2-iodo-dibenzo[b,f]thiepin-10-yl)-piperazine as a brown oil.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=[C:9]([Br:13])[CH:10]=2)[NH:5][C:4]1=[O:17].CN(C=O)C.C(N(CC)CC)C.[C:30](=O)([O:36]C(C)(C)C)[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]>O>[Br:13][C:9]1[CH:10]=[C:11]2[C:6](=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=1)[NH:5][C:4](=[O:17])[CH:3]([NH:2][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:12]2
Reactant: NC1Cc2cc(Br)cc([N+](=O)[O-])c2NC1=O
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1Cc2cc(Br)cc([N+](=O)[O-])c2NC1=O
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
3-Amino-6-bromo-8-nitro-3,4-dihydroquinolin-2(1H)-one hydrochloride (610 g) was added to N,N-dimethylformaldehyde (3 L), and triethylamine (554 mL) was added dropwise to the mixture under cooling on ice. Subsequently, di-tert-butyl carbonate (454 g) was added thereto, and the resultant mixture was stirred at room temperature for 30 minutes. Water (3 L) was added to the reaction mixture, and stirring was performed for 30 minutes under cooling on ice. The precipitates were recovered through filtration and washed sequentially with water and diisopropyl ether. The thus-obtained solid was dried, whereby the title compound (674 g) was yielded as a powdery compound.