Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[NH2:31][C:32]1[CH:33]=C(C=[CH:38][CH:39]=1)CN>>[NH2:31][C:32]1[CH:33]=[C:11]([CH:12]=[CH:38][CH:39]=1)[CH2:10][NH:13][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15]
Reactant: NCc1cccc(N)c1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: Nc1cccc(CNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)c1

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 3-aminobenzylamine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 364 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (1H, br. s.) 10.41 (1H, s) 8.58 (1H, t, J=5.93 Hz) 8.03 (1H, d, J=5.47 Hz) 7.80 (1H, d, J=5.42 Hz) 7.50 (1H, d, J=5.42 Hz) 7.31 (1H, dd, J=3.44, 2.32 Hz) 6.93 (1H, t, J=7.69 Hz) 6.85 (1H, d, J=5.47 Hz) 6.50 (1H, s) 6.35-6.46 (3H, m) 5.08 (2H, br. s.) 4.32 (2H, d, J=5.91 Hz)
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:25][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([B:11]3[O:12][C:13]([CH3:18])([CH3:19])[C:14]([CH3:17])([CH3:16])[O:15]3)[CH:4]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: COc1cccc(N)c1
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(NC(=O)c2ccc(C)c(B3OC(C)(C)C(C)(C)O3)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.5 %

Procedure:
4-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (Intermediate 4) (2 g) was dissolved in DMF (20 ml). To this was added 3-methoxyaniline (0.985 g), DIPEA (4 ml) and HATU (3.05 g). The mixture was stirred for 18 h at room temp. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate (250 ml) and water (50 ml). The organic layer was dried (magnesium sulphate) concentrated under vacuum and purified using a silica Biotage cartridge (90 g) eluting with 1:4 ethyl acetate/cyclohexane to give the title compound as a white solid (2.06 g).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[N:11]=[CH:12][N:13]=[C:14]3[C:21]=2[C:20]2[CH2:19][CH2:18][CH2:17][C:16]=2[S:15]3)[CH2:5][CH2:4]1.Cl[CH2:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][N:2]([CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[N:11]=[CH:12][N:13]=[C:14]3[C:21]=2[C:20]2[CH2:19][CH2:18][CH2:17][C:16]=2[S:15]3)[CH2:5][CH2:4]1)[CH2:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25]
Reactant: CNC1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Reactant: O=C(CCl)N1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CC(=O)N1CCCCC1)C1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.3 %

Procedure:
Note: For the preparation of the starting material compound 1, see Example 147. To a solution of 1-N-methyl-4-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]cyclohexane-1,4-diamine (90 mg, 0.30 mmol, 1.00 equiv) in DMF (10 mL) was added 2-chloro-1-(piperidin-1-yl)ethan-1-one (72 mg, 0.45 mmol, 1.50 equiv) and potassium carbonate (83 mg, 0.60 mmol, 2.00 equiv) at room temperature under nitrogen. The resulting solution was stirred overnight at ambient temperature. After completion of the reaction, the solids were removed by filtration and the filtrate was concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (SHIMADZU): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% NH4HCO3 and CH3CN (7.0% CH3CN up to 55.0% in 19 min); Flow rate, 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired 2-[methyl[4-([7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]amino)cyclohexyl]amino]-1-(piperidin-1-yl)ethan-1-one (18.4 mg) as a white solid. MS (ES, m/z): 428 (M+H+); 1H NMR (400 MHz, CD3OD): δ 8.23 (s, 1H), 4.08-4.09 (m, 1H), 3.54-3.59 (m, 4H), 3.39 (s, 2H), 3.08 (t, 2H, J=6.8 Hz), 2.99 (t, 2H, J=6.8 Hz), 2.54-2.59 (m, 3H), 2.34 (s, 3H), 2.16-2.19 (m, 2H), 1.94-1.97 (m, 2H), 1.45-1.70 (m, 10H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.[BH4-].[Na+]>CO.C1COCC1.O.O.O.O.O.O.[Ni](Cl)Cl>[N:18]1([CH:15]2[CH2:16][CH2:17][N:12]([C:5]3[CH:6]=[CH:7][C:8]([NH2:9])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:13][CH2:14]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1cc(N2CCC(N3CCCCC3)CC2)ccc1[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(N2CCC(N3CCCCC3)CC2)ccc1N
Reaction time: 3 h
Yield: 88.7 %

Procedure:
To 1′-[3-(methyloxy)-4-nitrophenyl]-1,4′-bipiperidine (47.9 g, 150 mmol) and nickel(II) chloride hexahydrate (17.8 g, 75.0 mmol) in MeOH (600 mL) and THF (300 mL) cooled to 0° C. was added NaBH4 (˜30 g, ˜750 mmol) at such a rate to control the foaming which occurred. NaBH4 was added until the yellow color disappeared from the foam (TLC confirms consumption of starting material). The mixture was rotovaped down and placed on the high vacuum overnight. EtOAc (1000 mL) was added to the solid and the slurry was stirred for 3 h. The mixture was filtered through a pad of celite, rinsing with generous amounts of EtOAc. The filtrate was washed with 0.1N NaOH (2×1000 mL), dried (MgSO4), filtered, and rotovaped down to give the title compound (38.3 g, 133 mmol, 89%) as a pink solid. 1H NMR (400 MHz, CDCl3) δ 6.60 (d, J=8.4 Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 6.38 (dd, J=8.4, 2.4 Hz, 1H), 3.80 (s, 3H), 3.52-3.45 (m, 4H), 2.61-2.47 (m, 6H), 2.36-2.27 (m, 1H), 1.90-1.63 (m, 4H), 1.61-1.52 (m, 4H), 1.45-1.36 (m, 2H).
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:38]=[CH:37][C:14]([C:15]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=4)[CH:20]=[CH:19][C:18]=3OS(C(F)(F)F)(=O)=O)=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:38]=[CH:37][C:14]([C:15]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=4)[CH:20]=[CH:19][C:18]=3[C:41]3[C:40]([F:39])=[CH:45][CH:44]=[CH:43][C:42]=3[F:46])=[O:16])=[CH:13][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: OB(O)c1c(F)cccc1F
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(-c3c(F)cccc3F)ccc2c1
Temperature: 100 °C

Procedure:
Charge a flask with trifluoromethanesulfonic acid 1-[4-(2-azepan-1-yl-ethoxy)-benzoyl]-6-methoxynaphthalen-2-yl ester (3.9 g, 7.06 mmol), 2,6-difluorophenyl boronic acid (2.23 g, 14.12 mmol), potassium phosphate (9.0 g, 42.20 mmol) and tetrakis(triphenylphosphine)palladium (0) (1.63 g, 1.40 mmol) followed by 125 mL dry DMF. Heat the mixture under nitrogen at 100° C. for 90 minutes. Cool, filter, evaporate the solvent and purify on an SCX cartridge, eluting with 2N ammonia/methanol. Purify further on a silica gel column eluting with 0-10% methanol/methylene chloride. The yield is 2.5 g (70%): 1H-NMR (CDCl3, 400 MHz) δ7.90 (d, J=8.4 Hz, 1H); 7.66-7.61 (m, 3H); 7.39 (d, J=8.4 Hz, 1H); 7.23-722 (m, 1H); 7.18-7.08 (m, 2H); 6.79-6.74 (m, 4H); 4.08-4.05 (t, 2H); 3.95 (s, 3H); 2.96-2.89 (t, 2H); 2.78-2.75 (m, 4H); 1.66-1.59 (m, 8H).
Reaction SMILES: [C:1]([O:20][CH:21]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:22][C:23]([OH:25])=O)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:43][C@H:44]([C:48]([OH:50])=[O:49])[CH:45]([CH3:47])[CH3:46]>>[C:1]([O:20][CH:21]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:22][C:23]([NH:43][C@H:44]([C:48]([OH:50])=[O:49])[CH:45]([CH3:47])[CH3:46])=[O:25])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCC=CCCCCCCCC(=O)OC(CCCCCCCC=CCCCCCCCC)CC(=O)O
Reactant: CC(C)[C@H](N)C(=O)O
Product: CCCCCCCCC=CCCCCCCCC(=O)OC(CCCCCCCC=CCCCCCCCC)CC(=O)N[C@H](C(=O)O)C(C)C
Yield: 72.3 %

Procedure:
Starting from 3-(9-octadecenoyloxy)-11-eicosenoic acid (3.2 g) prepared by the method described in Preparation 8 and L-valine (4.42 g), N-[3-(9-octadecenoyloxy)-11-eicosenoyl]-L-valine (2.7 g) was obtained as powders according to a similar manner to that of Example 6.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH:40]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)([CH3:42])[CH3:41].C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:46]1[CH2:47][CH2:48][N:43]([CH:40]([CH3:42])[CH3:41])[CH2:44][CH2:45]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: CC(C)N1CCNCC1
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2cc(C(=O)N3CCN(C(C)C)CC3)ccc2[nH]1
Reaction time: 0.17 h
Yield: 74.8 %

Procedure:
To the solution of 5.0 g (21.4 mmol) 1H-indole-2,5-dicarboxylic acid 2-ethyl ester (prepared according to J. Org. Chem. 1953, 18, 345-57) in 50 mL N,N-dimethylformamide, 8.6 g (26.8 mmol) O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available) were added. After 10 min., 3.44 g (26.8 mmol) 1-isopropylpiperazine (commercially available) and 18.3 mL (13.9 g, 107.4 mmol) N,N-diisopropylethylamine were added. After 45 min. the reaction mixture was poured on saturated aqueous sodium bicarbonate solution and was extracted three times with ethyl acetate. The combined organic layers were washed three times with water followed by brine, dried over magnesium sulfate, filtered and evaporated. The residue was flash-chromatographed on silica gel with dichloromethane:methanol:ammonia (9:1:0.1 v/v) and ethyl acetate:methanol (9:1) as eluant to give 5.5 g (74%) of the desired compound as a light yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.C([C:11]1([Br:21])[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([CH3:19])[CH3:18])[CH:12]1N)(C)C.[CH2:22](ON=O)[CH2:23][CH:24](C)C.O[PH2]=O>CCO>[CH:23]([C:16]1[CH:15]=[CH:14][C:13]([CH:17]([CH3:18])[CH3:19])=[CH:12][C:11]=1[Br:21])([CH3:24])[CH3:22]
Reactant: CC(C)CCON=O
Reactant: CC(C)C1=CC=CC(Br)(C(C)C)C1N
Agent: O=[PH2]O
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CC(C)c1ccc(C(C)C)c(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Trifluoroacetic acid (75 mL was added to a solution of Intermediate 34 in EtOH (100 mL) at 0° C. After stirring for 10 min, iso-amylnitrite (100 mL) was then added and the mixture was stirred for another 70 min. H3PO2 (70 mL) was added slowly and the mixture was warmed to ambient temperature over 5 hours. After dilution with ethyl acetate and sodium bicarbonate solution, the organic layer was separated, dried and concentrated to give the title compound in a crude form (17 g). Purification of the crude product by Kugelrohr distillation gave the title compound in pure form (13 g, 44% yield over 4 steps from 1,3-di-iso-propyl-benzene) as a colorless oil:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([CH2:10][CH3:11])[CH:3]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:29]1[CH:34]=[CH:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][O:29]2)=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: C1=COCCC1
Reactant: CCc1cc(Br)ccc1CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: CCc1cc(Br)ccc1COC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
To a solution of (4-bromo-2-ethylphenyl)methanol (CAS 877131-21-0) (2.8 g, 13 mmol) in methylene chloride (45 mL) were added pyridinium p-toluenesulfonate (327 mg, 1.3 mmol) and 3,4-dihydro-2H-pyran (2.4 mL, 26 mmol) and stirred at RT for 16 h. The reaction mixture was diluted with water, extracted with methylene chloride, dried with magnesium sulfate and concentrated. Purification by MPLC (30% ethyl acetate in hexanes) afforded 2.9 g of Intermediate 1 as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:23][CH2:24][CH2:25][CH3:26]>CC#N>[CH2:23]([O:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCI
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCCOc1cc(C(=O)OC)cc(C(=O)OC)c1
Reaction time: 16 h

Procedure:
Dimethyl 5-hydroxyisophthalate (0.40 g, 1.90 mmol), cesium carbonate (1.30 g, 3.80 mmol) and CH3CN (12 mL) were added to a round-bottom flask and stirred for 15-30 min. iodobutane (0.42 g, 2.28 mmol) was added, and the reaction was stirred for 16 h. The solvent was concentrated under reduced pressure, and the reaction mixture was partitioned between EtOAc (50 mL) and H2O (50 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (50 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the desired product which was used without further purification.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11](Cl)(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.[C:15]1([NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21]>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([NH:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH2:22])(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: Nc1ccccc1N
Product: Nc1ccccc1NS(=O)(=O)c1cccc2cccnc12

Procedure:
The sulfonamide was synthesized from 8-quinolinyl sulfonyl chloride (0.01 mol) and o-phenylene diamine (0.01 mol) by general Method C. It was purified by recrystallization from EtOH (0.82 g, 27%). EI-MS m/z 300 (M+H)+
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[N+:21]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][C:25]=1[C:31]([F:34])([F:33])[F:32])([O-:23])=[O:22]>ClCCl.N1C=CC=CC=1>[N+:21]([C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:28][C:27]2[CH:29]=[CH:30][C:24]([N+:21]([O-:23])=[O:22])=[C:25]([C:31]([F:32])([F:33])[F:34])[CH:26]=2)=[O:13])=[CH:26][C:25]=1[C:31]([F:32])([F:33])[F:34])([O-:23])=[O:22]
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1)c1ccccc1SSc1ccccc1C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Yield: 6.3 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 4-nitro-3-(trifluoromethyl)aniline (2.39 g, 11.6 mmol) in 19 mL of pyridine. The crude product was recrystallized from ethyl ether to yield 0.25 g of the title compound, mp 167°-169° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24](O)=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[F:27][C:28]1[CH:29]=[C:30]([C:34](=[N:36][OH:37])[NH2:35])[CH:31]=[CH:32][CH:33]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:24]3[O:37][N:36]=[C:34]([C:30]4[CH:31]=[CH:32][CH:33]=[C:28]([F:27])[CH:29]=4)[N:35]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1
Reactant: NC(=NO)c1cccc(F)c1
Product: CCc1ccc(C2CC(c3nc(-c4cccc(F)c4)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1

Procedure:
71 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-[(4-hydroxypiperidin-1-yl)carbonyl]piperidine-3-carboxylic acid (Example 59A) and 46 mg (0.30 mmol, 1.5 eq.) of 3-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 68 mg (72% of theory)
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(=O)([O-])[O-].[K+].[K+].C1(C(C2C=CC=CC=2)[N:18]2[CH2:21][CH:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:19]2)C=CC=CC=1.O>C(Cl)Cl>[F:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH:20]2[CH2:19][N:18]([C:1]([Cl:4])=[O:2])[CH2:21]2)=[CH:24][CH:25]=1
Reactant: O=C(Cl)Cl
Reactant: Fc1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(Cl)N1CC(Oc2ccc(F)cc2)C1
Reaction time: 18 h

Procedure:
A solution of 52.09 g (0.527 mole) of phosgene in 500 ml of methylene chloride was stirred with 73 g (0.53 mole) of potassium carbonate under nitrogen atmosphere for 30 min, then treated with 146.3 g (0.439 mole) of 1-diphenylmethyl-3-(4-fluorophenoxy)azetidine in 300 ml of methylene chloride added dropwise. After stirring for 18 hr, the reaction mixture was treated with 200 ml of water added slowly. The aqueous phase was separated and the organic solution dried by filtration through Whatman phase separating filter paper then concentrated in vacuo to a pale amber oil. Trituration of the oil with 30/60 petroleum ether yielded a crude tacky solid, 89.3 g (88.6%). A portion of this solid was recrystallized from 30/60 petroleum ether yielding a fine white crystalline product, m.p. 44°-52° C. A second recrystallization from isopropyl ether yielded fine white crystals, m.p. 57°-58.5° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([Cl:24])=[CH:5][C:6]2[C:7](=[O:23])[N:8]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:9](=[O:16])[C:10]3[C:15]=2[C:14]=1[CH:13]=[CH:12][CH:11]=3.[CH:25](=O)[CH3:26].C([BH3-])#N.[Na+]>CO.O>[NH2:2][C:3]1[C:4]([Cl:24])=[CH:5][C:6]2[C:7](=[O:23])[N:8]([CH:17]3[CH2:18][CH2:19][N:20]([CH2:25][CH3:26])[CH2:21][CH2:22]3)[C:9](=[O:16])[C:10]3[C:15]=2[C:14]=1[CH:13]=[CH:12][CH:11]=3
Reactant: CC=O
Reactant: Nc1c(Cl)cc2c3c(cccc13)C(=O)N(C1CCNCC1)C2=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCN1CCC(N2C(=O)c3cccc4c(N)c(Cl)cc(c34)C2=O)CC1
Reaction time: 2 h

Procedure:
To a solution of 6-amino-5-chloro-2,3-dihydro-2-(piperidin-4-yl)-1H-benz[de]isoquinoline-1,3-dione hydrochloride (0.9 g; 2.46 mmol), prepared as in Example 10, in methanol (30 mL) and water (5 mL), was added acetaldehyde (2 mL) and sodium cyanoborohydride (approximately 0.5 g) and the reaction mixture stirred for two hours. Additional sodium cyanoborohydride (0.4 g) was added and the mixture stirred for an additional 2 hours. The solution was concentrated to a small volume, acidified with concentrated hydrochloric acid, and then digested for 16 hours. Solid potassium carbonate was added and the solution was extracted twice with methylene chloride. The extracts were combined, dried over potassium carbonate, and concentrated. Purification by column chromatography (silica gel; 3% methanol in CH2Cl2 and approximately 1% NH4OH) gave 6-amino-5-chloro-2-(1-ethylpiperidin-4-yl)-2,3-dihydro-1H-benz[de]isoquinoline-1,3-dione (0.6 g; 1.68 mmol).
Reaction SMILES: [OH-].[Na+].[C:3]([C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19][CH2:20][CH:21]([OH:31])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1)[CH:13]=[CH:12][CH:11]=2)([O:5]CC)=[O:4]>C(O)C>[C:3]([C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19][CH2:20][CH:21]([OH:31])[CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([Br:30])=[CH:28][CH:29]=1)[CH:13]=[CH:12][CH:11]=2)([OH:5])=[O:4]
Reactant: CCOC(=O)c1cc(=O)c2c(OCC(O)COc3ccc(Br)cc3)cccc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(=O)c2c(OCC(O)COc3ccc(Br)cc3)cccc2o1
Yield: 97.6 %

Procedure:
A solution of sodium hydroxide (0.6 g) in ethanol (100 ml) was added to 1-(2-carbethoxychromon-5-yloxy)-2-hydroxy-3-p-bromophenoxypropane (6.6 g) and the mixture was heated under reflux for 1 hour. The resulting sodium salt was filtered, dissolved in the minimum volume of hot water and poured into a solution of acetic acid (100 ml: 2N). The solution was cooled, the precipitated acid was collected, washed with cold water and dried. Recrystallization from dilute acetic acid gave 1-(2-carboxychromon-5-yloxy)-2-hydroxy-3-p-bromophenoxypropane (6.05 g) as white needles, m.p. 192°-194° C.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])#[N:2].Br[CH2:11][C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][CH2:11][C:12]([O:14][CH3:15])=[O:13])#[N:2]
Reactant: COC(=O)CBr
Reactant: N#Cc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CNc1ccccc1C#N
Temperature: 152.5 °C
Yield: 80.4 %

Procedure:
A mixture of 2.2 g of 2-cyanoaniline, 2.0 g of methyl bromoacetate and 1.3 g of potassium carbonate in 12 ml of dry N,N-dimethylformamide is heated at 150-155° C. for 40 minutes. The cooled mixture is poured into ice-water and the mixture filtered to give 2 g of methyl [N-(2-cyanophenyl)amino]acetate as a yellow solid, m.p. 70-78° C. The preceding compound (2.0 g) is added to a solution of 0.5 g of sodium methoxide in 50 ml of methanol. The mixture is shaken under an atmosphere of hydrogen with the catalyst Raney-Ni for 19 hours. The mixture is filtered through diatomaceous earth and the filtrate evaporated. Water is added to the residue and the mixture filtered to give 2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-3-one as a yellow solid, m.p. 167-170° C.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)=O)(C)(C)C.Cl[C:19]1[C:20]([C:27]#[N:28])=[N:21][CH:22]=[C:23]([CH:25]=[CH2:26])[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CO>[CH:25]([C:23]1[CH:22]=[N:21][C:20]2[C:19]([CH:24]=1)=[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]1=[N:8][C:27]=2[NH2:28])=[CH2:26]
Reactant: C=Cc1cnc(C#N)c(Cl)c1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCO
Product: C=Cc1cnc2c(N)nc3ccccc3c2c1
Temperature: 25 °C

Procedure:
A solution of 2-(tert-butoxycarbonylamino)phenylboronic acid (1.0 eq.) and 3-chloro-5-vinylpicolinonitrile (from step 1) (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (2.0 eq.) in toluene/ethanol (2:1, 0.03 M) was stirred at 100° C. overnight. After cooling to ambient temperature, the reaction content was diluted with methanol. The insoluble solids were filtered off, and the filtrate was concentrated en vacuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 2-vinylbenzo[f][1,7]naphthyridin-5-amine as a yellow solid. 1H NMR (methanol-d4-CDCl3): δ 8.87 (d, 1H), 8.69 (d, 1H), 8.28 (d, 1H), 7.49-7.58 (m, 2H), 7.32 (dt, 1H), 6.90 (dd, 1H), 6.09 (d, 1H), 5.54 (d, 1H). LRMS [M+H]=222.1.