Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][N:10](CCCN)[CH2:9][CH2:8]1.C(N1CCC(C2C=CC=CN=2)CC1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1
Reactant: NCCCN1CCC(c2ccccn2)CC1
Agent: [Pd+2]
Agent: [OH-]
Agent: c1ccc(CN2CCC(c3ccccn3)CC2)cc1
Solvent: CO
Product: c1ccc(C2CCNCC2)nc1
Reaction time: 24 h
Yield: 99 %

Procedure:
3-[4-(2-Pyridyl)-piperidine-1-yl]propylamine (Scheme 6). To 1-Benzyl-4-(2-pyridyl)-piperidine (3.26 g, 12.9 mmol) in dry methanol (25 ml), 10, palladium hydroxide (1.9 g) was added and the solution was hydrogenated at 200 psi for 24 hours. The solution was filtered over celite, concentrated to give 2.1 g (99%) of 4-(2-pyridyl)-piperidine which was used as such for the subsequent step. A mixture of 3-bromopropylamine hydrobromide (20 g, 91.3 mmol), potassium carbonate (37.85 g, 273.9 mmol) and di-tert-butyldicarbonate (21.90 g, 100 mmol) in methanol was stirred at room temperature for 24 hours. The reaction mixture was concentrated and partitioned between 250 ml EtOAc and 50 ml water, dried over sodium sulfate, filtered and concentrated. Purification of the crude product by column chromatography (Hexane: EtOAc, 4.5:0.5) gave 17.5 g (80%) of the product as a pale yellow oil. To a stirred solution of the 4-(2-pyridyl)-piperidine (1.86 g, 11.4 mmol) in dioxane (20 ml), N-(tert-butoxycarbonyl)-3-bromopropylamine (2.82 g, 11.4 mmol) and potassium carbonate (3.16 g, 22.9 mmol) were added and the solution refluxed for 24 hours. The reaction mixture was cooled to room temperature, concentrated and partitioned between 40 ml chloroform and 5 ml water. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate:methanol, 4:1) to yield 1.86 g (49%) of the required product as a colorless oil; 1H-NMR (CDCl3): δ 1.45 (s, 9H), 1.54-1.69 (m, 8H), 2.21-2.68 (m, 2H), 2.74-2.80 (m, 1H), 3.02-3.22 (m, 4H), 5.41 (s, 1H), 7.13-7.17 (m, 1H), 7.33 (d, J=7.93 Hz, 1H).7.63 (t, J=7.6 Hz, 1H), 8.54 (d, J=4.6 Hz, 1H). To N-(tert-butoxycarbonyl)-3-[4-(2-pyridyl)-piperidin-1-yl]propylamine (0.15 g, 0.45 mmol) in 5 ml of dichloromethane, 1 ml of trifluoroacetic acid was added and the solution stirred at room temperature for 1 hour. The solution was concentrated, neutralized with 10% KOH solution and extracted into 25 ml of dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 0.098 g (100%) of 3-[4-(2-pyridyl)-piperidin-1-yl]propylamine which was used as such for the subsequent step (step h).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[C:10]([O:17][CH3:18])[CH:11]=[CH:12][CH:13]=2)[CH:8]=1)(=O)=O.[CH3:21][N:22](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[CH:8]=[C:7]([C:21]#[N:22])[CH:16]=[CH:15]2
Reactant: COc1cccc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1cccc2ccc(C#N)cc12
Temperature: 80 °C

Procedure:
A solution of 8-methoxy-2-naphthyl trifluoromethanesulfonate (871 mg, 2.8 mmol) in DMF (4 mL) is degassed by repeatedly evacuating the flask then flushing with N2. Zinc cyanide (200 mg, 1.7 mmol) is added followed by Pd(PPh3)4 (165 mg, 0.14 mmol). The resulting mixture is again degassed and heated to 80° C. for 3 hours. The reaction is allowed to cool, poured into water and washed four times with ether. The combined organic extracts are dried (Na2SO4), filtered, and concentrated. The resulting material is purified by column chromatography (step gradient, 10–30% CH2Cl2 in hexanes) to give 8-methoxy-2-naphthonitrile as a white solid (493, 84%). HRMS (EI) calculated for C12H9NO: 183.0684, found 183.0681.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:4][CH:3]1[NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.I[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1.C([O-])([O-])=O.[Cs+].[Cs+].N[C@@H]1CCCC[C@H]1N>O1CCOCC1.CCOC(C)=O.P([O-])([O-])([O-])=O.C([O-])(O)=O.[Na+]>[O:1]=[C:2]1[N:8]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:4][CH:3]1[NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Ic1ccccn1
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)OCc1ccccc1
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2N(c2ccccn2)C1=O)OCc1ccccc1
Temperature: 120 °C
Yield: 61.2 %

Procedure:
To a stirred mixture of benzyl 2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-ylcarbamate (1.20 g, 3.11 mmol, prepared according to J. Med. Chem., 49:2311-2319 (2006), compound #4a), 2-iodopyridine (1.00 g, 4.88 mmol), cuprous iodide (0.15 g, 0.788 mmol) and Cs2CO3 (3.05 g, 9.36 mmol) were combined in dioxane (25 mL). To this mixture was added (+/−)-trans-1,2-diaminocyclohexane (0.19 mL, 1.58 mmol) under nitrogen. The reaction mixture was then heated to 120° C. and gently refluxed for 10 min. It was then cooled to room temperature under nitrogen. This mixture was diluted with 100 mL of EtOAc, 40 mL of pH 4 phosphate buffer and 40 mL of saturated NaHCO3 solution. The insoluble material was removed by filtration through a 2′ pad of CELITE®, and rinsed with EtOAc (2×30 mL). The aqueous phase was separated and extracted with 160 mL of EtOAc. The combined EtOAc extracts were washed with saturated NaHCO3 solution (1×30 mL) and brine (1×20 mL), then dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (hexane/EtOAc) to afford benzyl 2-oxo-5-phenyl-1-(pyridin-2-yl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-ylcarbamate (0.88 g, 61%): 1H NMR (400 MHz, DMSO-d6) δ 8.61 (1H, d, J=8.14 Hz), 8.47 (1H, dd, J=4.73, 1.21 Hz), 7.94-8.03 (1H, m), 7.64 (2H, d, J=7.92 Hz), 7.47-7.60 (4H, m), 7.27-7.44 (9H, m), 6.97 (1H, d, J=8.14 Hz), 5.39 (1H, d, J=8.36 Hz), 5.10 (2H, s); HPLC: RT=2.930 min (CHROMOLITH® ODS 4.6×50 mm (4 min grad) eluting with 10-90% aqueous MeOH over 4 minutes containing 0.0% TFA, 4 mL/min, monitoring at 220 nm); MS(ES): m/z=463.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[C:14]([CH3:20])([CH3:19])[C:15](=[O:18])[NH:16][N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].CC1C=CC(S(O[CH:32]2[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]2)(=O)=O)=CC=1>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[C:14]([CH3:20])([CH3:19])[C:15](=[O:18])[N:16]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CCOc1ccc(C2=NNC(=O)C2(C)C)cc1OCC
Product: CCOc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OCC

Procedure:
Prepared analogously as described for the example B1 (Alternative 1) using 5-(3,4-diethoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound C2) and tert-butyl 4-(Toluene-4-sulfonyloxy)piperidine-1-carboxylate (compound E1) as starting compounds resulting in the hydrochloride salt of the title compound. (compound B2*HCl)
Reaction SMILES: [CH3:1][CH:2]([C:9]([O:11][CH3:12])=[O:10])[C@@H:3]([C:5]([O:7]C)=[O:6])[NH2:4].[NH4+]=S>O.C([O-])([O-])=O.O.O.[Cu].[Cu+2]>[NH2:4][C@@H:3]([CH:2]([CH3:1])[C:9]([O:11][CH3:12])=[O:10])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)C(C)[C@H](N)C(=O)OC
Agent: [Cu+2]
Agent: [Cu]
Agent: O=C([O-])[O-]
Solvent: O
Product: COC(=O)C(C)[C@H](N)C(=O)O
Temperature: 70 °C

Procedure:
A mixture of dimethyl 3-methyl-L-aspartate (Preparation 64, 23 g, 82.55 mmol), CuCO3.Cu(OH)2 (21.9 g, 99.05 mmol) in water (250 mL) was heated to 70° C. for 4 hours. The resulting precipitate was filtered and the filtrate cooled to 0° C. Ammonium sulfide (20% in water, 67.5 mL, 198 mmol) was added slowly ensuring the temperature did not rise above 5° C. The reaction was filtered through arbocel to remove the copper residues and the filtrate concentrated in vacuo. The residue was redissolved in MeOH and filtered through arbocel, with concentration of the filtrate to dryness to afford the title compound as an oil that was used directly in the next step.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]([NH:7][C:8]([C:10]1[C:15]([OH:16])=[CH:14][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:12][N:11]=1)=[O:9])([CH3:6])[CH3:5].[Li+].[OH-].O>C1COCC1>[Cl:23][C:19]1[CH:18]=[C:17]([C:13]2[CH:14]=[C:15]([OH:16])[C:10]([C:8]([NH:7][C:4]([CH3:5])([CH3:6])[C:3]([OH:24])=[O:2])=[O:9])=[N:11][CH:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)C(C)(C)NC(=O)c1ncc(-c2cccc(Cl)c2)cc1O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(NC(=O)c1ncc(-c2cccc(Cl)c2)cc1O)C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 81 %

Procedure:
To a solution of 2-{[5-(3-chlorophenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester, 20, (0.082 g, 0.24 mmol) in THF (4 mL) is added LiOH (0.024 g, 0.98 mmol) and H2O (1 mL) and the resulting solution stirred for 3 days at room temperature. The solvent is removed under reduced pressure and the pale yellow solid that remains is then acidified with 1M HCl to until the pH is approximately 1 and the solution extracted twice with EtOAc. The combined organic layers are combined, dried (Na2SO4), filtered and concentrated under reduced pressure to afford 0.064 g (81% yield) of the desired compound as a white solid. 1H NMR (250 MHz, DMSO-d6) δ ppm 12.99 (1H, br s), 12.25 (1H, s), 9.05 (1H, s), 8.53 (1H, d, J=2.0 Hz), 7.91 (1H, s), 7.74-7.83 (2H, m), 7.51-7.58 (2H, m), 1.58 (6H, s). HPLC-MS: m/z 335 [M+H]+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1>C1C=CC=CC=1>[C:1]1([C:11]2[CH2:4][CH2:3][CH2:2][CH2:1][CH2:6][CH:5]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: C1=C(c2ccccc2)CCCCC1
Temperature: 25 °C
Yield: 84 %

Procedure:
In a round bottom flask fitted with a Dean Stark and a condenser was added a solution of alcohol (obtained above) in benzene (90 mL) and a catalytic amount of p-toluenesulfonic acid. The reaction mixture was refluxed for 3 hours and then cooled to room temperature. The mixture was washed with water (30 mL), brine (30 mL), dried (MgSO4), and concentrated to afford the corresponding alkene 90 (3.1 g, 84% yield). 1H NMR (400 MHz, CDCl3: δ 7.70-7.35 (m, 9H), 6.15 (t, J=8.0 Hz, 1H), 2.75-2.68 (m, 2H), 2.43-2.35 (m, 2H), 1.80-1.60 (m, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[N:13]1[C:17](=[O:18])[NH:16][C:15](=[O:19])[O:14]1)([O-:3])=[O:2].[CH2:20]=[O:21].O>CO.C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[N:13]1[C:17](=[O:18])[N:16]([CH2:20][OH:21])[C:15](=[O:19])[O:14]1)([O-:3])=[O:2]
Reactant: C=O
Reactant: O=c1[nH]c(=O)n(-c2c([N+](=O)[O-])cccc2[N+](=O)[O-])o1
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: O=c1on(-c2c([N+](=O)[O-])cccc2[N+](=O)[O-])c(=O)n1CO
Reaction time: 2 h

Procedure:
2-(2,6-Dinitrophenyl)-1,2,4-oxadiazolidin-3,5-dione (0.05 mole) dissolved in methanol (100 ml) and aqueous formaldehyde (37% conc.; 0.06 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux, with stirring for a period of about 2 hours. After this time the reaction mixture is stripped of methanol and water, leaving a residue. This residue is dissolved in methylene chloride, and the resulting solution is washed with water. The washed solution is dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product 2-(2,6-dinitrophenyl)-4-hydroxymethyl-1,2,4-oxadiazolidin-3,5-dione.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([C:10](N3CCC(N4CCCC4)CC3)=[O:11])=[C:8]([CH3:23])[N:7]=[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=3)[N:5]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.Cl.[OH:68][CH2:69][C@H:70]1[N:74]([CH:75]2[CH2:80][CH2:79][NH:78][CH2:77][CH2:76]2)[CH2:73][C@H:72]([NH:81][C:82](=[O:84])[CH3:83])[CH2:71]1>CN(C=O)C>[CH:1]1([C:4]2[C:9]([C:10]([N:78]3[CH2:77][CH2:76][CH:75]([N:74]4[C@H:70]([CH2:69][OH:68])[CH2:71][C@@H:72]([NH:81][C:82](=[O:84])[CH3:83])[CH2:73]4)[CH2:80][CH2:79]3)=[O:11])=[C:8]([CH3:23])[N:7]=[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:33])([F:34])[F:32])[CH:25]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)N[C@@H]1C[C@@H](CO)N(C2CCNCC2)C1
Reactant: Cc1nc(-c2cccc(OC(F)(F)F)c2)nc(C2CC2)c1C(=O)N1CCC(N2CCCC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H]1C[C@@H](CO)N(C2CCN(C(=O)c3c(C)nc(-c4cccc(OC(F)(F)F)c4)nc3C3CC3)CC2)C1

Procedure:
In analogy to the procedure described for intermediate 2,4-cyclopropyl-6-methyl-2-(3-trifluoromethoxy-phenyl)-pyrimidine-5-carboxylic acid (example 36) was reacted with HATU, triethylamine and N-((3R,5S)-5-hydroxymethyl-1-piperidin-4-yl-pyrrolidin-3-yl)-acetamide dihydrochloride (intermediate 8) in DMF. Subsequent purification by preparative HPLC afforded the title compound as a gum. MS: 562.3 (MH+).
Reaction SMILES: [C:1]([O:23][CH:24]1[CH2:29][C:28]([CH3:31])([CH3:30])[N:27]([OH:32])[C:26]([CH3:34])([CH3:33])[CH2:25]1)(=[O:22])[C:2]1[CH:21]=[CH:20][CH:19]=[C:4]([C:5]([O:7][CH:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[N:11]([OH:16])[C:10]([CH3:18])([CH3:17])[CH2:9]2)=[O:6])[CH:3]=1.[C:35]([O:39][CH:40]1[CH2:45][C:44]([CH3:47])([CH3:46])[N:43]([O:48][CH3:49])[C:42]([CH3:51])([CH3:50])[CH2:41]1)(=[O:38])[CH:36]=[CH2:37]>>[C:5]([O:7][CH:8]1[CH2:13][C:12]([CH3:14])([CH3:15])[N:11]([O:16][CH2:37][CH2:36][C:35]([O:39][CH:40]2[CH2:41][C:42]([CH3:50])([CH3:51])[N:43]([O:48][CH3:49])[C:44]([CH3:46])([CH3:47])[CH2:45]2)=[O:38])[C:10]([CH3:18])([CH3:17])[CH2:9]1)(=[O:6])[C:4]1[CH:19]=[CH:20][CH:21]=[C:2]([C:1]([O:23][CH:24]2[CH2:25][C:26]([CH3:34])([CH3:33])[N:27]([O:32][CH2:37][CH2:36][C:35]([O:39][CH:40]3[CH2:41][C:42]([CH3:51])([CH3:50])[N:43]([O:48][CH3:49])[C:44]([CH3:46])([CH3:47])[CH2:45]3)=[O:38])[C:28]([CH3:31])([CH3:30])[CH2:29]2)=[O:22])[CH:3]=1
Reactant: CC1(C)CC(OC(=O)c2cccc(C(=O)OC3CC(C)(C)N(O)C(C)(C)C3)c2)CC(C)(C)N1O
Reactant: C=CC(=O)OC1CC(C)(C)N(OC)C(C)(C)C1
Product: CON1C(C)(C)CC(OC(=O)CCON2C(C)(C)CC(OC(=O)c3cccc(C(=O)OC4CC(C)(C)N(OCCC(=O)OC5CC(C)(C)N(OC)C(C)(C)C5)C(C)(C)C4)c3)CC2(C)C)CC1(C)C
Yield: 31 %

Procedure:
The title compound is prepared in a 31% yield as a colorless glass from bis(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl) isophthalate and 1-methoxy-2,2,6,6-tetramethylpiperidin-4-yl acrylate according to the general procedure of Example 12. The reaction is reduced from five days to 48 hours in this case.
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][CH3:17])=[CH:12][C:11]=3[O:18]C)[CH:8]=[CH:9][C:2]=12.[Al](Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][CH3:17])=[CH:12][C:11]=3[OH:18])[CH:8]=[CH:9][C:2]=12
Reactant: CNc1ccc(-c2ccc3nonc3c2)c(OC)c1
Agent: Br[Al](Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CNc1ccc(-c2ccc3nonc3c2)c(O)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
100 mg (0.4 mmol) of (4-benzo[1,2,5]oxadiazol-5-yl-3-methoxy-phenyl)-methyl-amine are stirred at −10 to 0° C. in 1.3 mL of CH2Cl2, then over 5 minutes treated with 1.3 mL AlBr3 (1.0 M solution in CH2Br2, 3 eq.) and stirred another 17 h under warming to rt. Then, the mixture is poured onto brine/ethyl acetate and the pH adjusted to 6 using NaHCO3. Then the aqueous phase is extracted with ethyl acetate, the combined organic layers dried with sodium sulfate and concentrated. The crude product is column chromatographed with ethyl acetate/hexanes 1:1 to yield after evaporation of the product-containing fractions the desired product as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:20][CH2:21][CH3:22])[C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:8][C:7]([OH:19])=[CH:6][CH:5]=2.[CH2:23]([O:25][C:26](=[O:31])[C:27](Br)([CH3:29])[CH3:28])[CH3:24]>>[CH2:23]([O:25][C:26](=[O:31])[C:27]([CH3:29])([O:19][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH2:20][CH2:21][CH3:22])[C:2]([CH3:1])=[C:10]2[CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:28])[CH3:24]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCn1c(C)c(CCc2ccccc2)c2cc(O)ccc21
Product: CCCn1c(C)c(CCc2ccccc2)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
The above compound was prepared from 2-methyl-3-(2-phenyl-ethyl)-1-propyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]1[N:18]2[C:19]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[CH:14]([CH2:24][NH:25][CH:26]=O)[NH:15][C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=32)[CH2:8]1>O1CCCC1>[CH3:26][NH:25][CH2:24][CH:14]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[CH2:8][CH2:7][N:18]([C:19]=23)[C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[NH:15]1
Reactant: O=CNCC1Nc2ccccc2N2CCc3cccc1c32
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCC1Nc2ccccc2N2CCc3cccc1c32
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
Lithium aluminium hydride (5.6 g) was charged to a solution of N-[1,2,6,7-tetrahydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine-6-ylmethyl]-formamide (10.3 g) in tetrahydrofuran (300 ml) at 0° C. under nitrogen in two portions (two hours apart). The mixture was stirred at room temperature overnight. The excess lithium aluminum hydride was destroyed carefully with water (6 ml) and sodium hydroxide (6 ml) at 0° C. The mixture was stirred with an additional 18 ml of water for 1 hour. The aluminium salts were filtered off. The tetrahydrofuran solution was concentrated to a foam. This material was dissolved in dichloromethane (200 ml) and washed with brine (200 ml). The solvent was removed and the crude product purified by flash chromatography over a silica gel column (100 g of silica, eluted with 2% methanol/dichloromethane) to afford 9.8 g of product. Recrystallization from hot ethanol (50 ml) yielded 6.18 g of crystals, m.p. 126°-127° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]3([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=4)[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[NH:19][C:18]3=[O:27])[CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:43](Cl)(=[O:45])[CH3:44]>O1CCCC1>[C:43]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]3([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=4)[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[NH:19][C:18]3=[O:27])[CH2:12]2)=[O:10])=[CH:6][CH:7]=1)(=[O:45])[CH3:44]
Reactant: CC(=O)Cl
Reactant: Nc1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.5 %

Procedure:
To a solution of rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-amino-phenyl)-amide (55 mg, 0.11 mmol) (from Example 76b supra) in tetrahydrofuran (2 mL) was added triethylamine (16 mg, 0.16 mmol) (Aldrich), followed by the addition of acetyl chloride (10 mg, 0.13 mmol) (Aldrich). The mixture was stirred at room temperature for 20 minutes. The crude was quenched with water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-acetylamino-phenyl)-amide as a white solid (Yield 30 mg, 50%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[NH2:15][CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17]([NH2:19])=[O:18].CN(C)C=O>C(#N)C>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([CH3:14])[CH:3]=[C:2]2[NH:15][CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17]([NH2:19])=[O:18]
Reactant: NC(=O)C(N)c1ccccc1
Reactant: COc1cccc2c(Cl)cc(C)nc12
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1cccc2c(NC(C(N)=O)c3ccccc3)cc(C)nc12

Procedure:
Preparation was made using a similar procedure as described in example 19, method 19.2. Starting materials were 4-chloro-8-methoxy-2-methylquinoline and 2-amino-2-phenyl-acetamide. Acetonitrile was used as solvent instead of dimethylformamide.
Reaction SMILES: CC1(C)COB([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3([NH:24][C:25](=[O:27])[CH3:26])[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]3)=[CH:10][CH:9]=2)OC1.[Br:29][C:30]1[CH:35]=[CH:34][C:33](I)=[C:32]([F:37])[CH:31]=1.C(=O)([O-])O.[Na+].O>COCCOC.C(OC(C)C)(C)C>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]3([NH:24][C:25](=[O:27])[CH3:26])[CH2:17][O:18][C:19]([CH3:23])([CH3:22])[O:20][CH2:21]3)=[CH:12][CH:13]=2)=[C:32]([F:37])[CH:31]=1
Reactant: Fc1cc(Br)ccc1I
Reactant: CC(=O)NC1(CCc2ccc(B3OCC(C)(C)CO3)cc2)COC(C)(C)OC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: O
Solvent: COCCOC
Product: CC(=O)NC1(CCc2ccc(-c3ccc(Br)cc3F)cc2)COC(C)(C)OC1
Temperature: 100 °C
Reaction time: 15 h
Yield: 62.3 %

Procedure:
A mixed solution of N-(5-{2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]ethyl}-2,2-dimethyl-1,3-dioxan-5-yl)acetamide (7.33 g) of Reference Example 6, 1-bromo-3-fluoro-4-iodobenzene (5.95 g), sodium hydrogen carbonate (9.48 g) and tetrakistriphenylphosphine palladium (434 mg) in 1,2-dimethoxyethane (120 mL)-water (40 mL) was heated under reflux for 8 hr. 1-Bromo-3-fluoro-4-iodobenzene (2.83 g) and tetrakistriphenylphosphine palladium (217 mg) were added to the reaction mixture, and the mixture was further stirred at 100° C. for 15 hr. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography, and the obtained crude crystals were suspended in diisopropyl ether and collected by filtration to give the title compound (5.28 g) as white crystals.