Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:11])[N:5]=[CH:4][N:3]=1.N[CH2:13][C:14]1C=C(C=CC=1)CN(CC1NC2C=CC=CC=2N=1)C1C2N=CC=CC=2CCC1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH2:13]([O:9][C:8]([C:7]1[C:2]([CH3:1])=[N:3][CH:4]=[N:5][C:6]=1[CH3:11])=[O:10])[CH3:14]
Reactant: Cc1ncnc(C)c1C(=O)O
Reactant: NCc1cccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)c1c(C)ncnc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure F: A solution of 4,6-dimethyl-pyrimidine-5-carboxylic acid from above (prepared as described in patent application PCT/US00/11632) (42 mg, 0.28 mmol), (3-aminomethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (100 mg, 0.25 mmol), HOBT (38 mg, 0.28 mmol) and 4-methylmorpholine (40 μL, 0.38 mmol) in DMF (0.8 mL) was flushed with N2. EDCI (54 mg, 0.28 mmol) was added and the mixture was stirred at room temperature overnight. Purification of the colorless syrup (150 mg) by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 100:2:1) followed by radial chromatography on silica gel (1 mm plate, CH2Cl2/MeOH/NH4OH, 100:2:1) afforded AMD11084 (80 mg, 60%) as a white foam. 1H NMR (CDCl3) δ 1.64-1.77 (m, 1H), 1.91-2.08 (m, 2H), 2.18-2.34 (m, 1H), 2.37 (s, 6H), 2.69-2.91 (m, 2H), 3.73 (s, 2H), 3.80 (d, 1H, J=16.5 Hz), 4.00 (d, 1H, J=16.5 Hz), 4.07-4.13 (m, 1H), 4.69 (d, 2H, J=5.7 Hz), 6.53 (t, 1H, J=5.7 Hz), 6.96-7.10 (m, 3H), 7.16-7.22 (m, 2H), 7.29-7.31 (m, 2H), 7.40-7.45 (m, 3H), 8.64 (d, 1H, J=3.6 Hz), 8.81 (s, 1H); 13C NMR (CDCl3) δ 21.71, 22.28, 24.38, 29.55, 44.29, 49.22, 55.11, 61.90, 111.12, 118.82, 121.68, 122.78, 127.32, 128.67, 129.09, 129.24, 130.48, 135.22, 137.66, 137.83, 140.30, 147.22, 156.42, 157.60,157.91, 163.43, 166.96. ES-MS m/z 532.4 (M+H). Anal. Calcd. for C32H33N7O.0.4CH2Cl2: C, 68.80; H, 6.02; N, 17.33. Found: C, 68.56; H, 6.09; N, 17.34.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:22])[C:4]1[C:14]2[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.[H-].[Na+].[C:25]([C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][C:36]=1[O:37][CH:38]([CH3:40])[CH3:39])[C:30](OC)=O)#[N:26]>C1COCC1>[C:25]([C:27]1[CH:28]=[C:29]([C:30]2[O:1][N:2]=[C:3]([C:4]3[C:14]4[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:10][CH2:9][C:8]=4[CH:7]=[CH:6][CH:5]=3)[N:22]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH:38]([CH3:39])[CH3:40])#[N:26]
Reactant: COC(=O)c1ccc(OC(C)C)c(C#N)c1
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(C(=N)NO)c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCN(C(=O)OC(C)(C)C)CC4)no2)cc1C#N
Yield: 85.8 %

Procedure:
1,1-Dimethylethyl 6-[(hydroxyamino)(imino)methyl]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (Preparation 15) (360 mg, 1.179 mmol) was dissolved in THF (50 ml) and stirred with sodium hydride (60% dispersion in mineral oil, 51.9 mg, 1.297 mmol) under argon at room temperature for 30 minutes. Then methyl 3-cyano-4-[(1-methylethyl)oxy]benzoate (may be prepared as described in WO2005058848) (388 mg, 1.768 mmol) was added as a THF solution (5 ml) and the reaction heated at reflux temperature for 1.5 hours. The cooled reaction was evaporated and partitioned between DCM (100 ml) and water (100 ml). The water layer was washed with DCM (50 ml) and the combined DCM layers dried (hydrophobic frit) and evaporated. The product was isolated by silica chromatography (eluting with DCM) to give 1,1-dimethylethyl 6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (505 mg, 1.011 mmol, 86% yield) as a white foam. δH (400 MHz, CDCl3) 8.41 (1H, s), 8.33 (1H, dd), 7.7 (1H, dd), 7.31-7.25 (2H, m), 7.13 (1H, d), 4.80 (1H, sept), 3.63-3.62 (4H, m), 3.3-3.2 (2H, m), 2.95-3.05 (2H, m), 1.47 (6H, d), 1.43 (9H, br.s); MS (ES) C27H30N4O4 requires 474; found 475 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10]C(C(OC)=O)=[CH:4][C:3]=1[CH3:12].[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].CC(C)([O-])C.[K+]>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:14]([C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:4][C:3]=1[CH3:12]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: CC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1Br
Reaction time: 0.17 h

Procedure:
To a mixture of methyl 4-bromo-3-methylbenzoate (4.85 g) and tert-butyl acetate (3 mL) was added 1M potassium tert-butoxide in THF (0.3 mL). The mixture was stirred under vacuum for 10 minutes and treated with another equivalent of tert-butyl acetate and 1 mol % of (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane. This procedure was repeated three times. The mixture was diluted with ethyl acetate (40 mL) and washed with 5% aqueous HCl, water and brine. After drying over Na2SO4, the mixture was concentrated.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH:18]1[C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]2[C:27]([O:29][C:30](=O)[C:20]=2[CH:19]=1)=[O:28]>>[CH3:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:4]3[CH:3]=[C:2]([N:1]4[C:27](=[O:28])[C:21]5[C:20](=[CH:19][CH:18]=[C:23]([C:24]([OH:26])=[O:25])[CH:22]=5)[C:30]4=[O:29])[CH:7]=[CH:6][CH:5]=3)[O:9][C:10]=2[CH:16]=1
Reactant: Cc1ccc2nc(-c3cccc(N)c3)oc2c1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: Cc1ccc2nc(-c3cccc(N4C(=O)c5ccc(C(=O)O)cc5C4=O)c3)oc2c1

Procedure:
Prepared by the method of Example 1b), from 2-(3-aminophenyl)-6-methylbenzoxazole (32 mg, 0.14 mmol) and 1,2,4-benzenetricarboxylic anhydride (30 mg, 0.16 mmol) the title compound was obtained, 42 mg (72%). 1H NMR (DMSO) δ 8.45(dd, 1H), 8.34(bd, 2H), 8.25(dt, 1H), 8.13(d, 1H), 7.75(m, 3H), 7.63(s, 1H), 7.26(d, 1H), 2.50(s, 3H). MS 397 m/z (M−H)−.
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[C:6]([O:17][CH3:18])[C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[C:9]=2[O:11][CH3:12])[CH2:4][CH:3]1[CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1.Cl>[C].[Pd].CO>[CH3:18][O:17][C:6]1[C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[C:9]([O:11][CH3:12])=[C:10]2[C:5]=1[CH2:4][CH:3]([CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH2:2]2
Reactant: COC(=O)c1ccc(OCCCCC2Cc3c(OC)c(OC)c(OC)c(OC)c3C2O)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(OCCCCC2Cc3c(c(OC)c(OC)c(OC)c3OC)C2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.3 %

Procedure:
A methanol (30 ml) suspension of methyl 4-[4-(1-hydroxy-4,5,6,7-tetramethoxyindan-2-yl)butoxy]benzoate (1.50 g, 3.26 mmols), concentrated hydrochloric acid (0.0652 ml, 0.652 mmols) and 10% palladium-carbon (300 mg) was stirred under a hydrogen stream at room temperature for 4 hours. The palladium-carbon was removed by filtration, and the filtrate was concentrated in vacuo. The resulting crude product was purified by recrystallization (from hexane) to obtain the entitled compound (1.25 g) as crystals.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9](I)[CH:8]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1B(O)O>>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:19]3[S:18][CH:22]=[CH:21][CH:20]=3)[CH:8]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1
Reactant: Nc1nc2ccccc2n1-c1cccc(I)c1
Reactant: OB(O)c1cccs1
Product: Nc1nc2ccccc2n1-c1cccc(-c2cccs2)c1

Procedure:
2-Amino-1-[3-(2-thienyl)phenyl]benzimidazole was prepared from 1-(2-amino-1-benzimidazolyl)-3-iodobenzene and 2-thienylboronic acid by method B. mp 142°-144° C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[CH2:6][N:7]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH:15]=3)[C:10]([OH:25])=[C:9]([C:26]([NH:28][CH3:29])=[O:27])[C:8]2=[O:30])[CH2:3][CH2:2]1.[OH-].[Na+:33]>>[CH:1]1([NH:4][C:5](=[O:31])[CH2:6][N:7]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH:15]=3)[C:10]([O-:25])=[C:9]([C:26]([NH:28][CH3:29])=[O:27])[C:8]2=[O:30])[CH2:3][CH2:2]1.[Na+:33]
Reactant: CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)NC2CC2)c1=O
Agent: [Na+]
Agent: [OH-]
Product: CNC(=O)c1c([O-])c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)NC2CC2)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
This compound was prepared by treating a mixture of the product from Example 473 with 1.5 equivalents of 1N NaOH solution. The mixture was stirred 4 h at rt and filtered to afford the product as a white solid: 1H NMR (d6-DMSO) δ 10.15 (1H, br), 8.25 (1H, s), 7.69 (1H, br), 7.27 (3H, m), 7.08 (2H, t, J=9 Hz), 4.70 (2H, br s), 4.05 (2H, s), 2.79 (3H, d, J=5 Hz), 2.60 (1H, m), 0.61 (2H, m), 0.40 (2H, m).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH:12]([OH:14])[CH3:13])=[C:8]([N:15]([CH3:17])[CH3:16])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[C:12]([C:9]1[C:10](=[O:11])[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:6]=[CH:7][C:8]=1[N:15]([CH3:16])[CH3:17])(=[O:14])[CH3:13]
Reactant: CC(O)c1c(N(C)C)cnn(C(C)(C)C)c1=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CC(=O)c1c(N(C)C)cnn(C(C)(C)C)c1=O
Temperature: 80 °C
Reaction time: 24 h

Procedure:
In toluene was dissolved 2-t-butyl-5-dimethylamino-4-(1-hydroxy)ethyl-3(2H)-pyridazinone (3.4 g) followed by addition of active manganese dioxide (17.0 g), and the mixture was stirred at 80° C. for 24 hours. The oxidizing agent was filtered off and the filtrate was concentrated. The residue was washed with n-hexane and diethyl ether and dried. Yellow powder, 2.5 g. 1 H-NMR (CDCl3) δ: 1.62(9H,s), 2.63(3H,s), 2.92(6H,s), 7.62(1H,s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[N+:27]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:34][C:33]4[CH:36]=[CH:37][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=4)[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3ccc([N+](=O)[O-])cc3)CC2)cc1

Procedure:
Using the general procedure described in Example 3, N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (0.14 mmol) was reacted with 4-nitrobenzaldehyde to provide 36 mg of the title product as the free base. Treatment with hydrochloric acid and concentration in vacuo yielded the salt of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.Cl[CH2:15][CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:12][O:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][C:7]2=[O:13])=[CH:3][C:2]=1[O:1][CH2:15][CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1
Reactant: COc1cc2c(cc1O)CCC2=O
Reactant: ClCCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1OCCCOC1CCCCO1)CCC2=O

Procedure:
A mixture of 5-Hydroxy-6-methoxy-indan-1-one (Intermediate H, 2.98 g, 0.017 mole), 2-(3-chloro-propoxy)-tetrahydro-pyran (Compound 18a) (6.0 g, 0.034 mole), and potassium carbonate (10.0 g, 0.0725 mole) were stirred in 50 mL of DMF at 80° C. overnight under Argon. The reaction mixture was then diluted with 200 mL of ethyl acetate and washed 3 times with water. After drying over sodium sulfate, the solvent was removed in vacuo. The crude material solidified on standing to yield the title compound, 6-Methoxy-5-[3-(tetrahydro-pyran-2-yloxy)-propoxy]-indan-1-one. MS m/z 309 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[CH2:13][CH2:12][N:11]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[CH2:13][CH2:12][NH:11]2)=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)C(CCc1ccc(F)cc1)=NCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)C(CCc1ccc(F)cc1)NCC2

Procedure:
A solution of 1-(2-p-fluorophenylethyl)-7-methoxy-3,4-dihydroisoquinoline (1.04 g, 3.67 mmol) in methanol (7 ml) was treated with sodium borohydride (0.56 g, 14.7 mmol) and heated at reflux for one hour. The mixture was cooled and evaporated. The residue was mixed with 1N sodium hydroxide and ethyl acetate and extracted into ethyl acetate. The pooled extracts were washed with saturated sodium chloride, dried, and evaporated to a brown oil (0.59 g, 57%). HPLC-MS (C-18, methanol/water/TFA linear gradient elution, 5 ml/min, 220 nm) single peak at 1.12 min; MS (ES+) obsd m/z=286.34.
Reaction SMILES: [Li+].[Cl-].[CH3:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11](OS(C(F)(F)F)(=O)=O)=[CH:12]2)=[CH:7][CH:6]=1.[CH2:23]([Sn](CCCC)(CCCC)C=C)[CH2:24]CC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:13](=[CH:12][C:11]([CH:23]=[CH2:24])=[CH:10][CH:9]=2)[CH:14]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc2ccc(OS(=O)(=O)C(F)(F)F)cc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Product: C=Cc1ccc2ccc(OC)cc2c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
To a mixture of (Ph3P)2PdCl2 (1.752 g), LiCl (6.36 g), and trifluoromethanesulfonic acid 7-methoxy-naphthalen-2-yl ester (15.3 g) was added dropwise tributyl(vinyl)tin (19.02 g). The resulting mixture was stirred over 4 h at 90° C. The reaction was quenched with water and extracted with CH2Cl2. The organic layer was washed with water and dried over MgSO4. After concentration, the crude product was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to give the title compound as an oil (9 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:32])=[C:27]([CH:31]=1)[C:28]([OH:30])=[O:29]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:32])=[C:27]([CH:31]=1)[C:28]([OH:30])=[O:29])=[O:5]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Reactant: Cc1ccc(N)cc1C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2cc(C(F)(F)F)ccc2F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 100 mL round-bottomed flask containing 2-fluoro-5-(trifluoromethyl)benzoyl chloride (0.44 ml, 2.9 mmol) in CH2Cl2 (30 mL) was added triethylamine (0.48 ml, 3.4 mmol). After 10 min, 5-amino-2-methylbenzoic acid (0.400 g, 2.6 mmol) was added. The solution was stirred at rt overnight. After cooling, the crude reaction mixture was concentrated to remove excess NEt3 then diluted with CH2Cl2 and washed with 1 N HCl once, and brine & salt once then dried over Na2SO4 to afford 5-(2-fluoro-5-(trifluoromethyl)benzamido)-2-methylbenzoic acid 32 as an off-white solid. MS m/z found: 342.1 (ESI, pos. ion).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[N:34]=[C:33]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[N:34]=[C:33]([NH:35][C:36](=[O:40])[CH:37]([CH3:38])[CH3:39])[CH:32]=[CH:31][CH:30]=3)[CH2:27][CH2:28]2)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)n1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)CC2)n1

Procedure:
Example 50 was prepared from bis(4-chlorophenyl)acetic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.06 (d, 1H, J=8.0 Hz), 7.96 (br s, 1H), 7.77 (s, 1H), 7.64 (t, 1H, J=8.4 Hz), 7.31–7.26 (m, 8H), 6.88 (dd, 1H, J=0.8, 7.6 Hz), 4.84 (s, 1H), 3.39 (dd, 2H, J=5.6, 11.6 Hz), 2.99 (d, 2H, J=11.6 Hz), 2.59 (m, 1H), 2.47 (t, 2H, J=6.0 Hz), 2.28 (m, 1H), 2.07–2.00 (m, 2H), 1.89 (dd, 2H, J=2.0, 12.4 Hz), 1.76–1.67 (m, 4H), 1.14 (d, 6H, J=6.8 Hz); ESMS m/e: 567.3 (M+H)+.
Reaction SMILES: O=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:5][CH:4]([C:17](O)=[O:18])[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C.C1COCC1>[F:15][C:13]([F:14])([F:16])[C:9]1[CH:8]=[C:7]([N:6]2[CH2:2][CH2:3][CH:4]([CH2:17][OH:18])[CH2:5]2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)C1CC(=O)N(c2cccc(C(F)(F)F)c2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCC1CCN(c2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
5-Oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidine-3-carboxylic acid (0.35 g, 1.28 mmol) in diethyl ether (5 ml) was added to a solution of lithium aluminium hydride (0.097 g, 2.56 mmol) in THF (5 ml) at temperature 0° C. over a period of 10 min. The mixture was refluxed for 2 hours and then stirred at room temperature for 20 hours. The reaction mixture was diluted with diethyl ether (15 ml) and quenched with water (10 ml). The organic layer was separated and aqueous layer was extracted with diethyl ether. The combined organic layer was washed with saturated brine solution, dried over Na2SO4 and evaporated to obtain a residue which was purified by preparative TLC to afford [1-(3-trifluoromethyl-phenyl)-pyrrolidin-3-yl]-methanol as a colorless mass (0.2 g, 64%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c(N2CCN(C(=O)OCc3ccccc3)CC2)c1
Temperature: 25 °C
Yield: 97.4 %

Procedure:
Piperazine-1-carboxylic acid benzyl ester (8.00 g; 36.3 mmol), 2-fluoro-4-methyl-1-nitro-benzene (4.70 g; 30.3 mmol) and potassium carbonate (8.5 g; 61.5 mmol) were stirred 3 hours in 50 mL DMSO at 80° C. The reaction mixture was cooled to room temperature and 250 mL Water was added. The mixture was extracted with diethyl ether (2×250 mL). The organic phase was washed with water (100 mL), 1 N HCl (2×100 mL), brine (2×100 mL), dried with MgSO4 and concentrated in vacuo to give 10.5 g (29.5 mmol; 97.6%) 4-(5-methyl-2-nitro-phenyl)-piperazine-1-carboxylic acid benzyl ester.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17]([C:48]([NH:50][CH2:51][CH:52]2[CH2:56][O:55]C(C)(C)[O:53]2)=[O:49])=[N:18][C:19]([NH:33][CH2:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH3:47])=[C:20]([C:22]([NH:24][CH2:25][CH:26]2[CH2:30][O:29]C(C)(C)[O:27]2)=[O:23])[N:21]=1.Cl>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17]([C:48]([NH:50][CH2:51][CH:52]([OH:53])[CH2:56][OH:55])=[O:49])=[N:18][C:19]([NH:33][CH2:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH3:47])=[C:20]([C:22]([NH:24][CH2:25][CH:26]([OH:27])[CH2:30][OH:29])=[O:23])[N:21]=1
Reactant: COCCOCCOCCOCCCNc1nc(C(=O)NCC2COC(C)(C)O2)c(NCCCOCCOCCOCCOC)nc1C(=O)NCC1COC(C)(C)O1
Agent: Cl
Solvent: C1CCOC1
Product: COCCOCCOCCOCCCNc1nc(C(=O)NCC(O)CO)c(NCCCOCCOCCOCCOC)nc1C(=O)NCC(O)CO
Reaction time: 5 h
Yield: 73.6 %

Procedure:
To a reddish solution of the above dicetonide 14 (1.00 mmol) in THF (25 mL), was added 1.0 N HCl (5 mL) and stirred for 5 h in an atmosphere of argon. Most of the THF was removed from the reaction mixture, neutralized by 1.0 N NaOH, and concentrated in vacuo. The crude product (2.40 g) was subjected to preparative RP-HPLC (XBridge, 10-50% B/12 min) to afford diastereomeric 13 (0.554 g, 74%) as red gum: UV (λmax) 499 nm; 1H NMR (CDCl3) 8.66, 8.56 (2 t, 2), 6.24 (broad s, 6), 4.40 (t, 1.5, J=4.2, 5.2), 4.23-4.15 (m, 1.5), 3.97-3.90 (m, 3), 3.70-3.50 (m, 36), 3.37, 3.36 (2 s, 6), 1.98-1.90 (quintet, 4); RP-HPLC (254 nm) 98% (tR=17.43 min, 5-50% B); RP-LC/MS (ESI) m/z 754.5 (M+H)+ (tR=3.58 min). HRMS (ESI) m/z calculated for C32H51N6O14 (M+H)+ 753.4240, found 753.4252.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]2[C:5]([CH2:6][CH:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=32)=[CH:4][N:3]=1.[CH3:26][N:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[CH2:32][CH2:33][NH2:34]>CN(C)C=O>[Cl:25][C:20]1[CH:19]=[C:18]([CH:7]2[CH2:6][C:5]3[C:10](=[C:11]([C:12]#[N:13])[C:2]([NH:34][CH2:33][CH2:32][CH:28]4[CH2:29][CH2:30][CH2:31][N:27]4[CH3:26])=[N:3][CH:4]=3)[C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]2=3)[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: CN1CCCC1CCN
Reactant: N#Cc1c(Cl)ncc2c1-c1ccccc1C(c1ccc(Cl)c(Cl)c1)C2
Solvent: CN(C)C=O
Product: CN1CCCC1CCNc1ncc2c(c1C#N)-c1ccccc1C(c1ccc(Cl)c(Cl)c1)C2
Yield: 50 %

Procedure:
A solution of 2-chloro-6-(3,4-dichlorophenyl)-5,6-dihydrobenzo[f]isoquinoline-1-carbonitrile (156 mg, 0.405 mmol) in N,N-dimethylformamide (3.5 ml) and 2-(1-methylpyrrolidin-2-yl)ethanamine (250 ul) was heated under microwave conditions at 20° C. for 40 minutes. The mixture was partitioned between ethyl acetate (50 ml) and water (30 ml). The aqueous layer was removed and the organic layer was washed with water (3×30 ml) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel using a gradient of dichloromethane-methanol as eluent to afford 6-(3,4-dichlorophenyl)-2-(2-(1-methylpyrrolidin-2-yl)ethylamino)-5,6-dihydrobenzo[f]isoquinoline-1-carbonitrile as a yellow solid (96 mg, 50%). M.p.=131-134° C. 400 MHz 1H NMR (DMSO-d6) δ 8.30 (m, 1H), 8.14 (s, 1H), 7.49 (m, 5H), 7.13 (m, 1H), 7.00 (dd, J=8 and 2 Hz, 1H), 4.30 (m, 1H), 3.43 (m, 2H), 3.08 (dd, J=15.2 and 7.2 Hz, 1H), 2.92 (dd, J=15.2 and 5.6 Hz, 1H), 2.37 (m, 6H), 1.97 (m, 1H), 1.89 (m, 1H), 1.68 (m, 3H), 1.55 (m, 1H). LCMS m/e 477 [M+H].
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)(=[O:7])[CH3:6].C1C=C[NH+]=CC=1.[Br:20][Br-]Br>C1COCC1>[Br:20][CH2:6][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:7]
Reactant: CC(=O)c1ccccn1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C(CBr)c1ccccn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 500 mL round bottomed flask with a stirring bar and an argon inlet is added CHCl3 (200 mL), THF (100 mL), 2-acetyl pyridine (8.57 mL, 76.46 mmol), and pyridinium bromide perbromide (26.85 g, 84.11 mmol). This solution is stirred at ambient temperature for 24 hours. The reaction mixture is washed with aqueous HCl, H2O, brine and dried (MgSO4). The solvent is evaporated in vacuo to afford the title compound which was used immediately in the next step.