Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:7]1[CH:20]=[CH:19][C:10]([C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][C:8]=1[N+:21]([O-])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.NN>C(O)C.[Pd]>[NH2:21][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:7]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:11]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[O:12]
Reactant: CCCCCCc1ccc(C(=O)N2CCOCC2)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CCCCCCc1ccc(C(=O)N2CCOCC2)cc1N
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
The compound ([5]-(54)-75) (700 mg) prepared in Example 62 was dissolved in ethanol (35 ml). After the solution was heated to 50° C., a suspension of 10% Pd/C (70 mg) in ethanol was added, and hydrazine monohydrate (0.35 ml) was added to the solution. The solution was stirred at 50° C. for 30 minutes. After the reaction was completed, the solution was filtered through celite 545 to remove the catalyst. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Kieselgel 60=20 g, ethyl acetate) to obtain the above-captioned compound ([5]-(55)-75) (631 mg) as colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Br:35])[CH2:25][CH2:24]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Br:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[N:26]1[CH2:25][CH2:24][N:23]([S:20]([C:17]2[CH:18]=[CH:19][C:14]([NH:13][C:2]3[C:11]4[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=4)[N:5]=[CH:4][CH:3]=3)=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH2:28][CH2:27]1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: Nc1ccc(S(=O)(=O)N2CCN(c3ccccc3Br)CC2)cc1
Product: O=S(=O)(c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1)N1CCN(c2ccccc2Br)CC1

Procedure:
In the manner given in Example 1C, 4,7-dichloroquinoline is heated with 1-[(p-aminophenyl)-sulfonyl]-4-(o-bromophenyl)piperazine to give 1-(o-bromophenyl)-4-[[4-[[7-chloro-4-quinolinyl]-amino]phenyl]sulfonyl]piperazine.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([C:15]2[CH2:16][CH2:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH:12]1[O:14][CH2:13]1)[CH:2]=[CH2:3].[CH:22]([NH2:25])([CH3:24])[CH3:23]>CO>[CH2:1]([C:4]1[CH:5]=[C:6]([C:15]2[CH2:16][CH2:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH:12]([OH:14])[CH2:13][NH:25][CH:22]([CH3:24])[CH3:23])[CH:2]=[CH2:3]
Reactant: CC(C)N
Reactant: C=CCc1cc(C2=NNC(=O)CC2)ccc1OCC1CO1
Solvent: CO
Product: C=CCc1cc(C2=NNC(=O)CC2)ccc1OCC(O)CNC(C)C
Yield: 119.4 %

Procedure:
A stirred mixture of 6-[3-allyl-4-(2,3-epoxypropoxy)-phenyl]-4,5-dihydro-3(2H)-pyridazinone (46g, 0.16 mole), methanol (500 ml) and isopropylamine (85 ml, 1 mole) was heated under reflux for 60 minutes. Evaporation of the solution under reduced pressure gave an oil (66 g) which was purified on a silica column by elution with mixtures of chloroform and methanol to give 6-[3-allyl-4-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (45g, 85%, m.p. 94°-96.5° C). The hemisulphate hemihydrate, crystallised from aqueous ethanol, had m.p. 238°-242° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11]([OH:13])=[O:12].[CH3:14][C:15]1[CH:20]=[C:19]([B:21]2[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]2)[CH:18]=[C:17]([CH3:30])[C:16]=1O.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1.O>[CH3:30][C:17]1[CH:18]=[C:19]([B:21]2[O:25][C:24]([CH3:26])([CH3:27])[C:23]([CH3:29])([CH3:28])[O:22]2)[CH:20]=[C:15]([CH3:14])[C:16]=1[O:12][C:11]([C:3]1[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[CH3:1])=[O:13]
Reactant: Cc1c(C(=O)O)oc2ccccc12
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1OC(=O)c1oc2ccccc2c1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 28 %

Procedure:
To 3-methyl-benzofuran-2-carboxylic acid (500 mg, 2.84 mmol, 1 eq) in 5 mL of dichloromethane under argon was added 2,6-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (704 mg, 2.84 mmol, 1 eq.), 1,3-dicyclohexylcarbodiimide (1.17 g, 5.68 mmol, 2 eq.), and 4-(dimethylamino)pyridine (173 mg, 1.42 mmol, 0.5 eq.). The resulting mixture was stirred at room temperature for 6 h. The reaction was then diluted with water and extracted with ethyl acetate. The organics were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified using flash column chromatography on silica gel to provide 3-methyl-benzofuran-2-carboxylic acid 2,6-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl ester in 28% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.3 (s, 12 H) 2.2 (s, 6 H) 2.7 (s, 3 H) 7.4 (m, 1 H) 7.5 (s, 2 H) 7.6 (m, 1 H) 7.8 (d, J=8.3 Hz, 1 H) 7.9 (m, 1 H).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17]Br>CC(C)=O>[CH3:8][O:7][C:1]([C:2]1([C:3](=[O:4])[CH3:5])[CH2:17][CH2:16]1)=[O:6]
Reactant: BrCCBr
Reactant: COC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C1(C(C)=O)CC1
Temperature: 65 °C
Reaction time: 17 h

Procedure:
To a solution of methyl acetoacetate (3 ml) in acetone (30 ml) were sequentially added potassium carbonate (11.54 g) and 1,2-dibromoethane (2.4 ml) at room temperature, and the mixture was stirred at 65° C. for 17 hours. This reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1) to give the titled compound (2.17 g).
Reaction SMILES: S(O[CH:12]1[CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]=2[CH2:14][CH2:13]1)(C1C=CC(C)=CC=1)(=O)=O.[CH3:25][NH2:26].C(OCCO)C.C(=O)(O)[O-].[Na+]>>[CH3:25][NH:26][CH:12]1[CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]=2[CH2:14][CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)OC2CCc3[nH]c4ccccc4c3C2)cc1
Reactant: CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCCO
Product: CNC1CCc2[nH]c3ccccc3c2C1
Reaction time: 8 h

Procedure:
A mixture of 17 g. of 3-tosyloxy-1,2,3,4-tetrahydrocarbazole and 25 g. of 40% methylamine in 200 ml. of 2-ethoxyethanol containing 5 g. of sodium bicarbonate was heated on a steam bath for 1 hour then left standing overnight at room temperature. The solvent was removed by distillation and the residue taken up in ether and the mixture filtered. Evaporation of the filtrate gave a residue which crystallized upon trituration with ether. The 3-(methylamino)-1,2,3,4-tetrahydrocarbazole thus obtained melted at 134°-136° C. (corr.).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7](Br)[CH:8]=1.CC1(C)C(C)(C)OB([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]3)O1>>[NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]3)[CH:6]=[N:5][CH:4]=1
Reactant: NCc1cncc(Br)c1
Reactant: CC1(C)OB(c2ccc3c(c2)CCC(=O)N3)OC1(C)C
Product: NCc1cncc(-c2ccc3c(c2)CCC(=O)N3)c1

Procedure:
In analogy to the procedure described for the preparation of example 45, reaction of 3-aminomethyl-5-bromopyridine and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one (intermediate A-34) gave the title compound as a light yellow amorphous solid. MS: 254.4 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH:3]1[O:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.[H-].[Na+].Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C.CCOCC>[CH2:13]([O:9][CH:6]1[CH2:7][O:8][CH:3]([O:2][CH3:1])[CH2:4][CH2:5]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: COC1CCC(O)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC1CCC(OCc2ccccc2)CO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C. to a solution of 6-methoxytetrahydro-2H-pyran-3-ol (222 mg, 1.680 mmol) in DMF (2 mL) was added 60% NaH (81 mg, 2.02 mmol) and the mixture was allowed to warm to rt and stirred at rt for 30 min. A solution of (bromomethyl)benzene (345 mg, 2.016 mmol) in DMF (1 ml) was added and the mixture was stirred at rt for 18 h. The reaction mixture was diluted with ether and quenched with water. The crude product was purified by silica gel FCC (20% EtOAc in hexanes) to afford 5-(benzyloxy)-2-methoxytetrahydro-2H-pyran. 1H NMR (400 MHz, CDCl3) δ ppm 7.29-7.41 (5H, m), 4.53-4.64 (3H, m), 3.90 (1H, dd, J=12.05, 2.51 Hz), 3.56-3.65 (1H, m), 3.46-3.53 (1H, m), 3.43 (3H, s), 1.97-2.14 (2H, m), 1.69-1.81 (1H, m), 1.48-1.60 (1H, m).
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)=[N:6][NH:7][CH:8]=1)([O-])=O.[H][H]>CN(C=O)C.[Pd]>[NH:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[C:5]1[C:4]([NH2:1])=[CH:8][NH:7][N:6]=1
Reactant: O=[N+]([O-])c1c[nH]nc1-c1nc2ccccc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Yield: 27.5 %

Procedure:
A mixture of 2-(4-nitro-1H-pyrazol-3-yl)-1H-benzimidazole (1.34 g, 5.85 mmol) and 10% Pd/C (0.13 g) in DMF (200 ml) was subjected to an atmosphere of hydrogen at room temperature for 36 h. The reaction mixture was filtered through a plug of Celite and reduced in vacuo. The residue was partitioned between EtOAc and water and the organic portion dried (MgSO4), filtered and reduced in vacuo. The residue was azeotroped with toluene (3×150 ml) yielding 3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine as a purple solid (0.32 g, 26%). (LC/MS: Rt 0.97, [M+H]+ 199.62).
Reaction SMILES: CO.[CH3:3][O:4][C:5](=[O:38])[C@H:6]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH:7][C:8](=[O:30])[C@H:9]([CH2:26][C:27](=[O:29])[OH:28])[NH:10][C:11](=[O:25])[C@@H:12]([CH3:24])[NH:13]C(OCC1C=CC=CC=1)=O.[H][H]>[C].[Pd].O>[CH3:3][O:4][C:5](=[O:38])[C@H:6]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH:7][C:8](=[O:30])[C@H:9]([CH2:26][C:27](=[O:28])[OH:29])[NH:10][C:11](=[O:25])[C@@H:12]([CH3:24])[NH2:13]
Reactant: [H][H]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](C)N

Procedure:
In a solvent mixture of 75 ml of methanol and 75 ml of water was dissolved 2.1 g of N-benzyloxycarbonyl-D-alanyl-α-L-aspartyl-L-phenylalanine methyl ester, followed by reduction at room temperature for 4 hours in a hydrogen flow using palladium-carbon as a catalyst. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was recrystallized from water-acetone. Yield, 1.3 g; m.p., 228°-230° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[OH:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH:32]=O>>[CH3:22][N:21]([CH3:23])[C:18]1[CH:19]=[CH:20][C:15]([C:14]([NH:13][C:6]2[CH:7]=[CH:8][C:9]3[NH:10][C:32]([C:31]4[CH:34]=[CH:35][CH:36]=[C:29]([O:28][CH2:27][CH2:26][OH:25])[CH:30]=4)=[N:1][C:4]=3[CH:5]=2)=[O:24])=[CH:16][CH:17]=1
Reactant: O=Cc1cccc(OCCO)c1
Reactant: CN(C)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Product: CN(C)c1ccc(C(=O)Nc2ccc3[nH]c(-c4cccc(OCCO)c4)nc3c2)cc1

Procedure:
Compound 219 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-dimethylaminobenzamide and 3-(2-hydroxyethyloxy)benzaldehyde. [M+H]+ calcd for C24H24N4O3: 417.19; found: 416.94.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[S:19])[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[OH-].[Na+].[CH3:22]I>C(OCC)C>[NH2:1][C:2]1[N:3]=[C:4]([S:19][CH3:22])[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1nc2ccc(-c3ccc(F)cc3)nc2c(=S)[nH]1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CSc1nc(N)nc2ccc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.6 %

Procedure:
To a solution of the 2-amino-6-(4-fluorophenyl)-pyrido(3,2-d)pyrimidin-4(3H)thione of example 7 (55 mg) in a 1 N NaOH solution (10 ml) was added methyl iodide (0.2 mmol). The reaction was stirred at room temperature for 12 hours. The reaction mixture was diluted with diethyl ether and the organic layer was extracted with water. The combined organic layers were evaporated in vacuo and the crude residue was purified by preparative thin layer chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane, in a volume ratio of 5:95, providing 41 mg of the pure title compound (yield: 72%) which was characterized by its mass spectrum as follows: MS (m/z): 287 ([M+H]+, 100).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].II.[CH2:18]([O:20][C:21](=[O:24])[CH2:22]Br)[CH3:19].Cl>C1C=CC=CC=1.[Zn]>[OH:3][C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([CH3:2])[CH2:22][C:21]([O:20][CH2:18][CH3:19])=[O:24]
Reactant: CC(=O)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: II
Agent: [Zn]
Solvent: c1ccccc1
Product: CCOC(=O)CC(C)(O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
To a refluxing mixture of 4-acetylbiphenyl (20 g), I2 (5 mg) and Zn (6.8 g) in benzene (200 ml) was added ethylbromoacetate (12 ml) dropwise during 30 minutes. The mixture was refluxed for 1 h and then cooled to room temperature. It was acidified with 10% HCl (100 ml) and benzene layer was separated out. The organic layer was washed with water, dried (Na2SO4) and concentrated. The crude product was purified by column chromatography on silica gel to give 20.6 g (72.1% yield) of ethyl 3-hydroxy-3-([1,1′-biphenyl]-4yl)butanoate (2e, formula 2, R=Ph) m.p. 58-60° C.
Reaction SMILES: C([Li])CCC.[CH2:6]([C:8]1[CH:9]=[C:10](Br)[CH:11]=[CH:12][CH:13]=1)[CH3:7].C[O:16][B:17](OC)[O:18]C.Cl>CCCCCC.O1CCCC1>[CH2:6]([C:8]1[CH:9]=[C:10]([B:17]([OH:18])[OH:16])[CH:11]=[CH:12][CH:13]=1)[CH3:7]
Reactant: CCc1cccc(Br)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1cccc(B(O)O)c1
Temperature: -70 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
n-Butyllithium (11 ml of a 2.5M solution in hexane, 28 mmol) was added to a stirred solution of 3ethylbromobenzene (Chem. Pharm. Bull., 1968, 16, 2456; 4.6 g, 25 mmol) in anhydrous tetrahydrofuran (50 ml), whilst keeping the internal temperature below −60° C. The mixture was stirred at about −70° C. for 1 hour, then trimethylborate (4.4 ml, 38 mmol) added dropwise, again whilst keeping the internal temperature below −60° C. The reaction mixture was stirred at −70° C. for 30 minutes, then slowly allowed to warm to room temperature. 2M Hydrochloric acid was added, the mixture was extracted with dichloromethane (3×50 ml) and the combined extracts concentrated under reduced pressure The residue was dissolved in ether (50 ml), the solution extracted with 1M aqueous sodium hydroxide solution (2×30 ml) and the aqueous phase acidified with 2M hydrochloric acid, then extracted with ether (3×50 ml). The combined extracts were dried (MgSO4) and evaporated under reduced pressure to give the title compound as a white solid (0.9 g, 24%). δ(DMSOd6): 1.17 (t,3H), 2.57 (q,2H), 7.22 (t,2H), 7.57 (t,1H), 7.61 (s,1H), 7.93 (s,2H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([S:36]([F:41])([F:40])([F:39])([F:38])[F:37])[CH:35]=1)[C:30](O)=[O:31])(=[O:26])=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:30](=[O:31])[C:29]2[CH:33]=[C:34]([S:36]([F:38])([F:39])([F:40])([F:41])[F:37])[CH:35]=[C:27]([S:24]([CH3:23])(=[O:26])=[O:25])[CH:28]=2)=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
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: Cc1ccc(NC(=O)c2cc(S(C)(=O)=O)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
66 mg (0.228 mmol) of the compound of Example 6A and 74 mg (0.228 mmol) of the compound of Example 32A were dissolved in 1.5 ml of anhydrous DMF, and 104 mg (0.273 mmol) of HATU and 48 μl (0.273 mmol) of N,N-diisopropylethylamine were added in succession. The reaction mixture was stirred at RT for 4 h and then separated completely into its components by preparative HPLC (Method 9). The product fractions were combined and concentrated to dryness on a rotary evaporator. This gave the title compound in the form of its formic acid salt. For conversion into the salt-free form, the formate was dissolved in about 5 ml of methanol and passed over a bicarbonate cartridge (from Polymerlabs, Stratospheres SPE, PL-HCO3 MP SPE, capacity 0.9 mmol). After re-evaporation, the residue was triturated with a little diisopropyl ether at RT. Filtration with suction and drying of the solid under high vacuum gave 72.6 mg (53% of theory) of the title compound.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][C@:9]([OH:58])([C@@H:17]([C:38](=[O:57])[NH:39][C@H:40]([C:53]([O:55][CH3:56])=[O:54])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]#[C:51][CH3:52])=[CH:44][CH:43]=1)/[CH:18]=[CH:19]/[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])OCC[O:27]1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[Cl-].[Na+].O>C(#N)C>[CH2:49]([O:48][C:45]1[CH:44]=[CH:43][C:42]([CH2:41][C@H:40]([NH:39][C:38]([C@@H:17](/[CH:18]=[CH:19]/[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26](=[O:27])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C@@:9]([OH:58])([CH2:8][CH2:7][OH:6])[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[O:57])[C:53]([O:55][CH3:56])=[O:54])=[CH:47][CH:46]=1)[C:50]#[C:51][CH3:52]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC2(CCCCCCC)OCCO2)[C@@](O)(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)OC(C)(C)C)C(=O)OC)cc1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 57 %

Procedure:
No. 5327507 Compound C (50.8 g, 59.2 mmol) was dissolved in acetonitrile (560 mL), and then an aqueous solution of 0.5 M citric acid (249 mL, 125 mmol) was added to the solution, which was stirred at 60° C. for 2.5 hours. After confirming that inner temperature had returned to room temperature, a mixture of a saturated aqueous solution of sodium chloride (51 mL) and water (813 mL) was added. The solution was extracted with 20% ethyl acetate/n-hexane (457 mL) 3 times. The organic layers were combined, then washed twice with a saturated aqueous solution (230 mL) of sodium chloride, dried over anhydrous sodium sulfate, and filtered. The solvent was then distilled off under reduced pressure and the residue was purified on Biotage (silica gel, n-hexane/acetone) to obtain 23.6 g (33.7 mmol, 57% yield) of No. 5217614 (Compound D).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]([CH:13]=1)[C:9]([NH:11][NH2:12])=[O:10])([O-:3])=[O:2].[F:21][C:22]([F:32])([F:31])[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O>>[F:21][C:22]([F:31])([F:32])[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=[N:12][NH:11][C:9](=[O:10])[C:8]1[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[O:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: NNC(=O)c1cc([N+](=O)[O-])ccc1Oc1ccccc1
Product: O=C(NN=Cc1cccc(C(F)(F)F)c1)c1cc([N+](=O)[O-])ccc1Oc1ccccc1

Procedure:
A mixture of 5-nitro-2-phenoxy-benzoic acid methyl ester (4.0 g, 14.7 mmol) and hydrazine (5 mL, 80%) was refluxed for 4 h to yield 5-nitro-2-phenoxy-benzoic acid hydrazide (2.97 g, 74%). The title compound was prepared from 5-nitro-2-phenoxy-benzoic acid hydrazide and 3-trifluoromethyl-benzaldehyde by a procedure similar to Example 22. 1H NMR (DMSO-d6): 12.20 (s, 1H), 8.52 (s, 1H), 8.43 (s, 1H), 8.35 (d, J=7.2 Hz, 1H), 8.17 (s, 1H), 8.10 (d, J=6.6 Hz, 1H), 7.81 (m, 1H), 7.75 (t, J=6.6 Hz, 1H), 7.54 (t, J=7.2 Hz, 1H), 7.35 (m, 2H), 7.27 (d, =J=7.2 Hz, 1H), 7.03 (m, 2H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:44])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]5[CH2:32][CH2:33][N:34](C(OC(C)(C)C)=O)[CH2:35][CH:36]=5)=[CH:27][CH:26]=3)[CH:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[ClH:45]>CO.O1CCOCC1>[ClH:45].[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:44])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]5[CH2:32][CH2:33][NH:34][CH2:35][CH:36]=5)=[CH:27][CH:26]=3)[CH:17]=[CH:16]4)[CH:12]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)cc3)ccc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(C4=CCNCC4)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of Example 6 step (iii) (0.2 g) in methanol (10 mL) was treated with 4.0M HCl in 1,4-dioxane (10 mL) and the solution stirred at room temperature for 2 hours. The volatiles were then removed under reduced pressure and the residue triturated with diethyl ether to give the product, after filtration as a solid (80 mg).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=O)[C:15]=4[N:14]=3)=[C:9]([C:25]([F:28])([F:27])[F:26])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:29]1([CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1>>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([NH:39][C:38]5[CH:37]=[CH:36][C:35]([CH2:34][N:29]6[CH2:33][CH2:32][CH2:31][CH2:30]6)=[CH:41][CH:40]=5)=[O:24])[C:15]=4[N:14]=3)=[C:9]([C:25]([F:27])([F:26])[F:28])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccc(CN2CCCC2)cc1
Reactant: O=C(O)c1cccc2[nH]c(-c3ccc(CN4CCCC4)cc3C(F)(F)F)nc12
Product: O=C(Nc1ccc(CN2CCCC2)cc1)c1cccc2[nH]c(-c3ccc(CN4CCCC4)cc3C(F)(F)F)nc12

Procedure:
2-(4-(pyrrolidin-1-ylmethyl)-2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxylic acid 159 was coupled with 4-(pyrrolidin-1-ylmethyl)aniline 160 to produce 2-(4-(pyrrolidin-1-ylmethyl)-2-(trifluoromethyl)phenyl)-N-(4-(pyrrolidin-1-ylmethyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide (Compound 869) using the same general procedure outlined in Example 39. MS (ESI) calcd for C31H32F3N5O: 547.26; found: 548 [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Br[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[O:19][CH2:18][CH2:17][CH2:16]2>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][CH2:18][CH2:17][CH2:16]3)[CH:3]=1
Reactant: Clc1ccnc2ccccc12
Reactant: Brc1ccc2c(c1)CCCO2
Product: Clc1cc(-c2ccc3c(c2)CCCO3)nc2ccccc12

Procedure:
The title compound, MS: m/e=295 (M+), was prepared from 4-chloro-quinoline and 6-bromo-chroman.