Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1F.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1[O:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:14][CH:13]=1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(CCCn3ccnc3)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.4 %

Procedure:
To a solution of 4-[3-(1H-imidazol-1-yl)propyl]phenol (405 mg) and 3-chloro-4-fluoronitrobenzene (370 mg) in N,N-dimethylformamide (4 mL) was added potassium carbonate (415 mg), and the mixture was stirred at room temperature for 16 hrs. Under ice-cooling, water was added and the mixture was extracted with ethyl acetate. The extract washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by basic silica gel column chromatography (eluent, ethyl acetate:hexane=80:20→100:0) to give the title compound (669 mg) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[CH:9]1([CH2:15][C@H:16]([N:20]2[C:24](=[O:25])[C@H:23]([CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[NH:22][C:21]2=[O:33])[C:17](O)=[O:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:17](=[O:18])[C@@H:16]([N:20]2[C:24](=[O:25])[C@H:23]([CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[NH:22][C:21]2=[O:33])[CH2:15][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)=[N:3][CH:4]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1C(=O)N[C@@H](CC2CCCCC2)C1=O
Product: O=C(Nc1ccc(Cl)cn1)[C@H](CC1CCCCC1)N1C(=O)N[C@@H](CC2CCCCC2)C1=O

Procedure:
By using the conditions described in Step (iv) of Example 17, 2-amino-5-chloropyridine was condensed with (S,S)-3-cyclohexyl-2-[4-(cyclohexyl)methyl-2,5-dioxoimidazolidinyl]propanoic acid [Example 17, Step (iii)] to give the title compound as a colorless foam: EI-HRMS m/e calcd for C24H33N4O3Cl (M+) 461.2319, found 461.2321.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.[NH2:10][CH:11]([CH2:19][CH3:20])[C:12]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13]>>[CH2:15]([O:14][C:12](=[O:13])[CH:11]([NH:10][C:7](=[O:9])[CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[CH2:19][CH3:20])[CH:16]([CH3:17])[CH3:18]
Reactant: CCC(N)C(=O)OCC(C)C
Reactant: O=C(O)Cc1ccsc1
Product: CCC(NC(=O)Cc1ccsc1)C(=O)OCC(C)C

Procedure:
Following General Procedure I′ above and using 3-thiopheneacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J′ above), the title compound was prepared. The reaction was monitored by tIc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH:11]=O)=[C:8]([CH3:13])[C:6]=2[N:7]=1.CC(O)=O.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([NH:31][CH3:32])[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:31]([CH3:32])[CH:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)=[C:8]([CH3:13])[C:6]=2[N:7]=1
Reactant: Cc1c(C=O)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CNC1CCN(C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1c(CN(C)C2CCN(C)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reaction time: 0.25 h
Yield: 88 %

Procedure:
2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde (0.5 g) was dissolved in 10 mL of 1,2-DCE and 1.0 eq. AcOH and 1.3 eq. of 1-methyl-4-(methylamino)piperidine was added and the reaction was stirred 15 minutes followed by the addition of sodium triacetoxyborohydride. The reaction was stirred for 24 hours and product formation was confirmed by LCMS. The reaction was diluted with sat. NaHCO3, extracted with dichloromethane, dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc/hexanes) to give 0.61 g N-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N,1-dimethylpiperidin-4-amine (88% yield). MS (Q1) 411 (M)+.
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:25][CH2:26][S:27][C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)(=O)=O)=CC=1.O>CN(C=O)C>[CH3:7][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[S:1][CH2:25][CH2:26][S:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)OCCSc2ccc([N+](=O)[O-])cc2)cc1
Reactant: Cn1ccnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccnc1SCCSc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 62 %

Procedure:
2-mercapto-1-methylimidazole (0.81 g) was dissolved in DMF (16.2 ml), potassium carbonate (1.37 g) was added to the mixture, 2-[(4-nitrophenyl)thio]ethyl 4-methylbenzene sulfonate (3.0 g) was added to the mixture, and the mixture was stirred for 12 hours at 60° C. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was washed with hexane/ethyl acetate, to give 1-methyl-2-[[2-[(4-nitrophenyl)thio]ethyl]thio]imidazole (1.3 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1B(O)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br)#[N:20].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[CH2:24][C:23]1[CH:22]=[C:21]([CH:28]=[CH:27][CH:26]=1)[C:19]#[N:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: N#Cc1cccc(Cc2cc(Cl)ccc2OCc2ccccc2)c1
Temperature: 80 °C

Procedure:
A mixture of 2-benzyloxy-5-chlorophenylboronic acid (2.1 g), 3-cyanobenzyl bromide (1.57 g), sodium carbonate (1.7 g) and tetrakis(triphenylphosphine)palladium (0) (0.46 g) in ethylene glycol dimethyl ether (30 ml) was heated at 80° C. for 5 h. The mixture was cooled, partitioned between water/diethylether, the organics separated, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 5% ethylacetate/isohexane, yield 0.53 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][O:14]1.[C:18]([CH:21]=[C:22]=[O:23])(=[O:20])[CH3:19]>CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:22](=[O:23])[CH2:21][C:18](=[O:20])[CH3:19])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][O:14]1
Reactant: CC(=O)C=C=O
Reactant: Nc1ccc(NCCCC2CCCO2)c(F)c1
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)Nc1ccc(NCCCC2CCCO2)c(F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
To a solution of 2-fluoro-N1-(3-(tetrahydrofuran-2-yl)propyl)benzene-1,4-diamine (260 mg, 1.09 mmol) in EtOAc (10 mL) was added acetyl ketene (110 mg, 1.31 mmol) and the mixture was stirred at 80° C. overnight. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:1) to give the title compound as yellow liquid (83 mg, 24%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH:15]([CH3:22])[CH2:16][C:17](OCC)=[O:18])[CH2:11][CH2:10]1.O.[NH2:24][NH2:25]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH:15]([CH3:22])[CH2:16][C:17]([NH:24][NH2:25])=[O:18])[CH2:11][CH2:10]1
Reactant: NN
Reactant: CCOC(=O)CC(C)N1CCN(c2ccccc2OC)CC1
Solvent: CCO
Solvent: O
Product: COc1ccccc1N1CCN(C(C)CC(=O)NN)CC1
Yield: 76 %

Procedure:
A solution of ethyl 3-[4-(2-methoxyphenyl)piperazin-1-yl]butanoate D11 (2.75 g, 8.97 mmol) and hydrazine monohydrate (2.7 g, 53.85 mmol) in ethanol (40 mL) was refluxed for 48 hrs. The solvent was evaporated under reduced pressure, toluene (50 mL) was added and the solvent was evaporated and the resulting light yellow oil was triturated with 50% AcOEt in hexane (10 mL). The resulting white solid was filtered, washed with hexane and dried to afford 2 g (76%) 3-[4-(2-methoxyphenyl)piperazin-1-yl]butanohydrazide D12.
Reaction SMILES: [CH3:1][C@:2]1([CH2:16][CH2:17]O)[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([CH3:14])=[C:7]([OH:13])[C:8]=2[CH3:12])[O:3]1.C(Cl)(Cl)[Cl:20]>>[CH3:1][C@:2]1([CH2:16][CH2:17][Cl:20])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([CH3:14])=[C:7]([OH:13])[C:8]=2[CH3:12])[O:3]1
Reactant: ClC(Cl)Cl
Reactant: Cc1c(C)c2c(c(C)c1O)CC[C@](C)(CCO)O2
Product: Cc1c(C)c2c(c(C)c1O)CC[C@](C)(CCCl)O2

Procedure:
(R)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-chloroethyl)-chroman was prepared from (R)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman by a procedure similar to that described in Example 10. [α]D20 =+9.0, (c=2, chloroform), mp.=111° C.
Reaction SMILES: [F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][OH:4].[H-].[Na+].[F:11][C:12]([F:27])([S:23](F)(=[O:25])=[O:24])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16]>CCOCC>[F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][O:4][S:23]([C:12]([F:11])([F:27])[C:13]([F:21])([F:22])[C:14]([F:19])([F:20])[C:15]([F:18])([F:17])[F:16])(=[O:25])=[O:24]
Reactant: OCC(F)(F)C(F)F
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: O=S(=O)(OCC(F)(F)C(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2,2,3,3-Tetrafluoropropanol (2.64 g) was added to a suspension of sodium hydride (1.08 g) in dry ether (50 ml) at 0° C. under an argon atmosphere. Stirred at 0° C. for 15 minutes. Perfluoro-1-butanesulphonyl fluoride (12.08 g) was slowly added. Stirred at reflux for 3 hours, cooled and carefully quenched with H2O. Extracted with ether, twice. The combined extracts were washed with saturated brine, dried over MgSO4, filtered and evaporated to give 2,2,3,3-tetrafluoropropyl-1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulphonate as an oil. Yield 5.47 g. NMR Spectrum: (CDCl3) δ 5.9 (tt, 1H), 4.75 (t, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([C:19]([NH:21][NH2:22])=[O:20])=[C:9]1[CH:23]([CH3:25])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:27](=N)(OCC)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CCO>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([C:19]2[O:20][C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:22][N:21]=2)=[C:9]1[CH:23]([CH3:25])[CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)c(C(=O)NN)c(C(C)C)n2Cc1ccccc1
Reactant: CCOC(=N)c1ccccc1
Agent: Cl
Solvent: CCO
Product: COc1ccc2c(c1)c(-c1nnc(-c3ccccc3)o1)c(C(C)C)n2Cc1ccccc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 1-benzyl-2-isopropyl-5-methoxy-1H-indole-3-carbohydrazide (Compound 35, 25 mg, 0.074 mmol) in EtOH (2.0 ml) was added ethyl benzimidate hydrochloride (Fluka, 21 mg, 0.11 mmol). The mixture was stirred at 80° C. for 4 h and was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 0-30% EtOAc-hexanes to yield 2-(1-benzyl-2-isopropyl-5-methoxy-1H-indol-3-yl)-5-phenyl-1,3,4-oxadiazole (Compound 36) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:28][CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)[C:3]1[S:4][C:5]2[CH:11]=[C:10]([NH:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[CH:17][CH:16]=3)=[O:14])[CH:9]=[CH:8][C:6]=2[N:7]=1.I[CH:35]([CH3:37])[CH3:36].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[CH:35]([N:31]1[CH2:32][CH2:33][CH:29]([CH2:28][N:2]([CH3:1])[C:3]2[S:4][C:5]3[CH:11]=[C:10]([NH:12][C:13]([C:15]4[CH:16]=[CH:17][C:18]([C:21]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=5)=[CH:19][CH:20]=4)=[O:14])[CH:9]=[CH:8][C:6]=3[N:7]=2)[CH2:30]1)([CH3:37])[CH3:36]
Reactant: CN(CC1CCNC1)c1nc2ccc(NC(=O)c3ccc(-c4ccc(F)cc4)cc3)cc2s1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)N1CCC(CN(C)c2nc3ccc(NC(=O)c4ccc(-c5ccc(F)cc5)cc4)cc3s2)C1
Yield: 90.9 %

Procedure:
Place 4′-fluoro-biphenyl-4-carboxylic acid [2-(methyl-pyrrolidin-3-ylmethyl-amino)-benzothiazol-6-yl]-amide (16 mg, 0.035 mmol), 2-iodopropane (0.007 mL, 0.070 mmol), and potassium carbonate (15 mg, 0.108 mmol) in DMF (2 mL) and stir at rt for 3 d. Dilute the reaction with ethyl acetate and wash the organic layer with water (5 times). Chromatograph (silica gel, eluting with 10% 2M NH3 in MeOH:DCM) to yield 16 mg (91%) of the title compound: mass spectrum (ion-spray): (m/z)=503.3 (M+1).
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3](=[O:11])O1.[NH2:13][C:14]1[CH:15]=[C:16]([CH:23]=[CH:24][C:25]=1[CH3:26])[C:17]([NH:19][CH:20]1[CH2:22][CH2:21]1)=[O:18]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[O:12]=[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3](=[O:11])[N:13]1[C:14]1[CH:15]=[C:16]([CH:23]=[CH:24][C:25]=1[CH3:26])[C:17]([NH:19][CH:20]1[CH2:21][CH2:22]1)=[O:18]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)NC2CC2)cc1N1C(=O)Cc2ccccc2C1=O
Temperature: 150 °C
Yield: 56.3 %

Procedure:
A suspension of 1H-isochromene-1,3(4H)-dione (400 mg) and 3-amino-N-cyclopropyl-4-methylbenzamide (514 mg) in toluene (3 ml) was heated under microwave irradiation conditions (Personal Chemistry Emrys Optimizer with 300 W magnetron) at 150° C. for 60 minutes. The reaction mixture was diluted with ethyl acetate and washed with 2N HCl, water, brine, dried (magnesium sulfate) and concentrated to a foam which was purified by column chromatography with a gradient of iso-hexane to 70% ethyl acetate/iso-hexane to yield 3-(1,3-dioxo-3,4-dihydroisoquinolin-2(1H)-yl)-N-cyclopropyl-4-methylbenzamide as a solid (464 mg); NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.69 (m, 2H), 2.09 (s, 3H), 2.85 (m, 1H), 4.33 (d, 1H), 4.41 (d, 1H), 7.42 (d, 1H), 7.49-7.55 (m, 2H), 7.65 (s, 1H), 7.74 (t, 1H), 7.80 (d, 1H), 8.09 (d, 1H), 8.39 (d, 1H); Mass Spectrum: M+H+ 335.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([NH:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH:25]=4)[CH2:20][CH2:19]3)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: CCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Product: CCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CC3)CC2)c1

Procedure:
Example 63 was prepared from 1-(4-chlorophenyl)cyclopropanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according to the procedures described in Scheme 10: ESMS m/e: 468.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]=[C:8]3[C:15]([CH3:23])([CH3:22])[C:16]4[C:21]([C:7]3=[CH:6][C:5]2=1)=[CH:20][CH:19]=[CH:18][CH:17]=4.[CH:24]1[C:32]2[C:31]3[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=3[O:29][C:28]=2[C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH:24]1[C:32]2[C:31]3[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=3[O:29][C:28]=2[C:27]([C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH:9]=[C:8]4[C:15]([CH3:23])([CH3:22])[C:16]5[C:21]([C:7]4=[CH:6][C:5]3=2)=[CH:20][CH:19]=[CH:18][CH:17]=5)=[CH:26][CH:25]=1
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccc(Br)cc13
Reactant: OB(O)c1cccc2c1oc1ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccc(-c2cccc4c2oc2ccccc24)cc13

Procedure:
32 g (90.6 mmol) of 7-bromo-12,12-dimethyl-10,12-dihydro-10-azaindeno-[2,1-b]fluorene, 19.9 g (94 mmol) of dibenzofuran-4-boronic acid and 164 ml of saturated NaHCO3 solution are suspended in 1640 ml of toluene and 164 ml of ethanol. 1.9 g (1.6 mmol) of Pd(PPh)3 are added to this suspension, and the reaction mixture is heated under reflux for 16 h. After cooling, the organic phase is separated off, filtered through silica gel, washed three times with 200 ml of water and subsequently evaporated to dryness. The yield is 26.7 g (59 mmol), corresponding to 65% of theory.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:37][C:38](=[O:40])[CH3:39])[CH2:16][N:17]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:18]2([CH3:29])[CH2:26][C:25]3[C:20](=[CH:21][C:22]([CH3:28])=[C:23]([CH3:27])[CH:24]=3)[CH2:19]2)=[CH:11][C:10]=1[N+:41]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.C1(C)C=CC=CC=1.O=[Pt]=O>[NH2:41][C:10]1[CH:11]=[C:12]([C@@H:15]([O:37][C:38](=[O:40])[CH3:39])[CH2:16][N:17]([CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:18]2([CH3:29])[CH2:26][C:25]3[C:20](=[CH:21][C:22]([CH3:28])=[C:23]([CH3:27])[CH:24]=3)[CH2:19]2)[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[C@@H](CN(Cc1ccccc1)C1(C)Cc2cc(C)c(C)cc2C1)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: O=[Pt]=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)O[C@@H](CN(Cc1ccccc1)C1(C)Cc2cc(C)c(C)cc2C1)c1ccc(OCc2ccccc2)c(N)c1

Procedure:
Acetic acid (R)-1-(4-benzyloxy-3-nitro-phenyl)-2-[benzyl-(2,5,6-trimethyl-indan-2-yl)-amino]-ethyl ester in a mixture of THF and toluene is stirred under hydrogen in the presence of PtO2 at room temperature for 15 hours. The mixture is filtered through celite and the filtrate is concentrated in vacuo. ES+ MS m/e 549 (MH+).
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH3:8])[NH:6][CH:7]=1)=[O:2].[H-].[Na+].Cl[CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22]>O1CCCC1>[CH:1]([C:3]1[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH3:8])[N:6]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:7]=1)=[O:2]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1c(C=O)c[nH]c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C=O)cn(COCC[Si](C)(C)C)c1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of Example 93b (8.826 g, 48.7 mmol) in tetrahydrofuran (325 mL) was chilled in an ice bath and treated with sodium hydride (dry, 95%) (2.454 g, 97 mmol) added portionwise over 15 minutes. The mixture was stirred under N2 for 10 minutes and treated with (2-(chloromethoxy)ethyl)trimethylsilane (12 mL, 67.8 mmol), then stirred for 50 minutes. The reaction vessel was removed from the ice bath and allowed to warm to ambient temperature. The reaction mixture was carefully quenched with 200 mL of saturated aqueous ammonium chloride, reduced in volume by rotovap and shaken in a separatory funnel with 350 mL each of ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous magnesium sulfate), filtered and concentrated. The crude material was chromatographed on a 330 g silica gel cartridge eluting with 0-50% ethyl acetate/heptane to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:10]([CH3:12])([CH3:11])[C:9](=[O:13])[N:8]2[CH:14]2[CH:21]3[CH2:22][C:17]4([C:24](O)=[O:25])[CH2:18][CH:19]([CH2:23][CH:15]2[CH2:16]4)[CH2:20]3)=[CH:4][CH:3]=1.O.OC1C2N=N[NH:36]C=2C=CC=1.CCN=C=NCCCN(C)C.Cl.N>ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:10]([CH3:12])([CH3:11])[C:9](=[O:13])[N:8]2[CH:14]2[CH:21]3[CH2:22][C:17]4([C:24]([NH2:36])=[O:25])[CH2:18][CH:19]([CH2:23][CH:15]2[CH2:16]4)[CH2:20]3)=[CH:27][CH:28]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: CC1(C)C(=O)N(C2C3CC4CC2CC(C(=O)O)(C4)C3)N1Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: ClCCl
Product: CC1(C)C(=O)N(C2C3CC4CC2CC(C(N)=O)(C4)C3)N1Cc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 24.9 %

Procedure:
A solution of 4-[2-(4-fluorobenzyl)-3,3-dimethyl-4-oxo-1,2-diazetidin-1-yl]adamantane-1-carboxylic acid (20.0 mg, 0.0520 mmol) prepared in Example 90 in dichloromethane (1 mL) was added with hydroxybenzotriazole monohydrate (12.0 mg, 0.0890 mmol), WSC.HCl (20.0 mg, 0.100 mmol), 30% aqueous solution of ammonia (0.1 mL) at room temperature, and the resultant was stirred at the same temperature for 30 minutes. The reaction solution was added with water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The obtained residue was purified using Preparative Thin-Layer chromatography (ethyl acetate), and the title compound (5.00 mg, 24.9%) was obtained as a white crystalline powder.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1.[CH2:33]([NH2:40])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].C(=O)(O)[O-].[Na+]>C(#N)C>[C:13]1([C:11]2[N:12]=[C:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:40][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:10]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[Si](C)(C)CCOCn1c(CCCCCCBr)nc(-c2ccccc2)c1-c1ccccc1
Reactant: CCCCCCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCCCCCCNCCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)n1COCC[Si](C)(C)C
Yield: 96.9 %

Procedure:
Part B. A solution of 6-bromo-1-(4,5-diphenyl-1-[(trimethylsilyl)ethoxymethyl]-1H-imidazol-2-yl)hexane (1.0 g, 0.00195 mol) and n-heptylamine (0.45 g, 0.00389 mol) in acetonitrile (25 mL) was heated to 60° for 8 hours. The reaction mixture was poured into 10% aqueous sodium bicarbonate and extracted with ethyl acetate (2×50 mL). The combined organic extract was washed with water, brine, dried over magnesium sulfate and concentrated to give N-[6-(4,5-diphenyl-1-[(trimethylsilyl)ethoxymethyl]-1H-imidazol-2-yl)hexyl]-N-heptylamine as a colorless viscous oil (1.04 g, 0.00189 mol). 1H NMR (CDCl3) δ7.52-7.2(m,10H), 5.11(s,2H), 4.7-4.2(bs,1H), 3.3(t,2H), 2.93-2.70(m,6H), 1.95-1.34(m,18H), 0.93(t,3H), 0.86(t,2H), 0.005(s,9H).
Reaction SMILES: [C:1]1([CH3:32])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:11]2[C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Br:33]N1C(=O)CCC1=O>O1CCCC1.O>[C:1]1([CH3:32])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[C:11]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:24][CH:23]=3)=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:13]=[C:14]2[Br:33])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc(-c3ccc(F)cc3)c2-c2ccc(S(C)(=O)=O)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(Br)cc(-c3ccc(F)cc3)c2-c2ccc(S(C)(=O)=O)cc2)cc1
Reaction time: 5 h
Yield: 87 %

Procedure:
A solution of 1-(4-toluenesulfonyl)-2-(4-methylsulfonylphenyl)-3-(4-fluorophenyl)pyrrole (10.0 g, 0.021 mole) in 100 ml tetrahydrofuran was cooled in an ice bath and treated with N-bromosuccinimide (3.8 g, 0.021 mole) and stirred for five hours. The mixture was diluted with one liter of water and the resulting solid was collected by filtration, washed with water and dried. The crude product was recrystallized from ethyl acetate/hexane to yield 10.0 g (87% yield); m.p. 207°-207.5°.