Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C>[CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)OCCO2
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Cc1cc2c(cc1[N+](=O)[O-])OCCO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.2 %

Procedure:
To a solution of 1 (20.0 g, 133.3 mmol) in acetic acid (135 mL) was added a solution of fuming HNO3 (10 mL) in acetic acid (50 mL) dropwise over 30 minutes. The mixture was stirred at ambient temperature for 10 minutes, then poured into a beaker containing ice to give a crystalline precipitate, which was collected by vacuum filtration and washed with water to afford the product (25.8 g, 99.2 %) as an off-white solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:13][C:14]([C:20]2[C:25]([F:26])=[CH:24][C:23]([C:27]([OH:30])([CH3:29])[CH3:28])=[CH:22][C:21]=2[F:31])=[CH:15][C:16]=1[C:17]([NH2:19])=[O:18]>>[F:31][C:21]1[CH:22]=[C:23]([C:27]([OH:30])([CH3:29])[CH3:28])[CH:24]=[C:25]([F:26])[C:20]=1[C:14]1[S:13][C:12]([NH:11][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][CH2:9][OH:10])[N:7]=2)=[C:16]([C:17]([NH2:19])=[O:18])[CH:15]=1
Reactant: OCCc1cccc(Br)n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(CCO)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using 2-(6-bromopyridin-2-yl)ethanol (48 mg, 0.24 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (75 mg, 0.24 mmol) as the starting materials.
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[ClH:13].Cl.[N:15]1([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[C:1]([N:18]1[CH2:17][CH2:16][N:15]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[ClH:13].[C:1]([N:18]1[CH2:17][CH2:16][N:15]([CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH2:20][CH2:19]1)(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CCOC(=O)CCCN1CCNCC1
Agent: Cl
Product: CCCCCCC/C=C/C(=O)N1CCN(CCCC(=O)O)CC1
Product: CCCCCCC/C=C/C(=O)N1CCN(CCCC(=O)OCC)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and ethyl 4-(1-piperazinyl)butyrate dihydrochloride as starting raw materials, to produce ethyl 4-[4-((E)-2-decenoyl)piperazin-1-yl)butanoate (ethyl ester of a free form of Compound 40).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:27]([NH2:29])=[O:28])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][C:15]3([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:17]C3)[C:6]=2[N:26]=1.[CH2:30]([O:37]C[C@H](NC(=O)OC(C)(C)C)CI)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OC(=O)N[C@@H](C)CI)(C)(C)C.N(C(OC(C)(C)C)=O)[C@H](CO)COCC1C=CC=CC=1.C(OC(=O)NC1(CI)CC1)(C)(C)C>>[NH2:1][C:2]1[C:3]([C:27](=[O:28])[NH2:29])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:17][O:37][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:6]=2[N:26]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CI)COCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(Cn2c3ccccc3c3cc(C(N)=O)c(N)nc32)CC1
Agent: CC(C)(C)OC(=O)NC1(CI)CC1
Agent: CC(C)(C)OC(=O)N[C@H](CO)COCc1ccccc1
Agent: C[C@@H](CI)NC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21

Procedure:
(R)-tert-butyl 1-(2-amino-3-carbamoyl-9H-pyrido[2,3-b]indol-9-yl)-3-(benzyloxy)propan-2-ylcarbamate (xvi-d) was prepared following the procedure detailed in the preparation of 63, substituting (S)-tert-butyl 1-(benzyloxy)-3-iodopropan-2-ylcarbamate (prepared as detailed in the synthesis of xxvii from commercial N-Boc-L-Ser(Bzl)-ol) for tert-butyl[1-(iodomethyl)cyclopropyl]carbamate. NH4OAc QC conditions. M+H=490.
Reaction SMILES: C(O[CH2:9][CH3:10])(OCC)OCC.[NH:11]([C:13]1[N:14]=[C:15]2[CH:21]=[CH:20][N:19]([S:22]([C:25]3[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:16]2=[N:17]C=1)[NH2:12]>CN(C=O)C>[S:22]([N:19]1[C:16]2[N:17]=[CH:9][C:10]3[N:14]([CH:13]=[N:11][N:12]=3)[C:15]=2[CH:21]=[CH:20]1)([C:25]1[CH:26]=[CH:27][C:28]([CH3:29])=[CH:30][CH:31]=1)(=[O:24])=[O:23]
Reactant: CCOC(OCC)OCC
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nncn23)cc1
Temperature: 100 °C
Reaction time: 17 h
Yield: 73.1 %

Procedure:
Triethyl orthoformate (76.0 mL, 456 mmol) was added to a mixture of 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (13.8 g, 45.4 mmol, Example #1, Step D) and DMF (45 mL) under nitrogen. A reflux condenser was attached and the mixture was warmed to about 100° C. After about 17 h, the solution was allowed to cool to ambient temperature. The volatiles were removed under reduced pressure. The residue was slurried in water (100 mL) and then filtered, rinsing with water. The aqueous phase was extracted with EtOAc (200 mL). The organics were dried over anhydrous Na2SO4, filtered, and concentrated. The material was combined with the precipitate and then purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to give 6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (10.4 g, 73%): LC/MS (Table 1, Method n) Rt=0.59 min; MS m/z 314 (M+H)+.
Reaction SMILES: C(O[CH2:5][C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH3:17])[CH:7]=1)(=O)C.[CH3:18][S:19]([O-:21])=[O:20].[Na+]>CC(C)=O.O>[CH3:17][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15](=[O:16])[C:6]([CH2:5][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:7]1
Reactant: CC(=O)OCc1cn(C)c2ccccc2c1=O
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cn1cc(CS(C)(=O)=O)c(=O)c2ccccc21

Procedure:
To a solution of 3-acetoxymethyl-1-methyl-4-quinolone (0.8 g.) in acetone (15 ml.) was added a solution of sodium methanesulphinate (0.53 g.) in water (10 ml.). The mixture was boiled under reflux for 24 hours. Further sodium methanesulphinate (0.14 g.) was added and the mixture was boiled under reflux for 4 hours. Acetone was evaporated from the mixture, causing the separation of a white solid which was recrystallised from industrial methylated spirit to give 1-methyl-3-methylsulphonylmethyl-4-quinolone, m.p. 195°-197°.
Reaction SMILES: [N:1]1(C(OCC2C3C(=CC=CC=3)C3C2=CC=CC=3)=O)[CH2:47][CH2:46][CH2:45][C@H:2]1[C:3]([N:5]1[CH2:44][CH2:43][CH2:42][C@H:6]1[C:7]([NH:9][C@H:10]([C:36]([C:38]([CH3:41])([CH3:40])[CH3:39])=[O:37])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:35])[NH:16][S:17]([C:20]1[C:33]([CH3:34])=[C:31]([CH3:32])[C:30]2[O:29][C:26]([CH3:28])([CH3:27])[CH2:25][CH2:24][C:23]=2[C:21]=1[CH3:22])(=[O:19])=[O:18])=[O:8])=[O:4]>N1CCCCC1.C(#N)C>[NH:1]1[CH2:47][CH2:46][CH2:45][C@H:2]1[C:3]([N:5]1[CH2:44][CH2:43][CH2:42][C@H:6]1[C:7]([NH:9][C@H:10]([C:36]([C:38]([CH3:39])([CH3:40])[CH3:41])=[O:37])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:35])[NH:16][S:17]([C:20]1[C:33]([CH3:34])=[C:31]([CH3:32])[C:30]2[O:29][C:26]([CH3:28])([CH3:27])[CH2:25][CH2:24][C:23]=2[C:21]=1[CH3:22])(=[O:19])=[O:18])=[O:8])=[O:4]
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)OCC2c3ccccc3-c3ccccc32)C(=O)C(C)(C)C)c(C)c2c1OC(C)(C)CC2
Solvent: C1CCNCC1
Solvent: CC#N
Product: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2)C(=O)C(C)(C)C)c(C)c2c1OC(C)(C)CC2

Procedure:
A solution of the Fmoc-Pro-Pro-Arg(Pmc)-t-Bu (4.15 g, 4.4 mmol) in 10% piperidine in acetonitrile (v/v, 50 ml) was stirred at RT for 30 min. All the volatiles were removed under reduced pressure and the residue was chromatographed on flash silica gel (360.0 g). All the fast moving impurities were removed by washing the column with 10% methanol in chloroform. Continued elution with 20% methanol in chloroform containing 0.1% TEA eluted the required amine. The fractions containing the amine were pooled and evaporated to furnish the amine as a colorless foam. Rf: 0.125 (20% methanol in chloroform). Yield: 3.0 g (98%). MS m/z 691.4 [M+H].
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:28](=[O:35])[N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=[O:39].C(N(CC)CC)C>C1(C)C=CC=CC=1.ClCCl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:28](=[O:35])[N:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[CH2:20][C:21]([OH:23])=[O:22])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1.[NH:18]([C:16]([O:15][CH2:14][CH:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:17])[C@H:19]([C:28]([OH:39])=[O:35])[CH2:20][C:21](=[O:22])[OH:23]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N1CCCCC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N1CCCCC1
Product: O=C(O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Tert-butyl (S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate (Compound SP403) (9.3 g, 19.4 mmol) was dissolved in toluene (300 mL), and the mixture was concentrated under reduced pressure. This operation was further repeated twice, and the residue was dried under reduced pressure overnight. Dehydrated dichloromethane (8.6 ml) was placed in the reaction vessel, and the mixture was stirred at 0° C. for 5 minutes under a nitrogen atmosphere, followed by dropwise addition of trifluoroacetic acid (8.6 ml, 116 mmol). After stirring at room temperature for 4 hours, triethylamine (16.2 ml, 116 mmol) was added dropwise at 0° C. The reaction mixture was diluted with dichloromethane (100 ml), and the organic layer was washed with a 5% aqueous sodium dihydrogenphosphate solution six times. The organic extract was dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was diluted again with dichloromethane (100 ml), and the organic layer was washed with a 5% aqueous sodium dihydrogenphosphate solution twice. The organic extract was dried over sodium sulfate and then concentrated under reduced pressure to afford (S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-oxo-4-(piperidin-1-yl)butanoic acid (Fmoc-Asp-pip, Compound SP401) (7.8 g, 96%). This compound was used in the next step without further purification.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:26]=[C:27]=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH2:44][OH:45])=[O:37])[CH2:32][CH2:31]1>ClCCl>[CH3:29][N:30]1[CH2:31][CH2:32][N:33]([C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH2:44][O:45][N:26]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:27]=[O:28])=[O:37])[CH2:34][CH2:35]1
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: CN1CCN(C(=O)c2ccccc2CO)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCN(C=O)OCc1ccccc1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 14.5 h

Procedure:
Triethylamine (6.50 ml) and octadecyl isocyanate (14.40 ml) were added to a solution of the syrup containing 2-(hydroxymethyl)phenyl 4-methylpiperazinyl ketone (9.83 g) in dichloromethane (100 ml). After being stirred for 14.5 hours at room temperature, the insoluble material was filtrated out under a vacuum. The filtrate was concentrated. The residue was purified by silica gel column chromatography (silica gel 225 g, chloroform:methanol=80:1), thereby yielding 12.00 g of the aimed compound as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.Br[CH:22]([CH3:36])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[C:32][CH2:33][CH2:34][OH:35])=[CH:27][CH:26]=1.CCN(CC)CC>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:15]2[CH2:16][CH2:17][N:18]([CH2:36][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]#[C:32][CH2:33][CH2:34][OH:35])=[CH:27][CH:26]=3)[CH2:19][CH2:20]2)=[CH:4][CH:3]=1
Reactant: CC(Br)COc1ccc(C#CCCO)cc1
Reactant: Clc1ccc([C@@H](c2ccccc2)N2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCCC#Cc1ccc(OCCCN2CCN([C@H](c3ccccc3)c3ccc(Cl)cc3)CC2)cc1
Yield: 73 %

Procedure:
[(1R)(4-chlorophenyl)phenylmethyl]piperazine (1.6 g, 5.6 mmol) and 4-[4(2-bromopropoxy)phenyl]but-3-yn-1-ol (2.0 g, 7.04 mmol) were dissolved in dichloromethane (10 mL). Et3N (1 mL, 7.04 mmol) was added dropwise, the solution was heated at reflux under Ar overnight. The solvent was evaporated and the compound was purified by silica gel chromatography, eluted with ethyl acetate. 2.0 g of the title compound were obtained as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([Br:12])=[CH:8][CH:9]=2)[N:4]([OH:13])[C:3]1=[O:14].Cl.NC(CC1C=CC(Br)=CC=1[N+]([O-])=O)C(O)=O.O.O.[Sn](Cl)Cl>CCO>[NH2:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([Br:12])=[CH:8][CH:9]=2)[N:4]([OH:13])[C:3]1=[O:14]
Reactant: NC1Cc2ccc(Br)cc2N(O)C1=O
Agent: Cl
Agent: Cl[Sn]Cl
Agent: NC(Cc1ccc(Br)cc1[N+](=O)[O-])C(=O)O
Solvent: O
Solvent: CCO
Product: N[C@@H]1Cc2ccc(Br)cc2N(O)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
3-Amino-7-bromo-1-hydroxy-3,4-dihydroquinolin-2(1H)-one (26) To a solution of 2-amino-3-(4-bromo-2-nitrophenyl)propanoic acid, hydrochloride salt (25) (343 mg, 1.06 mmol) in EtOH (10 mL) was added tin(II) chloride dihydrate (541 mg, 2.40 mmol), and the reaction was stirred at RT overnight. It was then quenched with aqueous ammonium hydroxide (1.5 mL), and the resulting precipitate was removed via filtration and washed with MeOH. The combined filtrates were concentrated in vacuo, and the residue was purified by chromatography on silica gel to provide the title product as a white powder (161 mg, 58%). LCMS m/z 258.9 (M+1). 1H NMR (500 MHz, DMSO-d6) δ 2.71 (dd, J=15.4, 12.9 Hz, 1H) 2.99 (dd, J=15.6, 6.1 Hz, 1H), 3.56 (dd, J=12.8, 6.0 Hz, 1H) 7.17-7.21 (m, 2H), 7.28 (d, J=1.7 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[N:15]1([C:21]([S:23][CH3:24])=[S:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:18]2[CH2:19][CH2:20][N:15]([C:21]([S:23][CH3:24])=[S:22])[CH2:16][CH2:17]2)=[CH:5][CH:4]=1
Reactant: CSC(=S)N1CCNCC1
Reactant: COc1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(CN2CCN(C(=S)SC)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
In a nitrogen atmosphere, 2.00 g (14.5 mmol.) of 4-methoxybenzyl alcohol was dissolved in 10 ml of dichloromethane. Under chilling with ice, to thesolution was dropwise added a solution of 1.05 ml (14.5 mmol.) of thionyl chloride in 2 ml of dichloromethane. The mixture was then stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was mixed with 2.90 g (14.5 mmol., purity 88.1%) of methyl 1-piperazinecarbodithioate, 1.54 g (14.5 mmol.) of anhydrous sodiumcarbonate and 25 ml of ethanol. The mixtrue was refluxed under heating for 14.5 hours. The solvent was distilled off under reduced pressure. The residue was mixed with 10 ml of dichloromethane and 10 ml of water. The mixture was allowed to give separated layers, and filtered to remove insolubles. The organic solvent portion was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill off the solvent. Theresidue was purified over a silica gel column to give 1.46 g of methyl 4-(4-methoxybenzyl)-1-piperazinecarbodithioate as a pale yellow oil, yield33.9%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][C:17]3[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:16]=3[N:15]=2)[CH2:10][C@@H:9]1[CH2:30][C:31]([OH:33])=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[CH3:46][CH:47](O)[CH2:48][C:49]([OH:52])([CH3:51])[CH3:50]>CN(C=O)C.CN(C)C1C=CN=CC=1>[Cl:29][C:27]1[CH:26]=[CH:25][C:17]2[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@@H:9]([CH2:30][C:31]([O:33][C@@H:47]([CH2:48][C:49]([OH:52])([CH3:51])[CH3:50])[CH3:46])=[O:32])[CH2:10]3)=[N:15][C:16]=2[CH:28]=1
Reactant: CC(O)CC(C)(C)O
Reactant: CC(C)(C)OC(=O)N1CCN(C2=Nc3cc(Cl)ccc3Oc3ccccc32)C[C@@H]1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: C[C@H](CC(C)(C)O)OC(=O)C[C@H]1CN(C2=Nc3cc(Cl)ccc3Oc3ccccc32)CCN1C(=O)OC(C)(C)C

Procedure:
(S)-2-(1-(tert-butoxycarbonyl)-4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)acetic acid (288 mg, 0.61 mmol) can be dissolved in DMF (5 ml). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (222 mg, 1.16 mmol), and 4-Dimethylaminopyridine (48 mg, 0.39 mmol) can be added respectively at room temperature under nitrogen. After about fifteen minutes R-(−)-2-Methyl-2,4-pentanediol (92 mg, 0.78 mmol) can be added and the mixture should be heated to about 50 C under nitrogen. The product can be purified by flash chromatography using 10% Acetone/Dichloromethane as the eluent to give (S)-tert-butyl 4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-2-(2-((R)-4-hydroxy-4-methylpentan-2-yloxy)-2-oxoethyl)piperazine-1-carboxylate. (S)-tert-butyl 4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-2-(2-((R)-4-hydroxy-4-methylpentan-2-yloxy)-2-oxoethyl)piperazine-1-carboxylate can be dissolved in dichloromethane (1.1 ml) and cooled in an ice bath. Trifluoroacetic acid (0.5 ml) should be added drop wise under nitrogen and slowly allowed to reach room temperature while running overnight. The mixture should be concentrated under vacuum and purified by flash chromatography using 10% Acetone/Dichloromethane as the eluent to give Compound ED.
Reaction SMILES: Br[C:2]1[O:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][CH:6]=1.C(N(CC)CC)C.[C:17]([C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1)#[CH:18]>C(#N)C.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>[N+:7]([C:4]1[O:3][C:2]([C:18]#[C:17][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)=[CH:6][CH:5]=1)([O-:9])=[O:8]
Reactant: C#Cc1ccc(C#N)cc1
Reactant: O=[N+]([O-])c1ccc(Br)o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ccc(C#Cc2ccc([N+](=O)[O-])o2)cc1
Reaction time: 8 h

Procedure:
To a solution of 2-bromo-5-nitrofuran (1.65 g) and triethylamine (34 ml) in anhydrous acetonitrile (55 ml) under nitrogen was added bis(triphenylphosphine)palladium dichloride (130 mg) and cuprous iodide (35 mg). 4-Ethynylbenzonitrile (1.09 g) was added and the reaction mixture was stirred under nitrogen overnight. The mixture was evaporated to dryness and the residue was dissolved in dichloromethane (200 ml), dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (ethyl acetate/hexane 1:10) and triturated with ethyl acetate/hexane (1:3) to give 4-[(5-nitro-2-furyl)-ethynyl]benzonitrile.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11]C[N:9]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:8]2=[O:19])=[C:4]([Cl:22])[CH:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:22][C:4]1[CH:3]=[C:2]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:5]=1[CH2:6][CH:7]1[CH2:12][CH2:11][N:9]([CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[C:8]1=[O:19]
Reactant: O=C1C(Cc2ccc(Br)cc2Cl)CCCN1C1CCCCC1
Reactant: Nc1ccccc1
Product: O=C1C(Cc2ccc(Nc3ccccc3)cc2Cl)CCN1C1CCCCC1
Yield: 61 %

Procedure:
Prepare essentially as described in Example 228, using 3-(4-bromo-2-chloro-benzyl)-1-cyclohexyl-piperidin-2-one and aniline. Evaporate the crude reaction mixture and purify by chromatography on silica gel to give the title compound (127 mg, 61%). MS (ES+) m/z=383 (M+H)+.
Reaction SMILES: S[C:2]1[O:3][C:4]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:5]=2[N:6]=1.[CH3:15][N:16]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(Cl)(Cl)Cl>[CH3:15][N:16]1[CH2:22][CH2:21][CH2:20][N:19]([C:2]2[O:3][C:4]3[CH:14]=[CH:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:5]=3[N:6]=2)[CH2:18][CH2:17]1
Reactant: CN1CCCNCC1
Reactant: Sc1nc2c(ccc3ccccc32)o1
Solvent: ClC(Cl)Cl
Product: CN1CCCN(c2nc3c(ccc4ccccc43)o2)CC1

Procedure:
2-Mercapto-naphtho[1,2-d]oxazole (200 mg) was dissolved in chloroform (20 ml), N-methylhomopiperazine (2.48 ml) was added dropwise to the solution and then the mixture was stirred with heating for 2 days. After evaporation of the solvent, the thus obtained mixture was purified by a silica gel column chromatography (methylene chloride:methanol=10:1) to obtain the title compound 2-(4-methyl-1-homopiperazinyl)naphtho[1,2-d]oxazole (137 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4]O.[C:7]([O-:13])([O-])([O:9][CH2:10][CH3:11])[CH3:8]>C(O)C>[CH3:1][C:2]([CH3:6])([CH:3]=[CH2:4])[CH2:8][C:7]([O:9][CH2:10][CH3:11])=[O:13]
Reactant: CCOC(C)([O-])[O-]
Reactant: CC(C)=CCO
Solvent: CCO
Product: C=CC(C)(C)CC(=O)OCC
Yield: 51.7 %

Procedure:
A mixture of 4.3 g of 3-methyl-2-buten-1-ol and 8.1 g of ethyl orthoacetate was heated with stirring. The temperature was increased slowly from room temperature to 165° over 2 hours, during which 2.21 g of ethanol was collected. The temperature was maintained at 165° for 26 hours, during which time an additional 1.52 g of ethanol was collected. The reaction mixture was then allowed to cool and diluted with diethyl ether. The ether solution was washed successively with dilute hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The washed solution was dried over magnesium sulfate and distilled to give 4.03 g (52% yield) of ethyl 3,3-dimethyl-4-pentenoate, b.p. 80°-85°/52 mm.
Reaction SMILES: [C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[N:34][N:35]=2)[N:32]=1.C(N(C(C)C)C(C)C)C.C(OCC)(=O)C>C(O)CCC>[C:20]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:27]3[CH:28]=[CH:29][C:30]4[N:31]([CH:33]=[N:34][N:35]=4)[N:32]=3)[CH2:11][CH2:10]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Clc1ccc2nncn2n1
Reactant: NCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(C(OC2CCN(CCCCNc3ccc4nncn4n3)CC2)c2ccccc2)cc1
Yield: 39.4 %

Procedure:
1.15 g of 4-(diphenylmethoxy)-1-piperidinebutanamine and 578 mg of 6-chloro[1,2,4]triazolo[4,3-b]pyridazine were dissolved in 20 ml of 1-butanol; 1.17 ml of N-ethyldiisopropylamine was added, followed by refluxing under heating for 14 hours. After cooling, ethyl acetate was added; the reaction mixture was washed with aqueous sodium bicarbonate and saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (50:5:1). The desired fraction was collected and concentrated under reduced pressure; the residue was crystallized from ethyl acetate and dried to yield 611 mg of the title compound.