Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[NH:13][CH3:14].CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24].O>C(Cl)Cl>[CH3:22][S:23]([O:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[NH:13][CH3:14])(=[O:25])=[O:24]
Reactant: CNc1nc2ccccc2n1CCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CNc1nc2ccccc2n1CCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a cooled (0° C.), stirred mixture of 1-(2-hydroxyethyl)-2-methylamino-1H-benzimidazole (8.05 g, 42.12 mmol), Et3N (4.26 g, 42.12 mmol), and CH2Cl2 (85 mL) was added a solution of MsCl (4.83 g, 42.12 mmol) in CH2Cl2 (10 mL). After 2 hours, H2O was added and the layers were separated. The aqueous phase was extracted with CH2Cl2. The combined extracts were washed with brine, dried, and concentrated to give 8.00 g (71%) of a white solid m.p. 48°-50° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]([CH2:11][OH:12])[O:7][C:6]=2[CH:13]=1.[CH3:14][S:15]([O-:17])=[O:16].[Na+].N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[CH3:14][S:15]([C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]([CH2:11][OH:12])[O:7][C:6]=2[CH:13]=1)(=[O:17])=[O:16]
Reactant: OCC1COc2ccc(Br)cc2O1
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc2c(c1)OC(CO)CO2
Temperature: 140 °C
Yield: 182.2 %

Procedure:
4 batches of a mixture of (7-bromo-2,3-dihydro-1,4-benzodioxin-2-yl)methanol (0.5 g, 2.0 mmol), sodium methanesulfinate (85%) (0.37 g, 3.1 mmol), CuI (0.039 g, 0.2 mmol), L-proline (0.047 g, 0.4 mmol) and K2CO3 (0.056 g, 0.4 mmol) in DMSO (4 ml) was heated under microwave radiation to 140° C. for 1 h in a nitrogen-flushed vial. The batches were mixed and diluted with water and HCl (1 N). The resulting solution was extracted with EtOAc. The combined organic phases were washed with brine, dried and purified on flash column chromatography (isooctane/EtOAc/MeOH) to give the title compound (0.89 g). MS m/z (rel. intensity, 70 eV) 244 (M+, bp), 213 (40), 165 (27), 134 (22), 79 (18).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:27]=[CH:26][C:25]([CH2:28]O)=[CH:24][C:12]=3[N:13]\2[C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH:36]1[CH2:41][CH2:40][CH:39]([C:42]([OH:45])([CH3:44])[CH3:43])[CH2:38][CH2:37]1>C(Cl)Cl>[F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:27]=[CH:26][C:25]([CH2:28][N:36]4[CH2:41][CH2:40][CH:39]([C:42]([OH:45])([CH3:44])[CH3:43])[CH2:38][CH2:37]4)=[CH:24][C:12]=3[N:13]\2[C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)(O)C1CCNCC1
Reactant: COC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CO)cc32)CC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCC(C(C)(C)O)CC4)cc32)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
To a 0° C. cooled solution of cis-methyl 4-((E)-2-(4-fluorobenzoylimino)-6-(hydroxymethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate (1 g, 2.350 mmol) in DCM (25 mL) was added thionyl chloride (0.858 mL, 11.75 mmol) dropwise, and the reaction was stirred at 0° C. for 30 minutes. After 30 minutes, the solvent was removed at reduced pressure, and the residue was suspended in ACN (5 mL) and re-concentrated to remove residual thionyl chloride. The residue was resuspended in ACN (15 mL), cooled to 0° C., and 2-(piperidin-4-yl)propan-2-ol (1.010 g, 7.05 mmol) and TEA (0.655 mL, 4.70 mmol) were added. The reaction was stirred overnight at RT. After 16 hours, the reaction mixture was concentrated and partitioned between EtOAc and water. The organic layer was concentrated and the residual product was purified by column chromatography, eluting with 0-100% (90:9:1 DCM/MeOH/NH4OH)/DCM to provide cis-methyl 4-((E)-2-(4-fluorobenzoylimino)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate as a white powder (1.05 g, 81% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (s, 6H), 1.09-1.35 (m, 3H), 1.56-1.91 (m, 8H), 2.21-2.29 (m, 2H), 2.53-2.64 (m, 2H), 2.77-2.95 (m, 3H), 3.50 (s, 2H), 3.77 (s, 3H), 3.99 (s, 1H), 4.74 (br. s., 1H), 7.14 (d, J=6.9 Hz, 1H), 7.26 (dd, J=8.8 Hz, 8.8 Hz, 2H), 7.37-7.58 (m, 2H), 8.26 (dd, J=8.7, 5.9 Hz, 2H), 12.77 (s, 1H). MS, m/z (C31H39FN4O4): calcd, 550.3. found, 551.1 [M+H].
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[O:7][CH:8]=[CH:9][C:10]=1[CH:11]=[O:12].C(O)=O.C([O-])(O)=O.[Na+].CCOC(C)=O>O>[O:7]1[CH:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:6]1[CH:2]=[O:1]
Reactant: O=Cc1ccoc1C1OCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=CO
Product: O=Cc1ccoc1C=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 114.1 %

Procedure:
2-(3-Bromo-2-furyl)-1,3-dioxolane (438 mg, 2.0 mmol) is dissolved in Et2O (5 mL) in a dry flask under nitrogen, cooled to −78° C., treated dropwise with tert-butyllithium (2.59 mL, 4.4 mmol) and stirred for 1 h. DMF (178 μL, 2.3 mmol) in Et2O (2 mL) is added dropwise, the mixture stirred for 4 h at −78° C., then treated with oxalic acid dihydrate (504 mg, 4.0 mmol) followed by water (2 mL). The cooling bath is removed and the mixture allowed to warm to RT over 1 h. The mixture is diluted with water (20 mL) and EtOAc (20 mL), the layers are separated and the aqueous layer extracted with EtOAc (1×20 mL). The organics are dried over Na2SO4 and concentrated to a yellow oil. The crude material is chromatographed over 12 g slurry-packed silica gel, eluting with 15% EtOAc/hexane. The appropriate fractions are combined and concentrated in vacuo to afford 228 mg (68%) of 2-(1,3-dioxolan-2-yl)-3-furaldehyde as a pale yellow oil. MS (EI) m/z: 168 (M+). 2-(1,3-Dioxolan-2-yl)-3-furaldehyde (2.91 g, 17.31 mmol) is combined with formic acid (17 mL, 451 mmol) and water (4.25 mL) and stirred at RT for 18 h. The mixture is slowly transferred into a solution of NaHCO3 (45 g, 541 mmol) in water (600 mL), then stirred for 0.5 h. EtOAc (200 mL) is added, the layers separated and the aqueous layer extracted with EtOAc (2×200 mL). The combined organics are dried over Na2SO4 and concentrated to a yellow oil (3.28 g). The crude material is chromatographed over 90 g slurry-packed silica gel, eluting with 20% EtOAc/hexane. The appropriate fractions are combined and concentrated to afford 2.45 g of furan-2,3-dicarbaldehyde slightly contaminated with ethylene glycol diformate as a yellow oil. 1H NMR (CDCl3): δ 7.00 (d, J=2 Hz, 1H), 7.67 (d, J=2 Hz, 1H), 10.07 (s, 1 H), 10.49 (s, 1 H) ppm.
Reaction SMILES: [CH2:1]([C:9]1[C:14]([CH3:15])=[C:13]([O:16]C)[C:12]([CH3:18])=[C:11]([CH3:19])[C:10]=1[O:20]C)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>O>[CH2:1]([C:9]1[C:10](=[O:20])[C:11]([CH3:19])=[C:12]([CH3:18])[C:13](=[O:16])[C:14]=1[CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1c(C)c(OC)c(C)c(C)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Product: CCCCCCCCC1=C(C)C(=O)C(C)=C(C)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
A flask was charged with 1-octyl-2,5-dimethoxy-3,4,6-trimethyl-benzene (204; 1.75 g, 7.5 mmol) and CAN (20 mL) then cooled to 0° C. A solution of CAN (8.4 g, 15.4 mmol) in water (10 mL) was added to the flask. After 1 h the reaction was complete. The reaction was diluted with water (50 mL) and the yellow precipitate was filtered and washed with water (20 mL). The fine yellow needles were dried under high vacuum to give pure 2-octyl-3,5,6-trimethyl-[1,4]benzoquinone (206; 1.69 g, 86%). 1H NMR (400 MHz; CDCl3; ppm): 2.49-2.45 (m, 2H), 2.04 (s, 3H), 2.03 (s, 6H), 1.45-1.19 (m, 12H), 0.89 (t,J=6.2 Hz, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][C:6]2[N:7]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:8](=[O:10])[NH:9][C:5]=2[CH:4]=1.C(N(CC)CC)C.[O:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.ClCCCl>[Cl:2][C:3]1[C:18]([C:19]([F:20])([F:21])[F:22])=[CH:17][C:6]2[N:7]([CH:11]3[CH2:16][CH2:15][N:14]([CH:33]4[CH2:34][CH2:35][O:30][CH2:31][CH2:32]4)[CH2:13][CH2:12]3)[C:8](=[O:10])[NH:9][C:5]=2[CH:4]=1
Reactant: O=c1[nH]c2cc(Cl)c(C(F)(F)F)cc2n1C1CCNCC1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1[nH]c2cc(Cl)c(C(F)(F)F)cc2n1C1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-Chloro-1-(4-piperidinyl)-6-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (0.228 mmol, 82 mg) was dissolved in dichloromethane (6 ml) and triethylamine (3 eq., 0.68 mmol, 50 microliters), tetrahydro-4H-pyran-4-one (7 eq., 1.6 mmol, 160 mg), sodium triacetoxyborohydride (7 eq., 1.6 mmol, 340 mg) were added at room temperature and the mixture was stirred at room temperature for 3 hours. More triethylamine (4 ml), tetrahydro-4H-pyran-4-one (3.5 eq, 0.8 mmol, 80 mg), sodium triacetoxyborohydride (3.5 eq, 0.8 mmol, 170 mg) were added at room temperature and the mixture was stirred at room temperature for two extra hours. The solvent was evaporated and the mixture was worked up with sodium bicarbonate and DCM. The solvent was evaporated and triethylamine (3 eq., 0.68 mmol, 50 microliters), tetrahydro-4H-pyran-4-one (7 eq, 1.6 mmol, 160 mg), sodium triacetoxyborohydride (7 eq, 1.59 mmol, 340 mg) and DCE (4 ml) were introduced and all mixed together for 1 hour at room temperature. The mixture was quenched with water/NaHCO3 (saturated solution) and DCM. The organic phase was separated from the aqueous phase (by hydrophobic filters) and the organic solvent was evaporated to afford the crude product that was purified by chromatography (MeOH—NH3-dichloromethane) to afford 5-chloro-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-6-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one, 29 mg, 31%, M++H=403, which was subsequently converted into the mono-hydrochloride salt using HCl (2 eq. from a 1M solution of HCl in diethyl ether).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C:6](=[O:9])[CH2:7][Cl:8])=O.[CH2:10]([O:17][C@@H:18]1[C@@H](CO)[O:21][C@@H:20]([N:25]2[CH:32]=[C:31]([F:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:19]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH2:10]([O:17][C@@H:18]1[C@@H:2]([CH2:3][O:5][C:6](=[O:9])[CH2:7][Cl:8])[O:21][C@@H:20]([N:25]2[CH:32]=[C:31]([F:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:19]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(CCl)OC(=O)CCl
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccccc3)[C@@H](CO)O2)cc1F
Solvent: c1ccncc1
Product: O=C(CCl)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OCc1ccccc1
Reaction time: 8 h
Yield: 45 %

Procedure:
Chloroacetic anhydride was added to a solution of 0.20 g of 3'-O-benzyl-2'-deoxy-5-fluorouridine in 10 ml of pyridine, and the mixture was left to stand at room temperature overnight. Then the same subsequent procedures as in Example 54 were conducted, giving 0.11 g of the title compound as an oil in a yield of 45%.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]([CH3:28])([CH3:27])[C:23]([NH:25][NH2:26])=[O:24].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:26][NH:25][C:23](=[O:24])[C:22]([CH3:28])([CH3:27])[CH3:21])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)C(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added 2,2-dimethylpropanehydrazide 253 (0.137 g, 1.358 mmol), 1-hydroxybenzotriazole (0.186 g, 1.358 mmol) and 1-ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 254 (0.32 g, 94%) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][CH2:11][NH2:12])=[CH:4][CH:3]=1.CS[C:15](SC)=[CH:16][N+:17]([O-:19])=[O:18].C(O)C>CO.ClCCl>[N+:17]([CH:16]=[C:15]1[NH:12][CH2:11][CH2:10][CH2:9][N:8]1[C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([O-:19])=[O:18]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCCNc1ccc(Cl)nc1
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: O=[N+]([O-])C=C1NCCCN1c1ccc(Cl)nc1
Yield: 38 %

Procedure:
A mixture of N-(6-chloro-3-pyridyl)-1,3-diaminopropane (6.0 g, 0.032 mol)(ex Example 2), 1,1-bis(methylthio)-2-nitroethene (5.34 g, 0.032 mol) and ethanol (100 ml) was heated under reflux for 24 hours. The resulting mixture was evaporated to leave a dark brown oil which was subjected to flash chromatography on a silica column using silica gel, 230 to 400 US mesh (0.062 mm to 0.037 mm), and with 2% w methanol in dichloromethane as eluent. The resulting product was recrystallized from ethanol to give 2-nitromethylene-1-(6-chloro-3-pyridyl)hexahydropyrimidine as a pale yellow solid (3.1 g, 38%), m.p. 202° C.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([CH3:9])=[CH:7][NH:6][C:5]2=[O:10])[CH2:3][CH2:2]1.[F:11][C:12]([F:22])([F:21])[C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br>>[CH:1]1([N:4]2[C:8]([CH3:9])=[CH:7][N:6]([CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[C:12]([F:11])([F:21])[F:22])[C:5]2=[O:10])[CH2:3][CH2:2]1
Reactant: Cc1c[nH]c(=O)n1C1CC1
Reactant: FC(F)(F)c1ccccc1CBr
Product: Cc1cn(Cc2ccccc2C(F)(F)F)c(=O)n1C1CC1

Procedure:
This material was obtained in analogy to the procedure outlined in example 28, Step B] from 1-cyclopropyl-5-methyl-1,3-dihydro-imidazol-2-one (obtained in example 28, step A), 150 mg) by alkylation with 2-trifluoromethylbenzyl bromide (285 mg). 3-Cyclopropyl-4-methyl-1-(2-trifluoromethyl-benzyl)-1,3-dihydro-imidazol-2-one was obtained as a colorless liquid (121 mg). MS (ESI): 297.1 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[CH:12][CH:11]=2)=O)[CH2:3][CH2:2]1.O.NN.[OH-].[Na+]>C(O)COCCO.O>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C(CC1CCNCC1)c1ccnc2ccccc12
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: c1ccc2c(CCC3CCNCC3)ccnc2c1
Temperature: 180 °C
Reaction time: 18 h
Yield: 81.4 %

Procedure:
A mixture of 13 g of 2-(4-piperidyl)-1-(4-quinolyl)-ethanone, prepared as indicated in Example 1, and 10 ml of 98% hydrazine hydrate in 150 ml of diethylene glycol is heated at 180° C. for 2 hours. After cooling, 15 g of sodium hydroxide pellets are added and the mixture is kept at 180° C. for 18 hours. The reaction mixture is diluted with water, extracted with chloroform. The organic phase is washed with water, dried and evaporated under reduced pressure. 10 g of the desired product are obtained, which is converted into the hydrochloride by the action of hydrochloric acid in ethanol. 7.2 g of 4-[2-(4-piperidyl)-ethyl]-quinoline are obtained in the form of monohydrated dihydrochloride which melts at 210° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:19]=[C:18]([CH:20]3[CH2:22][CH2:21]3)[NH:17][N:16]=2)[N:11]=[C:10]([N:23]2[CH2:27][C:26]([CH3:29])([CH3:28])[CH2:25][C@@:24]2([CH3:34])[C:30]([O:32][CH3:33])=[O:31])[N:9]=1>>[CH:20]1([C:18]2[NH:17][N:16]=[C:15]([NH:14][C:12]3[N:13]=[C:8]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[N:9]=[C:10]([N:23]4[CH2:27][C:26]([CH3:28])([CH3:29])[CH2:25][C@@:24]4([CH3:34])[C:30]([O:32][CH3:33])=[O:31])[N:11]=3)[CH:19]=2)[CH2:22][CH2:21]1
Reactant: COC(=O)[C@]1(C)CC(C)(C)CN1c1nc(Cl)nc(Nc2cc(C3CC3)[nH]n2)n1
Reactant: C1COCCN1
Product: COC(=O)[C@]1(C)CC(C)(C)CN1c1nc(Nc2cc(C3CC3)[nH]n2)nc(N2CCOCC2)n1

Procedure:
Compound 106F was prepared from morpholine and 106E as described for 1: LC/MS [M+H]+: 457; Ret time (Method F): 2.97 min.
Reaction SMILES: [C:1]([C:5]1[CH:33]=[CH:32][C:8]([C:9]([NH:11][C:12]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C>C(O)C.[Pd]>[C:1]([C:5]1[CH:33]=[CH:32][C:8]([C:9]([NH:11][C:12]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(NC(=O)c2cc([N+](=O)[O-])ccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(NC(=O)c2cc(N)ccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Reaction time: 5 h
Yield: 58.3 %

Procedure:
A mixture of 2-(4-tert-butylbenzoylamino)-5-nitro-N-(4-methoxyphenyl)benzamide (895 mg, 2.00 mmol), 10% palladium-on-carbon (90 mg) and ethyl acetate (5 ml) in ethanol (5 mL) was hydrogenated at one atmospheric pressure for 5 h. The reaction was degassed and a suspension of 10% palladium-on-carbon (45 mg) and ethyl acetate (3 mL) was added. This mixture was hydrogenated for 2 days at one atmosphere. The reaction was filtered through diatomaceous earth assisted by ethyl acetate/ethanol washes. The filtrate was concentrated in vacuo and chromatographed (silica gel, 10% ethyl acetate/90% methylene chloride to 35% ethyl acetate/65% methylene chloride) to give 487 mg (58%) of the title compound as a white solid; mp 212-214.5° C.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][C@@H:3]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[NH:2]2.Cl.[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][CH2:38][CH2:39][C@H:40]([NH:46][C@H:47]([C:49](O)=[O:50])[CH3:48])[C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:32][CH2:31]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC>CN(C)C=O.O>[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][CH2:38][CH2:39][C@H:40]([NH:46][C@H:47]([C:49]([N:2]2[C@H:3]([C:9]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:8][CH2:7][CH2:6]3)=[O:50])[CH3:48])[C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:32][CH2:31]1)=[O:29])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)[C@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](C)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@@H]2CCC[C@@H]2N1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](C)C(=O)N1[C@H](C(=O)OCc2ccccc2)C[C@@H]2CCC[C@@H]21
Yield: 37.3 %

Procedure:
In 10 ml of N,N-dimethylformamide are dissolved 0.56 g of benzyl (S,S,S)-2-azabicyclo[3,3,0]octane-3-carboxylate·hydrochloride and 0.5 g of N-[(S)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanine·hydrochloride, and 0.3 g of triethylamine is added to the solution under ice-cooling with stirring, followed by addition of 0.5 ml of diethyl phosphorocyanidate. After stirring for 30 minutes, there is added to the mixture 0.1 g of triethylamine, followed by stirring for 30 minutes and at room temperature for 1 hour. The reaction mixture is diluted with 100 ml of water and extracted with 100 ml of ethyl acetate. The extract is washed with 5% aqueous phosphoric acid and water, successively, and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography (hexane:acetone=3:1) to give 0.26 g of benzyl (S,S,S)-2-[N-[(S)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanyl]-2-azabicyclo-[3,3,0]octane-3-carboxylate as a colorless oil.
Reaction SMILES: C(O)(=O)C.Cl.[C:6]1([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20]N)=[CH:16][CH:15]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][CH2:30][C:29](=O)[CH2:28]1)=[O:26])[CH3:23]>O>[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][C:30]2[NH:20][C:17]3[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=4)=[CH:19][C:18]=3[C:29]=2[CH2:28]1)=[O:26])[CH3:23]
Reactant: CCOC(=O)C1CCC(=O)C1
Reactant: NNc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C1Cc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
To 250 ml of 80% acetic acid in water, were added 4-phenylmethoxyphenylhydrazine hydrochloride (30 g, 0.12 mole) and 3-oxocyclopentane carboxylic acid ethyl ester (20 g, 0.13 mole). After stirring at ambient temperature for one hour and then at 100° C. for four hours, the mixture was cooled and poured into one liter of water. After stirring for five minutes, the mixture was extracted with ethyl acetate (3×). The organic layer was washed successively with water (2×) and saturated sodium chloride solution, and thereafter dried over anhydrous MgSO4. After filtering, the solution was concentrated to a dark oil (~48 g), which was eluted on a silica gel column with 5% ethyl acetate/dichloromethane via HPLC. The desired fractions were combined and concentrated to give the product as a thick brown oil (24.1 g).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][CH2:9][CH2:10][CH2:11][C:12](=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]2)=[C:19]([O:29][CH3:30])[CH:18]=1)[C:13]([OH:15])=O.[F:31][C:32]1[CH:37]=[CH:36][C:35]([C@@H:38]([NH2:40])[CH3:39])=[CH:34][CH:33]=1.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)CCl.CN(C=O)C>[F:31][C:32]1[CH:37]=[CH:36][C:35]([C@@H:38]([NH:40][C:13](=[O:15])/[C:12](=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]3)=[C:19]([O:29][CH3:30])[CH:18]=2)/[CH2:11][CH2:10][CH2:9][Cl:8])[CH3:39])=[CH:34][CH:33]=1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: COc1cc(C=C(CCCCl)C(=O)O)ccc1-n1cnc(C)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1cc(/C=C(\CCCCl)C(=O)N[C@@H](C)c2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To a DMF (50 mL) solution of 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid trifluoroacetic acid salt (8.00 g) and (S)-1-(4-fluorophenyl)ethylamine (2.60 g), IPEA (12.4 mL), EDC (6.82 g) and HOBT (4.81 g) were added one by one, and the reaction solution was agitated at room temperature overnight. After confirming disappearance of the starting materials, the solvent was concentrated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was partitioned. After the organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (elution solvent:heptane-ethyl acetate=2:3→1:1→ethyl acetate), and 3.90 g of the title compound was obtained. The physical properties of the compound are as follows.