Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](O)([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[C:13]([N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[CH:14][C:15]([SH:20])=[C:16]([O:18][CH3:19])[CH:17]=1.O>ClCCCl.[I-].[Zn+2].[I-]>[Cl:11][C:12]1[C:13]([N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[CH:14][C:15]([S:20][C:7]([CH3:9])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])=[C:16]([O:18][CH3:19])[CH:17]=1
Reactant: COc1cc(Cl)c(N2C(=O)c3ccccc3C2=O)cc1S
Reactant: CC(C)(O)c1ccccc1
Agent: [I-]
Agent: [Zn+2]
Solvent: O
Solvent: ClCCCl
Product: COc1cc(Cl)c(N2C(=O)c3ccccc3C2=O)cc1SC(C)(C)c1ccccc1
Yield: 96.4 %

Procedure:
To a solution of 2-phenyl-2-propanol (0.45 g) in 1,2-dichloroethane (5 mL) were added zinc iodide (0.53 g) and a solution of 5-chloro-4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-mercaptoanisole (1 g) in 1,2-dichloroethane (5 mL) successively, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1) to give 5-chloro-4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-(1-methyl-1-phenylethylthio)anisole (1.32 g). This material was dissolved in tetrahydrofuran (20 mL). To the solution was added hydrazine monohydrate (0.73 mL), and the mixture was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature, and the insoluble material was removed by filtration. To the filtrate were added water and ethyl acetate, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1) to give the title compound (0.74 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[CH:16]([C:18]1([C:22]([O:24][CH3:25])=[O:23])[CH2:21][CH2:20][CH2:19]1)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>O1CCCC1>[C:1]([O:5][C:6]([NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:16][C:18]2([C:22]([O:24][CH3:25])=[O:23])[CH2:21][CH2:20][CH2:19]2)[CH2:13][CH2:14]1)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: COC(=O)C1(C=O)CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C1(CN2CCC(CNC(=O)OC(C)(C)C)CC2)CCC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
To a stirred mixture of tert-butyl(piperidin-4-ylmethyl)carbamate (12.8 g, 60 mmol) and methyl 1-formylcyclobutanecarboxylate (2.13 g, 15 mmol, Davis, Charles R.; Swenson, Dale C.; Burton, Donald J., J. Org. Chem., 1993, 58, 6843) in tetrahydrofuran (50 mL) was added acetic acid (8.6 mL, 150 mmol) at ambient temperature. After 30 min, sodium triacetoxyborohydride (12.7 g, 60 mmol) was added to the mixture. Then, the mixture was heated to 60° C. for 2 h. After cooling, the reaction mixture was poured into sat. NaHCO3 aq. The aqueous layer was extracted with CH2Cl2 for 3 times. The combined organic phase were washed with brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on a column of silica gel eluting with hexane/ethyl acetate (1:1) to give 4.25 g (83%) of the title compound as white solid.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].B([O-])O[CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.[Ag]=O>[CH2:14]([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11])[CH3:15]
Reactant: CCOB[O-]
Reactant: O=C1CCc2c(Br)cccc21
Agent: O=[Ag]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCc1cccc2c1CCC2=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
4-Bromoindan-1-one (600 mg, 2.84 mmol) was dissolved in toluene (10 mL), and ethyl boronate (105 mg, 8.52 mmol), silver oxide (I) (274 mg, 7.10 mmol), potassium carbonate (196 mg, 8.52 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane complex (46 mg, 0.0568 mmol) were added thereto, and then, the resulting mixture was stirred under a nitrogen atmosphere at 100° C. for 4 hours. After cooling to room temperature, the reaction solution was filtered, and the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 80:20 (v/v)), whereby the objective title compound was obtained as a colorless oily substance (421 mg, yield: 92%).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([NH:17][CH2:18][CH2:19][CH3:20])=[O:16])=[CH:11][CH:10]=2)[N:7]=[N:6][C:5]=1[C:21]([OH:23])=O)[CH2:2][CH3:3].C1C=C[C:27]2N(O)N=[N:30][C:28]=2[CH:29]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:28]1([NH:30][C:21]([C:5]2[N:6]=[N:7][N:8]([C:9]3[CH:10]=[CH:11][C:12]([C:15]([NH:17][CH2:18][CH2:19][CH3:20])=[O:16])=[CH:13][CH:14]=3)[C:4]=2[CH2:1][CH2:2][CH3:3])=[O:23])[CH2:29][CH2:27]1
Reactant: CCCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCC)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCC)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.8 %

Procedure:
5-Propyl-1-{4-[(propylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxylic acid (498 mg, 1.57 mmol) obtained in Example 55b), HOBt (215 mg, 1.57 mmol, 1.0 eq.) and cyclopropylamine (0.146 ml, 2.05 mmol, 1.3 eq.) were dissolved in acetonitrile (4 ml) and DMF (4 ml), WSC (370 mg, 1.89 mmol, 1.2 eq.) was added and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (50 ml), and washed with 5% aqueous sodium hydrogen carbonate solution, 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate-hexane (2:1, 20 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated, and diethyl ether was added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (542 mg, 1.52 mmol, 97.1%).
Reaction SMILES: Cl.CN[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]=[N:12][CH3:13])[C:6]=1[OH:14].C1C[O:19]CC1>O.CC(OC)(C)C>[CH3:13][NH:12][C:11](=[O:19])[C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH:4]=[O:15])[C:6]=1[OH:14]
Reactant: C1CCOC1
Reactant: CN=Cc1cccc(C(=O)NC)c1O
Agent: Cl
Solvent: O
Solvent: COC(C)(C)C
Product: CNC(=O)c1cccc(C=O)c1O
Temperature: 22.5 °C
Reaction time: 14 h

Procedure:
60 ml of concentrated aqueous hydrochloric acid were added at 20 to 25° C. to 14 g (65 mmol) of the methylamide of Example 3 in a mixture of 120 ml of THF and 100 ml of water. After the reaction mixture had been stirred for approximately 14 hours at 20 to 25° C., it was taken up in MTBE and washed with water. After drying, the solvent was distilled off. 8 g of the title compound, which corresponded to 71% of theory, were obtained from the residue. (m.p.: 129-131° C.)
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[C:17](=[O:18])[CH:16]=[CH:15][C:14]([C:19]#[N:20])=[C:13]1[S-:21].[Na+].O>CC#N>[NH2:20][C:19]1[C:14]2[CH:15]=[CH:16][C:17](=[O:18])[N:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[Cl:5])[C:13]=2[S:21][C:2]=1[C:3]#[N:4]
Reactant: N#Cc1ccc(=O)n(-c2ccccc2Cl)c1[S-]
Reactant: N#CCCl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#Cc1sc2c(ccc(=O)n2-c2ccccc2Cl)c1N
Temperature: 40 °C
Yield: 33.5 %

Procedure:
Chloroacetonitrile (0.35 mL, 5.5 mmol) was added to a solution of Example 2 (1.42 g, 5.0 mmol) in MeCN (50 mL) and the mixture heated at 40° C. for 3 h. H2O (100 mL) was added and the mixture concentrated in vacuo to remove some of the MeCN (remaining volume ˜120 mL). The mixture was cooled to 0° C. and the solid filtered off, washed with H2O (15 mL) and Et2O (2×15 mL) and dried to give the title compound as a pale brown solid (505 mg, 32%). δH (DMSO-d6) 8.10 (1H, d, J 9.7 Hz), 7.75-7.73 (1H, m), 7.65-7.54 (3H, m), 7.14 (2H, br s, NH2), 6.54 (1H, d, J 9.7 Hz). LCMS (ES+) RT 2.97 minutes, 302 (M+H)+.
Reaction SMILES: [C:1]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][C:10]([OH:12])=O)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(O)(=O)C.C(OC(=O)C)(=O)C.C([O-])(=O)C.[Mg+2].C([O-])(=O)C>C(OCC)(=O)C>[C:1]([NH:7][C@@H:8]1[C:13](=[O:14])[O:15][C:10](=[O:12])[CH2:9]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(=O)CC(=O)N[C@@H](CC(=O)O)C(=O)O
Agent: CC(=O)[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)CC(=O)N[C@H]1CC(=O)OC1=O
Reaction time: 0.33 h

Procedure:
N-acetoacetyl-L-aspartic acid, 21.7 parts, was mixed with 20 parts by volume of glacial acetic acid and 12.3 parts of acetic anhydride. Anhydrous magnesium acetate, 0.40 parts, was added to the slurry which thinned briefly and then thickened rapidly. After 20 minutes, the slurry was thinned by addition of 10 parts by volume of dry ethyl acetate. The resulting slurry was again thinned after an additional 15 minutes upon addition of 10 parts by volume of dry ethyl acetate. The product was collected on a filter under nitrogen after a total reaction time of 60 minutes. After the solid was rinsed with dry ethyl acetate, it was dried in a vacuum dessicator at 0.1 mm to afford 17.2 parts N-acetoacetyl-L-aspartic anhydride.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([NH:14][C:15](=[O:31])[C:16]3[C:21]([F:22])=[CH:20][CH:19]=[C:18]([NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[C:17]=3[F:30])[CH:12]=2)[NH:7][CH:6]=1)=[O:4].[CH3:32][NH:33][CH3:34].CO>CCO>[CH3:32][N:33]([CH3:34])[CH2:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([NH:14][C:15](=[O:31])[C:16]3[C:21]([F:22])=[CH:20][CH:19]=[C:18]([NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[C:17]=3[F:30])[CH:12]=2)[NH:7][CH:6]=1)=[O:4]
Reactant: CNC
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(=O)CCl)c3c2)c1F
Solvent: CCO
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(=O)CN(C)C)c3c2)c1F
Temperature: 60 °C
Reaction time: 4 h
Yield: 40.4 %

Procedure:
N-(3-(2-Chloroacetyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.181 mL, 0.0361 mmol), EtOH (0.2 mL), and dimethylamine as a solution in MeOH (0.181 mL, 0.361 mmol) was charged to a 2 dram vial. The vial was capped and stirred at 60° C. for 4 hours. The mixture was concentrated under reduced pressure. The residue was taken up in 1M HCL (1 mL) and washed with EtOAc (2×1 mL). The aqueous portion was neutralized and extracted with 25% isopropyl alcohol (“IPA”)-DCM (3×2 mL), which was concentrated to provide N-(3-(2-(dimethylamino)acetyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (7 mg, 40.4%) as a solid. 1H NMR (400 MHz, CD3OD) δ 9.03-9.06 (m, 1H), 8.56-8.58 (m, 1H), 8.46 (s, 1H), 7.63-7.69 (m, 1H), 7.12-7.16 (m, 1H), 3.11-3.14 (m, 2H), 3.03 (s, 6H), 2.90 (s, 2H), 1.85-1.90 (m, 2H), 1.05-1.08 (m, 3H); m/z (APCI-pos) M+1=480.1.
Reaction SMILES: C([N:5]([C:15](=[O:24])[C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=1)[NH:6][C:7](=O)[C:8]1C=CC=C[CH:9]=1)(C)(C)C.[H-].[Na+].C(Br)C#C>CN(C)C=O.C(OCC)(=O)C>[CH2:7]([NH:6][NH:5][C:15](=[O:24])[C:16]1[CH:17]=[C:18]([CH3:23])[CH:19]=[C:20]([CH3:22])[CH:21]=1)[C:8]#[CH:9]
Reactant: Cc1cc(C)cc(C(=O)N(NC(=O)c2ccccc2)C(C)(C)C)c1
Agent: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#CCNNC(=O)c1cc(C)cc(C)c1
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a stirred suspension of N'-t-butyl-N-benzoyl-N'-(3,5-dimethylbenzoyl)hydrazine (1.5 g) in dimethylformamide (DMF) (20 ml) was added sodium hydride (200 mg of 60% oil dispersion) portionwise. After 15 min., propargyl bromide (0.6 g) was added to the reaction mixture dropwise and the reaction stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (5×20 ml). The organic layer was then dried over magnesium sulfate and the solvent removed under vacuum to afford N-(2-propynyl)-N'-(3,5-dimethylbenzoyl)hydrazine as a yellow amorphous solid. The product, N-(2-propynyl)-N'-t-butyl-N-benzoyl-N'-(3,5-dimethylbenzoyl)hydrazine, was purified by column chromatography on silica gel (solvent system: methylene chloride) to afford a 70% yield as a white solid.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N+:7]([O-])=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C.[Fe]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c2ccccc12
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ccnc2ccccc12
Temperature: 110 °C
Yield: 79.3 %

Procedure:
A suspension of 4-nitroquinoline N-oxide (10 g, 52.5 mmol) and metal iron (26.4 g, 0.47 mol) in acetic acid (500 ml) was stirred under heating at 110° C. for 3 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. To the residue was added an aqueous sodium hydroxide solution to make the solution alkaline, which was followed by extraction with chloroform (50 ml×6). The organic layer was washed with water and saturated brine, dried over sodium sulfate and concentrated under reduced pressure to give 4-aminoquinoline (6.0 g, 79%, brown crystals).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C>[C:14]([Si:11]([CH3:13])([CH3:12])[N:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:4]3[CH:5]=[N:6][CH:7]=[CH:2][CH:3]=3)[CH:3]=[C:4]2[CH:10]=[CH:9]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)n1ccc2cc(Br)cnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)n1ccc2cc(-c3cccnc3)cnc21
Temperature: 25 °C
Yield: 113.4 %

Procedure:
To a solution of 19 (1.77 g, 0.0057 mol), 3-diethylpyridyl borane (1.0 g, 0.0068 mol) in 80 mL of DME, was added PdCl2(Ph3P)2 (320 mg, 0.455 mmol) and aqueous 2M sodium carbonate (8.5 mL, 0.017 mol) under nitrogen. The reaction mixture was refluxed for 3 h. Cooled to rt and diluted with ethyl acetate and washed with brine. The organic layer was dried and concentrated to an oil that was subjected to flash chromatography (30% EtOAc-70% hexanes) to give 1 g (57%) of the desired material 20. 1H NMR CDCl3 8.9 (s, 1H), 8.5 (d, 1H), 8.4 (d, 1H), 8.0 (d, 1H), 7.9 (d, 1H), 7.5 (d, 1H), 7.2 (d, 1H), 6.5 (d, 1H), 0.85 (s, 9H), 0.55 (s, 6H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[CH3:14][S-:15].[Na+].C(#N)C>O>[CH3:13][C:4]1[CH:3]=[C:2]([S:15][CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=1
Reactant: C[S-]
Reactant: Cc1ccc2nc(C)cc(Cl)c2c1
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CSc1cc(C)nc2ccc(C)cc12
Yield: 98 %

Procedure:
A mixture of 4-chloro-2,6-dimethylquinoline (0.5 g, prepared as described in Example 1), sodium thiomethoxide (0.55 g) and dry acetonitrile (20 ml) was heated to reflux under an atmosphere of argon for 15 hours. After cooling to laboratory temperature the mixture was poured into water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were dried over magnesium sulphate and evaporated to leave 2,6-dimethyl-4methylthioquinoline as a white solid (0.52 g) which was used without further purification.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10](O)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F-:20].N1C=CC=CC=1>C(Cl)Cl>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([F:20])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: [F-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)F

Procedure:
BOC-Phe (1 mmole) in dry CH2Cl2 under nitrogen is treated with cyannuric fluoride (8 mmol) and pyridine (1 mmole) to form the above-identified product.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[CH2:6]1)=O.[CH3:27][NH2:28].O>C(O)C>[CH3:27][NH:28][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[CH2:6]1)=[O:2]
Reactant: CN
Reactant: COC(=O)C1CC(=O)N(c2ccc(/C=C/c3ccc(OC)cc3)cc2)C1
Solvent: CCO
Solvent: O
Product: CNC(=O)C1CC(=O)N(c2ccc(/C=C/c3ccc(OC)cc3)cc2)C1

Procedure:
A solution of 400 mg (1.1 mmol) of (RS)-(E)-1-{4-[2-(4-methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid methyl ester in 1.4 ml of a solution of methylamine in ethanol (33%) is heated at 90° C. for 18 h in a sealed vial. For the working-up, the cooled solution is treated with water to precipitate the product. The solid material is collected on a filter funnel, washed with water, finally, with heptane. After crystallization of the crude amide from a mixture of N,N-dimethylformamide and methanol, 98 mg (25% of theory) of (RS)-(E)-1-{4-[2-(4-methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid methylamide are obtained as a light brown solid; MS: m/e=351 (M+H)+.
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25]OS(C)(=O)=O)[O:22][C:21]3=[O:31])=[CH:16][C:15]=2[F:32])[CH2:10][CH2:9]1)=O)(C)C.[N-:33]=[N+]=[N-].[Na+].[C:37]([O:40]CC)(=O)[CH3:38]>CN(C)C=O>[O:31]=[C:21]1[N:20]([C:17]2[CH:18]=[CH:19][C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[C:15]([F:32])[CH:16]=2)[CH2:24][C@H:23]([CH2:25][NH:33][C:37](=[O:40])[CH3:38])[O:22]1
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)c(F)c2)C(=O)O1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of (R)-(-)-4-[4-[5-[[(methylsulfonyl)oxy]methyl]-2-oxo-3-oxazolidinyl]-2- fluorophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (EXAMPLE 20, Step 6, 13.83 g) and sodium azide (7.62 g) in dry dimethylformamide (117 mL) under N2 is stirred at 60° C. for five hours and at ambient temperature for 16 hours. The mixture is then diluted with ethyl acetate (200 mL), washed with water (8×100 mL) and saline (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound, mp 109-110° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]([C@@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:18]=[CH2:19])=[N:14][N:15]=2)=[C:7]([N+:28]([O-:30])=[O:29])[CH:6]=1.C([O:36]C(N[C@@H](CC=C)C(O)=O)=O)(C)(C)C.CCOC(C)=O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:31])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:15][NH:14][C:13](=[O:12])[C@@H:16]([NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:17][CH:18]=[CH2:19])=[O:36])=[C:7]([N+:28]([O-:30])=[O:29])[CH:6]=1
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)c1nnc(-c2ccc(NC(=O)OC)cc2[N+](=O)[O-])o1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)NNC(=O)c1ccc(NC(=O)OC)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 5 h
Yield: 86 %

Procedure:
{4-[5-((S)-1-tert-Butoxycarbonylamino-but-3-enyl)-1,3,4-oxadiazol-2-yl]-3-nitro-phenyl}-carbamic acid methyl ester: 168B (0.3 g, 0.393 mmol) and (S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid (0.085 g, 0.393 mmol) were dissolved in DMF (2 mL) in a 15 mL rbf and TEA (0.274 mL, 1.967 mmol) was added. Mixture was stirred under nitrogen at room temperature while propane phosphonic acid anhydride (T3P), 50% in EtOAc (0.293 mL, 0.983 mmol) was added dropwise. The flask was fitted with a reflux condenser, and the resulting mixture was stirred in an 80° C. oil bath for 5 h. Reaction mixture was poured into ice water and extracted 3× with EtOAc. Combined extracts were washed with sat'd aq. NaHCO3, water and brine, dried over anh. Na2SO4, filtered and evaporated to provide {4-[N′-((S)-2-tert-butoxycarbonylamino-pent-4-enoyl)-hydrazinocarbonyl]-3-nitro-phenyl}-carbamic acid methyl ester, (0.46 g, 86%) as a light yellow solid which was used without further purification. The solid (0.46 g, 1.019 mmol) was dissolved in anhydrous THF (20 mL) under argon and the solution transferred to a 75 mL pressure flask. Burgess reagent (1.33 g, 5.58 mmol) was added, the flask was sealed with a pressure relief cap and then heated in a 75° C. oil bath for 2 h behind a blast shield then left standing overnight at room temperature. Reaction mixture was evaporated on rotary evaporator. Residue was purified by normal phase chromatography to give 168C as a light yellow foam (0.315 g, 71.3%). MS (ESI) m/z: 434.3 (M+H)+ 378.3 (M+H−tBu)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[Cl:14][C:15]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18].CN(C)CCCN>C1(C)C(C)=CC=CC=1.O>[Cl:14][C:15]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:16]=1[C:17]([C:6]1[N:2]([CH3:1])[C:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:5]=1[CH3:7])=[O:18]
Reactant: CCOC(=O)Cc1cc(C)cn1C
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: CN(C)CCCN
Solvent: O
Solvent: Cc1ccccc1C
Product: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2Cl)n1C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
A solution of 50 g (0.276 mole) of ethyl 1,4-dimethyl-1H-pyrrole-2-acetate and 64 g (0.303 mole) of 2,4-dichlorobenzoyl chloride in 310 mL of xylene was heated under reflux for 4 h under argon. After cooling, a 20% solution of 3-dimethylaminopropylamine in H2O was added and stirred one hour. The organic layer was washed twice with 1N HCl, water, brine, and dried (MgSO4). Evaporation of the solvent in vacuo gave a solid which was recrystallized from methanol to give 79.39 g of product: mp 90-92° C.; mass spectrum (Cl—CH4) m/z=354 (M+1); NMR 300 MHz (CDCl3) d 7.5 (s, 1H); 7.3 (dd, 2H); 6.0 (s, 1H); 4.2 (q, 2H); 3.9 (s, 3H); 3.65 (s, 2H); 1.6 (s, 3H); 1.25 (t, 3H). Anal Calcd for C17H17Cl2NO3: C, 57.64; H, 4.84; N, 3.95. Found: C, 57.52; H, 4.60; N, 3.80.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[C@H:10](N)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N(C1C=C(OC)C(OC)=C(OC)C=1)=C=[O:30].CCOC(C)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([OH:30])[C@H:11]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](N2CCC(Cc3ccc(Cl)cc3)CC2)C1
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N2CCC(Cc3ccc(Cl)cc3)CC2)C1

Procedure:
Following General Procedure C, (±)-trans-3-amino-4-[4-(4-chlorobenzyl)piperidin-1-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (394 mg, ˜0.9 mmol) and 5-isocyanato-1,2,3-trimethoxybenzene (250 mg, 1.2 mmol) were coupled in CH2Cl2 (6.0 mL) at 0° C. for 1 h. Chromatography of the crude product with 1:1 hexanes:EtOAc to 100% EtOAc gave the product (445 mg, 77% from (±)-trans-3-[4-(4-chlorobenzyl)piperidin-1-yl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester) as a white solid: mp 99.0-102.5° C.; IR 3371 (br), 2932, 1655, 1607, 1552, 1507 cm−1; 1H NMR δ 1.17-1.80 (m, 14H), 2.18 (m, 2H), 2.48 (d, J=7.0 Hz, 2H), 2.95-3.51 (m, 8H), 3.81 (m, 9H), 4.32 (br, 1H), 5.30 (br, 1H), 6.61 (s, 2H), 7.02 (m, 2H), 7.20 (m, 2H); MS m/z 603.2 (M+H)+.