Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([C:8]#[N:9])[CH2:2]1.I[CH2:11][CH2:12][CH2:13][CH3:14]>C(#N)C>[CH2:11]([N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([C:8]#[N:9])[CH2:2]1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCI
Reactant: N#CC1CCCCNC1
Solvent: CC#N
Product: CCCCN1CCCCC(C#N)C1

Procedure:
To 50 mL of acetonitrile is added 1 g (8.0 mmol) of hexahydro-1H-azepine-3-carbonitrile and 2.7 g (15 mmol) of iodobutane. Heat the reaction under reflux and monitor the reaction by thin-layer chromatography. Upon completion remove the solvent in vacuo and add 50 mL sat. sodium bicarbonate and 50 mL methylene chloride. Separate the organic layer and dry over Na2SO4. Filter off the drying agent and remove the solvent in vacuo to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:4][C:5]([CH3:21])=[C:6]([CH3:20])[C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].Cl.[Cl:30][CH2:31][C:32](=N)OCC>C(Cl)(Cl)Cl>[Cl:30][CH2:31][C:32]1[N:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:7]2[C:6]([CH3:20])=[C:5]([CH3:21])[N:4]=[C:3]([O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:2]=2[N:1]=1
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCCCNC(=O)OC(C)(C)C)c1C
Reactant: CCOC(=N)CCl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Cc1nc(Oc2ccccc2)c2nc(CCl)n(CCCNC(=O)OC(C)(C)C)c2c1C
Temperature: 60 °C
Reaction time: 72 h
Yield: 115.7 %

Procedure:
tert-Butyl 3-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]propylcarbamate (68.8 g, 178 mmol), prepared as described in U.S. Pat. No. 6,545,016, Example 17, Parts A through C, was dissolved in chloroform (600 mL). Ethyl 2-chloroacetimidate hydrochloride (56.0 g, 354 mmol) was added to the solution and the reaction mixture was stirred at 60° C. for 72 hours. The reaction mixture was diluted with chloroform (200 mL), washed with brine (2×600 mL), and the layers were separated. The combined organics were dried over magnesium sulfate, filtered through CELITE filter aid, and concentrated under reduced pressure to afford 91.62 g of tert-butyl 3-[2-(chloromethyl)-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]propylcarbamate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=O)[C:11]([F:16])([F:15])[CH2:12][O:13][CH3:14])=[N:6][CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C:11]([F:16])([F:15])[CH2:12][O:13][CH3:14])=[N:9][N:8]=2)[CH:7]=1
Reactant: COCC(F)(F)C(=O)NNc1ccc(Br)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COCC(F)(F)c1nnc2ccc(Br)cn12

Procedure:
N′-(5-bromopyridin-2-yl)-2,2-difluoro-3-methoxypropanehydrazide (0.25 g, 0.81 mmol) and p-toluenesulfonic acid monohydrate (0.12 g, 0.65 mmol) in 1,4-dioxane (3.5 mL) were put onto microwave at 160° C. for 80 min. The reaction mixture was diluted with EtOAc and washed sequentially with NaHCO3 aqueous solution and brine. The organic layer was dried over Na2SO4. Evaporation of the solvent and purification by HPLC gave 6-bromo-3-(1,1-difluoro-2-methoxyethyl)[1,2,4]triazolo[4,3-a]pyridine.
Reaction SMILES: [Na].[CH:2]([CH:6]([C:11]([O:13]C)=O)[C:7]([O:9]C)=O)([CH2:4][CH3:5])[CH3:3].[NH2:15][C:16]([NH2:18])=[O:17]>C(O)C>[CH:2]([CH:6]1[C:7](=[O:9])[NH:18][C:16](=[O:17])[NH:15][C:11]1=[O:13])([CH2:4][CH3:5])[CH3:3]
Reactant: NC(N)=O
Reactant: CCC(C)C(C(=O)OC)C(=O)OC
Agent: [Na]
Solvent: CCO
Product: CCC(C)C1C(=O)NC(=O)NC1=O
Yield: 43.4 %

Procedure:
110 mL of anhydrous ethanol was reacted with 7.72 g of sodium metal. Subsequently 17.6 g (0.1 mol) of dimethyl secbutylmalonate was added, followed (after about 5 minutes) by urea (6.72 g). The reaction mixture was refluxed for 15 hours and 60 mL of ethanol was distilled off. 200 mL of water was added to the residue followed by 20 mL of concentrated sulfuric acid. Precipitated crystals were filtered off. The product was then recrystallized from water to yield 8 g of colorless crystals.
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:49]=[CH:48][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:37]=[CH:38][C:39]([O:46][CH3:47])=[C:40]([CH:45]=4)[C:41]([O:43]C)=[O:42])[O:33][C:34]=3[CH3:35])=[C:26]([O:50][CH3:51])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:7]([O:6][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:49]=[CH:48][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:37]=[CH:38][C:39]([O:46][CH3:47])=[C:40]([CH:45]=4)[C:41]([OH:43])=[O:42])[O:33][C:34]=3[CH3:35])=[C:26]([O:50][CH3:51])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:15]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccc(OC)c(C(=O)OC)c3)oc2C)c(OC)c1)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccc(OC)c(C(=O)O)c3)oc2C)c(OC)c1)OCC
Temperature: 50 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To a mixture of methyl 5-{4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl}-2-methoxybenzoate (0.10 g), tetrahydrofuran (1 mL) and ethanol (1 mL) was added 1N aqueous sodium hydroxide solution (0.5 mL); and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture were added 1N hydrochloric acid (1 mL) and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 5-{4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl}-2-methoxybenzoic acid as colorless crystals (0.08 g, yield 80%). Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 171-172° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@@H:11]1[CH2:14][C@H:13]([OH:15])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:15][C@H:13]2[CH2:12][C@H:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:14]2)=[O:24])=[CH:26][CH:27]=1)([O-:18])=[O:17]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: O[C@H]1C[C@@H](CCOCc2ccccc2)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@H]1C[C@H](CCOCc2ccccc2)C1)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
In a 100 mL flask with cis-3-(benzyloxyethyl)cyclobutanol (1.84 g, 8.9 mmol), 4-nitrobenzoic acid (2.97 g, 17.8 mmol) and Ph3P (4.9 g, 18.7 mmol) inside, dry THF 25 mL was added under argon to give a colorless solution. This was cooled to 0° C. and DIAD (3.7 mL, 18.7 mmol) was added drop by drop. After 15 hr, the volatile materials were evaporated and the crude mixture was purified by silica gel flash chromatography (Hexane: EtOAc=9:1) to give off-white oil contaminated with some DIAD (3.74 g). 1H NMR (CDCl3, 400 MHz): δ 1.81-1.86 (m, 2H), 2.22-2.28 (m, 2H), 2.34-2.41 (m, 2H), 2.48-2.60 (m, 1H), 3.36-3.39 (t, J=6.4, 2H), 4.49 (s, 2H), 5.31-5.38 (m, 1H), 7.25-7.36 (m, 5H), 8.19-8.21 (dd, J=8.8, 2.0, 2H), 8.26-8.29 (dd, J=9.2, 2.0, 2H). 13C NMR (CDCl3, 100 MHz): δ 26.35, 34.84, 35.96, 68.82, 70.74, 73.17, 123.70, 127.76, 128.59, 130.88, 135.97, 138.65, 150.68, 164.42. MS (FAB): expected for C20H21NO5 (M−H)+ 354.38. Found 354.13378. IR (neat) νmax 2979, 2936, 2857, 1720, 1607, 1527, 1349, 1319, 1276, 1119, 1015, 874, 843, 738, 720, 698.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][N:14]([C:18]([NH:20][CH3:21])=[O:19])[C:15](Cl)=[O:16]>ClCCl>[CH3:13][N:14]([C:18]([NH:20][CH3:21])=[O:19])[C:15]([N:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1)=[O:16]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CNC(=O)N(C)C(=O)Cl
Solvent: ClCCl
Product: CNC(=O)N(C)C(=O)N1CCN(c2ccccc2)CC1
Yield: 72.6 %

Procedure:
Into 40 ml of dichloromethane, was dissolved 6.5 g of 1-phenylpiperazine. To the solution, while being stirred and cooled in ice, was added dropwise 3.0 g of 2,4-dimethylallophanoyl chloride. After 0.5 hour of reaction at room temperature, the reaction mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation and the residue was recrystallized from a mixture of ethanol and petroleum ether to obtain 4.0 g (72% yield) of 1-(2,4-dimethyl-allophanoyl)-4-phenylpiperazine having a melting point of 79°-80° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.[CH3:7][C:8]([CH3:10])=O.[C-]#N.[K+].[N-:14]=[C:15]=O>O.C(Cl)Cl>[CH3:7][C:8]([N:3]1[CH2:4][CH2:5][CH2:6][CH:2]1[CH3:1])([CH3:10])[C:15]#[N:14]
Reactant: CC1CCCN1
Reactant: CC(C)=O
Reactant: [N-]=C=O
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC1CCCN1C(C)(C)C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a stirred, ice-cooled mixture of 2-(RS)-methylpyrrolidine (4.25 g; 0.05 mol) and acetone (3.67 ml; 0.05 mol) was added a solution of potassium cyanide (3.25 g; 0.05 mol) in water (25 ml) dropwise over 10 min. After stirring at room temperature overnight, the crude reaction mixture was extracted with diethyl ether (2×200 ml) and the combined extracts washed with brine (200 ml), dried (Na2SO4) and evaporated under reduced pressure to afford a pale yellow oil. This was dissolved in DCM and PS-Isocyanate (4.5 g of resin loading 1.53 mmol/g) added. The mixture was stirred for 3 hours, filtered and the filtrate evaporated to afford the title compound as a colourless semi-solid (2.82 g; 37.5%). 1H NMR (CDCl3) δ(inter alia): 1.10 (3H, d), 1.45 (3H, s), 1.55 (3H, s), 1.75-2.00 (4H, m) 2.65 (1H, m) and 3.05-3.20 (2H, m).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[CH:15][N:16]=[CH:17][C:18]([Br:19])=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:20]([N-]C(C)C)(C)[CH3:21].[Li+].C(I)C>C1COCC1>[C:1]1([S:7]([N:10]2[C:14]3=[CH:15][N:16]=[CH:17][C:18]([Br:19])=[C:13]3[CH:12]=[C:11]2[CH2:20][CH3:21])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)cncc21
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1cc2c(Br)cncc2n1S(=O)(=O)c1ccccc1
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
To a solution of 1-benzenesulfonyl-4-bromo-1H-pyrrolo[2,3-c]pyridine (0.63 g, 1.86 mmol) in anhydrous THF (10 mL), at −35° C., was added a solution of lithium diisopropylamide (2.0M in heptane/THF/ethyl benzene, 1.86 mL, 3.77 mmol) dropwise. The reaction mixture was stirred at −35° C. for 30 min and then ethyl iodide (0.90 mL, 11.18 mmol) was added dropwise. The resulting solution was allowed to reach room temperature and was stirred for 4 h. The reaction mixture was quenched by addition of a solution of 1N HCl (5 mL); the solution was diluted with water (15 mL) and extracted with EtOAc (2×75 mL). The organic extracts were combined, washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, EtOAc:cyclohexane 0:100 to 70:30). The residue was triturated in EtOAc (2 mL) and collected by filtration to give the title compound as a white solid (0.27 g, 40%). LCMS (Method H): RT=4.65 min, [M+H]+ 367 (79Br), 369 (81Br)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH:32]([OH:35])([CH3:34])[CH3:33].O[C:37]1[CH:42]=[CH:41][C:40]2[C:43]3([CH2:59][O:60][C:39]=2[CH:38]=1)[C:51]1[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=1)[N:45]([CH2:52][C@H:53]1[CH2:57][CH2:56][CH2:55][O:54]1)[C:44]3=[O:58]>>[CH3:33][CH:32]([O:35][C:37]1[CH:42]=[CH:41][C:40]2[C:43]3([CH2:59][O:60][C:39]=2[CH:38]=1)[C:51]1[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=1)[N:45]([CH2:52][C@H:53]1[CH2:57][CH2:56][CH2:55][O:54]1)[C:44]3=[O:58])[CH3:34]
Reactant: O=C1N(C[C@H]2CCCO2)c2ccccc2C12COc1cc(O)ccc12
Reactant: CC(C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)Oc1ccc2c(c1)OCC21C(=O)N(C[C@H]2CCCO2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.9 %

Procedure:
To a stirred solution of triphenylphosphine (0.23 g, 0.89 mmol) in anhydrous tetrahydronfuran (200 mL) at 0° C. under nitrogen were added diethyl azodicarboxylate (0.14 mL, 0.89 mmol), isopropanol (0.23 mL, 2.97 mmol) and 6-hydroxy-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.20 g, 0.59 mmol). The reaction mixture was stirred at ambient temperature for 16 h, and then the reaction was quenched with ammonium chloride solution. The solvent was removed, and the residue was dissolved in ethyl acetate (100 mL), which was washed with water, brine, dried over sodium sulfate and filtered. The filtrate was concentrated to dryness, and the residue was purified by flash chromatograph with 25% ethyl acetate in hexanes to afford 6-(1-methylethoxy)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.19 g, 85%) as colorless liquid; 1H NMR (300 MHz, CDCl3) δ7.33-7.25 (m, 1H), 7.16-6.99 (m, 3H), 6.58 (d, J=8.4 Hz, 1H), 6.50 (d, J=1.8 Hz, 1H), 6.33 (dd, J=8.4, 2.1 Hz, 1H), 4.93 (d, J=9.0 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.53-4.43 (m, 1H), 4.33-4.23 (m, 1H), 4.00-3.66 (m, 4H), 2.10-1.66 (m, 4H), 1.31 (d, J=6.0 Hz, 6H); MS (ES+) m/z 380.0 (M+1), 402.0 (M+23).
Reaction SMILES: S(=O)(=O)(O)[OH:2].O[CH:7]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[CH2:8][CH2:9][S:10]([C:13]1[S:17][C:16]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[C:30](#[N:32])[CH3:31]>>[C:30]([NH:32][CH:7]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[CH2:8][CH2:9][S:10]([C:13]1[S:17][C:16]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])(=[O:2])[CH3:31]
Reactant: COc1ccc(C(O)CCS(=O)(=O)c2ccc(S(N)(=O)=O)s2)cc1
Reactant: O=S(=O)(O)O
Reactant: CC#N
Product: COc1ccc(C(CCS(=O)(=O)c2ccc(S(N)(=O)=O)s2)NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To sulfuric acid (5.2 ml), cooled to 0° C. was added a solution of product from Step B (2.0 g, 5.1 mmol) in acetonitrile (17 ml) dropwise and the solution was stirred at room temperature overnight. The mixture was poured into ice (100 ml) and stirred for 1 hour. The solution was extracted with ethyl acetate and the organic layers were washed with water and saturated NaHCO2 solution. Drying and solvent evaporation gave the title compound (2.0 g, 91%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CCN=C=NCCCN(C)C.Cl.[Cl:20][C:21]([F:26])([F:25])[C:22](O)=[O:23]>ClCCl.CN(C1C=CN=CC=1)C>[Cl:20][C:21]([F:26])([F:25])[C:22]([N:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1)=[O:23]
Reactant: O=C(O)C(F)(F)Cl
Reactant: Nc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(N=c1cccc[nH]1)C(F)(F)Cl
Reaction time: 8 h
Yield: 24 %

Procedure:
2-aminopyridine in an amount of 200 mg (2.13 mmol) was dissolved in 5 mL of dichloromethane, following which 491 mg (2.55 mmol) of EDC-HCl, 311 mg (2.55 mmol) of DMAP and 187 μL (2.23 mmol, 290 mg) of chlorodifluoroacetic acid were added in this order and the mixture was stirred overnight. Following reaction completion, the reaction mixture was diluted with dichloromethane, washed with water and 1% hydrochloric acid, then dried over anhydrous magnesium sulfate, giving 105 mg of 2-chloro-2,2-difluoro-N-(pyridin-2(1H)-ylidene)acetamide (yield, 24%).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:14][CH2:13][NH:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C.Cl[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=1>C1COCC1.C([O-])(O)=O.[Na+]>[CH3:1][N:2]([CH:10]1[CH2:14][CH2:13][N:12]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=2)[CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc([N+](=O)[O-])cn2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.4 %

Procedure:
To a solution of tert-butyl methyl(pyrrolidin-3-yl)carbamate (1.00 g, 5.0 mmol) in THF (25 mL) was added triethylamine (0.70 mL, 5.0 mmol) and 2-chloro-5-nitropyridine (500 mg, 3.15 mmol). The reaction mixture was then stirred at room temperature for 16 h, diluted with a saturated NaHCO3 solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica, ethyl acetate/hexanes) afforded the desired product (1.02 g, 100%) as a yellow solid. ESI MS m/z 323 [C15H22N4O4+H]+
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[SH:41][C@@H:42]1[CH2:46][N:45]([C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=2)=[O:48])[C@H:44]([C:60]([N:62]2[CH2:66][CH2:65][C@@H:64]([CH2:67][NH:68][C:69](=[NH:84])[CH2:70][C:71]([O:73][CH2:74][C:75]3[CH:80]=[CH:79][C:78]([N+:81]([O-:83])=[O:82])=[CH:77][CH:76]=3)=[O:72])[CH2:63]2)=[O:61])[CH2:43]1.C(OCC)(=O)C>C(#N)C.C(N(CC)C(C)C)(C)C>[OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])=[C:8]([S:41][C@@H:42]3[CH2:46][N:45]([C:47]([O:49][CH2:50][C:51]4[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=4)=[O:48])[C@H:44]([C:60]([N:62]4[CH2:66][CH2:65][C@@H:64]([CH2:67][NH:68][C:69](=[NH:84])[CH2:70][C:71]([O:73][CH2:74][C:75]5[CH:76]=[CH:77][C:78]([N+:81]([O-:83])=[O:82])=[CH:79][CH:80]=5)=[O:72])[CH2:63]4)=[O:61])[CH2:43]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: N=C(CC(=O)OCc1ccc([N+](=O)[O-])cc1)NC[C@@H]1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@@H](CNC(=N)CC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 60.8 %

Procedure:
To a solution of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(diphenylphosphoryloxy)-1-carbapen-2-em-3-carboxylate (0.58 g) in anhydrous acetonitrile (10 ml), N,N-diisopropylethylamine (0.17 ml) and a solution of (2S,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-[(3S)-3-(4-nitrobenzyloxycarbonylacetimidoylaminomethyl)pyrrolidin-1-ylcarbonyl]pyrrolidine (0.93 g) in anhydrous acetonitrile (10 ml) were added while stirring in an ice bath. The resulting mixture was stirred overnight at 0° C. To the reaction mixture, ethyl acetate was added. The resulting mixture was washed with water and saturated saline solution, dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column (ethyl acetate/methanol=9/1), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-I -(4-nitrobenzyloxycarbonyl)-2-[(3S)-3-(4-nitrobenzyloxycarbonylacetimidoylaminomethyl)pyrrolidin-1-ylcarbonyl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (0.61 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@H:10]1[C:14](=[O:15])[CH2:13][C@@H:12]([O:16][Si](C(C)(C)C)(C)C)[C@@H:11]1[C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH:29]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)[CH2:28][CH2:27]2.O.C1COCC1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:43])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@H:10]1[C:14](=[O:15])[CH2:13][C@@H:12]([OH:16])[C@@H:11]1[C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH:29]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)[CH2:28][CH2:27]2
Reactant: COC(=O)CCC/C=C\C[C@H]1C(=O)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1c1ccc2c(c1)CCC2OCc1ccc(OC)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)CCC/C=C\C[C@H]1C(=O)C[C@@H](O)[C@@H]1c1ccc2c(c1)CCC2OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 69.8 %

Procedure:
A mixture of 15-4 (20 mg, 0.032 mmol) in acetic acid (0.3 mL)/water (0.1 mL)/THF (0.1 mL) was stirred at room temperature. After two days, saturated NaHCO3 solution was added and the resulting mixture was extracted with dichloromethane (3×20 mL). The combined dichloromethane solution was dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography on silica gel (20% ethyl acetate/hexanes→30% →40%) which gave the title compound (11 mg, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH:14]=O.Br[CH2:22][CH2:23][CH2:24][CH3:25]>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:14]([C:4]1[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[N:6]([CH2:10][CH2:2][CH2:3][CH3:4])[CH:5]=1)[C:13]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:12]=1[Cl:11])=[CH:5][N:6]2[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCBr
Reactant: Clc1cccc2[nH]ccc12
Reactant: O=Cc1ccc(F)cc1Cl
Product: CCCCn1cc(C(c2ccc(F)cc2Cl)c2cn(CCCC)c3cccc(Cl)c23)c2c(Cl)cccc21

Procedure:
The compound Bis(4-chloro-1-butylindol-3-yl)-(2-chloro-4-fluorophenyl)methane was prepared following procedure A, starting from 4-chloro indole and 2-chloro 4-fluorobenzaldehyde, and the resulting compound was reacted with 1-bromobutane following procedure B. LC: Tr 2.83 min, MS: 555 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:38]1[CH:42]=[C:41]([CH2:43]O)[CH:40]=[N:39]1)=O)(C)(C)C>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:22]1[CH:23]=[CH:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=1)[CH2:43][C:41]1[CH:42]=[N:38][NH:39][CH:40]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)n1cc(CO)cn1
Reactant: CC(C)c1ccc(NC(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Product: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 42.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 82 using 5-benzyloxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (5.94 g) and 1-(tert-butoxycarbonyl)-4-(hydroxymethyl)pyrazole (2.95 g) as starting materials, 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (3.00 g) was obtained.