Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:18][CH:19]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20]1>>[CH2:24]([N:21]1[CH2:22][CH2:23][CH:19]([NH:18][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[C:3]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:4][C:5]=2[O:11][CH3:12])[CH2:20]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: NC1CCN(Cc2ccccc2)C1
Reactant: CCN(CC)c1cc(OC)c(C(=O)O)cc1Cl
Product: CCN(CC)c1cc(OC)c(C(=O)NC2CCN(Cc3ccccc3)C2)cc1Cl

Procedure:
Following the procedure set forth in general method A supra using 1.29 g. of 5-chloro-4-diethylamino-2-methoxybenzoic acid and 0.97 g. of 3-amino-1-benzylpyrrolidine, 0.93 g. of oily N-(1-benzyl-3-pyrrolidinyl)-5-chloro-4-diethylamino-2-methoxybenzamide was obtained (purified by a silica gel column chromatography using a mixture of chloroform, ether and methanol (volume ratio 5:2:1) as an eluting solution).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.I[C:20]1[N:25]=[CH:24][N:23]=[C:22]([C:26]([C:28]2[CH:37]=[C:36]([CH3:38])[C:31]3[O:32][CH2:33][CH2:34][O:35][C:30]=3[CH:29]=2)=[O:27])[CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:38][C:36]1[C:31]2[O:32][CH2:33][CH2:34][O:35][C:30]=2[CH:29]=[C:28]([C:26]([C:22]2[N:23]=[CH:24][N:25]=[C:20]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]3)[CH:21]=2)=[O:27])[CH:37]=1
Reactant: Cc1cc(C(=O)c2cc(I)ncn2)cc2c1OCCO2
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc2c1OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
64 mg (0.22 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one-dihydrochloride, 84 mg (0.22 mmol) (6-iodo-pyrimidin-4-yl)-(8-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone and 0.15 mL (0.88 mmol) DIPEA were combined in 2.5 mL DMF and stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down. The residue was mixed with 1N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH:41]3[CH2:43][CH2:42]3)[CH:36]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH:41]3[CH2:42][CH2:43]3)[CH:36]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C3CC3)c2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(C3CC3)c2)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(2-cyclopropyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K60) (253 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous white substance (315 mg, 75%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].N1C=CC=CC=1.[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[C:17]([O:10][C:4]1[CH:5]=[CH:6][C:7]([S:8][CH3:9])=[C:2]([CH3:1])[CH:3]=1)(=[O:19])[CH3:18]
Reactant: CSc1ccc(O)cc1C
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CSc1ccc(OC(C)=O)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
3-Methyl-4-methylsulfanylphenol (1.00 g) was dissolved in dichloromethane (10 ml) to prepare a solution. Pyridine (724 mg) and acetyl chloride (615 mg) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography using chloroform to give 3-methyl-4-methylsulfanyl-phenyl acetate (1.00 g, yield 80%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.C(Cl)(=O)C(Cl)=O.[F:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[F:18][C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[C:23]([C:9](=[O:11])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:24]=1
Reactant: O=C(O)Cc1ccccc1F
Reactant: COc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cc1ccccc1F)c1cc(F)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
2-Fluorophenylacetic acid (2.0 g, 13.14 mmoles) was dissolved in 20 ml dichloromethane. To this mixture, oxalylchloride (1.66 g, 13.14 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 20 ml dichloromethane. To this mixture, 4-fluoroanisole (1.10 g, 8.76 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (1.75 g, 13.14 mmoles) was added and the reaction mixture was warmed to RT and stirred for 12 h. The reaction mixture was quenched by the addition of 2N HCl, extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as off-white solid (1.17 g, 54% yield. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 11.25(s,1H), 7.73(dd, J=9.5,3.2 Hz, 1H), 7.43(dt, J=8.8,3.1 Hz, 1H), 7.35(d, J=6.2 Hz, 1H), 7.31(d, J=7.2 Hz, 1H), 7.19(d, J=8.2 Hz, 1H), 7.03(dd, J=9.1,4.6 Hz, 1H),4.50(s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7]
Reactant: O=C(O)c1ccnc(Br)c1
Reactant: Nc1ccccc1
Product: O=C(Nc1ccccc1)c1ccnc(Br)c1

Procedure:
In a manner similar to that described in Preparation 17, 2-bromoisonicotinic acid and aniline were converted to the title compound
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][CH:42]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([NH:26][CH:27]5[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]5)=[CH:22][CH:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1>CO.CCOCC.Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][CH:42]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([NH:26][CH:27]5[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]5)=[CH:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Fc1cccc(Cn2cc(-c3c[nH]c4ncc(-c5ccc(NC6CCNCC6)cc5)cc34)cn2)c1
Yield: 75.4 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-((4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amino)piperidine-1-carboxylate (60 mg, 0.10 mmol) was deprotected in methanol/ether HCl (3.0/0.3 ml). This afforded 40 mg (75.4% yield) of the titled. 1H NMR (CD3OD, 400 MHz): δ 9.01-9.00 (d, 1H), 8.71-8.70 (d, 1H), 8.39 (s, 1H), 8.05 (s, 1H), 7.95 (s, 1H), 7.90-7.87 (m, 2H), 7.37-7.34 (m, 3H), 7.14-7.12 (s, 1H), 7.04-7.01 (m, 2H), 5.46 (s, 2H), 3.95-3.85 (m, 1H), 3.54-3.51 (d, 2H), 3.81-3.72 (t, 2H), 3.30-3.26 (d, 2H), 2.00-1.90 (m, 2H). MS: m/z=466.9 (M+1), HPLC: 96.60% in method A.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH2:9]([NH:16][CH:17]([CH3:19])[CH3:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[CH2:9]([N:16]([CH:17]([CH3:19])[CH3:18])[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(C)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)N(Cc1ccccc1)c1cncc(Cl)n1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
A mixture of 2,6-dichloropyrazine (7.45 g), N-benzylpropan-2-amine (12.5 mL), potassium carbonate (10.4 g) and DMA (50 mL) was stirred at 80° C. for 15 hr. Water (100 mL) was added, and the mixture was extracted with ethyl acetate.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[C:28]1([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1OCCOCCOCCOCCOCCOC1>CC#N.O>[C:28]1([N:34]2[CH2:39][CH2:38][N:37]([CH2:2][C:3]([NH:5][C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([C:12]4[CH:21]=[N:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[N:13]=4)[CH:7]=3)=[O:4])[CH2:36][CH2:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(CCl)Nc1cccc(-c2cnc3ccccc3n2)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(CN1CCN(c2ccccc2)CC1)Nc1cccc(-c2cnc3ccccc3n2)c1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
A slurry of 2-chloro-N-(3-quinoxalin-2-ylphenyl)acetamide (1.64 g, 5.5 mmol), K2CO3 (0.92 g, 6.87 mmol), 1-phenylpiperazine (1.05 mL, 5.5 mmol) and a catalytical amount of 18-crown-6 in MeCN (20 mL) was refluxed for 7 hrs, cooled to room temperature, and diluted with water. The resulting solid was filtered, washed with water, and dried to afford 2-(4-phenylpiperazin-1-yl)-N-[3-(quinoxalin-2-yl)phenyl]acetamide (2.1 g, 90% yield). LCMS calculated for C26H25N50 (M+H): 424.52. found 424. 1H-NMR (DMSO-d6, 250 Mhz) δH: 10.5 (1H, br. s), 9.52 (1H, s), 8.58 (1H, br. s), 8.20-7.80 (6H, m), 7.55 (1H, m), 7.25-7.15 (2H, m), 6.98-6.90 (2H, m), 6.80-6.72 (1H, m), 3.28-3.25 (6H, m), 2.75-2.65 (4H, m).
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.CS(O[CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[N:3]=[CH:4][C:5]([O:8][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[N:6][CH:7]=1
Reactant: Oc1cnc(Br)cn1
Reactant: CC(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)OC(=O)N1CCC(COc2cnc(Br)cn2)CC1
Temperature: 70 °C

Procedure:
A mixture of 5-bromo-2-pyrazinol (and tautomers thereof) (0.2 g, 1.14 mmol), 1-methylethyl 4-{[(methylsulfonyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 131, Step 4, 0.51 g, 1.71 mmol) and K2CO3 (0.32 g, 2.29 mmol) in DMF (12 mL) was stirred at ambient temperature for 30 min, then heated at 70° C. overnight. The mixture was cooled to ambient temperature and poured into water, and then extracted with EtOAc (60 mL×2). The combined organic extract was washed with water, brine and dried over Na2SO4, filtered, and the filtrate was concentrated to give crude 1-methylethyl 4-{[(5-bromo-2-pyrazinyl)oxy]methyl}-1-piperidinecarboxylate a brown oil, which was used without further purification.
Reaction SMILES: C1C=CC(C(NC(C(N[C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=O)CCCN=C(N)N)=O)=CC=1.Cl.CS(C)=[O:33]>Cl>[CH:23]1[C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=[C:21]([OH:33])[CH:22]=1
Reactant: NC(N)=NCCCC(NC(=O)c1ccccc1)C(=O)Nc1ccc([N+](=O)[O-])cc1
Reactant: CS(C)=O
Agent: Cl
Product: O=[N+]([O-])c1ccc(O)cc1
Reaction time: 5.5 h

Procedure:
Substrate stock solutions were prepared by dissolving ˜50 mg BAPNA or suc-AAPF-PNP in DMSO; these stock solutions were then diluted with DMSO and 0.1 M TRIS/HCl buffer (pH 7.4) to provide substrate solutions of various concentrations (final concentration of DMSO in each substrate solution was 15% v/v). A measured quantity of particles, 30-100 mg, were placed in a microcentrifuge tube, 1.3 ml of substrate solution was added, and the mixture was bath-sonicated to completely disperse the particles. The mixture was then placed in a water bath at 30° C. for 5-6 hours, with additional agitation provided every 45-60 minutes. The mixture was then removed from the water bath and centrifuged at 14,000 rpm for 30 minutes. The reaction time was measured from initial sonication to the beginning of centrifugation. Catalytic activity was determined from the increase in free p-nitrophenol concentration, measured by UV/VIS spectroscopy at 410 nm with an extinction coefficient of 8500 M−1 cm−1. The measured absorbance was compared to that of the substrate solution at 410 nm and from the absorbance due to light scattering of the particle dispersion of particles in 0.1 M Tris buffer (prepared identically as above) at 410 nm. These contributions to the absorbance were subtracted from the total absorbance at 410 nm to obtain the absorbance due to free p-nitrophenol. Each data point was calculated based on the average of 3 to 7 trials.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[N:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=3[CH:15]=[C:7]2[C:6]2[N:17]=[C:18]([C:21]3[C:22]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:44])=[O:43])=[CH:23][C:24]4[O:28][C:27]([C:29]5[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=5)=[C:26]([C:36]([NH:38][CH3:39])=[O:37])[C:25]=4[CH:40]=3)[CH:19]=[CH:20][C:5]=2[O:4]1.[CH3:47][O:48][C:49]([N:51]1[CH2:55][CH2:54][CH2:53][C@H:52]1[C:56](O)=[O:57])=[O:50].CCN=C=NCCCN(C)C.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:16][C:13]1[C:14]2[CH:15]=[C:7]3[C:6]4[N:17]=[C:18]([C:21]5[C:22]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:43])=[O:44])=[CH:23][C:24]6[O:28][C:27]([C:29]7[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=7)=[C:26]([C:36](=[O:37])[NH:38][CH3:39])[C:25]=6[CH:40]=5)[CH:19]=[CH:20][C:5]=4[O:4][CH:3]([CH2:2][NH:1][C:56]([C@@H:52]4[CH2:53][CH2:54][CH2:55][N:51]4[C:49]([O:48][CH3:47])=[O:50])=[O:57])[N:8]3[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CN)O4)cc12
Reactant: COC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CNC(=O)[C@@H]3CCCN3C(=O)OC)O4)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
A mixture of 5-(6-(aminomethyl)-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (70 mg, 0.11 mmol), (S)-1-(methoxycarbonyl)pyrrolidine-2-carboxylic acid (38 mg, 0.22 mmol), EDCI (12 mg, 0.27 mmol), DMAP (40 mg, 0.33 mmol) and triethylamine (33 mg, 0.33 mmol) in CH2Cl2 (2 mL) was stirred at room temperature overnight. The mixture was then purified using Prep-TLC(CH2Cl2:EtOAc=1:1) to provide (2S)-methyl 2-(((11-fluoro-2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-6-yl)methyl)carbamoyl)pyrrolidine-1-carboxylate (60 mg, yield: 69.0%). 1H-NMR (CDCl3, 400 MHz) δ 7.86˜8.05 (m, 3H), 7.28˜7.69 (m, 4H), 7.16˜7.27 (m, 5H), 6.85 (d, J=9.2 Hz, 1H), 6.60 (dd, J=5.2, 7.2 Hz, 1H), 5.98˜6.25 (m, 1H), 4.31 (br. s, 1H), 3.65 (br. s, 5H), 3.39 (s, 5H), 2.97 (d, J=3.2 Hz, 3H), 2.72 (br. s, 3H), 1.90˜2.49 (m, 2H), 1.63˜1.79 (m, 2H). MS (M+H)+: 799.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([N:14]3C[CH2:17][CH2:16][C@H:15]3[CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[C:4](=[O:27])[C:3]1=[O:28].O(C[C@@H]1CCN1S(C1C=C2C(=CC=1)NC(=O)C2=O)(=O)=O)C1C=CC=CC=1.[CH3:55][S:56][C:57]1[CH:64]=[CH:63][C:60](CBr)=[CH:59][CH:58]=1>>[CH3:55][S:56][C:57]1[CH:64]=[CH:63][C:60]([CH2:1][N:2]2[C:10]3[C:5](=[CH:6][C:7]([S:11]([N:14]4[CH2:17][CH2:16][C@H:15]4[CH2:19][O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:13])=[O:12])=[CH:8][CH:9]=3)[C:4](=[O:27])[C:3]2=[O:28])=[CH:59][CH:58]=1
Reactant: CSc1ccc(CBr)cc1
Reactant: CN1C(=O)C(=O)c2cc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)ccc21
Agent: O=C1Nc2ccc(S(=O)(=O)N3CC[C@H]3COc3ccccc3)cc2C1=O
Product: CSc1ccc(CN2C(=O)C(=O)c3cc(S(=O)(=O)N4CC[C@H]4COc4ccccc4)ccc32)cc1
Yield: 45 %

Procedure:
(S)-1-(4-Methylthiobenzyl)-5-(2-phenoxymethyl-azetidine-1-sulfonyl)-1H-indole-2,3-dione (18d) was prepared according to the same procedure for compound 11a, except using compound 17 and 4-methylthiobenzyl bromide, and purified with hexanes-ether (1:2) to afford 57 mg (45%) of 18d as an orange solid, mp 167.6-169.2° C. 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J=1.5 Hz, 1H), 7.96 (dd, J=8.4 Hz, J=1.8 Hz, 1H), 7.25 (m, 6H), 6.95 (t, J=7.2 Hz, 1H), 6.86-6.78 (m, 3H), 4.89 (s, 2H), 4.46 (m, 1H), 4.11 (m, 2H), 3.82 (m, 2H), 2.49 (s, 3H), 2.39-2.25 (m, 2H). Anal. Calcd for C26H24N2O5S2: C, 61.40, H, 4.76; N, 5.51. Found: C, 60.99, H, 4.71; N, 5.36.
Reaction SMILES: C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[NH2:13][C@@H:14]1[C:31](=[O:32])[N:16]2[C:17]([C:28]([OH:30])=[O:29])=[C:18]([S:21][C:22]3[N:26]([CH3:27])[N:25]=[N:24][N:23]=3)[CH2:19][S:20][C@H:15]12.[N:33]1([CH2:38][C:39](Cl)=[O:40])[CH:37]=[N:36][N:35]=[N:34]1>C(Cl)Cl>[N:33]1([CH2:38][C:39]([NH:13][C@@H:14]2[C:31](=[O:32])[N:16]3[C:17]([C:28]([OH:30])=[O:29])=[C:18]([S:21][C:22]4[N:26]([CH3:27])[N:25]=[N:24][N:23]=4)[CH2:19][S:20][C@H:15]23)=[O:40])[CH:37]=[N:36][N:35]=[N:34]1
Reactant: O=C(Cl)Cn1cnnn1
Reactant: Cn1nnnc1SC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: ClCCl
Product: Cn1nnnc1SC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cn3cnnn3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
0.306 ml (1.27 mmols) of bis-trimethylsilylacetamide is added to a suspension of 200 mg (0.63 mmol) of 7β-amino-3-(1-methyl-5-tetrazolylthio)-3-cephem-4-carboxylic acid in 3.2 ml of methylene chloride and the mixture is stirred under nitrogen at room temperature for 40 minutes. The solution is cooled to 0° C., 224 mg (1.52 mmols) of tetrazol-1-ylacetyl chloride are added and the mixture is stirred for 11/2 hours at 0° C. and extracted with aqueous sodium bicarbonate solution. The pH of the aqueous phase is adjusted to 1.5 and this phase is extracted with ethyl acetate. The organic phase is dried over sodium sulphate and evaporated in a rotary evaporator and gives 7β-[2-(tetrazol-1-yl)-acetylamino]-3-(1-methyl-5-tetrazolylthio)-3-cephem-4-carboxylic acid; thin layer chromatogram (silica gel; butanol/acetic acid/water, 75:7.5:21), Rf value 0.17; IR spectrum (nujol); characteristic bands at 3400, 1780, 1720 and 1690 cm-1.
Reaction SMILES: C([O:4][C@@H:5]([C@@H:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH3:14])[C:6]([NH:8][CH:9]1[CH2:11][CH2:10]1)=[O:7])(=O)C.[OH-].[Na+].CO>O>[CH:9]1([NH:8][C:6](=[O:7])[C@@H:5]([OH:4])[C@@H:12]([NH:15][C:16](=[O:17])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH2:13][CH3:14])[CH2:11][CH2:10]1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)[C@H](OC(C)=O)C(=O)NC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an atmosphere of argon, (2S,3S)-3-(tert-butoxycarbonylamino)-1-(cyclopropylamino)-1-oxopentan-2-yl acetate (1.09 g, 3.47 mmol, Eq: 1.00) and NaOH 1N in H2O (5.2 ml, 5.2 mmol, Eq: 1.5) were combined with methanol (10 ml) to give a colorless solution. The reaction was stirred for 2 h at RT. The reaction mixture was poured into 25 mL H2O and extracted with ethyl acetate (2×50 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. The title compound was obtained as a light brown solid (540 mg, 57.2%, MS (m/e)=273.4 [M+H+]).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([C:23](=[O:29])[NH:24][CH2:25][CH2:26][O:27][CH3:28])=[CH:11][N:10]=1)(C)(C)C.Cl.C(OCC)C>O1CCOCC1>[CH3:28][O:27][CH2:26][CH2:25][NH:24][C:23]([C:12]1[C:13]2[C:18](=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[C:9]([CH2:8][NH2:7])=[N:10][CH:11]=1)=[O:29]
Reactant: COCCNC(=O)c1cnc(CNC(=O)OC(C)(C)C)c2cc(OC)c(OC)cc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COCCNC(=O)c1cnc(CN)c2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of [6,7-dimethoxy-4-(2-methoxy-ethylcarbamoyl)-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl ester (45 mg, 0.11 mmol) in dioxane (2 ml) was treated with 4M HCl in dioxane (2 ml) and the mixture was stirred overnight at room temperature. Diethyl ether was added and the HCl salt was collected by suction filtration (38 mg, quant.): 1H NMR (DMSO-d6) δ 3.28 (s, 3H), 3.47-3.53 (m, 4H), 3.89 (s, 3H), 3.99 (s, 3H), 4.72 (m, 2H), 7.46 (s, 1H), 7.70 (s, 1H), 8.42 (s, 1H), 8.65 (br s, 3H), 8.82 (m, 1H); MS (APCI) m/z 320.1 [M+1]+.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][NH:24][CH2:25][C:26]3[NH:27][CH:28]=[CH:29][N:30]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[CH3:31][N:32]1[CH:36]=[CH:35][N:34]=[C:33]1[CH:37]=O.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH2:1]([N:4]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH2:25][C:26]3[NH:30][CH:29]=[CH:28][N:27]=3)[CH2:37][C:33]3[N:32]([CH3:31])[CH:36]=[CH:35][N:34]=3)=[CH:21][CH:22]=2)=[CH:13][CH:14]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)Cc1ccc(NCc2ccc(CNCc3ncc[nH]3)cc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)Cc1ccc(NCc2ccc(CN(Cc3ncc[nH]3)Cc3nccn3C)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The compound (72.7 mg) obtained in Example 43-1 was dissolved in methanol (3.5 ml) and then added with 1-methyl-2-imidazole carboxaldehyde (28.6 mg) and sodium cyanoborohydride (22.8 mg). The reaction solution was adjusted to pH 5 with the addition of acetic acid, followed by stirring at room temperature for 14 hours. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then extracted with chloroform. Then, the organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. After the solvent had been distilled off, the residue obtained was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining hydrochloride (71.3 mg) of the subject compound as a yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[N:12]1>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:12]2[N:13]=[CH:14][CH:15]=[N:11]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: c1c[nH]nn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2nccn2)cc1
Yield: 66.4 %

Procedure:
4-Fluoronitrobenzene (21 g) was reacted with 1H-1,2,3-triazole (12.4 g) in the same manner as in Reference Example 9. The resultant was cooled and poured into water. The precipitated crystals were collected by filtration and purified by silica gel chromatography (eluent: dichloromethane to dichloromethane/acetone=8/1). The first eluted fraction was recrystallized from dichloromethane-diisopropyl ether to give 2-(4-nitrophenyl)-2H-1,2,3-triazole (18.8 g) as pale yellow prisms.