Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:13]([N+:14]([O-])=O)=[CH:12][C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]>[Fe].C(O)(=O)C>[N+:1]([C:4]1[C:13]([NH2:14])=[CH:12][C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])OCCO2
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cc2c(cc1[N+](=O)[O-])OCCO2
Yield: 28.4 %

Procedure:
To a mixture of 6,7-dinitro-2,3-dihydrobenzo[1,4]dioxin (Takakis, I. M.; Hadjimihalakis, P. M. J. Heterocyclic. Chem., 1991, 28, 625., 13 g, 57.8 mmol) and acetic acid (150 mL) was added iron powder (9.6 g, 172.5 mmol) at room temperature, then the mixture was refluxed for 30 min. After cooling, the mixture was filtered through a pad of Celite and the filtrate was concentrated. The residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 1:1 to 1:2) to afford 3.22 g (28%) of the title compound as orange solid: 1H-NMR (CDCl3) δ 7.67 (1H, s), 6.23 (1H, s), 5,85 (2H, br.s), 4.19-4.33 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=4)[CH:15]=3)[N:11]([C@H:26]([C:28]3[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=3)[CH3:27])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[C:38]([O:42][C:43](=[O:47])[CH2:44][CH2:45][NH2:46])([CH3:41])([CH3:40])[CH3:39].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=4)[CH:15]=3)[N:11]([C@H:26]([C:28]3[CH:29]=[CH:30][C:31]([C:32]([NH:46][CH2:45][CH2:44][C:43]([O:42][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:47])=[O:33])=[CH:35][CH:36]=3)[CH3:27])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)CCN
Reactant: COc1ccc2cc(-c3cc(-c4cc(Cl)cc(Cl)c4)nn3[C@@H](C)c3ccc(C(=O)O)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc2cc(-c3cc(-c4cc(Cl)cc(Cl)c4)nn3[C@@H](C)c3ccc(C(=O)NCCC(=O)OC(C)(C)C)cc3)ccc2c1
Reaction time: 3 h

Procedure:
4-{(1S)-1-[3-(3,5-Dichlorophenyl)-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoic acid (3.5 g, 6.76 mmol), beta-alanine t-butyl ester hydrochloride (3.7 g, 20 mmol), DIEA (3.53 ml, 20 mmol), and DMAP (40 mg, 5%) were dissolved in DCM (50 ml), followed by addition of solid EDC HCl (1.6 g, 8.1 mmol). More EDC HCl (1.8 g) was added after one hour. The reaction was completed in about 3 hr as monitored by LC-MS. Ethyl acetate was added to the reaction mixture, and this was washed with 1N HCl 3× and brine 2×. The crude product was then purified by column chromatography (SiO2, 0-6% ethyl acetate in DCM) to give tert-butyl N-(4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoyl)-β-alaninate as a dry foam. NMR (500 MHz, DMSO-d6) δ: 1.36 (s, 9H); 1.90 (d, J=6.9 Hz, 3H); 2.44 (t, J=6.8 Hz, 2H); 3.41 (q, J=6.8 Hz, 2H); 3.89 (s, 3H); 5.76 (q, J=6.9 Hz, 1H); 7.15 (s, 1H); 7.21 (d, J=8.4 Hz, 2H); 7.22 (dd, J=2.6, 9.0 Hz, 1H); 7.38 (d, J=2.6 Hz, 1H); 7.43 (dd, J=1.9, 8.5 Hz, 1H); 7.55 (t, J=1.9 Hz, 1H); 7.71 (d, J=8.4 Hz, 2H); 7.81 (d, J=9.0 Hz, H); 7.85 (d, J=1.9 Hz, 1H); 7.90 (d, J=8.5 Hz, 1H); 7.92 (d, J=1.9 Hz, 2H); 8.44 (t, J=5.2 Hz, 1H).
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]([CH3:32])([CH3:31])[CH:5]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][CH:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[CH3:28])[N:21]([CH3:29])[CH2:20]2)[C:10]1=[O:30])[CH2:6][O:7][CH3:8]>O1CCOCC1.O>[CH3:29][N:21]1[C:22]2[C:27](=[C:26]([CH3:28])[CH:25]=[CH:24][CH:23]=2)[CH:19]([CH2:18][N:11]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:9]([CH:5]([CH2:6][O:7][CH3:8])[C:4]([CH3:31])([CH3:32])[C:3]([OH:33])=[O:2])[C:10]2=[O:30])[CH2:20]1
Reactant: COCC(n1c(=O)n(CC2CN(C)c3cccc(C)c32)c2ccccc21)C(C)(C)C(=O)OC
Solvent: C1COCCO1
Solvent: O
Product: COCC(n1c(=O)n(CC2CN(C)c3cccc(C)c32)c2ccccc21)C(C)(C)C(=O)O
Temperature: 50 °C
Reaction time: 16 h
Yield: 31.2 %

Procedure:
To a solution of 3-[3-(1,4-dimethyl-3H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-4-methoxy-2,2-dimethyl-butyric acid methyl ester (50 mg, 0.11 mmol) in dioxane (2.5 ml) was added a solution of LiOH monohydrate (20 mg, 0.48 mmol) in H2O (2.5 mL). The solution was stirred at 50° C. for 16 hours. The reaction mixture was allowed to cool to rt and quenched with 4M HCl in dioxane (500 □L) and concentrated. The resulting residue was purified by CombiFlash with 3% MeOH in dichloromethane as the eluent to afford the desired 3-[3-(1,4-dimethyl-3H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-4-methoxy-2,2-dimethyl-butyric acid (15 mg, 31%). LCMS (ESMS): 436.12 (M+H+).
Reaction SMILES: [CH:1]([C:4]1([CH3:30])[C:8](=[O:9])[NH:7][C:6]([C:10]2[N:19]=[CH:18][C:17]([CH2:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[N:5]1)([CH3:3])[CH3:2].[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:31]([N:7]1[C:8](=[O:9])[C:4]([CH:1]([CH3:3])[CH3:2])([CH3:30])[N:5]=[C:6]1[C:10]1[N:19]=[CH:18][C:17]([CH2:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:22])=[O:23])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1cc(CS(=O)(=O)c2ccccc2)cnc1C1=NC(C)(C(C)C)C(=O)N1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COC(=O)c1cc(CS(=O)(=O)c2ccccc2)cnc1C1=NC(C)(C(C)C)C(=O)N1C(=O)c1ccccc1
Reaction time: 8 h

Procedure:
A solution of 5.9 g of 2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-5 -[(phenylsulfonyl)methyl]nicotinic acid, methyl ester, and 0.3 g p-dimethylaminopyridine in 50 mL pyridine is stirred at room temperature and 1.75 mL benzoyl chloride is added in one portion. After stirring overnight, the reaction is concentrated in vacuo and the residue is partitioned between methylene chloride and aqueous sodium bicarbonate. The aqueous phase is further extracted with methylene chloride, and the combined organic phases are dried and concentrated in vacuo. Chromatography of the residue on silica gel using hexane-ethyl acetate mixtures affords the desired product, mp 162°-166°.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[N:12][N:13]([CH2:15][CH2:16][C@@:17]([CH3:32])([S:28]([CH3:31])(=[O:30])=[O:29])[C:18]([NH:20][O:21]C2CCCCO2)=[O:19])[CH:14]=1.Cl>CCO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[N:12][N:13]([CH2:15][CH2:16][C@@:17]([CH3:32])([S:28]([CH3:31])(=[O:30])=[O:29])[C:18]([NH:20][OH:21])=[O:19])[CH:14]=1
Reactant: C[C@@](CCn1cc(-c2nc3ccccc3o2)cn1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CCO
Product: C[C@@](CCn1cc(-c2nc3ccccc3o2)cn1)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
To a solution of (2R)-4-[4-(1,3-benzoxazol-2-yl)-1H-pyrazol-1-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (0.410 g, 0.886 mmol) in EtOH (40 mL) was added 1M HCl (20 mL). The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was concentrated and was purified via reverse-phase chromatography, using 5%-95% acetonitrile/water with 0.1% formic acid modifier. The target fractions were combined and evaporated to give (2R)-4-[4-(1,3-benzoxazol-2-yl)-1H-pyrazol-1-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (120 mg, 36% yield) as a light peach solid. 1H NMR (400 MHz, DMSO-d6) δ 1.50 (s, 3H) 2.21-2.40 (m, 1H) 2.70-2.87 (m, 1H) 3.06 (s, 3H) 4.03-4.21 (m, 1H) 4.26-4.51 (m, 1H) 7.27-7.44 (m, 2H) 7.63-7.78 (m, 2H) 8.14 (s, 1H) 8.64 (s, 1H) 9.23 (br. s., 1H) 10.99 (br. s., 1H) LC-MS M+H+379.1.
Reaction SMILES: O[C@H]1CN[C@H](C(O)=O)C1.C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:20][O:21][C:22](=[O:36])[C@@H:23]1[CH2:27][C@@H:26]([OH:28])[CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C(N(CC)CC)C>CO.C(Cl)Cl.C(OCC)(=O)C>[CH3:20][O:21][C:22]([CH:23]1[CH2:27][C:26](=[O:28])[CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:36]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)[C@@H]1C[C@@H](O)CN1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CC(=O)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a stirred solution of (2S, 4R)-4-hydroxyproline (Aldrich) (25 g, 108 mmol) in methanol (50 mL) at 0° C. was added trimethylsilyldiazomethene (24.6 g, 216 mmol). The mixture was stirred at 0° C. for 1 hour. The residue obtained on removal of solvent and purification by column chromatography using 50% ethyl acetate in hexanes (27 g, 100%) was used in the next step. To oxalyl chloride (15 g, 118 mmol) in DCM (15 mL) at −78° C., DMSO (18.6 mL, 236 mmol) was added slowly over 15 minutes. After the completion of addition, the above product (2S, 4R)-N-Boc-4-hydroxyproline methylester (26.5 g, 108 mmol) in DCM (100 mL) was added at −78° C. dropwise over 20 minutes. Triethylamine (54.6 g, 540 mmol) was added followed by stirring at room temperature for 2 hours. The reaction mixture was then washed with 10% aq HCl (200 mL) and the organic layer was separated and dried over sodium sulfate. The crude product obtained on removal of solvent was purified on silica gel column chromatography using 50% EtoAc in hexanes to obtain 4-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (20 g, 78%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9](=[O:16])[CH2:10][CH2:11]2)(=O)=O.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9](=[O:16])[CH2:10][CH2:11]2
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: O=C1CCc2cccc(OS(=O)(=O)C(F)(F)F)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1CCc2cccc(-c3ccc(Cl)cc3Cl)c21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.7 %

Procedure:
A solution containing 3-oxo-2,3-dihydro-1H-inden-4-yl trifluoromethanesulfonate (0.666 g, 2.38 mmol), 2,4-dichlorobenzeneboronic acid (0.907 g, 4.75 mmol), and potassium carbonate (0.657 g, 4.75 mmol) in toluene (10 mL) stirred at room temperature for 15 minutes. Pd(PPh3)4 (1.37 g, 1.19 mmol) was added and the mixture was stirred at 90° C. for 2 hours. The catalyst was removed by filtration and concentrated. Flash chromatography gave the desired product as a brown solid (0.572 g, 87%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Si:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C1C2C(=CC=CC=2)CCC1.[Cu]>[CH3:9][Si:8]([CH3:11])([CH3:10])[C:5]1[CH:6]=[CH:7][C:2]([N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[CH:13]2)=[CH:3][CH:4]=1
Reactant: c1ccc2[nH]cnc2c1
Reactant: C[Si](C)(C)c1ccc(Br)cc1
Agent: [Cu]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Solvent: c1ccc2c(c1)CCCC2
Product: C[Si](C)(C)c1ccc(-n2cnc3ccccc32)cc1
Yield: 81.9 %

Procedure:
To a 1L 3-neck flask equipped with a mechanical stir arm was added 14.5 g (65.1 mmol) of 1-bromo-4-trimethylsilylbenzene, 9.2 g (78.1 mmol) of benzimidazole, 9.1 g (143 mmol) of copper power, 31.4 g (228 mmol) of potassium carbonate, and 1.7 g (6.5 mmol) of 18-crown-6. These chemicals were stirred vigorously in 400 mL tetrahydronaphthalene at 180° C. under N2 atmosphere. After 20 hours of heating, the mixture was filtered warm. The solids on the funnel were repeatedly washed with dichloromethane to remove all organic products as filtrate. The mother liquor was then evaporated in vacuo and pooled with a small batch of crude material from a previous reaction. This residue was purified by distilling on a Kugelrohr apparatus twice. At 160° C., the removal of organic impurities was evidenced. At 200° C. the product distilled. Purification gave 14.2 g N-(p-trimethylsilylphenyl)benzimidazole as a white solid.
Reaction SMILES: Cl.[C:2]1([S:8]([CH2:11][C:12]2[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([CH2:22][CH2:23][CH2:24][NH:25]C(OC(C)(C)C)=O)[C:15]([C:33]3[CH:37]=[CH:36][O:35][CH:34]=3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1.O>[NH2:25][CH2:24][CH2:23][CH2:22][C:16]1[C:15]([C:33]2[CH:37]=[CH:36][O:35][CH:34]=2)=[CH:14][CH:13]=[C:12]([CH2:11][S:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:10])=[O:9])[C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1CCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1CCCN
Reaction time: 0.5 h

Procedure:
Concentrated hydrochloric acid was added to a solution of methyl 6-(benzenesulphonylmethyl)-2-(3-t-butoxycarbonylaminopropyl)-3-(furan-3-yl)benzoate (Intermediate 131) in 1,4-dioxane (8 ml) and water (2 ml) and the mixture was stirred for 30 minutes. This was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of DCM:MeOH:AcOH:water (120:15:3:2) to give methyl 2-(3-aminopropyl)-6-(benzenesulphonylmethyl)-3-(furan-3-yl)benzoate as a colourless gum. This material was dissolved in a mixture of dioxane and water (3:1) and lithium hydroxide monohydrate (0.188 g) was added. The reaction was heated in the microwave at 150° C. for one hour. After cooling, concentrated hydrochloric acid was added and the mixture was evaporated to dryness. The residue was purified by chromatography on silica eluting with a mixture of DCM:MeOH:AcOH:water (240:20:3:2), then again with DCM:MeOH:AcOH:water (120:15:3:2). The volume of the product containing fractions was reduced to 5 ml by evaporation and concentrated hydrochloric acid (1 ml) was added to the mixture. The mixture was evaporated to dryness and the residue was triturated with diethyl ether and the solid was collected by filtration and dried under vacuum at 60° C. to give 2-(3-aminopropyl)-6-(benzenesulphonylmethyl)-3-(furan-3-yl)benzoic acid hydrochloride (0.045 g), as a white solid.
Reaction SMILES: CS([C:4]1[N:13]2[C:7]([C:8](=[O:18])[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[CH:11]=[CH:12]2)=[N:6][N:5]=1)=O.[CH3:19][O-:20].[Na+]>>[CH3:19][O:20][C:4]1[N:13]2[C:7]([C:8](=[O:18])[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[CH:11]=[CH:12]2)=[N:6][N:5]=1
Reactant: C[O-]
Reactant: CS(=O)c1nnc2c(=O)c3ccccc3ccn12
Agent: [Na+]
Product: COc1nnc2c(=O)c3ccccc3ccn12

Procedure:
The reaction of 3-methylsulfinyl-11H-s-triazolo [3,4-b][3]benzazepin-11-one with sodium methoxide yielded 3-methoxy-11H-s-triazolo[3,4-b][3]benzazepin-11-one. Colorless platelets (as recrystallized from methanol), melting point: 149°-150° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][C:12]=1[N+:19]([O-])=O)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H][H]>CO.[Pd]>[CH2:7]([O:6][P:4]([CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][C:12]=1[NH2:19])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(COc1ccc(C=O)cc1[N+](=O)[O-])OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(COc1ccc(CO)cc1N)OCC

Procedure:
A solution of 2-diethylphosphonomethyloxy-5-formylnitrobenzene (1 mmole) in methanol (5 mL) was treated with 10% palladium on carbon (0.05 mmole) under 1 atmosphere of hydrogen at room temperature for 12 h. Filtration followed by evaporation gave 2-diethylphosphonomethyloxy-5-hydroxymethylaniline which was subjected to Step B of Example 29 followed by Step D of Example 27 to give 2-amino-7-hydroxymethyl-6-thiocyanato-4-phosphonomethoxybenzothiazole (32.1). mp 181-184° C. Anal. calcd. for C10H10N3O5PS2+0.35H2O: C: 33.97; 11:3.05; N: 11.88. Found: C: 33.76; 11:2.66; N: 11.61.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[CH:10]1[C:27]([O-:29])=[O:28].[OH-].[K+]>CCO.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[CH:10]1[C:27]([OH:29])=[O:28]
Reactant: COc1ccccc1C1c2ccccc2C(c2ccc3c(c2)OCO3)C1C(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccccc1C1c2ccccc2C(c2ccc3c(c2)OCO3)C1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a solution of ethyl (1RS, 2RS, 3RS)-1-(2-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate (90 mg, 0.22 mmol) in EtOH (2 ml) containing a few drops of THF was added 6M KOH (0.22 ml, 1.32 mmol). The resulting mixture was allowed to stir at room temperature overnight, then was concentrated under reduced pressure. The residue was partitioned between H2O and Et2O. The aqueous phase was acidified with 3M HCl and extracted with EtOAc. The EtOAc extract was washed successively with H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo to afford the title compound (40 mg, 49%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([OH:13])=O)=[CH:8][C:9]=1[Cl:10])=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[C:55]([Si:59]([CH3:70])([CH3:69])[O:60][C:61]1[CH:62]=[C:63]([CH:66]=[CH:67][CH:68]=1)[CH2:64][NH2:65])([CH3:58])([CH3:57])[CH3:56]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11](=[O:13])[NH:65][CH2:64][C:63]2[CH:66]=[CH:67][CH:68]=[C:61]([O:60][Si:59]([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:69])[CH3:70])[CH:62]=2)=[CH:8][C:9]=1[Cl:10])=[O:4]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CN)c1
Reactant: COC(=O)c1sc(C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 26 %

Procedure:
To a solution of 3-Chloro-thiophene-2,5-dicarboxylic acid 2-methyl ester (500 mg, 2.27 mmol) in anhydrous DMF (10 mL) was added triethylamine (1.0 mL, 6.81 mmol), HBTU (1.03 g, 2.72 mmol), HOBT (370 mg, 2.72 mmol), and 3-(tert-Butyl-dimethyl-silanyloxy)-benzylamine (650 mg, 2.72 mmol). The mixture was stirred at room temperature 15 h, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-30% EtOAc in hexane to afford the desired product (0.26 g, 26% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:14]=[C:13]([CH3:26])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[C:28]1[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=3)[CH:14]=[C:13]([CH3:26])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)Nc2ccnc(Cl)c2)n1
Reactant: Cc1cc(Br)ccn1
Product: Cc1cc(-c2cc(C)nc(C(=O)Nc3ccnc(Cl)c3)c2)ccn1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid (2-chloro-pyridin-4-yl)-amide in accordance with the general method of example 131, step 2 using 4-Bromo-2-methylpyridine instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a white solid, MS (ISP): m/e=339.1, 341.1 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14](O)=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.S(Cl)([Cl:24])=O.C(N(CC)C=O)C>C(Cl)(Cl)Cl>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([Cl:24])=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Reactant: O=S(Cl)Cl
Agent: CCN(C=O)CC
Solvent: ClC(Cl)Cl
Product: CC(C(=O)Cl)c1ccc2c(=O)c3ccccc3ccc2c1
Reaction time: 1 h

Procedure:
1.0 G. of 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid is dissolved in 25 ml. of chloroform, and 1 ml. of thionyl chloride and 0.1 ml. of diethylformamide are added thereto. The mixture is left for 1 hour then evaporated under high vacuum to afford 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionyl chloride. In similar manner, substituting the acids prepared in Preparations 3 and 5-8 for the 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid used above, the corresponding acid chlorides are prepared.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:36](=[O:38])[NH2:37])=[CH:11][N:12]2[CH2:15][C:16]([N:18]2[CH2:22][C@H:21]([F:23])[CH2:20][C@H:19]2[C:24](=[O:35])[NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[F:34])=[O:17])=[CH:8][CH:7]=1.[OH-].[Na+]>C1COCC1.O>[C:36]([C:10]1[C:9]2[C:13](=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:39])=[O:2])=[CH:7][CH:8]=2)[N:12]([CH2:15][C:16]([N:18]2[CH2:22][C@H:21]([F:23])[CH2:20][C@H:19]2[C:24](=[O:35])[NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[F:34])=[O:17])[CH:11]=1)(=[O:38])[NH2:37]
Reactant: COC(=O)COc1ccc2c(C(N)=O)cn(CC(=O)N3C[C@H](F)C[C@H]3C(=O)NCc3cccc(Cl)c3F)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(OCC(=O)O)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (3-carbamoyl-1-{2-[(2S,4R)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-pyrrolidin-1-yl]-2-oxo-ethyl}-1H-indol-6-yloxy)-acetic acid methyl ester Example 592 (18 mg, 0.032 mmol) in a mixture of THF (2 mL) and water (0.2 mL) was added 1N NaOH (0.064 mL), followed by stirring at RT for 4 h. The reaction mixture was partitioned between CH2Cl2 and water. The aqueous phase was adjusted to pH=2 by addition of 1N HCl, followed by extraction with CH2Cl2 (3×). The combined organics were dried (phase separator) and concentrated under reduced pressure to afford the title compound as a white solid. MS: 549 [M+H]+; tR (HPLC conditions c): 3.74 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[N:9]/[N:10]([CH3:14])[C:11]([NH2:13])=[O:12])=[CH:4][CH:3]=1.BrBr.CCOCC>CC(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:13][C:11](=[O:12])[N:10]([CH3:14])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CN(/N=C/c1ccc(Br)cc1)C(N)=O
Agent: BrBr
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cn1nc(-c2ccc(Br)cc2)[nH]c1=O
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound 51a (5.8 g, 23 mmol) in AcOH (20 mL) was added Br2 (7.3 g, 46 mmol) dropwise at 95° C. The reaction mixture was stirred for another 30 min at 95° C. and allowed to cool to rt. Et2O (100 mL) was added. The solids formed were collected by filtration and washed with Et2O (2×30 mL) to obtain compound 51b as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C9H8BrN3O: 254.0 (M+H). Found 254.1.
Reaction SMILES: C[Si]([Br:5])(C)C.[CH2:6]([O:13][C:14]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16]O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)(Cl)Cl>[CH2:6]([O:13][C:14]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16][Br:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)c1ccc(CO)c(OCc2ccccc2)c1
Reactant: C[Si](C)(C)Br
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccc(CBr)c(OCc2ccccc2)c1
Reaction time: 1 h

Procedure:
2.9 ml of trimethylsilyl bromide are added to a solution, stirred at room temperature, of 4 g of 2-benzyloxy-4-tert-butyl-benzyl alcohol in 100 ml of chloroform. The reaction mixture is stirred for a further 1 hour and then partitioned between trichloromethane and water. The organic phases are dried with Na2SO4 and concentrated by evaporation, yielding the title compound: Rf (dichloromethane/hexane=8:2)=0.95.