Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6](=[O:60])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[O:59])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:25][C:24]=3[C:35]([C:37]3[N:38](S(C4C=CC=CC=4)(=O)=O)[C:39]4[C:44]([CH:45]=3)=[CH:43][CH:42]=[C:41]([C:46]([F:49])([F:48])[F:47])[CH:40]=4)=[O:36])[CH:16]=2)[CH:8]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CO.C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6](=[O:60])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[O:59])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]4)=[CH:25][C:24]=3[C:35]([C:37]3[NH:38][C:39]4[C:44]([CH:45]=3)=[CH:43][CH:42]=[C:41]([C:46]([F:48])([F:49])[F:47])[CH:40]=4)=[O:36])[CH:16]=2)[CH:8]=1
Reactant: COCCNC(=O)c1cccc(SCc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3C(=O)c3cc4ccc(C(F)(F)F)cc4n3S(=O)(=O)c3ccccc3)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CO
Product: COCCNC(=O)c1cccc(SCc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3C(=O)c3cc4ccc(C(F)(F)F)cc4[nH]3)c2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask was placed a solution of N-(2-methoxyethyl)-3-(3-(2-(1-(phenylsulfonyl)-6-(trifluoromethyl)-1H-indole-2-carbonyl)-4-(piperidin-1-yl)phenylcarbamoyl)benzylthio)-benzamide (200 mg, 0.23 mmol, 1.00 equiv) in methanol (3.5 mL), and 3.5 mL of a 1.0 N solution of tetrabutylammonium fluoride in THF. The resulting solution was stirred overnight at 80° C. The resulting mixture was concentrated under vacuum. The residue was dissolved in 50 mL of ethyl acetate. The resulting mixture was washed with 3×20 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (100 mg) was purified by HPLC with the following conditions (Waters 2767-3): Column, SunFire Prep C18, 19×150 mm Sum; mobile phase, water with 0.05% TFA and CH3CN (gradient of 49% to 61% CH3CN over 6 min); Detector, Waters 2545 UV Detector 254 and 270 nm. This resulted in 38.1 mg (17%) of N-(2-methoxyethyl)-3-(3-(4-(piperidin-1-yl)-2-(6-(trifluoromethyl)-1H-indole-2-carbonyl)-phenylcarbamoyl)benzylthio)benzamide as a orange solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.38 (d, J=9 Hz, 1H), 8.01 (d, J=3 Hz, 1H), 7.91-7.87 (m, 2H), 7.78-7.73 (m, 4H), 7.62-7.59 (m, 1H), 7.53-7.51 (m, 1H), 7.47-7.26 (m, 5H), 4.23 (s, 2H), 3.62-3.57 (m, 4H), 3.53 (s, 3H), 3.35-3.34 (m, 2H), 1.98-1.96 (m, 4H), 1.79-1.77 (m, 2H). MS (ES, m/z): 715 [M+H]+.
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH2:7][CH2:6][C:5]1=O)(=O)[CH3:2].[NH2:12][NH2:13]>CO>[CH3:2][C:1]1[C:4]2[C:9](=[O:10])[CH2:8][CH2:7][CH2:6][C:5]=2[NH:13][N:12]=1
Reactant: NN
Reactant: CC(=O)C1C(=O)CCCC1=O
Solvent: CO
Product: Cc1n[nH]c2c1C(=O)CCC2
Temperature: 0 °C

Procedure:
To an ice-cold solution of 33.3 grams of 2-acetyl1,3-cyclohexanedione in 400 ml of methanol was added dropwise a solution of 7.2 ml of hydrazine in 50 ml of methanol and the resulting reaction mixture was heated at reflux for 20 hours. The solvent was then removed under reduced pressure and the residue was triturated in ethyl ether to give 1,5,6,7-tetrahydro-3-methyl-4H-indazol-4-one as a yellow crystalline solid melting at about 154°-157° C.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[O:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][NH2:11]>CO>[O:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][NH:11][C:3]([NH:2][CH3:1])=[O:4]
Reactant: CN=C=O
Reactant: NCc1ccco1
Solvent: CO
Product: CNC(=O)NCc1ccco1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.1 %

Procedure:
A solution of methyl isocyanate (34.0 g) in methanol (30 ml) was added dropwise to a solution of furan-2-ylmethylamine (57.9 g) in methanol (300 ml) at 5° to 15° C. After being stirred at room temperature for three hours, the solvent was evaporated in vacuo. The residue was treated with diisopropyl ether (400 ml) to give N-(furan-2-ylmethyl)-N'-methylurea (81.9 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([OH:32])[CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:20]([O:23]CC2C=CC=CC=2)=[C:19]2[C:14]=1[CH2:15][CH2:16][C:17](=[O:31])[NH:18]2.C(O)C.[ClH:41].[H][H]>CO.[C].[Pd]>[ClH:41].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([OH:32])[CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]2[C:14]=1[CH2:15][CH2:16][C:17](=[O:31])[NH:18]2
Reactant: [H][H]
Reactant: COc1ccc(CCNCC(O)COc2ccc(OCc3ccccc3)c3c2CCC(=O)N3)cc1OC
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: COc1ccc(CCNCC(O)COc2ccc(O)c3c2CCC(=O)N3)cc1OC
Temperature: 25 °C

Procedure:
2.0 g of 5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-8-benzyloxy-3,4-dihydrocarbostyril was suspended in 50 ml of methanol, and an ethanol solution containing hydrogen chloride was added to the suspension until the mixture showed acidity. After the mixture became homogenous, 0.7 g of 10% palladium carbon was added thereto followed by stirring at room temperature and at atmospheric pressure thereby absorbing hydrogen. The reaction completed when the absorption of hydrogen ceased. The catalyst was removed by filtration, and the methanol evaporated. A small amount of ethanol was added to the residue to crystallize the product. Recrystallization from ethanol gave 1.5 g of 5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-8-hydroxy-3,4-dihydrocarbostyril hydrochloride as colorless powdery crystals having a melting point of 171°-173° C.
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[C:25]([CH3:27])[CH:26]=1)[NH:23][CH2:22][CH2:21]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:23]2[C:24]3[C:20](=[CH:19][C:18]([O:17][CH3:16])=[CH:26][C:25]=3[CH3:27])[CH2:21][CH2:22]2)[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=1
Reactant: COc1cc(C)c2c(c1)CCN2
Reactant: CCC(CC)n1cc(Cl)nc(Cl)c1=O
Agent: Cl
Product: CCC(CC)n1cc(Cl)nc(N2CCc3cc(OC)cc(C)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-(1-ethylpropyl)-2(1H)-pyrazinone and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 164–165° C.; 1H NMR (300 MHz, CDCl3): δ 6.67 (s, 1 H), 6.66 (s, 1 H), 6.59 (d, J=2.2 Hz, 1 H), 4.82–4.80 (m, 1 H), 4.39 (t, J=7.9 Hz, 2 H), 3.79 (s, 3 H), 3.05 (t, J=7.7 Hz, 2 H), 2.06 (s, 3 H), 1.84–1.73 (m, 2 H), 1.70–1.59 (m, 2 H), 0.89 (t, J=7.3 Hz, 6 H); HRMS (ESI) calcd for C19H25N3O2Cl (M+H)+: 362.1635; found m/z 362.1648.
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22](O)=O)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:25][N:26]=[C:27]([C:29]1[CH:33]=[C:32]([CH3:34])[O:31][N:30]=1)[NH2:28]>>[CH:1]1([C:6]([N:8]2[CH2:9][CH:10]([C:22]3[O:25][N:26]=[C:27]([C:29]4[CH:33]=[C:32]([CH3:34])[O:31][N:30]=4)[N:28]=3)[CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:13]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C(N)=NO)no1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4cc(C)on4)no3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
66 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 31 mg (0.22 mmol, 1.1 eq.) of N′-hydroxy-5-methylisoxazole-3-carboximidamide were reacted according to the General Method 1. Yield: 50 mg (58% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[CH2:21]O)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[CH2:21][N:27]2[C:23](=[O:33])[C:24]3=[CH:32][CH:31]=[CH:30][CH:29]=[C:25]3[C:26]2=[O:28])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: O=C(c1ccccc1)c1cc(Br)ccc1-n1ccnc1CO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(c1ccccc1)c1cc(Br)ccc1-n1ccnc1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 17, 5-bromo-2-[2-(hydroxymethyl)imidazol-1-yl]benzophenone is treated with phthalimide and triphenylphosphine and finally with diethyl azodicarboxylate to give 5-bromo-2-[2-(phthalimidomethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: [O:1]=[C:2]([CH3:11])[CH2:3][C:4]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:6][CH2:5]1.[C:12]1(C)C=C(C)C=C(C)C=1.Cl>CO>[CH3:12][O:9][C:8](=[O:10])[CH2:7][C:4]1([CH2:3][C:2](=[O:1])[CH3:11])[CH2:6][CH2:5]1
Reactant: Cc1cc(C)cc(C)c1
Reactant: CC(=O)CC1(CC(=O)O)CC1
Agent: Cl
Solvent: CO
Product: COC(=O)CC1(CC(C)=O)CC1

Procedure:
To a solution of 4.9 g crude [1-(2-oxo-propyl)-cyclopropyl]-acetic acid (31 mmole) in 73.5 ml methanol are added 1 ml of mesitylene (GC standard) and 2.5 ml of conc. hydrochloric acid. The mixture is heated to reflux for 1 hour and then concentrated to dryness. 40 ml of water are added to the residue and the resulting mixture is extracted with 100 ml of methyl tert-butyl ether in two portions. The combined organic phases are concentrated to dryness. The resulting crude product is directly used in the next step (spiro[2.5]octane-5,7-dione).
Reaction SMILES: [CH2:1]([O:8][C@:9]1([CH3:32])[C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:12]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:11][C:10]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C@:9]1([CH3:32])[C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:12]([CH2:22][O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[O:11][CH:10]1[OH:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]1(OCc2ccccc2)C(=O)O[C@H](COCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@]1(OCc2ccccc2)C(O)O[C@H](COCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -65 °C
Reaction time: 0.25 h
Yield: 103.1 %

Procedure:
To a solution of (3R,4R,5R)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)-3-methyl-dihydrofuran-2(3H)-one (250 mmol) in toluene (625 mL) cooled to −70° C. was added dropwise a 1.5 M solution of Dibal in Toluene (250 mL, 375 mmol) at such a rate so that the reaction temperature does not go above −65° C. The reaction was further stirred at −65° C. for 15 mins (TLC analysis showed completion of reaction, 25% ethyl acetate in hexanes). The excess Dibal was destroyed by adding acetone (40 mL) to the reaction mixture while maintaining the temperature below −60° C. The reaction was diluted with cold 2.5 N HCl (300 mL), water (475 mL) and allowed to warm to 0° C. The reaction was extracted with ethyl acetate (625 mL). The organic layer was separated and washed with brine (500 mL), dried over MgSO4, filtered and the filtrate was concentrated in vacuum to dryness to furnish (3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxymethyl)-3-methyl-tetrahydrofuran-2-ol (112 g) as an oil, which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[Br:24][C:25]1[CH:26]=[N:27][C:28](F)=[N:29][CH:30]=1>>[Br:24][C:25]1[CH:26]=[N:27][C:28]([N:21]2[CH2:22][CH2:23][CH:18]([N:4]([CH:1]3[CH2:3][CH2:2]3)[C:5](=[O:17])[C:6]3[CH:7]=[CH:8][C:9]([C:12]4[O:16][CH:15]=[N:14][CH:13]=4)=[CH:10][CH:11]=3)[CH2:19][CH2:20]2)=[N:29][CH:30]=1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: Fc1ncc(Br)cn1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2ncc(Br)cn2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 5-bromo-2-fluoro-pyrimidine following a procedure analogous to that described in Example 19. LC (method 9): tR=2.32 min; Mass spectrum (ESI+): m/z=468/470 (Br) [M+H]+.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][S:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:31]([NH2:35])([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][S:7][CH2:6][C@H:2]1[C:3]([NH:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:5]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N1CSC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)[C@@H]1CSCN1C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 84.1 %

Procedure:
To a solution of 3.0 g (12.9 mmol) of Boc-Thz-OH and 2.15 ml (15.5 mmol) of triethylamine in 25 ml of DMF, 2.02 ml (15.5 mmol) of isobutyl chloroformate was added dropwise at -15° C. After stirring for 10 min at that temperature. 4.06 ml (38.7 mmol) of tert-butylamine was added. The reaction mixture was stirred for 10 min at that temperature and 100 min under ice cooling, concentrated under reduced pressure, diluted with 50 ml of ethyl acetate, washed with 5% NaHCO3 aqueous solution, 5% citric acid aqueous solution, and saturated NaCl aqueous solution successively, dried over Na2SO4, and evaporated under reduced pressure to give 3.13 g (Y. 84%) of Boc-Thz-NH-tBu which was convened to Qoa-Mta-AHPBA-Thz-NH-tBu by a similar method with processes 2-5 of Example 3.
Reaction SMILES: [CH:1]1([O:6][N:7]=[C:8]([C:38]2[N:39]=[C:40]([NH:43]C=O)[S:41][CH:42]=2)[C:9]([NH:11][CH:12]2[C:36](=[O:37])[N:14]3[C:15]([C:33]([OH:35])=[O:34])=[C:16]([CH2:19][S:20][C:21]4[N:25]([CH2:26][C:27]([C:30]([OH:32])=[O:31])=[N:28][OH:29])[N:24]=[N:23][N:22]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH2:5][CH2:4][CH:3]=[CH:2]1.Cl>CO.O1CCCC1>[CH:1]1([O:6][N:7]=[C:8]([C:38]2[N:39]=[C:40]([NH2:43])[S:41][CH:42]=2)[C:9]([NH:11][CH:12]2[C:36](=[O:37])[N:14]3[C:15]([C:33]([OH:35])=[O:34])=[C:16]([CH2:19][S:20][C:21]4[N:25]([CH2:26][C:27]([C:30]([OH:32])=[O:31])=[N:28][OH:29])[N:24]=[N:23][N:22]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: O=CNc1nc(C(=NOC2C=CCC2)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnnn4CC(=NO)C(=O)O)CS[C@H]23)cs1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(C(=NOC2C=CCC2)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnnn4CC(=NO)C(=O)O)CS[C@H]23)cs1

Procedure:
A solution of 7-[2-(2-cyclopenten-1-yl)oxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-[1-(2-carboxy-2-hydroxyiminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer: in the 7-position) (1.1 g) and conc. hydrochloric acid (0.12 g) in methanol (10 ml) and tetrahydrofuran (2 ml) was stirred at room temperature for 2.5 hours. After removal of organic solvents under reduced pressure, the residue was dissolved in an aqueous solution of sodium bicarbonate and the solution was adjusted to pH 7.5. The aqueous solution was washed with ethyl acetate (15 ml) and then adjusted to pH 3.0 with 10% hydrochloric acid to give precipitates which were filtered and washed with water to give 7-[2-(2-cyclopenten-1-yl)oxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[1-(2-carboxy-2-hydroxyiminoethyl)-1H-tetrazole-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer: in the 7-position).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11]2)=[CH:2]1.[H-].[Na+].[F:18][C:19]1[CH:38]=[CH:37][C:22]([CH2:23][NH:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[O:26])=[CH:21][CH:20]=1>CN(C=O)C>[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][NH:24][C:25](=[O:26])[C:27]2[CH:32]=[CH:31][C:30]([S:33]([N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]([CH:10]4[CH2:14][CH2:13][C:12](=[O:15])[CH2:11]4)=[CH:2]3)(=[O:34])=[O:35])=[CH:29][CH:28]=2)=[CH:37][CH:38]=1
Reactant: O=C1CCC(c2c[nH]c3ccccc23)C1
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCC(c2cn(S(=O)(=O)c3ccc(C(=O)NCc4ccc(F)cc4)cc3)c3ccccc23)C1
Yield: 29.7 %

Procedure:
Add a 3 nm DMF solution of 3-(1H-Indol-3-yl)-cyclopentanone (500 mg, 2.57 mmol, 1 eq) to a 3 ml DMF solution of NaH (155 mg, 60% by weight, 3.86 mmol, 1.1 eq) under N2 atmosphere. Stir reaction for 15 minutes and then add a 5 ml DMF solution of 4-(4-Fluoro-benzylcarbamoyl)-benzenesulfonyl chloride (1.27 g, 3.86 mmol, 1.1 eq). Stir reaction for 48 hours, remove solvent on rotovap, and purify by silica gel chromatography to give N-(4-Fluoro-benzyl)-4-[3-(3-oxo-cyclopentyl)-indole-1-sulfonyl]-benzamide (375 mg, 22% yield). Mass Spectrum (m/e): 490.53 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[CH2:14][CH2:15][OH:16])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[CH2:14][CH2:15][OH:16]
Reactant: CC(C)(C)OC(=O)Nc1ccncc1CCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccncc1CCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
A solution of [3-(2-hydroxy-ethyl)-pyridin-4-yl]-carbamic acid tert-butyl ester (91 mg, 0.38 mmol) in CH2Cl2 (3 mL) was treated with TFA (2 mL) and stirred at room temperature for 3 hours. Concentrated under vacuum to provide 21 mg (23%) of desired product. MS (DCI) m/e 139 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[CH:18]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].N1C=CC=CC=1>CCO>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][CH:10]1[CH2:11][CH2:12][CH:13]2/[CH:18]=[N:21]/[OH:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: O=C[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: O=C1N2CC(CCC2/C=N/O)N1OCc1ccccc1
Yield: 42.3 %

Procedure:
A solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbaldehyde (510 mg, 1.96 mmol), hydroxylamine hydrochloride (158 mg, 2.27 mmol) and pyridine (621 mg, 7.85 mmol) in EtOH (15 mL) was stirred at rt for 2 hrs. Then, the reaction mixture was concentrated and the residue was diluted with DCM (25 mL), washed with water (3×), and saturated sodium chloride, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (3:1 to 3:2 petroleum ether/EtOAC) to afford (E)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbaldehyde oxime (228 mg, 42%) as a white solid. ESI-MS (EI+, m/z): 276 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:35])[CH2:15][CH2:16][C:17]([C:19]3[CH:28]=[C:27]4[C:22]([CH2:23][CH2:24][N:25](C(=O)C(F)(F)F)[CH2:26]4)=[CH:21][CH:20]=3)=[O:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:35])[CH2:15][CH2:16][C:17]([C:19]3[CH:28]=[C:27]4[C:22]([CH2:23][CH2:24][NH:25][CH2:26]4)=[CH:21][CH:20]=3)=[O:18])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(CCC(=O)N1CCC(c2ccc(Cl)cc2)CC1)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(CCC(=O)N1CCC(c2ccc(Cl)cc2)CC1)c1ccc2c(c1)CNCC2
Yield: 90.8 %

Procedure:
A solution of 4-[4-(4-chlorophenyl)-1-piperidinyl]-4-oxo-1-[2-(trifluoroacetyl)-1,2,3,4-tetrahydro-7-isoquinolinyl]-1-butanone (1.1 g, 2.17 mmol) and potassium carbonate (900 mg, 6.5 mmol) in a mixed solvent of water (10 ml) and methanol (40 ml) was stirred at room temperature for 2 hours and then extracted with ethyl acetate. The extract was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, whereby 810 mg of the title compound was obtained as colorless powder.
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:4]=2[C:5]([CH3:13])=[N:6][C:7]=1[C:8](OCC)=[O:9].[NH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+]>C(=O)(O)[O-].[Na+]>[OH:1][C:2]1[C:3]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:4]=2[C:5]([CH3:13])=[N:6][C:7]=1[C:8]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:9]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C)c2c(-c3ccc(OC)cc3)noc2c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(-c2noc3c(O)c(C(=O)NCC(=O)O)nc(C)c23)cc1
Temperature: 25 °C
Yield: 48.3 %

Procedure:
Ethyl 7-hydroxy-3-(4-methoxyphenyl)-4-methylisoxazolo[4,5-c]pyridine-6-carboxylate (35 mg, 0.11 mmol) and glycine (320 mg, 4.27 mmol) were added to sodium methoxide solution (6.4 mL, 3.20 mmol, 0.5 M in MeOH) and the mixture was refluxed for 3 days. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in minimum amount of water and 0.25 M hydrochloric acid was added until pH was 3. The precipitate was isolated by filtration and dried under vacuum to give 22 mg of crude solid. The solid was dissolved in 10 mL of saturated sodium bicarbonate solution and washed with hexanes and EtOAc. The aqueous layer was acidified to pH 3 with concentrated hydrochloric acid and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 19 mg of the title compound. MS: (+) m/z 358.37 (M+1).
Reaction SMILES: N[C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.[I-:12].[K+].N([O-])=O.[Na+]>C(O)(=O)C.O>[I:12][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: [I-]
Agent: O=N[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c[nH]nc1I
Yield: 58.6 %

Procedure:
Ethyl 3-amino-1H-pyrazole-4-carboxylate (860.0 mg, 5.54 mmol) was dissolved in acetic acid (5 mL) and water (5 mL). Potassium iodide (921 mg, 5.54 mmol) was added and the mixture was stirred until all solids had dissolved. A solution of sodium nitrite (386 mg, 5.54 mmol) in water (2 mL) was then added dropwise. The reaction was stirred at room temperature for 2 minutes when stirring became hindered due to precipitate formation. Additional water (5 mL) was added and the reaction was allowed to stir overnight. The acetic acid was removed under reduced pressure. The brown residue was taken up in saturated aqueous sodium bicarbonate and was extracted with ethyl acetate (2×50 mL). The combined organics were washed with saturated aqueous sodium thiosulfate (50 mL), dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (10-80% ethyl acetate/heptanes) gave the title compound (863 mg, 59%) as a white solid. +APCI (M+H) 267.2; 1H NMR (400 MHz, CDCl3, δ): 12.63 (br. s., 1H), 8.13 (s, 1H), 4.34 (q, J=7.0 Hz, 2H), 1.38 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:16](Cl)(=[O:18])[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(=S)=S>[C:16]([C:13]1[CH:12]=[CH:11][C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)=[CH:15][CH:14]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: COc1ccc(-c2ccccc2)cc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COc1ccc(-c2ccc(C(C)=O)cc2)cc1F
Yield: 29.3 %

Procedure:
Into a flask were charged 150 g (0.74 mol) of the above 3-fluoro-4-methoxy biphenyl, 1 l of carbon disulfide and 58 g (0.74 mol) of acetyl chloride, to which was added 120 g (0.90 mol) of anhydrous aluminum chloride over about 2.5 hours with stirring under ice cooling. The resulting mixture was further stirred for 2 hours and refluxed for 3 hours. After the air cooling, the reaction mixture was poured into 3 l of 1 normal hydrochloric acid. The precipitated solid was filtered and recrystallized with 2-propanol two times and with methanol to obtain 53 g (yield: 29%) of 4-acetyl-3'-fluoro-4'-methoxy biphenyl.