Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:35]1[N:36]=[C:37]([NH:40]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:38][CH:39]=1)\[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:18])=[C:12]([CH2:15]I)[CH2:13][S:14][C@H:9]12)=[O:6].[N:60]1([C:65]([NH:67][C:68]2[S:69][C:70]3[CH:75]=[CH:74][N:73]=[CH:72][C:71]=3[N:76]=2)=[O:66])[CH2:64][CH2:63][CH2:62][CH2:61]1.C(O)(C(F)(F)F)=O>CS(C)=O.C1(OC)C=CC=CC=1>[NH2:40][C:37]1[S:38][CH:39]=[C:35](/[C:4](=[N:3]/[O:2][CH3:1])/[C:5]([NH:7][CH:8]2[C:33](=[O:34])[N:10]3[C:11]([C:17]([O-:19])=[O:18])=[C:12]([CH2:15][N+:73]4[CH:74]=[CH:75][C:70]5[S:69][C:68]([NH:67][C:65]([N:60]6[CH2:64][CH2:63][CH2:62][CH2:61]6)=[O:66])=[N:76][C:71]=5[CH:72]=4)[CH2:13][S:14][C@H:9]23)=[O:6])[N:36]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C(Nc1nc2cnccc2s1)N1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: COc1ccccc1
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc4sc(NC(=O)N5CCCC5)nc4c3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51.3 %

Procedure:
A solution of diphenylmethyl 7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate [VIIa] (466 mg, 0.5 mmole) and 2-(pyrrolidin-1-yl-carbonylamino)thiazolo[4,5-c]pyridine (124 mg, 0.5 mmoles) in 2 ml DMSO was allowed to stand at room temperature for 1.5 hours and then triturated with ether to give 606 mg of crude quaternary salt as a powder. The powder was added to a mixture of 5 ml of TFA and 3 drops of anisole and stirred 30 minutes at room temperature. The mixture then was evaporated under reduced pressure and triturated with ether to give 375 mg of crude It, which was purified on a column of HP-20 resin (40 ml) using 50% aqueous CH3OH as an eluant to give 165 mg (51%) of the desired product It. Mp. 184°~198° C. (dec.). Estimated purity by HPLC: 65%.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[N:6][C:7]([S:10]([CH2:13]P(OCC)(=O)OCC)(=[O:12])=[O:11])=[N:8][CH:9]=1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>C1C=CC=CC=1>[CH:13](/[S:10]([C:7]1[N:8]=[CH:9][C:4]([Cl:3])=[CH:5][N:6]=1)(=[O:11])=[O:12])=[CH:22]\[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOP(=O)(CS(=O)(=O)c1ncc(Cl)cn1)OCC
Reactant: O=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: O=S(=O)(/C=C/c1ccccc1)c1ncc(Cl)cn1

Procedure:
Sodium hydride dispersion (55-60%, 2 mmol) was further dispersed in benzene (4 ml) and added gradually to a solution of diethyl (5-chloropyrimidin-2-sulfonyl)methanephosphonate (0.66 g, 2 mmol) in benzene (4 ml). The mixture was stirred for 10 min before a solution of benzaldehyde (0.21 g, 2 mmol) in benzene (2 ml) was added. The resultant mixture was stirred at room temperature overnight before extraction with water. Evaporation of the dried (MgSO4) benzene solution left the product which was recrystallised from ethanol; yield 0.20 g 35%, m.p. 150° C. 1H NMR (CDCl3): δ7.24 and 7.90 (2H-vinyl, Jvic 16 Hz), 7.60 (Ph, m.), 8.90 (2H-4,6).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.O>CS(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([O:8][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(O)(c2ccccc2)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN1CCC(Oc2ccc([N+](=O)[O-])cc2)(c2ccccc2)CC1
Reaction time: 1 h
Yield: 48.8 %

Procedure:
A solution of 1-methyl-4-phenyl-4-piperidinol (7.65 g, 40 mM) in dry DMSO (100 ml) was treated with sodium hydride (2.0 g of a 50% dispersion in oil, 42 mM). The reaction mixture was stirred for 1 hour then treated with 4-fluoronitrobenzene (5.65 g, 40 mM). After 24 hours the reaction mixture was poured on to water (500 ml) and extracted with ether (4×500 ml). The organic extracts were washed with brine, dried and the solvents removed under reduced pressure. Recrystallisation of the residue from IPA gave the title compound (6.1 g) m.p. 136°-8°.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH3:12])=[CH:5][C:6]=1[C:7]([O:9]C)=O.ClC(Cl)(O[C:17](=[O:23])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37][CH2:38][NH2:39]>C(Cl)Cl>[CH2:11]([C:4]1[S:3][C:2]2[NH:1][C:17](=[O:23])[N:39]([CH2:38][CH2:37][C:33]3[S:32][CH:36]=[CH:35][CH:34]=3)[C:7](=[O:9])[C:6]=2[CH:5]=1)[CH3:12]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCCc1cccs1
Reactant: CCc1cc(C(=O)OC)c(N)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc2c(=O)n(CCc3cccs3)c(=O)[nH]c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
To a solution (50 mL) of methyl 2-amino-5-ethylthiophene-3-carboxylate (0.5 g) in methylene chloride were added triphosgene (0.35 g) and triethylamine (0.56 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 2-(2-thienyl)ethanamine (1 g), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (20 mL), sodium methoxide (28% methanol solution, 1.3 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was neutralized with hydrochloric acid (10% methanol solution), insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.26 g, 31%).
Reaction SMILES: CC[O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH:9]([CH3:12])[CH2:8][N:7]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:5].O.[OH-].[Li+]>CO.O>[C:16]([O:15][C:13]([N:7]1[CH2:8][CH:9]([CH3:12])[CH2:10][CH2:11][C@H:6]1[C:4]([OH:5])=[O:3])=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: CCOC(=O)[C@@H]1CCC(C)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1CC[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-5-methyl-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (1.4 g, 5.16 mmol) in methanol (15 mL) and water (5 mL) was added lithium hydroxide monohydrate (650 mg, 15.48 mmol). The reaction mixture was stirred at RT overnight and concentrated to give the residue, which was extracted with EtOAc/water. The aqueous layer was acidified with 1 N HCl, and extracted with EtOAc to give the organic layer, which was dried and concentrated to give the crude product.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:30][C@H:29]([CH2:31][O:32][Si](C(C)(C)C)(C)C)[C@@H:20]([O:21][Si](C(C)(C)C)(C)C)[C@@H:12]2[O:13][C:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18])=[C:4]([O:40][CH3:41])[N:3]=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>O1CCCC1>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:30][C@H:29]([CH2:31][OH:32])[C@@H:20]([OH:21])[C@@H:12]2[O:13][C:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18])=[C:4]([O:40][CH3:41])[N:3]=1
Reactant: CCCCC(=O)O[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@H]1n1cnc2c(OC)nc(N)nc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCCCC(=O)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(OC)nc(N)nc21
Temperature: 5 °C
Reaction time: 18 h
Yield: 82.1 %

Procedure:
2-Amino-9-(3,5-di-O-tert-butyldimethylsilyl-2-O-valeryl-β- D-arabinofuranosyl)-6-methoxy-9 H-purine (1.4 g, 2.3 mmol) was taken up in tetrahydrofuran (THF, 40 mL) and cooled in an ice bath to 5° C. Acetic acid (0.06 mL, 10 mmol) was added, followed by tetrabutylammonium fluoride (TBAF) as a 1M solution in THF (10 mL, 10 mmol). After 18 hours at 5° C., the reaction mixture was diluted with CCHl3 (40 mL) and passed through a pad of silica gel (230-400 mesh, 5×5 cm) with 1:1 acetone:CHCl3 (500 mL).The filtrate was concentrated and purified on a Chromatotron fitted with a 4 mm rotor and eluted with neat ethyl acetate. Pure product was obtained from the column as a white foam 0.72 g (78%) after drying and was shown to be the desired 2'-O-valeryl derivative: m.p.: 83°-86° C. (uncorrected); UV λmax (.di-elect cons.): pH=7.00: 280.0 nm (7,800), 247.8 nm (8,400); 0.1N HCl: 278.6 (8,000), 248.7 (7,400); 0.1N NaOH: 286.2 (7,600), 244.9 (7,200); MS (EI): m/z 381 (C16H23N5O6), 351 (C15H21N5O5), 292 (C13H:8N5O3), 279 (C11H13N5O4), 249 (C10H11N5O3), 217 (C10H17O5), 194 (C7H8N5O2), 165 (C6H7N5O), 135 (C5H5N4), 85 (C5H9O). IR (KBr) 1745.2, 1613.3 and 1588.7 cm-1. 1H-NMR (Me2SO-d6): δ7.93 (s, 1 H, H-2), 6.46 (brs, 2 H, NH2), 6.26 (d, 1 H, H-1', J=5.9 Hz), 5.79 (d, 1 H, 3'-OH, J=5.1 Hz), 5.23 (t, 1 H, H-2', J=5.8 Hz), 5.02 (t, 1 H, 5'-OH, J=5.6 Hz), 4.36 (ddd, 1 H, H-3', J3',3'-OH =5.1 Hz, J2',3' =5.7 Hz, J3',4' =5.8 Hz), 3.93 (s, 3 H, Pur-OCH3), 3.83-3.78 (m, 1 H, H-4'), 3.68-3.61 (m, 2 H, H-5'), 2.09 (dt, 1 H, C(O)CH2, J=7.5 Hz, J=15 Hz), 1.93 (dt, 1 H, C(O)CH2, J=7.5 Hz, J=15 Hz), 1.30-0.90 (m, 4H, --CH2CH2 --), 0.65 (t, 3 H, --CH3, J=7 Hz).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]>C1C=CC=CC=1>[Br-:20].[C:24]([CH2:23][CH2:22][CH2:21][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([OH:26])=[O:25]
Reactant: O=C(O)CCCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: O=C(O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
Refer to Chart D. 3-Carboxypropyltriphenylphosphonium bromide is prepared by heating triphenylphosphine (156.8 g.) and 4-bromobutyric acid (100 g.) in 125 ml. of benzene at reflux for 18 hrs. The crystalline product is filtered off, washed with benzene, and recrystallized from ethanol-acetonitrile-ether, 150 g., m.p. 247°-249° C.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:21][C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[O:41][CH:40]=[N:39][CH:38]=3)=[C:33]([OH:42])[CH:32]=2)=[O:29])=[C:26](Br)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)(C)(C)C.C(OCC)(=O)C>[NH2:21][C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[O:41][CH:40]=[N:39][CH:38]=3)=[C:33]([OH:42])[CH:32]=2)=[O:29])=[C:26]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:25]=[CH:24][N:23]=1
Reactant: Nc1ncnc(Br)c1C(=O)Nc1ccc(-c2cnco2)c(O)c1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Agent: [Cs+]
Agent: [F-]
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3C(=O)Nc3ccc(-c4cnco4)c(O)c3)n(-c3ccccc3)c(=O)c12
Temperature: 120 °C
Reaction time: 8 h
Yield: 1.4 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.37 mmol), 4-amino-6-bromo-N-(3-hydroxy-4-(oxazol-5-yl)phenyl)pyrimidine-5-carboxamide (220 mg, 0.58 mmol), DIEA (325 μl, 1.87 mmol) and cesium fluoride (113 mg, 0.74 mmol) were suspended in tert-butanol (10 ml) and the mixture was stirred overnight at 120° C. in a sealed tube. The reaction mixture was diluted with ethyl acetate and washed with water and brine. After evaporation of the solvent, the residue was purified by reverse phase using SP1® Purification System to give 3 mg (1% yield) of the title compound as a solid. Purity 97%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:7][C:8]=1Cl)#[N:2].[C:14]([N:16]=[C:17]([NH2:19])[NH2:18])#[N:15].[OH-].[K+].[CH3:22][O:23][CH2:24][CH2:25][OH:26]>O>[NH2:15][C:14]1[N:16]=[C:17]([NH2:19])[N:18]=[C:1]([C:3]2[C:8]([O:26][CH2:25][CH2:24][O:23][CH3:22])=[CH:7][CH:6]=[C:5]([C:10]([F:13])([F:12])[F:11])[CH:4]=2)[N:2]=1
Reactant: COCCO
Reactant: N#CN=C(N)N
Reactant: N#Cc1cc(C(F)(F)F)ccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COCCOc1ccc(C(F)(F)F)cc1-c1nc(N)nc(N)n1

Procedure:
6.3 g of 3-cyano-4-chlorobenzotrifluoride, 3.1 g of dicyanodiamide and 1.0 g of caustic potash are refluxed in 10 ml of methyl cellosolve for 5 hours. After cooling, the mixture is diluted with water and the separated crystals are recrystallized from methanol. Melting point: 224°-226° C.; yield: 4.3 g.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[N:48]=[C:17]2[N:18]([CH2:41][CH:42]([OH:47])[C:43]([F:46])([F:45])[F:44])[C:19](=[O:40])[C:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:28][CH:27]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:16]2[N:15]=1>C(OCC)(=O)C>[CH3:13][C:14]1[N:48]=[C:17]2[N:18]([CH2:41][CH:42]([OH:47])[C:43]([F:45])([F:44])[F:46])[C:19](=[O:40])[C:20]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]4[NH:3][C:4](=[O:7])[O:5][N:39]=4)=[CH:30][CH:31]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:16]2[N:15]=1
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(O)C(F)(F)F)c2nc(C)nn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(O)C(F)(F)F)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
A mixture of hydroxylammonium chloride (1.6 g), sodium hydrogen carbonate (2.6 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[2-methyl-5-oxo-7-propyl-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.76 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.025 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.41 g, 49%).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]2[N:26]=[C:25]([C:27]3[O:35][C:34]4[CH:33]=[CH:32][N:31]=[CH:30][C:29]=4[CH:28]=3)[O:24][N:23]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]2[N:26]=[C:25]([C:27]3[O:35][C:34]4[CH:33]=[CH:32][N:31]=[CH:30][C:29]=4[CH:28]=3)[O:24][N:23]=2)[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2noc(-c3cc4cnccc4o3)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc2oc(-c3nc(CC4CCNCC4)no3)cc2cn1
Reaction time: 1 h

Procedure:
TFA (10 mL) was added to a stirred solution of 4-(5-furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)piperidine-1-carboxylic acid tert-butyl ester (Example 44, 1.76 g, 4.56 mmol) in anhydrous CH2Cl2 (20 mL). After 1 h, the solvents were removed under reduced pressure. The residue was taken up in CH2Cl-MeOH (9:1, 100 mL), before being washed with 2M NaOH (100 mL). The aqueous phase was extracted with CH2Cl2-MeOH (9:1, 2×100 mL), then the organic extracts were combined, dried (MgSO4), and concentrated to furnish the title compound: m/z (ES+)=285.0 [M+H]+.
Reaction SMILES: Br.[N:2]1([CH2:8][C:9]2[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=2)[S:12][CH2:13][CH2:14][CH2:15][N:16]2C(=O)C3=CC=CC=C3C2=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.O.NN>C(O)C.CCOCC>[N:2]1([CH2:8][C:9]2[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=2)[S:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1c2ccccc2C(=O)N1CCCSc1cccc(CN2CCCCC2)c1
Agent: Br
Agent: NN
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: NCCCSc1cccc(CN2CCCCC2)c1
Yield: 44.4 %

Procedure:
To a solution of N-{3-[3-(piperidinomethyl)thiophenoxy]propyl}phthalimide hydrobromide (58.0 g, 0.12 mole) [prepared in Step A] in 1650 mL of 95% ethanol was added hydrazine hydrate (26.9 g, 0.54 mole) and the reaction mixture was heated at 45° for 4.5 hours. The mixture was diluted with 500 mL of ether, filtered and the filtrate evaporated to dryness to give the title compound as an amber oil (14.1 g). An aliquot was distilled to a colorless oil, b.p. 154°-155°/0.15 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)(=[O:22])=[O:21])[C:5]([C:8]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)=O)=[N:6][CH:7]=1.O.[NH2:35][NH2:36]>C(O)C>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([NH:19][C:4]2[C:5]([C:8]3[C:10]4[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:12](=[O:14])[NH:36][N:35]=3)=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:21])=[O:22])=[CH:24][C:25]=1[C:30]([F:33])([F:32])[F:31]
Reactant: O=C(O)c1ccccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc(-c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c2ccccc12
Temperature: 25 °C
Yield: 67.1 %

Procedure:
A mixture of 2-[5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-benzoic acid (18 mg, 0.0347 mmol) and 2.3 mg of hydrazine hydrate in 1.0 ml of ethanol was refluxed for 4 hours. After cooled to room temperature the mixture was concentrated and the residue was purified via preparative TLC to afford 12 mg of title compound as a white powder. MS: (M+H)/z=515.2.
Reaction SMILES: [CH2:1]([O:4][NH:5][CH:6]1[CH2:11][NH:10][C@@H:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[CH:7]1)[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C.Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:4][N:5]1[C:27](=[O:29])[N:10]2[CH2:11][C@H:6]1[CH:7]=[C:8]([CH2:15][CH3:16])[C@H:9]2[C:12]([NH2:14])=[O:13])[CH:2]=[CH2:3]
Reactant: C=CCONC1C=C(CC)[C@H](C(N)=O)NC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C=CCON1C(=O)N2C[C@H]1C=C(CC)[C@H]2C(N)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 255.3 %

Procedure:
To a solution of (R)-5-(allyloxyamino)-3-ethyl-1,2,5,6-tetrahydropyridine-2-carboxamide (Intermediate 214, 0.35 g, 1.55 mmol) and diisopropylethyl amine (1.082 mL, 6.21 mmol) in acetonitrile (110 mL) at 0° C. was added triphosgene (0.157 g, 0.53 mmol) as a solution in acetonitrile (4 mL). The triphosgene solution was added at a rate of 4 mL/hour. Once addition was complete the reaction was stirred at 0° C. for ˜1 hour. The reaction mixture was diluted with ethyl acetate, then washed with saturated sodium bicarbonate and brine. The aqueous washes were extracted once with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-100% ethyl acetate/hexanes) afforded the title compound (0.340 g, 87%) as a colorless oil.
Reaction SMILES: [O:1]1[CH2:28][CH:2]1[CH2:3][N:4]1[C:23]([CH3:25])([CH3:24])[CH2:22][C:7]2([NH:11][C:10](=[O:12])[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:8]2=[O:21])[CH2:6][C:5]1([CH3:27])[CH3:26].[C:29]([OH:38])(=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35]>C1(C)C(C)=CC=CC=1>[OH:1][CH:2]([CH2:3][N:4]1[C:5]([CH3:26])([CH3:27])[CH2:6][C:7]2([NH:11][C:10](=[O:12])[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:8]2=[O:21])[CH2:22][C:23]1([CH3:25])[CH3:24])[CH2:28][O:35][C:34](=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][C:29]([O:38][CH2:28][CH:2]([OH:1])[CH2:3][N:4]1[C:23]([CH3:25])([CH3:24])[CH2:22][C:7]2([NH:11][C:10](=[O:12])[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:8]2=[O:21])[CH2:6][C:5]1([CH3:26])[CH3:27])=[O:37]
Reactant: CCCCCCCCN1C(=O)NC2(CC(C)(C)N(CC3CO3)C(C)(C)C2)C1=O
Reactant: O=C(O)CCCCC(=O)O
Solvent: Cc1ccccc1C
Product: CCCCCCCCN1C(=O)NC2(CC(C)(C)N(CC(O)COC(=O)CCCCC(=O)OCC(O)CN3C(C)(C)CC4(CC3(C)C)NC(=O)N(CCCCCCCC)C4=O)C(C)(C)C2)C1=O

Procedure:
A mixture of 4.3 g of 8-(2,3-epoxypropyl)-7,7,9,9-tetramethyl-3-octyl-1,3,8-triazaspiro[4.5]decane-2,4-dione and 0.74 g of adipic acid in 20 ml of xylene was refluxed for 16 hours. After completion of the reaction, the xylene was distilled from the reaction mixture in vacuo and the residue was purified by column chromatography through silica gel eluted with ethyl acetate, giving the desired Compound No. 328 in the form of a pale yellow oil. The compound had an Rf value of 0.46 on thin-layer chromatography when developed with ethyl acetate.
Reaction SMILES: ClCl.[Cl:3][C:4]1([C:7]([OH:23])([CH2:16][N:17]2[C:21]([SH:22])=[N:20][CH:19]=[N:18]2)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[CH2:6][CH2:5]1.[C-:24]#[N:25].[K+]>C(O)(=O)C.ClCCl>[Cl:3][C:4]1([C:7]([OH:23])([CH2:16][N:17]2[C:21]([S:22][C:24]#[N:25])=[N:20][CH:19]=[N:18]2)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[CH2:6][CH2:5]1
Reactant: [C-]#N
Reactant: OC(Cc1ccccc1Cl)(Cn1ncnc1S)C1(Cl)CC1
Agent: ClCl
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: N#CSc1ncnn1CC(O)(Cc1ccccc1Cl)C1(Cl)CC1
Temperature: 20 °C
Reaction time: 20 h
Yield: 65 %

Procedure:
At 20° C., chlorine gas is introduced into a mixture of 1.72 g (5 mmol) of 2-(1-chloro-cyclopropyl)-1-(2-chloro-phenyl)-3-(5-mercapto-1,2,4-triazol-1-yl)-propan-2-ol and 0.65 g (10 mmol) of potassium cyanide in 20 ml of acetic acid. The reaction mixture is stirred at 20° C. for 20 hours and then diluted with dichloromethane. The mixture is then extracted repeatedly with dilute aqueous sodium hydroxide solution and the organic phase is dried over sodium sulphate and concentrated under reduced pressure. The product that remains is purified over silica gel using petroleum ether/ethyl acetate=1:1 as mobile phase. Concentration of the eluate gives 1.2 g (64% of theory) of 2-(1-chloro-cyclopropyl)-1-(2-chloro-phenyl)-3-(5-thiocyanato-1,2,4-triazol-1-yl)-propan-2-ol in the form of an oil.
Reaction SMILES: Br[CH:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[C:3]([C:5]1[S:19][C:8]2[C:9]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:10]=3[O:11][CH2:12][CH2:13][C:7]=2[CH:6]=1)=O.CC(C)=O.[NH2:31][C:32]([NH2:34])=[S:33]>>[Br:18][C:15]1[CH:16]=[CH:17][C:9]2[C:8]3[S:19][C:5]([C:3]4[N:31]=[C:32]([NH2:34])[S:33][C:2]=4[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])=[CH:6][C:7]=3[CH2:13][CH2:12][O:11][C:10]=2[CH:14]=1
Reactant: O=C(c1cc2c(s1)-c1ccc(Br)cc1OCC2)C(Br)c1ccccc1Cl
Reactant: NC(N)=S
Solvent: CC(C)=O
Product: Nc1nc(-c2cc3c(s2)-c2ccc(Br)cc2OCC3)c(-c2ccccc2Cl)s1
Temperature: 80 °C
Yield: 84.6 %

Procedure:
2-Bromo-1-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-2-(2-chlorophenyl)ethanone (ca. 2.3 mmol) was suspended in acetone (15 mL, 0.20 mol) and treated with thiourea (0.26 g, 0.0034 mol;). The mixture was sealed and heated at 80° C. for 3 h. After cooling to room temperature, the reaction mixture was concentrated, suspended in water and the solid was collected by filtration. The solid was rinsed with water to give 953 mg of 271 as a light yellow solid. 1H NMR (dmso-d6, 500 MHz) δ 7.64 (m, 1H), 7.53 (m, 2H), 7.45 (m, 1H), 7.35 (m, 1H), 7.23 (m, 1H), 7.17 (m, 1H), 6.47 (s, 1H), 4.19 (t, 2H), 2.95 (t, 2H). MS (ESI) 491.0