Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][C:20]1([CH2:26][C:27]([NH:29][CH3:30])=[O:28])[CH2:23][S:22](=[O:25])(=[O:24])[CH2:21]1>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([NH:19][C:20]3([CH2:26][C:27]([NH:29][CH3:30])=[O:28])[CH2:23][S:22](=[O:25])(=[O:24])[CH2:21]3)=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: CNC(=O)CC1(N)CS(=O)(=O)C1
Product: CNC(=O)CC1(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)CS(=O)(=O)C1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example 48c) and 2-(3-amino-1,1-dioxo-thietan-3-yl)-N-methyl-acetamide (example 282a) as starting materials and isolated (56 mg, 76%); MS (ESI, m/z): 436.3 (M+H+).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:12](Cl)[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[C:15]1([CH:14]=[CH:13][CH2:12][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1nc[nH]n1
Reactant: ClCC=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C(=Cc1ccccc1)Cn1cncn1
Reaction time: 12 h

Procedure:
A mixture of 14 parts by weight of 1,2,4-triazole, 200 parts by weight of acetonitrile, 32 parts by weight of potassium carbonate and 39.2 parts by weight of cinnamyl chloride is stirred for 12 hours, and then filtered. The filtrate is concentrated, dissolved in dichloromethane, washed with water, evaporated and distilled. There is obtained 26 parts by weight of 1-(3-phenyl-2-propenyl)-1,2,4-triazole; b.p. (0.27 mbar): 130°-134° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[S:15][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:28]([O:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:29]>CC(C)=O>[C:28](=[O:29])([O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[S:15][C:14]([S:16](=[O:17])(=[O:18])[NH2:19])=[CH:13][CH:12]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1)[O:30][CH2:31][CH:32]([CH3:34])[CH3:33]
Reactant: CC(C)COC(=O)Cl
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)c2ccc(O)cc2)s1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)COC(=O)Oc1ccc(S(=O)(=O)c2ccc(S(N)(=O)=O)s2)cc1
Reaction time: 0.5 h

Procedure:
A solution of 5-[(4-hydroxyphenyl)sulfonyl]thiophene-2-sulfonamide (2.50 g; 0.00783 mole) in acetone (50 ml) at 0° was treated with triethylamine (0.87 g; 0.00861 mole) followed by isobutyl chloroformate (1.17 g; 0.00861 mole) dropwise, during 30 minutes at 0°-2°.
Reaction SMILES: O=[C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4]N1S(C1C=CC=CC=1)(=O)=O.O=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C([O-])(=O)C.[NH4+].[OH-].[Na+]>C(O)C>[C:8]([C:5]1[CH:6]=[N:7][CH:2]=[C:20]([CH:4]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22])#[N:9]
Reactant: N#Cc1cnc(=O)n(S(=O)(=O)c2ccccc2)c1
Reactant: CCOC(=O)C=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cncc(C#N)c1
Temperature: 25 °C
Yield: 68.7 %

Procedure:
31.4 g (120 mmol) of 2-oxo-1-(phenylsulfonyl)-1,2-dihydropyrimidine-5-carbonitrile and 10.2 g (100 mmol) of ethyl oxo-acetate were dissolved in 250 ml of ethanol, and allowed to undergo the reaction at 70° C. for 2 hours. 30.4 g (400 mmol) of ammonium acetate was added to the reaction solution to carry out the reaction at 90° C. for 4 hours. After completion of the reaction, this was cooled to room temperature, neutralized with 100 g (600 mmol) of 25% sodium hydroxide aqueous solution and then extracted twice with 40 ml of toluene. By concentrating the organic layer, 12.1 g (yield 68.7%) of the title compound was obtained (purity 98.2%, melting point 58-59° C.)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:21][C:22]1([CH3:34])[O:26][C@H:25]([CH2:27][CH2:28]OS(C)(=O)=O)[CH2:24][O:23]1>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:28][CH2:27][C@@H:25]3[CH2:24][O:23][C:22]([CH3:34])([CH3:21])[O:26]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1(C)OC[C@@H](CCOS(C)(=O)=O)O1
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Product: CC1(C)OC[C@@H](CCN2CCN(C(=O)/C=C/c3ccc(Cl)c(Cl)c3)CCC2=O)O1

Procedure:
In analogy to the procedure described for example 167A, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A]) and methanesulfonic acid 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl ester (prepared from 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethanol and methanesulfonyl chloride) gave after reaction at RT, the title compound as an off-white foam. MS: 441.1 (MH+, 2Cl).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:22]4[N:23]([N:37]=[CH:38][N:39]=4)[C:24]([C:27]4[CH:28]=[C:29]5[C:33](=[CH:34][CH:35]=4)[C:32](=[O:36])[NH:31][CH2:30]5)=[CH:25][N:26]=3)=[CH:16][CH:15]=2)[C:10](=[O:40])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.C([O-])(O)=O.[Na+]>[O:40]=[C:10]1[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21]2[C:22]3[N:23]([N:37]=[CH:38][N:39]=3)[C:24]([C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=3)[C:32](=[O:36])[NH:31][CH2:30]4)=[CH:25][N:26]=2)=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(-c4ccc5c(c4)CNC5=O)n4ncnc34)cc2)C(=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCc2cc(-c3cnc(Nc4ccc(N5CCNCC5=O)cc4)c4ncnn34)ccc21
Yield: 86.3 %

Procedure:
A solution of 3-oxo-4-{4-[5-(1-oxo-2,3-dihydro-1H-isoindol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (59 mg, 0.1 mmol) in 3:1 DCM:TFA (1.2 mL) is stirred at room temperature for 1 hour. The reaction mixture is diluted with DCM and basified with sat. NaHCO3. The aqueous layer is extracted with DCM (3×) and the organic layers are combined, dried over MgSO4, filtered and concentrated under vacuum to afford the title compound as a yellow solid (38 mg, 86%). 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 3.07 (2H, m), 3.44 (2H, s), 3.64 (2H, m), 4.50 (2H, s), 7.32 (2H, d), 7.83 (1H, d), 8.04-8.10 (4H, m), 8.22 (1H, s), 8.70 (1H, br s), 8.74 (1H, s), 10.25 (1H, s). LCMS: Rt 7.17 min (93.7%), m/z (APCI) 441 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[O:18].C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:17](=[O:18])[CH2:16][N:11]2[CH2:12][CH2:13][CH2:14][C@H:9]([CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:10]2)=[CH:20][CH:21]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: c1ccc(CC[C@H]2CCCNC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CN1CCC[C@H](CCc2ccccc2)C1)c1ccc(Cl)cc1
Reaction time: 12 h
Yield: 0 %

Procedure:
A solution of (S)-3-phenethyl-piperidine (4.23 mmol, 801 mg), 2-bromo-4′-chloroacetophenone (1.5 equiv, 6.35 mmol, 1.48 g) and K2CO3 (2.0 equiv, 8.46 mmol, 1.17 g) in CH3CN (10 mL) was heated to 60° C. and stirred for 12 h. The reaction mixture was quenched with H2O (25 mL) and then extracted with EtOAc (2×50 mL). The combined organics were dried with NaCl(sat) and Na2SO4(s). The solvents were removed in vacuo and chromatography (Isco Combi-Flash, 110 g cartridge, 9:1 Hexane-EtOAc) provided the desired product (0.556 mg, 1.45 mg theoretical, 38%) as a colorless oil: Rf 0.37 (SiO2, 5:1 hexane-EtOAc); LRMS m/z 342 (M++1, C21H24ClNO, requires 342).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=[CH:5][N:4]=1.[C:18]([O:22][C@@H:23]([C:29]1[C:44]([CH3:45])=[CH:43][C:32]2[N:33]=[C:34]([C:36]3[CH:41]=[CH:40][N:39]=[C:38](Cl)[CH:37]=3)[S:35][C:31]=2[C:30]=1[C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.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>[C:18]([O:22][C@@H:23]([C:29]1[C:44]([CH3:45])=[CH:43][C:32]2[N:33]=[C:34]([C:36]3[CH:41]=[CH:40][N:39]=[C:38]([C:8]4[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=4)[CH:37]=3)[S:35][C:31]=2[C:30]=1[C:46]1[CH:47]=[CH:48][C:49]([Cl:52])=[CH:50][CH:51]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:19])([CH3:20])[CH3:21]
Reactant: COc1ncccc1B1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
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: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4cccnc4OC)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A mixture of 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (13 mg, 0.0878 mmol), (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (31 mg, 0585 mmol) and 2M potassium carbonate solution (88 μL, 0.178 mmol) in dioxane (0.5 mL) was sparged with nitrogen for 10 minutes. Pd(PPh3)4 (6.9 mg, 0.0059 mmol) was added and reaction mixture was heated in microwave at 100° C. for 1 h . Reaction mixture was diluted with ethyl acetate, washed with brine. The aqueous layer was back extracted with ethyl acetate and the combined organic layer was dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 40% EtOAc/Hex) to give product. LCMS-ESI+: calc'd for C33H33ClN3O4S: 602.1 (M+H+); Found: 602.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([CH3:10])[CH:4]=1.C([Li])CCC.CN(C)[C:18](=[O:20])[CH3:19].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([CH2:10][C:18](=[O:20])[CH3:19])[CH:4]=1
Reactant: COc1cc(C)nc(C)c1
Reactant: CC(=O)N(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(C)nc(CC(C)=O)c1
Temperature: 0 °C

Procedure:
To a stirred solution of 4-methoxy-2,6-dimethylpyridine (1.56 g) in tetrahydrofuran (15 ml) was added a solution of n-butyllithium in n-hexane (1.63M, 9.1 ml) dropwise at −50° C. under a nitrogen atmosphere, and the mixture was warmed to 0° C. The mixture was cooled to −50° C., and N,N-dimethylacetamide (1.59 ml) was added dropwise. Then the mixture was warmed to room temperature, poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (100 ml×2). The combined organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 100 g, n-hexane:ethyl acetate=2:1) to give 1-(4-methoxy-6-methylpyridin-2-yl)propan-2-one (1.75 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:12]([NH:20][C:21]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[CH:8][CH:9]=[CH:10][N:11]=1)=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCCSCc1ncccn1
Reactant: O=C(N=C=S)c1ccccc1
Product: O=C(NC(=S)NCCSCc1ncccn1)c1ccccc1

Procedure:
By the procedure of Example 18, 2-[(2-aminoethyl)-thiomethyl]pyrimidine is reacted with benzoyl isothiocyanate to give N-benzoyl-N'-[2-(2-pyrimidylmethylthio)ethyl]thiourea. Removing the benzoyl group by the procedure of Example 18 gives N-[2-(2-pyrimidylmethylthio)ethyl]thiourea.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([NH2:23])[CH2:19][CH2:20][CH2:21][NH2:22].ClC1C=CC=CC=1Cl>O>[C:2]1([C:1]23[NH:23][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[C:11](=[O:13])[C:10]2[C:9]3=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCCN
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: O=C1c2ccccc2C2(c3ccccc3)NCCCCN12

Procedure:
22.6 Parts of o-benzoyl-benzoic acid and 10.1 parts of 1,4-butanediamine in 100 parts by volume of o-dichlorobenzene are heated within 2 hours to 179° whereby reaction water and a little dichlorobenzene azeotropically distill off. The solvent is then distilled off in vacuo whereupon an oil remains which spontaneously crystallises after some time. On recrystallising from benzene, the pure 11b-phenyl-1,2,3,4,5,11b-hexahydro-7H-[1,3]-diazepino[2,1-a]isoindol-7-one is obtained of the formula ##STR21## It melts at 180°-181°. On using o-(p'-chlorobenzoyl)-benzoic acid, 11b-(p-chlorophenyl)-1,2,3,4,5,11b-hexahydro-7H-[1,3]diazepino[2,1-a]isoindol-7-one is obtained in the same manner. It melts at 134°-135°.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[C:4](Cl)=[N:5][C:6]1[C:11]([F:12])=[CH:10][N:9]=[CH:8][C:7]=1F.NC(N)=[S:22].N1C=CC=CC=1.CCN(CC)CC>C(O)(C)C>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[C:4]1[S:22][C:7]2[CH:8]=[N:9][CH:10]=[C:11]([F:12])[C:6]=2[N:5]=1
Reactant: NC(N)=S
Reactant: Fc1cncc(F)c1N=C(Cl)c1c(F)cccc1Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Fc1cccc(Cl)c1-c1nc2c(F)cncc2s1
Temperature: 150 °C
Reaction time: 18 h
Yield: 41.3 %

Procedure:
A stirred suspension of 2-chloro-N-(3,5-difluoropyridin-4-yl)-6-fluorobenzimidoyl chloride (12.0 g, 39.4 mmol), thiourea (9.0 g, 118 mmol) and pyridine (12.7 mL, 198 mmol) in isopropanol (200 mL) was heated at 150° C. for 3.5 hours. After stirring for one additional hour, the resulting precipitate was collected by filtration. The filtrate was treated with Et3N (27 mL, 0.197 mol) and heating was continued at 150° C. for 18 hours. After cooling to room temperature, the volatiles were removed under reduced pressure and the resultant residue was partitioned between EtOAc (300 mL) and water (500 mL). The aqueous phase was extracted with EtOAc (2×300 mL) and the combined organic layers were dried and concentrated under reduced pressure. The resultant residue was purified by column chromatography on silica gel eluting with 0-100% Et2O in petroleum ether and then triturated with a mixture 3:1 diethyl ether:pentane (25 mL) to afford the title compound as a cream coloured solid (4.6 g, 41%). LCMS (Method F): RT=3.39 min, m/z: 283 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]2[NH:14]C(=O)N[C:11]2=[O:16])=[CH:5][C:4]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=[O:32]>C(O)(=O)C.CO.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([C:11]([OH:16])=[O:32])[NH2:14])=[CH:5][C:4]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: COc1ccc(CC2NC(=O)NC2=O)cc1OCc1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc(CC(N)C(=O)O)cc1OCc1ccccc1

Procedure:
This compound is prepared from the corresponding hydantoin derivative (Example 7) by a procedure similar to that in Example 9; tlc (1:5:20 acetic acid-methanol-chloroform system); Rf 0.4 (ninhydrin).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]([OH:13])=O)[NH:3]1.[C:14]1([C:20]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:24]3[CH2:25][NH:26][CH2:27][CH2:28][N:23]3[C:22](=[O:29])[O:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(N(CC)CC)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]([N:26]2[CH2:27][CH2:28][N:23]3[C:22](=[O:29])[O:21][C:20]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:24]3[CH2:25]2)=[O:13])[NH:3]1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Reactant: O=C1NC(C(=O)O)c2ccccc21
Solvent: CCN(CC)CC
Product: O=C1NC(C(=O)N2CCN3C(=O)OC(c4ccccc4)(c4ccccc4)C3C2)c2ccccc21
Yield: 14 %

Procedure:
In the same manner as in Reference Example 19, the reaction was performed using 2,3-dihydro-3-oxo-1H-isoindole-1-carboxylic acid instead of 1,4-bis(phenylmethyl)-2-piperazine carboxylic acid, and using hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one instead of N,O-dimethylhydroxylamine hydrochloride and triethylamine. The reaction solution was extracted with ethyl acetate, washed with a 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue was added hexane-ethyl acetate. Then, the obtained crystals were collected by filtration and washed with hexane to obtain the title compound. Yield 14%.
Reaction SMILES: [N:1]([CH:4]1[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1)=[N+:2]=[N-:3].[CH3:14][Si:15]([CH3:20])([CH3:19])[C:16]#[C:17]C>>[O:11]1[C:7]2([CH2:6][CH2:5][CH:4]([N:1]3[CH:17]=[C:16]([Si:15]([CH3:20])([CH3:19])[CH3:14])[N:3]=[N:2]3)[CH2:13][CH2:12]2)[O:8][CH2:9][CH2:10]1
Reactant: CC#C[Si](C)(C)C
Reactant: [N-]=[N+]=NC1CCC2(CC1)OCCO2
Product: C[Si](C)(C)c1cn(C2CCC3(CC2)OCCO3)nn1
Reaction time: 2 h

Procedure:
A mixture of 8-azido-1,4-dioxa-spiro[4.5]decane (1.00 g, 5.43 mmol) and 1-(trimethylsilyl)propyne (3.76 mL, 27.1 mmol) is submitted to microwave at 120° C. for 2 h. The mixture is concentrated under vacuum to remove the excess of 1-(trimethylsilyl)propyne and crude 1-(1,4-dioxa-spiro[4.5]dec-8-yl)-4-trimethylsilanyl-1H-[1,2,3]triazole is obtained.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2([CH2:33][C:34](O)=[O:35])[S:13](=[O:15])(=[O:14])[CH2:12][CH2:11][N:10]([C:16]([O:18][CH2:19][CH:20]3[C:32]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:26]4[C:21]3=[CH:22][CH:23]=[CH:24][CH:25]=4)=[O:17])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[O:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]1[O:43][NH2:44].ON1C2C=CC=CC=2N=N1>CN(C)C=O>[O:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]1[O:43][NH:44][C:34](=[O:35])[CH2:33][C:7]1([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)[S:13](=[O:14])(=[O:15])[CH2:12][CH2:11][N:10]([C:16]([O:18][CH2:19][CH:20]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[C:27]3[C:32]2=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:17])[CH2:9][CH2:8]1
Reactant: NOC1CCCCO1
Reactant: O=C(O)CC1(c2ccc(Br)s2)CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CCS1(=O)=O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CC1(c2ccc(Br)s2)CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CCS1(=O)=O)NOC1CCCCO1
Reaction time: 8 h
Yield: 67 %

Procedure:
To a solution of 2-[7-(5-bromo-2-thienyl)-4-(9-fluorenylmethoxycarbonyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetic acid (400 mg), O-(2-tetrahydropyranyl)-hydroxylamine (95.2 mg) and 1-hydroxybenzotriazole (110 mg) in N,N-dimethylformamide (10 ml) was added WSCD-HCl (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) (156 mg) at room temperature. After being stirred at the same temperature overnight, the mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (30 ml) and the solution was washed successively with 5% aqueous citric acid solution, a saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by SiO2 column chromatography (eluent; 1% MeOH in chloroform (CHCl3)) to afford N-(2-tetrahydropyranyloxy)-2-[7-(5-bromo-2-thienyl)-4-(9-fluorenylmethoxycarbonyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (313 mg) as an amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C@@H:10]2[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([O:33]C)=[O:32])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[C:19]([O:18][C:16]([N:12]1[CH2:11][C@H:10]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([OH:33])=[O:32])[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:15][CH2:14][CH2:13]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)c1ccccc1OC[C@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@@H](COc2ccccc2C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
To a solution of tert-butyl (6R*,7R*)-7-(3,4-dichlorophenyl)-6-{[2-(methoxycarbonyl)phenoxy]methyl}-1,4-oxazepane-4-carboxylate (160 mg) in methanol (2 mL) was added 8 N aqueous sodium hydroxide solution (1 mL) at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (110 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[S:12][C:11]([S:13]([NH:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)(=[O:15])=[O:14])=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:47]([O:55][CH3:56])(=[O:54])[CH2:48][CH2:49][CH2:50][C:51]([O-])=[O:52].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:7][C:5]1[N:6]=[C:2]([NH:1][C:51](=[O:52])[CH2:50][CH2:49][CH2:48][C:47]([O:55][CH3:56])=[O:54])[S:3][C:4]=1[C:8]1[S:12][C:11]([S:13]([NH:16][CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)(=[O:15])=[O:14])=[CH:10][CH:9]=1
Reactant: Cc1nc(N)sc1-c1ccc(S(=O)(=O)NCCN2CCOCC2)s1
Reactant: COC(=O)CCCC(=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)NCCN3CCOCC3)s2)s1
Temperature: 25 °C
Reaction time: 72 h
Yield: 60.3 %

Procedure:
To a degassed solution of 5-(2-amino-4-methyl-1,3-thiazol-5-yl)-N-(2-morpholin-4-ylethyl)thiophene-2-sulfonamide (6) (100 mg; 0.22 mmol; 1 eq) in anhydrous THF (10 ml), N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (104.4 mg; 0.33 mmol; 1.50 eq), mono-methyl glutarate (68 μl; 0.54 mmol; 2.50 eq) and N,N-diisopropylethylamine (148 μl; 0.87 mmol; 4 eq) are added successively. The reaction mixture is stirred at room temperature for three days. Solvents are evaporated under vacuum. The resulting crude product is dissolved in EtOAc and washed with NH4Cl sat. solution, water, brine and dried over MgSO4. After evaporation of the solvents, the crude product is purified by flash chromatography (CH3C1/MeOH gradient from 1/0 to 1/1 over 40 min), affording Compound (7) as a yellow solid (68.5 mg; 61.18%).