Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.[CH:3]([OH:5])=O.[CH2:6]([O:13][C:14]1[C:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:20]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)C=C[C:15]=1[CH:16]=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>C(Cl)Cl.[O-]S([O-])=O.[Na+].[Na+].C[O-].[Na+]>[CH2:31]([O:30][C:20]1[C:21]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:14]([O:13][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:15]=[CH:16][C:3]=1[OH:5])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=CO
Reactant: O=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1OCc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: O=S([O-])[O-]
Solvent: ClCCl
Product: Oc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
Kolonits, P. et al., Acta Chim Hung. 113:367 (1983). A solution of 30% H2O2 (6 mL, 57.8 mmol) and 85% formic acid (32 mL, 600 mmol) was added dropwise to a solution of 2,3,4-tribenzyloxybenzaldehyde 10 (9.8 g, 23.1 mmol) in CH2Cl2 (50 mL) over 30 min at 0° C. After 1 h of stirring at 0° C., the reaction was stirred at room temperature for 24 h. The reaction was subsequently cooled to 4° C. and diluted with 10% (w/v) aqueous Na2SO3 (50 mL). The aqueous phase was washed with CH2Cl2 (3×40 mL). Drying and: concentration afforded a brown oil which was dissolved in a methanolic solution of NaOMe (30 mL, 0.1 N) and refluxed. After 10 min, the solution was cooled to 4° C. and acidified with 6 N HCl. MeOH was removed in vacuo. The mixture was diluted with H2O (15 mL) followed by extraction of the aqueous phase with benzene (3×40 mL). Drying and concentration afforded 11 (9.0 g, 95%) as a brown oil. 1H NMR (CDCl3): δ7.45-7.31 (m, 15 H), 6.65 (d, J=9 Hz, 1 H), 6.58 (d, J=9 Hz, 1 H), 5.28 (s, 1 H), 5.12 (s, 2 H), 5.11 (s, 2 H), 5.04 (s, 2 H). 13C NMR (CDCl3): δ146.0, 144.0, 142.0, 139.6, 137.3, 137.1, 136.8, 128.4, 128.3 (2), 128.2, 127.9, 127.7, 127.4, 110.4, 109.0, 75.6, 75.3, 71.7. Anal. Calcd for C27H24O4: C, 78.62; H, 5.87. Found: C, 78.71; H, 5.86. HRMS (FAB) calcd for. C27H24O4 (M+H+): 412.1675. Found: 412.1673.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:28])[O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17](CC2C=CC=CC=2)[CH2:16][CH2:15]3)=[CH:5][CH:4]=1>C(Cl)(Cl)Cl.CO>[CH3:1][N:2]([CH3:29])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:28])[O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH2:16][CH2:15]3)=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(NC(=O)Oc2ccc3c(c2)CCN3Cc2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN(C)c1ccc(NC(=O)Oc2ccc3c(c2)CCN3)cc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-yl 4-dimethylaminophenylcarbamate (30 mg, 77 μmol) using the same procedure employed for Example 123 (silica gel column chromatography: chloroform/methanol=99/1 to 90/10). The product was obtained as a white solid (4.0 mg, 17%) having the following characteristics.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6](C(O)=O)[CH2:5][CH2:4]1.CN(C)CCCN=C=NCC.Cl.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:41][C:42]1[C:50]([NH2:51])=[CH:49][CH:48]=[CH:47][C:43]=1[C:44]([NH2:46])=[O:45]>O1CCCC1.O>[NH2:41][C:42]1[C:50]([NH:51][CH:6]2[CH2:7][CH2:8][CH:3]([O:2][CH3:1])[CH2:4][CH2:5]2)=[CH:49][CH:48]=[CH:47][C:43]=1[C:44]([NH2:46])=[O:45]
Reactant: NC(=O)c1cccc(N)c1N
Reactant: COC1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC1CCC(Nc2cccc(C(N)=O)c2N)CC1
Reaction time: 1 h
Yield: 64 %

Procedure:
1.4 g (8.9 mmol) of 4-methoxycyclohexanecarboxylic acid were dissolved in 30 ml of tetrahydrofuran and, at 0° C., successively 1.9 g (1.8 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide×hydrochloride, 1.8 g (11.6 mmol) of N-hydroxybenzotriazole and 1.95 g (19.2 mmol) of triethylamine were added. The mixture was stirred for 1 hour. Then 2.0 g (8.9 mmol) of 2,3-diaminobenzamide×2 hydrochloride and 1.95 g (19.2 mmol) of triethylamine were added. The mixture was then stirred at 0° C. for 1 hour and at room temperature for 16 hours. The mixture was diluted with a large amount of water and extracted several times with ethyl acetate. The organic phases were combined, dried and concentrated in vacuo. 1.5 g of the product were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][C:16]([O:18]C)=[O:17])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:20].[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][C:16]([OH:18])=[O:17])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:20]
Reactant: COC(=O)C=Cc1ccc2nc(C)n(Cc3ccccc3Cl)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2ccc(C=CC(=O)O)cc2n1Cc1ccccc1Cl
Yield: 34.9 %

Procedure:
The above-mentioned crude methyl 1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acrylate (3.29 g) was dissolved in 20 ml of ethanol, and 10.1 g of a 5% sodium hydroxide aqueous solution were added thereto. The mixture was refluxed for 2 hours. The reaction solution was neutralized with a hydrochloric acid aqueous solution. The solvent was distilled off under reduced pressure, and the residue was purified through silica-gel chromatography (eluent: a mixture of chloroform and methanol at a ratio of from 9:1 to 6:1) to give 1.10 g of 1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acrylic acid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][N:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH2:6][CH2:5][C:4]2[N:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:3]1=2.C1C(=O)N([I:27])C(=O)C1>C(O)(C(F)(F)F)=O.CC(O)=O>[I:27][C:17]1[C:16]([OH:19])=[N:15][C:4]2[CH2:5][CH2:6][N:7]([C:9](=[O:14])[C:10]([F:13])([F:11])[F:12])[CH2:8][CH:2]([CH3:1])[C:3]=2[CH:18]=1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2nc(O)ccc21
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC1CN(C(=O)C(F)(F)F)CCc2nc(O)c(I)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.3 %

Procedure:
To a solution of 5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol hydrobromide (1.76 g, 6.79 mmol) in DCM (50 ml) and DMF (10 ml) was added Et3N (2.90 ml, 20.7 mmol) and TFAA (1.00 ml, 6.90 mmol). The mixture was stirred for 2 h at ambient temperature, concentrated in vacuo and parted between sat. aq. NaHCO3 and EtOAc. The organic phase was dried, concentrated in vacuo and purified by column chromatography to yield 1.46 g (77%) of 5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol. 1H-NMR (DMSO-d6) δ 11.43 (br s, 1H), 7.30 (m, 1H), 6.18 (m, 1H), 3.95-3.42 (m, 4H), 3.06-2.96 (m, 2H), 2.95-2.87 (m, 1H), 1.12 (2× d, 3H) ppm. A mixture of 5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol (1.36 g, 4.96 mmol) and NIS (1.12 g, 4.96 mmol) in TFA (2 ml) and AcOH (36 ml) was stirred at room temperature for 16 h. Evaporation of TFA and AcOH followed by chromatographic purification of the resulting residue gave 1.95 g (98%) of 3-iodo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol. 1H-NMR (CDCl3) δ 7.86 (s, 1H), 4.17-3.41 (m, 4H), 3.20-2.94 (m, 3H), 1.26 (2× d, 3H) ppm. A mixture of 3-iodo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol (50.0 mg, 125 μmol) and K2CO3 (17.3 mg, 125 μmol) in MeOH (10 ml) was heated at reflux for 4 h. The reaction mixture was concentrated in vacuo and purified by column chromatography rendering 20.2 mg (53%) of 3-iodo-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol. 1H-NMR (CDCl3) δ 7.90 (s, 1H), 3.09-2.80 (m, 7H), 1.28 (d, 3H) ppm.
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:54]([OH:56])=[O:55])[C@H:50]([CH2:52][CH3:53])[CH3:51])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37].[NH:57]1[C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[C:59]([CH2:66][CH2:67][NH-:68])=[CH:58]1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:54]([OH:56])=[O:55])[C@H:50]([CH2:52][CH3:53])[CH3:51])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:37])[CH3:38])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:57]1[C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[C:59]([CH2:66][CH2:67][NH-:68])=[CH:58]1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)C(C)C)C(=O)O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [NH-]CCc1c[nH]c2ccccc12
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(C)C)C(=O)O

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 92 mg of Z-Phe-His-OH, 79 mg of H-Leu-Val-Ile-2-(3-indolyl)-ethyl amide, 32 mg of HOBt and 44 mg of DCCI, the title compound is obtained after flash chromatography (65 g of silica gel 60, 40-63 μm, eluant system B7). Rf (B7)=0.34.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][O:44][CH2:45][CH3:46])=[C:37]([F:47])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[CH2:45]([O:44][CH2:43][CH2:42][O:41][C:38]1[CH:39]=[CH:40][C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:36][C:37]=1[F:47])[CH3:46]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCOCCOc1ccc(OB([O-])[O-])cc1F
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
Solvent: O
Solvent: CCO
Product: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 4-(2-ethoxyethoxy)-3-fluorophenyl borate (145 mg) and potassium carbonate (160 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (33 mg), and the mixture was refluxed for 7 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethanol/ethyl acetate=1:3) to give crystals, which were recrystallized from ethanol to give colorless crystals of 7-[4-(2-ethoxyethoxy)-3-fluorophenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 65) (244 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36]Br)[CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN1CCCC1=O>[CH2:22]([O:29][C:30]1[CH:31]=[C:32]([CH:33]=[CH:34][CH:35]=1)[CH2:36][N:15]1[CH:14]=[CH:13][N:12]=[C:11]1[C@H:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1])[CH3:10])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cccc([C@H](C)c2ncc[nH]2)c1C
Reactant: BrCc1cccc(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Cc1cccc([C@H](C)c2nccn2Cc2cccc(OCc3ccccc3)c2)c1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of the compound of Example 58 (90 mg, 0.45 mmol) and caesium carbonate (244 mg, 0.75 mmol) in 1-methyl-2-pyrrolidinone (1 ml) was added 1-(benzyloxy)-3-(bromomethyl)benzene (139 mg, 0.50 mmol). The reaction mixture was stirred at room temperature for 48 h and then filtered through a Whatman PTFE filter tube (5 μm).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[N:12]1[C:16]([CH2:17][NH2:18])=[CH:15][N:14]=[CH:13]1.[N:20]([CH3:23])=[C:21]=[O:22]>ClC(Cl)Cl>[CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[N:12]1[C:16]([CH2:17][NH:18][C:21]([NH:20][CH3:23])=[O:22])=[CH:15][N:14]=[CH:13]1
Reactant: CC1(C)CCc2ccccc2C1n1cncc1CN
Reactant: CN=C=O
Solvent: ClC(Cl)Cl
Product: CNC(=O)NCc1cncn1C1c2ccccc2CCC1(C)C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
To a stirred mixture of 5.1 parts of 1-(1,2,3,4-tetrahydro-2,2-dimethyl-1-naphthalenyl)-1H-imidazole-5-methanamine and 75 parts of trichloromethane were added 1.2 parts of isocyanatomethane. After stirring for 1 hour, the reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone and 2,2'-oxybispropane. The product was filtered off and dried, yielding 2.9 parts (46.4%) of N-[[1-(1,2,3,4-tetrahydro-2,2-dimethyl-1-naphthalenyl)-1H-imidazol-5-yl]-methyl]-N'-methylurea; mp. 120.1° C. (compound 2.54).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:14]=[CH:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[C:24]1([C:30]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[O:34][C:33]3[CH:35]=[CH:36][C:37]([S:39](Cl)(=[O:41])=[O:40])=[CH:38][C:32]=3[O:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][N:12]([S:39]([C:37]3[CH:36]=[CH:35][C:33]4[O:34][C:30]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)([C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)[O:31][C:32]=4[CH:38]=3)(=[O:40])=[O:41])[CH2:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Reactant: Clc1ccc(C2C=CNCC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2)N1CC=C(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 4.9 %

Procedure:
4-(4-Chlorophenyl)-1,2,3,4-tetrahydropyridine hydrochloride (19.37 mg, 0.10 mmol) was suspended in methylene chloride (2 ml). Ethyldiisopropylamine (0.035 ml, 0.20 mmol) was added and the solution was shaken for 10 minutes at room temperature. 2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl chloride (37.28 mg, 0.10 mmol) was added and the reaction was shaken at room temperature for 12 hours. Aqueous HCl (0.1 N, 1.0 ml) was added and the mixture shaken for 30 minutes, the aqueous layer removed and the organic phase concentrated and purified by preparative reverse phase HPLC (YMC, ODS-AQ packing; 20%→95% CH3CN/H2O) to yield the sulfonamide (2.6 mg, 5%).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:36])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=5)=[C:25]([F:35])[CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[F:35][C:25]1[CH:24]=[C:23]([C:20]2([C:17]3[N:13]4[CH2:14][CH2:15][S:16][C:10]([CH2:9][OH:8])([CH3:36])[CH2:11][C:12]4=[N:19][N:18]=3)[CH2:22][CH2:21]2)[CH:28]=[CH:27][C:26]=1[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5cccnc5)c(F)c4)CC3)n2CCS1
Agent: Cl
Solvent: CO
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5cccnc5)c(F)c4)CC3)n2CCS1
Yield: 86 %

Procedure:
A solution of the compound (517 mg, 1.0 mmol) obtained in Example 26-1), and 4 M hydrochloric acid (1,4-dioxane solution, 2 mL) in methanol (2 mL) was stirred at room temperature for 15 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (353 mg, 87%) as a colorless solid.
Reaction SMILES: [C:1]([C:3](=[N:15][O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:4]([N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)=[N:5][O:6][CH:7]([CH3:9])[CH3:8])#[N:2].Cl.[NH2:22][OH:23].C([O-])(=O)C.[Na+]>>[OH:23][NH:22][C:1]([C:3](=[N:15][O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:4]([N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)=[N:5][O:6][CH:7]([CH3:9])[CH3:8])=[NH:2]
Reactant: CC(C)CON=C(C#N)C(=NOC(C)C)n1cncn1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: CC(C)CON=C(C(=N)NO)C(=NOC(C)C)n1cncn1
Temperature: 50 °C
Reaction time: 3 h
Yield: 48.4 %

Procedure:
(6.04 mmol) of the 1-[2-cyano-2-isobutoxyimino-1-isopropoxyiminoethyl]-1H-1,2,4-triazole produced based on Example 1 were added 0.46 g (6.62 mmol) of hydroxylamine hydrochloride and 0.54 g (6.58 mmol) of sodium acetate, followed by stirring at 50° C. for 3 hours. The solvent in the reaction mixture was distilled off under reduced pressure. The resulting crystal was washed with water and isopropyl ether, to obtain 0.91 g (yield: 48%) of 1-[2-(N-hydroxyamidino)-2-isobutyloxyimino-1-isopropoxyiminoethyl]-1H-1,2,4-triazole.
Reaction SMILES: CC(CC(C)C)=O.[CH3:8][C:9]([NH2:17])([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.[Br:25][CH:26]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:27](Br)=[O:28]>O>[CH3:8][C:9]([NH:17][C:27](=[O:28])[CH:26]([C:30]([CH3:33])([CH3:32])[CH3:31])[Br:25])([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: CC(C)(C)C(Br)C(=O)Br
Solvent: CC(=O)CC(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(NC(=O)C(Br)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.8 %

Procedure:
Into a 500 ml four-necked flask, there were charged methylisobutylketone (150 ml), α,α-dimethylbenzylamine (33.8 g) and triethylamine (27.8 g), and α-bromo-tert-butylacetylbromide (64.5 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. After completion of the reaction, water (200 ml) was added thereto and the reaction mixture was gradually heated to remove methylisobutylketone, followed by cooling at room temperature. The precipitated crystals were filtered, washed with water, dried and recrystallized from ethanol to give N-(α,α-dimethylbenzyl)-α-bromo-tert-butylacetamide (61.5 g).
Reaction SMILES: OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC.Cl.[NH2:33][CH:34]1[C:40](=[O:41])[N:39]([CH3:42])[C:38]2[CH:43]=[CH:44][CH:45]=[CH:46][C:37]=2[C:36]2[CH:47]=[CH:48][CH:49]=[CH:50][C:35]1=2.[C:51](O)(=[O:55])[C@H:52]([CH3:54])[OH:53]>C1COCC1>[OH:53][C@@H:52]([CH3:54])[C:51]([NH:33][CH:34]1[C:40](=[O:41])[N:39]([CH3:42])[C:38]2[CH:43]=[CH:44][CH:45]=[CH:46][C:37]=2[C:36]2[CH:47]=[CH:48][CH:49]=[CH:50][C:35]1=2)=[O:55]
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Reactant: C[C@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@H](O)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydroxybenzotriazole (344 mg, 2.55 mmol), diisopropylethylamine (659 mg, 5.1 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (488 mg, 2.55 mmol) were added to a cooled (0° C.) solution of 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one hydrochloride (700 mg, 2.55 mmol) and L-(+)-lactic acid (252 mg, 2.8 mmol) in THF (7 ml) and stirred overnight at r.t. The solvent was evaporated, the residue was taken up in dichloromethane and washed with water. The organic phase was dried over Na2SO4 and evaporated. Upon chromatographic purification (silica gel, dichloromethane/methanol=1:0−9:1) the title compound (820 mg, quant.) was obtained as a white solid.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19][CH2:18]1)=[CH:13][C:12]([C:31]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([OH:39])=[C:33]([Cl:40])[CH:32]=1)=[CH:11][CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4].O.Cl>C1COCC1>[NH2:23][C@H:20]1[CH2:21][CH2:22][C@H:17]([NH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:31]4[CH:36]=[C:35]([O:37][CH3:38])[C:34]([OH:39])=[C:33]([Cl:40])[CH:32]=4)[CH:13]=3)[N:8]=[CH:7][C:6]=2[C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH2:18][CH2:19]1
Reactant: CCCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(OC)c3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(OC)c3)cc2c1N[C@H]1CC[C@H](N)CC1

Procedure:
To a suspension of tert-butyl (trans-4-((3-butyryl-6-(3-chloro-4-hydroxy-5-methoxyphenyl)quinolin-4-yl)amino)cyclohexyl)carbamate (36 mg, 0.063 mmol) in THF (3 mL) was added water (2 mL) and 6N aqueous HCl (2 mL). The resultant solution was heated at 65° C. for 4 h. The reaction mixture was cooled and concentrated. The resultant residue was triturated with diethyl ether. The residue was eluted through an ion-exchange column (using methanol and 7 N methanol in ammonia) to obtain the desired product (22 mg, 75%) as a yellow solid. 1H NMR (500 MHz, MeOD) δ 8.96 (s, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.02 (dd, J=8.7, 2.0 Hz, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.28 (d, J=2.1 Hz, 1H), 7.20 (d, J=2.1 Hz, 2H), 4.24-4.18 (m, 1H), 3.98 (s, 3H), 3.11-3.00 (m, 3H), 2.37 (d, J=12.9 Hz, 2H), 2.10 (d, J=12.2 Hz, 2H), 1.84-1.74 (m, J=7.4 Hz, 2H), 1.71-1.65 (m, J=12.6 Hz, 2H), 1.49-1.43 (m, 2H), 1.04 (t, J=7.4 Hz, 3H). ESI MS m/z 468 [C26H30ClN3O3+H]+; HPLC>99% (AUC), tR=10.17 min.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[CH:22])=[N:19][CH:20]=2)=[CH:11][CH:10]=1.Br[C:24]1[CH:25]=[N:26][C:27]([O:30][CH2:31][CH2:32][N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[N:28][CH:29]=1>CN(C=O)C.O.[Cu]I>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[C:22][C:24]3[CH:29]=[N:28][C:27]([O:30][CH2:31][CH2:32][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[N:26][CH:25]=3)=[N:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: Brc1cnc(OCCN2CCCC2)nc1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Clc1ccc(-c2ccc(C#Cc3cnc(OCCN4CCCC4)nc3)nc2)cc1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
Under an argon atmosphere 0.11 mL (0.79 mmol) triethylamine, 7 mg (0.01 mmol) tetrakis-triphenylphosphane-palladium and 1.3 mg (0.01 mmol) CuI are added successively to a solution of 56 mg (0.26 mmol) 5-(4-chloro-phenyl)-2-ethynyl-pyridine and 71 mg (0.26 mmol) 5-bromo-2-(2-pyrrolidin-1-yl-ethoxy)-pyrimidine in 3.0 mL DMF. The mixture is stirred for 20 min at 100° C. and at 300 Watt in the microwave. The reaction solution is diluted with 10 mL water and the aqueous phase is extracted with 20 mL EtOAc. The organic phase is extracted with saturated NaCl solution and dried over Na2SO4. The solvent is eliminated i.vac. and further purification is carried out by column chromatography with HPLC-MS.