Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[NH:18]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH2:22][CH2:21][CH2:20][CH2:19]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([N:18]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:6]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: c1ccc2c(c1)CCCCN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1CCCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
A solution of 42.6 g (0.211 mol) of 2-chloro-4-nitrobenzoic acid is reacted with 420 ml of thionyl chloride (refluxed for 3 hours and the excess thionyl chloride removed). Toluene is added several times and the solvent removed. The residue is dissolved in 400 ml of CH2Cl2 and added dropwise to a cold (ice bath) solution of 28.2 g (0.192 mol) of 1,2,3,4-tetra-hydro-5H-1-benzazepine and 29.4 ml of triethylamine in 320 ml of dichloromethane. The mixture is stirred at room temperature overnight and is washed with H2O, 10% HCl and 10% NaHCO3. Activated carbon is added to the organic layer and the mixture is filtered through a layer of MgSO4. The solvent is removed under vacuum and the residue chromatographed on silica gel (in two batches) with ethyl acetate-CH2Cl2 (5:95) as eluent. The fractions containing product are combined and the solvent removed. The residue is dissolved in ethyl acetate and the solvent removed (foams). The residue is heated with hexane to give a solid (lumps broken up) and the mixture is filtered. The solid is washed with hexane and dried to give 59.9 g of 1,2,3,4-tetrahydro-1-(2-chloro-4-nitrobenzoyl)-5H-l-benzazepine as off-white crystals, m.p. 112°-114° C., mass spectrum (CI) 321 (MH+)
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([C:8](Cl)=[O:9])[CH2:5][CH2:4][O:3]1.CCOCC.[Mg+2].[Br-].[Br-].[CH3:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)=[O:22].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:29][C:26]1[CH:27]=[CH:28][C:23](/[C:21](/[OH:22])=[CH:20]/[C:8]([CH:6]2[CH2:5][CH2:4][O:3][C:2]([CH3:11])([CH3:1])[CH2:7]2)=[O:9])=[CH:24][CH:25]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: CC1(C)CC(C(=O)Cl)CCO1
Agent: [Br-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC(C(=O)/C=C(\O)c2ccc(Cl)cc2)CCO1
Reaction time: 8 h
Yield: 58.3 %

Procedure:
To a mixture of 2,2-dimethyltetrahydro-2H-pyran-4-carbonyl chloride (0.55 g, 3.14 mmol), magnesium bromide diethyl etherate (1.35 g, 5.23 mmol), and 4-chloroacetophenone (0.34 mL, 2.62 mmol) in 12 mL of DCM at RT was added dropwise DIEA (1.45 mL, 7.85 mmol). The mixture was stirred overnight and then diluted with 50 mL of DCM and washed with 1N HCl (100 mL) and brine (100 mL). The organic layer was dried over Na2SO4, concentrated, and the crude product was purified by silica gel chromatography (Thomson Scientific 25-g cartridge, 2-20% EtOAc/heptane in 10 column volumes) to give 0.45 g (58%) of the title compound as a light orange solid. The NMR of this compound shows that it exists in the enone form in CDCl3.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([S:16]([NH:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])(=[O:18])=[O:17])=[CH:15][C:9]=3[C:8]([N+:28]([O-:30])=[O:29])=[CH:7][C:6]=2[NH:5][CH2:4]1.Cl.[CH3:32][N:33]([CH3:49])[CH2:34][CH2:35][O:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41]([C:46](O)=[O:47])=[CH:40]2.CCN=C=NCCCN(C)C.CC1C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([S:16]([NH:19][NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])(=[O:17])=[O:18])=[CH:15][C:9]=3[C:8]([N+:28]([O-:30])=[O:29])=[CH:7][C:6]=2[N:5]([C:46]([C:41]2[NH:42][C:43]3[C:39]([CH:40]=2)=[CH:38][C:37]([O:36][CH2:35][CH2:34][N:33]([CH3:49])[CH3:32])=[CH:45][CH:44]=3)=[O:47])[CH2:4]1
Reactant: CC(C)(C)OC(=O)NNS(=O)(=O)c1ccc2c3c(cc([N+](=O)[O-])c2c1)NCC3CCl
Reactant: CN(C)CCOc1ccc2[nH]c(C(=O)O)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CN(C)CCOc1ccc2[nH]c(C(=O)N3CC(CCl)c4c3cc([N+](=O)[O-])c3cc(S(=O)(=O)NNC(=O)OC(C)(C)C)ccc43)cc2c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 94 %

Procedure:
A mixture of 119 (59.4 mg, 0.13 mmol), 5-[2-(dimethylamino)ethoxy]indole-2-carboxylic acid hydrochloride (48 mg, 0.17 mmol), EDCI (100 mg, 0.52 mmol), and TsOH (4.5 mg, 0.03 mmol) in DMA (2 mL) was stirred at room temperature for 4.5 h and then cooled to 0° C. Ice-cold aqueous NaHCO3 was added and the precipitate was filtered off, washed with water, and dried to give tert-butyl 2-{[1-(chloromethyl)-3-({5-[2-(dimethylamino)ethoxy]indol-2-yl}carbonyl)-5-nitro-1,2-dihydro-3H-benzo[e]indol-7-yl]sulfonyl}hydrazinecarboxylate (120) (84 mg, 94%) as a yellow solid: mp 175-180° C. (dec.); 1H NMR [(CD3)2SO] δ 11.72 (d, J=1.8 Hz, 1H), 9.85 (br s, 1H), 9.30 (v br s, 1H), 9.29 (s, 1H), 8.83 (d, J=1.5 Hz, 1H), 8.44 (d, J=8.9 Hz, 1H), 7.98 (dd, J=8.9, 1.7 Hz, 1H, 7.42 (d, J=8.9 Hz, 1H), 7.21 (d, J=1.6 Hz, 1H), 7.18 (d, J=2.4H, 1H), 6.95 (dd, J=8.9, 2.4 Hz, 1H), 5.02-4.96 (1,1H), 4.72 (dd, J=10.9, 2.4 Hz, 1H), 4.70-4.64 (m, 1H), 4.17-4.09 (m, 2H), 4.07 (t, J=5.9 Hz, 2H), 2.66 (t, J=5.7 Hz, 2H), 2.25 (s, 6H), 1.10 (br s, 9H). HRMS (FAB) calcd. for C3H3635ClN6O8S (MH+) m/z 687.2004, found 687.2002.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:32](=[O:33])[CH2:31][C:30](=[O:34])[NH:29][C:28]3[C:35]4[C:40]([CH:41]=[CH:42][C:27]2=3)=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:22][CH:21]=1>>[CH3:12][N:2]([CH3:1])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:32](=[O:33])[CH2:31][C:30](=[O:34])[NH:29][C:28]3[C:35]4[C:40]([CH:41]=[CH:42][C:27]2=3)=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:22][CH:21]=1)=[O:7]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: CN(C)c1ccccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Product: CN(C)c1ccccc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 81.8 %

Procedure:
2-Dimethylaminobenzoic acid (50 mg, 0.3 mmol) was treated with oxalyl chloride in the same manner as that of Example 40, and then by using the resultant together with 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.1 mmol) obtained in Example 1, (3), the title compound (38 mg, yield 82%) was obtained as pale yellow crystals in the same manner as that of Example 1, (4).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=3)=[N:14][O:15][C:16]=2/[CH:17]=C/C2C=CC=CC=2)=[N:6][CH:5]=1.I([O-])(=O)(=O)=[O:35].[Na+].C(OCC)(=O)C.CCCCCCC>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=3)=[N:14][O:15][C:16]=2[CH:17]=[O:35])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2/C=C/c2ccccc2)nc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: O
Product: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2C=O)nc1
Yield: 60.6 %

Procedure:
6-[3-(3,4-Difluoro-phenyl)-5-([E]-styryl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (5.0 g, 11.2 mmol), osmium(VIII) oxide (70.9 mg, 0.28 mmol), sodium metaperiodate (9.54 mg, 44.6 mmol), benzyltriethylammonium chloride (1.04 mg, 4.46 mmol) in dioxane (75 mL) and water (25 mL) were heated for 15 min at 120° C. in a microwave. Addition of water and extraction with ethyl acetate and chromatography (silica, ethyl acetate:heptane=1:4 to 1:1) afforded the title compound (2.54 g, 61%) as a white solid. MS: m/e=375.1 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:36])[C@@H:4]([NH:23][C:24]([C:26]1([CH2:31][CH2:32][N:33]=[N+:34]=[N-:35])[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:21])=[CH:8][CH:7]=1.[OH-].[Na+]>C1COCC1.C(O)C.O>[N:33]([CH2:32][CH2:31][C:26]1([C:24]([NH:23][C@@H:4]([CH2:5][C:6]2[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:22])[C:14]3[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=3[Cl:20])=[CH:10][CH:11]=2)[C:3]([OH:36])=[O:2])=[O:25])[CH2:30][CH2:29][CH2:28][CH2:27]1)=[N+:34]=[N-:35]
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)C1(CCN=[N+]=[N-])CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: [N-]=[N+]=NCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)CCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.1 %

Procedure:
To a suspension of (S)-2-[[1-(2-azidoethyl)cyclopentanecarbonyl]amino]-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid methyl ester (14.77 g, 27.7 mmol) in THF (200 mL) and ethanol (200 mL) was added aqueous 1.0N sodium hydroxide (150 mL) at room temperature. The mixture was stirred for 15 h at room temperature at which time TLC analysis of the mixture indicated the absence of starting material. Then, it was diluted with water (20 mL) and the THF and ethanol were removed by rotary evaporation and diluted with 100 mL of water and extracted with ether (200 mL) to remove any neutral impurities. The aqueous layer was neutralized with 1N HCl and the resulting white solids were collected by filtration and washed with water and hexanes. After air-drying, 13.37 g (93% yield) of (S)-2-[[1-(2-azidoethyl)cyclopentanecarbonyl]amino]-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid was obtained as a white solid. ES(+)-HRMS m/e calcd. for C24H25Cl2N5O4 (M+Na)+ 540.1176, obsd. 540.1177.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][C:20](OS(C(F)(F)F)(=O)=O)=[CH:21][C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Cl-].[Li+]>O1CCOCC1.O.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>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][C:20]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:21][C:15]=3[O:14]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3ccc(OS(=O)(=O)C(F)(F)F)cc3O2)cc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCC2Cc3ccc(-c4ccccc4)cc3O2)cc1
Temperature: 90 °C
Yield: 10.1 %

Procedure:
To a solution of (±)-(6-hydroxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (8.67 g, 27.2 mmol) in anhydrous dichloromethane (300 mL) at 0° C. was added diisopropylethylamine (4.22 g, 32.6 mmol) followed by trifluoromethanesulfonic anhydride (8.45 g, 29.9 mmol) and the reaction mixture was allowed to stir at 0° C. for 1 h. The reaction mixture was quenched with water (300 mL) and diluted with dichloromethane (400 mL), The combined organic layers were washed with saturated aqueous sodium chloride, dried (magnesium sulfate), and the solvent removed in vacuo to provide a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:4→2:3) afforded 10.3 g (84%) of (±)-(6-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a tan solid. To a solution of (±)-(6-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.0 g, 4.43 mmol) in dioxane (50 mL) was added phenylboronic acid (1.08 g, 8.86 mmol), tetrakis(triphenylphosphine)palladium(0) (1.0 g, 0.884 mmol), and lithium chloride (0.787 g, 17.43 mmol) and the reaction mixture was heated at 90° C. for 12 h. The reaction mixture was cooled to room temperature and diluted with water (500 mL) and ethyl acetate (500 mL). The organic layer was separated and washed with water (200 mL), saturated aqueous sodium chloride (200 mL), dried (magnesium sulfate) and the solvent removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:9) provided 0.170 g (10%) of (±)-(6-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as an oil. 1H NMR (DMSO d6) δH 7.75 (d, 2H); 7.56 (d, 2H); 7.42 (m, 4H); 7.28 (t, 1H); 7.21 (d, 1H); 7.08 (d, 1H); 6.92 (s, 1H); 4.98 (m, 1H); 4.24 (dd, 1H); 4.18 (q, 1H); 3.29 (dd, 1H); 2.88 (dd, 1H); 2.46 (s, 3H).
Reaction SMILES: Cl.[F:2][C:3]([F:34])([F:33])[C:4]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10](/[CH:13]=[C:14]2/[C:15]([NH:20][CH2:21][C:22](O)=[O:23])=[N:16][C:17](=[O:19])[S:18]/2)[CH2:9][CH2:8]1.C(N(C(C)C)C(C)C)C.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.F[P-](F)(F)(F)(F)F.C(C(=NO[C+](N(C)C)N1CCOCC1)C(OCC)=O)#N>CN(C=O)C.O>[F:34][C:3]([F:2])([F:33])[C:4]1[CH:28]=[C:27]([C:29]([F:31])([F:32])[F:30])[CH:26]=[CH:25][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10](/[CH:13]=[C:14]2/[C:15]([NH:20][CH2:21][C:22]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[O:23])=[N:16][C:17](=[O:19])[S:18]/2)[CH2:9][CH2:8]1
Reactant: O=C(O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: C1COCCN1
Agent: CCOC(=O)C(C#N)=NO[C+](N(C)C)N1CCOCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCC(=O)N2CCOCC2)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[(5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]piperidin-4-yl}methylidene)-2-oxo-2,5-dihydro-1,3-thiazol-4-yl]glycine hydrochloride (500 mg), N-ethyl-N-(1-methylethyl)propan-2-amine (0.49 mL) and morpholine (0.25 mL) in DMF (5 mL) was added (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (403 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate), and the solid was recrystallized from diisopropyl ether/heptane to give the title compound (160 mg).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][C:6]([NH:8][CH2:9][C:10]1[CH:31]=[CH:30][C:13]2[NH:14][C:15]3[S:16][C:17]([CH3:29])=[CH:18][C:19]=3[C:20]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)=[N:21][C:12]=2[CH:11]=1)=[O:7].[Li+].[OH-].Cl>C1COCC1.O>[CH3:29][C:17]1[S:16][C:15]2[NH:14][C:13]3[CH:30]=[CH:31][C:10]([CH2:9][NH:8][C:6](=[O:7])[CH2:5][CH2:4][C:3]([OH:32])=[O:2])=[CH:11][C:12]=3[N:21]=[C:20]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[C:19]=2[CH:18]=1
Reactant: COC(=O)CCC(=O)NCc1ccc2c(c1)N=C(N1CCN(C)CC1)c1cc(C)sc1N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2c(s1)Nc1ccc(CNC(=O)CCC(=O)O)cc1N=C2N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of N-[2-methyl-10-(4-methyl-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulen-7-ylmethyl]-succinamic acid methyl ester, prepared as described in the previous step, (80 mg, 0.18 mmol) in THF (1.5 mL) was added LiOH (14 mg) in water (0.5 mL). The solution was stirred at room temperature for 3 h, acidified with dilute HCl, and concentrated to dryness. LC-MS: m/z 442 (M+1 of the parent).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[CH:5]=[C:6]([CH:12]=1)[O:7][CH2:8][C:9]([OH:11])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:58][C:59]1[CH:64]=[CH:63][N:62]=[CH:61][CH:60]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[CH:5]=[C:6]([CH:12]=1)[O:7][CH2:8][C:9]([NH:58][C:59]1[CH:64]=[CH:63][N:62]=[CH:61][CH:60]=1)=[O:11]
Reactant: COC(=O)c1cc(Br)cc(OCC(=O)O)c1
Reactant: Nc1ccncc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc(OCC(=O)Nc2ccncc2)c1
Yield: 49.3 %

Procedure:
A solution of 2-(5-bromo-3-methoxycarbonyl-phenoxy)-acetic acid (10.6 g), TBTU (19.3 g) and HOBt (5.1 g) in dry DMF (50 ml) was treated with DIPEA (9.9 ml). The resulting solution was stirred under a nitrogen atmosphere and was then treated with 4-aminopyridine (3.6 g) after 30 min. The resulting mixture was stirred for 18 h and then concentrated at reduced pressure to give a yellow viscous gum which was partitioned between ethyl acetate and water. The aqueous layer was removed and the organic phase washed with further water, 1M sodium hydroxide solution, aqueous saturated ammonium chloride, water and dried with brine and over sodium sulphate. The organic phase was concentrated under reduced pressure giving the title compound as a yellow solid (6.60 g).
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9](=[O:20])[CH2:10][CH2:11][C:12]([O:14][CH:15]([CH2:18][OH:19])[CH2:16][OH:17])=[O:13])[O:5][C@@H:4]([N:21]2[C:31]3[N:30]=[C:28]([NH2:29])[NH:27][C:25](=[O:26])[C:24]=3[N:23]=[CH:22]2)[CH2:3]1.[C:32]([NH:42][C@H:43]([C:47](O)=[O:48])[CH:44]([CH3:46])[CH3:45])([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9](=[O:20])[CH2:10][CH2:11][C:12]([O:14][CH:15]([CH2:16][OH:17])[CH2:18][O:19][C:47](=[O:48])[C@H:43]([CH:44]([CH3:45])[CH3:46])[NH:42][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])=[O:13])[O:5][C@@H:4]([N:21]2[C:31]3[N:30]=[C:28]([NH2:29])[NH:27][C:25](=[O:26])[C:24]=3[N:23]=[CH:22]2)[CH2:3]1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](F)[C@@H](COC(=O)CCC(=O)OC(CO)CO)O2)c(=O)[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(CO)OC(=O)CCC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2′,3′-dideoxy-3′-fluoro-5′-O-[3-(1,3-dihydroxy-2-propyloxy carbonyl)-propanoyl] guanosine (1.3 g, 2.93 mmole), N-CBZ-L-valine (1.00 g, 4 mmole), HOBT (0.54 g, 4 mmole) and DMAP (48.8 mg, 0.4 mmole) was coevaporated two times with DMF and reduced to about 60 ml. DCC (0.91 g, 4.4 mmole) was added and the mixture was stirred for 72 hours at room temperature. The mixture was filtered and the solution evaporated under reduced pressure. Ethyl acetate (150 ml) was added and the organic phase washed twice with 5% acetic acid, 5% sodium hydrogen carbonate and water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Yield: 0.99 g
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=O)=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11](=[O:12])[N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:27])([F:26])[F:28])=[N:20][C:21]([C:22]([N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)=[O:24])=[C:15]2[CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCCC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 73.6 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (150 mg, 0.27 mmol), pyrrolidine (38.4 mg, 0.54 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (0.138 g, 0.54 mmol) were dissolved in 8 mL of dichloromethane under stirring, and triethylamine (0.25 mL, 1.62 mmol) was then added to the solution. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-oxo-3-[1-(pyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 12a (120 mg, yield 74%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:12](=[O:20])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cu](C#N)[C:22]#[N:23].O.N>N1C=CC=CC=1>[C:22]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:12](=[O:20])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1)#[N:23]
Reactant: O=C1CCCC(c2ccc(Cl)cc2)N1c1ccccc1
Reactant: N#C[Cu]C#N
Agent: N
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1ccc(C2CCCC(=O)N2c2ccccc2)cc1
Temperature: 240 °C
Reaction time: 19 h
Yield: 42.1 %

Procedure:
To 8.55 g of 6-(4-chlorophenyl)-1-phenyl-2-piperidone were added 5.58 g of copper cyanide and 14 ml of pyridine, and the mixture was heated with stirring at 240° C. for 19 hours. The mixture was treated with diluted ammonia water, and then extracted with ethyl acetate. The extracts were washed with water, dried and treated with activated charcoal. After removal of charcoal and the solvent, the residue was purified by silica gel column chromatography (solvent; ethyl acetate:n-hexane=1:1 to 3), and recrystallized from a mixture of ethyl acetate and isopropyl ether to give 3.48 g of 6-(4-cyanophenyl)-1-phenyl-2-piperidone as pale yellow prisms.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][CH2:19][CH:18]3[CH3:27])=[C:12]([O:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36].[OH-].[Na+].C(=O)([O-])O.[Na+]>CO.O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][CH2:19][CH:18]3[CH3:27])=[C:12]([O:28][S:29]([CH3:32])(=[O:30])=[O:31])[CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:33][CH2:34][C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)CCc1ccc(NCc2ccc(CN3c4ccccc4CCC3C)c(OS(C)(=O)=O)c2)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1CCc2ccccc2N1Cc1ccc(CNc2ccc(CCC(=O)O)c(F)c2)cc1OS(C)(=O)=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
To a solution of ethyl 3-[2-fluoro-4-({4-[(2-methyl-3,4-dihydroquinolin-1(2H)-yl)methyl]-3-[(methylsulfonyl)oxy]benzyl}amino)phenyl]propanoate (0.60 g, 1.07 mmol) in a mixture of methanol (3.0 mL) and tetrahydrofuran (6.0 mL) was added 1 N aqueous sodium hydroxide solution (2.14 mL, 2.14 mmol), and the mixture was stirred at 50° C. for 1 hr. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with 10% aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (gradient cycle A) to give a colorless oil. The obtained oil was dissolved in ethyl acetate, and the solution was neutralized with saturated aqueous sodium hydrogencarbonate solution, washed with saturated brine and dried to give the title compound (0.25 g, yield 56%) as a colorless oil.