Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH2:16][CH2:17][CH:18]=[C:19]([CH3:22])[CH2:20][CH3:21])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][O:13]2)=[CH:8][CH:7]=1.C([O-])(=[O:25])C.[Na+].C(OO)(=O)C>C(Cl)(Cl)Cl>[O:25]1[C:19]([CH3:22])([CH2:20][CH3:21])[CH:18]1[CH2:17][CH2:16][C:2]([CH3:1])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][O:13]2)=[CH:8][CH:7]=1
Reactant: CCC(C)=CCCC(C)=CCOc1ccc2c(c1)OCCC2
Reactant: CC(=O)[O-]
Agent: CC(=O)OO
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCC1(C)OC1CCC(C)=CCOc1ccc2c(c1)OCCC2
Reaction time: 0.25 h

Procedure:
A mixture of 118.8 g. of 7-(3,7-dimethyl-2,6-nonadienyloxy)-chromane, 26 g. of anhydrous sodium acetate in 910 ml. of chloroform is treated over a period of 1 hour with 80 g. of 40% peracetic acid while stirring and flushing with nitrogen at 0°-2°C. The resulting mixture is subsequently stirred for an additional 15 minutes. The mixture is washed successively with a saturated sodium chloride solution, 10% sodium bicarbonate 0.1-N sodium thiosulphate solution and water, dried over sodium sulphate and concentrated. By filtration over 600 g. of silica gel with hexane/ether (9:1) and subsequent molecular distillation, there is obtained 7-(6,7-epoxy-3,7-dimethyl-2-nonenyloxy)-chromane, nD20 = 1.5295.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[F:27][C:28]([F:35])([F:34])[CH:29]([OH:33])[CH2:30][CH2:31]O>ClCCl>[F:27][C:28]([F:35])([F:34])[CH:29]([OH:33])[CH2:30][CH2:31][I:25]
Reactant: OCCC(O)C(F)(F)F
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: OC(CCI)C(F)(F)F
Reaction time: 0.33 h
Yield: 72.6 %

Procedure:
A solution of triphenylphosphine (1.09 g, 4.16 mmol) in dichloromethane (14 mL) was treated with imidazole (0.283 g, 4.16 mmol) and iodine (1.06 g, 4.16 mmol), respectively, to give an orange suspension. A solution of 4,4,4-trifluoro-1,3-butanediol (0.500 g, 3.47 mmol) in dichloromethane (4 mL) was added to the suspension and stirred for 20 minutes. The solid was removed by filtration and the filtrate was concentrated under reduced pressure without heat to yield a black oil. The crude oil was purified by silica gel chromatography, eluting with 100% dichloromethane, to give the product as an oil (0.640 g, 72%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:10](=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:2]1
Reactant: CCCCCCCCCCCCCC=O
Reactant: c1ccc2[nH]ccc2c1
Product: CCCCCCCCCCCCCC(c1c[nH]c2ccccc12)c1c[nH]c2ccccc12
Yield: 80 %

Procedure:
The compound was prepared as described in example 2/4, reacting the indole with tetradecane aldehyde. Yield 80%.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1CCCCC1>C1C=CC=CC=1>[C:14]1([CH:13]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[C:10](=[O:12])[CH3:11])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: CSc1ccc(CC(C)=O)cc1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CSc1ccc(C(=Cc2ccccc2)C(C)=O)cc1

Procedure:
A solution of 1-(4-methylthiophenyl)-2-propanone [G. Y. Lesher, U.S. Pat. No. 4,517,192, May 14, 1985; L. M. Werfel et al, J. Med. Chem., 29, 924-36 (1986)] (11.2 g, 0.062 mol) and benzaldehyde (6.6 g, 0.062 mol) in benzene (75 ml) containing piperidine (200 mg) was heated at reflux for 24 hours. After cooling, the solvent was removed and the residue was purified by chromatography on silica gel using mixtures of ethyl acetate and toluene to give the ketone. This material was recrystallized from ethyl acetate and hexane to give 14 g (82%) of pure ketone as a crystalline solid: mp 91°-93° C. Anal. Calc'd. for C17H16OS (268.38): C, 76.08; H, 6.01; S, 11.95. Found: C, 76.15; H, 6.08; S, 11.79.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:27]=1.[CH3:28][O:29][CH2:30][C:31](Cl)=[O:32].CO.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C.O1CCCC1>[CH3:28][O:29][CH2:30][C:31]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:27]=1)=[O:32]
Reactant: COCC(=O)Cl
Reactant: Cc1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)cn4c3)c2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: COCC(=O)Nc1cn2cc(Oc3cccc(NC(=O)c4cccc(C)n4)c3)ccc2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 31.9 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-6-methylpyridine-2-carboxamide (300 mg, 0.835 mmol) in N,N-dimethylacetamide (5 mL) was added methoxyacetyl chloride (92.0 μL, 1.01 mmol), and the mixture was stirred at room temperature for 15 hr. Methanol, tetrahydrofuran and aqueous sodium carbonate solution were added to the reaction mixture, and the mixture was stirred at 60° C. for 17 hr. The reaction mixture was concentrated under reduced pressure, diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, 0%→85% ethyl acetate-hexane) to give the title compound (115 mg, 32%) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]([CH3:12])[CH3:11])[N:4]=1.C[O:14][C:15](=[O:27])[CH2:16][CH:17]1[C:21]2[CH:22]=[CH:23][C:24]([OH:26])=[CH:25][C:20]=2[O:19][CH2:18]1>>[CH:10]([S:9][C:5]1[N:4]=[C:3]([CH2:2][O:26][C:24]2[CH:23]=[CH:22][C:21]3[CH:17]([CH2:16][C:15]([OH:27])=[O:14])[CH2:18][O:19][C:20]=3[CH:25]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:12])[CH3:11]
Reactant: CC(C)Sc1cccc(CCl)n1
Reactant: COC(=O)CC1COc2cc(O)ccc21
Product: CC(C)Sc1cccc(COc2ccc3c(c2)OCC3CC(=O)O)n1
Yield: 83.5 %

Procedure:
2-Chloromethyl-6-isopropylsulfanyl-pyridine (20 mg, 0.10 mmol) obtained in Step C of Preparation Example 16 and (6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester (20 mg, 0.10 mmol) obtained in Preparation Example 52 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (30 mg, 84%).
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=2)[C:7](=[O:16])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>>[CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=2)[C:7](=[O:16])[CH:6]=[CH:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCC(=O)c2cc(F)c(F)cc21
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Product: C=CCn1ccc(=O)c2cc(F)c(F)cc21
Yield: 93.3 %

Procedure:
1-Allyl-6,7-difluoro-1,2,3,4-tetrahydro-4-oxoquinoline(13.3 g) and p-chloranil (29.3 g) were reacted in the same method as described in Preparation 1-B to give the white above-indicated compound(12.3 g).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].N1C=CC=CC=1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25].C(OCC)(=O)C>O1CCCC1>[CH2:11]([O:10][C:8]([C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]=1[NH:1][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][Br:19])=[O:9])[CH3:12]
Reactant: O=C(Cl)CCCCBr
Reactant: CCOC(=O)C1=C(N)CCCC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(NC(=O)CCCCBr)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
In 150 ml of tetrahydrofuran, 42.3 g of ethyl 2-aminocyclohex-1-enecarboxylate as synthesized in above Step 7-1-B was dissolved, to which 40 g of pyridine was added, and then 5-bromovaleryl chloride was dropped thereinto under cooling with ice. Stirring the system for an overnight at room temperature, ethyl acetate was added, followed by washing with saturated aqueous sodium hydrogencarbonate solution, 10% aqueous citric acid and saturated brine, and drying over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the residue was purified on silica gel column chromatography (n-hexane:ethyl acetate=8:1) to provide 76.6 g (92%) of 2-(5-bromopentanoylamino)-cyclohex-1-enecarboxylic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[Mg].[CH2:12]1[O:14][CH2:13]1.[Cl-].[NH4+]>C1COCC1>[CH2:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:12][CH2:13][OH:14])=[CH:3][CH:4]=1)[CH3:10]
Reactant: C1CO1
Reactant: CCSc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCSc1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
1-Bromo-4-(ethylthio)benzene (16.0 g) in THF (80 ml) was added dropwise to magnesium (1.82 g) to maintain gentle reflux. The resulting cloudy solution was cooled to 0° and ethylene oxide (6.6 g) in THF (10 ml) was added dropwise. The mixture was stirred at room temperature for 30 min and at reflux for 1 h. Saturated aqueous ammonium chloride (200 ml) was added and the mixture was extracted with ER (2×200 ml). The dried extracted was evaporated and the residue was purified by [C] eluting with cyclohexane-ER (7.3) to give the title alcohol (2.15 g). T.l.c. (cyclohexane-ER 1:1) Rf 0.4.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[N:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20](=[O:24])[NH:21]2)=[C:16]([CH3:25])[CH:15]=1)C1C=CC=CC=1.CCOCC>CCO.[Pd]>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[N:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20](=[O:24])[NH:21]2)=[C:16]([CH3:25])[CH:15]=1
Reactant: Cc1cc(OCCCCOCc2ccccc2)nc2[nH]c(=O)ccc12
Agent: [Pd]
Solvent: CCO
Solvent: CCOCC
Product: Cc1cc(OCCCCO)nc2[nH]c(=O)ccc12
Yield: 81.5 %

Procedure:
A sixth intermediate compound, 7-(4-Hydroxy-butoxy)-5-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one, was produced as follows: 7-(4-Benzyloxy-butoxy)-5-methyl-1H-[1,8]naphthyridin-2-one (7.31 g, 21.6 mmol) was hydrogenated using 20% Pd/C (1.0 g) in EtOH (100 mL). The product precipitated out of solution before the double bond was reduced. DMF (75 mL) was added and the mixture was heated to dissolve the solids. More 20% Pd/C (1.0 g) was added and the hydrogenation was continued, however the double bond was resistant to further hydrogenation under these conditions. The reaction mixture was filtered and the solvent was concentrated to give a slurry. Et2O was added and the solid was collected by filtration and dried to give 7-(4-hydroxy-butoxy)-5-methyl-1H-[1,8]naphthyridin-2-one (4.37 g, 17.6 mmol, 81%). 7-(4-Hydroxy-butoxy)-5-methyl-1H-[1,8]naphthyridin-2-one (3.0 g, 12.08 mmol) was hydrogenated using 20% Pd/C in acetic acid (mL) for x h. The reaction mixture was filtered and concentrated to give a mixture of the sixth intermediate compound and the corresponding acetylated compound. The mixture was suspended in MeOH (30 mL) and H2O (10 mL) and the pH was adjusted to 14 by addition of 50% aqueous NaOH. The mixture was warmed to 45° C. Glacial acetic acid was added to bring the pH to 7.5 and the MeOH was removed under reduced pressure. The resulting solid was filtered, washed with H2O and dried to give the sixth intermediate compound as a solid (2.78 g, 11.1 mmol, 92%). MS: APCI: M+1: 251.1 (Exact Mass: 250.13).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:21][N:5]2[C:6](=[O:20])[N:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)[CH2:8][C@@H:4]2[CH2:3]1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.CCN(CC)CC>C(Cl)Cl>[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:1][C@@H:2]2[CH2:21][N:5]3[C:6](=[O:20])[N:7]([C:9]4[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:17])[F:18])=[CH:11][CH:10]=4)[CH2:8][C@@H:4]3[CH2:3]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N[C@H]1C[C@H]2CN(c3ccc(OC(F)(F)F)cc3)C(=O)N2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N[C@H]2C[C@H]3CN(c4ccc(OC(F)(F)F)cc4)C(=O)N3C2)cc1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
A mixture of (6S,7aS)-6-Amino-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-3-one (example 20, step d) (80 mg, 0.266 mmol), 4-Methyl-benzenesulfonyl chloride (101 mg, 0.53 mmol) and NEt3 (100 mg, 0.99 mmol) in DCM (10 mL) was stirred at 10° C. overnight. The mixture was washed with water (5 mL×3), dried with anhydrous sodium sulfate and then purified with silica gel column chromatography (eluting with DCM/MeOH=150:1) to 58 mg (46%) of the title compound as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.72 (d, 2H, J=9 Hz), 7.31 (d, 2H, J=9 Hz), 7.24 (d, 2H, J=6 Hz), 7.04 (d, 2H, J=9 Hz), 6.00 (d, 1H, J=9 Hz), 4.07-4.00 (m, 1H) 3.76-3.74 (m, 2H), 3.49-3.36 (m, 2H), 3.22-3.19 (m, 1H), 2.47 (s, 3H), 2.23-2.15 (m, 1H), 1.55-1.44 (m, 1H); LC-MS: 456.1 [M+1]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][C@H:18]3[CH3:30])=[O:16])[CH2:11][CH2:10]2)[C:5]([N+:31]([O-:33])=[O:32])=[CH:4][N:3]=1.[N:34]1([CH2:40][CH2:41][OH:42])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH3:30][C@H:18]1[N:17]([C:15]([C@H:12]2[CH2:13][CH2:14][C@@H:9]([NH:8][C:6]3[C:5]([N+:31]([O-:33])=[O:32])=[CH:4][N:3]=[C:2]([O:42][CH2:41][CH2:40][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)[CH:7]=3)[CH2:10][CH2:11]2)=[O:16])[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]1
Reactant: OCCN1CCCCC1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)[C@H]1CC[C@@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)[C@H]1CC[C@@H](Nc2cc(OCCN3CCCCC3)ncc2[N+](=O)[O-])CC1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-tert-butyl 4-(cis-4-(2-chloro-5-nitropyridin-4-ylamino)cyclohexanecarbonyl)-3-methylpiperazine-1-carboxylate (0.4 g, 0.830 mmol) in toluene (8.30 mL) was added 2-(piperidin-1-yl)ethanol (0.536 g, 4.15 mmol), 18-crown-6 (0.329 g, 1.245 mmol), and cesium carbonate (0.811 g, 2.490 mmol). The reaction was purged with argon and stirred at 75° C. overnight. The mixture was diluted with EtOAc to about 50 mL total volume and washed sequentially with water (50 mL), brine (50 mL), and aqueous NH4Cl (2×50 mL). The organic layer was dried over sodium sulfate and concentrated to afford an orange residue. The residue was purified by silica gel chromatography (1-5% MeOH/DCM, 1% NH4OH) to afford (R)-tert-butyl 3-methyl-4-(cis-4-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarbonyl)piperazine-1-carboxylate as a tan solid (0.33 g, 69.2% yield). MS m/z=575.4 [M+H]. Calc'd for C29H46N6O6: 574.4.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].[S-:11][C:12]#[N:13].[K+].BrBr.C(=O)([O-])O.[Na+]>C(O)(=O)C>[F:1][C:2]1[C:3]([O:9][CH3:10])=[CH:4][C:5]2[N:6]=[C:12]([NH2:13])[S:11][C:7]=2[CH:8]=1
Reactant: COc1cc(N)ccc1F
Reactant: N#C[S-]
Agent: BrBr
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(=O)O
Product: COc1cc2nc(N)sc2cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.7 %

Procedure:
A suspension of 4-fluoro-3-methoxyaniline (1.00 g) and potassium thiocyanate (2.07 g) in acetic acid (20 mL) was stirred at room temperature for 20 min, and a solution of bromine (0.380 mL) in acetic acid (1 mL) was added thereto over 5 min. The reaction mixture was stirred at room temperature for 30 min, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (670 mg).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2)=[O:3].C(=O)([O-])[O-].[Na+].[Na+].[CH3:26][N:27]1[CH2:32][CH2:31][CH:30]([NH:33][CH3:34])[CH2:29][CH2:28]1>C(#N)C>[CH3:34][N:33]([C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2)=[O:3])[CH:30]1[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]1
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ccccc21
Reactant: CNC1CCN(C)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CN1CCC(N(C)C(=O)N2c3ccccc3NC(=O)c3ccccc32)CC1

Procedure:
Nine grams (0.033 mol) of 5-chlorocarbonyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 5.3 gm (0.05 mol) of sodium carbonate, and 5.2 gm (0.036 mol) of 1-methyl-4-methylamino-piperidine were refluxed in 150 ml of acetonitrile for 15 minutes under stirring. The mixture was filtered while hot, and then the filtrate was placed on a silica gel column and eluted first with acetonitrile and then with a methylene chloride/ethyl acetate/cyclohexane/methanol/ammonia (175:75:23:23:3) mixture. The desired fraction was concentrated by evaporation in vacuo, and the residue was recrystallized from acetonitrile.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]1[N:27]([C:40]2[CH:41]=[C:42]3[C:46](=[CH:47][CH:48]=2)[N:45]([CH3:49])[CH:44]=[CH:43]3)[C:28]([NH:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:29][N:30]=1)C1C=CC=CC=1.CN(C)CCN(C)C1C=C(N2C(S)=NN=C2C2C=C(C(C)C)C(O)=CC=2O)C=CC=1OC>>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]1[N:27]([C:40]2[CH:41]=[C:42]3[C:46](=[CH:47][CH:48]=2)[N:45]([CH3:49])[CH:44]=[CH:43]3)[C:28]([NH:31][C:32](=[O:39])[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[N:29][N:30]=1
Reactant: CC(C)c1cc(-c2nnc(NC(=O)c3ccccc3)n2-c2ccc3c(ccn3C)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: COc1ccc(-n2c(S)nnc2-c2cc(C(C)C)c(O)cc2O)cc1N(C)CCN(C)C
Product: CC(C)c1cc(-c2nnc(NC(=O)c3ccccc3)n2-c2ccc3c(ccn3C)c2)c(O)cc1O

Procedure:
A flask was charged with [5-(5-Isopropyl-2,4-dibenzyloxy-phenyl)-4-(1-methyl-1H-indol-5-yl)-4H-[1,2,4]triazol-3-yl]-phenyl-amine (0.33 mmol, 183 mg.), dichloromethane (10 mL), diisopropylethylamine (3 eq., 0.2 mmol), and benzoyl chloride (2 eq., 70 mg.), and the reaction was stirred for 16 hours. The organic solution was washed with saturated ammonium chloride (2×5 mL), dried and the product was purified by column chromatography to give N-(5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)benzamide and also N-benzoyl-N-(5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)benzamide. The N-benzoyl-N-(5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)benzamide was dissolved in methanol (5 mL), and 10% aqueous potassium carbonate (1 mL) was added, and the reaction was stirred for 16 hours. The solvent was then evaporated, and the solid was dissolved in ethyl acetate (10 mL), washed with water (2×5 mL), dried and evaporated to give more N-(5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)benzamide. The N-(5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)benzamide was hydrogenolyzed in a fashion analgous to N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)acetamide (Compound 4) to give N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)benzamide. MS: expected ion=467.2; observed ion=467.3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([NH2:12])=[O:11])[CH:5]=[N:4][C:3]=1[C:17]#[N:18].[NH2:19][C:20]1[CH:21]=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:17]([C:3]1[N:4]=[CH:5][C:6]([NH:8][C@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([NH2:12])=[O:11])=[N:7][C:2]=1[NH:19][C:20]1[CH:21]=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)#[N:18]
Reactant: CC(C)C[C@@H](Nc1cnc(C#N)c(Cl)n1)C(N)=O
Reactant: Nc1cnc2ccccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)C[C@@H](Nc1cnc(C#N)c(Nc2cnc3ccccc3c2)n1)C(N)=O
Reaction time: 20 h

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-4-methylpentanamide (70 mg, 0.261 mmol), 3-aminoquinoline (60 mg, 0.416 mmol), K2CO3 (60 mg, 0.434 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 100 C for 20 h. Water and EtOAc were added. Organic phase was separated, dried over Na2SO4, concentrated in vacuo to give (R)-2-(5-cyano-6-(quinolin-3-ylamino)pyrazin-2-ylamino)-4-methylpentanamide as a crude residue (131 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](O)([C:30]([F:33])([F:32])[F:31])[CH2:10][C:11]([C:13]2[CH:28]=[CH:27][C:16]([C:17]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:18])=[C:15]([CH3:29])[CH:14]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1(C)C=CC=CC=1.C(OC(=O)C)(=O)C.C(N(CCCC)CCCC)CCC>CN(C)C1C=CN=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:30]([F:33])([F:32])[F:31])=[CH:10][C:11]([C:13]2[CH:28]=[CH:27][C:16]([C:17]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:18])=[C:15]([CH3:29])[CH:14]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NCc1ccccn1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Product: Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NCc1ccccn1
Temperature: 30 °C
Reaction time: 2.5 h
Yield: 85 %

Procedure:
0.78 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methyl-N-(pyridin-2-ylmethyl)benzoic acid amide, 4.3 g of toluene, 0.58 g of acetic anhydride, 20 mg of 4-dimethylaminopyridine, 0.40 g of tri-n-butylamine were fed and the mixture was stirred for 2.5 hours at 30° C. 2 ml of iced water was added to the reaction solution, and the reaction solution was concentrated under reduced pressure. The residue was passed through a column filled with silica gel, and the silica gel was washed with a small amount of 1:1 mixed solution of n-hexane:ethyl acetate. The organic phases were combined and the solvent was distilled off under reduced pressure to obtain 0.64 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methyl-N-(pyridin-2-ylmethyl)benzoic acid amide as a yellow solid.