Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].[CH:3]([C:5]1[CH2:11][C:10]2[CH:12]=[C:13]3[O:18][CH2:17][O:16][C:14]3=[CH:15][C:9]=2[C:8]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[N:7][N:6]=1)=[O:4]>O.O1CCOCC1.[N+]([O-])([O-])=O.[Ag+]>[N+:25]([C:22]1[CH:21]=[CH:20][C:19]([C:8]2[C:9]3[CH:15]=[C:14]4[O:16][CH2:17][O:18][C:13]4=[CH:12][C:10]=3[CH2:11][C:5]([C:3]([OH:1])=[O:4])=[N:6][N:7]=2)=[CH:24][CH:23]=1)([O-:27])=[O:26]
Reactant: [OH-]
Reactant: O=CC1=NN=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2C1)OCO3
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C1=NN=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2C1)OCO3
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
42 ml of a 4% NaOH solution is added to a solution of 3.0 g of AgNO3 in water (50 ml). The solution of 3.0 g of 8-formyl-5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h-][2,3]-benzodiazepine in 120 ml of dioxane is slowly added to the heterogeneous mixture, and the reaction mixture is stirred for 30 minutes at 25° C. After activated carbon is added, it is filtered, the filtrate is concentrated by evaporation in a vacuum at 50-60° C., the suspension that is produced is diluted with 30 ml of water and cooled. After standing overnight, it is filtered off, the precipitate is washed with 2×10 ml of ice water, and 1.94 g of sodium salt, which is dissolved in 60 ml of hot water and, after cooling, acidified with 1 ml of acetic acid, is obtained. After filtration and washing with water, 1.66 g (53%) of product with a melting point of 196-198° C. (decomposition) is obtained.
Reaction SMILES: N[CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:21]([OH:23])=[O:22])=[C:6](CSC3N(CS(O)(=O)=O)N=NN=3)[CH2:7][S:8][C@H:3]12.[OH-].[Na+].C(=O)(O)[O-].[Na+].Cl.C(O)(=O)C.C(O)(=O)C.[CH:42]1([NH:48][CH2:49][CH2:50][NH:51][CH:52]2[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]2)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>O.C(O)(C)C>[CH:52]1([NH:51][CH2:50][CH2:49][NH:48][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57]1.[S:8]1[C@@H:3]2[CH2:2][C:24](=[O:25])[N:4]2[C:5]([C:21]([OH:23])=[O:22])=[CH:6][CH2:7]1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CS(=O)(=O)O)CS[C@H]12
Agent: C1CCC(NCCNC2CCCCC2)CC1
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: O
Solvent: CC(C)O
Product: O=C(O)C1=CCS[C@@H]2CC(=O)N12
Temperature: 7.5 °C
Reaction time: 2.5 h
Yield: 286.7 %

Procedure:
7-amino-3-(sulfomethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (5 g), was dissolved in water (19 ml) using 30% w/w sodium hydroxide (1.5 g in 8 ml water) and sodium bicarbonate (1 g), O-formylmandeloyl chloride (2.45 g) was added at 0-5° C. and maintained at 5-10° C. over a period of 1-2 hours. After the completion of reaction, the reaction mixture was acidified with conc. HCl (2.6 g) and maintained the reaction at 28-30° C. for about 2-3 hours. After the completion of reaction, sodium bicarbonate (˜3.5 g) was added to set the pH 5±1 and the solution was added to a solution of N,N′-dicyclohexylethylenediamine diacetate (9.26 g) in water (40 mL) and isopropyl alcohol (40 mL) and stirred well at 25-30° C. for about 2-3 hours. The reaction mixture was cooled to 5-10° C., filtered, washed with chilled water (0-5° C.) and isopropyl alcohol (0-5° C.) and dried the material under vacuum at ˜40° C. to get N,N′-dicyclohexylethylenediamine salt of 7-D-mandelamido-3-(1-sulfomethyl-1H-tetrazol-5-yl)thio)methyl)-3-cephem-4-carboxylic acid (6.5 g). Step-(ii)
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[B:19]1(B2OCC(C)(C)CO2)[O:24]CC(C)(C)C[O:20]1.C([O-])(=O)C.[K+]>CS(C)=O>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C@H:10]2[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11]2)=[CH:3][C:2]=1[B:19]([OH:24])[OH:20]
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Reactant: COC(=O)[C@H]1CC[C@H](c2ccc(OC)c(I)c2)C1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)[C@H]1CC[C@H](c2ccc(OC)c(B(O)O)c2)C1
Temperature: 80 °C

Procedure:
A mixture of methyl trans-3-(3-iodo-4-methoxyphenyl)cyclopentanecarboxylate (Step C) (64 mg, 0.178 mmol), bis(neopentyl glycolato)diboron (48.2 mg, 0.213 mmol), potassium acetate (100 mg, 1.019 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (10 mg, 0.012 mmol) in DMSO (3 ml) was degassed flushing with nitrogen and heated at 80° C. for 1 hour. Then, added ethyl acetate and washed with water followed by brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc in hexanes to afford the titled compound. 1H NMR (500 MHz, CDCl3): δ 7.71 (d, J=2.5 Hz, 1H); 7.29 (m, 1H); 6.85 (m, 1H); 6.10 (s, 2H); 3.90 (s, 3H); 3.70 (s, 3H); 3.19 (m, 1H); 3.02 (m, 1H); 2.35 (ddd, J=13.3, 8.0, 4.6 Hz, 1H); 2.19-2.11 (m, 2H); 2.01-1.85 (m, 2H); 1.72-1.63 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]2[C:21]3[N:28]([CH2:29][CH2:30][O:31][CH2:32][CH2:33]O)[CH:27]=[CH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=O)=O.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]2[C:21]3[N:28]([CH2:29][CH2:30][O:31][CH2:32][CH2:33][S:43][CH3:42])[CH:27]=[CH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1
Reactant: OCCOCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSCCOCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Reaction time: 1 h

Procedure:
The compound (150 mg) of Example 147 was dissolved in tetrahydrofuran (10 mL) and triethylamine (1.50 mL) and methanesulfonyl chloride (0.70 mL) were added under ice-cooling, and the mixture was stirred for 1 hr. Saturated aqueous sodium hydrogen carbonate was added to this reaction solution under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated, and the residue was dissolved in a mixed solvent of N,N-dimethylformamide (5.0 mL) and tetrahydrofuran (4.0 mL). Sodium methanethiolate (180 mg) was added, and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated. The residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0→ethyl acetate:methanol=90:10) to give the title compound (123 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([O:12][CH3:13])[CH:3]=1.B(Br)(Br)Br.O>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]2[O:10][CH2:11][CH2:13][O:12][C:4]=2[CH:3]=1
Reactant: COc1cc(F)c(C=O)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1cc2c(cc1F)OCCO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.2 %

Procedure:
To a solution of 6-fluoroveratraldehyde (1.2 g, 6.2 mmol) in CH2Cl2 (62 mL) was added BBr3 (6.2 mL, 62 mmol) and the solution was stirred at RT for 4 h. The solution was then cooled to 0° C., diluted with EtOAc (120 mL) and slowly treated with H2O (60 mL). The organic layer was washed with brine (2×100 mL), dried, filtered and concentrated to provide the desired catechol intermediate as a dark brown solid (1.0 g, 6.4 mmol). This solid was immediately treated with 1,2-dibromoethane (0.60 mL, 7.1 mmol) and heated to 100° C. The suspension was treated with NaOH (0.50 g, 13 mmol) in H2O (30 mL) dropwise over 1 h and stirred at 100° C. for 2 days. The suspension was then filtered. The collected solid was re-suspended in CHCl3 and filtered. The filtrate was concentrated to provide 0.22 g (19%) of the title compound as a tan solid. MS (ESI): exact mass calculated for C9H7FO3, 182.04; m/z not found. 1H NMR (500 MHz, CDCl3): 10.21 (s, 1H), 7.35 (d, J=6.7, 1H), 6.66 (d, J=10.9, 1H), 4.33 (m, 2H), 4.25 (m, 2H).
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([C:8]2[C:9]3[CH:16]=[CH:15][S:14][C:10]=3[N:11]=[CH:12][N:13]=2)[C@@H:6]([CH3:17])[CH2:5][N:4]([CH2:18][C:19](NC2C=CC=C3C=2C=CN=C3)=[O:20])[CH2:3]1.[ClH:32].[O:33]1CCOCC1>>[ClH:32].[CH3:17][C@H:6]1[N:7]([C:8]2[C:9]3[CH:16]=[CH:15][S:14][C:10]=3[N:11]=[CH:12][N:13]=2)[C@@H:2]([CH3:1])[CH2:3][N:4]([CH2:18][C:19]([OH:20])=[O:33])[CH2:5]1
Reactant: C[C@@H]1CN(CC(=O)Nc2cccc3cnccc23)C[C@H](C)N1c1ncnc2sccc12
Reactant: C1COCCO1
Agent: Cl
Product: C[C@@H]1CN(CC(=O)O)C[C@H](C)N1c1ncnc2sccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from step (i) (1.0 g) in 1,4-dioxane was treated with 4M hydrogen chloride in 1,4-dioxane (40 ml). The mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure to give the subtitle compound as a white 15 solid. Yield 1.9 g.
Reaction SMILES: C(O)(=O)/C=[CH:3]/[C:4]([OH:6])=[O:5].[CH:9]1([N:14]2[CH2:19][CH2:18][CH:17]([N:20]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[C:21](=[O:30])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12][CH2:11][CH2:10]1.[OH-:37].[Na+]>>[C:4]([OH:6])(=[O:5])[C:3]([OH:30])=[O:37].[CH:9]1([N:14]2[CH2:19][CH2:18][CH:17]([N:20]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[C:21](=[O:30])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: [OH-]
Reactant: O=C(O)/C=C/C(=O)O
Agent: Cc1cccc(CC(=O)N(c2cccnc2)C2CCN(C3CCCC3)CC2)c1
Agent: [Na+]
Product: O=C(O)C(=O)O

Procedure:
From 3.9 parts of N-(1-cyclopentyl-4-piperidinyl)-3-methyl-N-(3-pyridinyl)benzeneacetamide (E)-2-butenedioate, the free base is liberated in the conventional manner with a diluted sodium hydroxide solution. After extraction with 2,2'-oxybispropane, the latter is washed with water, dried, filtered and evaporated. The residue is converted into the ethanedioate salt in ethanol. The salt is filtered off and crystallized from a mixture of ethanol and 2,2'-oxybispropane, yielding 3 parts of N-(1-cyclopentyl-4-piperidinyl)-3-methyl-N-(3-pyridinyl)benzeneacetamide ethanedioate; mp. 192.6° C.
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].[C:15]1(=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[OH:21][C:15]1([CH:2]([CH3:3])[C:1]([N:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][C:6]2=[O:14])=[O:4])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1CCCCC1
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Product: CC(C(=O)n1c(=O)oc2ccccc21)C1(O)CCCCC1

Procedure:
Prepared according to the method of paragraph C by reaction of N-propionyl-2-benzoxazolone with cyclohexanone; mp 58–9° C. 1H NMR (CDCl3): δ 8.09 (m, 1 H); 7.25 (m, 3 H); 4.11 (q, 1 H, J=7 Hz); 2.90 (br s, 1 H); 1.82 (br d, 1 H, J=13 Hz); 1.59 (m, 8 H); 1.34 (d, 3 H, J=7 Hz); 1.23 (m, 1 H). 13C NMR (CDCl3): δ 177.20, 151.42, 142.03, 127.69, 125.55, 124.91, 116.38, 109.88, 72.89, 46.77, 37.03, 33.37, 25.64, 21.73, 21.40, 12.16.
Reaction SMILES: [CH3:1][CH2:2][CH:3]1[CH:15]([OH:16])[N:14]2[CH:6]3[CH:7]4[N:23]([CH3:24])[C:22]5[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=5[C:8]54[C@H:12]([OH:13])[CH:11]([CH:4]1[CH2:5]3)[CH:10]2[CH2:9]5.C(Cl)(Cl)Cl.ClC1C=CC=C(C(OO)=[O:37])C=1>CO>[CH3:1][CH2:2][C@H:3]1[CH:4]2[CH:11]3[C@@H:12]([OH:13])[C:8]45[C:17]6[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=6)[N:23]([CH3:24])[C@H:7]4[C@H:6]([CH2:5]2)[N+:14]([O-:37])([C@H:10]3[CH2:9]5)[C@@H:15]1[OH:16]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC1C2CC3C4N(C)c5ccccc5C45CC(C2[C@H]5O)N3C1O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC[C@H]1C2C[C@H]3[C@@H]4N(C)c5ccccc5C45C[C@@H](C2[C@H]5O)[N+]3([O-])[C@@H]1O

Procedure:
200 mg of ajmaline were put in solution in an organic solvent such as chloroform or a mixture of chloroform and methanol (5 ml). A solution of 200 mg of metachloroperbenzoic acid in 5 ml of the same solvent was slowly added, with stirring, the mixture being cooled in ice. The kinetics of the reaction were followed by thin layer chromatography (alkaline Kieselgel plate; solvent CHCl3 90-MeOH 10). At the same time as the N-oxy-ajmaline, there were formed more polar secondary products, already in a important amount whereas the whole of the ajmaline was not yet transformed. The solution was diluted with chloroform, washed with an 15% aqueous solution of KHCO3, dried, filtered and dry distilled. The residue obtained, chromatographed on a silica column of activity V, gave 104 mg of N-oxyajmaline (Yield 49.5%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:24])[C:4]1[C:5]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])=[CH:6][CH:7]=[CH:8][C:9]=1[O:10][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)c1c(O)cccc1OCCCCNC(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(OCCCCNC(=O)OC(C)(C)C)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-tert-butoxycarbonylamino-butoxy)-6-hydroxy-benzoic acid methyl ester (1.5 g, 4.4 mmol) in 20 mL of DMF is added benzyl bromide (0.56 mL, 4.6 mmol) and K2CO3 (1.8 g, 13.0 mmol) and the suspension is stirred at RT for 3 h. The mixture is poured into water and extracted with EtOAc. The organic layer is dried, filtered, and the solvent is removed under reduced pressure to give an oil that is purified by flash chromatography using a gradient of hexane/EtOAc (5:1 to 1:1) to give the product as a colorless liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[CH:24])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1.C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)nc1
Yield: 6 %

Procedure:
3,4-bis(Benzyloxy)-6-ethynylpyridazine (Intermediate 5; 530 mg, 1.68 mmol) and 2-bromo-5-(trifluoromethyl)pyridine (379 mg, 1.68 mmol) were dissolved in tetrahydrofuran (5 ml) to produce an orange solution. The reaction mixture was purged with nitrogen and then triethylamine (1.40 ml, 10.05 mmol), dichlorobis(triphenylphosphine)palladium(II) (58.8 mg, 0.08 mmol) and copper(I) iodide (31.9 mg, 0.17 mmol) were added before it was subjected to microwave irradiation for 1 hour at 80° C. Upon cooling, the mixture was diluted with ethyl acetate and washed with brine. The organic layer was concentrated in vacuo and the crude residue was then purified by silica chromatography (eluting with 0-50% ethyl acetate in petrol) to yield 3,4-bis(benzyloxy)-6-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridazine (460 mg, 0.10 mmol, 60% yield).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[CH2:10][CH:5]2[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:3]1.[H-].[Na+].[CH3:34]I>O1CCCC1>[CH3:34][N:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:11]([N:9]1[CH2:8][CH2:7][N:6]2[C:2](=[O:1])[O:3][C:4]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:5]2[CH2:10]1)=[O:12]
Reactant: CI
Reactant: O=C(Nc1ccccc1)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
To a solution of tetrahydro-3-oxo-N,1,1-triphenyl-3H-oxazolo[3,4-a]pyrazine-7(1H)-carboxamide (60 mg, 0.15 mmol) in tetrahydrofuran (2 mL) was added 60% sodium hydride (10 mg, 0.25 mmol), and the mixture was stirred at room temperature for 1 hour. Next, methyl iodide (0.15 g, 1.1 mmol) was added thereto, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated. Then, the residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1) and crystallized from diisopropyl ether to obtain the title compound (30 mg, yield 48%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:6](=[O:20])[C:5]2=O.Cl.[NH2:23][NH:24][C:25]([NH2:27])=[O:26]>>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:6](=[O:20])/[C:5]/2=[N:23]/[NH:24][C:25]([NH2:27])=[O:26]
Reactant: NNC(N)=O
Reactant: CC(C)N(CCN1C(=O)C(=O)c2cc(N)ccc21)C(C)C
Agent: Cl
Product: CC(C)N(CCN1C(=O)/C(=N/NC(N)=O)c2cc(N)ccc21)C(C)C
Yield: 74 %

Procedure:
By using 5-amino-1-(2-diisopropylaminoethyl)isatin and semicarbazide hydrochloride, a method analogous to that described in Example 4 was carried out to obtain (E)-5-amino-1-(2-diisopropylaminoethyl)isatin 3-semicarbazone having a melting point of 221°-222° C. (decomposition) (yield: 74.0%, recrystallizing solvent: chloroform-methanol).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:18]2[CH:22]=[CH:21][S:20][C:19]=2[C:23]([O:25][CH3:26])=[O:24])[CH2:15][O:16][CH3:17])(=[O:13])=[O:12])=[C:7]([CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:18]2[CH:22]=[CH:21][S:20][C:19]=2[C:23]([O:25][CH3:26])=[O:24])[CH2:15][O:16][CH3:17])(=[O:12])=[O:13])=[C:7]([CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCN(c1ccsc1C(=O)OC)S(=O)(=O)c1ccc(C(C)(C)C)cc1C=Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COCN(c1ccsc1C(=O)OC)S(=O)(=O)c1ccc(C(C)(C)C)cc1CCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
A suspension of 25 (206.0 mg; 0.47 mmol) and palladium on carbon (103.0 mg; 0.91 mmol) in ethanol (2.3 mL) was evacuated and filled with hydrogen gas (3×) and then stirred at room temperature under hydrogen overnight. Additional palladium on carbon (103.0 mg) was added and stirring was continued at room temperature for 16 hours. The reaction mixture filtered through celite and the filtrate concentrated under reduced pressure to afford the title compound as a clear oil (143 mg).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]2[N:24]=[C:23]([N:25]([CH3:27])[CH3:26])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl.C(N(C(C)C)CC)(C)C.[Br:39][C:40]1[CH:45]=[CH:44][C:43]([S:46](Cl)(=[O:48])=[O:47])=[C:42]([O:50][C:51]([F:54])([F:53])[F:52])[CH:41]=1>CCOC(C)=O.C(Cl)Cl>[Br:39][C:40]1[CH:45]=[CH:44][C:43]([S:46]([NH:7][C@H:8]2[CH2:13][CH2:12][C@H:11]([NH:14][C:15]3[N:24]=[C:23]([N:25]([CH3:27])[CH3:26])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[CH2:10][CH2:9]2)(=[O:48])=[O:47])=[C:42]([O:50][C:51]([F:53])([F:52])[F:54])[CH:41]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: CN(C)c1nc(N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)nc2ccccc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)c1nc(N[C@H]2CC[C@H](NS(=O)(=O)c3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of trans-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester (500 mg, 1.30 mmol) in EtOAc (5 mL) was added 4 M hydrogen chloride in EtOAc (5 mL). The mixture was stirred at ambient temperature for 1 hr and concentrated to give a white solid. To a suspension of the above solid in CH2Cl2 (7 mL) was added diisopropylethylamine (905 μL, 5.20 mmol). The mixture was cooled to 4° C. and a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (462 mg, 1.36 mmol) in CH2Cl2 (2 mL) was added below 5° C. The reaction mixture was stirred at 4° C. for 1.5 hr. To the reaction mixture was added a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (88 mg, 0.26 mmol) in CH2Cl2 (0.5 mL) and the mixture was stirred at 4° C. for 1 hr. To the reaction mixture was added diisopropylethylamine (230 μL, 1.32 mmol) and the mixture was stirred at 4° C. for 1.5 hr. The reaction was quenched with saturated aqueous NaHCO3 The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 50% EtOAc in hexane) to give trans-4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzenesulfonamid (339 mg, 44%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][N:12]([CH2:23][C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=2)[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)=[C:7]([CH2:9][OH:10])[CH:8]=1.[C:32]1([C@H:38]([CH2:42][CH3:43])[C:39](O)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:30][C:29]1[C:24]([CH2:23][N:12]([CH2:11][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:39](=[O:40])[CH:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:42][CH3:43])=[CH:8][C:7]=2[CH2:9][OH:10])[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: Cc1cnc(CN(Cc2ccc(CN)cc2CO)C2CCCc3cccnc32)c(C)c1
Reactant: CC[C@H](C(=O)O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(C(=O)NCc1ccc(CN(Cc2ncc(C)cc2C)C2CCCc3cccnc32)c(CO)c1)c1ccccc1
Yield: 54.7 %

Procedure:
Using General Procedure G: To a solution of (5-aminomethyl-2-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-phenyl)-methanol (0.12 g, 0.26 mmol) dissolved in CH2Cl2 (10 mL) was added (S)-2-phenylbutyric acid (60 μl, 0.39 mmol), EDCI (0.08 g, 0.39 mmol), HOBT (0.05 g, 0.39 mmol), and DIPEA (67 μl, 0.39 mmol). Purification via column chromatography on silica gel (CH2Cl2:MeOH, 97:3, v/v) afforded the product as a colorless oil (0.08 g, 53%). 1H NMR (CDCl3) δ 0.88 (m, 3H), 1.51 (m, 1H), 1.86 (m, 1H), 2.05 (m, 1H), 2.11 (m, 3H), 2.14 (s, 3H), 2.24 (s, 3H), 2.79 (m, 2H), 3.20 (m, 1H), 3.70 (m, 4H), 4.09 (m, 2H), 4.33 (m, 3H), 5.69 (s, 1H), 6.95 (m, 2H), 7.13 (m, 2H), 7.22 (m, 7H), 8.15 (s, 1H), 8.35 (s, 1H); ES-MS m/z 564 (M+H).
Reaction SMILES: COC(=O)C1C=CC([CH:10]2C[N:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C@@H:21]4[O:26][C:25]5[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=5[O:23][CH2:22]4)=[CH:17][CH:16]=3)[CH2:11]2)=CC=1.N1[CH2:38][CH2:37][CH2:36][CH:35]([C:39]([OH:41])=[O:40])CC1>>[O:26]1[C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[O:23][CH2:22][C@@H:21]1[C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:12]2[CH2:38][CH2:37][CH2:36][CH:35]([C:39]([OH:41])=[O:40])[CH2:10][CH2:11]2)=[CH:20][CH:19]=1
Reactant: O=C(O)C1CCCNCC1
Reactant: COC(=O)c1ccc(C2CN(Cc3ccc([C@H]4COc5ccccc5O4)cc3)C2)cc1
Product: O=C(O)C1CCCN(Cc2ccc([C@H]3COc4ccccc4O3)cc2)CC1

Procedure:
Compound 266 is synthesized from Intermediate A and azepane-4-carboxylic acid according to General Method B. (LC/MS method 16: ES+ m/z 368.3 [M+H]+, Rt=2.76 min)