Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:18]([O:20][CH3:21])=[O:19])=[CH:5][C:4]=2[N:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN1C(=O)CCC1>[CH3:17][S:16][C:13]1[N:14]=[CH:15][C:10]2[C:9]3[CH:8]=[CH:7][C:6]([C:18]([O:20][CH3:21])=[O:19])=[CH:5][C:4]=3[N:3]=[C:2]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:11]=2[N:12]=1
Reactant: COC(=O)c1ccc2c(c1)nc(Cl)c1nc(SC)ncc12
Reactant: Nc1ccccc1
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)nc(Nc1ccccc1)c1nc(SC)ncc12
Temperature: 120 °C

Procedure:
methyl 5-chloro-3-(methylthio)pyrimido[4,5-c]quinoline-8-carboxylate (1.0 eq, 182 mg, 0.57 mmol) was mixed with aniline (0.5 ml) in NMP (1 ml). The mixture was heated under microwave for 10 minutes at 120° C. Water was added and the resulting solid was filtered and dried. The compound was triturated in EtOAc and hexanes and filtered to afford methyl 3-(methylthio)-5-(phenylamino)pyrimido[4,5-c]quinoline-8-carboxylate as a yellow solid. LCMS (ES): >95% pure, m/z 377 [M+1]+. This material was suspended in CH2Cl2 (4 ml) and meta-chloroperbenzoic acid (77% pure, 2.5 eq, 165 mg, 0.737 mmol) was added in small portions. After one hour, an additional amount (100 mg) of mcpba was added and the mixture stirred for 1.5 hours. After addition of more CH2Cl2, the organic phase was washed with water (4×), dried over Na2SO4 and the solution was filtered through a pad of silica gel, eluting with a MeOH/CH2Cl2 mixture. After evaporation of the solvents, methyl 3-(methylsulfonyl)-5-(phenylamino)pyrimido[4,5-c]quinoline-8-carboxylate was isolated as a yellow solid (166 mg, 72% yield). LCMS (ES): >95% pure, m/z 409 [M+1]+, 1H NMR (DMSO-d6, 400 MHz) δ 3.77 (s, 3H), 3.93 (s, 3H), 7.15 (t, J=7.2, 1H), 7.45 (t, J=7.6, 2H), 7.99 (dd, J=2.0, J=8.4, 1H), 8.16 (d, J=7.6, 2H), 8.28 (d, J=2.0, 1H), 8.89 (d, J=8.8, 1H), 9.76 (s, 1H), 10.61 (s, 1H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([CH2:14][CH2:15][C:16]([OH:18])=O)[CH:10]=2)=[CH:5][CH:4]=1.[NH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=[O:34])[NH:26][N:25]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[C:11]([CH2:14][CH2:15][C:16]([NH:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27](=[O:34])[NH:26][N:25]=3)=[O:18])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cc(CCC(=O)O)no2)cc1
Reactant: NCCCNc1n[nH]c(=O)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(CCC(=O)NCCCNc3n[nH]c(=O)c4ccccc34)no2)cc1

Procedure:
3-[5-(4-Methoxy-phenyl)-isoxazol-3-yl]-propionic acid (124 mg, 0.50 mmol) and 4-(3-amino-propylamino)-2H-phthalazin-1-one (100 mg, 0.46 mmol) were dissolved in DMF (2 mL) and treated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (95 mg, 0.50 mmol) and triethylamine (76 mg, 0.75 mmol). 3-[5-(4-Methoxy-phenyl)-isoxazol-3-yl]-N-[3-(4-oxo-3,4-dihydro-phthalazin-1-ylamino)-propyl]-propionamide was isolated by preparative RPLC.
Reaction SMILES: [C:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:17]([OH:19])=[O:18])=[N:10][C:11]=2[O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[CH2:5][CH2:4][CH2:3][CH:2]=1.[H][H]>C(O)C.[Pd]>[CH:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:17]([OH:19])=[O:18])=[N:10][C:11]=2[O:12][CH2:13][CH:14]2[CH2:15][CH2:16]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1ccc(C2=CCCC2)c(OCC2CC2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(O)c1ccc(C2CCCC2)c(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.7 %

Procedure:
The mixture of 5-cyclopentenyl-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid (0.95 g, 4 mmol), Pd/C (10% w/w, 0.2 g) in 30 mL of ethanol in a hydrogen atmosphere was stirred for 4 h at room temperature. The mixture was filtered and the filtrate was evaporated to dryness to obtain the product (0.76 g, 79%) as white solid. The product was directly used for the next step; MS (LC/MS): 262.1 [M+H]+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[CH3:16][N:17]([CH3:20])C=O>O>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[N:17]1[C:20]2[C:6](=[C:3]([CH3:4])[CH:2]=[CH:9][CH:8]=2)[CH:7]=[CH:16]1)#[N:5]
Reactant: CN(C)C=O
Reactant: N#Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cccc2c1ccn2-c1ccccc1C#N
Temperature: 150 °C

Procedure:
The title B compound of Example 4 (1.042 g, 7.94 mmol, 1.0 eq.) was combined with 2-fluorobenzonitrile (1.29 ml, 11.91 mmol, 1.5 eq.) and potassium carbonate (2.195 g, 15.88 mmol, 2.0 eq.) in dimethylformamide (7.94 ml, 1M) and heated at 150° C. for 4 hours. The reaction was then cooled to room temperature, diluted with water (20 ml), and extracted three times with ethyl acetate. The organic extracts were washed with water and aqueous saturated sodium chloride, dried over sodium sulfate, filtered through magnesium sulfate and concentrated. The residue was chromatographed on Merck silica gel (50 g) eluting with chloroform:hexane (1:3) followed by (1:1) to give the title A compound (1.57 g).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][C:9]2[C:10](=[O:14])[CH:11]=[CH:12][O:13][C:8]=2[CH:7]=1)(=[O:4])=[O:3].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[C:24]([N:5]([C:6]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][C:9]2[C:10](=[O:14])[CH:11]=[CH:12][O:13][C:8]=2[CH:7]=1)[S:2]([CH3:1])(=[O:3])=[O:4])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CS(=O)(=O)Nc1cc2occc(=O)c2cc1Oc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CS(=O)(=O)N(C(=O)c1ccccc1)c1cc2occc(=O)c2cc1Oc1ccccc1

Procedure:
7-Methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was reacted with benzoyl chloride in the presence of aluminum chloride to obtain 7-(N-benzoyl-N-methylsulfonylamino)-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: B.CSC.[C:5]([CH2:8][C:9]1[C:10]([Cl:18])=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])(O)=[O:6]>C1COCC1>[Cl:18][C:10]1[C:11]([CH2:12][OH:13])=[CH:15][CH:16]=[CH:17][C:9]=1[CH2:8][CH2:5][OH:6]
Reactant: O=C(O)Cc1cccc(C(=O)O)c1Cl
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: OCCc1cccc(CO)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of borane-methyl sulfide complex (2M in THF, 20 mL) was added portionwise over 5 minutes to a suspension of 3-(carboxymethyl)-2-chlorobenzoic acid (example 80, step b) (4.11 g) in dry THF (100 mL) at room temperature. The resulting effervescing suspension was stirred at room temperature for 30 minutes, then heated to reflux for 60 minutes, and allowed to cool to room temperature overnight. The mixture was quenched by the portionwise addition of methanol (15 mL) over 15 minutes. The mixture was diluted further with methanol to give a solution, which was then concentrated in vacuo to give a syrup. The syrup was purified by flash chromatography on silica eluted with 2% methanol in dichloromethane to the afford the crude subtitled compound as a white solid. Yield 1.44 g.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[S:15][C:14]([NH2:16])=[N:13][C:12]=2[C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[O:10])=[CH:5][N:4]=1.Br.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[O:2]=[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[S:15][C:14]([NH2:16])=[N:13][C:12]=2[C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[O:10])=[CH:5][NH:4]1
Reactant: COc1ccc(C(=O)c2sc(N)nc2-c2ccco2)cn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1nc(-c2ccco2)c(C(=O)c2ccc(=O)[nH]c2)s1
Temperature: 100 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
Compound 318 (1.36 g, 4.51 mmol) was dissolved in acetic acid (4 mL), and 48% hydrobromic acid (4 mL) was added thereto, followed by stirring at 100° C. for 1 hour. The reaction mixture was poured into aqueous saturated sodium carbonate solution, and the precipitated solid was collected by filtration to afford the entitled Compound 358 (1.20 g, 93%).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=[O:2].[CH2:13]([Mg]Br)[CH2:14][CH3:15]>O1CCCC1>[OH:2][CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[CH2:13][CH2:14][CH3:15]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CCC[Mg]Br
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
A solution of methyl 4-formylbenzoate (2.092 g, 12.74 mmol) in tetrahydrofuran (50 mL) was cooled to 0° C. To this solution was added n-propylmagnesium bromide (6.4 mL, 2.0M in THF) dropwise over 20 minutes. The reaction was stirred at 0° C. for 2 hours. The reaction was then quenched by addition of saturated ammonium chloride. This mixture was extracted with ethyl acetate twice. The organics were dried over magnesium sulfate, filtered and concentrated. Purification by column chromatography (0-40% ethyl acetate in heptanes) gave (+/−)-methyl 4-(1-hydroxybutyl)benzoate (1.252 g, 47%) as a colorless oil. 1H NMR (400 MHz, CDCl3, δ): 7.97-8.02 (m, 2H), 7.40 (d, J=8.4 Hz, 2H), 4.74 (dd, J=7.8, 5.7 Hz, 1H), 3.90 (s, 3H), 1.61-1.82 (m, 2H), 1.23-1.49 (m, 2H), 0.92 (t, J=7.32 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:27]12[CH2:35][C:31]([CH2:36][NH2:37])([CH2:32][CH2:33][CH2:34]1)[CH2:30][CH2:29][CH2:28]2>O1CCCC1.CO>[N:27]12[CH2:35][C:31]([CH2:36][NH:37][C:7](=[O:9])[C:6]3[CH:10]=[C:2]([Cl:1])[C:3]([NH:13][CH3:14])=[CH:4][C:5]=3[O:11][CH3:12])([CH2:32][CH2:33][CH2:34]1)[CH2:30][CH2:29][CH2:28]2
Reactant: CNc1cc(OC)c(C(=O)O)cc1Cl
Reactant: NCC12CCCN(CCC1)C2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CO
Solvent: C1CCOC1
Product: CNc1cc(OC)c(C(=O)NCC23CCCN(CCC2)C3)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
A solution of 5-chloro-2-methoxy-4-(methylamino)benzoic acid (1.08 g, 5 mmol) in anhydrous tetrahydrofuran (7 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (0.90 g, 5.5 mmol), stirred one hour, degassed under a stream of nitrogen for 10 minutes, and cooled (0° C.). A solution of 1-azabicyclo[3.3.1]nonane-5-methanamine (0.82 g, 5.3 mmol) in tetrahydrofuran (3 mL) was added dropwise, and stirring was continued at room temperature for 18 hours. The suspension was diluted with enough methanol to dissolve the solid, then the solution was filtered through a short column of alumina (eluted with 20% methanol/tetrahydrofuran). The filtrate was concentrated in vacuo, triturated from cold ether, and recrystallized from acetonitrile to afford 1.29 g (73%) of colorless crystals; mp 188°-190° C. (second phase), first phase melting point 175° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:9]#[N:10])[CH2:8][CH2:7]1.[ClH:11]>O1CCCC1>[ClH:11].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([CH2:9][NH2:10])[CH2:8][CH2:7]1
Reactant: N#CC1(c2cccs2)CC1
Agent: Cl
Solvent: C1CCOC1
Product: NCC1(c2cccs2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(thiophen-2-yl)cyclopropanecarbonitrile (14.9 g) in tetrahydrofuran (100 mL) was added 1.1M borane•tetrahydrofuran complex (100 mL) at room temperature, and the mixture was stirred at 60° C. overnight. 6M Aqueous hydrochloric acid solution (20 mL) was carefully added to the reaction mixture, and the mixture was stirred at 60° C. for 0.5 hr. The reaction mixture was allowed to cool to room temperature, and tetrahydrofuran was evaporated under reduced pressure. The obtained residue was diluted with water, and washed with ethyl acetate. The aqueous layer was basified with 8M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethyl acetate, 4M hydrochloric acid/ethyl acetate solution (30 mL) was added, and the solvent was evaporated under reduced pressure. The obtained solid was recrystallized from ethanol-ethyl acetate to give the title compound (10.5 g) as white needle crystals.
Reaction SMILES: Br[C:2]1[C:3]([O:28][CH3:29])=[C:4]([CH:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][N:41]([CH:43]3[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]3)[CH:42]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>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.O>[Cl:9][C:6]1[C:7]([CH3:8])=[C:2]([C:38]2[CH:39]=[N:40][N:41]([CH:43]3[CH2:44][CH2:45][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:47][CH2:48]3)[CH:42]=2)[C:3]([O:28][CH3:29])=[C:4]([CH:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH3:11])[CH:5]=1
Reactant: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1Br
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1-c1cnn(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 120 °C
Yield: 93.1 %

Procedure:
Into a microwave vial was added N-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (0.032 g, 0.066 mmol, from Example 113, Step 2, chiral intermediate), tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (0.030 g, 0.080 mmol, from Combi-Blocks), sodium carbonate (0.014 g, 0.13 mmol), 1,4-dioxane (0.6 mL)/water (0.2 mL) and tetrakis(triphenylphosphine)palladium(0) (4.6 mg, 0.0040 mmol). The mixture was degassed with N2 for 5 minutes, and then heated at 120° C. overnight. The mixture was diluted with EtOAc, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated to give the crude product (0.040 g) which was used in the next step directly. LCMS calculated for C33H44ClN8O4 (M+H)+: m/z=651.3. found: 651.2.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10](I)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[C:14]([C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)#[N:15].C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1>[C:14]([C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:10]3[CH:11]=[CH:12][C:7]([N:3]4[CH:4]=[CH:5][N:6]=[C:2]4[CH3:1])=[CH:8][CH:9]=3)[CH:23]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)#[N:15]
Reactant: N#CC1(c2cccc(O)c2)CCOCC1
Reactant: Cc1nccn1-c1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: Cc1nccn1-c1ccc(Oc2cccc(C3(C#N)CCOCC3)c2)cc1
Temperature: 130 °C
Yield: 38.3 %

Procedure:
A mixture of 4-(2-methylimidazol-1-yl)phenyl iodide (1.28 g, 4.5 mmol), 4-cyano-4-(3-hydroxyphenyl)-3,4,5,6-tetrahydro-2H-pyran (1.20 g, 5.9 mmol) and K2CO3 (4.15 g, 30 mmol) in pyridine (50 ml) was heated at 130° C., cupric oxide (636 mg, 8.0 mmol) added and the reaction mixture was heated under reflux for 2 days. The reaction mixture was cooled and filtered through a celite pad and the solids were washed with ethyl acetate (100 ml). The filtrate was concentrated in vacuo, and the resulting residue was diluted with water (100 ml) and extracted with ethyl acetate (50 ml×3). The combined organic extracts were washed with 1N aqueous NaOH (100 ml), water (100 ml) and brine (100 ml), dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography {LiChroprep NH2 (Merck), 100 g; eluted with hexane/ethyl acetate (1/1)} to afford 620 mg (38%) of the titled compound as a yellow oil.
Reaction SMILES: [C:1]([NH:8][N:9]1[C:15](=[O:16])[CH2:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]1=2)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>CN(C=O)C.C(Cl)Cl>[C:1]([NH:8][N:9]1[C:15](=[O:16])[CH:14]([CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]1=2)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NN1C(=O)Cc2ccccc2-c2ccccc21
Reactant: CC(C)(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NN1C(=O)C(CC(=O)C(C)(C)C)c2ccccc2-c2ccccc21
Temperature: 60 °C
Reaction time: 17 h

Procedure:
A solution of 5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (0.2 g, 0.617 mmol) (Example 3-E) in DMF was treated with Cs2CO3 (0.3 g, 0.925 mmol) and warmed to 60° C. To the reaction mixture was added 1-chloro-3,3-dimethyl-2-butanone (0.096 mL, 0.74 mmol) (Aldrich) and stirring continued for 17 hours. After cooling to 23° C., the mixture was diluted with CH2Cl2, washed with several portions of brine and dried over Na2SO4. The title compound was isolated as a colorless solid.
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[N:15]1([CH2:21][CH2:22][NH2:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C(OCC)(=O)C>[N:15]1([CH2:21][CH2:22][NH:23][C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NCCN1CCCCC1
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(NCCN2CCCCC2)cc1
Yield: 64.5 %

Procedure:
tert-Butyl 4-fluorobenzoate 185 (0.502 g, 2.55 mmol) and 2-(piperidin-1-yl)ethanamine 186 (1.46 mL, 10.21 mmol) were stirred neat at 120° C. overnight then diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate (1×), brine (1×), dried over magnesium sulfate and evaporated to give 187 (0.501 g, 64%). 1H NMR: (DMSO) δ (ppm): 400 MHz, (DMSO) d (ppm): 7.59 (d, J=8.8 Hz, 2H), 6.55 (d, J=8.8 Hz, 2H), 6.24 (t, J=5.1 Hz, 1H), 4.11 (m, 2H), 3.21 to 3.13 (m, 6H), 2.44 (t, J=7.1 Hz, 2H), 2.37 (m, 2H), 1.49 (s, 9H), 1.47 to 1.38 (m, 2H). MS: 304.22 (calc), 249.1 (M-tBu).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17](O)=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]([NH:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C=C1c2ccccc2C=Cc2ccccc21
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCNC(=O)C=C1c2ccccc2C=Cc2ccccc21

Procedure:
173 mg (0.70 mmol) of 5H-dibenzo[a,d][7]annulen-5-ylidenacetic acid, 130 mg (0.75 mmol) of t-butyl N-(3-aminopropyl)carbamate, 149 mg (0.78 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride and 0.11 ml (0.79 mmol) of triethylamine were stirred in 5 ml of dichloromethane at room temperature overnight. The reaction mixture was washed with 0.5 N aqueous sodium hydroxide solution and the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane:ethyl acetate=7:3) to obtain the title compound.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:33]=[CH:32][C:13]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([NH2:31])[CH:29]=4)[CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1>C(#N)C>[F:9][C:10]1[CH:33]=[CH:32][C:13]([CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([N:22]3[C:30]4[C:25](=[CH:26][C:27]([Cl:1])=[C:28]([NH2:31])[CH:29]=4)[CH2:24][CH2:23]3)[CH2:20][CH2:21]2)=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Solvent: CC#N
Product: Nc1cc2c(cc1Cl)CCN2C1CCN(CCc2ccc(F)cc2)CC1
Yield: 34.5 %

Procedure:
N-Chlorosuccinimide (0.24 g) was added at room temperature to a solution of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminoindoline (0.5 g) in acetonitrile (50 ml) and the resultant mixture was stirred for 1 hr. Then the reaction mixture was filtered and concentrated under reduced pressure. Next, a 5 N aqueous solution of sodium hydroxide and ethyl acetate were added thereto and the layers were separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The resulting residue was purified by silica gel column chromatography (methylene chloride/ethanol system) to give the title compound (0.19 g) as a brown oil (yield: 34%).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=1)=[O:5].[C:16]1([CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[O:13]=[C:11]1[NH:10][C:9]2[CH:14]=[CH:15][C:6]([C:4](=[O:5])[CH2:3][CH2:2][N:26]3[CH2:27][CH2:28][N:23]([CH2:22][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:24][CH2:25]3)=[CH:7][C:8]=2[O:12]1
Reactant: O=C(CCCl)c1ccc2[nH]c(=O)oc2c1
Reactant: c1ccc(CN2CCNCC2)cc1
Product: O=C(CCN1CCN(Cc2ccccc2)CC1)c1ccc2[nH]c(=O)oc2c1
Yield: 66.9 %

Procedure:
Using 0.6 g of 3-chloro-1-(2,3-dihydro-2-oxobenzoxazol-6-yl)-1-propanone and 0.47 g of 1-(phenylmethyl)piperazine, 0.65 g of the title compound was obtained as colorless crystals, m.p. >300° C., in the same manner as in Example 6.
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16](OS(C(F)(F)F)(=O)=O)[CH:17]=[CH:18][C:4]1=2)[CH3:2].[C:27]([O:31][CH2:32][CH3:33])(=[O:30])[CH:28]=[CH2:29].[Cl-].[Li+].C(N(CC)CC)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.CN(C=O)C>[CH2:32]([O:31][C:27](=[O:30])/[CH:28]=[CH:29]/[C:16]1[CH:17]=[CH:18][C:4]2[N:3]([CH2:1][CH3:2])[C:9](=[O:10])[C:8]([CH3:11])([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]=2[CH:15]=1)[CH3:33]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: C=CC(=O)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc2c(c1)N(C)C(=O)C(C)(C)C(=O)N2CC
Temperature: 180 °C
Yield: 103.1 %

Procedure:
Trifluoromethane sulfonic acid 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl ester (0.40 g), ethyl acrylate (0.13 g), dichlorobis(triphenylphosphine)palladium (II) (35 mg), lithium chloride (64 mg), and triethylamine (0.19 ml) were added to DMF (4 ml). The mixture was heated at 180° C. (microwave reactor) for 20 minutes. The reaction liquid was cooled to room temperature, and subjected to celite filtration. The filtrate was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30→30:70). The purified product was condensed under reduced pressure to give the title compound (0.36 g) as a pale yellow solid.