Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:28])C(=O)C1.CCOC(C)=O>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][C:3]=1[Br:28]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)cc2)C1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)c(Br)c2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 101.7 %

Procedure:
To a stirred solution of tert-butyl (RS)-2-(4-aminophenyl)morpholine-4-carboxylate (3.07 g, CAS-1002726-96-6) in DMF (30 ml) was added NBS (1.96 g) and the mixture was stirred at room temperature for 15 min. The reaction mixture was then poured into EtOAc and extracted sequentially with water and with saturated brine. The organic layer was dried over Na2SO4 and then concentrated in vacuo to afford tert-butyl (RS)-2-(4-amino-3-bromophenyl)morpholine-4-carboxylate (4.0 g, quant.) as a light brown solid which was used in the next step without further purification. MS (ISP): 359.0 ([{81Br}M+H]+), 357.0 ([{79Br}M+H]+), 303.0 ([{81Br}M+H—C4H8]+), 301.0 ([{79Br}M+H—C4H8]+).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:31]([O-:33])=[O:32])=[C:6]([CH:30]=1)[C:7]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:8].[CH2:34]([NH:36][CH2:37][CH3:38])[CH3:35]>CN(C=O)C>[CH2:34]([N:36]([CH2:37][CH3:38])[C:2]1[CH:3]=[CH:4][C:5]([N+:31]([O-:33])=[O:32])=[C:6]([CH:30]=1)[C:7]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:8])[CH3:35]
Reactant: CCNCC
Reactant: O=C(NCC1CCN(C(c2ccccc2)c2ccccc2)CC1)c1cc(F)ccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc([N+](=O)[O-])c(C(=O)NCC2CCN(C(c3ccccc3)c3ccccc3)CC2)c1
Yield: 97.3 %

Procedure:
Step 1): To a solution of 5-fluoro-2-nitro-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide (prepared according to Preparation 24) (2.1 g, 4.68 mmol) in DMF (30 ml) was added diethylamine (1.46 ml, 14.06 mmol). The solution was refluxed overnight and evaporated under reduced pressure to give 5-diethylamino-2-nitro-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide (2.28 g, 97.5%): mp 167°-168° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([NH2:10])[CH:7]=[CH:6][CH:5]=1)[CH3:2].Cl[C:12]1[CH:17]=[C:16]([Cl:18])[N:15]=[N:14][C:13]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(#N)C>[Cl:18][C:16]1[N:15]=[N:14][C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12]([NH:10][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([O:3][CH2:1][CH3:2])[N:9]=2)[CH:17]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Reactant: CCOc1cccc(N)n1
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(OCC)n1
Temperature: 130 °C
Reaction time: 36 h
Yield: 4.5 %

Procedure:
In a sealed reaction tube, 6-ethoxypyridin-2-amine (775 mg, 5.61 mmol) and ethyl 4,6-dichloropyridazine-3-carboxylate (620 mg, 2.8 mmol) were combined with acetonitrile (14 mL) and stirred at 130° C. for 36 h. The mixture was cooled, concentrated to a brown solid, and then chromatographed (80 g Silicycle column, eluent 0 to 10% acetone in dichloromethane, 20 min, then held at 10% for 10 min) to give ethyl 6-chloro-4-(6-ethoxypyridin-2-ylamino)pyridazine-3-carboxylate (40.3 mg, 125 μmol, 4%) as a white solid. MS (EI/CI) m/z: 323.2 [M+H].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](I)[C:5]([OH:9])=[CH:4][CH:3]=1.[C:10]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]#[CH:23])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>CN(C=O)C.CCOCC.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>[C:10]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[O:9][C:5]2[C:6](=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:23]=1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: Oc1ccc(Cl)nc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc2nc(Cl)ccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 3.07 g (12.0 mmol) sample of 6-chloro-2-iodo-3-pyridinol, from step 11c above, was dissolved in 10 mL of DMF, and (Ph3P)2PdCl2 (0.38 g, 0.50 mmol), CuI (0.380 g, 1.98 mmol) and triethylanue (1.7 mL, 12 mmol) were added. The mixture was stirred under N2 at room temperature for 1 hour, then 1.95 g (10.0 mmol) of 1-BOC-2-(S)-ethynylpyrrolidine, from Example 1a above, dissolved in 5 mL of DMF, was added carefully. The reaction mixture was stirred at 60° C. for 16 hours, cooled to room temperature, diluted with ether, washed with 50% brine and dried over MgSO4, then the solvent was removed. The residue was chromatographed on silica gel, eluting with 100:0 to 50:50 hexane:EtOAc to give 1.54 g of title compound: 1H NMR (DMSO, 300 MHz, 130° C.) δ 1.37 (two s, 9H), 1.89-2.07 (m, 3H), 2.37 (m, 1H), 3.40-3.54 (m, 1H), 4.98 (m, 1H), 6.72 (s, 1H), 7.26-7.29 (d, 1H, J=8.6 Hz), 7.93-7.96 (d, 1H, J=8.6 Hz); MS m/z: 323 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:16]=O)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[C:24]([O:28][C:29]([NH:31][CH2:32][C@@H:33]([C:35]([OH:37])=[O:36])[NH2:34])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29]([NH:31][CH2:32][C@@H:33]([C:35]([OH:37])=[O:36])[NH:34][CH2:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[O:18][CH3:19])[N:9]=[CH:8][N:7]=[C:6]2[NH:5][C:4]1[CH:20]=[CH:21][CH:22]=[C:2]([Cl:1])[C:3]=1[F:23])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)NC[C@H](N)C(=O)O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN[C@@H](CNC(=O)OC(C)(C)C)C(=O)O

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxyquinazoline-6-carbaldehyde was coupled with 3-[(tert-butoxycarbonyl)amino]-L-alanine (Tetrahedron Letters (1993), 34(20), 3201-4) using an analogous method to that described for the equivalent step in Example 1 to give 3-[(tert-butoxycarbonyl)amino]-N-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-L-alanine; 1H NMR Spectrum: (DMSO-d6) 1.32 (s, 9H); 3.26 (m, 3H); 3.86 (d, 1H); 3.97 (m, 4H); 6.73 (s, 1H); 7.21 (s, 1H); 7.27 (t, 1H); 7.47 (t, 1H); 7.54 (t, 1H); 8.40 (s, 1H); 8.44 (s, 1H); 9.86 (s, 1H); Mass Spectrum: (M+H)+ 520.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12](=[S:15])SC)(=[O:10])=[O:9].CS.[NH2:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([CH3:27])[N:20]=1>C1(C)C(C)=CC=CC=1.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([NH:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([CH3:27])[N:20]=1)=[S:15])(=[O:9])=[O:10]
Reactant: COc1cc(C)nc(N)n1
Reactant: CSC(=S)NS(=O)(=O)c1ccccc1Cl
Agent: CS
Solvent: Cc1ccccc1C
Solvent: CC#N
Product: COc1cc(C)nc(NC(=S)NS(=O)(=O)c2ccccc2Cl)n1
Temperature: 145 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
A solution of 5.0 g of methyl N-(2-chlorophenylsulfonyl)dithiocarbamate in 20 ml of xylene is stirred for 3.5 hours with heating at 145° C. During the heating, methylmercaptan gas is generated. After the reaction is completed, xylene is removed under reduced pressure to yield a pale yellow oil (IR: strong absorption band of -SO2NCS at 1900 cm-1). The oily substance is dissolved in 50 ml of acetonitrile, to which 2.8 g of 2-amino-4-methoxy-6-methylpyrimidine is added and stirred for 30 minutes at 50° C. The precipitated crystals are collected by filtration, and recrystallized from acetonitrile to give 5.6 g of the title compound as a white prism. mp 186.5°~187.5° C.
Reaction SMILES: [H-].[Na+].[Br-].[CH:4]1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5]1.[CH3:26][O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([CH:36]=O)=[CH:32][CH:31]=1)=[O:29].O>O1CCCC1>[C:4]1(=[CH:36][C:33]2[CH:34]=[CH:35][C:30]([C:28]([O:27][CH3:26])=[O:29])=[CH:31][CH:32]=2)[CH2:6][CH2:5]1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: c1ccc([P+](c2ccccc2)(c2ccccc2)C2CC2)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C=C2CC2)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
To a suspension of sodium hydride (60%, 0.27 g) in tetrahydrofuran (40 mL) was added cyclopropyltriphenylphosphonium bromide (2.6 g), and the mixture was stirred at 70° C. for 2 hours. To the reaction mixture was added methyl terephthalaldehydate (1.0 g), and the mixture was stirred at 70° C. for 7 days. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/dichloromethane=1/1) to give methyl 4-(cyclopropylidenemethyl)benzoate (0.80 g).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)O1.FC(F)(F)S(O[C:32]1[CH:33]=[N:34][CH:35]=[C:36]([CH3:38])[CH:37]=1)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:38][C:36]1[CH:37]=[C:32]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:23])[CH3:24])(=[O:20])=[O:21])[CH2:12]3)[CH:33]=[N:34][CH:35]=1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Reactant: Cc1cncc(OS(=O)(=O)C(F)(F)F)c1
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: C1COCCO1
Solvent: O
Product: Cc1cncc(-c2ccc3c(c2)C[C@@H](NS(=O)(=O)C(C)C)C3)c1

Procedure:
To a solution of N-[(2S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (250 mg, 0.68 mmol) in dry 1,4 dioxane (5 ml), polymer supported Pd(PPh3)4 (70 mg, 0.11 mmol/g, 0.0068 mmol) was added along with 5-methyl-3-pyridinyl trifluoromethanesulfonate (241 mg, 1.026 mmol) and 680 μl of a 2M Na2CO3 solution in water and the resulting mixture was heated at 90° degrees for 3 hours. Then after cooling the resin was removed by filtration and then the solvent was removed under reduced pressure. The residue was taken up with DCM, washed with water and loaded on a 25M+ silica cartridge eluating with a cyclohexane/AcOEt 75/25 mixture. 95 mg of title compound were recovered as whitish solid (42%). Due to the use of chiral Intermediate 7, the final compound is believed to be N-[(2S)-5-(5-methyl-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10])(=[O:5])[CH3:4].O>CCOCC>[Br:1][CH2:4][C:3]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10])=[O:5]
Reactant: CC(=O)c1cccc(C#N)c1
Reactant: BrBr
Solvent: CCOCC
Solvent: O
Product: N#Cc1cccc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Br2 (1 mmol) was dropwise added to a solution of 3-acetylbenzonitrile (1 mmol) in Et2O (15 ml) at 0° C., and then the mixture was stirred at r.t. for 4 h. Water was added, and the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, and was concentrated to give an oil, i.e., 3-(2-bromoacetyl)benzonitrile, which was directly used for the next step without purification.
Reaction SMILES: [OH2:1].[OH-].[Li+].OO.[CH:6]1([CH2:11][C@H:12]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:13](N2[C@H](C)[C@H](C3C=CC=CC=3)OC2=O)=[O:14])[CH2:10][CH2:9][CH2:8][CH2:7]1>C1COCC1>[CH:6]1([CH2:11][C@H:12]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:13]([OH:14])=[O:1])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: O
Reactant: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)[C@H](CC1CCCC1)c1ccccc1
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)[C@H](CC1CCCC1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Lithium hydroxide monohydrate (1.28 g, 30.6 mmol) is suspended in THF (50 mL) and cooled to 0° C. Hydrogen peroxide (50 wt % in water, 2.81 mL, 91.79 mmol) is added dropwise. Reaction is stirred at 0° C. for 15 min and the title C compound, (4R,5S)-3-((R)-3-cyclopentyl-2-phenyl-propionyl)-4-methyl-5-phenyl-oxazolidin-2-one (3.85 g, 10.2 mmol) is added in five separate portions, allowing portions to dissolve completely between additions. The reaction is allowed to stir and warm to RT overnight. The reaction is then concentrated to a sticky white solid. This is dissolved in ethyl acetate (25 mL)/1 N HCl (25 mL). The organic solution is dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product as a yellow oil. The crude product is chromatographed over silica eluting with 5→65% ethyl acetate in hexanes to afford (R)-3-cyclopentyl-2-phenyl -propionic acid as a white solid: 1H NMR (400 MHz, CDCl3) δ 1.1 (m, J=11.6, 7.8, 7.8, 3.9 Hz, 2 H) 1.5 (m, 2 H) 1.6 (m, 2 H) 1.7; LC/MS 217.2 (M−1).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.Cl[C:10]1[CH:19]=[N:18][C:17]2[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:20][CH3:21])[CH:16]=2)[N:11]=1>C(O)C>[CH3:21][O:20][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][C:14]=1[O:22][CH3:23])[N:11]=[C:10]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1)[CH:19]=[N:18]2
Reactant: N[C@H]1CC[C@@H](O)CC1
Reactant: COc1cc2ncc(Cl)nc2cc1OC
Solvent: CCO
Product: COc1cc2ncc(N[C@H]3CC[C@@H](O)CC3)nc2cc1OC
Temperature: 180 °C

Procedure:
A mixture of cis-4-aminocyclohexanol (400 mg, 3.48 mmole) and 2-chloro-6,7-dimethoxyquinoxaline (450 mg, 2 mmole) in 5 mL of ethanol is placed in sealed tube and then heated at 180° C. for 3 hours. The dark-brown mixture is chromatographed on silica gel and eluted with ethyl acetate to provide the desired product (m.p. 65-67° C.). Anal. Calcd. for C16H21N3O3.0.6H2O: C, 61.17; H, 7.12; N, 13.37; Found: C, 61.22; H, 7.19; N, 12.19.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:22][C:23](=[O:28])[CH2:24][CH2:25][C:26]#[CH:27])[CH2:19][CH2:20][CH3:21]>CCN(CC)CC.[Cu]I>[CH2:18]([O:22][C:23](=[O:28])[CH2:24][CH2:25][C:26]#[C:27][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:7]=1)[CH2:19][CH2:20][CH3:21]
Reactant: C#CCCC(=O)OCCCC
Reactant: COc1ccc(CNc2cccc(Br)n2)cc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCCCOC(=O)CCC#Cc1cccc(NCc2ccc(OC)cc2)n1
Reaction time: 12 h
Yield: 79.6 %

Procedure:
To a mixture of 6-2 (8.64 g, 29.48 mmol) and 6-4 (5.0 g, 32.4 mmol) in Et3N (50 mL) at 0° was added CuI (0.14 g, 0.74). The solution was purged with argon and [(C6H5)3P]2PdCl2 (0.52 g, 0.74 mmol) was added. After 1 h the cooling bath was removed and the solution was stirred for an additional 12 h. The solution was diluted with diethyl ether (250 mL) and washed with water (4×100 ml) followed by brine (100 mL). The etheral layer was dried (Na2SO4), concentrated, and chromatographed (silica gel, 30% ethyl acetate/hexanes) to give 8.6 g of 6-5.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[CH:27][C:26]=1[C:35](O)=[O:36].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[CH:27][C:26]=1[C:35]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:36]
Reactant: O=C(O)c1cnc2ccccc2n1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3cnc4ccccc4n3)cc2)c2ccc3ccccc3c2N1
Yield: 20.9 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.101 mmol) obtained in Example 1, (3), quinoxaline-2-carboxylic acid (35 mg, 0.202 mmol), and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (42 mg, 0.111 mmol) were dissolved in DMF (2.0 mL), then the solution was added with triethylamine (20 mg, 0.202 mmol), and the mixture was stirred over night. The reaction mixture was treated in a conventional manner to obtain the title compound (10 mg, yield 21%) as yellow crystals.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])(=O)=O.[C:42](=[O:45])([O-])[O-].[K+].[K+].O>C(COC)OC>[OH:45][C:42]1[CH:14]=[CH:15][C:7]([C:7]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[C:18]4[C:23]([CH:24]=3)=[CH:22][C:21]([CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:20][CH:19]=4)=[C:12]3[C:8]=2[CH2:9][NH:10][C:11]3=[O:39])=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(-c3ccc(O)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 131.9 %

Procedure:
In a similar manner to Step 1 of Example 152, 4-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (300 mg, 0.505 mmol) was dissolved in dimethoxyethane (21 mL), and the solution was treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenol (222 mg, 1.01 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (33.0 mg, 0.0404 mmol), potassium carbonate (349 mg, 2.53 mmol) and water (0.182 mL), followed by purification by flash column chromatography (chloroform/methanol=90/10 to 80/20) to obtain 4-(4-hydroxyphenyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (179 mg, yield 66%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]2[C:18](=[O:19])[CH:17]=[CH:16][C:15]([C:20]#[N:21])=[N:14]2)[CH:7]=1)[CH3:2].[Cl-].C([NH2+]CC)C.O.[S-2:30].[Na+].[Na+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:22])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]2[C:18](=[O:19])[CH:17]=[CH:16][C:15]([C:20](=[S:30])[NH2:21])=[N:14]2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Nc1cccc(Cn2nc(C#N)ccc2=O)c1
Reactant: [S-2]
Agent: CC[NH2+]CC
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Nc1cccc(Cn2nc(C(N)=S)ccc2=O)c1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
200 mg (0.67 mmol) of ethyl[3-(3-cyano-6-oxo-6H-pyridazin-1-ylmethyl)-phenyl]carbamate are dissolved in 1 ml of DMF, and 219 mg (2 mmol) of diethylammonium chloride and 165 mg (2 mmol) of sodium sulfide hydrate are added. The yellow suspension is stirred at 55° C. for 2 hours. 10 ml of water are added to the reaction mixture. The precipitate is filtered off with suction, washed with water and dried in vacuo. The substance is reacted further without further purification.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:17][C@@H:18]([NH2:21])[CH2:19][CH3:20].CCN(C(C)C)C(C)C>CS(C)=O>[C@H:18]([NH:21][C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)([CH2:19][CH3:20])[CH3:17]
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: CC[C@@H](C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC[C@@H](C)Nc1nc2cc(C(=O)OC)ccc2[nH]c1=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 73.5 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (0.5 g, 2.1 mmol) in DMSO (10 mL) was added (R)-butan-2-amine (570 mg, 7.79 mmol) and DIEA (850 mg, 6.58 mmol). The resulting solution was stirred for 4 hours at 70° C. and then quenched by the addition of water (50 mL). The solids were collected by filtration to afford (R)-methyl 3-(sec-butylamino)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a white solid (425 mg, 75%).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26].O>C1COCC1>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:14]4=[N:19][S:25](=[O:27])(=[O:26])[CH2:24][CH2:23][N:15]4[CH:16]=[CH:17][CH:18]=3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncccc1-c1ccc(C2CCCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(c3ccc(C4CCCCC4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
A mixture of 3-(4-cyclohexylphenyl)pyridin-2-amine (57 mg) in dehydrated THF (5 mL) was added to a mixture of sodium hydride (60%, 45.2 mg) and 2-chloroethanesulfonyl chloride (110 mg) in dehydrated THF (5 mL) under ice-cooling. The reaction mixture was stirred at room temperature overnight, and water was added. The resulting precipitate was collected by filtration, and washed with water and diisopropyl ether to give the title compound (40.3 mg) as a white solid. The obtained solid was crystallized from acetonitrile and diisopropyl ether to give a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7]([F:13])=[C:8]([F:12])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].C([Li])CCC.[O:19]1[C:23]2([CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]2)[O:22][CH2:21][CH2:20]1.Cl>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:26]2([OH:29])[CH2:27][CH2:28][C:23]3([O:22][CH2:21][CH2:20][O:19]3)[CH2:24][CH2:25]2)=[C:8]([F:12])[C:7]=1[F:13])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CCCCOc1cccc(F)c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCOc1ccc(C2(O)CCC3(CC2)OCCO3)c(F)c1F
Reaction time: 2 h
Yield: 99.7 %

Procedure:
3-Butoxy-1,2-difluorobenzene (7) (30.0 g) and THF (500 ml) were added to a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. n-Butyllithium (1.66 M in n-hexane solution; 120 ml) was added dropwise in the temperature range of −74° C. to −70° C. and the stirring was continued for another 2 hours. Successively, 1,4-dioxaspiro[4.5]decan-8-one (8) (30.2 g) in THF (200 ml) solution was added dropwise in the temperature range of −75° C. to −70° C., and the stirring was continued for another 8 hours while the mixture was allowed to come to 25° C. The resulting reaction mixture was poured into a 1N—HCl aqueous solution (500 ml) and ethyl acetate (500 ml) in a vessel and mixed with them. The mixture was then allowed to stand until it had separated into organic and aqueous phases, and the extraction into an organic phase was carried out. The resulting organic phase was separated, and washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure to leave 8-(4-butoxy-2,3-difluorophenyl)-1,4-dioxaspiro[4.5]decan-8-ol (9) (55.0 g). The resulting compound (9) was a pale yellow oil.