Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([O:12][CH3:11])=[CH:14][C:15]=2[N+:20]([O-:22])=[O:21])=[O:7])=[CH:9][CH:10]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: COc1ccc(NC(=O)c2ccc(Cl)nc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 4-methoxy-2-nitroaniline and was obtained as a yellow solid as described in Example 1. 1H NMR (CDCl3): 11.13 (s, 1H), 9.01 (d, J=2.7, 1H), 8.83 (d, J=9.3, 1H), 8.24-8.20 (m, 1H), 7.76 (d, J=2.7, 1H), 7.52 (d, J=8.7, 1H), 7.35-7.31 (m, 1H), 3.90 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]([CH2:26][F:27])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]3[CH:17]=[C:18]([CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[N:19]=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1)[OH:4].C(N(CC)CC)C.[F:35][CH:36]([F:42])[C:37](OCC)=[O:38]>CO>[F:35][CH:36]([F:42])[C:37]([NH:1][C@H:2]([CH2:26][F:27])[C@H:3]([OH:4])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]3[CH:17]=[C:18]([CH2:20][NH:21][S:22]([CH3:25])(=[O:23])=[O:24])[N:19]=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1)=[O:38]
Reactant: CCOC(=O)C(F)F
Reactant: CS(=O)(=O)NCc1cn2ccc(-c3ccc([C@@H](O)[C@H](N)CF)cc3)cc2n1
Solvent: CO
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCc1cn2ccc(-c3ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc3)cc2n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution N-{7-[4-((1R,2S)-2-Amino-3-fluoro-1-hydroxy-propyl)-phenyl]imidazo[1,2-a]pyridin-2-ylmethyl}-methane sulfonamide (88 mg, crude) in methanol (1 mL) is added triethyl amine (0.05 mL, 0.346 mmol) followed by addition of ethyl difluoroacetate (0.02 mL, 0.208 mmol) at 0° C. then stirred at room temperature for 20 h. The reaction mixture is concentrated and purified by flash column chromatography eluting in 2.1% MeOH in CH2Cl2 followed by re-purification by preparative TLC to afford 5 mg and which is re-crystallized in
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:17])[CH2:14][CH2:15][CH:16]=1)([OH:3])=[O:2].[CH2:18](O)[CH3:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:17])[CH2:14][CH2:15][CH:16]=1)([O:3][CH2:18][CH3:19])=[O:2]
Reactant: O=C(O)CCCCCCCCC1=CCCC1=O
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)CCCCCCCCC1=CCCC1=O

Procedure:
The acid ketone from Example 22 is Fisher esterified with 100 ml. of absolute ethanol, 100 ml. of benzene, and 20 mg. of p-toluenesulfonic acid for 6 hours, cooled, and the solvent is evaporated. The resulting oil is dissolved in 3:1 benzene-ether and the solution is passed through a column of 100 g. of Florisil®. The filtrate is evaporated and the residue is distilled to yield 2.97 g. of a colorless oil, b.p. 137°-139° C. (0.05 Torr).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:11])[CH:5]=[N:6][C:7]=1[N:8]([CH3:10])[CH3:9].[F:12][C:13]([F:35])([F:34])[C:14]1[CH:15]=[C:16]2[CH:22]=[C:21]([C:23](O)=[O:24])[N:20]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)[C:17]2=[N:18][CH:19]=1>>[F:1][C:2]1[CH:3]=[C:4]([NH:11][C:23]([C:21]2[N:20]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)[C:17]3=[N:18][CH:19]=[C:14]([C:13]([F:12])([F:35])[F:34])[CH:15]=[C:16]3[CH:22]=2)=[O:24])[CH:5]=[N:6][C:7]=1[N:8]([CH3:9])[CH3:10]
Reactant: O=C(O)c1cc2cc(C(F)(F)F)cnc2n1Cc1cccc(F)c1
Reactant: CN(C)c1ncc(N)cc1F
Product: CN(C)c1ncc(NC(=O)c2cc3cc(C(F)(F)F)cnc3n2Cc2cccc(F)c2)cc1F
Yield: 385.6 %

Procedure:
Compound No. 35 was prepared by a method similar to that described in Stage 1.4 by reacting 0.4 g (1.18 mmol) of 5-fluoro-6-(N,N-dimethylamino)-3-aminopyridine (WO2004/110986), with 0.4 g (0.18 mmol) of 5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid obtained in Stage 1.3. We thus obtain 0.33 g of the expected product in the form of a solid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[CH3:31][O:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[CH:35][C:34]=1[NH:48][C:49](=[O:61])[C:50]1[CH:55]=[CH:54][C:53]([C:56]([F:59])([F:58])[F:57])=[CH:52][C:51]=1[F:60].O.C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC.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>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:3]=[C:2]([C:37]3[CH:36]=[CH:35][C:34]([NH:48][C:49](=[O:61])[C:50]4[CH:55]=[CH:54][C:53]([C:56]([F:58])([F:59])[F:57])=[CH:52][C:51]=4[F:60])=[C:33]([O:32][CH3:31])[CH:38]=3)[C:10]=12
Reactant: Nc1ncnc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
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: COCCOC
Solvent: O
Product: COc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 85 °C
Yield: 89.5 %

Procedure:
A mixture of 3-iodo-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.10 g, 0.19 mmol), N1-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-fluoro-4-trifluoromethylbenzamide (0.13 g, 0.29 mmol), tetrakis(triphenylphosphine)palladium(0) (0.01 g, 0.01 mmol) and sodium carbonate monohydrate (0.06 mg, 0.48 mmol) in water (2 mL) and ethylene glycol dimethyl ether (4 mL) was heated at 85° C. overnight. The solvents were removed under reduced pressure. Water was added into the residue and the mixture was extracted with ethyl acetate three times. The combined organics were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to yield a brown solid which was purified by flash column chromatography on silica using Isco system to provide N1-[4-(4-amino-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-2-fluoro-4-trifluoromethylbenzamide (0.12 g, 0.17 mmol) as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 9.89 (dd, 1H), 8.25(d, 1H), 8.28 (s, 1H), 8.00 (t, 1H), 7.94 (s, 1H), 7.88 (d, 1H), 7.73 (d, 1H), 7.24 (m, 15H), 3.90 (s, 3H); MS: MH+ 689.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([NH:7][CH2:8][CH:9]([OH:21])[CH2:10][N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:6].[CH3:25][C:26]1([CH3:33])[CH2:31][C:30](=O)[CH2:29][CH2:28][O:27]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH2:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH2:20][N:11]1[CH2:10][CH:9]([OH:21])[CH2:8][NH:7][C:5](=[O:6])[C:4]1[CH:22]=[CH:23][CH:24]=[C:2]([NH:1][CH:30]2[CH2:29][CH2:28][O:27][C:26]([CH3:33])([CH3:25])[CH2:31]2)[CH:3]=1
Reactant: CC1(C)CC(=O)CCO1
Reactant: Nc1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC1(C)CC(Nc2cccc(C(=O)NCC(O)CN3CCc4ccccc4C3)c2)CCO1
Temperature: 22 °C
Reaction time: 12 h
Yield: 3.1 %

Procedure:
A solution of 3-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)benzamide (130 mg, 0.4 mmol), 2,2-dimethyldihydro-2H-pyran-4(3H)-one (52 mg, 0.4 mmol) and AcOH (0.1 mL) in MeOH (10 mL). The mixture was stirred at 22° C. for 12 h, then NaBH3CN (76 mg, 1.2 mmol) was added and the resulting mixture was stirred at 22° C. for 2 h. The reaction mixture was concentrated and quenched with water. The aqueous mixture was extracted with DCM, the combined organic layers were concentrated and the residue was purified by prep-HPLC to give the title compound (5.5 mg, Yield 3.1%). 1H NMR (CD3OD, 400 MHz): δ 8.42 (brs, 1H) 7.00-7.33 (m, 7H) 6.84 (d, J=7.8 Hz, 1H) 4.21-4.41 (m, 3H) 3.40-3.92 (m, 8H) 3.11-3.20 (m, 3H) 1.91-2.07 (m, 2H) 1.18-1.44 (m, 8H). LCMS (m/z): 438.3 (M+1).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([C:31]([CH3:35])([CH3:34])[CH:32]=O)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]>>[CH3:35][C:31]([C:29]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([O:22][CH3:21])[CH:30]=1)([CH3:32])[CH2:34][N:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][C:4]2[C:3]([CH3:2])=[C:11]3[C:7](=[CH:6][CH:5]=2)[C:8](=[O:12])[O:9][CH2:10]3)[CH2:16][CH2:17]1
Reactant: Cc1c(CCN2CCNCC2)ccc2c1COC2=O
Reactant: COc1cc(C(C)(C)C=O)ccc1C#N
Agent: Cl
Product: COc1cc(C(C)(C)CN2CCN(CCc3ccc4c(c3C)COC4=O)CC2)ccc1C#N

Procedure:
4-[1,1-Dimethyl-2-[4-[2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]-2-methoxy-benzonitrile was prepared in a similar fashion to that described for the synthesis of Example 38 starting from 4-methyl-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride and 2-methoxy-4-(2-methyl-1-oxopropan-2-yl)benzonitrile. LC-MS (IE, m/z): 448.6 [M+1]+. (0.30 μM)
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH2:18][OH:19])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:22])[CH3:21])[S:14]2)[C@H:10]1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>ClCCl>[CH3:31][S:32]([O:19][CH2:18][C@H:17]1[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:22])[CH3:21])[S:14]2)[C@@H:10]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:9]1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](CO)O[C@@H]2S1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](COS(C)(=O)=O)O[C@@H]2S1
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To a solution of ((3aR,5R,6S,7R,7aR)-6,7-bis(benzyloxy)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methanol (94) (8 g, 18 mmol) (Prepared according to the synthesis of Example 149, step 2) in dichloromethane (50 mL) was added methanesulfonyl chloride (4.3 g, 37 mmol) and triethylamine (3.8 g, 37 mmol) at 0° C. After kept 2 hours at 25° C., the reaction was quenched by water (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic layer was washed with brine (2×30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, which was purified by a silica gel column, eluted with 20%-30% ethyl acetate in petroleum ether to afford the title compound as a brown syrup (8.5 g, 90%); (ES, m/z) [M+H]+ 507.0; 1HNMR (300 MHz, CDCl3) δ 7.28-7.48 (m, 10H), 6.38 (d, J=6.6 Hz, 1H), 5.04-5.08 (m, 1H), 4.72-4.86 (m, 4H), 4.19-4.24 (m, 3H), 3.70-3.83 (m, 1H), 3.56-3.58 (m, 1H), 3.19 (s, 3H), 2.94 (s, 6H).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21](OC)=[O:22])[CH:17]=[CH:18][CH:19]=1>C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21](=[O:22])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])[CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)Cc1cccc(Cl)c1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)Cc1cccc(Cl)c1)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.8 %

Procedure:
To a solution of dimethyl methylphosphonate (4.32 mL, 40 mmol) in anhydrous THF (40 mL), cooled at −78° C. was added n-BuLi (1.6 M in hexane, 27.5 mL, 44 mmol). The mixture was stirred for 30 minutes at this temperature under nitrogen. Methyl 3-chlorophenylacetate (3.69 mL, 20 mmol) was added dropwise for 10 minutes. The mixture was stirred for 2 hours at −78° C., gradually was warm to room temperature. The mixture was quenched with addition of 1N HCl to pH 4-5. The organic layer was separated, washed with brine and dried over MgSO4. The residue was purified through flash chromatography on silica gel (MeOH/CH2Cl2 1.5/98.5) to give the product (1.43 g) with colorless oil in 26% yield. 1H-NMR (CDCl3) δ 3.07 (d, J=21 Hz, 2H), 3.750 (s, 3H), 3.775 (s, 3H), 3.873 (s, 2H), 7.01 (t, J=8.0 Hz, 1H), 7.19 (s, 1H), 7.28 (d, J=8.0 Hz, 2H).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=O)C1C=CC=CC=1.[ClH:25]>C(O)C.[Pd]>[ClH:25].[NH2:11][C@H:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C[C@H](NC(=O)OCc1ccccc1)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C[C@H](N)c1ccccc1

Procedure:
10.29 g of ethyl (S)-3-benzyloxycarbonylamino-3-phenylpropionate (31.44 mmol) are dissolved in 125 ml of ethanol and hydrogenated catalytically over Pd/active charcoal at a Ph of 4 using an automated burette and while adding 2N ethanolic HCl. The catalyst is filtered off with suction through kieselguhr and the filtrate is concentrated. The residue is triturated with diethyl ether, filtered off with suction, washed with diethyl ether and dried over phosphorus pentoxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](/[CH:24]=[CH:25]/[CH:26]([OH:35])[CH2:27][CH:28]([OH:34])[CH2:29][C:30]([O:32][CH3:33])=[O:31])=[C:10]([CH:21]([CH3:23])[CH3:22])[N:11]3[N:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]=23)=[CH:4][CH:3]=1.CCCCCC>C(OCC)C.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](/[CH:24]=[CH:25]/[C:26](=[O:35])[CH2:27][CH:28]([OH:34])[CH2:29][C:30]([O:32][CH3:33])=[O:31])=[C:10]([CH:21]([CH3:23])[CH3:22])[N:11]3[N:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]=23)=[CH:4][CH:3]=1
Reactant: COC(=O)CC(O)CC(O)/C=C/c1c(-c2ccc(F)cc2)c2c3ccccc3cnn2c1C(C)C
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCCCCC
Solvent: CCOCC
Product: COC(=O)CC(O)CC(=O)/C=C/c1c(-c2ccc(F)cc2)c2c3ccccc3cnn2c1C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.2 %

Procedure:
A solution of methyl (E)-7-{1-(4-fluorophenyl)-3-isopropylpyrrolo[2,1-a]phthalazin-2-yl}-3,5-dihydroxyhept-6-enoate (3.16 g) in anhydrous diethyl ether (100 ml) was treated with activated manganese dioxide (12.61 g) and the mixture was stirred at room temperature under an argon atmosphere with the exclusion of light for 18 hours. The mixture was then filtered through diatomaceous earth. The filter pad was washed with diethyl ether (2×150 ml) and the combined filtrate and washings were concentrated to give an orange foam. This foam was subjected to flash chromatography on silica gel, using a mixture of diethyl ether and hexane (4:1 v/v) as eluant, to give methyl (E)-7-{1-(4-fluorophenyl)-3-isopropylpyrrolo[2,1-a]phthalazin-2-yl)-3-hydroxy-5-oxohept-6-enoate (1.61 g), in the form of an orange foam. [NMR (in CDCl3): 1.59 (6H, d, J=8 Hz), 2.55 (4 H, m), 3.45-4.15 (5 H, m), 4.40 (1H, m), 5.82 (1H, d, J=16 Hz), 7.05-7.70 (8H, m), 7.85 (1H, d, J=16 Hz), 8.30 (1H, s)].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15]C(=O)OC(C)(C)C)[CH2:10][CH2:9]2)[C:5]([CH:23]2[CH2:25][CH2:24]2)=[CH:4][N:3]=1.[NH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])[CH2:31][CH2:30]2>C(O)CCC.C(O)(C(F)(F)F)=O>[NH2:15][CH2:14][CH:11]1[CH2:10][CH2:9][N:8]([C:6]2[C:5]([CH:23]3[CH2:24][CH2:25]3)=[CH:4][N:3]=[C:2]([NH:26][C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][CH:36]=3)[NH:33][C:32](=[O:37])[CH2:31][CH2:30]4)[N:7]=2)[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2nc(Cl)ncc2C2CC2)CC1
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCO
Product: NCC1CCN(c2nc(Nc3ccc4c(c3)CCC(=O)N4)ncc2C2CC2)CC1
Temperature: 140 °C
Reaction time: 20 h
Yield: 15.1 %

Procedure:
A solution of tert-butyl (1-(2-chloro-5-cyclopropylpyrimidin-4-yl)piperidin-4-yl)methylcarbamate (99 mg, 0.27 mmol) and 6-amino-3,4-dihydroquinolin-2(1H)-one (50 mg, 0.30 mmol) in nBuOH (3 mL) was stirred at 116° C. for 20 h. It was then stirred at 140° C. for another 20 h. It was concentrated in vacuo. The residue was purified by HPLC to give a powder, which was then dissolved in TFA (3 mL). After being stirred at room temperature for 20 h, TFA was removed in vacuo. The residue was purified by HPLC to give the titled compound (16 mg). MS 393.5 (M+H); UV 208.9, 264.5 nm
Reaction SMILES: C(O[C@H:5]1[C@H:10]2[C:11]([CH2:14]OC(=O)C)=[CH:12][CH2:13][C@@H:9]2[C:8]([C:19]([O:21][CH3:22])=[O:20])=[CH:7][O:6]1)(=O)C.[H][H]>C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[CH3:14][CH:11]1[C@H:10]2[CH2:5][O:6][CH:7]=[C:8]([C:19]([O:21][CH3:22])=[O:20])[C@H:9]2[CH2:13][CH2:12]1
Reactant: COC(=O)C1=CO[C@@H](OC(C)=O)[C@H]2C(COC(C)=O)=CC[C@H]12
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COC(=O)C1=COC[C@@H]2C(C)CC[C@H]12
Yield: 81.5 %

Procedure:
After methyl (1S, 4aS, 7aR)-1-acetoxy-7-(acetoxymethyl)-1,4a,5,7a-tetrahydrocyclopenta[c]pyran-4-carboxylate (100 mg, 0.0003 mol) obtained in Example 21 was dissolved in 5 ml of ethyl acetate, 20% Pd(OH)2 - C (5 mg) was added to the solution, and the reaction mixture was stirred for 24 hours in a hydrogen gas atmosphere of 1 atm. The catalyst was removed by celite filtration and the filtrate was concentrated. The residual substance was purified by chromatography using silica gel, and the solvent of the fraction obtained from hexane:ether=2:8 eluent was distilled, and a colorless oily substance was obtained, i.e., methyl (4aS, 7aR)-1,4a,5,6,7,7a-hexahydro-7-methylcyclopenta[c]pyran-4-carboxylate (48 mg, yield=30.4%). This methyl (4aS, 7aR)-1,4a,5,6,7,7a-hexahydro-7-methylcyclopenta[c]pyran-4-carboxylate had the following physicochemical properties.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[C:25]([C:29]1[CH:30]=[C:31]([CH3:55])[C:32](=[C:34]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=2)[CH:33]=1)([CH3:28])([CH3:27])[CH3:26].Cl>C(OCC)C>[C:25]([C:29]1[CH:30]=[C:31]([CH3:55])[CH:32]([C:34]([C:1]2[C:13]3[CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[CH:4]=[CH:3][CH:2]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:42])([F:43])[F:44])[CH:36]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=2)[CH:33]=1)([CH3:26])([CH3:27])[CH3:28]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC1=CC(C(C)(C)C)=CC1=C(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1=CC(C(C)(C)C)=CC1C(c1cccc(C(F)(F)F)c1)(c1cccc(C(F)(F)F)c1)c1cccc2c1Cc1ccccc1-2
Temperature: 25 °C

Procedure:
In a 200 ml three-necked flask equipped with a magnetic stirrer chip and three-way cock thoroughly purged with nitrogen, 1.44 g of fluorene (8.69 mmol) was dissolved in 60 ml of dehydrated diethylether in a nitrogen atmosphere. To the solution, 5.8 ml of n-butyl lithium/hexane solution (1.58M: 9.16 mmol) was gradually added dropwise in an ice bath and stirred at room temperature over night. To the reaction solution, 4.15 g of 3-tert-butyl-1-methyl-6,6-di(3-trifluoromethyl-phenyl)fulvene (9.50 mmol) was added and stirred under reflux for several days. The reaction mixture was gradually added dropwise to 30 ml of a hydrochloric acid aqueous solution set (1N) in an ice bath, and stirred at room temperature briefly. Therein, diethyl ether was added to separate an organic phase. The organic phase was washed with distilled water and saturated brine. The organic phase was dried with anhydrous magnesium sulfate, thereafter the drying agent was filtered off and the solvent was distilled off from the filtrate under reduced pressure to give a dark red solid. The solid was purified with a column chromatography using 220 g of silica gel (developing solvent: n-hexane) and the developing solvent was distilled off under reduced pressure. Thereafter, the remaining product was re-crystallized using hexane and dried under reduced pressure, and thereby the aimed compound was obtained in an amount of 1.69 g (2.72 mmol) as a white solid (yield: 31%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([S:12]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].B(O)(O)[C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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>[CH:15]1([S:12]([C:10]2[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=[C:2]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[CH:11]=2)(=[O:14])=[O:13])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)c1cc(Br)cc(S(=O)(=O)C2CCCC2)c1
Reactant: Cc1ccc(B(O)O)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: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc(-c2ccc(C)cc2)cc(S(=O)(=O)C2CCCC2)c1

Procedure:
A microwave vial was charged with methyl 3-bromo-5-(cyclopentylsulfonyl)benzoate (0.50 g, 1.44 mmol), p-tolylboronic acid (0.44 g, 3.25 mmol), toluene (7 mL), and a solution of cesium carbonate (1.06 g, 3.26 mmol) in water (0.3 mL). The vial was degassed and purged with argon, and then tetrakis(triphenylphosphine)palladium(0) (0.16 g, 0.14 mmol) was added. The reaction mixture was subjected to microwave irradiation at 100° C. for 2 h. After cooling, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified via flash column (0-25% EtOAc/hexane) to yield the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[N+:7]=1[O-:8].[N+:16]([O-])([OH:18])=[O:17].[OH-].[Na+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:3]=[C:4]([N+:16]([O-:18])=[O:17])[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[N+:7]=1[O-:8]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(-c2cccc(C)[n+]2[O-])n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(-c2cc([N+](=O)[O-])cc(C)[n+]2[O-])n1
Temperature: 0 °C

Procedure:
6,6'-Dimethyl-2,2'-bipyridine-N-oxide (1.50 g, 0.00749 moles) was dissolved in concentrated sulfuric acid (8.0 ml) and fuming nitric acid (6.0 ml) and the mixture was heated at 100° C. for four hours. The solution was poured slowly into ice-water and the pH was adjusted to 5.5 with 10% sodium hydroxide. The product was filtered and dried.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH2:37])[CH:29]=3.[CH3:39][N:40]1[CH:44]=[CH:43][C:42]([C:45](Cl)=[O:46])=[N:41]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH:37][C:45]([C:42]1[CH:43]=[CH:44][N:40]([CH3:39])[N:41]=1)=[O:46])[CH:29]=3
Reactant: Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Reactant: Cn1ccc(C(=O)Cl)n1
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccc(C(=O)Nc2cc3cc(c2)Nc2nc(ncc2Cl)Nc2cccc(c2)CC3)n1
Yield: 47 %

Procedure:
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-11-amine bis(trifluoroacetate) and 1-methyl-1H-pyrazole-3-carbonyl chloride as the starting materials in 47% yield. LCMS for C23H21ClN7O (M+H)+: m/z=446.2. 1H NMR (400 MHz, DMSO-d6): δ 9.93 (s, 1H), 9.76 (s, 1H), 9.70 (s, 1H), 8.20 (s, 1H), 7.88 (m, 1H), 7.82 (d, 1H), 7.64 (m, 1H), 7.42 (m, 1H), 7.36 (m, 1H), 7.11 (dd, 1H), 6.87 (m, 2H), 6.73 (d, 1H), 3.94 (s, 3H), 2.86 (m, 4H).