Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C:13]([CH3:41])([CH3:40])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([S:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.ClC1C=CC=C(C(OO)=[O:52])C=1>ClCCl>[F:43][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([C:13]([CH3:41])([CH3:40])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([S:31]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)=[O:52])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cccc(Sc2cc(-c3ccccc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)c1
Solvent: ClCCl
Product: COc1cccc(S(=O)c2cc(-c3ccccc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)c1
Temperature: 25 °C
Yield: 6.8 %

Procedure:
To a solution of 130 mg (0.210 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-methoxy-phenylsulfanyl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide (Example 103) in 1 ml dichloromethane a solution of 52 mg (0.21 mmol) 3-chloroperbenzoic acid in 1.5 ml dichloromethane was added at 0° C. After completed addition the reaction mixture was allowed to warm to room temperature and stirred over night. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium carbonate solution. The aqueous layer was extracted with three portions of dichloromethane. The combined organic layers were dried with sodium sulfate and concentrated. Column chromatography afforded 9 mg (7%) of the title compound as a colorless viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][C:5]2[N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:4]=2[C:3]=1[OH:21].CI.[C:24]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.CCOC(C)=O>[F:1][C:2]1[C:3]([O:21][CH3:24])=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(O)c(F)cnc32)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(F)cnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ol, 68a, (0.70 g, 2.29 mmol) in DMF (25 mL) was added methyliodide (0.14 mL, 2.29 mmol) and K2CO3 (0.32 g, 2.29 mmol). The reaction mixture was stirred for 3 hours at ambient temperature. The reaction was diluted with deionized water and EtOAc. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford 720 mg of the desired product that was used in next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[NH:13][CH:14]=[CH:15][N:16]=1)[C:5]([O:7][CH3:8])=[O:6].Br[CH2:18][CH2:19]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N:16]1[CH:15]=[CH:14][N:13]2[C:12]=1[C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[O:1][CH2:19][CH2:18]2
Reactant: BrCCBr
Reactant: COC(=O)c1ccc(-c2ncc[nH]2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)OCCn1ccnc1-2
Temperature: 90 °C
Yield: 81.9 %

Procedure:
A mixture of methyl 3-hydroxy-4-(1H-imidazol-2-yl)benzoate (2.2 g, 10 mmol), 1,2-dibromoethane (3.12 mL, 36 mmol) and cesium carbonate (13.14 g, 40 mmol) in DMF (100 mL) was heated at 90° C. for 12 hours. The mixture was filtered, the mother liquor was concentrated in vacuo, and the residue was partitioned between water and ethyl acetate. The suspension was filtered and the solid was pure byproduct. The organic layer was washed with water, brine and dried over MgSO4 and concentrated to give crude methyl 5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (2 g, 80%).
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15]([OH:17])=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH2:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][NH:21]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2[N:6]([CH2:14][C:15]([N:21]3[CH2:22][CH2:23][C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20]3)=[O:17])[C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=3[C:18]=2[CH2:19]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)O)CCN(C)C1
Reactant: c1ccc2c(c1)CCNC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(=O)N2CCc3ccccc3C2)CCN(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.3 %

Procedure:
A mixture of 2-(1, 2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetic acid (50 mg, 0.205 mmol), 1, 2, 3, 4 Tetrahydroisoquinoline (25 mg, 0.205 mmol), DCC (46 mg, 0.22 mmol), and DMAP (27 mg, 0.22 mmol) in dry DCM (2.0 mL) was stirred at room temperature for 3 h. The reaction mixture was filtered through Celite and concentrated using rotary evaporator afforded 7.9 mg of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(3,4-dihydroisoquinolin-2(1H)-yl)ethanone as TFA Salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:17]([N:21]1[C:25]([CH:26]=O)=[CH:24][C:23]([CH2:28][CH:29]([CH3:31])[CH3:30])=[N:22]1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([N:21]1[C:25]([CH2:26][NH:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:13][CH2:12]2)=[CH:24][C:23]([CH2:28][CH:29]([CH3:31])[CH3:30])=[N:22]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)Cc1cc(C=O)n(C(C)(C)C)n1
Reactant: NCCN1CCN(c2cccc(Cl)c2)CC1
Product: CC(C)Cc1cc(CNCCN2CCN(c3cccc(Cl)c3)CC2)n(C(C)(C)C)n1
Yield: 54.8 %

Procedure:
Compound 78 was prepared using the same method as that of Example 1 except that 4-(3-chlorophenyl)piperazin-1-ylethylamine and 2-t-butyl-5-iso-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:2]=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:49][CH:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)[C:40]([NH:42][C:43]2[CH:47]=[CH:46][N:45]([CH3:48])[N:44]=2)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].C(N1C=CC(N)=N1)CC.N1C(C)=CC=CC=1C>C(Cl)Cl.C(OCC)(=O)C>[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:49][CH:50]2[CH2:51][CH2:52][CH2:53][CH2:54]2)[C:40]([NH:42][C:43]2[CH:47]=[CH:46][N:45]([CH2:48][CH2:1][CH3:2])[N:44]=2)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: CCCn1ccc(N)n1
Agent: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
Triphenylphosphine (173 mg, 0.66 mmol) was dissolved in methylene chloride (8 mL) and cooled to 0° C. To this solution was added N-bromosuccinimide (133 mg, 0.75 mmol) and was stirred at 0° C. until it was completely dissolved and became light purple in color. The 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 146 mg, 0.44 mmol) was then added and it was stirred at 0° C. for 15 min and then warmed to 25° C. and stirred for 30 min. The mixture was chilled to 0° C. and 1-propyl-1H-pyrazol-3-ylamine (54 mg, 0.43 mmol) was added followed by 2,6-lutidine (154 μL, 1.32 mmol). The mixture was continued to stir at 0° C. for 30 min and then at 25° C. for 3 h. The reaction was diluted with ethyl acetate (50 mL), washed with water (3×20 mL) and saturated aqueous brine solution (2×20 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 10% ethyl acetate/hexanes to 70% ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-propyl-1H-pyrazol-3-yl)-propionamide (104 mg, 55%) as a white foam: ESI-LRMS m/e calcd for C21H28ClN3O3S [M+] 437.2, found 438.3 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 0.85 (t, J=7.4 Hz, 1H, CH3), 1.04-1.16 (m, 2H, CH2), 1.38-1.93 (m, 10H, 5×CH2), 2.10-2.41 (m, 1H, CH), 3.24 (s, 3H, SO2CH3), 3.59 (t, J=7.5 Hz, 1H, CH), 3.89 (t, J=7.0 Hz, 2H, NCH2), 6.61 (d, J=2.2, 1H, Ar), 7.23 (d, J=2.2, 1H, Ar), 7.44 (dd, Jo=8.2, Jm=1.3 Hz. 1H, Ar), 7.57 (d, Jm=1.3 Hz, 1H, Ar), 8.02 (d, Jo=8.2 Hz, 1H, Ar), 8.61 (s, 1H, NH).
Reaction SMILES: [N:1]([CH:4]([CH3:19])[CH2:5][N:6]1[C:10]2=[CH:11][C:12]3[C:17]([CH2:16][CH:15]=[CH:14][C:13]=3[CH3:18])=[C:9]2[CH:8]=[N:7]1)=[N+]=[N-].[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24]>C(O)C.C(OCC)C.CO.[Pt]=O>[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24].[CH3:18][C:13]1[CH:14]=[CH:15][CH2:16][C:17]2[C:12]=1[CH:11]=[C:10]1[C:9]=2[CH:8]=[N:7][N:6]1[CH2:5][CH:4]([NH2:1])[CH3:19]
Reactant: CC1=C2C=c3c(cnn3CC(C)N=[N+]=[N-])=C2CC=C1
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCO
Solvent: CCOCC
Product: CC1=C2C=c3c(cnn3CC(C)N)=C2CC=C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.6 %

Procedure:
1.38 g (5.45 mmol) of (RS)-1-(2-azido-propyl)-7-methyl-1,4-dihydro-indeno[2,1-c]pyrazole dissolved in 60 ml of anhydrous ethanol were hydrogenated over 140 mg of platinum oxide for 2 hours. The catalyst was subsequently filtered off, rinsed with ethanol and the solvent was removed in a vacuum. The colorless oil obtained was dissolved in 80 ml of anhydrous diethyl ether, filtered and treated while stirring with a solution of 633 mg (5.45 mmol) of fumaric acid in 10 ml of methanol. The mixture was stirred at room temperature for 15 hours and the white crystals were subsequently filtered off. 1.62 g (87%) of (RS)-2-(7-methyl-1,4-dihydroindeno[2,1-c]pyrazol-1-yl )-1-methyl-ethylamine fumarate (1:1) with m.p. 205° were obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1([O:8][C:9]2[C:14]([O:15][CH3:16])=[C:13]([Cl:17])[N:12]=[C:11]([Cl:18])[N:10]=2)[CH2:7][CH2:6]1)=O.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[Cl:18][C:11]1[N:10]=[C:9]([O:8][C:5]2([CH2:3][OH:2])[CH2:6][CH2:7]2)[C:14]([O:15][CH3:16])=[C:13]([Cl:17])[N:12]=1
Reactant: COC(=O)C1(Oc2nc(Cl)nc(Cl)c2OC)CC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: COc1c(Cl)nc(Cl)nc1OC1(CO)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 83 %

Procedure:
To a solution of 1-(2,6-dichloro-5-methoxy-pyrimidin-4-yloxy)-cyclopropanecarboxylic acid methyl ester (293 mg, 1.00 mmol) in DCM (8 mL) at −78° C. was added DIBAL-H (4.00 mL, 4.00 mmol, 1M solution in THF) and the resulting mixture warmed to 0° C. and stirred for 90 minutes. The reaction mixture was quenched with methanol followed by Rochelle's salt (1M aqueous solution) and the mixture extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo affording [1-(2,6-Dichloro-5-methoxy-pyrimidin-4-yloxy)-cyclopropyl]-methanol as an oil (220 mg, 83%). LCMS: RT=2.86 min, [M+H]+ 195/197/199.
Reaction SMILES: CC([O:4][C@@H:5]1[C:19](=[O:20])[C@H:18]2[C@@:8]([CH3:27])([CH2:9][CH2:10][C@@H:11]3[C@:17]2([CH3:21])[CH2:16][C@H:15]([C:22]2[CH:23]=[CH:24][O:25][CH:26]=2)[O:14][C:12]3=[O:13])[C@H:7]([C:28]([O:30][CH3:31])=[O:29])[CH2:6]1)=O.C([O-])(O)=O.[Na+]>C1COCC1.O.CCOC(C)=O>[CH3:27][C@:8]12[C@H:7]([C:28]([O:30][CH3:31])=[O:29])[CH2:6][C@H:5]([OH:4])[C:19](=[O:20])[C@@H:18]1[C@:17]1([CH3:21])[C@H:11]([C:12]([O:14][C@@H:15]([C:22]3[CH:23]=[CH:24][O:25][CH:26]=3)[CH2:16]1)=[O:13])[CH2:10][CH2:9]2
Reactant: COC(=O)[C@@H]1C[C@H](OC(C)=O)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@@H](c3ccoc3)C[C@]21C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@@H]1C[C@H](O)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@@H](c3ccoc3)C[C@]21C
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
12-epi-Salvinorin A (52 mg, 0.12 mmol) was dissolved in THF (3 mL) and H2O (3 mL). To this solution was added NaHCO3 (202 mg, 2.4 mmol), and the reaction was stirred at rt for two hours. The mixture was then diluted with EtOAc, washed with brine, and dried over MgSO4. After evaporation of the solvent, flash chromatography (0% to 5% MeOH in hexanes) gave alcohol 35 as an off-white solid. (27 mg, 58% yield); Rf 0.16 (98:2, CH2Cl2/MeOH); 1H NMR (300 MHz, CDCl3) δ 7.43 (m, 1H), 7.41 (t, J=1.6, 1H), 6.41 (m, 1H), 5.30 (dd, J=6.1, 11.5, 1H), 4.21-3.97 (m, 1H), 3.72 (s, 3H), 2.73 (dd, J=3.1, 13.5, 1H), 2.53-2.41 (m, 3H), 2.34 (dd, J=11.6, 14.6, 1H), 2.18-1.93 (2H), 1.92-1.69 (m, 4H), 1.63 (m, 1H), 1.39 (s, 3H), 1.04 (s, 3H).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([N:8]=[C:9]=[O:10])=[N:5][N:4]=1.[CH2:11]([NH:13][CH:14]([CH2:17][O:18][CH3:19])[CH:15]=[O:16])[CH3:12]>C1C=CC=CC=1>[CH2:11]([N:13]([CH:14]([CH2:17][O:18][CH3:19])[CH:15]=[O:16])[C:9]([NH:8][C:6]1[S:7][C:3]([S:2][CH3:1])=[N:4][N:5]=1)=[O:10])[CH3:12]
Reactant: CCNC(C=O)COC
Reactant: CSc1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: CCN(C(=O)Nc1nnc(SC)s1)C(C=O)COC

Procedure:
5-Methylthio-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-ethylamino-3-methoxypropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 30 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. This residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-ethyl-3-(5-methylthio-1,3,4-thiadiazol-2-yl)-ureido]-3-methoxypropionaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[N:23]=[CH:22][N:21]=[C:20]([NH:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[CH:19]=2)=[CH:4][CH:3]=1.Cl[C:31]1C=CC(C2N=C3C=CC=CN3C=2CC2C=C(Cl)N=CN=2)=CC=1.CN1CCNCC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[CH:19]=[C:20]([N:24]3[CH2:31][CH2:29][N:27]([CH3:28])[CH2:26][CH2:25]3)[N:21]=[CH:22][N:23]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2nc3ccccn3c2Cc2cc(Cl)ncn2)cc1
Reactant: CN(C)CCNc1cc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)ncn1
Agent: CN1CCNCC1
Product: CN1CCN(c2cc(Cc3c(-c4ccc(Cl)cc4)nc4ccccn34)ncn2)CC1

Procedure:
The title compound was prepared according to Method D and the experimental for compound 243 from 2-(4-chlorophenyl)-3-((6-chloropyrimidin-4-yl)methyl)imidazo[1,2-a]pyridine and 1-methylpiperazine. (59 mg, 45%) m/e+=419 (M+H+). 1H-NMR (400 MHz, CDCl3, δ): 8.57 (s, 1H), 7.93 (d, 1H, D, J=7.0 Hz), 7.73 (d, 2H, D, J=8.4 Hz), 7.67 (d, 1H, D, J=8.8 Hz), 7.42 (d, 2H, D, J=8.8 Hz), 7.25 (t, 1H, D, J=7.7 Hz), 6.81 (t, 1H, D, 7.7 Hz), 6.05 (s, 1H), 4.39 (s, 2H), 3.48 (m, 4H), 2.37 (m, 4H), 2.28 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[F:13][C:14]([F:24])([F:23])[C:15](=O)[CH2:16][C:17]([O:19][CH2:20]C)=[O:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:12][O:11][C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:15]([C:14]([F:24])([F:23])[F:13])=[CH:16][C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:6]=1)=[O:10]
Reactant: COC(=O)Cc1ccc(N)cc1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COC(=O)C=C(Nc1ccc(CC(=O)OC)cc1)C(F)(F)F
Yield: 53.4 %

Procedure:
Methyl p-aminophenylacetate (7 g), ethyl trifluoroacetoacetate (8.19 g) and p-toluenesulfonic acid (500 mg) were dissolved into benzene (100 ml) and, providing Dean Stalk dehydrating apparatus placed molecular sieve (MS 4 angstroms) therein, the solution was refluxed for 10 hours under heat. Solvent was distilled off under reduced pressure and the residue was purified by means of silica gel column chromatography (development solvent: ethyl acetate:hexane=1:4) to obtain methyl 3-(4-methoxycarbonylmethylphenylamino)-3-trifluoromethylacrylate (7.18 g) as colorless prismatic crystals. Melting point: 50°-51° C. (recrystallization solvent: ethyl acetate-n-hexane)
Reaction SMILES: [C:1]([O:16][C@@H:17]([CH3:42])[C@H:18]([NH:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[C:19]([NH:21][CH2:22][CH2:23][CH:24](OCC)[O:25]CC)=[O:20])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:1]([O:16][C@@H:17]([CH3:42])[C@H:18]([NH:31][C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])[C:19](=[O:20])[NH:21][CH2:22][CH2:23][CH:24]=[O:25])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCC(=O)O[C@@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)NCCC(OCC)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCC(=O)O[C@@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)NCCC=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.7 %

Procedure:
To a solution of (1S,2S)-2-{[(benzyloxy)carbonyl]amino}-3-[-(3,3-diethoxypropyl)amino]-1-methyl-3-oxopropyl myristate (1.06 g, 1.79 mmol, obtained from Reference Example 47) in anhydrous tetrahydrofuran was added 0.5 N hydrochloric acid (4.3 ml). The resulting solution was stirred at room temperature for 5 hours. The reaction mixture was brought to pH 9 with aqueous sodium bicarbonate, extracted with ethyl acetate (3×75 ml), the combined organics were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (flash column, silica gel, 45% ethyl acetate in hexane) to provide (1S,2S)-2-{[(benzyloxy)carbonyl]amino}-1-methyl-3-oxo-3-[(3-oxopropyl)amino]propyl myristate (694 mg, 75%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[CH3:14][C@@H:15]1[CH2:19][O:18][C:17](=[O:20])[NH:16]1>>[CH3:13][O:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[N:16]1[C@H:15]([CH3:14])[CH2:19][O:18][C:17]1=[O:20])[C:6]([OH:8])=[O:7]
Reactant: C[C@@H]1COC(=O)N1
Reactant: COC(=O)c1ccc(Br)c(OC)c1
Product: COc1cc(C(=O)O)ccc1N1C(=O)OC[C@H]1C
Yield: 97.5 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 45 and using methyl 4-bromo-3-methoxybenzoate (1 g) and (R)-4-methyloxazolidin-2-one (607 mg) described in Preparation Example 25, the title compound (1 g) was obtained.
Reaction SMILES: [CH:1]1([O:6][N:7]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.NN.[N+:20]([C:23]1[CH:24]=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1)([O-:22])=[O:21].C(N(CC)C(C)C)(C)C>O1CCCC1>[CH:1]1([O:6][NH:7][S:29]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([N+:20]([O-:22])=[O:21])[CH:24]=2)(=[O:30])=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: O=C1c2ccccc2C(=O)N1OC1CCCC1
Agent: NN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cccc(S(=O)(=O)NOC2CCCC2)c1
Reaction time: 2.5 h
Yield: 86.7 %

Procedure:
A mixture of 2-(cyclopentyloxy)-1H-isoindole-1,3(2H)-dione (3.00 g, 12.99 mmol) in anhydrous tetrahydrofuran (25 mL) under an Argon atmosphere was treated with anhydrous hydrazine (0.448 mL, 14.29 mmol). After stirring vigorously for 2.5 hours, the resulting slurry was filtered and washed with approximately 15 mL of anhydrous tetrahydrofuran. The filtrate was combined with 3-nitro-1-benzenesulphonyl chloride (3.17 g, 14.29 mmol) and N,N-diisopropylethylamine (2.72 mL, 15.6 mmol). After stirring at ambient temperature for approximately 18 hours, the reaction mixture was evaporated in vacuo to a residue and partitioned between ethyl acetate and 1N hydrochloric acid. The phases were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with 5% w/v potassium carbonate and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue. The crude material was purified on flash grade silica gel eluting with 15:85 ethyl acetate:hexane. Fractions containing the product were combined, evaporated in vacuo, and dried under high vacuum to provide N1-(cyclopentyloxy)-3-nitro-1-benzenesulfonamide (3.224 g, 87%) as a solid. H1-NMR (chloroform-D3): 1.71 (m, 8H), 4.71 (m, 1H), 6.93 (bs, 1H), 7.83 (m, 1H), 8.28 (m, 1H), 8.55 (m, 1H), 8.81 (m, 1H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[O:28]=[C:29]1[NH:37][C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[C@@:30]21[CH2:48][C:40]1=[N:41][CH:42]=[C:43]([C:45]([OH:47])=O)[CH:44]=[C:39]1[CH2:38]2.Cl.[NH2:50][C@H:51]1[CH2:56][C@@H:55]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([CH3:63])[C:58]=2[F:64])[C@@H:54]([CH3:65])[N:53]([CH2:66][C:67]([F:70])([F:69])[F:68])[C:52]1=[O:71].C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:64][C:58]1[C:59]([CH3:63])=[CH:60][CH:61]=[CH:62][C:57]=1[C@H:55]1[C@@H:54]([CH3:65])[N:53]([CH2:66][C:67]([F:69])([F:70])[F:68])[C:52](=[O:71])[C@@H:51]([NH:50][C:45]([C:43]2[CH:44]=[C:39]3[CH2:38][C@@:30]4([C:31]5[C:32](=[N:33][CH:34]=[CH:35][CH:36]=5)[NH:37][C:29]4=[O:28])[CH2:48][C:40]3=[N:41][CH:42]=2)=[O:47])[CH2:56]1
Reactant: O=C(O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reactant: Cc1cccc([C@@H]2C[C@H](N)C(=O)N(CC(F)(F)F)[C@@H]2C)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccc([C@@H]2C[C@H](NC(=O)c3cnc4c(c3)C[C@@]3(C4)C(=O)Nc4ncccc43)C(=O)N(CC(F)(F)F)[C@@H]2C)c1F
Temperature: 23 °C
Reaction time: 16 h

Procedure:
(Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (239 mg, 0.416 mmol) was added to a solution of (6S)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylic acid (described in Intermediate 1) (140 mg, 0.499 mmol), (3S,5S,6R)-3-amino-5-(2-fluoro-3-methylphenyl)-6-methyl-1-(2,2,2-trifluoroethyl)piperidin-2-one hydrochloride (described in Intermediate 5) (147 mg, 0.416 mmol), and N,N-diisopropylethylamine (0.363 mL, 2.08 mmol) in DMF (4.0 mL), and the resulting mixture was stirred at 23° C. for 16 h. The reaction mixture was purified by reverse-phase HPLC, eluting with 5% acetonitrile in water (0.1% TFA used as a modifier) initially, grading to 95% acetonitrile in water. The desired fractions were partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give the title compound. HRMS: m/z=582.2134, calculated m/z=582.2123 for C30H28F4N5O3. 1H NMR (500 MHz, CDCl3) δ 8.90 (s, 1H), 8.34 (s, 1H), 8.17 (dd, 1H, J=5.4, 1.5 Hz), 8.05 (s, 1H), 7.27 (obscured m, 1H), 7.29 (t, 1H, J=7.3 Hz), 7.12 (dd, 1H, J=7.3, 1.5 Hz), 7.03 (t, 1H, J=7.8 Hz), 6.98 (t, 1H, J=6.8 Hz), 6.89 (dd, 1H, J=7.3, 5.1 Hz), 4.96-4.87 (m, 1H), 4.55 (dt, 1H, J=11.5, 5.8 Hz), 4.09 (p, 1H, J=5.8 Hz), 3.94 (dt, 1H, J=13.4, 3.2 Hz), 3.78 (d, 1H, J=17.3 Hz), 3.67 (d, J=16.4 Hz), 3.36-3.28 (m, 1H), 3.28 (d, 1H, J=17.3 Hz), 3.18 (d, 1H, J=16.4 Hz), 2.75 (m, 1H), 2.57 (q, 1H, J=12.5 Hz), 2.30 (s, 3H), 1.08 (d, 3H, J=6.6 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.C[N:22]1[CH:26]=[C:25](B(O)O)[CH:24]=[N:23]1>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:25]3[CH:26]=[N:22][NH:23][CH:24]=3)[C:11]3[C:6]([CH:5]=2)=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[CH:19]=1
Reactant: Cn1cc(B(O)O)cn1
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Product: COc1cccc2c(-c3cn[nH]c3)nc(Nc3cc(C)[nH]n3)cc12

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and N-methyl-pyrazole-4-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-[1-(1H-pyrazol-4-yl)-5-methoxy-isoquinolin-3-yl]-amine. LC-MS m/e 335(MH+).