Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9](N)=[O:10].[OH:21][S:22]([OH:25])(=[O:24])=[O:23].[C:26](=O)([O-])[O-:27].[Na+].[Na+]>CO>[S:22](=[O:23])(=[O:21])([OH:25])[OH:24].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9]([O:27][CH3:26])=[O:10]
Reactant: NC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 67.5 °C
Reaction time: 0.5 h

Procedure:
5 g of (+)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetamide was dissolved in 20 ml methanol and the solution warmed to 65 to 70° C. 15 mL (0.28 mol) of chilled conc. H2SO4 (98%, −15° C.) was added slowly in 1 hr maintaining the temperature till −15° C. After the completion of addition the reaction mixture was heated at 70° C. for 16 hrs. The solvent was distilled off under reduced pressure and to the residue 50 mL of water was added and stirred for 30 min followed by cooling to −5° C. The pH of reaction mixture was adjusted between 9 to 10 using aq. sodium carbonate. The residue was extracted with 100 mL ethyl acetate. The organic layer was dried over anhydrous Na2SO4, and evaporated under vacuum. The combined eluent was evaporated at reduced pressure to yield 2.8 g of crude product purified by column chromatography, using hexane:ethyl acetate (9:1) as eluent to give 2 g of titled compound (1) and 1 g of the starting material (S)-(+)-(II).
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][OH:6])[CH3:2].[H-].[Na+].[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[C:29](Cl)[N:28]=[N:27][C:26]=2[CH2:32][CH2:33][CH2:34][CH3:35])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C1COCC1>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[C:29]([O:6][CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])[N:28]=[N:27][C:26]=2[CH2:32][CH2:33][CH2:34][CH3:35])=[CH:21][CH:20]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCN(CC)CCO
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nnc(OCCN(CC)CC)cc1-c1ccc(OCc2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 2-diethylamino-ethanol (0.42 mmol, 50 mg) in THF at room temperature was added NaH (0.85 mmol, 20 mg). Stirring continued for 10 min then 4-(4-benzyloxy-phenyl)-3-butyl-6-chloro-pyridazine (Example 1, 0.14 mmol, 50 mg) was added. The resulting mixture was stirred at 50-55° C. overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The product was purified by column chromatography using 10% methanolic solution of ammonia (2.0 M ammonia in methanol) in ethyl acetate to provide {2-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxy]-ethyl}-diethyl-amine.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:17])[C:11]([CH3:16])([N+:13]([O-])=O)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Ni].O>[NH2:13][C:11]([CH3:16])([CH3:12])[CH:10]([OH:17])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C(O)COCc1ccccc1)[N+](=O)[O-]
Agent: [Ni]
Solvent: O
Solvent: CO
Product: CC(C)(N)C(O)COCc1ccccc1
Reaction time: 24 h
Yield: 87.6 %

Procedure:
To a solution of 1-(benzyloxy)-3-methyl-3-nitrobutan-2-ol (5.2 g, 21.7 mmol) in MeOH (40 ml) was added a slurry of Raney Nickel in H2O (50%, 1 ml). The vessel was pressurized with H2 (450 psi) and the suspension stirred for 24 h. The mixture was filtered through Celite and concentrated in vacuo to give the title compound as a clear liquid (4.0 g, 19 mmol, 89%). 1H NMR (CDCl3, 400 MHz) δ 1.09 (s, 3H), 1.14 (s, 2H), 1.90 (br s, 2H) 3.50-3.54 (m, 2H), 3.61-3.67 (m, 1H), 4.57 (s, 2H), 7.28-7.39 (m, 5H). LRMS (ESI/APCI) m/z 210 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[C:4]([F:11])[CH:3]=1.N1C=CC=CC=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>CC(C)=O>[F:11][C:4]1[CH:3]=[C:2]([NH:1][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][CH2:9][OH:10]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(CCO)c(F)c1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: O=C(Nc1ccc(CCO)c(F)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a stirred solution of 2-(4-amino-2-fluorophenyl)ethanol (1.3 g, 8.38 mmol, 1.0 eq) in acetone (50 mL) was added pyridine (1.32 g, 16.7 mmol, 2.0 eq) and phenyl chloroformate (1.45 g, 9.23 mmol, 1.1 eq) at 0° C. and the mixture was stirred at RT for 2 h. The solvent was evaporated, the residue diluted with EtOAc (50 mL), washed with water (100 mL) followed by brine and the solvent evaporated. The resulting residue was purified by CC using EtOAc/PE (1:4) to get phenyl 3-fluoro-4-(2-hydroxyethyl)phenylcarbamate (1.5 g, 65%, white solid). (TLC system: EtOAc/PE (1:1), Rf: 0.3).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:15]=[C:11]3[N:10]=[C:9]([S:22][CH3:23])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:24]N1C(=O)CCC1=O>ClCCl>[Br:24][C:15]1[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:13][N:12]2[C:7]([NH:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:8][C:9]([S:22][CH3:23])=[N:10][C:11]=12
Reactant: CSc1nc(NC2CCCC2)n2nc(-c3ccccc3)cc2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CSc1nc(NC2CCCC2)n2nc(-c3ccccc3)c(Br)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
N-Cyclopentyl-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine (0.49 g, 1.5 mmol) was dissolved in dichloromethane. To this solution was added N-bromosuccinimide (330 mg, 1.85 mmol) and the resulting solution was stirred at room temperature for 30 minutes. Additional dichloromethane was added and the reaction mixture was extracted with 1N aqueous sodium hydroxide and with water. The organic phase was dried (magnesium sulfate), filtered and concentrated to give a solid. This solid was purified by silica gel chromatography (ethyl acetate:hexane 1:2) to give 0.5 g (82%) of 8-bromo-N-cyclopentyl-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine as a solid. 1H-NMR (CDCl3): δ 8.05 (m,2H), 7.55 (m,3H), 6.52 (d, 1H), 4.60 (m,1H), 2.66 (s, 3H), 2.3–2.1 (m, 2H), 2.0–1.6 (m, 6H); MS m/z 405 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH:5]([N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([N:21]3[CH2:26][CH2:25][CH:24]([C:27]([OH:29])=O)[CH2:23][CH2:22]3)[C:15]=2[N:14]=[CH:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Br.[NH2:63][C:64]1[NH:65][CH2:66][CH2:67][CH2:68][N:69]=1>CN(C=O)C>[C:6]1([CH:5]([N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([N:21]4[CH2:22][CH2:23][CH:24]([C:27]([NH:63][C:64]5[NH:69][CH2:68][CH2:67][CH2:66][N:65]=5)=[O:29])[CH2:25][CH2:26]4)[C:15]=3[N:14]=[CH:13]2)[CH2:4][C:3]([O:2][CH3:1])=[O:30])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)CC(c1ccccc1)n1cnc2c(N3CCC(C(=O)O)CC3)cccc21
Reactant: NC1=NCCCN1
Agent: Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CC(c1ccccc1)n1cnc2c(N3CCC(C(=O)NC4=NCCCN4)CC3)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[1-(3-methoxy-3-oxo-1-phenylpropyl)-1H-benzimidazol-4-yl]-4-piperidinecarboxylic acid (70 mg, 172 μmol) in DMF was added N,N-diisopropylethylamine (60 μL, 344 μmol) and TBTU (66 mg, 206 μmol). The solution was stirred at room temperature for 0.5 hour, then 2-amino-1,4,5,6-tetrahydropyrimidine hydrobromide (34 mg, 189 μmol) was added. The mixture was heated to 80° C. for 8 hours, cooled to room temperature, and evaporated in vacuo. The residue was purified by RP-HPLC to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=4.66 min, MH+ 489].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:14]3[C:25](=[O:29])[NH:26][C:27](=[O:28])[C:13]=3[C:12]=2[C:11]2[CH:10]=[C:9]([OH:30])[CH:8]=[CH:7][C:6]1=2.[CH:31]1[CH:36]=[C:35]([C:37]([OH:39])=[O:38])[C:34]([NH2:40])=[CH:33][CH:32]=1>>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:15]1[C:14]2[C:25](=[O:29])[NH:26][C:27](=[O:28])[C:13]=2[C:12]2[C:11]3[CH:10]=[C:9]([OH:30])[CH:8]=[CH:7][C:6]=3[N:5]([CH2:4][CH2:3][CH2:2][NH:40][C:34]3[CH:33]=[CH:32][CH:31]=[CH:36][C:35]=3[C:37]([OH:39])=[O:38])[C:17]=2[CH:16]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C1NC(=O)c2c1c(-c1ccccc1Cl)cc1c2c2cc(O)ccc2n1CCCBr
Product: O=C(O)c1ccccc1NCCCn1c2ccc(O)cc2c2c3c(c(-c4ccccc4Cl)cc21)C(=O)NC3=O
Yield: 88 %

Procedure:
Reaction of the bromide (58) prepared as described in example 172 with o-anthranilic acid using the procedure described in example 179 gave the aniline (60) (88%), mp 261–263° C. 1H NMR δ [(CD3)2SO] 11.05 (s, 1H), 9.38 (s, 1H), 8.39 (d, J=2.4 Hz, 1H), 7.76 (m, 1H), 7.75 (s, 1H), 7.59 (d, J=8.7 Hz, 1H), 7.55 (m, 1H), 7.46 (m, 1H), 7.40 (m, 1H), 7.33 (m, 1H), 7.27 (m, 1H), 7.12 (dd, J=8.7, 2.4 Hz, 1H), 6.59–6.50 (m, 2H), 4.57 (t, J=6.7 Hz, 2H), 3.22–3.10 (m, 2H), 2.15–2.05 (m, 2H). FABMS found M+: 541.1230, 539.1234. C30H22ClN3O5 requires 541.1218, 539.1248.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH2:10][CH3:11])=[CH:4][CH:3]=1.[BH3-]C#[N:15].[Na+]>CC(O)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH2:15])[CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: CCC(=O)Cc1ccc(I)cc1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)O
Product: CCC(N)Cc1ccc(I)cc1
Temperature: 90 °C

Procedure:
5.95 g (21.7 mmol) 1-(4-iodophenyl)-butane-2-one (I39) are added to 150 mL 2-propanol and transferred into an autoclav. 25.1 g (326 mmol) NH4OAc and 4.09 g (65.1 mmol) NaCNBH3 are added and the mixture is stirred at 90° C. over night. The reaction is quenched by the addition of sat. aq. NaHCO3 solution and extracted with EtOAc (3×). The combined organic layers are washed with brine, dried with Na2SO4 and the solvent is removed in vacuo. The compound is used without further purification.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([OH:14])(=O)=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:16]>P(Cl)(Cl)(Cl)=O.C(Cl)(Cl)Cl>[CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([Cl:16])(=[O:14])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1cccc2cnccc12
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1cccc2cnccc12
Temperature: 120 °C
Yield: 96.6 %

Procedure:
A mixture of 5-isoquinolinesulfonic acid (4.18 g, 20 mmol), and phosphorus pentachloride (6.24 g, 30 mmol) in phosphorus oxychloride (20 mL) was heated at 120° C. for two days. The reaction mixture was cooled to ambient temperature and diluted with dry chloroform (60 mL). The white precipitate was collected, washed with dry chloroform and dried under high vacuum to give the title compound as a white solid (4.40 g, 83%) which was used for the next step without further purification. 1H-NMR (300 MHz, CDCl3) δ 9.95 (s, 1H), 9.16 (d, J=6.8 Hz, 1H), 8.74 (d, J=6.8 Hz, 1H), 8.52 (t, J=7.0 Hz, 2H), 7.99 (t, J=7.3 Hz, 1H).
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[CH2:17][CH2:18][C:19]([OH:21])=O)=[O:8])=[CH:3][CH:2]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([CH2:17][CH2:18][C:19]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:21])[N:9]([C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:2][CH:3]=2)=[O:8])[CH2:13]1
Reactant: CON=C1C[C@@H](CCC(=O)O)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: C1COCCN1
Product: CON=C1C[C@@H](CCC(=O)N2CCOCC2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 97 %

Procedure:
The same method as employed in the preparation of Example 7, but starting from 3-[(2R,4EZ)-1-(biphenyl-4-ylcarbonyl)-4-(methoxyimino)pyrrolidin-2-yl]propanoic acid (Intermediate 8) and morpholine, gave the title compound. Yield: 97%. HPLC purity: 96%
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH:24]([CH3:26])[CH3:25])[C:5]1([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:15].CCN(C(C)C)C(C)C.[C:36]([N:39]1[CH2:44][CH2:43][N:42]([C:45](Cl)=[O:46])[CH2:41][CH2:40]1)(=[O:38])[CH3:37]>C(Cl)Cl>[Br:14][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([N:4]([CH:24]([CH3:26])[CH3:25])[CH2:3][CH2:2][NH:1][C:45]([N:42]3[CH2:43][CH2:44][N:39]([C:36](=[O:38])[CH3:37])[CH2:40][CH2:41]3)=[O:46])([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[C:6](=[O:15])[NH:7]2)=[CH:12][CH:11]=1
Reactant: CC(C)N(CCN)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Br)ccc21
Reactant: CC(=O)N1CCN(C(=O)Cl)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(C(=O)NCCN(C(C)C)C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Br)ccc32)CC1
Reaction time: 8 h

Procedure:
To a solution of rac-3-[(2-Amino-ethyl)-isopropyl-amino]-6-bromo-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (270 mg, 0.48 mmol) and DIPEA (167 uL, 0.96 mmol) in 5 mL of DCM was added 4-acetyl-piperazine-1-carbonyl chloride (137 mg, 0.72 mmol) at room temperature, and stirred at same temperature overnight. The reaction mixture was rinsed with 20 mL water. The organic layer was dried over Na2SO4, and concentrated in vacuo, then purified by flash column chromatopgraphy to 180 mg white solid. MS: [M+H]+=590.
Reaction SMILES: [H-].[Na+].CCCCCC.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:12][CH:11]=1.Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CN(C=O)C>[CH2:20]([O:19][C:17]([CH2:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:15][CH:14]=1)=[O:18])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(Cc1ccc(O)cc1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(CC(=O)OCc2ccccc2)cc1
Temperature: 4 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (50% w/w dispersion in mineral oil, 2.1 g) was treated under argon with repeated washes of hexane. The oil-free residue was suspended in dry DMF (130 ml) and the product from step (i) (10 g) added in three portions to the cooled (4° C.) stirred mixture. Stirring was continued for a further 15 minutes when tertiary butyl bromoacetate (7.0 ml) was added dropwise over 15 minutes. After 1 hour at 4° C., the mixture was stirred for 6 hours at ambient temperature. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate and water. The aqueous phase was re-extracted with further ethyl acetate and the combined organic phases washed with water and brine, then dried (MgSO4) and evaporated. The residue, after purification by flash chromatography on silica eluting with dichloromethane, gave tertiary butyl 4-(benzyloxycarbonylmethyl)phenoxyacetate, 7.5 g, as a colourless oil: NMR (CDCl3) d 7.31(5H, m), 7.20(2H, m), 6.85(2H, m), 5.12(2H, s), 4.49(2H, s), 3.60(2H, s), 1.48(9H, s); m/e 356 (M.)+.
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:5]2[N:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1.[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][NH2:25])[CH3:21]>C(O)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([N:6]2[C:7](=[O:8])[C:2]([NH:25][CH2:24][CH2:23][N:22]([CH2:26][CH3:27])[CH2:20][CH3:21])=[N:3][C:4]3[CH:19]=[CH:18][CH:17]=[N:16][C:5]2=3)=[CH:10][CH:11]=1
Reactant: CCN(CC)CCN
Reactant: O=c1c(Cl)nc2cccnc2n1-c1ccc(Cl)cc1
Solvent: CCO
Product: CCN(CC)CCNc1nc2cccnc2n(-c2ccc(Cl)cc2)c1=O

Procedure:
Preparation as in Example 39 but using 2-chloro-4-(4-chlorophenyl)-3,4-dihydro-3-oxopyrido[2,3-b]pyrazine and N,N-diethylethylene diamine in refluxing ethanol gave the title compound mp 149°-150° C.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)(=[O:4])[CH2:2][CH3:3].[H][H]>CO.[Pd]>[C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: CCC(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CCC(=O)Nc1ccc(N)cc1

Procedure:
250 mg (2 mmol) of N-propionyl-4-nitroaniline are dissolved in 200 ml of methanol and combined with 0.6 g of 10% palladium/charcoal. The product is hydrogenated in a hydrogen atmosphere at 2 bar for 30 minutes. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH:11][C:12]([CH:14]2[CH2:17][CH2:16][CH2:15]2)=[O:13])=[CH:4][CH:3]=1.Br[CH2:19][C:20]1[CH:39]=[CH:38][C:23]2/[C:24](=[C:34](/[CH3:37])\[C:35]#[N:36])/[C:25]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:26]=3[O:27][CH2:28][C:22]=2[CH:21]=1>>[C:35](/[C:34](=[C:24]1/[C:25]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:26]=2[O:27][CH2:28][C:22]2[CH:21]=[C:20]([CH2:19][N:11]([C:5]3[C:6]([N+:8]([O-:10])=[O:9])=[N:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]([CH:14]3[CH2:15][CH2:16][CH2:17]3)=[O:13])[CH:39]=[CH:38][C:23]/1=2)/[CH3:37])#[N:36]
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: O=C(Nc1ccc(F)nc1[N+](=O)[O-])C1CCC1
Product: C/C(C#N)=C1/c2ccc(CN(C(=O)C3CCC3)c3ccc(F)nc3[N+](=O)[O-])cc2COc2cc(F)ccc21
Yield: 50 %

Procedure:
[step 3] Using N-(6-fluoro-2-nitropyridin-3-yl)cyclobutanecarboxamide (200 mg, 0.836 mmol) obtained in step 2 and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (250 mg, 0.697 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, (E)-N-{[11-(1-cyanoethylidene)-3-fluoro-6,11-dihydrodibenzo[b,e]oxepin-8-yl]methyl}-N-(6-fluoro-2-nitropyridin-3-yl)cyclobutanecarboxamide (180 mg, 50%) was obtained.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][O:5][CH:6]1[C:11](OC)([O:12]C)[CH2:10][CH2:9][N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7]1.O.C(O)(C(F)(F)F)=O.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>>[F:1][CH2:2][CH2:3][CH2:4][O:5][CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7]1
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1OCCCF
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=O)C(OCCCF)C1

Procedure:
The same operation as in Example (90b) was performed using tert-butyl 3-(3-fluoropropoxy)-4,4-dimethoxypiperidine-1-carboxylate obtained in Example (127a) (2.27 g, 21.2 mmol), a water/TFA mixed solution (3/1, 12 mL) and di-tert-butyl dicarbonate (2.18 g, 10 mol). The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=10/1, 5/1, 2/1, 1/1) to obtain 1.71 of the title compound as a colorless oily substance (88%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([CH3:16])[C:10]=2[C:17]([O:19]CC2C=CC=CC=2)=[O:18])[CH:6]=[CH:7][CH:8]=1)#[N:2].[H][H]>C(O)C.O1CCCC1.[Pd]>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([CH3:16])[C:10]=2[C:17]([OH:19])=[O:18])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1cc(-c2cccc(C#N)c2)c(C(=O)OCc2ccccc2)c(C)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(-c2cccc(C#N)c2)c(C(=O)O)c(C)n1
Yield: 75.4 %

Procedure:
A solution of benzyl 4-(3-cyanophenyl)-2,6-dimethyl-3-pyridinecarboxylate (0.45 g) in a mixture of ethanol (9 ml) and tetrahydrofuran (9 ml) was hydrogenated under an atmospheric pressure of hydrogen over 10% palladium charcoal (90 mg) at 60° C. for 1.5 hours. After removal of the catalyst, the solvent was evaporated in vacuo. The residue was triturated with diethyl ether and dried to give 4-(3-cyanophenyl)-2,6-dimethyl-3-pyridinecarboxylic acid (0.25 g).
Reaction SMILES: [CH2:1]([Li])[CH3:2].[C@@H:4]12[O:9][C@@H:8]1[CH2:7][CH:6]([C:10]([O:12][CH3:13])=[O:11])[CH2:5]2>CCOCC.[Cu]I>[CH2:1]([C@H:8]1[C@H:4]([OH:9])[CH2:5][C@@H:6]([C:10]([O:12][CH3:13])=[O:11])[CH2:7]1)[CH3:2]
Reactant: COC(=O)C1C[C@@H]2O[C@@H]2C1
Reactant: [Li]CC
Agent: [Cu]I
Solvent: CCOCC
Product: CC[C@@H]1C[C@H](C(=O)OC)C[C@H]1O
Temperature: -25 °C
Reaction time: 1 h

Procedure:
To a suspension of copper(I) iodide (4.95 g, 26.0 mmol) in 50 ml ether at −25° C. was added ethyllithium (1.7M, 30.6 ml, 52.0 mmol) dropwise. The solution was stirred for 1 hr at −25° C. followed by dropwise addition of an ether solution (50 ml) of methyl (1S,5R)-6-oxabicyclo[3.1.0]hexane-3-carboxylate (1.848 g, 13 mmol) maintaining at −25° C. The reaction was allowed to warm to rt until TLC showed complete reaction. Cooled in ice and quenched with NH4Cl (sat)(5 ml) and stirred for 10 minutes. Filtered thru celite and washed with ether (3×10 ml) and the combined filtrates were washed with brine and dryed over sodium sulfate. Silica gel chromatagraphy on a 25 g Biotage SNAP column with 10-50% MTBE/Hexane afforded title compound. 1H NMR (500 MHz, CDCl3) δ 0.96 (t, J=7.3 Hz, 3H), δ 1.24-1.48 (m, 2H), δ 1.54-1.77 (m, 3H), δ 1.83-1.90 (m, 1H), δ 2.12-2.29 (m, 2H), δ 3.02 (m, 1H), δ 3.69 (s, 3H), δ 3.98 (m, 1H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH:10](OC(OC2C=CC=CC=2)=S)[C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1.CC(N=NC(C#N)(C)C)(C#N)C.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([F:13])([F:12])[F:14])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(C(OC(=S)Oc2ccccc2)C(F)(F)F)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CC(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
4-(2,2,2-Trifluoro-1-phenoxythiocarbonyloxy-ethyl)-benzoic acid methyl ester (462.8 mg, 1.25 mmol) and AIBN (41.0 mg, 0.25 mmol) were dissolved in ultrasonically degassed toluene (12.5 mL). Tri-n-butyltin hydride (0.50 mL, 1.874 mmol) was added and the mixture was heated with stirring at 80° C. for two hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 4-(2,2,2-trifluoro-ethyl)-benzoic acid methyl ester as white crystals (254.6 mg, 93%).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12]CNCC2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[N:20]([S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[C:21]([C:23]3[C:31]4[C:26](=[CH:27][C:28]([O:34]CCI)=[C:29]([O:32][CH3:33])[CH:30]=4)[N:25]([CH3:38])[CH:24]=3)=[CH:22][C:15]=12>>[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[N:20]([S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=3)(=[O:40])=[O:41])[C:21]([C:23]3[C:31]4[C:26](=[CH:27][C:28]([O:34][CH2:12][CH2:7][N:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]5[CH:4]5[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]5)=[C:29]([O:32][CH3:33])[CH:30]=4)[N:25]([CH3:38])[CH:24]=3)=[CH:22][C:15]=12
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: COc1cc2c(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCI
Product: COc1cc2c(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCN1CCCCC1C1CCNCC1
Yield: 97.6 %

Procedure:
4-Chloro-2-[1-methyl-5-methoxy-6-(2-(4-piperidylpiperidin-1-yl)ethoxy)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is prepared by following the procedure described in example 147b, but using 0.212 g of 4-piperidinopiperidine and 0.400 g of 4-chloro-2-[1-methyl-5-methoxy-6-(2-iodoethoxy)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine. 0.415 g of 4-chloro-2-[1-methyl-5-methoxy-6-(2-(4-piperidylpiperidin-1-yl)ethoxy)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is obtained, the characteristics of which are as follows: