Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:12]3=[CH:13][C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][C:16](=[O:17])[N:11]3[CH2:10][CH2:9]2)[CH:5]=[N:4][CH:3]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[CH2:76]([NH2:84])[CH2:77][C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1>C1(C)C=CC=CC=1>[CH2:76]([NH:84][C:2]1[N:7]=[C:6]([N:8]2[C:12]3=[CH:13][C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][C:16](=[O:17])[N:11]3[CH2:10][CH2:9]2)[CH:5]=[N:4][CH:3]=1)[CH2:77][C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1
Reactant: NCCc1ccccc1
Reactant: O=c1cc(-c2ccccc2)cc2n1CCN2c1cncc(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: O=c1cc(-c2ccccc2)cc2n1CCN2c1cncc(NCCc2ccccc2)n1
Temperature: 70 °C

Procedure:
To a mixture of 1-(6-chloro-pyrazin-2-yl)-7-phenyl-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one (85 mg, 0.26 mmol), sodium tert-butoxide (70 mg, 2.8 eq), BINAP (24 mg, 15% eq), and Pd (OAc)2 (9 mg, 15% eq) was added toluene (5 mL) and phenethylamine (39 μL, 1.2 eq). After purged with N2 for 10 min, the overall mixture was heated at 70° C. for 3 h prior to being cooled to room temperature. The resulting material was filtered through Celite and the filtrated cake was washed with DCM/MeOH (98:2) and the filtrates were concentrated. The residual material was purified by a preparative thin-layer chromatography (2% MeOH in DCM) to provide the title compound as a pale yellow solid. MS m/e 410 (M+H)+. Biological Assays
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([O:10][C:11]3[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([NH2:21])=[O:20])=[CH:13][C:12]=3[CH2:22][N:23]([CH3:25])[CH3:24])[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.O>C1COCC1>[S:1]1[C:5]2[CH:6]=[C:7]([O:10][C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([NH2:21])=[O:20])=[CH:13][C:12]=3[CH2:22][N:23]([CH3:25])[CH3:24])[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CN(C)Cc1cc(/C=C/C(N)=O)ccc1Oc1ccc2c(c1)SCC2
Solvent: O
Solvent: C1CCOC1
Product: CN(C)Cc1cc(CCC(N)=O)ccc1Oc1ccc2c(c1)SCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.9 %

Procedure:
A solution of Sml2 in THF (0.1 M, 21.9 mL, 2.19 mmol) was added to a solution of the alkene of Example 50 (194 mg, 0.55 mmol) in THF (5 mL) under nitrogen followed by water (1 mL). After stirring at room temperature for 10 min the reaction was quenched with 6M NaOH (10 mL) and stirred for 30 min. The organic phase was separated and the aqueous phase was extracted with EtOAc (2×20 mL). The combined organic layers were dried (MgSO4) and evaporated to an oil, which was purified by column chromatography [SiO2; 93:7:1 (DCM/MeOH/880 NH3) increasing polarity to 90:10:1] to give the title compound (90 mg, 46%); δH (CDCl3, 400 MHz) 2.25 (6H, s), 2.54 (2H, t), 2.97 (2H, t), 3.22 (2H, t), 3.36 (2H, t), 3.42 (2H, s), 5.20-5.46 (2H, br), 6.54 (1H, d), 6.73 (1H, s), 6.81 (1H, d), 7.05 (2H, m), 7.31 (1H, s); MS m/z (TS+) 357 (MH+).
Reaction SMILES: C1CO[C:3]([C:7]2[CH:8]=[CH:9][C:10]([O:20][CH3:21])=[C:11]([CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=2)([CH3:4])[O:2]1.Cl>CCOCC>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([O:20][CH3:21])=[C:11]([CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=1)(=[O:2])[CH3:4]
Reactant: CCOC(=O)C=Cc1cc(C2(C)OCCO2)ccc1OC
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)C=Cc1cc(C(C)=O)ccc1OC
Reaction time: 12 h

Procedure:
9.6 g of the ester obtained in step (a) are dissolved in 150 ml of ether and 20 ml of 5 N hydrochloric acid are added. Stirring is carried out for 12 hours. After extraction by the (1:1) v/v ether-CH2Cl2 mixture, then washings with water, 7.5 g of the expected product are obtained after evaporation of the organic phases. m.p.=90° C.
Reaction SMILES: ClCCl.Br[C:5]1[CH:6]=[C:7]2[CH:13]=[CH:12][N:11]([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[C:8]2=[N:9][CH:10]=1.[C:24](O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:24][C:5]1[CH:6]=[C:7]2[CH:13]=[CH:12][N:11]([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[C:8]2=[N:9][CH:10]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)cnc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1cnc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
In a round bottom flask, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 1:1 complex with dichloromethane (0.04 g, 0.05 mmol) is combined with 10 mL of toluene under an atmosphere of nitrogen, and 5-bromo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (5, 0.3 g, 0.8 mmol) in 1 mL of toluene is added dropwise. The reaction is stirred at 60° C. for 1 hour, then at 90° C. for 30 minutes. The reaction is cooled to room temperature, an ice/water solution of 0.1 N citric acid at pH 4 is added, and the mixture extracted with ethyl acetate. The organic layer is washed with brine, de-colored with charcoal, filtered through celite and the filtrate dried over sodium sulfate. The sodium sulfate is removed by filtration and the filtrate concentrated under vacuum to provide the desired compound (6, 218 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11](OS(C(F)(F)F)(=O)=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][C:28]1(C)[C:32](C)(C)OB(C(C)=C)O1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([C:28]([CH3:32])=[CH2:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)c1cc(OCc2ccccc2)ccc1C(=O)OC
Temperature: 75 °C
Reaction time: 24 h

Procedure:
Methyl 4-(benzyloxy)-2-(trifluoromethylsulfonyloxy)benzoate (i-1c) (6.8 g, 17.4 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (2.9 g, 17.4 mmol), Pd(OAc)2 (195 mg, 0.87 mmol), S-Phos (71 mg, 0.174 mmol) and K3PO4 (11 g, 52 mmol) were mixed in THF (70 ml). The mixture was stirred at 75° C. for 24 h. The mixture was diluted with H2O, and extracted with EtOAc. The combined organics were dried and concentrated. The residue was purified by flash chromatography (PE/EA=10:1) to afford the title compound. LCMS (ESI) calc'd for C18H18O3 [M+H]+: 391. found: 391.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][NH:11][C:12]([CH2:14][O:15][CH:16]1[CH:21]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][CH3:41])=[CH:24][CH:23]=2)[CH2:20][CH2:19][N:18]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:17]1)=[O:13].[C:49](Cl)(=[O:51])[CH3:50]>ClCCl.C(N(CC)CC)C>[C:49]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][NH:11][C:12]([CH2:14][O:15][CH:16]1[CH:21]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][CH3:41])=[CH:24][CH:23]=2)[CH2:20][CH2:19][N:18]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:17]1)=[O:13])(=[O:51])[CH3:50]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC(=O)NCc2ccccc2CCN)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC(=O)NCc2ccccc2CCNC(C)=O)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 0.49 g of tert-butyl 3-({[2-(2-aminoethyl)phenyl]methylcarbamoyl}methoxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 10 ml of dichloromethane and 0.22 ml of triethylamine is admixed at 0° C. with 0.15 ml of acetyl chloride and stirred at room temperature over 17 hours. The reaction mixture is diluted with dichloromethane, washed with 1N HCl (2×), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.09 (EtOAc); Rt=5.10.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[S:23][N:22]=[C:21]([N:24]4[CH2:29][CH2:28][N:27]([C:30](=[O:40])[CH2:31][NH:32]C(=O)OC(C)(C)C)[CH2:26][CH2:25]4)[N:20]=3)[CH2:15][CH2:14]2)=[O:12])=[N:2]1.[ClH:41]>CO.O1CCCC1>[ClH:41].[ClH:41].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[S:23][N:22]=[C:21]([N:24]4[CH2:25][CH2:26][N:27]([C:30](=[O:40])[CH2:31][NH2:32])[CH2:28][CH2:29]4)[N:20]=3)[CH2:17][CH2:18]2)=[O:12])=[N:2]1
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCN(c2nsc(N3CCN(C(=O)Nc4noc5ccccc45)CC3)n2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: NCC(=O)N1CCN(c2nsc(N3CCN(C(=O)Nc4noc5ccccc45)CC3)n2)CC1
Yield: 90.4 %

Procedure:
A solution of tert-butyl {2-[4-(5-{4-[(1,2-benzisoxazol-3-ylamino)carbonyl]piperazin-1-yl}-1,2,4-thiadiazol-3-yl)piperazin-1-yl]-2-oxoethyl}carbamate (70.0 mg, 0.122 mmol) and a solution of 2 N hydrogen chloride in methanol (5 ml) in tetrahydrofuran (5 ml) was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of methanol and diethyl ether to give 60.0 mg (90.4%) of the desired product as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:12][C@@H:13]([CH3:27])[CH2:14][CH2:15][O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][C@@H:29]1[CH2:34][O:33]C(=O)[CH2:30]1>>[CH2:9]([NH:8][C:34](=[O:33])[C:29](=[CH2:30])[CH2:28][C@H:10]([OH:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:12][C@@H:13]([CH3:27])[CH2:14][CH2:15][O:16][Si:17]([CH:18]([CH3:19])[CH3:20])([CH:21]([CH3:23])[CH3:22])[CH:24]([CH3:26])[CH3:25])[CH2:12][CH2:13][CH3:14]
Reactant: C[C@@H]1COC(=O)C1
Reactant: CC(C)[Si](OCC[C@H](C)C[C@@H](C=O)NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Product: C=C(C[C@H](O)[C@H](C[C@@H](C)CCO[Si](C(C)C)(C(C)C)C(C)C)NC(=O)OC(C)(C)C)C(=O)NCCCC

Procedure:
In a manner analogous to that described in Example 72g), the title compound is obtained starting from 3.2 g of 2(S)-tert-butoxycarbonylamino-4(R)-methyl-6-triisopropylsilyloxyhexanal (Rf (D)=0.36), which is prepared by processes analogous to those described in Examples 72h to 72n), starting from (S)-3-methylbutyrolactone, and is purified by FC over 400 g of silica gel (mobile phase gradient from E to B), the two stereoisomers being separated. This gives the title compound (diastereomer I): Rf (A)=0.58; and diastereomer II: Rf (A)=0.47.
Reaction SMILES: [F:1][CH:2]1[C:7]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[NH:10][CH:9]=2)=[CH:6][CH2:5][N:4]([CH3:18])[CH2:3]1.I.CS[C:22]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)=[NH:23]>C(O)C>[F:1][CH:2]1[C:7]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:22]([C:24]4[S:25][CH:26]=[CH:27][CH:28]=4)=[NH:23])[CH:15]=3)[NH:10][CH:9]=2)=[CH:6][CH2:5][N:4]([CH3:18])[CH2:3]1
Reactant: CN1CC=C(c2c[nH]c3ccc(N)cc23)C(F)C1
Reactant: CSC(=N)c1cccs1
Agent: I
Solvent: CCO
Product: CN1CC=C(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)C(F)C1
Reaction time: 20 h
Yield: 58.2 %

Procedure:
A solution of compound 133 (0.062 g, 0.252 mmol) in dry ethanol (5 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.144 g, 0.505 mmol) at room temperature and stirred for 20 h. Solvent was evaporated, crude was diluted with sat. NaHCO3 solution (20 mL) and product was extracted into CH2Cl2 (2 20 mL). The combined CH2Cl2 layer was washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 0:100 to 1:9) to obtain compound 134 (0.052 g, 58%) as a solid. mp 127-129° C.; 1H NMR (DMSO-d6) δ 2.29 (s, 3H), 2.42-2.57 (m, 1H), 2.72-2.81 (m, 1H), 3.00-3.09 (m, 1H), 3.32-3.42 (m, 1H), 5.41 (d, 1H, J=49.2 Hz), 6.30-6.40 (m, 3H), 6.69 (dd, 1H, J=1.2, 8.4 Hz), 7.10 (t, 1H, J=3.9 Hz), 7.22 (s, 1H), 7.34 (d, 1H, J=8.4 Hz), 7.42 (s, 1H), 7.60 (d, 1H, J=4.8 Hz), 7.73 (d, 1H, J=2.7 Hz), 11.05 (s, 1H); ESI-MS m/z (%): 355 (MH+, 100), 335 (21), 312 (33); ESI-HRMS calculated for C19H20FN4S (MH+), Calculated: 355.1391; Observed: 355.1387.
Reaction SMILES: [F:1][C:2]1[C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[C:5]([F:13])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:20][CH2:21][CH2:22][CH2:23]I>>[Cl:20][CH2:21][CH2:22][CH2:23][N:8]1[C:7]2[C:2]([F:1])=[CH:3][CH:4]=[C:5]([F:13])[C:6]=2[O:11][CH2:10][C:9]1=[O:12]
Reactant: ClCCCI
Reactant: O=C1COc2c(F)ccc(F)c2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C1COc2c(F)ccc(F)c2N1CCCCl
Yield: 16.8 %

Procedure:
5,8-Difluoro-4H-benzo[1,4]oxazin-3-one (1.86 g, 10 mmol), Cs2CO3 (4.91 g, 15 mmol), and 1-chloro-3-iodopropane (2.04 g, 10 mmol) were mixed according to GP2. Purified by column chromatography (SiO2; heptanes/EtOAc, gradient 0 to 50% EtOAc) to give the title compound (0.44 g, 17%). Rf=0.74 (heptanes/EtOAc 1:1); 1H NMR (CDCl3) d 6.86-6.73 (m, 2H), 4.60 (s, 2H), 4.18-4.12 (m, 2H), 3.56 (t, J=6.4 Hz, 2H), 2.20-2.12 (m, 2H); 13C NMR (CDCl3) d 164.7, 148.4 (dd, J=243.9 Hz, J=2.8 Hz), 147.5 (dd, J=243.7 Hz, J=3.0 Hz), 136.6 (dd, J=16.2 Hz, J=5.0 Hz), 119.8 (dd, J=11.2 Hz, J=2.7 Hz), 111.5 (dd, J=20.4 Hz, J=9.6 Hz), 110.4 (dd, J=24.8 Hz, J=7.9 Hz), 68.6, 42.4 (d, J=10.0 Hz), 42.1, 31.1 (d, J=3.5 Hz).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Br:9]C1C(=O)C(Br)=CC(Br)(Br)C=1.[OH-].[Na+]>C(Cl)Cl>[Br:9][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[CH:3][C:2]=1[I:1]
Reactant: O=C1C(Br)=CC(Br)(Br)C=C1Br
Reactant: Nc1cccc(I)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Nc1ccc(Br)c(I)c1
Temperature: -10 °C
Reaction time: 4 h

Procedure:
To a solution of 3-iodoaniline (12 mL, 100 mmol) in 400 mL CH2Cl2 at −10° C. was added in portions 2,4,4,6-tetrabromo-2,5-cyclohexadienone (45.1 g, 110 mmol) while maintaining an internal temperature of −10° C. After stirring for 4 hours, 150 mL of 1N NaOH was added, and the product was extracted with CH2Cl2. The combined extracts were washed with water and then brine and dried over Na2SO4. After concentration in vacuo the crude product was recrystallized with 2:1 hexanes:toluene to yield the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][C@H:9]([C:11]2[CH:12]=[C:13]([C:17]([O:19]C)=[O:18])[CH:14]=[CH:15][CH:16]=2)[CH3:10])[C:5]([C:21]#[N:22])=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:25][CH:24]=2)[C:3]=1[C:33]#[N:34].[OH-].[Li+].Cl>O1CCCC1>[NH2:1][C:2]1[N:7]=[C:6]([S:8][C@H:9]([C:11]2[CH:12]=[C:13]([C:17]([OH:19])=[O:18])[CH:14]=[CH:15][CH:16]=2)[CH3:10])[C:5]([C:21]#[N:22])=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:25][CH:24]=2)[C:3]=1[C:33]#[N:34]
Reactant: COC(=O)c1cccc([C@H](C)Sc2nc(N)c(C#N)c(-c3ccc(OCCO)cc3)c2C#N)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@H](Sc1nc(N)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
85 mg (0.179 mmol) of rac-methyl 3-[(1S)-1-({6-amino-3,5-dicyano-4-[4-(2-hydroxyethoxy)phenyl]pyridin-2-yl}sulfanyl)ethyl]benzenecarboxylate (Example 62A) were dissolved in 4 ml of tetrahydrofuran. 8.58 mg (0.358 mmol) of lithium hydroxide were added, and the mixture was then stirred at RT overnight. The reaction solution was adjusted to pH 4 using 1N hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and evaporated.
Reaction SMILES: [CH2:1]([N:3]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH3:32])[CH:27]=2)[CH2:22]1)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:2].Cl.Cl[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH2:1]([N:3]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH3:32])[CH:27]=2)[CH2:22]1)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCN(CCc1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Reactant: ClCCN1CCCCC1
Agent: Cl
Product: CCN(CCc1ccc(OCCN2CCCCC2)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Yield: 95.8 %

Procedure:
Synthesized from 4-{2-{ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amino}ethyl}phenol (302 mg) and 1-(2-chloroethyl)piperidine hydrochloride (168 mg) according to an analogous synthetic method to Preparation Example 40, the title compound (364 mg) was obtained.
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=3[O:20][CH2:21][O:22][CH3:23])[O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:24][O:25]C1C(OC)=CC(C2OC3C=CC=C(C)C=3N=2)=C(OCOC)C=1>>[Br:1][CH2:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:25][CH3:24])=[CH:14][C:13]=3[O:20][CH2:21][O:22][CH3:23])[O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COCOc1ccc(OC)cc1-c1nc2c(CBr)cccc2o1
Reactant: COCOc1cc(OC)c(OC)cc1-c1nc2c(C)cccc2o1
Product: COCOc1cc(OC)c(OC)cc1-c1nc2c(CBr)cccc2o1

Procedure:
4-bromomethyl-2-(4,5-dimethoxy-2-methoxymethoxyphenyl)benzoxazole (F13) was prepared in a similar manner for the preparation of 4-bromomethyl-2-(5-methoxy-2-methoxymethoxyphenyl)benzoxazole (F12) by using 2-(4,5-dimethoxy-2-methoxymethoxyphenyl)-4-methylbenzoxazole (F9) (1.39 g, 4.23 mmol) instead of 2-(5-methoxy-2-methoxymethoxyphenyl)-4-methylbenzoxazole (F8) in 66% (1.14 g): 1H-NMR (500 MHz, CDCl3) δ3.60 (s, 3H), 3.97 (s, 3H), 3.99 (s, 3H), 4.96 (s, 2H), 5.31 (s, 2H), 6.85 (s, 1H), 7.30 (t, 1H, J=8.0 Hz), 7.40 (d, 1H, J=8.0 Hz), 7.51 (d, 1H, J=8.0 Hz), 7.66 (s, 1H).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[N:14]=[C:13]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:12]=[C:11]([CH3:23])[CH:10]=1.[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(O)C>[CH3:23][C:11]1[CH:10]=[CH:9][N:14]=[C:13]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:12]=1
Reactant: [H][H]
Reactant: Cc1cc(Cl)nc(C=Cc2ccccc2)n1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccnc(C=Cc2ccccc2)n1

Procedure:
9.02 ml of triethylamine and 1.365 g of Lindlar catalyst are added to 13.65 g (59.17 mmol) of 6-chloro-4-methyl-2-(2-phenylethenyl)-pyrimidine in 220 ml of absolute ethanol and hydrogenation is carried out at room temperature under normal pressure. When 1 equivalent of hydrogen has been absorbed, hydrogenation is terminated (after about 7.5 hours), and the reaction mixture is filtered with suction over Hyflo Super Cel® and concentrated in a rotary evaporator. Chromatography twice on silica gel with chloroform and then n-hexane/ethyl acetate 5-20% as eluants yields the pure title compound; m.p. 65°-67°.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:10]2)=[CH:5][CH:4]=1.[CH3:26][N:27]=[C:28]=[O:29]>C1(C)C=CC=CC=1>[CH3:26][NH:27][C:28]([N:21]1[CH2:20][CH2:19][CH:18]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:24])[F:25])=[CH:4][CH:5]=3)[N:10]=2)[CH2:23][CH2:22]1)=[O:29]
Reactant: CN=C=O
Reactant: FC(F)(F)c1ccc(-n2nc(C3CCNCC3)c3ccccc32)cc1
Solvent: Cc1ccccc1
Product: CNC(=O)N1CCC(c2nn(-c3ccc(C(F)(F)F)cc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
A stirred mixture of 4-[1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl]piperidine-1-carbonitrile of Example 101 (15 g, 0.041 moles) and 25% H2SO4 (100 ml) was refluxed for 20 hours. The mixture was cooled. poured into H2O and basified with a 25% NaOH solution. The product was extracted (dichloromethane), dried (MgSO4), and concentrated to yield 13 g (93%) of 1-[4-(trifluoromethyl)phenyl]-3-(4-piperidinyl)-1H-indazole as an oil. To a stirred suspension of the indazole (4.0 g, 0.012 moles) in toluene (60 ml) was added methyl isocyanate (0.75 ml., 0.013 moles). The temperature of the reaction mixture rose to 35° C. following the addition. The mixture was stirred for 2 hours at ambient temperature and then concentrated to yield 4.6 g of a solid. The product was purified by high pressure liquid chromatography (3.5% methanol-CHCl3 ; silica gel) and then recrystallized three times from toluene-hexane to yield 2.93 g (63%) of N-methyl-4-[1-(4-trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carboxamide, m.p.: 150°-152° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][N:42]=5)=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][N+:42]=5[O-:58])=[CH:38][CH:39]=4)=[O:32])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccc(Cl)cn4)cc2)CCN3C(=O)C(F)(F)F)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccc(Cl)c[n+]4[O-])cc2)CCN3C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 33.5 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(5-chloropyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (682 mg) in dichloromethane (15 ml) was added 3-chloroperbenzoic acid (70%, 0.29 g) at 0° C. and the mixture was stirred for 24 hours at room temperature. 3-chloroperbenzoic acid (70%, 0.29 g) was further added to the mixture at room temperature and the mixture was stirred for 18 hours. To the reaction solution was added sodium thiosulfate solution and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate) to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(5-chloro-1-oxidopyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 108) (233.8 mg) as colorless crystals.