Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8](CC)[C:9]1[N:13]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]4)[N:20]3[CH3:23])=[C:16]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:15]=2)[C:12]2[CH:41]=[CH:42][CH:43]=[CH:44][C:11]=2[N:10]=1)[C:2]1C=CC=CC=1.C(O)(=O)C>[Pd].C(O)C>[CH2:1]([NH:8][C:9]1[N:13]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([CH2:24][N:25]4[CH2:26][CH2:27][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:29][CH2:30]4)[N:20]3[CH3:23])=[C:16]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:15]=2)[C:12]2[CH:41]=[CH:42][CH:43]=[CH:44][C:11]=2[N:10]=1)[CH3:2]
Reactant: CCN(Cc1ccccc1)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCNc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Temperature: 65 °C
Reaction time: 18 h
Yield: 8.9 %

Procedure:
A mixture of 2-(1-((2-(2-(benzyl(ethyl)amino)-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (0.6 mmol) and palladium on carbon (10 wt %, 0.3 g) and acetic acid (0.1 mL) in ethanol (20 mL) was stirred under a hydrogen atmosphere at 65° C. for 18 hours. The reaction mixture was then filtered though celite and concentrated. The crude product was purified by RP-HPLC to give 255 (28.5 mg, 17%). LCMS m/z: 534.3 (MH+)
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19](O)=[O:20])[CH2:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:24]1([C@H:30]2[CH2:34][O:33][C:32](=[O:35])[NH:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>C1(C)C=CC=CC=1.Cl>[O:35]=[C:32]1[N:31]([C:19]([C@H:16]2[CH2:17][CH2:18][C@H:13]([NH:12][S:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:23])([F:1])[F:22])=[CH:8][CH:7]=3)(=[O:11])=[O:10])[CH2:14][CH2:15]2)=[O:20])[C@@H:30]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:34][O:33]1
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Reactant: O=C(O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1OC[C@H](c2ccccc2)N1C(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a mixture of trans-4-(4-(trifluoromethyl)phenylsulfonamido)cyclohexanecarboxylic acid (Intermediate 18, 110 mg, 0.313 mmol,), (S)-4-phenyloxazolidin-2-one (25.5 mg, 0.157 mmol) in toluene (2 ml) was added triethylamine (0.087 ml, 0.626 mmol). The mixture was heated to 80° C. to obtain a solution. Pivaloyl chloride (0.039 ml, 0.313 mmol) in toluene (1 ml) was added to the reaction mixture, and it was heated to 110° C. with stirring for 18 hr. The reaction mixture was then diluted with 1M HCl and extracted with DCM. The DCM layer was dried (MgSO4), then filtered and concentrated in vacuo to a tanned solid. The crude material was purified via normal phase chromatography on biotage SP1, using 25+M column and a calculated gradient from 50% EtOAc in heptane, to yield the title compound as a white solid (8 mg, 10%). MS MH+ 497.2
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][N:8]=[C:9]([C:13]1[N:14]=[C:15]([NH:18]C=O)[S:16][CH:17]=1)[C:10]([OH:12])=[O:11])=[O:5])[CH3:2].Cl.C(O)C>O1CCCC1>[CH2:1]([O:3][C:4]([CH2:6][O:7][N:8]=[C:9]([C:13]1[N:14]=[C:15]([NH2:18])[S:16][CH:17]=1)[C:10]([OH:12])=[O:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CON=C(C(=O)O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.4 %

Procedure:
A mixture of 2-ethoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (7.2 g.), conc. hydrochloric acid (10 ml.), ethanol (70 ml.) and tetrahydrofuran (20 ml.) was stirred for 2 hours at ambient temperature. After removing the solvent from the reaction mixture in vacuo, water was added thereto and the mixture was adjusted to pH 3.3 with an aqueous solution of sodium bicarbonate under ice-cooling. Precipitates were collected by filtration and dried to give 2-ethoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetic acid (syn isomer) (4.6 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].CS(O)(=O)=O>C(O)CCCCC>[CH2:23]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:2]([NH:1][CH2:4][CH2:3][CH2:2][CH2:10][CH2:9][CH3:8])[CH:3]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCBr
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: CS(=O)(=O)O
Solvent: CCCCCCO
Product: CCCCCCNc1cc(C(=O)OCCCCCC)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
A mixture of 3-amino-4-phenoxy-5-sulphamyl-benzoic acid (4.62 g), 1-bromo-n-hexane (5 g), methanesulphonic acid (0.05 ml), and n-hexanol (40 ml) was refluxed for 60 hours. After cooling, the precipitated n-hexyl-3-n-hexylamino-4-phenoxy-5-sulphamyl-benzoate was collected and recrystallized from hexanol. The melting point was 137°-138° C.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][NH:11][CH3:12]>COCCOC>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:11]([CH3:12])[CH3:10])[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CNC
Solvent: COCCOC
Product: CN(C)c1nc(Cl)nc(Cl)n1
Temperature: -5 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
Cyanuric chloride (11.0 g, 59.6 mmol) was dissolved in ethylene glycol dimethyl ether (100 ml), cooled to -5° C. and gradually added dropwise with 50% aqueous dimethylamine solution (10.8 ml, 120 mmol). This reaction mixture was stirred at the same temperature for 2 hours and then stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure. The obtained residue was added with dichloromethane and water, and then shaken for mixing. The organic layer was separated from the mixture, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed to obtain 11.0 g (yield: 95.4%) of 2,4-dichloro-6-dimethylamino-1,3,5-triazine as colorless crystals having melting point of 122.5° C.-123° C. (2) The obtained 2,4-dichloro-6-dimethylamino-1,3,5-triazine (1.93 g, 10.0 mmol) was dissolved in DMF (8 ml), added with anhydrous potassium carbonate (1.40 g, 10.1 mmol) and cooled to -5° C.-0° C. This mixture was gradually added with imidazole (695 mg, 10.2 mmol). The reaction mixture was stirred at room temperature overnight and evaporated under reduced pressure. The residue was added with ethyl acetate and water, and then shaken for mixing. The organic layer was separated from the mixture, washed with water, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography, using ethyl acetate and methanol (95:5) as eluant, to obtain 873 g (yield: 38.8%) of 2-chloro-4-(1-imidazolyl)-6-dimethylamino-1,3,5-triazine as colorless crystals having melting point of 88° C.-92° C.
Reaction SMILES: Br[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:21][C@@H:22]([C:26]1[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1)[CH2:23][CH2:24][OH:25].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:21][C@@H:22]([C:26]4[CH:27]=[N:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=4)[CH2:23][CH2:24][OH:25])[C:3]=3[CH2:11]2)=[C:13]([CH:16]=1)[C:14]#[N:15]
Reactant: N[C@H](CCO)c1ccc(C(F)(F)F)nc1
Reactant: N#Cc1cc(Cl)ccc1N1CCc2ncnc(Br)c2C1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)ccc1N1CCc2ncnc(N[C@H](CCO)c3ccc(C(F)(F)F)nc3)c2C1

Procedure:
A reaction mixture of 2-(4-bromo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-chlorobenzonitrile (35 mg, 0.10 mmol) and (R)-3-amino-3-(6-(trifluoromethyl)pyridin-3-yl)propan-1-ol (22 mg, 0.10 μmol) in acetonitrile (1 mL) and N,N-diisopropylethylamine (0.035 mL, 0.20 mmol) was subjected to microwave irradiation at 200° C. for 2 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC (100×20.2 mm, C18 column; 30-70% CH3CN-water [10 mM Et2NH]) to yield an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:17]([CH3:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=3[O:20][CH3:21])[N:7]([CH2:22][CH2:23][OH:24])[C:6]=2[C:5]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:4][CH:3]=1.[OH-:30].[Na+].O.Cl>CO>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:17]([CH3:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=3[O:20][CH3:21])[N:7]([CH2:22][C:23]([OH:30])=[O:24])[C:6]=2[C:5]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Nc3c(C)cc(Cl)cc3OC)n(CCO)c12
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3c(C)cc(Cl)cc3OC)n(CC(=O)O)c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.1 %

Procedure:
To a solution of 2-[4-chloro-2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]ethanol (861 mg, 1.75 mmol) in methanol (5 mL) was added 8N aqueous sodium hydroxide (1.5 mL), and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture, followed by neutralization with 6N hydrochloric acid. The mixture was concentrated in vacuo, and the residue was dissolved in methanol. The precipitate was removed by filtration, and the filtrate was concentrated in vacuo to give 781 mg (1.73 mmol, 99.1%) of the title compound as an amorphous.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]1[C:10]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:11]=2[S:12][C:13]=1[C:14]([NH2:16])=[O:15].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CN(C=O)C.C(OCC)(=O)C>[CH3:22][O:21][C:19]1[CH:18]=[CH:17][C:11]2[S:12][C:13]([C:14]([NH2:16])=[O:15])=[C:9]([S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:10]=2[CH:20]=1
Reactant: COc1ccc2sc(C(N)=O)c(Cl)c2c1
Reactant: Sc1ccccc1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2sc(C(N)=O)c(Sc3ccccc3)c2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
Thiophenol (116 μL, 1.13 mmol) is added to a suspension of 3-chloro-5-methoxybenzo[b]thiophene-2-carboxamide (250 mg, 1.03 mmol) in 2 mL of DMF. Diazabicycloundecene (DBU) (169 μL, 1.13 mmol) is added and the mixture is warmed to 80° C. After 2 hours, the reaction mixture is allowed to cool and is diluted with ethyl acetate and washed with 1N NaOH, 1N HCl, water, and brine. The organic layer is dried over MgSO4. Filtration followed by concentration in vacuo and recrystallization from ethyl acetate:hexane gives 5-methoxy-3-(phenylthio)benzo[b]thiophene-2-carboxamide in 84% yield; mp 194°-196° C.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li:15]CCCC>CCCCC>[Li:15][N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:14]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1
Reactant: [Li]CCCC
Solvent: CCCCC
Product: [Li]N(C(=O)OC(C)(C)C)c1ccccc1
Reaction time: 1 h
Yield: 77.4 %

Procedure:
Pentane (350 mL) was added to tert-butyl phenylcarbamate (20.81 g, 107.7 mmol) to form a suspension. BuLi (67.3 mL, 107.7 mmol) in hexanes was added dropwise over 1 hour. During the addition a clear solution formed briefly then a white precipitate formed. After the addition was complete the mixture was stirred for 1 hour then the solid was collected on a glass frit, washed with pentane (2×20 mL), and dried under reduced pressure to afford LiN(Boc)Ph (16.6 g, 77.4%). 2-Bromomethylphenyl boronic acid pinacol ester (compound 9) (4.66 g, 15.7 mmol) and N,N-dimethylformamide (DMF) (35 mL) were combined to form a clear colorless solution. Then solid LiN(Boc)Ph (3.13 g, 15.7 mmol) was added in small portions over three minutes. The mixture was stirred for 2 hours then the white suspension was poured into water (250 mL). Et2O (150 mL) was added and the organics were separated, dried with brine then magnesium sulfate. Filtration followed by evaporation afforded the product as a white solid. 1H NMR (CDCl3, 250 MHz): 7.77 (d, 1H), 7.0-7.5 (m, 8H), 5.19 (s, 2H), 1.39 (s, 9H), 1.27 (s, 12H).
Reaction SMILES: [CH3:1][Li].[CH3:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)=[O:5].[Cl-].[NH4+]>O1CCCC1>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]([OH:5])([CH3:1])[CH3:3])=[CH:7][CH:8]=1
Reactant: [Li]C
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
Methyllithium (1.10 mol/l solution in diethyl ether, 502 mL, 0.552 mol) was added to a solution of 4-bromoacetophenone (100 g, 0.502 mol) in tetrahydrofuran (500 mL) in a nitrogen atmosphere at −78° C., and the mixture was stirred at the same temperature for one hour. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give crude 2-(4-bromo-phenyl)-propan-2-ol.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:41])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>ClCCl>[C:35]([NH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1)(=[O:41])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Reactant: CCCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC(=O)NCCOc1ccc(NC(=O)c2cccc(OC)c2)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a mixture of N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide (0.020 g, 0.15 mmol) and triethylamine (0.038 mL, 0.27 mmol) in dichloromethane was added hexanoyl chloride (50 mg, 0.14 mmol), dropwise at room temperature. The mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with dichloromethane (3×20 mL) and dried over anhydrous MgSO4. The crude product was purified by flash column chromatography. (EtOAc/Hexane=50-90%). N-[4-(2-Hexanoylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide was obtained as white solid in 43% yield. LCMS m/z (%)=465 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ ppm 0.9 (t, J=7.1 Hz, 3 H), 1.3 (m, 4 H), 1.6 (m, 2 H), 2.1 (m, 2 H), 3.5 (q, J=5.4 Hz, 2 H), 3.8 (s, 3 H), 3.9 (s, 3 H), 4.0 (t, J=5.1 Hz, 2 H), 5.5 (m, 1 H), 6.3 (d, J=2.0 Hz, 1 H), 7.0 (d, J=9.1 Hz, 1 H), 7.1 (m, 1 H), 7.4 (m, 2 H), 7.4 (d, J=2.0 Hz, 1 H), 7.6 (d, J=2.0 Hz, 1 H), 7.6 (d, J=3.0 Hz, 1 H), 7.7 (dd, J=8.8, 2.8 Hz, 1 H), 7.8 (s, 1 H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([CH3:8])=[N:3]1.N1C=CC([NH:14][C:15](N)=[S:16])=N1>>[CH3:1][N:2]1[C:6]([NH:7][C:15]([NH2:14])=[S:16])=[CH:5][C:4]([CH3:8])=[N:3]1
Reactant: Cc1cc(N)n(C)n1
Reactant: NC(=S)Nc1cc[nH]n1
Product: Cc1cc(NC(N)=S)n(C)n1

Procedure:
This material is prepared from 2,5-dimethyl-2H-pyrazol-3-ylamine following the procedure described for (1H-pyrazol-3-yl)-thiourea (35a)
Reaction SMILES: [C:1]1([NH:11][C:12]([N:14]2[CH2:19][CH2:18][NH:17][C@H:16]([C@@H:20]([NH:22][C:23]3[N:28]=[C:27]([N:29]4[C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=5[N:31]=[CH:30]4)[CH:26]=[CH:25][N:24]=3)[CH3:21])[CH2:15]2)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47]>CC(C)=O.O>[CH2:49]([O:48][C:46]([CH2:45][N:17]1[CH2:18][CH2:19][N:14]([C:12](=[O:13])[NH:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH2:15][C@H:16]1[C@@H:20]([NH:22][C:23]1[N:28]=[C:27]([N:29]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[N:31]=[CH:30]2)[CH:26]=[CH:25][N:24]=1)[CH3:21])=[O:47])[CH3:50]
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)[C@@H]1CN(C(=O)Nc2cccc3ccccc23)CCN1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)CN1CCN(C(=O)Nc2cccc3ccccc23)C[C@H]1[C@H](C)Nc1nccc(-n2cnc3ccccc32)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 28.5 %

Procedure:
To a solution of 2-[1-(4-(N-naphth-1-yl-carbamoyl)-piperazin-2-yl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (EXAMPLE 36, Step C; 26 mg) in 0.5 mL of acetone was added potassium carbonate (11 mg) and ethyl bromoacetate (13.2 mg). The solution was stirred for 48 hours at room temperature, then diluted with 0.5 mL of water and extracted with 3×0.5 mL of CH2Cl2. The combined organics were washed with 1 mL of brine, dried with Na2SO4, and concentrated. The residue was purified by preparative HPLC (60:40 95% H2O-5% TFA:95% CH3CN-5% TFA) followed by preparative thin-layer chromatography, eluting with 95:5 25 CHCl3-isopropanol to provide 8.7 mg of the title compound. Mass spectrum (ESI) 579.3 (M+1).
Reaction SMILES: [CH:1]1([C:7]([N:9]2[CH2:14][CH2:13][N:12](CC3C=CC=CC=3)[CH2:11][CH2:10]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:22].[H][H]>C(O)C.[Pd]>[ClH:22].[CH:1]1([C:7]([N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(C1CCCCC1)N1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C(C1CCCCC1)N1CCNCC1

Procedure:
14.3 g (0.05 mole) of 1-cyclohexanecarbonyl-4-benzylpiperazine dissolved in 250 ml of ethanol and acidified with conc. HCl was treated with hydrogen over a palladium catalyst at 1500 psi and 100° C. The catalyst was removed by filtration and the solvent removed under reduced pressure. The residue was dissolved in isopropanol. On short standing a white crystalline precipitate appeared which was collected by filtration to give 10.0 g of 1-cyclohexanecarbonylpiperazine hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([Br:18])[C:3]=1[N:19]([CH3:39])[C:20]([C:22]1[C:23]([O:37][CH3:38])=[C:24]([NH:28][C:29]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[O:30])[CH:25]=[CH:26][CH:27]=1)=[O:21].[H-].[Na+].I[CH3:43]>CN(C)C=O.CO>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])[CH:5]=[C:4]([Br:18])[C:3]=1[N:19]([CH3:39])[C:20]([C:22]1[C:23]([O:37][CH3:38])=[C:24]([N:28]([CH3:43])[C:29]([C:31]2[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=2)=[O:30])[CH:25]=[CH:26][CH:27]=1)=[O:21]
Reactant: CI
Reactant: COc1c(NC(=O)c2ccncc2)cccc1C(=O)N(C)c1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1c(C(=O)N(C)c2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Br)cccc1N(C)C(=O)c1ccncc1
Reaction time: 0.17 h

Procedure:
To the colorless solution of N-[3-[[2,6-dibromo-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]-methyl-carbamoyl]-2-methoxy-phenyl]pyridine-4-carboxamide (example G-16 above) (0.120 g, 0.175 mmole) in N,N-dimethylformamide (5 ml), magnetically stirred under argon atmosphere was added sodium hydride (60% suspension in oil) (0.008 g, 0.192 mmole). After the gas evolution stopped, the resulting yellow solution was treated with iodomethane (0.012 ml, 0.027 g, 0.192 mmole). After 10 minutes, two drops of methanol was added and the reaction mixture was evaporated under reduced pressure. The residue was taken up in dichloromethane (5 ml) and water (10 ml). After phase separation, the aqueous solution was extracted twice with dichloromethane. The organic extracts were dried over sodium sulfate and evaporated. The residue was purified on a silica gel column using a gradient of ethyl acetate 20%-cyclohexane 80% to ethyl acetate 60%-cyclohexane 40%. The title product was a pale yellow oil showing, by LC-MS analysis (method 6 described hereunder) a retention time of 1.09 min and a M+H+ mass peak of 700.
Reaction SMILES: C([O:8][C:9](=[O:25])[C@H:10]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[NH:11][C:12]([O:14][CH3:15])=[O:13])C1C=CC=CC=1.O1CCCC1>[Pd].O>[CH3:15][O:14][C:12]([NH:11][C@H:10]([C:9]([OH:25])=[O:8])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[O:13]
Reactant: COC(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
A mixture of N-methoxycarbonyl-O-methyl-L-tyrosine benzyl ester (14.5 g), 10% palladium on carbon (0.73 g), and tetrahydrofuran (145 ml)-water (14.5 ml) was shaken under hydrogen at ambient temperature for 2 hours. An additional 10% palladium on carbon (0.73 g) was added to the mixture and shaking was continued for an additional 2 hours. The catalyst was filtered off and washed with tetrahydrofuran. The filtrate and washings were combined and concentrated in vacuo to afford N-methoxycarbonyl-O-methyl-L-tyrosine (10.5 g).
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=C[N:25]=[C:24]4C)=[CH:19][CH:18]=3)[CH:11]=2)[CH2:8][CH2:7][O:6][CH:5](C)[CH2:4]1)#[N:2].[NH:29]1C=C(C2C=CC(I)=CC=2)N=N1.C(C1(C2C=CC=C(S[Si](C(C)C)(C(C)C)C(C)C)C=2)CCOCC1)#N.C(C1(C2C=CC=C(S[Si](C(C)C)(C(C)C)C(C)C)C=2)CCOC(C)C1)#N>>[C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:24]=[N:25][N:29]=[CH:27]4)=[CH:19][CH:18]=3)[CH:11]=2)[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1)#[N:2]
Reactant: Cc1nccn1-c1ccc(Sc2cccc(C3(C#N)CCOC(C)C3)c2)cc1
Reactant: Ic1ccc(-c2c[nH]nn2)cc1
Agent: CC(C)[Si](Sc1cccc(C2(C#N)CCOCC2)c1)(C(C)C)C(C)C
Agent: CC1CC(C#N)(c2cccc(S[Si](C(C)C)(C(C)C)C(C)C)c2)CCO1
Product: N#CC1(c2cccc(Sc3ccc(-n4cnnc4)cc3)c2)CCOCC1

Procedure:
The titled compound was prepared according to the procedure described in example 29E for the preparation of (2SR,4RS)-4-cyano-2-methyl-4-[3-[4-(2-methylimidazol-1-yl)phenylthio]phenyl]-3,4,5,6-tetrahydro-2H-pyran using 4-(triazol-4-yl)phenyl iodide and 4-cyano-4-(3-triisopropylsilylthiophenyl)-3,4,5,6-tetrahydro-2H-pyran in place of 4-(2-methylimidazol-1-yl)phenyl iodide and (2SR,4RS)-4-cyano-2-methyl-4-(3-triisopropylsilylthiophenyl)-3,4,5,6-tetrahydro-2H-pyran, respectively. MS(EI):m/z 362(M+)
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=O)=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[ClH:15].Cl.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC>CN(C)C=O>[ClH:15].[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([N:26]3[CH2:25][CH2:24][N:23]([CH2:22][C:21]4[CH:29]=[C:30]([O:34][CH3:35])[C:31]([O:32][CH3:33])=[C:19]([O:18][CH3:17])[CH:20]=4)[CH2:28][CH2:27]3)=[O:14])=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Reactant: O=C(O)c1ccc2c(c1)CCCC2=O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(CN2CCN(C(=O)c3ccc4c(c3)CCCC4=O)CC2)cc(OC)c1OC
Yield: 75.1 %

Procedure:
Using 1-oxo-1,2,3,4-tetrahydro-6-naphthoic acid [Itoh et al., Chem. Pharm. Bull., 32, 130 (1984)] (0.8 g), 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (2.25 g), triethylamine (1.7 g), N,N-dimethylformamide (10 ml) and diethyl phosphorocyanidate (1.6 ml), an amidation as that described in Example 6 is carried out. The product is purified by silica gel column chromatography (hexane:acetone=1:1), and converted to the hydrochloride in a mixture of ethanol, ethyl acetate and ethyl ether to give 1-(1-oxo-1,2,3,4-tetrahydro-6-naphthoyl)-4-(3,4,5-trimethoxybenzyl)piperazine hydrochloride (1.5 g) as colorless crystals, m.p. 210°-215° C. (decomp.).