Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6]O)[CH3:2].P(Br)(Br)[Br:16].O>ClCCl>[O:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][Br:16])[CH3:2]
Reactant: BrP(Br)Br
Reactant: COc1cc(CO)cc(OC)c1OC
Solvent: O
Solvent: ClCCl
Product: COc1cc(CBr)cc(OC)c1OC
Yield: 86.7 %

Procedure:
Dissolving 3,4,5-trimethoxyl benzyl alcohol (14.05 g, 70.89 mmol) in dichlormethane (100 ml) in a 250 ml three-necked flask; phosphorus tribromide (6.73 ml, 70.89 mmol) in dichlormethane (25 ml) was added dropwise and allowed to react at room temperature for 50 minutes, cooling in ice bath, slowly adding deionized water (18 ml, 1.0 mol) dropwise to quench the reaction, washing with deionized water (100 ml) twice, drying with anhydrous magnesium sulfate, filtering, washing the filter residue with dichlormethane (20 ml), the combined organic layer was concentrated in rotatory evaporater to dry, and was further dried under vacuum to afford 3,4,5-trimethoxyl benzyl bromide (16.05 g of faint yellow solid), yield 84.44%.
Reaction SMILES: CN(C)CCN(C)C.C([Li])(CC)C.C(N(CC)[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C.[CH3:27][N:28]([CH3:37])[C:29]1[CH:36]=[CH:35][C:32]([CH:33]=[O:34])=[CH:31][CH:30]=1>O1CCCC1.C1CCCCC1>[CH3:27][N:28]([CH3:37])[C:29]1[CH:36]=[CH:35][C:32]([CH:33]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[O:34]2)=[CH:31][CH:30]=1
Reactant: CCN(CC)C(=O)c1ccccc1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CN(C)c1ccc(C2OC(=O)c3ccccc32)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 21.3 %

Procedure:
To a solution of 1.28 g of N,N,N',N'-tetramethylethylene-diamine in 25 ml of tetrahydrofuran was added 10.5 ml of 1.05 M cyclohexane solution of sec-butyl lithium under a nitrogen gas atmosphere, and a solution of 1.77 g of N,N-diethylbenzamide in 15 ml of tetrahydrofuran was added to the solution at -78° C. After stirring for 10 minutes at -78° C., a solution of 2.24 g of 4-dimethylaminobenzaldehyde in 10 ml of tetrahydrofuran was added to the mixture. After stirring at -78° C. for 1.5 hours, the temperature was gradually elevated to 5° C. and the reaction mixture was concentrated under reduced pressure. To the residue were added 50 ml of water and 50 ml of ethyl ether, and pH of the mixture was adjusted to 0.5 with 4N-hydrochloric acid. After shaking, the organic layer was discarded and 50 ml of methylene chloride was added to the aqueous layer. The pH was adjusted to 12 with 10N-sodium hydroxide solution. After shaking, the aqueous layer was discarded and the organic layer was washed with saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the organic layer was concentrated under reduced pressure. The crude product obtained was subjested to silica gel column chromatography (eluting solvent, ethyl acetate:hexane:triethylamine=50:50:5). A fraction eluted secondly was concentrated under reduced pressure and the concentrate was tritylated with methyl alcohol to give 0.54 g of 3-(4-dimethylaminophenyl)-1,3-dihydro-isobenzofuran-1-one (Compound A).
Reaction SMILES: [CH:1]1([N:7]=[C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[C:10]([O:19][CH3:20])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[CH:1]1([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([O:18][C:21](=[O:23])[CH3:22])=[C:10]([O:19][CH3:20])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: COC1=CC(=NC2CCCCC2)c2ccccc2C1=O
Product: COc1cc(NC2CCCCC2)c2ccccc2c1OC(C)=O

Procedure:
A suspension of 4-cyclohexylimino-1-oxo-2-methoxy-1,4-dihydronaphthalene in acetic anhydride is hydrogenated according to the procedure in Example 1 to obtain 4-cyclohexylamino-1-acetoxy-2-methoxynaphthalene, m.p. 134°-136° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19](O)=[O:20])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:22]([F:25])([F:24])[F:23])([O-:3])=[O:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH2:55][CH2:56][CH2:57][N:58]([CH2:70][CH2:71]Cl)[C:59]1[CH:68]=[CH:67][C:66]2[C:61](=[CH:62][CH:63]=[C:64]([Cl:69])[CH:65]=2)[N:60]=1>ClCCl>[Cl:69][C:64]1[CH:65]=[C:66]2[C:61](=[CH:62][CH:63]=1)[N:60]=[C:59]([N:58]1[CH2:70][CH2:71][N:55]([C:19](=[O:20])[CH2:18][O:17][CH:14]3[CH2:13][CH2:12][CH:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:22]([F:23])([F:24])[F:25])[CH:6]=4)[CH2:16][CH2:15]3)[CH2:56][CH2:57]1)[CH:68]=[CH:67]2
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reactant: NCCN(CCCl)c1ccc2cc(Cl)ccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(c2ccc3cc(Cl)ccc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
To a solution of 2-[(4-[4-nitro-3-(trifluoromethyl)phenyl]aminocyclohexyl)oxy]acetic acid (100 mg, 0.28 mmol) in dichloromethane (20 ml) was added EDAC.HCl (79.4 mg, 0.41 mmol, 1.5 eq), HOBt (56 mg, 0.41 mmol, 1.5 eq), triethylamine (111.6 mg, 1.10 mmol, 4 eq), and N-(2-aminoethyl)-6-chloro-N-(2-chloroethyl)quinolin-2-amine (93.8 mg, 0.33 mmol, 1.2 eq). The resulting solution was stirred overnight at room temperature and then quenched by the addition of water (50 ml), extracted with dichloromethane (3×30 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The crude material was purified by Pre-TLC using 4% methanol in dichloromethane to elute. The product-containing fractions were combined and concentrated under vacuum to afford 1-[4-(6-chloroquinolin-2-yl)piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one as a yellow solid (69.8 mg, 42%). (ES, m/z): [M+H]+ 592.35; 1H NMR (300 MHz, CDCl3): δ 8.00 (d, J=9.0 Hz, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.61 (s, 2H), 7.52 (s, 1H), 7.01 (d, J=9.0 Hz, 1H), 6.91 (s, 1H), 6.84 (d, J=2.4 Hz, 1H), 6.61-6.65 (m, 1H), 4.45 (d, J=7.5 Hz, 1H), 4.26 (s, 2H), 3.75-3.78 (m, 7H), 3.37-3.50 (m, 2H), 2.14 (d, J=10.5 Hz, 4H), 1.44-1.51 (m, 2H), 1.24-1.35 (m, 2H).
Reaction SMILES: [CH:1]1([NH:7][N:8]2[NH:12][CH:11]=[C:10]([C:13]3[N:14]([CH3:21])[C:15]([N+:18]([O-:20])=[O:19])=[CH:16][N:17]=3)[S:9]2)[CH2:6]CCC[CH2:2]1.[C:22](N)(C)(C)C.C1(N)CCCCC1>>[C:1]([NH:7][N:8]1[NH:12][CH:11]=[C:10]([C:13]2[N:14]([CH3:21])[C:15]([N+:18]([O-:20])=[O:19])=[CH:16][N:17]=2)[S:9]1)([CH3:2])([CH3:6])[CH3:22]
Reactant: CC(C)(C)N
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(NC2CCCCC2)S1
Solvent: NC1CCCCC1
Product: Cn1c([N+](=O)[O-])cnc1C1=CNN(NC(C)(C)C)S1

Procedure:
The preparation of the above compound is accomplished essentially by the procedure described for the 2-cyclohexylamino derivative (Example 38), an equivalent of t-butylamine replacing the cyclohexylamine. Recrystallization of the crude product from a mixture of ethyl acetate and acetone gives the pure compound melting at 249°-251° C.
Reaction SMILES: Cl[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][C:14]=3[CH:27]=2)=[CH:6][CH:5]=1)=[O:3].CCN(C(C)C)C(C)C.[F:37][CH:38]([F:41])[CH2:39][NH2:40]>O1CCCC1>[F:37][CH:38]([F:41])[CH2:39][NH:40][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][C:14]=3[CH:27]=2)=[CH:6][CH:5]=1)=[O:3]
Reactant: NCC(F)F
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(C(=O)Cl)cc3)cc2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(C(=O)NCC(F)F)cc3)cc2C1
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a solution of 1,1-dimethylethyl 7-[4-(chlorocarbonyl)phenyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1.0 g, 2.6 mmol) and DIPEA (2.2 mL, 13 mmol) in tetrahydrofuran (10 mL) was added 2,2-difluoroethylamine (0.21 g, 2.6 mmol). The reaction mixture was stirred for 2 h and then partitioned between ethyl acetate (20 mL) and 1M hydrochloric acid (20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by column chromatography on silica (30% ethyl acetate in hexanes) provided 1,1-dimethylethyl 7-(4-{[(2,2-difluoroethyl)amino]carbonyl}phenyl)-2,3-dihydro-1,4-benzoxazepine-4 (5H)-carboxylate (0.95 g, 85% yield). MS (EI) for C23H26F2N2O4: 433 (MH1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=1.[OH-].[NH4+:14]>CO>[NH2:14][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=1
Reactant: Nc1cccc(OCCCCl)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NCCCOc1cccc(N)c1
Temperature: 100 °C

Procedure:
The 3-(3-chloropropoxy)phenylamine (1.98 g, 11.6 mmol) was dissolved in methanol (25 mL) and added to concentrated ammonium hydroxide solution (29.7%, 14.8 M, 50 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 6 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (10 mL) was added to the residue, and the solution (pH 6) was extracted with ether (3×25 mL) to remove impurities. The aqueous layer was basified to pH 10 with 10% NaOH solution, and the mixture was extracted with chloroform (4×25 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 1.37 g of an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].S(Cl)(Cl)=O.[CH3:27]O>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([CH2:18][CH2:19][C:20]([O:22][CH3:27])=[O:21])[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2nc(CCC(=O)O)cs2)cc1OCC
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CCOc1ccc(-c2nc(CCC(=O)OC)cs2)cc1OCC
Temperature: 25 °C
Yield: 68 %

Procedure:
A solution (2.3 l) of 3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionic acid (254.5 g) in methanol was ice-cooled, and 58 ml of thionyl chloride was added dropwise. After completion of the addition, the resulting mixture was heated under reflux for 2 hours and cooled to room temperature. The solvent was distilled off under reduced pressure, and the residue was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). The solvent was distilled off under reduced pressure, and the residue was recrystallized from an ethyl acetate/n-hexane mixed solvent, to thereby obtain 219.35 g (yield: 68%) of methyl 3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionate as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:24][CH2:23][C:14]2([C:18](=[O:19])[N:17]([O:20][CH3:21])[C:16](=O)[CH2:15]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:24][CH2:23][C:14]2([C:18](=[O:19])[N:17]([O:20][CH3:21])[C:16](=[S:34])[CH2:15]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CON1C(=O)CC2(CCN(C(=O)OCc3ccccc3)CC2)C1=O
Solvent: Cc1ccccc1
Product: CON1C(=O)C2(CCN(C(=O)OCc3ccccc3)CC2)CC1=S
Yield: 102.4 %

Procedure:
To a solution of 8-benzyloxycarbonyl-2-methoxy-2,8-diazaspiro[4,5]decane-1,3-dione (2.9 g) in toluene (30 ml) was added a Lawesson reagent ([2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphethane-2,4-disulfide]) (2.38 g), and the mixture was heated for 3 hours under reflux. The solvent was then evaporated off under reduced pressure, and the residual oil was dissolved in ethyl acetate (50 ml), which was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated off, and the residual oil was subjected to a silica gel column chromatography [eluent; methanol:dichloromethane=1.50 (V/V)]. The earlier eluate fraction and the later eluate fraction were separated. The solvent for the later eluate fraction was evaporated off and the residual solid was recrystallized from ethyl ether to obtain 2.1 g of a pale yellow solid, m.p. 89° to 90° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([N+]([O-])=O)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].NC1C=CC=CC=1.NC1C=CC(C(OC)=[O:28])=C(Br)C=1.S(=O)(=O)(O)O.N([O-])=O.[Na+]>O>[Br:1][C:2]1[CH:11]=[C:10]([OH:28])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(N)cc1Br
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Nc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(O)cc1Br
Temperature: 90 °C
Reaction time: 5 h

Procedure:
2-Bromo-4-nitrobenzoic acid (6.2 g, 25.3 mmol) was dissolved in MeOH (120 mL), and SOCl2 (5.5 mL, 75.9 mmol) was added dropwise at 0° C. The reaction mixture was refluxed for 6 h. The reaction solvent was concentrated to dryness. Residual SOCl2 was removed by co-evaporation with CH2Cl2 (×3). The solid was dried under vacuum to afford methyl 2-bromo-4-nitrobenzoate in 99.5% (6.52 g) yield as a light yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.50 (1H, s, Ar), 8.21 (1H, d, J=8.4 Hz, Ar), 7.91 (1H, d, J=8.4 Hz, Ar), 3.97 (3H, s, OCH3); 13C-NMR (CDCl3, 100 MHz) δ 165.2, 149.2, 137.9, 131.7, 129.1, 122.1, 122.0, 53.1; MS (ESI) m/z Calcd for C8H6BrNO4 (M+): 259.0, Found: 260.1 (M+H+). Next, the nitro group of methyl 2-bromo-4-nitrobenzoate (6.38 g, 24.6 mmol) was chemoselectively reduced with 5 nCl2.2H2O (27.8 g, 123.2 mmol) in a manner similar to that described for compound 6 to deliver methyl 4-amino-2-bromobenzoate in 96.0% (5.41 g) yield as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 7.74 (1H, d, J=8.8 Hz, Ar), 6.90 (1H, d, J=1.6 Hz, Ar), 6.55 (1H, dd, J=8.8 Hz, 1.6 Hz, Ar), 4.06 (2H, s, NH2), 3.83 (3H, s, OCH3); 13C-NMR (CDCl3, 100 MHz) δ 165.9, 150.4, 133.6, 124.1, 119.7, 119.6, 112.7, 51.8; MS (ESI) m/z Calcd for C8H8BrNO2 (M+): 229.0, Found: 230.1 (M+H+). Finally, a solution of sulfuric acid (98%, 6 mL) in H2O (75 mL) was added to methyl 4-amino-2-bromobenzoate (1.23 g, 5.38 mmol) and the resulting suspension was heated to 90° C., then stirred for 5 h at this temperature. The reaction mixture was cooled to 0° C. and a solution of NaNO2 (384 mg, 5.57 mmol) in H2O (5 mL) was added dropwise, then the reaction was allowed to warm to ambient temperature. The reaction mixture was then added to a solution of sulfuric acid (98%, 6 mL) in H2O (75 mL) that had been preheated to 90° C. The reaction mixture was stirred at 90° C. for 1 h, and then allowed to cool. The reaction mixture was partitioned between EtOAc (200 mL) and aqueous solution. The organic layer was collected, dried over anhydrous Na2SO4, filtered, concentrated and purified by silica column chromatography (35% EtOAc in hexanes) to afford compound 10 in 41.1% (508 mg) yield as a light brown solid. 1H-NMR (CDCl3, 400 MHz) δ 7.76 (1H, d, J=8.8 Hz, Ar), 7.09 (1H, s, Ar), 6.75 (1H, d, J=8.8 Hz, Ar), 3.84 (3H, s, OCH3); 13C-NMR (CDCl3, 100 MHz) δ 166.2, 160.3, 133.5, 123.4, 122.1, 121.4, 114.3, 52.1; MS (ESI) m/z Calcd for C8H7BrO3 (M+): 230.0, Found: 231.0 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[O:11][C:10]([CH2:12][OH:13])=[CH:9][CH:8]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].C([O-])(=O)C.[Na+]>C1C=CC=CC=1.O>[C:15]([O:13][CH2:12][C:10]1[O:11][C:7]([CH2:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:14])=[CH:8][CH:9]=1)(=[O:17])[CH3:16]
Reactant: CN(C)CCCCc1ccc(CO)o1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)OCc1ccc(CCCCN(C)C)o1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 5-[4-(dimethylamino)butyl]-2-furanmethanol (4.9 g), acetic anhydride (25 g) and fused and powdered sodium acetate (10 g) in benzene (25 ml) was stirred at room temperature for 24 hr. The reaction was diluted with water (100 ml) and extracted with ethyl acetate. The combined extracts were distilled to afford a clear colourless oil b.p. 100°, 0.5 mm Hg. Found: C, 65.62; H, 9.03; N, 5.95. Calc. for C13H21NO3 : C, 65.24; H, 8.85; N, 5.85%.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][NH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C(Cl)Cl>[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([N:10]2[C:11]3[CH2:12][CH2:13][C:4]4[CH:3]=[C:2]([Cl:1])[CH:15]=[CH:14][C:5]=4[C:6]=3[CH2:7][CH2:8][CH2:9]2)=[O:30])=[CH:27][CH:26]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Clc1ccc2c(c1)CCC1=C2CCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCCC3=C2CCc2cc(Cl)ccc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
15.0 g (0.06 mol) of 8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline were dissolved in 150 ml of methylene chloride, treated with 6.68 g (0.066 mol) of triethylamine and 11.2 g (0.066 mol) of p-methoxybenzoyl chloride in 50 ml of methylene chloride were added dropwise thereto at 0°. After stirring at room temperature for 1 hour the mixture was extracted with water, dried with magnesium sulphate and the solvent was distilled off in vacuo. Crystallization (methylene chloride-ether) gave 4-(p-methoxybenzoyl)-8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline as white crystals of melting point 182°-183°.
Reaction SMILES: [C:1]([N:9]1[CH2:20][CH2:19][C:12]2[N:13]=[N:14][C:15]([NH:17][NH2:18])=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]([CH3:24])=O>C(O)(=O)C>[C:1]([N:9]1[CH2:20][CH2:19][C:12]2[N:13]=[N:14][C:15]([NH:17][N:18]=[C:22]([CH3:24])[CH3:21])=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: NNc1cc2c(nn1)CCN(C(=O)c1ccccc1)C2
Solvent: CC(=O)O
Product: CC(C)=NNc1cc2c(nn1)CCN(C(=O)c1ccccc1)C2

Procedure:
A solution of 0.5 g of 6-benzoyl-3-hydrazino-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine in 15 cc of absolute acetone, to which 4 drops of glacial acetic acid have been added, is heated on a water bath for 1 hour. The solution is concentrated in a vacuum, and the crude title compound, obtained as an oil, is crystallized with ether. The title compound has a M.P. of 188°-190° (decomp.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([N:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[CH:36]=O)[CH:25]=[CH2:26].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:36][C:28]2[N:27]([CH2:24][CH:25]=[CH2:26])[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[N:29]=2)[CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cnc(CNC2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Reactant: C=CCn1c(C=O)nc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCn1c(CN(Cc2ncc(C)cc2C)C2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21

Procedure:
Using General Procedure B: Reaction of the 4-[(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester and 1-allyl-1H-benzoimidazole-2-carbaldehyde in CH2Cl2 with NaBH(OAc)3 gave 4-[(1-allyl-1H-benzoimidazol-2-ylmethyl)-(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as white foam. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.57-1.65 (m, 2H), 1.86-1.89 (m, 2H), 2.25 (s, 3H), 2.27 (s, 3H), 2.57 (t, 2H, J=12.0 Hz), 2.72 (td, 2H, J=10.5, 3.0 Hz), 3.78 (s, 2H), 3.98 (s, 2H), 4.15-4.17 (m, 2H), 4.53 (d, 2H, J=3.0 Hz), 4.65 (d, 1H, J=18.0 Hz), 4.98 (d, 1H, J=9.0 Hz), 5.51-5.63 (m, 1H), 7.20-7.24 (m, 4H), 7.70-7.73 (m, 1H), 8.19 (s, 1H). Deprotection with TFA using General Procedure F gave (1-allyl-1H-benzoimidazol-2-ylmethyl)-(3,5-dimethyl-pyridin-2-ylmethyl)-piperidin-4-yl-amine as a yellow solid. 1H NMR (CDCl3) δ 1.72 (br t, 2H, J=10.5 Hz), 1.93 (d, 2H, J=11.1 Hz), 2.25 (s, 3H), 2.26 (s, 3H), 2.54 (t, 2H, J=12.0 Hz), 2.69 (t, 1H, J=11.4 Hz), 3.17 (d, 2H, J=11.4 Hz), 3.38 (br s, 2H), 3.82 (s, 2H), 3.99 (s, 2H), 4.55 (s, 2H), 4.65 (d, 1H, J=17.4 Hz), 4.97 (d, 1H, J=10.2 Hz), 5.53-5.62 (m, 1H), 7.20-7.23 (m, 4H), 7.71 (d, 1H, J=4.8 Hz), 8.18 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:3]([CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[N:4][CH:5]=[C:6]([O:8][CH3:9])[N:7]=1.[CH3:22][O-:23].[Na+].[NH4+].[Cl-]>C1COCC1>[CH3:22][O:23][C:2]1[C:3]([CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[N:4][CH:5]=[C:6]([O:8][CH3:9])[N:7]=1
Reactant: COc1cnc(Cn2ccnc2-c2ncccn2)c(Cl)n1
Reactant: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cnc(Cn2ccnc2-c2ncccn2)c(OC)n1

Procedure:
To a solution of 2-[1-(3-chloro-5-methoxy-pyrazin-2-ylmethyl)-1H-imidazol-2-yl]-pyrimidine (30 mg, 0.094 mmol) in THF (5 mL) is added sodium methoxide (25% w/w in methanol, 0.5 mL). The mixture is refluxed for 1 hour. On cooling, saturated NH4Cl (0.7 mL) is added to quenched the reaction. Solvent is removed in vacuo and to the residue is added DCM (30 mL). The mixture is then dried and solvent removed to give 21 mg of 2-[1-(3,5-dimethoxy-pyrazin-2-ylmethyl)-1H-imidazol-2-yl]-pyrimidine as an oil. 1H NMR (CDCl3) 8.79 (d, 2H), 7.62 (s, 1H), 7.15–7.21 (m, 2H, 7.07 (s, 1H), 5.95 (s, 2H), 3.88 (s, 3H), 3.82 (s, 3H) I. 2-[1-(5-Methoxy-3-piperidin-1-yl-pyrazin-2-ylmethyl)-1H-imidazol-2-yl]-pyrimidine (Compound 10)
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:21])=[N:8][CH:9]=[C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[CH:15]3)[CH:11]=1.FC(F)(F)C(O)=O.[CH3:34][N:35]1[CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]1>C(O)(=O)C>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:21])=[N:8][CH:9]=[C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[C:15]3[C:38]2[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH:37]=2)[CH:11]=1
Reactant: Nc1ncc(-c2ccc3[nH]ccc3c2)cc1OCc1c(Cl)cccc1Cl
Reactant: CN1CCC(=O)CC1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CN1CC=C(c2c[nH]c3ccc(-c4cnc(N)c(OCc5c(Cl)cccc5Cl)c4)cc23)CC1
Yield: 41 %

Procedure:
To a solution of 3-(2,6-Dichloro-benzyloxy)-5-(1H-indol-5-yl)-pyridin-2-ylamine (example I-58, 200 mg, 0.52 mmol) in acetic acid (4 mL) and trifluoroacetic-acid (1 mL) was added 1-methyl-4-piperidone (0.32 mL, 2.6 mmol). The solution was refluxing for over night, and evaporated. The residue was dissolved in ethyl acetate, washed with saturated NaHCO3 and brine, dried over Na2SO4, and condensed. The crude product was purified on a silica gel column eluting with dichloromethane-methanol-triethyl amine (95:5:0.1) to provide 3-(2,6-dichloro-benzyloxy)-5-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-5-yl]-pyridin-2-ylamine (103.5 mg, 41% yield) as an orange crystalline solid.