Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12](=[O:22])[O:13][CH:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>CC([O-])=O.CC([O-])=O.[Pd+2]>[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[CH:14]([O:13][C:12](=[O:22])[NH:11][C:8]1([C:5]3[CH:6]=[CH:7][C:2]([C:28]4[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=4)=[CH:3][CH:4]=3)[CH2:10][CH2:9]1)[CH2:15]2
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C(NC1(c2ccc(Br)cc2)CC1)OC1CN2CCC1CC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: COc1ccc(-c2ccc(C3(NC(=O)OC4CN5CCC4CC5)CC3)cc2)cc1
Yield: 0.1 %

Procedure:
Using general procedure E, quinuclidin-3-yl 1-(4-bromophenyl)cyclopropylcarbamate (0.485 g, 1.33 mmol), 4-methoxyphenyl boronic acid (0.404 g, 2.66 mmol) and Pd(OAc)2 (0.016 g, 0.071 mmol) gave the title compound as a grey solid (0.337 mg, 65%). 1H NMR (CDCl3) δ 7.48 (dd, J=8.6, 5.5 Hz, 4H), 7.29 (d, J=7.6 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 5.58 (d, J=48.7 Hz, 1H), 4.83-4.63 (m, 1H), 3.84 (s, 3H), 3.20 (dd, J=24.0, 15.5 Hz, 1H), 2.97-2.42 (m, 5H), 1.97 (d, J=30.9 Hz, 1H), 1.81 (s, 1H), 1.75-1.33 (m, 3H), 1.28 (d, J=6.8 Hz, 4H) ppm. 13C NMR major rotomer (CDCl3) δ 159.1, 156.0, 141.4, 139.0, 133.4, 128.0, 126.7, 125.9, 114.2, 71.5, 55.7, 55.3, 47.4, 46.5, 35.3, 25.5, 24.6, 19.6, 17.8 ppm. Purity: LCMS >97.1% (214 nm & 254 nm): retention time 0.88 min: (M+1) 393.4.
Reaction SMILES: C(OC([NH:11][C@H:12]([CH2:22][CH3:23])/[CH:13]=[CH:14]/[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=O)C1C=CC=CC=1.C(O)(=O)C>CO.[C].[Pd]>[C:15]([OH:17])(=[O:16])[CH3:14].[NH2:11][C@H:12]([CH2:22][CH3:23])[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16]
Reactant: CC[C@H](/C=C/C(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC[C@@H](N)CCC(=O)OC(C)(C)C
Reaction time: 7 h

Procedure:
To a solution of tert-butyl (2E, 4R)-4-{[(benzyloxy)carbonyl]amino}-2-hexenoate (9.73 g, 30.5 mmol) in methanol (200 ml) were added acetic acid (3.5 ml, 61 mmol) and 10% Palladium carbon (3.2 g). The mixture was stirred under hydrogen atmosphere for 7 hours. Catalyst was filtered off under a nitrogen atomosphere and the filtrate was condensed with an evaporator to give tert-butyl (4R)-4-aminohexanoate acetic acid salt (7.5 g, quantitatively).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[CH3:15]OC(OC)N(C)C.N1(C2CCCCCCC2)CCCCCCN1>CN(C)C=O>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:15])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: Cc1cc2c(cn1)[nH]c1ccccc12
Reactant: COC(OC)N(C)C
Agent: C1CCCC(N2CCCCCCN2)CCC1
Solvent: CN(C)C=O
Product: Cc1cc2c3ccccc3n(C)c2cn1

Procedure:
0.182 g of 3-methyl-β-carboline (example 5), 0.5 ml of N,N-dimethylformamide-dimethylacetal (90%) and 0.02 g of diazabicyclooctane (Dabco) are stirred in 30 ml of absolute N,N-dimethylformamide for 15 hours at 110° C. The solvent is distilled off under vacuum and the residue is chromatographed on silica gel. (Methylene chloride/ethanol: 9+1). 0.095 g of 3,9-dimethyl-β-carboline with a 134° C. melting point (decomposition) is obtained.
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[CH:3]=[N:2]1.[Cl:10][C:11]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](O)=[O:14].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:10][C:11]1[C:19]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([N:7]1[CH2:8][CH2:9][C:4]2[CH:3]=[N:2][NH:1][C:5]=2[CH2:6]1)=[O:14]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Reactant: c1n[nH]c2c1CCNC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2cn[nH]c2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (1.01 g, 5.15 mmol) in DMF (17 mL) was added 2-chloro-3-(trifluoromethyl)benzoic acid (2.31 g, 10.30 mmol), Hunig's base (3.55 mL, 20.60 mmol) and HATU (2.31 g, 10.30 mmol). The solution was allowed to stir for 30 min at rt then poured into ice water (300 mL). The resulting solid was collected by suction filtration and allowed to air dry. The solid was purified by chromatography on silica gel (0-100% ethyl acetatehexanes). The product fractions were concentrated to a white solid which was dissolved in ethanol (20 mL) and 1M NaOH (20 mL) and stirred at 80° C. for 1 h. Water (50 mL) and CH2Cl2 (50 mL) were added. The layers were separated and the water layer was extracted two times with CH2Cl2. The organic layers were combined, dried over anhydrous MgSO4, filtered and concentrated to an oil (1.37 g, 81%). MS (ESI) mass calcd. C14H11ClF3N3O, 329.1. m/z found, 330.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 7.79-7.73 (m, 1H), 7.52-7.41 (m, 2H), 7.37 (br s, 1H), 5.11 (d, J=16.6 Hz, 0.5H), 4.85 (d, J=16.6 Hz, 0.5H), 4.46 (d, J=15.9 Hz, 0.5H), 4.36 (d, J=15.9 Hz, 0.5H), 4.22-4.18 (m, 0.5H), 3.94-3.88 (m, 0.5H), 3.49-3.44 (m, 1H), 2.85-2.80 (m, 1H), 2.75-2.65 (m, 1H), 2.62-2.54 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:9][CH2:8][C:6]=2[N:7]=1.[CH3:20][O:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24].CCOC(C)=O>C(O)(C)C>[CH3:20][O:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: O=C(c1cccnc1)N1CCc2nc(Cl)ncc2C1
Reactant: COc1ccccc1N
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: COc1ccccc1Nc1ncc2c(n1)CCN(C(=O)c1cccnc1)C2
Temperature: 60 °C
Reaction time: 8 h
Yield: 33.5 %

Procedure:
A solution of (2-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(pyridin-3-yl)methanone, Intermediate 5 (0.025 g, 0.091 mmol) in isopropanol (0.1 mL) was treated with 2-methoxyaniline (0.012 g, 0.100 mmol). The resulting mixture was heated to 60° C. and allowed to stir overnight. After being allowed to cool to room temperature EtOAc (10 mL) was added to the reaction mixture, and the resulting solution was then washed twice with brine (10 mL). The combined aqueous layers were washed once with EtOAc (10 mL). The organic layers were combined, then dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The resulting crude residue was then purified over silica using a MeOH/CHCl3 gradient. The desired product was obtained in 33.5% yield (0.011 g, 0.030 mmol).
Reaction SMILES: [Si](O[CH:9]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:10]1)(C(C)(C)C)(C)C.C[Si]([Br:25])(C)C>C(Cl)Cl>[Br:25][CH:9]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:10]1
Reactant: C[Si](C)(C)Br
Reactant: CC(C)(C)[Si](C)(C)OC1CC[C@@H](c2ccc(F)cc2)O1
Solvent: ClCCl
Product: Fc1ccc([C@@H]2CCC(Br)O2)cc1
Temperature: -70 °C
Reaction time: 1.5 h

Procedure:
(5S)-2-(t-Butyldimethylsilyloxy)-5-(4-fluorophenyl) tetrahydrofuran (212, 1 g, 3.4 mmol) was dissolved in 10 mL of dry methylene chloride (degassed by bubbling argon prior to use). This solution was cooled to −70° C. and, while stirring at the same temperature under dry argon, trimethylsilyl bromide (550 μL, 4.1 mmol) was added dropwise. The stirring was continued for an additional 1.5 hours to yield (5S)-2-bromo-5-(4-fluorophenyl) tetrahydrofuran which was used without isolation (see below). In a separate flask, 3-t-butyldimethylsilyloxy-but-1-yne (840 mg, 4.5 mmol) was dissolved in dry THF (10 mL). The solution was cooled to −60° C. and, while stirring at the same temperature under dry argon, n-butyllithium (1.8 mL of 2.5M solution in hexane, 4.5 mmol) was added dropwise. The stirring was continued for an additional 0.5 hours. The resulting solution was added dropwise, through a cannula to the stirred solution of the 2-bromotetrahydrofuran (made above) at −70° C. The stirring was continued at −78° C. for additional 1.5 hours. The reaction flask was then left in the freezer (−78° C.) over night (though the TLC did not show any change). The reaction mixture was poured into 2M solution of ammonium chloride (100 mL) and extracted with methylene chloride (3×75 mL). The solution was dried over sodium sulfate and the solvent removed in vacuo. The residue was purified via flash column chromatography (eluent, 10% ethyl acetate in hexane) to obtain two components. From the proton NMR analysis, the less polar one was identified as (2S,5S)-trans-2-(3-t-butyldimethylsilyloxy-but-1-ynyl)-5-(4-fluorophenyl) tetrahydrofuran (213, 765 mg, 65%). 1H-NNR (CDCl3) δ 7.29 (2H, m), 7.01 (2H, t, J=8.7 Hz), 5.09 (1H, t, J=7.1 Hz), 4.91-4.97 (2H, m), 4.55-4.62 (1H, m), 2.26-2.50 (2H, m), 2.05-2.17 (1H, m), 1.75-1.88 (1H, m), 1.38 (3H, d, J=6.6 Hz), 0.90 (9H,s), 0.12 (6H, s). The more polar component was assigned to be (2R,5S)-cis-2-(3-t-butyldimethylsilyloxy-but-1-ynyl)-5-(4-fluorophenyl) tetrahydrofuran (214, 190 mg, 16%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][CH2:20][CH2:21][OH:22])(=[O:12])=[O:11])=[C:5]([CH3:23])[CH:4]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:22][CH2:21][CH2:20][CH2:19][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][N:13]1[S:10]([C:6]1[C:5]([CH3:23])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=1[CH3:9])(=[O:11])=[O:12])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCO)c(C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCOS(C)(=O)=O)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
3-(1-(4-Methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)propan-1-ol (1.19 mmol, 1 eq) was dissolved in methylene chloride (5 ml), and triethylamine (2.99 mmol, 2.5 eq) and methanesulfonic acid chloride (1.43 mmol, 1.2 eq) were added at 0° C. The mixture was stirred at room temperature for 1 h. The reaction mixture was then diluted with methylene chloride (20 ml), washed with water (10 ml) and saturated sodium chloride solution (8 ml), dried over sodium sulfate and concentrated. The crude product was employed in the next stage without further purification. Yield: 89%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[C:8](Cl)=[O:9].C(Cl)Cl.[NH3:15]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[C:8]([NH2:15])=[O:9]
Reactant: N
Reactant: O=C(Cl)c1c(Cl)cncc1Cl
Solvent: ClCCl
Product: NC(=O)c1c(Cl)cncc1Cl
Temperature: 0 °C

Procedure:
3,5-Dichloropyridine-4-carboxylic acid chloride (0.54 g, 2.6 mmol) was dissolved in CH2Cl2 (2.6 mL, 2.6 mmol) and NH3 (2.0 M in dioxane) (6.5 mL) was added. The reaction mixture was cooled to 0° C. for 30 min. The residue was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by preparative HPLC on silica gel to yield 3,5-dichloropyridine-4-carboxamide (0.135 g).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[I:12]I>C(O)C.[N+]([O-])([O-])=O.[Ag+]>[I:12][C:7]1[CH:8]=[C:2]([CH3:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]=1[NH2:6]
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: II
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CCO
Product: Cc1cc(I)c(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
4-Methyl-2-nitroaniline (20 g, 131.5 mmol) was dissolved in ethanol (300 ml), silver nitrate (27 g, 157.7 mmol) and iodine (40 g, 157.7 mmol) were added, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, the reaction mixture was filtered through celite, washed with ethyl acetate (100 ml) and concentrated. Water was added, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate to give 2-iodo-4-methyl-6-nitro-phenylamine (29 g, Yield 69%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH:10]1([NH2:13])[CH2:12][CH2:11]1>>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:13][CH:10]1[CH2:12][CH2:11]1
Reactant: NC1CC1
Reactant: O=Cc1ccccc1Br
Product: Brc1ccccc1CNC1CC1

Procedure:
Synthesized according to typical procedure J from 2-bromobenzaldehyde and cyclopropylamine.
Reaction SMILES: [CH2:1]([C:6]1[CH:38]=[CH:37][C:9]([CH2:10][N:11]([C:23](=[O:36])[CH:24]=[CH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13](O)=[O:14])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Br.[C:71]([N:88]1[CH2:93][CH2:92][NH:91][CH2:90][CH2:89]1)([O:73][CH2:74][CH:75]1[C:87]2[C:82](=[CH:83][CH:84]=[CH:85][CH:86]=2)[C:81]2[C:76]1=[CH:77][CH:78]=[CH:79][CH:80]=2)=[O:72]>C(#N)C>[CH:86]1[C:87]2[CH:75]([CH2:74][O:73][C:71]([N:88]3[CH2:89][CH2:90][N:91]([C:13](=[O:14])[C@@H:12]([N:11]([CH2:10][C:9]4[CH:37]=[CH:38][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:7][CH:8]=4)[C:23](=[O:36])[CH:24]=[CH:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:28][CH:27]=4)[CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:92][CH2:93]3)=[O:72])[C:76]3[C:81](=[CH:80][CH:79]=[CH:78][CH:77]=3)[C:82]=2[CH:83]=[CH:84][CH:85]=1
Reactant: CCCCCc1ccc(CN(C(=O)C=Cc2ccc(C(F)(F)F)cc2)[C@@H](Cc2ccccc2)C(=O)O)cc1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCNCC1
Agent: Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCc1ccc(CN(C(=O)C=Cc2ccc(C(F)(F)F)cc2)[C@@H](Cc2ccccc2)C(=O)N2CCN(C(=O)OCC3c4ccccc4-c4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.2 %

Procedure:
2-{(4-pentyl-benzyl)-[3-(4-trifluoromethyl-phenyl)-acryloyl]-amino}-(S)-3-phenyl-propionic acid (1.5 g, 2.86 mmol) and TBTU (1.1 g, 3.43 mmol) was dissolved in acetonitrile (30 mL) and DIPEA (1.5 mL, 8.6 mmol) and stirred at rt for 5 min, followed by the addition of Fmoc-piperazine hydrobromide (1.22 g, 3.15 mmol). The reaction mixture was stirred at rt for 16 h and concentrated under reduced pressure. The residue was dissolved in EtOAc (150 ml) and washed with brine (100 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silicagel, EtOAc/heptane=3/7) to give 1.75 g (75%) of 4-(2-{(4-pentyl-benzyl)-[3-(4-trifluoromethyl-phenyl)-acryloyl]-amino}-(S)-3-phenyl-propionyl)-piperazine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester. LC-MS: tR=1.25 min; [M+H]+=814.5.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:12])=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:14][C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].C1OC1C>C(COC)OC>[Cl:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2]3[N:3]2[CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:1]=3)=[CH:8][CH:7]=1
Reactant: Nc1ccc2ccc(Cl)cc2n1
Reactant: CCOC(=O)C(=O)CBr
Agent: CC1CO1
Solvent: COCCOC
Product: CCOC(=O)c1cn2c(ccc3ccc(Cl)cc32)n1
Reaction time: 1 h

Procedure:
2.0 g of 2-amino-7-chloroquinoline [Chem. Abs., Vol. 79, p. 92024t] were dissolved in 40 ml of dimethoxyethane and then a mixture of 2.5 g of ethyl bromopyruvate and 0.5 g of propylene oxide in 5 ml of dimethoxyethane was added thereto. The mixture obtained was allowed to stand at room temperature for 1 hour and the quaternary salt thus precipitated was filtered off, washed with ether and then was dissolved in 50 ml of ethanol. The solution was refluxed for 1 hour and on subsequent cooling in ice, the solution precipitated ethyl 8-chlorimidazo-[1,2-a]-quinoline-2-carboxylate hydrobromide as pale lemon hygroscopic crystals. This salt was partitioned between 50 ml of dilute sodium carbonate solution and 100 ml of chloroform and the organic solution was separated, washed with 50 ml of water, dried over MgSO4 and was evaporated to dryness under reduced pressure. The residue was crystallized from chloroform/diethyl ether to give colorless crystals of ethyl 8-chloroimidazo-[1,2-a]-quinoline-2-carboxylate melting at 221°-222° C.
Reaction SMILES: [C:1]1([C:11]([N:13]2[C:17](=[O:18])[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:15][C:14]2=[O:31])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[CH2:32]([N:15]1[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17](=[O:18])[N:13]([C: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)=[O:12])[C:14]1=[O:31])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1C(=O)c1cccc2ccccc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1cccc2ccccc12)N1C(=O)N(Cc2ccccc2)C(c2ccccc2)(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
3-Naphthylcarbonyl-5,5-diphenylimidazolidine-2,4-dione (200 mg) was dissolved in DMF (2 mL), benzyl bromide (45 mg) was added, and potassium carbonate (36 mg) was further added. The reaction solution was stirred at room temperature overnight. Ethyl acetate (100 mL) was added to the reaction solution, and the solution was washed with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution and a saturated brine in turn. After the solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was recrystallized from IPE to obtain 55 mg of white crystals.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.Cl.[I:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][NH2:18].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:18][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([I:13])[CH:15]=2)[N:3]=1
Reactant: NCc1cccc(I)c1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Clc1nc(NCc2cccc(I)c2)c2[nH]cnc2n1
Yield: 56.8 %

Procedure:
A solution of 2,6-dichloropurine (Aldrich Chemical Co., 1 g, 5.3 mmol), 3-iodobenzylamine hydrochloride (1.7 g, 5.8 mmol), and triethylamine (2.2 ml, 15.35 mmol) in ethanol (10 ml) was stirred for 5 days at room temperature. The colorless solid formed was collected by suction, washed with small amount of cold ethanol, and dried to yield 2-chloro-N6 -(3-iodobenzyl)adenine (1.16 g, 60%): m.p. 222°-224° C.; mass (EI) 385: 1H NMR (DMSO-d6 d 4.59 (br s, 2H, --CH2), 7.13 (pseudo t, J=8.2 and 7.5 Hz, 1H, Bn), 7.36 (d, J=7.5 Hz, 1H, Bn), 7.61 (d, J=7.5 Hz, 1H, Bn), 7.74 (s, 1H, Bn), 8.14 (s, 1H, H-8), 8.76 (br s, 1H, exchangeable with D2O, NH), 13.14 (br s, 1H, exchangeable with D2O, NH). UV (MeOH) 1max 281.7, 257.5, 232.5 nm.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:15][O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:4]([C:8](=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.[O:22]([NH2:24])[CH3:23].C([O-])(=O)C.[Na+]>C(O)C>[F:1][C:2]1[C:3]([CH2:15][O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:4]([C:8](=[N:24][O:22][CH3:23])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cccc(F)c1COC(C)(C)C
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=NOC)c1cccc(F)c1COC(C)(C)C
Temperature: 60 °C
Yield: 98.8 %

Procedure:
To a solution of 79 g (0.28 mole) of ethyl 3-fluoro-2-[(1,1-dimethylethoxy)methyl]-α-oxo-benzeneacetate in 300 mL of ethyl alcohol was added 100 mL (0.39 mole, 30% aq) of methoxylamine HCl followed by 33 g (0.4 mole) of sodium acetate. The mixture was then heated at 60° C. for three hours. After cooling to room temperature, the salts were filtered and the mixture was concentrated in vacuo. Water and EtOAc were added, the layers separated, and the organics were washed with saturated NaHCO3, brine and dried over MgSO4. After filtration, the solution was concentrated in vacuo to give 86.1 g of ethyl 3-fluoro-2-[(1,1-dimethylethoxy)methyl]-α-(methoxyimino)-benzeneacetate as a lightly tinted oil, 1:2 ratio of oxime isomers by gas chromatography.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.O>[N:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N+:2]=[N-:3]
Reactant: COC(=O)CCCCCCCCCCBr
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCCCCCCCN=[N+]=[N-]
Temperature: 60 °C

Procedure:
Sodium azide (4.66 g, 72 mmol) and tetrabutylammonium iodide (66 mg, 0.18 mmol) were successively added to a solution of methyl 11-bromoundecanoate (commercially available at Aldrich, 5.00 g, 17.9 mmol) in N,N-dimethylformamide (50 ml). The reaction mixture was heated to 60° C. for 16 h and cooled to room temperature. It was diluted with water (200 ml) and extracted with ethyl acetate (200 ml). The aqueous phase was washed with water (2×200 ml). The organic phase was dried over sodium sulphate. The solvent was removed in vacuo to give 4.28 g of methyl 11-azidoundecanoate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:16][C:17]([F:29])([F:28])[O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:22]2[CH:21]=[CH:20][C:19]([O:18][C:17]([F:16])([F:28])[F:29])=[CH:24][CH:23]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: FC(F)(F)Oc1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Yield: 35.9 %

Procedure:
A reaction mixture comprising 6.7 g of 4-benzyloxybromobenzene, 5.0 g of 4-(trifluoromethoxy)benzeneboronic acid, 0.3 g of tetrakis(triphenylphosphine)palladium(0), 5.1 g of sodium carbonate, 100 ml of ethylene glycol dimethyl ether and 20 ml of pure water was refluxed for 5 hours. The reaction mixture was extracted with toluene, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the resulting residue was purified through silica gel chromatography (elution solvent: heptane/toluene=7/3) and recrystallized from heptane, and 3.0 g of 4-benzyloxy-4′-(trifluoromethoxy)biphenyl was obtained. m.p.: 136-137.2° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([C:17]#[N:18])=[CH:11][CH:10]=2)=[O:5])[CH3:2].C(N(CC)CC)C>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([C:17]#[N:18])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2ccc(C#N)cc2c1Cl
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc2ccc(C#N)cc2c1
Reaction time: 3.5 h

Procedure:
To a suspension of 4-chloro-6-cyanoquinoline-3-carboxylic acid ethyl ester [CAS Reg. No 403841-76-9] (5 g) in ethanol (30 ml) were added triethylamine (3.90 g) and Pd (5% on charcoal, 200 mg). The mixture was stirred under a hydrogen atmosphere for 3.5 h using a balloon. The catalyst was filtered off and the filtrate was concentrated. Since the reaction was not finished, the hydrogenation was repeated using the same conditions. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:0=>0:1) to give the title compound (2.1 g) as a colorless solid. MS (m/e)=227.2 [M+H+].