Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:19][CH2:18][C:17]3[C:16]4[CH2:15][C:14]([CH3:21])([CH3:20])[CH2:13][C:12]=4[S:11][C:10]=3[C:9]2=[O:22])[C:3]=1[CH:23]=[O:24].[CH3:25][O:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][N:32]2[N:35]=[C:36]([NH:38][C:39]3[C:40](=[O:55])[N:41]([CH3:54])[CH:42]=[C:43](B4OC(C)(C)C(C)(C)O4)[CH:44]=3)[CH:37]=[C:31]2[CH2:30]1>>[CH3:20][C:14]1([CH3:21])[CH2:13][C:12]2[S:11][C:10]3[C:9](=[O:22])[N:8]([C:4]4[C:3]([CH:23]=[O:24])=[C:2]([C:43]5[CH:44]=[C:39]([NH:38][C:36]6[CH:37]=[C:31]7[CH2:30][N:29]([CH2:28][CH2:27][O:26][CH3:25])[CH2:34][CH2:33][N:32]7[N:35]=6)[C:40](=[O:55])[N:41]([CH3:54])[CH:42]=5)[CH:7]=[CH:6][N:5]=4)[CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:15]1
Reactant: CC1(C)Cc2sc3c(c2C1)CCN(c1nccc(Cl)c1C=O)C3=O
Reactant: COCCN1CCn2nc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)cc2C1
Product: COCCN1CCn2nc(Nc3cc(-c4ccnc(N5CCc6c(sc7c6CC(C)(C)C7)C5=O)c4C=O)cn(C)c3=O)cc2C1

Procedure:
Following the procedure in Example 304, and starting with 4-chloro-2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.02,6]dodeca-1(8),2(6)-dien-10-yl}pyridine-3-carbaldehyde 109a (250 mg, 0.693 mmol) and 3-(5-(2-methoxyethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 304d (595 mg, 0.1.386 mmol), 308a was obtained as a yellow solid (250 mg, 57%). MS-ESI: [M+H]+ 628.3
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>S(=O)(=O)(O)O>[C:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCC1Cc1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)N1CCCC1Cc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
Dissolve 5.0 g of 1-acetyl-2-benzylpyrrolidine (at 0°) in 25 ml of concentrated sulfuric acid. At this temperature add (dropwise, with stirring) 20 ml of concentrated nitric acid to the thus-prepared solution. After warming the obtained reaction mixture to room temperature, pour it into 200 ml of ice water and extract it with diethyl ether. After drying over sodium sulfate, treat the extract with activated charcoal and then distil off the solvent to obtain the title compound as reddish oil.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CO[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[O:24][CH2:25][C:26]([CH3:29])([CH3:28])[N:27]=1>O1CCCC1>[CH2:1]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[O:24][CH2:25][C:26]([CH3:29])([CH3:28])[N:27]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC[Mg]Br
Reactant: COc1ccccc1C1=NC(C)(C)CO1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1ccccc1C1=NC(C)(C)CO1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To freshly prepared dodecylmagnesium bromide (from 30.13 mmoles of dodecyl bromide and 26.20 mmoles of magnesium) in distilled tetrahydrofuran (50 ml) was added 2-(2-methoxyphenyl)-4,4-dimethyloxazoline [A. I. Meyers et al., J. Org. Chem., 43, 1372 (1978)] (17.88 mmoles) in tetrahydrofuran (30 ml). The resultant yellow solution was stirred under argon at ambient temperature for 20 hours. The solution was cooled in an ice water bath and quenched with aqueous ammonium chloride (100 ml). The reaction product was extracted into diethyl ether (100 ml) and the organic phase was washed with saturated sodium chloride solution (50 ml) and then dried over anhydrous magnesium sulfate. Evaporation of the organic phase afforded a colorless oil which was purified by flash chromatography over silica gel with 5 percent ethyl acetate in hexane as eluant to afford the desired product as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:20][C:19](=[O:21])[N:18]([CH3:22])[C:17]([NH:23]C(=O)OC(C)(C)C)=[N:16]3)[C:14]3[CH:13]=[C:12]([Cl:31])[N:11]=[C:10]([F:32])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:33][C:34]1[C:39](B(O)O)=[CH:38][CH:37]=[CH:36][N:35]=1>>[NH2:23][C:17]1[N:18]([CH3:22])[C:19](=[O:21])[CH2:20][C@@:15]2([C:14]3[CH:13]=[C:12]([Cl:31])[N:11]=[C:10]([F:32])[C:9]=3[O:8][C:5]3[C:4]2=[CH:3][C:2]([C:39]2[C:34]([F:33])=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:7][CH:6]=3)[N:16]=1
Reactant: CN1C(=O)C[C@@]2(N=C1NC(=O)OC(C)(C)C)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Reactant: OB(O)c1cccnc1F
Product: CN1C(=O)C[C@@]2(N=C1N)c1cc(-c3cccnc3F)ccc1Oc1c2cc(Cl)nc1F

Procedure:
The title compound was synthesized by procedures and steps analogous to those described in Example 12 above, but using (R)-tert-butyl 7-bromo-3-chloro-1-fluoro-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′-ylcarbamate (Intermediate 1-A) and 2-fluoropyridin-3-ylboronic acid.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH3:32])/[C:27]([OH:29])=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:34][C@@H:35]1[C:60](=[O:61])[N:37]2[C:38]([C:44]([O:46][CH:47]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:45])=[C:39]([CH2:42][Cl:43])[CH2:40][S:41][C@H:36]12.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH3:32])/[C:27]([NH:34][C@@H:35]2[C:60](=[O:61])[N:37]3[C:38]([C:44]([O:46][CH:47]([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)=[O:45])=[C:39]([CH2:42][Cl:43])[CH2:40][S:41][C@H:36]23)=[O:29])[N:25]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C

Procedure:
To 25 ml of N,N-dimethylformamide were added 1.3 g (3 mmol) of (Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetic acid and 1.35 (3 mmol) of diphenylmethyl 7 β-amino-3-chloromethyl-ceph-3-em-4-carboxylate hydrochloride. The mixture was cooled to 0° C., and 0.53 g (3.9 mmol) of N-hydroxybenzotriazole hydrate and then 0.80 g (3.9 mmol) of N,N-dicyclohexylcarbodiimide were added thereto.
Reaction SMILES: [C:1]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][CH:20]([F:22])[F:21])[N:14]=[CH:13][CH:12]=[C:11]2[Cl:23])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25]1[C:29]([CH3:30])=[C:28]([NH2:31])[NH:27][N:26]=1.CCO>Cl.CC#N>[ClH:23].[C:1]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][CH:20]([F:22])[F:21])[N:14]=[CH:13][CH:12]=[C:11]2[NH:31][C:28]1[NH:27][N:26]=[C:25]([CH3:24])[C:29]=1[CH3:30])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)S(=O)(=O)c1cc2c(Cl)ccnc2cc1OCC(F)F
Reactant: Cc1n[nH]c(N)c1C
Agent: Cl
Solvent: CCO
Solvent: CC#N
Product: Cc1n[nH]c(Nc2ccnc3cc(OCC(F)F)c(S(=O)(=O)C(C)(C)C)cc23)c1C
Temperature: 80 °C
Yield: 84.2 %

Procedure:
To 6-(tert-butylsulfonyl)-4-chloro-7-(2,2-difluoroethoxy)quinoline (85 mg, 0.234 mmol) and 3,4-dimethyl-1H-pyrazol-5-amine (33.8 mg, 0.304 mmol) in a microwave vial was added EtOH (779 μl) followed by 1 drop of 1N aq HCl (8.52 mg, 0.234 mmol). The vial was sealed and heated to 80° C. behind a blast shield overnight. LCMS showed full conversion to product. Concentrated reaction and triturated resulting residue with ˜2 mL of MeCN using ˜1 min of sonication. Filtered resulting solid, rinsing with MeCN, and dried under vacuum resulting in the product 6-(tert-butylsulfonyl)-7-(2,2-difluoroethoxy)-N-(3,4-dimethyl-1H-pyrazol-5-yl)quinolin-4-amine, hydrochloride (93.5 mg, 0.197 mmol, 84% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.70 (s, 1H), 11.25 (br. s., 1H), 9.26 (br. s., 1H), 8.51 (d, J=7.07 Hz, 1H), 7.57 (s, 1H), 6.67 (d, J=7.33 Hz, 1H), 6.47 (tt, J=3.28, 53.81 Hz, 1H), 4.63 (td, J=3.16, 14.46 Hz, 2H), 2.24 (s, 3H), 1.84 (s, 3H), 1.34 (s, 9H). MS: m/z: 439.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([CH3:19])=[C:12]2[C:3]=1[CH:4]=[CH:5][C:6]1[S:11][CH2:10][CH2:9][S:8][C:7]=12.[C:20](Cl)(=[O:24])[C:21](Cl)=O>O1CCCC1.CN(C)C=O>[CH3:1][C:2]1[CH:15]=[C:14]([C:16]([O:18][C:2]2[CH2:3][CH2:4][CH2:21][C:20](=[O:24])[CH:1]=2)=[O:17])[C:13]([CH3:19])=[C:12]2[C:3]=1[CH:4]=[CH:5][C:6]1[S:11][CH2:10][CH2:9][S:8][C:7]=12
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(C(=O)O)c(C)c2c3c(ccc12)SCCS3
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)OC2=CC(=O)CCC2)c(C)c2c3c(ccc12)SCCS3
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of 0.40 g of the title compound of Step D in 25 mL of tetrahydrofuran was added 0.34 mL of oxalyl chloride (purchased from Aldrich Chemical Co.) and 2 drops of N,N-dimethylformamide. The mixture was refluxed for 2 h and was then concentrated under reduced pressure to dryness. To the resulting residue was added 25 mL of tetrahydrofuran and evaporated to dryness again. Another 25 mL of tetrahydrofuran was added to the residue and the solution was cooled to about 0° C. To this mixture was added 0.16 g of 1,3-cyclohexanedione (purchased from Aldrich Chemical Co.) followed by addition of 0.52 mL of triethylamine. The mixture was stirred overnight at room temperature. To the reaction mixture was added saturated aqueous sodium bicarbonate and the mixture was extracted with methylene chloride. The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to dryness. Chromatography of the crude product on silica gel eluting with a mixture of hexanes:ethyl acetate (8:1 and then 4:1) yielded 0.21 g of the title compound of Step E as a yellow solid melting at 126°-130° C. 1H NMR (CDCl3): δ 2.18 (m, 2H), 2.49 (t, 2H), 2.64 (s, 3H), 2.72 (t, 2H), 2.90 (t, 2H), 3.06 (s, 3H), 3.52 (t, 2H), 6.07 (s, 1H), 7.50 (d, 1H), 7.62 (s, 1H), 7.70 (d, 1H).
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].[C:17]1([CH:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[C:2]([NH:5][C:6]([CH:23]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3]
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(NC(C)=O)(C(=O)OCC)C(c1ccccc1)c1ccccc1
Reaction time: 0.08 h

Procedure:
Dissolve sodium (2 g) in 400 ml ethanol and add diethyl acetamidomalonate (10.4 g). Stir 5 minutes, add diphenyl bromomethane (12.4 g), and stir 7 hours at room temperature. Acidify the reaction mixture, partition between water and methylene chloride (CH2Cl2), dry the organic layer over magnesium sulfate (MgSO4), filter, and evaporate the solvent to obtain the crude title compound as a pale yellow oil. Rf (silica gel; Et2O)=0.89.
Reaction SMILES: C(Cl)(Cl)Cl.[N+:5]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[C:10]([F:16])[CH:9]=1)([O-:7])=[O:6].[CH2:17]([Si](C)(C)C)[CH:18]=[CH2:19]>C(OCC)(=O)C.[Ti](Cl)(Cl)(Cl)Cl>[F:16][C:10]1[CH:9]=[C:8]([N+:5]([O-:7])=[O:6])[CH:15]=[CH:14][C:11]=1[CH:12]([OH:13])[CH2:19][CH:18]=[CH2:17]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1F
Reactant: C=CC[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: C=CCC(O)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.65 ml of titanium tetrachloride was added to a chloroform (12 ml) solution of 2.00 g of 4-nitro-2-fluoro-benzaldehyde produced according to the method described in U.S. Pat. No. 6,239,152, and the reaction liquid was stirred at room temperature for 10 minutes, and then 2.4 ml of allyl-trimethyl-silane was added to it, and the reaction liquid was stirred at room temperature for 20 minutes. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=3/1) to obtain the entitled compound as an orange solid.
Reaction SMILES: [O:1]=[C:2]1[C:14]2[N:6]([N:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH2:5][CH2:4][N:3]1[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22](OC(C)(C)C)=[O:23])[CH2:18][CH2:17]1.[C:29]1([CH2:35]C(Cl)=O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:29]1([CH2:35][C:22]([N:19]2[CH2:20][CH2:21][CH:16]([CH2:15][N:3]3[CH2:4][CH2:5][N:6]4[N:7]=[C:8]5[C:13]([CH:12]=[CH:11][CH:10]=[CH:9]5)=[C:14]4[C:2]3=[O:1])[CH2:17][CH2:18]2)=[O:23])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCn3nc4ccccc4c3C2=O)CC1
Reactant: O=C(Cl)Cc1ccccc1
Product: O=C(Cc1ccccc1)N1CCC(CN2CCn3nc4ccccc4c3C2=O)CC1

Procedure:
The product was prepared using the method described in example 2e), using tert-butyl 4-[(1-oxo-3,4-dihydropyrazino[1,2-b]indazol-2(1H)-yl)methyl]piperidine-1-carboxylate (example 1d) and benzeneacetyl chloride as reagents. The product was purified by flash chromatography on silica gel, using the mixture chlorofom:methanol in a ratio of 9:1 as eluent. Thus, 104 mg of 2-{[1-(phenylacetyl)piperidin-4-yl]methyl}-3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one were obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[NH2:15][C:16]1[NH:17][N:18]=[C:19]([CH3:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[CH3:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:15][C:16]3[NH:17][N:18]=[C:19]([CH3:21])[CH:20]=3)[N:7]=2)[CH2:9][CH2:10]1
Reactant: Cc1cc(N)[nH]n1
Reactant: CC1CCN(c2ccnc(Cl)n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: Cc1cc(Nc2nccc(N3CCC(C)CC3)n2)[nH]n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a solution of 2-chloro-4-(4-methylpiperidin-1-yl)-pyrimidine (prepared using a procedure similar to the one reported in Eur. J. Med. Chem., 26(7) 729(1991))(222 mg, 1.05 mmol) in BuOH (5 mL) was added 3-amino-5-methyl-2H-pyrazole (305 mg, 3.15 mmol) and the reaction mixture was then heated under reflux overnight. The solvent was evaporated and the residue dissolved in a mixture ethanol/water (1/3, 4 mL). Potassium carbonate (57 mg, 0.41 mmol) was added and the mixture was stirred at room temperature for 2 hours. The resulting suspension was filtered, washed with water twice and rinsed with ether twice to give the title compound as a white solid (143 mg, 50%): mp 193–195° C.; 1H NMR (DMSO) δ 0.91 (3H, d), 1.04 (2H, m), 1.67 (3H, m), 2.16 (3H, s), 2.83 (2H, t), 4.31 (2H, m), 6.19 (2H, m), 7.87 (1H, d), 8.80 (1H, br s), 11.71 (1H, s); IR (solid) 1627, 1579, 1541, 1498, 1417, 1388, 1322, 1246; MS 273.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[Cl:31][CH2:32][CH2:33][CH2:34][CH2:35]I>>[Cl:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([S:3][C:2]([F:14])([F:1])[F:15])=[CH:9][CH:8]=1)[C:11]([OH:13])=[O:12]
Reactant: ClCCCCI
Reactant: O=C(O)Cc1ccc(SC(F)(F)F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)C(CCCCCl)c1ccc(SC(F)(F)F)cc1
Yield: 47.2 %

Procedure:
Step AAM (1): 2-(4-(Trifluoromethylthio)phenyl)acetic acid (4.7 g, 19.9 mmol) was deprotonated with NaHMDS 2.0 M in THF (19.9 mL, 39.8 mmol) and reacted with 1-chloro-4-iodobutane (2.44 mL, 19.9 mmol) using a procedure analogous to Step AC (1) to afford 6-chloro-2-(4-(trifluoromethylthio)-phenyl)hexanoic acid (3.07 g, 9.40 mmol, 47% yield) as a pale-yellow oil. LC-MS (M−H)− 325.2. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.32-1.51 (m, 2 H) 1.69-1.87 (m, 3 H) 2.01-2.17 (m, 1 H) 3.49 (t, J=6.56 Hz, 2 H) 3.59 (t, J=7.63 Hz, 1 H) 7.36 (d, J=8.24 Hz, 2 H) 7.61 (d, J=8.24 Hz, 2 H).
Reaction SMILES: CS(Cl)(=O)=O.O[CH2:7][CH2:8][C:9]1[CH2:18][CH2:17][C:16]2[CH:15]=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[CH:13]=[CH:12][C:11]=2[CH:10]=1.[CH2:23]([N:25](CC)[CH2:26][CH3:27])[CH3:24].N1CCCC1>CN(C)C=O>[N:25]1([CH2:7][CH2:8][C:9]2[CH2:18][CH2:17][C:16]3[CH:15]=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[CH:13]=[CH:12][C:11]=3[CH:10]=2)[CH2:26][CH2:27][CH2:24][CH2:23]1
Reactant: CC(=O)Nc1ccc2c(c1)CCC(CCO)=C2
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc2c(c1)CCC(CCN1CCCC1)=C2
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
Methanesulfonyl chloride (0.131 ml, 1.69 mmol) was added to a dimethylformamide solution (7 ml) of N-[6-(2-hydroxyethyl)-7,8-dihydro-2-naphthalenyl]acetamide (355 mg, 1.53 mmol) obtained in Reference Example 102 and triethylamine (0.235 ml, 1.69 mmol) under ice-cooling, which was stirred for 30 minutes. Pyrrolidine (0.384 ml, 4.60 mmol) was added to the reaction mixture, which was stirred at 60° C. for 4 hours. The solvent was distilled out under reduced pressure. Ethyl acetate was added to the residue, and extraction was conducted using 1N hydrochloric acid. Potassium carbonate was added to the extract to make it alkaline, and extraction was conducted using ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled out under reduced pressure. The resulting residue was purified by alumina column chromatography (development solvent; ethyl acetate), to give the titled compound (294 mg).
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[CH2:5][C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH3:21].[CH2:23]([O:25][NH2:26])[CH3:24]>CO>[CH2:23]([O:25][N:26]=[C:19]([C:3]1[C:4](=[O:18])[CH2:5][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[CH2:7][C:2]=1[OH:1])[CH2:20][CH3:21])[CH3:24]
Reactant: CCC(=O)C1=C(O)CC(c2ccc(C(=O)OC)cc2)CC1=O
Reactant: CCON
Solvent: CO
Product: CCON=C(CC)C1=C(O)CC(c2ccc(C(=O)OC)cc2)CC1=O
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Into 20 ml of methanol was dissolved 2.5 g of 3-hydroxy-5-(4-methoxycarbonylphenyl)-2-propionyl-2-cyclohexen-1-one and to the solution was added 0.7 g of ethoxyamine. The mixture was kept for 15 hours at room temperature and it was poured into ice water. The crystal sedimented was collected with a filtering step and recrystallized with mixture solvent of methanol-water. Thus, 1.9 g of the desired compound which was in the form of colorless crystals having a melting point of 75°-76° C. was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1.Cl.[CH:16]1([C:19]2[CH:20]=[C:21]([CH3:31])[C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:23][CH:24]=2)[CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:28]2[CH2:29][CH2:30][N:25]([C:22]3[C:21]([CH3:31])=[CH:20][C:19]([CH:16]4[CH2:17][CH2:18]4)=[CH:24][N:23]=3)[CH2:26][CH2:27]2)=[O:8])=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Agent: Cl
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2S(C)(=O)=O)CC1
Yield: 94.1 %

Procedure:
Using 4-bromo-2-methanesulfonylbenzoic acid (558 mg) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine hydrochloride (508 mg) described in Preparation Example 82 and by the reaction and treatment in the same manner as in Preparation Example 119, the title compound (0.9 g) was obtained.
Reaction SMILES: [Mg].O(CC)CC.Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH:24]=[O:25])[CH:22]=2)[CH:17]=[CH:16][CH:15]=1>O1CCCC1>[C:8]1([CH:24]([C:21]2[CH:22]=[C:23]3[C:18]([CH:17]=[CH:16][CH:15]=[N:14]3)=[CH:19][CH:20]=2)[OH:25])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccc2cccnc2c1
Reactant: Brc1ccccc1
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1ccc2cccnc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 26.6 %

Procedure:
To a stirred mixture of 1.25 parts of magnesium, 14 parts of 1,1'-oxybisethane and 8 parts of bromobenzene was added a solution of 8 parts of intermediate 1, namely 7-quinolinecarboxaldehyde, in 72 parts of tetrahydrofuran, keeping the temperature between 0° C. and 5° C. After stirring for 12 hours at room temperature, the reaction mixture was poured into 300 parts of ice-water. The product was extracted with 1,1'-oxybisethane (3×70 parts). The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 98:2). The eluent of the desired fraction was evaporated, yielding 3.2 parts (26.6%) of α-phenyl-7-quinolinemethanol; mp. 118° C. (interm. 2). In a similar manner there were also prepared the intermediates listed in Table 1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10](Br)[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1)=[O:4].[CH2:16]([O:18]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:17].Cl.O>O1CCOCC1.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>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([C:16](=[O:18])[CH3:17])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccnc2c(Br)cccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccnc2c(C(C)=O)cccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
8-Bromo4-quinoline carboxylic acid methyl ester, D16 (E. R. Buchman et al., J. Amer. Chem. Soc., 1946, 68, 2692), (0.712 g), (1-ethoxyvinyl)tributyltin (1.60 g) and tetrakis(triphenylphosphine)palladium (O) in 1,4-dioxane (50 ml) were heated at reflux for 16 h. The reaction mixture was cooled to ambient temperature, HCl (5M, 1 ml) and water (15 ml) added and the resulting mixture stirred for 3 h. The solvent was removed at reduced pressure, the residue suspended in EtOAc and the solid removed by filtration. The organic phase was washed with saturated sodium bicarbonate, dried (Na2SO4), removal of the solvent under reduced pressure gave a dark oil which was chromatographed (silica gel, hexane diethyl ether) to give the title compound (0.500 g).