Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][C:3]1=[O:17].[CH2:18](O)[CH2:19][OH:20].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH2:18]1[CH2:19][O:20][C:3]2([CH2:4][CH2:5][CH2:6][CH:7]([S:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)(=[O:10])=[O:9])[CH:2]2[CH3:1])[O:17]1
Reactant: OCCO
Reactant: CC1C(=O)CCCC1S(=O)(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CC1C(S(=O)(=O)c2ccccc2)CCCC12OCCO2
Yield: 95 %

Procedure:
To a solution obtained by dissolving 1.4 g of 2-methyl-3-(phenylsulfonyl)-cyclohexan-1-one in 20 ml of benzene, were added 0.41 ml of 1,2-ethanediol and 0.1 g of anhydrous paratoluenesulfonic acid. The resulting mixture was heated under reflux for 4 hours. After the reaction, a 2M aqueous sodium bicarbonate solution was added and the resulting mixture was extracted with ethyl acetate three times. The combined organic layers were washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl ether, whereby 1,1-(ethylenedioxy)-2-methyl-3-(phenylsulfonyl)-cyclohexane was obtained in the form of white crystals. Yield: 95%
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[CH2:7][NH:8][C:9](=[O:12])[O:10][CH3:11])(=O)[CH3:2].Cl.[CH3:17][O:18][NH2:19].C([O-])(=O)C.[Na+].O>C(O)C.C(OCC)(=O)C>[CH3:17][O:18][N:19]=[C:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[CH2:7][NH:8][C:9](=[O:12])[O:10][CH3:11])[CH3:2]
Reactant: CON
Reactant: COC(=O)NCc1cccc(C(C)=O)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CON=C(C)c1cccc(CNC(=O)OC)c1
Yield: 87.7 %

Procedure:
0.40 g of methyl N-(3-acetylbenzyl)carbamate was dissolved in 10 ml of ethanol, and 0.36 g of methoxyamine hydrochloride and 5 ml of an aqueous solution of 0.54 g of sodium acetate were added thereto, followed by reflux under heating for 8 hours. After completion of the reaction, water was added to the reaction mixture, extraction with ethyl acetate was carried out, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crystals were washed with hexane to obtain 0.40 g of methyl N-[3-(1-methoxyiminoethyl)benzyl]carbamate as a pale yellow oily substance.
Reaction SMILES: Cl.[C:2]([N:10]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]([C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)[CH2:39][CH2:40][CH2:41]Br)=[CH:34][CH:33]=1>CN(C)C=O>[C:2]([N:10]1[CH2:16][CH2:15][N:14]([CH2:41][CH2:40][CH2:39][CH:38]([C:35]2[CH:34]=[CH:33][C:32]([F:31])=[CH:37][CH:36]=2)[C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)[CH2:13][CH2:12][N:11]1[C:17](=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(c1ccccc1)N1CCNCCN1C(=O)c1ccccc1
Reactant: Fc1ccc(C(CCCBr)c2ccc(F)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)N1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred mixture of 1,2-dibenzoylhexahydro-1H-1,2,5-triazepine hydrochloride (13.0 g), powdered anhydrous sodium carbonate (17.8 g) in N,N-dimethylformamide (100 ml, dried over 4A molecular sieves) under a purging nitrogen atmosphere was added 4,4-bis(4-fluorophenyl)butyl bromide (13.66 g) in N,N-dimethylformamide (30 ml) over a period of 40 minutes. The mixture was stirred under a purging nitrogen atmosphere at room temperature for 3 days. The mixture was filtered through sintered glass and the filter pad washed with N,N-dimethylformamide. The filtrate and washings were evaporated at 30° under oil pump vacuum. The residual oil was extracted with ether and the extract was filtered. The solution was slurried with 200 g of silica gel for 20 minutes. The mixture was then filtered through a sintered glass filter. The silica gel was stirred repeatedly with fresh ether (10-15 times) until no more product was removed from the silica gel. The filtrate and washings were evaporated to an oil. To the oil dissolved in 2-propanol (125 ml) was added 75 ml of a saturated solution of etheral hydrogen chloride. The hydrochloride salt of the titled product crystallized slowly on standing at room temperature; wt. 18.8 g (76%), mp=211°-212°.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[S:7][CH2:6][CH2:5][NH:4][CH:3]1[C:8]([OH:10])=[O:9].[CH2:12]=O.Cl>C(O)=O>[CH3:1][C:2]1([CH3:11])[S:7][CH2:6][CH2:5][N:4]([CH3:12])[CH:3]1[C:8]([OH:10])=[O:9]
Reactant: C=O
Reactant: CC1(C)SCCNC1C(=O)O
Agent: Cl
Solvent: O=CO
Product: CN1CCSC(C)(C)C1C(=O)O

Procedure:
A mixture of 2,2-Dimethyl-thiomorpholine-3-carboxylic acid (3.51 g, 20 mmol, BE 893025), formic acid (5.12 g of 90%) and formalin (4.5 mL of 37%) is heated at reflux for 8 hours. The reaction mixture is then cooled and treated with hydrochloric acid (10 mL of 4N) and evaporated to dryness. A portion of this residue is purified by HPLC to give 2,2,4-trimethyl-thiomorpholine-3-carboxylic acid, which is used as is. 2,2,4-Trimethyl-thiomorpholine-3-carboxylic acid (388 mg, 2.05 mmol) is stirred with dichloromethane (4 mL) and dimethylformamide (4 mL). To this is added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP, 1.07 g, 2.05 mmol). After 15 min, ethyl (2E,4S)-2,5-dimethyl-4-[methyl(3-methyl-L-valyl)amino]hex-2-enoate (0.640 g, 2.05 mmol, WO 99/32509) is added in dichlormethane (5 mL) followed by diisopropylethylamine (0.8 mL, 4.4 mmol). This is stirred at room temperature overnight. The reaction mixture is evaporated in vacuo and the residue treated with ethyl acetate and water. The ethyl acetate layer is dried over sodium sulfate, filtered and concentrated. The resulting material (314 mg, 0.65 mmol) is treated with aqueous 1 M lithium hydroxide solution (3.3 mL, 3.3 mmol), water (1.6 mL) and methanol (6.5 mL), to provide the trifluoroacetic acid salt of the title compound as a white solid after preparative HPLC, MS (ES): m/z 456.29 (M+H).
Reaction SMILES: O=S(Cl)[Cl:3].[C:5]1([NH:11][CH2:12][C:13]([OH:15])=[O:14])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:16](O)[CH3:17]>>[ClH:3].[CH2:16]([O:14][C:13](=[O:15])[CH2:12][NH:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:17]
Reactant: CCO
Reactant: O=C(O)CNc1ccccc1
Reactant: O=S(Cl)Cl
Product: CCOC(=O)CNc1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
22 mL of SOCl2 were added dropwise to a solution of 30 g of phenylglycin 1 (198.5 mmol) in 200 mL of anhydrous ethanol. A gentle reflux occurred spontaneously and it was maintained for 3 h. The reaction was allowed to cool to room temperature and was stirred overnight. The solvent was removed under vacuum to afford 41.8 g of 2 as a white powder (98% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[C:8]2[CH2:12][C:13](=O)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17]C=1)[CH3:2].[CH3:22][O:23][CH:24](OC)[O:25]C.O.O.O.[N+]([O-])([O-])=O.[Tl+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[Tl+]>CCOCC.CO>[CH3:22][O:23][C:24](=[O:25])[CH:12]([CH2:13][C:14]1[CH:15]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:8]1[C:7]2[C:11](=[C:3]([CH2:1][CH3:2])[CH:4]=[CH:5][CH:6]=2)[NH:10][CH:9]=1
Reactant: CCc1cccc2c(CC(=O)Cc3ccccc3)c[nH]c12
Reactant: COC(OC)OC
Agent: O=[N+]([O-])[O-]
Agent: [Tl+3]
Agent: [Tl+]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: CCc1cccc2c(C(Cc3ccccc3)C(=O)OC)c[nH]c12

Procedure:
According to the procedure of E. C. Taylor et al, J. Amer. Chem. Soc., 98, 3037 (1976), a solution of 1-(7-ethyl-1H-indol-3-yl)-3-phenylpropanone (2.77 g, 10 mmol) in a 1:1 mixture of methanol and trimethylorthoformate (25 mL) was added to thallium (III) nitrate trihydrate (4.88 g, 11 mmol), and the mixture was heated under reflux until precipitation of thallium (I) nitrate was complete (about 3 hours). The dark brown mixture was diluted with 25 mL of ether, and the thallium (I) nitrate was removed by filtration. The filtrate was washed successively with 1×50 mL portions of water, 5% aqueous sodium bicarbonate, and water and was then dried over anhydrous MgSO4. Concentration of the filtrate and flash chromatography of the crude product (20% ethyl acetate/hexane, silica gel) have the ester as a red-brown oil (0.98 g, 31.9%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[CH:11]=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=2[C:6](=[O:14])[C:5]2[N:15]([CH3:18])[N:16]=[CH:17][C:4]1=2)[CH3:2].CS(OC1C[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:18][N:15]1[C:5]2[C:6](=[O:14])[C:7]3[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][C:12]=3[N:3]([CH:1]3[CH2:25][CH2:26][NH:27][CH2:28][CH2:2]3)[C:4]=2[CH:17]=[N:16]1
Reactant: CCn1c2ccc(C)cc2c(=O)c2c1cnn2C
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1ccc2c(c1)c(=O)c1c(cnn1C)n2C1CCNCC1
Temperature: 85 °C
Yield: 35.2 %

Procedure:
A mixture of 1,7-dimethyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one (EXAMPLE 47, step 2, 0.1 g, 0.47 mmol), tert-butyl 4-[(methylsulfonyl)oxy]-1-piperidinecarboxylate ((Leeson et al., Bioorg. Med. Chem. Lett., 1999, 9, 1285), 0.66 g, 2.4 mmol) and potassium carbonate (0.13 g, 0.94 mmol) in dimethylsulfoxide (15 ml) was heated at 85° C. for 46.5 h. The reaction mixture was diluted with toluene/ethyl acetate (1:3, 30 ml), washed with water (30 ml), and dried over sodium sulfate. Removal of solvent gave a residue, which was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (1:1) to afford 49 mg (26%) of the title compound as a pale brown solid.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([C:7]#[N:8])=[CH:3][CH:2]=1.C[O-].[Na+].[Cl-:13].[NH4+:14]>CO>[ClH:13].[C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([C:7]([NH2:14])=[NH:8])=[CH:3][CH:2]=1
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: Cc1ccc(C#N)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(C(=N)N)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 120 h
Yield: 31 %

Procedure:
To a solution of p-tolunitrile (10.0 g) in methanol (85 mlb) was added sodium methoxide (0.46 g) and the reaction was stirred at room temperature for 5 days. Ammonium chloride (4.6 g) was added and the reaction was stirred overnight. The reaction was filtered and the filtrate concentrated to an oil. After the addition of ether the off-white precipitate was collected and dried to give the title compound (4.52 g). Electrospray MS m/z 135 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[O:18]1[C:22]2[CH:23]=[C:24](O)[CH:25]=[CH:26][C:21]=2[CH2:20][CH2:19]1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([O:10][C:24]2[CH:25]=[CH:26][C:21]3[CH2:20][CH2:19][O:18][C:22]=3[CH:23]=2)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: Oc1ccc2c(c1)OCC2
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Product: COC(=O)[C@@H]1C[C@H](Oc2ccc3c(c2)OCC3)CN1C(=O)OC(C)(C)C
Yield: 41.6 %

Procedure:
The title compound was prepared from (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl-ester 2-methyl ester and 2,3-dihydro-benzofuran-6-ol by the method of Preparation 14 in 41.6% yield as a white solid.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:31]=[CH:30][C:12]([O:13][CH2:14][C:15]([N:17]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=3[N+:27]([O-])=O)[CH3:18])=O)=[CH:11][CH:10]=2)[S:3]1.CO.[ClH:34].[H][H]>[C].[Pd].CC(N(C)C)=O>[ClH:34].[CH3:26][O:25][C:23]1[CH:22]=[CH:21][C:20]2[N:27]=[C:15]([CH2:14][O:13][C:12]3[CH:30]=[CH:31][C:9]([CH2:8][CH:4]4[S:3][C:2](=[O:1])[NH:6][C:5]4=[O:7])=[CH:10][CH:11]=3)[N:17]([CH3:18])[C:19]=2[CH:24]=1
Reactant: COc1ccc([N+](=O)[O-])c(N(C)C(=O)COc2ccc(CC3SC(=O)NC3=O)cc2)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CO
Product: COc1ccc2nc(COc3ccc(CC4SC(=O)NC4=O)cc3)n(C)c2c1
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 48 %

Procedure:
To a solution of 2-{4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy}-N-(5-methoxy-2-nitrophenyl)-N-methylacetamide (444.7 mg) in a mixed solvent of methanol (20 ml) and dimethylacetamide (5 ml) were added successively concentrated hydrochloric acid (0.344 ml) and a 10% wet palladium-carbon catalyst (244 mg). The atmosphere in the reaction flask was replaced with hydrogen gas (5 kg/cm2), and the resulting mixture was shaken at 50° C. for 3.5 hours. After shaking, the reaction mixture was cooled to room temperature and filtered to obtain a pale yellow filtrate. When the filtrate obtained was concentrated to about 5 g, the product crystallized out of solution. The crystals precipitated were collected by filtration and washed with methanol to afford the title compound (210 mg, yield: 48%) as a white crystalline solid.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C@@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1)=[C:8]2[C:12]([OH:14])=[O:13])[CH3:3].Cl.[C:21](=[NH:26])(OCC)[CH3:22].[OH-].[Na+]>O>[C:21]([N:17]1[CH2:18][CH2:19][C@@H:15]([C:7]2[CH2:6][C@H:5]3[N:9]([C:10](=[O:11])[C@@H:4]3[C@H:2]([OH:1])[CH3:3])[C:8]=2[C:12]([OH:14])=[O:13])[CH2:16]1)(=[NH:26])[CH3:22]
Reactant: CCOC(C)=N
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C([C@@H]3CCNC3)C[C@H]12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=N)N1CC[C@@H](C2=C(C(=O)O)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)C1
Reaction time: 0.5 h
Yield: 47.7 %

Procedure:
To a solution of (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(3S)-pyrrolidin-3-yl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (1.0 g) in water (30 ml) was added ethyl acetimidate hydrochloride (2.8 g) at 0° C while adjusting pH to 8.5 with 30% sodium hydroxide solution. After stirring for 30 minutes at the same temperature, the solution was adjusted to pH 6.5 with lN-hydrochloric.acid, washed with ethyl acetate, and then concentrated in vacuo. The residue was chromatographed on nonionic adsorption resin "Diaion HP-20" eluting with aqueous isopropyl alcohol (3%). The farctions containing the desired compound were collected and lyophilized to give (5R,6S)-3-[(3S)-1-acetimidoylpyrrolidin-3-yl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (550 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:8]C)[CH:5]=[N:6][CH:7]=1.[H-].[Na+].C[O-].[Na+]>CO.CN(C)C=O>[BrH:1].[Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1
Reactant: COc1cncc(Br)c1
Agent: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Br
Product: Oc1cncc(Br)c1

Procedure:
The synthesis route to prepare nifrolidine 9 is shown in FIG. 2. Starting with 3,5-dibromopyridine 1,3-bromo-5-methoxypyridine 2 was prepared in approximately 60%-89% yield by treatment with sodium hydride in methanol. Using an alternate procedure of sodium methoxide in N,N-dimethylformamide, more reproducible results were obtained in this reaction. Demethylation of 2 with refluxing hydrogen bromide provided 3-bromo-5-pyridinol 3 in 82% yield. The mixture generally had to be refluxed for longer times than reported (36 h rather than 16 h) for the high yields. Protection of (S)-pyrrolidinemethanol 4 was performed with di-tert-butyldicarbonate to provide 1-BOC-2-(S)-pyrrolidinemethanol 5 in 88% yield (alternatively, 5 is also available from Aldrich Chemical Co.). Mitsonobu reaction coupling of 3 and 5 was performed by diethyl azodicarboxylate in the presence of triphenylphosphine to provide the bromopyridyl ether 6 in 44% yield, which is somewhat lower than reported. To introduce a 3′-propanolic group at the 5-position, an allyl group was introduced. Using reported procedures, allylation of this bromo derivative 6 was first performed by allyltributyl tin in the presence of catalytic amounts of tetrakis(triphenylphosphine)palladium to provide the 5-allylpyridyl ether derivative 7 in 57% yield. Hydroboration of the allyl group followed by alkaline hydrogen peroxide treatment using previously described conditions led to the important alcohol intermediate, 8 in 26% yield. The low yield in this step was probably a result of the formation of a BH3 complex of the alcohol 8. Some preliminary efforts to neutralize this BH3 complex were not successful. Similar BH3-complex formation has recently been reported for other amines. The substituted alcohol 8 was treated with DAST to convert the alcohol to the corresponding fluoride using methods that we have previously used. Removal of the N—BOC group was achieved by treating with TFA to provide 9 in 25% yield. Final product 9, nifrolidine, was used as a p-toluenesulfonate salt for in vitro binding assays. For radiolabeling with 18F, the tosylate 10 was prepared from the BOC-protected key alcohol intermediate 8 by reacting with toluenesulfonyl chloride in yields of 40%-50%. The tosylate 10 was found to be stable and suitable for 18F radiolabeling and was stored at 0° C. to 20° C.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.ClC(Cl)(O[C:15](=[O:21])OC(Cl)(Cl)Cl)Cl.Cl.[F:24][C:25]([S:28]([O:31][C:32]1[CH2:38][CH:37]2[NH:39][CH:34]([CH2:35][CH2:36]2)[CH:33]=1)(=[O:30])=[O:29])([F:27])[F:26].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.ClCCl>[F:27][C:25]([F:24])([F:26])[S:28]([O:31][C:32]1[CH2:33][CH:34]2[N:39]([C:15]([N:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:4][CH2:3][CH2:2]3)=[O:21])[CH:37]([CH2:36][CH2:35]2)[CH:38]=1)(=[O:30])=[O:29]
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=S(=O)(OC1=CC2CCC(C1)N2)C(F)(F)F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N1CCCc2ccccc21)N1C2C=C(OS(=O)(=O)C(F)(F)F)CC1CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 274.3 %

Procedure:
1.13 g of 1,2,3,4-tetrahydroquinoline, 85 ml of dichloromethane and 1.54 ml of triethylamine are placed in a 250 ml three-necked flask under a nitrogen atmosphere. 0.834 g of triphosgene is added at 0° C., and the reaction is then left to stir at ambient temperature for 4 h. 2.27 g of 8-azabicyclo[3.2.1]oct-2-ene-3-yl trifluoromethylsulfonate hydrochloride and 1.19 ml of triethylamine are subsequently added and the reaction mixture is then refluxed for 18 h. 200 ml of a saturated aqueous solution of sodium hydrogen carbonate are added and the aqueous phase is extracted three times with dichloromethane. The organic phases are combined, dried over sodium sulfate and evaporated under reduced pressure. The residue is chromatographed on silica gel with an 8/2 mixture of heptane/ethyl acetate. 3.21 g of 8-(3,4-dihydroquinolin-1(2H)-ylcarbonyl)-8-azabicyclo[3.2.1]oct-2-ene-3-yl trifluoromethanesulfonate are obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:16]Br)=[C:4]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:5]([O:7]C)=O.Cl.[NH2:19][CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1.C(N(CC)CC)C>C1COCC1>[Br:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:4]2[C:3]=1[CH2:16][N:19]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=1)[C:5]2=[O:7]
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: COC(=O)c1cc(OC)c(OC)c(Br)c1CBr
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CN2Cc3c(cc(OC)c(OC)c3Br)C2=O)cc1
Temperature: 25 °C
Yield: 92.9 %

Procedure:
Methyl 3-bromo-2-(bromomethyl)-4,5-dimethoxybenzoate (1.5 g, 4.1 mmol) and methyl 4-(aminomethyl)benzoate hydrochloride (1.6 g, 2 equiv.) in the step 1 were dissolved in a mixture of THF and distilled water (mixture ratio=4:1 (v/v), 10 mL). Triethyl amine (1.7 mL, 3 equiv.) was added thereto and stirred at room temperature for 1 night. The reaction proceeded until no methyl 3-bromo-2-(bromomethyl)-4,5-dimethoxybenzoate was detectable by thin-layer chromatography (TLC). The resulting mixture thus obtained was distilled under a reduced pressure to remove THF. The resulting material was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution and the distilled water. The isolated organic layer was collected, dried over anhydrous MgSO4, and distilled under a reduced pressure to remove solvent. The resulting residue was subjected to a silica gel column chromatography (EtOAc/hexane=1:1) to obtain the title compound (1.6 g, 93%).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=O)[C:5]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=3[S:8][C:6]=2[N:7]=1.O=P(Cl)(Cl)[Cl:18].C(Cl)(Cl)Cl.CCCCCC>C(OC(=O)C)(=O)C>[Cl:18][C:4]1[C:5]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=3[S:8][C:6]=2[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: Nc1nc2sc3c(c2c(=O)[nH]1)CCCC3
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: Nc1nc(Cl)c2c3c(sc2n1)CCCC3
Yield: 44 %

Procedure:
To a 50 mL flask was added 10 (221 mg, 1 mmol) and 10 mL POCl3. The resulting mixture was refluxed for 2 h, and the solvent was removed under reduced pressure to afford a dark residue. To this was added 30 mL of CHCl3 and 300 mg of silica gel. The solvent was evaporated to afford a plug. Column chromatography of the plug with hexane: acetyl acetate=20:1 as eluent afford 105 mg (44%) of 11 as a yellow solid:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH:24]([CH3:26])[CH3:25])=[N:7][C:8]([CH:21]([CH3:23])[CH3:22])=[C:9]([CH2:18][CH:19]=O)[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O.O.[C:28](OCC)(=O)C.CCCCCC>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:24]([C:6]1[C:5]([CH2:3][OH:2])=[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:9]([CH2:18][CH:19]=[CH2:28])=[C:8]([CH:21]([CH3:22])[CH3:23])[N:7]=1)([CH3:25])[CH3:26]
Reactant: COC(=O)c1c(C(C)C)nc(C(C)C)c(CC=O)c1-c1ccc(F)cc1
Reactant: CCOC(C)=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: O
Product: C=CCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from methyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-(2-oxoethyl)-3-pyridinecarboxylate (Example 82, Step A) and methyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps F-H. 1H NMR (300 MHz, CDCl3): δ 7.13 (m, 4 H), 5.73 (m, 1H) 4.81 (dd, J=4.8, 1.8 Hz, 2 H), 4.35 (s, 2 H), 3.43 (septet, J=6.6 Hz, 1 H), 3.21 (septet, J =6.6 Hz, 1 H), 3.07 (d, J=1.8 Hz, 2 H), 1.24 (m, 13 H). FAB-MS: calcd for (C21H26FNO) 327, found 328 (M+H). Anal. Calcd for C21H26FNO: C, 74.17; H, 7.71; N, 4.12; F, 5.59+0.7 H2O. Found: C, 74.17; H, 7.57; N, 3.94; F, 5.26. mp 69-71° C. Rf=0.35 (15% ethyl acetate/hexane).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([C:19](N(OC)C)=[O:20])=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:25][Mg]Br>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([C:19](=[O:20])[CH3:25])=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CON(C)C(=O)c1ccc2cccnc2c1-c1cc(F)cc(F)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1ccc2cccnc2c1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 8-(3,5-difluorophenyl)-N-methoxy-N-methylquinoline-7-carboxamide (67 mg, 0.20 mmol) in tetrahydrofuran (0.5 mL) was added 1.40 M methylmagnesium bromide in tetrahydrofuran (0.87 mL, 1.2 mmol). The reaction was stirred at room temperature overnight, quenched with saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and then concentrated to dryness under reduced pressure. The resultant residue was used directly in next step. LCMS calculated for C17H12F2NO(M+H)+: m/z=284.1; found: 284.0.