Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@:2]12[C@@H:26]([OH:27])[CH2:25][C@@:24]3([CH3:28])[C@@H:12]([CH2:13][CH:14]=[C:15]3[C:16](=[O:23])[CH2:17]OS(C)(=O)=O)[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:30])[CH:4]=[CH:5][C:6](=[O:29])[CH:7]=1.[Cl-:31].[Li+].O>CN(C)C=O>[Cl:31][CH2:17][C:16](=[O:23])[C:15]1[C@:24]2([CH3:28])[C@H:12]([C@H:11]3[C@:2]([F:1])([C@@H:26]([OH:27])[CH2:25]2)[C@:3]2([CH3:30])[C:8](=[CH:7][C:6](=[O:29])[CH:5]=[CH:4]2)[CH2:9][CH2:10]3)[CH2:13][CH:14]=1
Reactant: [Cl-]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CC=C(C(=O)COS(C)(=O)=O)[C@@]3(C)C[C@H](O)[C@@]12F
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CC=C(C(=O)CCl)[C@@]3(C)C[C@H](O)[C@@]12F

Procedure:
To a solution of 17.5g of 9-fluoro-11β-hydroxy-21-methanesulfonyloxypregna-1,4,16-triene-3,20-dione in dry dimethylformamide (250 ml) is added lithium chloride (30g). The mixture is heated, with stirring, from 30° to 100° C. over a 30-minute period. It is cooled and poured into cold water (1.51) and the precipitated solid is isolated and crystallized from methanol to afford 12g of the title compound, melting point 258°-260° C.(dec.).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH2:1]([O:3][C:4](=[O:5])[CH2:6][N:7]1[CH2:8][CH2:9][N:10]([C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:11][CH2:12]1)[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C

Procedure:
1-(Ethoxycarbonylmethyl)piperazine (5.1 g) was dissolved in tetrahydrofuran (300 ml) under a nitrogen atmosphere, and triethylamine (8.25 ml) and benzoyl chloride (3.44 ml) were added thereto while stirring in an ice water bath. The reaction mixture was allowed to warm up to room temperature and stirred for 4 hr. The reaction mixture was partitioned between ethyl acetate (200 ml) and a saturated aqueous solution of sodium hydrogencarbonate (100 ml). The separated organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (100 ml), water (100 ml) and brine (100 ml), and dried over sodium sulfate. The solvent was removed under reduced pressure to provide the titled compound as a colorless oil (8.19 g, quantitative).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[Cl-].[Al+3].[Cl-].[Cl-].Cl[CH:14]([O:16]C)Cl.Cl>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[F:8])[CH:14]=[O:16]
Reactant: COC(Cl)Cl
Reactant: Fc1ccccc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=Cc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
57 g (0.5 mol) of ortho-difluorobenzene in 250 ml of methylene chloride is added to 100 g (0.75 mol) of anhydrous aluminum chloride. The mixture is stirred mechanically at 0° C. (ice bath) while 85.5 g (0.75 mol) of dichloromethyl methylether is added dropwise. Vigorous HCl evolution takes place, and the reaction mixture turns orange-red. After the addition, the mixture is stirred at room temperature for 15 minutes, and the liquid phase is decanted into 500 ml of ice and water. The residue in the reaction flask is washed with methylene chloride until colorless, and the washings are added to the water. The mixture is shaken well in a separatory funnel until the methylene chloride layer is green. The organic layer is washed with saturated potassium carbonate solution until neutral, is dried MgSO4) and is distilled to give 3,4-difluorobenzaldehyde, B.P. 70-74° C./20 mm. The dark residue in the distillation pot solidifies on cooling to give tris-(3,4-difluorophenyl)methane, M.P. 95-96° C.
Reaction SMILES: C(OC([O:6][CH2:7][CH2:8][C:9]#[C:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])C)C.Cl>CC(C)=O.O.C(OCC)(=O)C>[OH:6][CH2:7][CH2:8][C:9]#[C:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: CCOC(C)OCCC#CC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: O=C(C#CCCO)OCc1ccccc1
Reaction time: 6 h
Yield: 99.9 %

Procedure:
A solution of the product from Example 31B (122.1 g, 0.442 mole) in acetone (400 mL) was treated at ambient temperature with an aqueous hydrochloric acid solution (0.5 N, 200 mL). The reaction mixture was stirred for 6 hours and then diluted with water and ethyl acetate. The layers were separated, and the organic layer was dried over magnesium sulfate, filtered and concentrated to provide the title compound as a colorless oil (90.17 g, 100%). 1H NMR (300 MHz, CDCl3) δ 2.61 (t, 2H), 3.79 (t, 2H), 5.19 (s, 2H), 7.32-7.40 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C>>[Cl:1][C:2]1[N:11]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc2nc(Cl)nc(Cl)c2c1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2nc(Cl)nc(Nc3ccccc3)c2c1

Procedure:
In a procedure analogous to that of Example la 2,4-dichloro-6-methoxy-quinazoline (1.53 g) (prepared as described in J. Chem. Soc. 1948, 1759), aniline (0.8 g) (0.184 g) and N,N-diisopropyl-ethylamine (1.72 g) are reacted together to give 2-chloro-6-methoxy-4-phenylamino-quinazoline as light yellow crystals melting at 177-179° C., Rf (A2) 0.59.
Reaction SMILES: [C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([N+:28]([O-:30])=[O:29])=[C:25]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:24]=2[CH:37]=1>CC(C)=O>[BrH:18].[C:1]1([N:7]2[C:11]3([CH2:12][CH2:13][N:14]([CH2:19][C:20]4[CH:21]=[CH:22][C:23]5[O:27][C:26]([N+:28]([O-:30])=[O:29])=[C:25]([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=6)[C:24]=5[CH:37]=4)[CH2:15][CH2:16]3)[C:10](=[O:17])[NH:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: O=[N+]([O-])c1oc2ccc(CBr)cc2c1-c1ccccc1
Solvent: CC(C)=O
Product: Br
Product: O=C1NCN(c2ccccc2)C12CCN(Cc1ccc3oc([N+](=O)[O-])c(-c4ccccc4)c3c1)CC2
Temperature: 20 °C

Procedure:
A mixture of 1.7 g. (0.0066 mole) of 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (available from the Aldrich Chemical Company) and 2 g. (0.006 mole) of 5-bromomethyl-2-nitro-3-phenylbenzofuran in 50 ml. of acetone is heated at its reflux temperature for about 75 hours. The mixture is cooled to 20° C. and filtered. The precipitate is washed with acetone to provide yellow 1-phenyl-8-N-[(2-nitro-3-phenylbenzofuran-5-yl)methyl]-1,3,8-triazaspiro[4.5]decan-4-one hydrobromide salt, m.p. 243°-244° C., having the structure ##STR18## after recrystallization from ethanol.
Reaction SMILES: O[N:2]=[C:3]([NH2:27])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:19][C@H:18]3[N:14]([CH2:15][CH2:16][CH2:17]3)[C:13]3[N:20]=[C:21]([S:24][CH3:25])[N:22]=[CH:23][C:12]=3[C:11]2=[O:26])[CH:5]=1.[C:28](N1C=CN=C1)(N1C=CN=C1)=[S:29].C1C[O:43]CC1>C(OCC)(=O)C>[CH3:25][S:24][C:21]1[N:22]=[CH:23][C:12]2[C:11](=[O:26])[N:10]([C:6]3[CH:5]=[C:4]([C:3]4[NH:27][C:28](=[O:43])[S:29][N:2]=4)[CH:9]=[CH:8][CH:7]=3)[CH2:19][C@H:18]3[N:14]([CH2:15][CH2:16][CH2:17]3)[C:13]=2[N:20]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: C1CCOC1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(N)=NO)c1)C2=O
Solvent: CCOC(C)=O
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nsc(=O)[nH]3)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
(S)—N′-Hydroxy-3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzamidine (200 mg, 0.52 mmol) obtained in Step 1 of Example 75 was suspended in THF (3.0 mL), and the mixture was stirred at room temperature for 2 hours after adding 1,1′-thiocarbonyldiimidazole (155 mg, 0.78 mmol). After diluting the mixture with ethyl acetate, the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained upon concentration under reduced pressure was then purified by silica gel column chromatography to give (S)-3-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,2,4-thiadiazol-5(4H)-one (205 mg, 92%).
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1)(=O)=O.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C)C=O>[N:25]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
To a solution of 4-methanesulfonyloxy-1-(p-nitrobenzyloxycarbonyl)piperidine (3.31 g, 9.24 mmol) (obtained as described in Reference Example 51(2)) in dimethylformamide (100 ml) was added sodium azide (660 mg, 10.2 mmol), and the mixture was stirred in an oil bath (100° C.) for 3 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (3:1→1:1) as the eluant to afford 4-azido-1-(p-nitrobenzyloxycarbonyl)piperidine (2.81 g, yield 100%) as pale yellow crystals.
Reaction SMILES: [Mg].[CH2:2](Br)[C:3]([CH3:6])([CH3:5])[CH3:4].[CH2:8]([Si:11](OC)([O:14][CH3:15])[O:12][CH3:13])[CH2:9][CH3:10].CO.[CH2:20](OCC)[CH3:21]>BrCCBr>[CH2:2]([Si:11]([CH2:8][CH2:9][CH2:10][CH2:20][CH3:21])([O:14][CH3:15])[O:12][CH3:13])[C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: CCC[Si](OC)(OC)OC
Reactant: CC(C)(C)CBr
Reactant: CCOCC
Agent: [Mg]
Solvent: BrCCBr
Solvent: CO
Product: CCCCC[Si](CC(C)(C)C)(OC)OC
Reaction time: 0.83 h
Yield: 59.5 %

Procedure:
473.9 mg (19.5 mmols) of metal magnesium and 19.5 ml of diethyl ether were put into a 100-ml three-neck flask, to which were added a few drops of 1,2-dibromoethane. Then, 2.65 g (17.6 mmols) of neopentyl bromide was dropwise added thereto over a period of 50 minutes. This was ripened under reflux for 8 hours, and the disappearance of neopentyl bromide from it was confirmed. After restored to room temperature, the resulting solution was dropwise added to a solution of 2.60 g (15.8 mmols) of n-propyltrimethoxysilane in diethyl ether, and then refluxed for 14 hours. The disappearance of n-propyltrimethoxysilane from it was confirmed. 5 ml of methanol was added to this, and the resulting solution was filtered, dried, distilled and passed through a separation column to obtain 1.91 g of neopentyl-n-pentyldimethoxysilane. Its purity was 98.9%, and its yield was 59.5%.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[F-].C([N+:10]([CH2:19][CH2:20][CH2:21][CH3:22])(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[N+:1]([CH2:4][C:21]1([CH2:20][C:19]#[N:10])[CH2:22][CH2:22][CH2:21][CH2:20][CH2:19]1)([O-:3])=[O:2]
Reactant: C[N+](=O)[O-]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#CCC1(C[N+](=O)[O-])CCCCC1
Yield: 91.1 %

Procedure:
The nitrile (compound 2, 0.78 g, 6.44 mmol), nitromethane (0.80 g, 13.11 mmol) and tetrabutyl ammonium fluoride (1.0 M in tetrahydrofuran, 10 mL, 10 mmol) were heated in 20 mL tetrahydrofuran to 70° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with dilute hydrochloric acid and water, dried over magnesium sulphate, filtered, and evaporated to dryness. The residue was purified by chromatography on silica eluting with heptane/ethyl acetate 3:1 to give the required product as a yellow oil (0.83 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:19])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]([O:15]CC)=[O:14])[C:6]=2[CH:18]=1.[Li+].[OH-]>C1COCC1.O>[Cl:1][C:2]1[C:3]([Cl:19])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]([OH:15])=[O:14])[C:6]=2[CH:18]=1
Reactant: CCOC(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CN1C(=O)COc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Yield: 123.3 %

Procedure:
Ethyl (6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetate (22.0 g, 0.072 mol) was suspended in 400 mL of THF and treated with LiOH (3.46 g, 0.144 mol) dissolved in 80 mL of water at room temperature. The reaction was magnetically stirred and maintained at room temperature for 20 hours. The reaction was then quenched with 30 mL of concentrated HCl and stirred for 20 minutes. HPLC (Eclipse XDB-C18, 4.6×250 mm, 5 micron, 1-99% CH3CN/H2O with 0.1% trifluoroacetic acid) showed that all of the starting material (Rt=7.5 min) was gone and that a single product (Rt=6.0 min) had formed. The solvent was removed by rotary evaporation to give an off-white solid that was further dried under high vacuum to give 24.5 g of a mixture of the title compound (77% by mass) and LiCl (23% by mass) which was used in subsequent reactions without further purification. Actual product yield is 18.9 g (0.068 mol, 95%). MS (ES) m/e 276 [M+H]+.
Reaction SMILES: [C:1]([C:6]1[C:15](=O)[C:14]2[C:9](=[C:10]([O:26][CH3:27])[CH:11]=[C:12]([O:17][C:18](=O)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:30])=O>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:30])=[CH:13][C:12]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:11][C:10]=2[O:26][CH3:27])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1c[nH]c2c(OC)cc(OC(=O)c3ccccc3)cc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCCC(=O)c1cnc2c(OC)cc(OCc3ccccc3)cc2c1Cl

Procedure:
3-Butyryl-6-benzoyloxy-8-methoxy-4(1H)-quinolone (18.0 g) was heated under reflux in phosphorus oxychloride (100 ml) for 40 minutes. The solvent was evaporated and the residue dissolved in dichloromethane and poured into a vigorously stirred mixture of ice and sodium hydrogen carbonate solution. The organic phase was washed with sodium hydrogen carbonate solution, dried, filtered and evaporated to give 3-butyryl-6-benzyloxy-4-chloro-8-methoxy quinoline as a brown oil (25 g).
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:17]([CH3:22])([CH3:21])[CH2:16][CH2:15][C:14]([CH3:24])([CH3:23])[C:13]=3[CH:12]=2)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[C:27](OC(=O)C)(=[O:29])[CH3:28].C(N(CC)CC)C.O>ClCCl>[C:27]([N:10]([C:11]1[CH:20]=[CH:19][C:18]2[C:17]([CH3:21])([CH3:22])[CH2:16][CH2:15][C:14]([CH3:24])([CH3:23])[C:13]=2[CH:12]=1)[CH2:9][C:8]1[CH:25]=[CH:26][C:5]([C:1]([O:3][CH3:4])=[O:2])=[CH:6][CH:7]=1)(=[O:29])[CH3:28]
Reactant: COC(=O)c1ccc(CNc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CN(C(C)=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
4.2 g (12 mmol) of N-(4-carbomethoxybenzyl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine (from Example 21) and 1.6 ml (16 mmol) of acetic anhydride and 2.3 ml (17 mmol) of triethylamine in 100 ml of dichloromethane were stirred at room temperature. After the reaction was complete, the solution was poured into water and extracted with ethyl acetate, and the organic phase was separated off and evaporated; the residue was recrystallized from ethanol and yielded N-acetyl-N-(4-carbomethoxybenzyl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine. 2.5 g of this product and 5.0 g of potassium hydroxide in 90 ml of 5:3:1 ethanol/water/dimethyl sulfoxide were then refluxed for 1 hour and, after cooling, three times the volume of ice-water was added and the pH was adjusted to 4 with 2N hydrochloric acid. The precipitate was filtered off and dried, yielding 1.5 g of the title compound of melting point 219°-223° C.
Reaction SMILES: [CH3:1][N+:2]([CH2:5][CH:6]([OH:11])[CH2:7][C:8]([OH:10])=[O:9])([CH3:4])[CH3:3].[Cl-].[OH-].[Na+]>C(O)C>[OH:11][CH:6]([CH2:7][C:8](=[O:9])[O-:10])[CH2:5][N+:2]([CH3:4])([CH3:1])[CH3:3]
Reactant: C[N+](C)(C)CC(O)CC(=O)O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[N+](C)(C)CC(O)CC(=O)[O-]

Procedure:
A solution of DL-carnitine hydrochloride (1.0 g, 5.05 mmol) and sodium hydroxide (0.303 g, 7.58 mmol) in ethanol (15 ml) was stirred at room temperature for 2 h. The formed white precipitate (NaCl) was removed by filtration, and the solvent was evaporated under reduced pressure to give a white solid, carnitine inner salt. A suspension of the carnitine inner salt and 1 -iodooctadecane (2.31 g, 6.06 mmol) in DMF-dioxane (3:5, 40 ml) was heated with an oil-bath at 120° C. under Ar2 for 4 h. The solvent was removed by rotavapor and vacuum, and the residue was chromatographied with silica gel column using CH3OH--CH3Cl as eluant to give 2.22 g (81%) of stearyl carnitine ester as a white solid: 1H NMR (CDCl3) δ4.79 (m, 1 H), 4.43 (d, J=5.3, 1 H), 4.09 (t, J=6.9, 2 H), 4.03 (d, J=13.0, 1 H), 3.67 (dd, J=10.3, 13.3, 1 H), 3.51 (s, 9 H), 2.79 (dd, J=5.7, 17.0, 1 H), 2.66 (dd, J=7.0, 17.1, 1 H), 1.80-1.60 (m, 4 H), 1.26 (broad s, 28 H), 0.88 (t, J=6.6, 3 H). LSIMS (NBA): m/e 414.4 for C25H52NO3 (cation).
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[C:16]([CH2:17][CH2:18][CH3:19])=[C:15]2[C:10]([C:11]([C:21]([F:24])([F:23])[F:22])=[CH:12][C:13](=[O:20])[O:14]2)=[CH:9][CH:8]=1.[Br:25][CH2:26][CH2:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-].[K+].[K+]>O>[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][O:6][C:7]1[C:16]([CH2:17][CH2:18][CH3:19])=[C:15]2[C:10]([C:11]([C:21]([F:24])([F:22])[F:23])=[CH:12][C:13](=[O:20])[O:14]2)=[CH:9][CH:8]=1
Reactant: BrCCCCBr
Reactant: CCCc1c(O)ccc2c(C(F)(F)F)cc(=O)oc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCBr)ccc2c(C(F)(F)F)cc(=O)oc12
Yield: 105.4 %

Procedure:
An N,N-dimethylformamide (5 mL) solution of 7-hydroxy-8-propyl-4-(trifluoromethyl)-2H-chromen-2-one (500 mg, 1.84 mmol), 1,4-dibromobutane (2.19 mL, 18.36 mmol), and potassium carbonate (375 mg, 2.76 mmol) was stirred overnight at room temperature. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated under vacuum. The obtained residue was purified using silica-gel chromatography (hexane:ethyl acetate=10:1), and the title compound (0.79 g) was obtained as yellow oil.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[C:14]([CH:16]([OH:30])[C@@H:17]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:18])#[N:15].O>C(Cl)Cl>[Si:1]([O:30][C@@H:16]([C:14]#[N:15])[C@@H:17]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:1]([O:30][C@H:16]([C:14]#[N:15])[C@@H:17]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(O)C#N
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: C[C@H](NC(=O)OCc1ccccc1)[C@@H](C#N)O[Si](C)(C)C(C)(C)C
Product: C[C@H](NC(=O)OCc1ccccc1)[C@H](C#N)O[Si](C)(C)C(C)(C)C
Reaction time: 8 h

Procedure:
tert-Butyldimethylsilyl chloride (471 mg, 3.12 mmol) and imidazole (483 mg, 7.10 mmol) were added successively to a stirred solution of benzyl [(1S)-2-cyano-2-hydroxy-1-methylethyl]carbamate (665 mg, 2.84 mmol) in dry CH2Cl2 (13 mL) at room temperature under N2 and the mixture was stirred overnight. Water (30 mL) was added and the mixture was extracted with Et2O (3×30 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 40×160 mm, 0-15% EtOAc in hexanes gradient) to afford benzyl ((1S,2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-cyano-1-methylethyl)carbamate and benzyl ((1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-cyano-1-methylethyl)carbamate. (1S,2R)-diastereoisomer: Rf=0.29 (10% EtOAc in hexanes). LCMS calc.=349.2; found=349.1 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 7.39-7.33 (m, 5H), 5.16 (d, J=12.1 Hz, 1H), 5.07 (d, J=12.1 Hz, 1H), 4.89 (br d, J=6.6 Hz, 1H), 4.68 (br, d, 3.6 Hz, 1H), 3.92 (m, 1H), 1.31 (d, J=6.7 Hz, 3H), 0.91 (s, 9H), 0.21 (s, 3H), 0.17 (s, 3H). (1S,2S)-diastereoisomer: Rf=0.24 (10% EtOAc in hexanes). LCMS calc.=349.2; found=349.1 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 7.38-7.32 (m, 5H), 5.10 (s, 2H), 4.76 (br d, J=6.9 Hz, 1H), 4.63 (br s, 1H), 4.00 (m, 1H), 1.31 (d, J=6.8 Hz, 3H), 0.90 (d, J=2.9 Hz, 9H), 0.17 (s, 3H), 0.08 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[C:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)([OH:14])=[O:13].[C:24](C1C=CC(B(O)O)=CC=1)(O)=O>>[CH3:24][O:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=[CH:2][C:7]=1[C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([C:12]([OH:14])=[O:13])[CH:20]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: O=[N+]([O-])c1ccc(Br)cc1O
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: COc1c(-c2cccc(C(=O)O)c2)cccc1[N+](=O)[O-]

Procedure:
Following the procedure of Example 1b), except substituting the compound from Example 3b) for 5-bromo-2-nitrophenol and substituting 3-carboxyphenylboronic acid for 4-carboxyphenylboronic acid, the title compound was prepared (2.13 g; 47%) as a tan powder. 1H NMR (300 MHz, d6-DMSO) δ 8.12 (s, 1H), 8.03 (d, J=7.9 Hz, 1H), 7.94 (dd, J=7.9 Hz, 1.5 Hz, 1H), 7.85 (d, J=7.9 Hz, 1H), 7.76 (dd, J=7.5, 1.5 Hz, 1H), 7.66 (t, J=7.5 Hz, 1H), 7.46 (t, j=7.9 Hz, 1H), 3.46 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=[O:22])[CH:14]([NH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:15])[CH:7]=[CH:6]2.[CH:23]([O-])([O-])[O:24]C.[CH3:28]S(O)(=O)=O.C(=O)(O)[O-].[Na+]>CO>[CH3:28][O:22][C:13]([O:24][CH3:23])([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1)[CH:14]([NH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:15]
Reactant: CS(=O)(=O)O
Reactant: CCOC(=O)NC(C)C(=O)c1ccc2cc(OC)ccc2c1
Reactant: COC([O-])[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)NC(C)C(OC)(OC)c1ccc2cc(OC)ccc2c1

Procedure:
902 mg (3.00 mmols) of (+)-1-(6-methoxy-2-naphthyl)-2-(ethoxycarbonyl)amino-1-propanone and 6 ml of methyl orthoformate were stirred in 6 ml of anhydrous methanol at room temperature. 0.05 ml of methanesulfonic acid was added to the mixture which was then refluxed for 48 hours while stirring. The reaction mixture was cooled with ice and 20 ml of a saturated aqueous sodium bicarbonate solution was added in one portion. The mixture was extracted with methylene chloride (20 ml×2) and the extract was washed with water (20 ml×1), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The oily residue was purified by column chromatography [silica gel, ethyl acetate-hexane (1:2)] to obtain 781 mg of (+)-1-(6-methoxy-2-naphthyl)-2-(ethoxycarbonyl)amino-1-propanone dimethyl acetal as a colorless oily substance. Yield, 75%.