Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]=[C:7]([CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]3[CH2:28][CH2:27][C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[CH:20](O)[C:19]=3[CH:30]=1)[CH:6]=[CH:5]2.[ClH:31].[CH2:32]([O:34][C:35](=[O:40])[C@H:36]([CH2:38][SH:39])[NH2:37])[CH3:33]>FC(F)(F)C(O)=O>[CH2:32]([O:34][C:35](=[O:40])[C@@H:36]([NH2:37])[CH2:38][S:39][CH:20]1[C:21]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:27][CH2:28][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[CH:10][C:11]([Cl:31])=[C:2]([F:1])[CH:3]=4)[N:8]=3)=[CH:30][C:19]1=2)[CH3:33]
Reactant: CCOC(=O)[C@@H](N)CS
Reactant: OC1c2cc(OCc3ccc4cc(F)c(F)cc4n3)ccc2CCc2ncccc21
Reactant: Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H](N)CSC1c2cc(OCc3ccc4cc(F)c(Cl)cc4n3)ccc2CCc2ncccc21
Temperature: 60 °C
Reaction time: 48 h

Procedure:
A mixture of 10.0 g (23.76 mmol) of the product from Example 23, step 7, 9.7 g (52.3 mmol) of L-cystein ethyl ester hydrochloride and 105 ml of trifluoroacetic acid is stirred at 60° C. for 48 hr. The solvent is evaporated and the residue partitioned between sat. NaHCO3 and chloroform. The organic layer is washed with water, dried and concentrated, giving an oil, which is crystallised from ethyl ether/diisopropyl ether. Yield 10.4 g (80%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:19])[C:8](=[O:18])[N:9]2C2CCCCC2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].[CH:23]([CH:25]1[CH2:29][CH:28](OC)O[CH:26]1OC)=[O:24].[C:34]1(C)[CH:39]=[CH:38][C:37](S(O)(=O)=O)=[CH:36][CH:35]=1>CN(C)C=O.C1(C)C=CC=CC=1>[CH:34]1([N:6]2[C:5]3[C:10](=[CH:11][C:2]([N:1]4[CH:28]=[CH:29][C:25]([CH:23]=[O:24])=[CH:26]4)=[C:3]([N+:20]([O-:22])=[O:21])[CH:4]=3)[NH:9][C:8](=[O:18])[C:7]2=[O:19])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: Nc1cc2c(cc1[N+](=O)[O-])[nH]c(=O)c(=O)n2C1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC1CC(C=O)C(OC)O1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=Cc1ccn(-c2cc3[nH]c(=O)c(=O)n(C4CCCCC4)c3cc2[N+](=O)[O-])c1
Yield: 22 %

Procedure:
4 g (13 mmol) of the product 37b, 2.3 g (14 mmol) of 3-formyl-2,5-dimethoxytetrahydrofuran and a spatula tip of 4-toluenesulfonic acid in 200 ml of dimethylformamide/toluene (1:1) were refluxed with a water trap. After the reaction was complete (TLC check), the mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic phase was dried and concentrated under reduced pressure. This residue was purified by chromatography on silica gel (mobile phase: toluene/acetone/glacial acetic acid=40/20/1) to yield 1.1 g (22%) of the product.
Reaction SMILES: [C:1]1([CH2:6][CH2:7][CH2:8][C:9](=[O:11])[CH3:10])[CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:12][Mg]Br.Cl>C(OCC)C>[C:1]1([CH2:6][CH2:7][CH2:8][C:9]([CH3:12])([OH:11])[CH3:10])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Mg]Br
Reactant: CC(=O)CCCC1=CCCC1
Agent: Cl
Solvent: CCOCC
Product: CC(C)(O)CCCC1=CCCC1
Temperature: 25 °C
Yield: 11 %

Procedure:
5-(Cyclopent-1-enyl)-2-pentanone (5.95 g; 39 mmol) in ethyl ether (6 ml) was added dropwise to a 3M solution of methylmagnesium bromide in the same solvent (17 ml; 51 mmol) during 15 minutes. After 2 hours at reflux, the mixture was cooled down to room temperature, poured into ice (20 g), acidified with 5N HCl (20 ml) and extracted with MTBE (60 ml). The aqueous phase was separated and extracted again with MTBE (2×100 ml). The combined organic phases were washed with saturated NaHCO3 (80 ml), H2O (80 ml), brine (80 ml), dried over MgSO4 and concentrated in vacuo. Bulb-to-bulb distillation (80° C./0.06 torr) yielded quantitatively 5.84 g of 5-(cyclopent-1-enyl)-2-methylpentan-2-ol containing 11% of 5-cyclopentylidene-2-methylpentan-2-ol.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[CH2:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:15]([O:13][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(CCCCCCCCCCBr)OCc1ccccc1

Procedure:
30 g (113.1 mmol) of 11-bromoundecanoic acid, 18.35 g (169.7 mmol) of benzyl alcohol and 0.5 g of p-toluenesulfonic acid are heated in 200 ml of toluene for 12 hours in a water separator. It is allowed to reach room temperature, and the organic phase is washed twice with 100 ml of 5% aqueous potassium carbonate solution each. The organic phase is dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel (mobile solvent: n-hexane/acetone=30:1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([SH:17])=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)=O>C(O)C.O>[CH2:18]([S:17][C:11]1[CH:10]=[CH:9][C:8]([CH3:7])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ccc(S)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(SCc2ccccc2)c(C(=O)O)c1
Yield: 89 %

Procedure:
To a solution of 4.15 g. (0.030 moles) of potassium carbonate in 50 ml. of water is successively added 100 ml. of ethanol, 5.05 g. (0.030 moles) of 5-methyl-2-mercaptobenzoic acid, and 3.8 g. (0.030 moles) of benzyl chloride. After the evolution of carbon dioxide ceases (about 10 minutes), the mixture is refluxed on a steam bath for one hour. The mixture is cooled, and the major portion of the solvent is evaporated under reduced pressure. The cloudy, white liquid residue is diluted to a volume of about 600 ml. with water. The mixture is filtered, cooled, and acidified with 6 N hydrochloric acid. The white precipitate which forms is separated, filtered, and triturated with about 400 ml. of water. Filtration and drying under high vacuum provides 6.9 g. (89 percent yield) of 2-benzylthio-5-methylbenzoic acid, m.p. 169°-171°C. sint. 167°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH2:6][CH2:7][NH:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C.Cl[C:25]([O:27][CH3:28])=[O:26]>C(OCC)C>[CH:9]1([N:8]([CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:25](=[O:26])[O:27][CH3:28])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COc1cccc(CCNC2CCCC2)c1
Reactant: COC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)N(CCc1cccc(OC)c1)C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
To a solution of N-(3-methoxyphenethyl)cyclopentanamine (1.31 g, 6 mmol) in diethyl ether (50 mL) was added triethylamine (1.3 mL, 9 mmol) and methyl chloroformate (0.7 mL, 9 mmol) at 0° C. The reaction mixture was gradually warmed to room temperature and stirred for 30 min. Filtration and removal of solvent under reduced pressure followed by silica gel column chromatography using hexanes/ethyl acetate afforded methyl cyclopentyl(3-methoxyphenethyl)-carbamate as a pale yellow liquid (1.41 g, 84%). 1H NMR (400 MHz, CDCl3): δ 7.19 (t, 1H, J=7.6 Hz), 6.78-6.73 (overlapping doublets and singlet, 3H), 4.27-4.24 (m, 1H), 3.78 (s, 3H), 3.70 (s, 3H), 3.28 (t, 2H, J=7.9 Hz), 2.80 (t, 2H, J=7.9 Hz), 1.68-1.67 (m, 2H), 1.53-1.50 (m, 6H). LC-MS (ESI) Calcd for C16H23NO3 [M+H]+: 278.17. Found: 278.00.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([C@@H:18]([CH3:20])[OH:19])[NH:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([CH3:16])[CH:8]=1.[H][H].C(=O)(O)[O-].[Na+].Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>C(O)C.[Pd].C1COCC1.O>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([C@@H:18]([CH3:20])[OH:19])[NH:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[C:9]([CH3:16])[CH:8]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@H](NC(=O)c1ccc([N+](=O)[O-])c(C)c1)[C@@H](C)O
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COC(=O)[C@@H](NC(=O)c1ccc(NC(=O)OCc2ccccc2)c(C)c1)[C@@H](C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
10% Pd/C (1.2 g) was added to a solution of N-(3-methyl-4-nitrobenzoyl)threonine methyl ester obtained in Example (108a) (7.2 g, 24.3 mmol) in ethanol (40 mL), and the mixture was stirred in a hydrogen atmosphere at room temperature for one hour and 20 minutes. Pd/C was filtered off, and the filtrate was concentrated under reduced pressure. Water (20 mL), THF (20 mL), sodium bicarbonate (2.52 g, 30 mmol) and benzyl chloroformate (5.37 g, 30 mmol) were added to the resulting residue, and the mixture was stirred at room temperature for one hour. Following extraction with dichloromethane, the organic layer was washed with water, a 1 N aqueous hydrochloric acid solution and brine, dried over magnesium sulfate, and concentrated. Thereafter, the resulting residue was purified by silica gel column chromatography (elution solvent: chloroform/methanol=1/0, 95/5, 90/10, 85/15) to obtain 7.4 g of the title compound as a colorless solid (76%).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[N+:2]=[N-:3].[C:17]1([CH3:28])[CH:22]=[CH:21][C:20]([S:23]([C:26]#[N:27])(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[C:10]([N:6]1[CH2:7][CH2:8][CH2:9][C@H:5]1[CH2:4][N:1]1[C:26]([S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:28])=[CH:18][CH:19]=2)(=[O:25])=[O:24])=[N:27][N:3]=[N:2]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Product: Cc1ccc(S(=O)(=O)c2nnnn2C[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reaction time: 48 h
Yield: 91.2 %

Procedure:
(S)-2-(azidomethyl)-1-Boc-pyrrolidine (480 mg, 2.1 mmol) was added to a flask containing p-toluenesulfonyl cyanide (420 mg, 2.3 mmol) and a stir bar (no solvent). The flask was placed in a 80° C. bath and reaction proceeded for 48 hours. The reaction was concentrated in vacuo. The crude amber oil was purified by flash silica gel chromatography using a hexane/ethyl acetate gradient. The product (780 mg, 91% yield) was obtained as a colorless oil. 1H-NMR (500 MHz, CDCl3): δ 8.01 (broad d, J=18 Hz, 2H), 7.44 (m, 3H), 4.85-4.70 (m, 2H), 4.52-4.48 (m, 1H), 3.50-3.34 (m, 2H), 2.49 (s, 3H), 2.01-1.71 (m, 4H), 1.40 & 1.33 (2 s, 9H). ESI-MS (m/z) for C18H25N5O4S (exact mass 407.16): [M+H]+ calc. 408.2, obs. 408.2; [M+Na]+ calc. 430.2, obs. 430.2.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.CN(C)CCCCCCN(C)C.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C1(C)C=CC=CC=1.O>[CH3:36][C:26]1[CH:31]=[CH:30][C:29]([S:32]([O:6][CH2:5][CH2:4][CH2:3][S:2][CH3:1])(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CSCCCO
Agent: CN(C)CCCCCCN(C)C
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CSCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
A solution of 3-(methylthio)-1-propanol (5.30 g, 50.0 mmol), triethylamine (10.5 mL, 75.0 mmol) and N,N,N′,N′-tetramethyl-1,6-hexanediamine (0.861 g, 5.00 mmol) in toluene (50 mL) was ice-cooled, and a solution of p-toluenesulfonyl chloride (14.3 g, 75.0 mmol) in toluene (50 mL) was added dropwise under nitrogen atmosphere. After completion of the dropwise addition, the mixture was stirred for 3 hr, during which the mixture was allowed to warm to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-40:60) to give the title compound (12.2 g, yield 94%) as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[ClH:9].[CH3:10][NH:11][CH3:12].Cl.[CH:14](O)(C)C>>[ClH:9].[CH3:10][N:11]([CH3:14])[CH2:12][CH2:2][C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)=[O:3]
Reactant: CNC
Reactant: CC(=O)c1cccs1
Reactant: CC(C)O
Agent: Cl
Product: CN(C)CCC(=O)c1cccs1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A mixture of 8.18 g of 2-acetylthiophene, 6.66 g of dimethylamine hydrochloride, 2.9 g of paraformaldahyde and 0.31 g of concentrated hydrochloric acid in 20 ml of isopropanol was heated to reflux and stirred for 6 hours. The mixture was then cooled to 0° C. and stirred for one hour more. The slurry was then filtered, and the solid was washed with cold ethanol. The washed solid was dried for 16 hours at 50° C. to obtain 12.5 g of 2-thienyl 2-dimethylaminoethyl ketone hydrochloride, as a white solid. A 12.0 g portion of that intermediate product was stirred in 40 ml of ethanol at ambient temperature, and the pH of the solution was raised to 11-12 by slow addition of sodium hydroxide. A 1.03 g portion of sodium borohydride was added, and the mixture was stirred at ambient temperature for 4 hours. Then 7.5 ml of acetone was added, and the mixture was stirred for 20 minutes more. The mixture was then concentrated by evaporation to a white slurry, and 120 ml of methyl t-butyl ether was added. The mixture was acidified to pH 1-1.5 by addition of concentrated hydrochloric acid, and the solution was stirred for ten minutes. The pH was then made basic to pH 12 by slow addition of sodium hydroxide.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)(=[O:5])=[O:4])[CH3:2].[OH:17][S:18]([Cl:21])(=O)=[O:19]>C(Cl)Cl>[C:14]([NH:13][C:9]1[CH:10]=[CH:11][C:12]([S:18]([Cl:21])(=[O:19])=[O:17])=[C:7]([CH2:6][S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH:8]=1)(=[O:16])[CH3:15]
Reactant: O=S(=O)(O)Cl
Reactant: CCS(=O)(=O)Cc1cccc(NC(C)=O)c1
Solvent: ClCCl
Product: CCS(=O)(=O)Cc1cc(NC(C)=O)ccc1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.9 %

Procedure:
To N-(3-(ethylsulfonylmethyl)phenyl)acetamide (1 g, 4 mmol) was added HOSO2Cl (4.8 g) dropwise at 0° C. The mixture was stirred at r.t. for 3 hrs. The reaction mixture was diluted with DCM and washed with water, the organics was dried over Na2SO4, concentrated under reduced pressure to give 4-acetamido-2-(ethylsulfonylmethyl)benzene-1-sulfonyl chloride (0.8 g, yield 57%).
Reaction SMILES: C(N[C@H]([C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1C=CC=CC=1)=[O:10])CC(=O)O)=O.[OH2:23].[Na+].[NH2:25][C@H:26]([C:34]([O-:36])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]([NH:25][C@H:26]([C:34]([OH:36])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:23])=[O:10]
Reactant: N[C@@H](Cc1ccccc1)C(=O)[O-]
Reactant: O=CN[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O
Agent: [Na+]
Product: O=CN[C@@H](CC(=O)N[C@@H](Cc1ccccc1)C(=O)O)C(=O)O
Yield: 30 %

Procedure:
Thereafter, the N-formyl-L-α-aspartyl-L-phenylalanine (hereinafter simply referred to as For-α-AP) in the reaction mixture was quantitatively analyzed by HPLC (High performance Liquid Chromatography), to find that it had been formed in a Yield of 68.2% based on the L-phenylalanine sodium salt monohydrate. In addition, 30.0% of N-formyl-L-β-aspartyl-L-phenylalanine (For-β-AP), etc. had been by-produced.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1.Br[CH2:13][CH2:14][C:15]([CH3:17])=[CH2:16].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH2:14][C:15]([CH3:17])=[CH2:16])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1
Reactant: C=C(C)CCBr
Reactant: CC(C)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)CCOc1ccc(Br)cc1C(C)C
Temperature: 60 °C

Procedure:
4-Bromo-2-isopropylphenol (897 mg, 4.17 mmol) was dissolved in DMF (4.17 mL) and 4-bromo-2-methylbut-1-ene (1.24 g, 8.34 mmol) was added followed by K2CO3 (1.15 g, 8.34 mmol). The reaction mixture was heated to 60° C. overnight, cooled to room temperature, and diluted with Hexanes:EtOAc (1:1). Water was added and the organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel chromatography, eluting with 0-15% EtOAc/Hexanes to give the title compound as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:13]([CH3:14])=[C:12](O)[C:11]2[C:6](=[C:7]([F:20])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)[N:5]=1.[C:21]([O:24][CH2:25][C:26](Cl)=[O:27])(=[O:23])[CH3:22]>O1CCCC1>[CH3:3][C:4]1[C:13]([CH3:14])=[C:12]([C:26](=[O:27])[CH2:25][O:24][C:21](=[O:23])[CH3:22])[C:11]2[C:6](=[C:7]([F:20])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)[N:5]=1
Reactant: Cc1nc2c(F)cc(C(C)(C)C)cc2c(O)c1C
Reactant: CC(=O)OCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)c1c(C)c(C)nc2c(F)cc(C(C)(C)C)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In tetrahydrofuran (10 ml) was suspended 60% sodium hydride (44 mg). The compound 1 (200 mg) was added to the suspension under ice cooling, and the mixture was stirred for 30 min. Further, acetoxyacetyl chloride (100 μl) was added thereto, and the mixture was stirred for 3 hr. The reaction solution thus obtained was poured into ice water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed under the reduced pressure. The crude product was purified by chromatography on silica gel (Wako Gel C-200, elution solvent: n-hexane-ethyl acetate (3:1)) to give 2,3-dimethyl-6-t-butyl-8-fluoro-4-acetoxyacetylquinoline (compound 11, 140 mg). 1H-NMR data on this compound in deutro-chloroform were as shown below.
Reaction SMILES: [C:1]([C:4](=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)[C:5]([NH:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:6])(=O)[CH3:2].[NH2:26][C:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[CH:28][C:29]([O:31][CH2:32]C)=[O:30]>>[CH3:2][C:1]1[NH:26][C:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:28]([C:29]([O:31][CH3:32])=[O:30])[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:4]=1[C:5]([NH:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:6]
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)NCC(=O)OC(C)(C)C
Reactant: CCOC(=O)C=C(N)c1ccccc1
Product: COC(=O)C1=C(c2ccccc2)NC(C)=C(C(=O)NCC(=O)OC(C)(C)C)C1c1cccc([N+](=O)[O-])c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 19.3 %

Procedure:
More specifically a mixture of 330 mg (1 mmol) of t-butyl 2-[N-[2-acetyl-3-(3-nitrophenyl)-2-propenoyl]amino]acetate and 191 mg (1 mmol) of ethyl 3-amino-3-phenyl-2-propenoate was stirred under a light-shielding condition at 110° C. overnight. After cooling to room temperature, the reaction mixture was chromatographed on a silica gel column for purification, whereby 98 mg (22%) of the captioned compound was obtained as an oily material.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)CC)C.[C:23](Cl)(=[O:26])[CH:24]=[CH2:25].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:23]([N:13]1[CH2:12][CH2:11][N:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=2)[CH2:15][CH2:14]1)(=[O:26])[CH:24]=[CH2:25]
Reactant: C=CC(=O)Cl
Reactant: N#Cc1ccc(N2CCNCC2)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N1CCN(c2ccc(C#N)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-fluoro-4-(piperazin-1-yl)-benzonitrile (0.53 g, 2.56 mmol) and triethylamine (0.5 ml, 3.59 mmol) in CH2Cl2 (13 ml) is added dropwise to a cooled solution (0-5° C.) of acryloyl chloride (0.25 ml, 3.15 mmol) in CH2Cl2 (3 ml). After complete addition, the mixture is stirred at rt for 1 h, sat. aq. Na2CO3 solution is added and stirring is continued for 20 min. The organic layer is separated off, dried over Na2SO4 and evaporated. Upon addition of AcOEt, 4-(4-acryloyl-piperazin-1-yl)-2-fluoro-benzonitrile crystallizes out, is filtered off, washed with AcOEt and air-dried.
Reaction SMILES: C([O:5][C:6](=[O:27])[CH:7]=[C:8]([CH3:26])[CH:9]=[CH:10][CH:11]=[C:12]([CH3:25])[CH:13]=[CH:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[C:17]([CH3:23])[C:16]=1[CH3:24])CCC.[Cl-].CC1C(C)=C(C)C=C(C)C=1C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OC(=O)C=C(C)C=CC=C(C=O)C)CCC>>[CH3:24][C:16]1[C:17]([CH3:23])=[C:18]([CH3:22])[CH:19]=[C:20]([CH3:21])[C:15]=1[CH:14]=[CH:13][C:12]([CH3:25])=[CH:11][CH:10]=[CH:9][C:8]([CH3:26])=[CH:7][C:6]([OH:27])=[O:5]
Reactant: CCCCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)cc(C)c(C)c1C
Agent: CCCCOC(=O)C=C(C)C=CC=C(C)C=O
Agent: Cc1cc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1C
Agent: [Cl-]
Product: CC(C=Cc1c(C)cc(C)c(C)c1C)=CC=CC(C)=CC(=O)O

Procedure:
By the procedure of Example 14, 9-(2,3,4,6-tetramethylphenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid butyl ester is manufactured from 2,3,4,6-tetramethyl-benzyltriphenylphosphonium chloride by reaction with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid butyl ester. From this product, there is produced by the procedure of Example 15 9-(2,3,4,6-tetra-methyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid of melting point 201°-202° C.
Reaction SMILES: COC1C=CC=CC=1C1NC(=O)C2C(=CC=CC=2)N=1.[NH2:20][C:21]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24].[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=O>>[CH3:31][O:32][C:33]1[CH:34]=[C:35]([C:36]2[NH:25][C:23](=[O:24])[C:22]3[C:21](=[CH:29][CH:28]=[C:27]([Cl:30])[CH:26]=3)[N:20]=2)[CH:38]=[CH:39][CH:40]=1
Reactant: NC(=O)c1cc(Cl)ccc1N
Reactant: COc1cccc(C=O)c1
Agent: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Product: COc1cccc(-c2nc3ccc(Cl)cc3c(=O)[nH]2)c1
Yield: 94.6 %

Procedure:
According to the preparation of 42, 2-amino-5-chlorobenzamide (31) (1.0 g, 5.9 mmol)and 3-methoxybenzaldehyde (34) (0.8 g, 5.9 mmol) were used to afford 50 (1.6 g, 94.3%) as pale yellow needles.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6]=[C:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]2)=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(=Cc2ccc(F)cc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(Cc2ccc(F)cc2)C1
Reaction time: 16 h

Procedure:
To a stirring solution of the t-Butyl 3-(4-fluorobenzylidene)-1-piperidinecarboxylate (3.82 g, 13.1 mmol) and 10% palladium on carbon (0.76 g) in degassed methanol (200 mL) was added hydrogen gas to 55 psi. The reaction was stirred for 16 h and then filtered through a pad of celite. The celite was washed with methanol (200 mL). The filtrates were combined and concentration in vacuo to yield 2.76 g as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.12-7.07 (m, 2H), 6.98-6.93 (m, 2H), 3.89 (dt, J=13, J′=4, 1H), 3.84-3.74 (m, 1H), 2.57-2.43 (m, 4H), 1.75-1.60 (m, 4H), 1.42 (s, 9H), 1.15-1.09 (m, 1H).