Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:24]([O:34]CC2C=CC=CC=2)=[CH:23][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])[CH3:2].[OH-].[Na+]>C(O)C.Cl>[CH2:1]([C:3]1[CH:26]=[C:25]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[C:24]([OH:34])=[CH:23][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH3:2]
Reactant: CCOC(=O)CCc1ccccc1OCCCOc1cc(OCc2ccccc2)c(-c2ccc(F)cc2)cc1CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc(-c2ccc(F)cc2)c(O)cc1OCCCOc1ccccc1CCC(=O)O
Reaction time: 16 h
Yield: 93 %

Procedure:
A solution of 375 mg of ethyl 3-(2-(3-(2-ethyl-4-(4-fluorophenyl)-5-benzyloxyphenoxy)propoxy)phenyl)-propionate in 25 ml of ethanol was mixed with 5 ml of 5.0 N sodium hydroxide and stirred 16 hours. The mixture was diluted with 1.0 N hydrochloric acid and extracted with 3:1 dichloromethane/isopropanol. The organic phase was washed with saturated sodium chloride, dried over sodium sulfate, and evaporated in vacuo providing the desired 3-(2-(3-(2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy) propoxy)phenyl) propionic acid in 93% yield. NMR.
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]1[O:10][CH2:9]1)(=[O:5])[C:2]([CH3:4])=[CH2:3].S(=O)(=O)(O)[OH:12].[OH-].[Na+]>O>[C:1]([O:6][CH2:7][CH:8]([CH2:9][OH:12])[OH:10])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCC1CO1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=C(C)C(=O)OCC(O)CO
Yield: 2.19 %

Procedure:
Two hundred grams (1.406 mole) of glycidyl methacrylate, 300 ml of water and 0.5 ml of concentrated sulfuric acid are stirred for 5 days at 24-29° C. A clear solution forms having a pH of 2.0 which is neutralized with 10% sodium hydroxide. The solution is extracted with six 100 ml portions of ethyl ether. The aqueous layer is stirred and saturated with sodium sulfate which is then extracted with six 100 ml portions of methylene chloride. The methylene chloride extracts are concentrated under reduced pressure to yield 118.7 grams of glyceryl methacrylate containing 2.19% unreacted glycidyl methacrylate. 62.6 gm of this material is mixed with 26.1 gm of methyl methacrylate. The mixture is combined with 18.2 mg of isopropyl percarbonate, and separated into four test tubes. Nitrogen is bubbled through each tube, the tubes arecooled to - 30° C, evacuated, filled with nitrogen, sealed under vacuum, and put into a constant temperature bath at 40° C for 5 hours. The tubes are then put in an oven held at 75° C overnight. The next morning, the temperature is increased to 90° C for one hour. The tubes are then cooled and broken to provide a solid rod of polymer.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:4][CH2:3]1.[Li+].[OH-].[H][H]>C1COCC1.O>[CH3:1][C:2]1([CH3:29])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=3)=[CH:7][C:6]=2[C:5]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:4][CH2:3]1
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C(C)(C)C)=CCC3(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
A solution of 24.0 mg (0.06 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl]benzoate (Compound 71) and 6.5 mg (0.16 mmol) of LiOH-H2 0 in 3 mL THF/water (3:1, v/v) was stirred overnight (22 hours) at room temperature. The reaction mixture was extracted with Et2O and the layers were separated. The aqueous layer was acidified with HCl (1M aqueous solution) and then extracted with EtOAc. The organic phase was dried over Na2 SO4 and concentrated in vacuo to give the title compound as a colorless solid.
Reaction SMILES: [NH:1]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][CH2:17][C:18]([NH:20][C@H:21]([C:25]([NH:27][CH2:28][C:29]([O:31]CC1C=CC=CC=1)=[O:30])=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].N(C(OC(C)(C)C)=O)[C@H](C(NCC(O)=O)=O)C>>[NH:1]([C:39]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:40])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][CH2:17][C:18]([NH:20][C@H:21]([C:25]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: CC(C)[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Product: CC(C)[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)O

Procedure:
IV was hydrogenated and worked up as described for VIII to obtain the product in quantitative yield. Rf3 0.16. Anal. calcd. for C25H37N5O8 ·H2O: C 54.23, H 7.10, N 12.65%. Found: C 54.14, H 6.93, N 12.21%.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:10]=[C:11]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)=C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mn]([O-])(=O)(=O)=[O:21].[K+].S(=O)(=O)(O)O.S([O-])([O-])=O.[Na+].[Na+]>C1C=CC=CC=1.O>[C:7]([C:9]1[CH:10]=[C:11]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:21])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(c1ccccc1)c1cccc(C(C)C(=O)O)c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Reaction time: 18 h

Procedure:
α-(3-(1-Phenylethenyl)phenyl)propionic acid (35 g) obtained in Example 5 was dissolved in 250 ml of benzene and 250 ml of water was further added thereto with vigorous stirring to prepare a suspension. Then, 2 liter of 2% aqueous solution of potassium permanganate was dropped little by little over 1.5 hours. After the dropping, stirring was continued for 18 hours at room temperature. After the reaction, it was acidified by adding concentrated sulfuric acid and was treated by adding 35 g of sodium sulfite. After that, 500 ml of water was added and extraction was carried out three times with 150 ml of ether. The ether solution was washed with water and it was extracted three times with 200 ml of 5% aqueous solution of sodium hydroxide. It was then acidified by adding hydrochloric acid and extracted again three times with 150 ml of ether, which was followed by washing with water, drying with anhydrous magnesium sulfate, and filtration. The ether was then removed by reduced-pressure evaporation. Finally, 20 g of α-(3-benzoylphenyl)propionic acid (ketoprofen) was obtained by re-crystallization from benzene/petroleum ether mixture. The melting point and spectrum were the same as those of an authentic sample.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]([C:15](OCC)=[O:16])=[O:14])=[C:4]([N+:20]([O-:22])=O)[CH:3]=1.CN(C)C=O.N>O1CCCC1.[Pd]>[OH:22][N:20]1[C:4]2[CH:3]=[CH:2][C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]=2[NH:12][C:13](=[O:14])[C:15]1=[O:16]
Reactant: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])cc(Br)c2ccccc12
Agent: [Pd]
Agent: N
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=c1[nH]c2c3ccccc3ccc2n(O)c1=O
Yield: 64.4 %

Procedure:
A solution of 0.5 g (1.36 mmol) 4-bromo-1-ethoxalylamino-2-nitronaphthalene in 30 ml tetrahydrofuran was added 10 ml dimethylformamide and 0.7 ml 25% aqueous ammonia. The mixture was hydrogenated at atm. pressure by using 50 mg 5% Pd-C as a catalyst. The precipitated product was filtered off and washed with tetrahydrofuran. The filter cake was washed several times with 5% aqueous potassium hydroxide. Acidification of the filtrate with 4N hydrochloric acid and recrystallization (dimethylformamide-water) of the precipitated product gave 0.2 g (65%) 4-hydroxy-benzo[f]quinoxaline-2,3(1H,4H)-dione. M.p. 270° C. decomp. 1H-N (1H, broad s), 8.6 (1H, m), 7.7 (5H, m). MS (m/e): 228 (M+, 90%).
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21](=[O:33])[C@@H:22]([NH2:32])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1>C(OCC)(=O)C>[CH3:19][O:20][C:21](=[O:33])[CH:22]([NH:32][C:12](=[O:14])[CH:11]([NH:10][C:8]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:26][CH:25]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1ccc(OCc2ccccc2)cc1)NC(=O)C(CC(C)C)NC(=O)N1CCCCCC1
Yield: 151 %

Procedure:
A solution of the product from Example Z (2(S)-[(azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid) (0.20 g, 0.78 mmol) and 2(S)-amino-3-(4-methoxy-phenyl)-propionic acid methyl ester (Bachem, 0.277 g, 0.86 mmol) were coupled according to the procedure described in Example 3. The residue was passed through a plug of silica gel eluting with ethyl acetate. The material obtained was purified by crystallization from hot hexane/ethyl acetate to give the title compound as a white solid (0.34 g, 83%), mp=72-74° C.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[CH2:4][C:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[N:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]=1[CH3:19].ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[CH2:4][C:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[N+:7]([O-:33])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]=1[CH3:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)n1c(C)c(Cc2ccc(Cl)cc2Cl)c2ncccc21
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[N+]1([O-])C(C)=C(Cc2ccc(Cl)cc2Cl)c2ncccc21
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of ethyl 3-(2,4-dichlorobenzyl)-2-methylpyrrolo[3,2-b]pyridine-1-carboxylate (400 mg) in chloroform (6 ml) was added m-chloroperbenzoic acid (462 mg) at room temperature, and the mixture was stirred overnight. The reaction mixture was subjected to silica gel chromatography (silica gel, 40 ml, eluted with ethyl acetate and then with ethyl acetate-methanol=10-1), and crystallized from ether to give the objective compound (417 mg) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@@H:4]([CH:5]=[C:6]([CH3:8])[CH3:7])[C@@H:3]1[C:9](O)=[O:10].S(Cl)([Cl:15])=O>CCCCC>[CH3:1][C:2]1([CH3:12])[C@@H:4]([CH:5]=[C:6]([CH3:8])[CH3:7])[C@@H:3]1[C:9]([Cl:15])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: CC(C)=C[C@H]1[C@H](C(=O)O)C1(C)C
Solvent: CCCCC
Product: CC(C)=C[C@H]1[C@H](C(=O)Cl)C1(C)C
Reaction time: 0.33 h
Yield: 97.1 %

Procedure:
In a 300 ml flask, there were charged n-pentane (100 ml) and (-)-trans-2,2-dimethyl-3-isobutenylcyclopropane-1-carboxylic acid (50.0 g), and thionyl chloride (46.0 g) was added thereto from a dropping funnel in 20 minutes with stirring under reflux. After completion of the addition, stirring was continued for a further 3 hours, and then the solvent and excess of the thionyl chloride were removed by distillation. The residue was distilled to give (-)-trans-2,2-dimethyl-3-isobutenylcyclopropane-1-carboxylic acid chloride (53.9 g) having a boiling point of 50° C/0.5 mmHg - 56° C/0.6 mmHg. Other cyclopropanecarboxylic acid halides were prepared in the same manner as above.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=2)O1.Br[C:24]1[CH:25]=[C:26]2[N:45]([CH3:46])[CH:44]=[CH:43][C:27]2=[N:28][C:29]=1[C@@H:30]([NH:32][C:33](=[O:42])[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH3:31]>>[CH2:35]([O:34][C:33]([NH:32][C@H:30]([C:29]1[N:28]=[C:27]2[CH:43]=[CH:44][N:45]([CH3:46])[C:26]2=[CH:25][C:24]=1[C:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH:14]=1)[CH3:31])=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)c1nc2ccn(C)c2cc1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: C[C@H](NC(=O)OCc1ccccc1)c1nc2ccn(C)c2cc1C1=CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared similar to STEP A in PREPARATION 17 using tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate and benzyl (S)-(1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)carbamate as starting materials.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:9]2[NH:10][C:11](=O)[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:11]1[S:12][CH:13]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:16])([F:15])[F:1])[CH:4]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(-c2cccc(C(F)(F)F)c2)cs1
Product: FC(F)(F)c1cccc(-c2csc(Cl)n2)c1
Yield: 64.8 %

Procedure:
A mixture of 24.55 g (100.1 mmole) of 4-(3-trifluoromethyl-phenyl)-3H-thiazol-2-one and 75 mL (0.811 mole) of phosphorus oxychloride was heated at reflux for 3 hours. The cooled mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate and poured onto ice. The mixture was made basic by the addition of saturated sodium carbonate solution. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate-hexanes (gradient 10:90-20:80) to give 17.09 g of 2-chloro-4-(3-trifluoromethyl-phenyl)-thiazole as a light brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[C:10]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[OH:19])#[N:11].[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][O:19][C:13]1[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=1[C:10]#[N:11]
Reactant: BrCc1ccccc1Br
Reactant: N#Cc1cc(Cl)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)ccc1OCc1ccccc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.1 %

Procedure:
To a stirred mixture of 2-bromo-benzyl bromide (5.00 g, 20.0 mmol) and 2-cyano-4-chloro-phenol (13.2 g, 21.0 mmol) in anhydrous DMF under argon was added 95% NaH (0.56 g, 22.0 mmol) portionwise. This reaction mixture was stirred at room temperature for 1.5 hours and then quenched with water. The resulting mixture was diluted with ether (400 mL), and washed sequentially with water (3×100 mL), 1N NaOH solution (2×30 mL), saturated NaHCO3 solution (1×60 mL) and brine (1×60 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give 5.30 g of 2-(2-Bromo-benzyloxy)-5-chloro-benzonitrile Example 348A in 82% yield. HPLC Rt=3.89 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm) LC/MS: M+H=322
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]([F:39])([F:38])[S:7]([O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:21])[CH:17]=2)[C:12]=1[O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:25][CH:24]=1)(=[O:9])=[O:8].C(N(C(C)C)CC)(C)C>>[C:1]([O:21][C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([O:10][S:7]([C:6]([F:38])([F:5])[F:39])(=[O:9])=[O:8])[C:12]=2[O:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:27][CH:28]=2)[CH:17]=1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(Oc1ccc2cc(O)ccc2c1Oc1ccc(OCCN2CCCCC2)cc1)C(F)(F)F
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Oc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reaction time: 1 h
Yield: 90 %

Procedure:
Add acetyl chloride (0.67 mL, 9.41 mmol) to a solution of 6-hydroxy-1-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)naphthalen-2-yl trifluoromethanesulfonate (2.4 g, 4.69 mmol) and diisopropylethylamine (2.45 mL, 14.05 mmol). Stir the mixture for 1 hour and then quench with aqueous sodium bicarbonate. Extract the mixture 3 times with dichloromethane. Combine the extracts, dry over sodium sulfate, filter, and concentrate to obtain the title compound (2.33 g, 4.22 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21].O>CN(C)C=O.C(OCC)(=O)C>[CH2:21]([O:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11])[CH:20]=[CH2:19]
Reactant: COc1ccc(C(C)=O)c(O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCOc1cc(OC)ccc1C(C)=O

Procedure:
5.00 g of 2′-hydroxy-4′-methoxyacetophenone was dissolved in 40 ml of N,N-dimethylformamide at room temperature. Thereafter, 4.16 g of potassium carbonate and 2.80 ml of allyl bromide were successively added to the reaction solution. After the disappearance of materials had been confirmed, water and ethyl acetate were added to the reaction solution, so as to separate an organic layer. The obtained organic layer was washed with water and a saturated sodium chloride aqueous solution, and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure, and the residue was then purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 5.60 g of the subject compound.
Reaction SMILES: [N:1]1([C:6]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:22]([O:24][C:25]([O:27][C:28]1[CH:38]=[CH:37][C:31]([CH:32]=[CH:33][C:34](Cl)=[O:35])=[CH:30][CH:29]=1)=[O:26])[CH3:23]>C(Cl)(Cl)Cl>[CH2:22]([O:24][C:25]([O:27][C:28]1[CH:29]=[CH:30][C:31]([CH:32]=[CH:33][C:34]([N:12]2[CH2:11][CH2:10][N:9]([CH2:8][C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[O:7])[CH2:14][CH2:13]2)=[O:35])=[CH:37][CH:38]=1)=[O:26])[CH3:23]
Reactant: CCOC(=O)Oc1ccc(C=CC(=O)Cl)cc1
Reactant: O=C(CN1CCNCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Oc1ccc(C=CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cc1
Yield: 54 %

Procedure:
In 140 ml of chloroform were dissolved 17.7 g of 1-(pyrrolidinocarbonylmethyl)piperazine and 8.4 ml of triethylamine. To the solution was added 15.2 g of 4-(ethoxycarbonyloxy)cinnamoylchloride with ice-cooling, followed by stirring the resultant mixture overnight at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and dissolved in ethyl acetate. Any insoluble matter was removed by filtration, and the filtrate was extracted with 140 ml of 1N-hydrochloric acid. The extract was washed with ethyl acetate, neutralized with sodium bicarbonate and then extracted with chloroform. The chloroform layer was successively washed with water and then with brine. The layer was then dried and subjected to distillation to remove the solvent. The resultant crystals were recrystallized from ethyl acetate, thereby obtaining 13.4 g (yield: 54.0%) of 1-[4-(ethoxycarbonyloxy)cinnamoyl]-4-(pyrrolidinocarbonylmethyl)piperazine as crystals having a melting point of 128°-130° C.
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:16])[CH:8]=[CH:7][C:6]([C:9]([NH:11][CH2:12][C:13](=[O:15])[CH3:14])=[O:10])=[CH:5][CH:4]=1.I[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C)C=O>[C:13]([CH:12]([NH:11][C:9]([C:6]1[CH:5]=[CH:4][C:3]([CH3:16])=[CH:8][CH:7]=1)=[O:10])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:15])[CH3:14]
Reactant: CCOC(=O)CCCCCI
Reactant: CC(=O)CNC(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCC(NC(=O)c1ccc(C)cc1)C(C)=O
Yield: 65.6 %

Procedure:
A suspension (100 ml) of 60% sodium hydride (2.64 g) in N,N-dimethylformamide was cooled to −18° C. with an ice-sodium chloride bath, and 31 ml of a solution of 12.62 g of 1-(p-toluoylamino)-2-propanone in N,N-dimethylformamide was added dropwise slowly. After 1-hour-stirring, 31 ml of a solution of 16.21 g of ethyl 6-iodohexanoate in N,N-dimethylformamide was added dropwise slowly. The ice-bath was removed and the mixture was stirred for 18 hours at room temperature. After addition of ice-cold water, the reaction solution was extracted with ethyl acetate, washed with water and brine sequentially, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane: ethyl acetate=3:1) to provide 13.13 g of the objective compound as yellow oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:32][N:33]([CH3:37])[C:34](Cl)=[O:35]>ClCCl>[CH3:32][N:33]([CH3:37])[C:34]([N:2]([CH3:1])[CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)=[O:35]
Reactant: CN(C)C(=O)Cl
Reactant: CNCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)N(C)CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reaction time: 8 h
Yield: 34.7 %

Procedure:
To a stirred solution of methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}amine (200 mg, 0.60 mmol) and triethylamine (102 μL, 0.72 mmol) in anhydrous dichloromethane (8 mL) under nitrogen atmosphere was added dropwise a solution of dimethylcarbamoylchloride (67 μL, 0.72 mmol) in anhydrous dichloromethane (2 mL). After stirring overnight, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated, washed with a saturated aqueous solution of NaHCO3 and water then dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with DCM:MeOH (95:5) followed by DCM:MeOH:NH3 (90:5:5) to give the title compound (84 mg, 39%). 1H NMR (400 MHz, CDCl3) δ7.19 (d, 2H), 6.90-6.88 (d, 2H), 4.03 (t, 2H), 3.81-3.78 (m, 2H), 3.56-3.52 (m, 4H), 2.70 (s, 6H), 2.66 (t, 2H), 2.29 (s, 3H), 2.05-2.01 (m, 4H), 1.86-1.81 (m, 6H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=[O:6])[CH3:5].[F:7][C:8]([F:13])([F:12])[C:9](O)=[O:10]>ClCCl>[F:7][C:8]([F:13])([F:12])[C:9]([NH:2][CH2:3][C:4](=[O:6])[CH3:5])=[O:10]
Reactant: CC(=O)CN
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Product: CC(=O)CNC(=O)C(F)(F)F
Reaction time: 1 h

Procedure:
Aminoacetone hydrochloride (13.29 g, 121 mmol) was slurried in 200 mL of dichloromethane and stirred vigorously as 22 mL (146 mmol) of trifluoroacetic acid was added. The mixture was heated to reflux with stirring for about 1 hour at which time the evolution of gas had ceased. The resulting mixture was concentrated by evaporation at 60° C. and the residue was dissolved in 200 mL of ether. Solid sodium bicarbonate was cautiously added with stirring until foaming ceased. The resulting slurry was filtered through a 2×5 cm silica gel plug and the plug was eluted with an additional 100 mL of ether. The combined filtrates were concentrated by evaporation at temperatures up to 60° C. The residue was kugelrohr distilled at a pot temperature of 100°-110° C. and a pressure of 18 torr (2.4 kPa) to obtain 9.7 g (47 percent of theory) of the title compound as a waxy white solid. An analytical sample prepared by recrystallization from pentane was a white solid melting at 71°-73° C.