Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[H-].[Na+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])[CH:14](C)[CH2:13][C:12]2=[O:29].C(OCC)=O>C1C=CC=CC=1.C(O)C>[OH:1][CH:2]=[C:3]1[C:12](=[O:29])[C:11]2[C:16](=[CH:17][C:18]([O:19][CH3:20])=[C:9]([O:8][CH3:7])[CH:10]=2)[N:15]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])[CH:14]1[CH3:13]
Reactant: CC[O-]
Reactant: CCCCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)CC1C
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOC=O
Solvent: CCO
Product: CCCCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CO)C1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To sodium ethoxide freshly prepared from 4.8 g. of sodium hydride and 6.0 ml. of ethanol is added 16.0 g. of butyl 6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline-1-carboxylate and 19.8 ml. of ethyl formate in 150 ml. of benzene over a 30 min. period. The reaction mixture, after stirring at room temperature for 4 hrs., is poured onto 250 ml. of ice-water. The aqueous layer is retained and the organic layer extracted with 1N aqueous sodium hydroxide. The base extracted is combined with the separated aqueous and backwashed with benzene. The aqueous layer is then added to 250 ml. of 12N hydrochloric acid. The resulting yellow oil is extracted with chloroform and the chloroform layer dried over magnesium sulfate. The solvent is removed under reduced pressure and the residual product used in subsequent reactions without further purification.
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Cl)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][C:22]([O:24]C)=[O:23])[CH:17]=[CH:18][C:19]=1[OH:20]>CO.O>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][C:22]([OH:24])=[O:23])[CH:17]=[CH:18][C:19]=1[O:20][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=1
Reactant: CC(C)Cc1ccc(CCl)cc1
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Solvent: O
Solvent: CO
Product: CC(C)Cc1ccc(COc2ccc(CC(=O)O)cc2Cl)cc1

Procedure:
3-chloro-4-(4'-isobutylbenzyloxy) phenylacetic acid was prepared in accordance with the procedure designated (f) above by reacting 4-isobutylbenzyl chloride and methyl 3-chloro-4-hydroxyphenylacetate. The resultant product evidenced a melting point of 97°-99° C. (methanol-water 4:1), the yield being 61%.
Reaction SMILES: Cl.[CH2:2]([C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH3:3].[O:17]=[C:18]1[NH:27][C:26]2[N:25]=[C:24]([O:28][CH2:29][CH2:30][CH2:31][CH:32]=O)[CH:23]=[CH:22][C:21]=2[CH2:20][CH2:19]1>>[CH2:2]([C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[N:11]1[CH2:12][CH2:13][N:14]([CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:24]2[N:25]=[C:26]3[C:21]([CH2:20][CH2:19][C:18](=[O:17])[NH:27]3)=[CH:22][CH:23]=2)[CH2:15][CH2:16]1)[CH3:3]
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Reactant: CCc1c(F)cccc1N1CCNCC1
Agent: Cl
Product: CCc1c(F)cccc1N1CCN(CCCCOc2ccc3c(n2)NC(=O)CC3)CC1

Procedure:
In a manner similar to that of other examples above, 1-(2-ethyl-3-fluoro-phenyl)-piperazine hydrochloride was coupled by reductive amination to 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 427.2 (Exact Mass: 426.24).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][Si:8]([O:19][Si:20]([CH3:23])([CH3:22])[CH3:21])([O:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[O:9][Si:10]([CH3:13])([CH3:12])[CH3:11].N1C=CC=CC=1.Cl[C:31]([O:33][CH:34]=[CH2:35])=[O:32]>CCOCC>[C:31](=[O:32])([O:33][CH:34]=[CH2:35])[O:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][Si:8]([O:9][Si:10]([CH3:11])([CH3:12])[CH3:13])([O:19][Si:20]([CH3:22])([CH3:21])[CH3:23])[O:14][Si:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: C=COC(=O)Cl
Reactant: C[Si](C)(C)O[Si](CCCNCCO)(O[Si](C)(C)C)O[Si](C)(C)C
Solvent: CCOCC
Solvent: c1ccncc1
Product: C=COC(=O)OCCNCCC[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 250 mL 3-neck round bottom flask fitted with a magnetic stirrer, condenser, nitrogen blanket, dropping funnel, ice-water bath and thermometer was added 6.3 g (15.8 mmol) N-(2-hydroxyethyl)-3-aminopropyltris(trimethylsiloxy) silane, 1.37 g (17.4 mmol) of pyridine and 100 mL ether. To the reaction mixture was added 1.68 g (15.8 mmol) of vinyl chloroformate so that the temperature remained below 5° C. After stirring at room temperature for 24 hours the reaction mixture was washed with 100 mL 2N HCl, 100 mL 2N NaOH and the organic phase was dried over magnesium sulfate. The solvent was removed on a rotary evaporator and the resulting oil, 4.3 g, chromatographed (silica gel, ethyl acetate 20% methylene chloride 80%). The oil recovered weighed 2.99 g (6.4 mmol, 25.4% yield). FTIR (neat, capillary) 2957.62, 2899.00, 1720.60, 1702.33, 1648.16, 1470.55, 1420.23, 1373.91, 1291.12, 1249.88, 1196.62, 1152.74, 1039.27, 951.52, 833.44, 753.18, 715.26, 686.53, 658.78. NMR (CDCl 3) 6.85-7.20 (1H,dd), 4.20-4.69 (2H,m), 3.36-3.71 (2H,bd), 3.00-3.36 (4H,m), 1.00-1.65 (2H,m), 0.09-0.40 (2H,m), 0.00 (27H,s). ##STR39##
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][N:3]=1.[NH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1.C(N(CC)CC)C>CC(O)C>[C:31]([O:30][C:28]([N:25]1[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][NH:19][C:2]2[N:7]=[C:6]3[NH:8][N:9]=[C:10]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=4)[C:5]3=[CH:4][N:3]=2)[CH2:27][CH2:26]1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Reactant: CSc1nccc(-c2n[nH]c3nc(Cl)ncc23)n1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CSc1nccc(-c2n[nH]c3nc(NCCN4CCN(C(=O)OC(C)(C)C)CC4)ncc23)n1

Procedure:
To a solution of 6-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (from Example 7 supra) (500 mg, 1.79 mmol) in 2-propanol (40 mL) was added tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (613 mg, 1.97 mmol) followed by triethylamine (200 mg, 1.98 mmol). The reaction mixture was stirred at reflux for 15 hours and the solvent was then removed under reduced pressure. The residue was extracted with dichloromethane (3×30 mL), washed with water (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 4-{2-[3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-ethyl}-piperazine-1-carboxylic acid tert-butyl ester. (Yield 600 mg, crude).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:16][CH2:15][CH2:14][C@H:13]3[N:9]2[C:10](=[O:18])[CH:11](I)[CH2:12]3)=[CH:4][CH:3]=1.[P:19]([O:26]CC)([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:16][CH2:15][CH2:14][C@H:13]3[N:9]2[C:10](=[O:18])[CH:11]([P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])[CH2:12]3)=[CH:4][CH:3]=1
Reactant: O=C1C(I)C[C@H]2CCC[C@@H](c3ccc(F)cc3)N12
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(OCC)C1C[C@H]2CCC[C@@H](c3ccc(F)cc3)N2C1=O
Temperature: 120 °C
Reaction time: 14 h

Procedure:
A mixture of (5S*,8aR*)-5-(4-fluorophenyl)-2-iodohexahydroindolizin-3-one (120 mg) with triethyl phosphite (2 mL) was stirred at 120° C. for 14 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure to obtain 123 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([Br:19])[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:23])=O>C(#N)C>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([Br:19])[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(O)c2cc(Br)ccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCCCOC(=O)c1nc(Cl)c2cc(Br)ccc2c1O
Yield: 43.5 %

Procedure:
170 mg (0.5 mmol) of 7-bromo-1,4-dihydroxy-isoquinoline-3-carboxylic acid butyl ester (from Example D-21c) was dissolved in 2 ml of anhydrous acetonitrile. Phosphorous oxychloride (536 mg, 3.5 mmol) was added and the resulting mixture was stirred at reflux for 4 h. After cooling, the mixture was concentrated and the residue was taken into ethyl acetate. Ethyl acetate mixture was poured into saturated sodium bicarbonate solution with efficient stirring for 1 h. Two phases were separated. Aqueous layer was extracted with ethyl acetate. Combined organic layer was dried over magnesium sulfate, filtered and concentrated. Crude product was purified by silica gel chromatography eluting with methylene chloride to give 78 mg of product as white solid. MS-(+)-ion: M+1=359.96, 357.98
Reaction SMILES: [Cl:1][C:2]1[N:6]=[C:5](Cl)[S:4][N:3]=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.C([O-])([O-])=O.[K+].[K+].CC#N>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:6]=[C:5]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH3:8])[S:4][N:3]=1
Reactant: Clc1nsc(Cl)n1
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccccc1-c1nc(Cl)ns1
Temperature: 100 °C

Procedure:
A mixture of 3,5-dichloro-1,2,4-thiadiazole (0.14 g, 0.93 mmol), 2-methoxyphenylboronic acid (0.16 g, 1.0 mmol), Pd(PPh3)4 (11 mg, 9.3 μmol), K2CO3 (0.26 g, 1.9 mmol), and CH3CN (3 mL containing 10% H2O) was sealed in a microwave vessel and heated by microwave irradiation at 100° C. for three minutes. The reaction was cooled to room temperature, diluted with water, and extracted with CH2Cl2. The combined extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure to yield 3-chloro-5-(2-methoxyphenyl)-1,2,4-thiadiazole. LC/MS: m/z 227 (M+H)+ at 3.45 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][C:21]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:20][C:19]=3[N:18]=[C:17]([NH2:34])[C:16]=2[N:15]=[C:14]1[CH2:35][CH3:36])(C)(C)C>C(O)C>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][C:21]([O:26][CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:20][C:19]=3[N:18]=[C:17]([NH2:34])[C:16]=2[N:15]=[C:14]1[CH2:35][CH3:36]
Reactant: CCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CCCCN
Reaction time: 0.25 h
Yield: 99.8 %

Procedure:
Concentrated hydrochloric acid (18 mL) was added to a solution of tert-butyl[4-(4-amino-7-benzyloxy-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate (9.0 g, 18 mmol) in ethanol (100 mL), and the reaction was stirred for 15 minutes. The ethanol was removed under reduced pressure, and the residue was twice dissolved in ethanol and concentrated under reduced pressure. The solid residue was stirred with brine (25 mL) and water (100 mL), and the pH of the mixture was adjusted to 14 with the addition of 50% aqueous sodium hydroxide. Dichloromethane was added, and the layers were separated. The aqueous layer was extracted twice with dichloromethane (100 mL) and twice with chloroform (100 mL). The combined organic fractions were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 7.00 g of 1-(4-aminobutyl)-7-benzyloxy-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine as an off-white powder.
Reaction SMILES: [BH4-].[Na+].C(N)CN.[CH3:7][O:8][C:9](=[O:32])[CH2:10][CH2:11][CH2:12][C:13]#[C:14][CH2:15][N:16]1[CH:21](/[CH:22]=[CH:23]/[C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19][CH2:18][C:17]1=[O:31].[H][H]>C(O)C.Cl[Ni]Cl>[CH3:7][O:8][C:9](=[O:32])[CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][N:16]1[CH:21](/[CH:22]=[CH:23]/[C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19][CH2:18][C:17]1=[O:31]
Reactant: CCCCCC(=O)/C=C/C1CCCC(=O)N1CC#CCCCC(=O)OC
Reactant: [H][H]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: NCCN
Product: CCCCCC(=O)/C=C/C1CCCC(=O)N1C/C=C\CCCC(=O)OC
Reaction time: 0.25 h
Yield: 42.6 %

Procedure:
A 50 mL round bottom flask was charged with nickel (11) chloride (273 mg, 2.10 mmol) and sodium borohydride (40 mg, 1.05 mmol), then 95% ethanol (2.0 mL) was added. The mixture immediately turned black. After 15 min at rt, ethylene diamine (0.23 mL, 3.36 mmol) was added. After another 15 min at rt, 7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-ynoic acid methyl ester (152 mg, 0.42 mmol) in 95% ethanol (2.0 mL) was added via cannula. A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 19 h. The reaction mixture was filtered through celite, washing with ethanol, and the filtrate was concentrated in vacuo. Purification of the resulting residue by flash column chromatography (10→50% EtOAc/CH2Cl2, gradient) afforded 65 mg (43%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[S:3]([N:6]1[CH:10]=[CH:9][C:8]([C:11](=O)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)=[N:7]1)(=[O:5])=[O:4].[CH3:21][C:22]([S:25]([NH2:27])=[O:26])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1.[Cl-].[Na+].O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:1][N:2]([CH3:20])[S:3]([N:6]1[CH:10]=[CH:9][C:8]([C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)=[N:27][S:25]([C:22]([CH3:24])([CH3:23])[CH3:21])=[O:26])=[N:7]1)(=[O:5])=[O:4]
Reactant: CC(C)(C)S(N)=O
Reactant: CN(C)S(=O)(=O)n1ccc(C(=O)c2cccc(Cl)c2)n1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)S(=O)(=O)n1ccc(C(=NS(=O)C(C)(C)C)c2cccc(Cl)c2)n1
Temperature: 110 °C
Reaction time: 24 h
Yield: 97.3 %

Procedure:
Titanium(IV)isopropoxide (3.22 mL, 10.71 mmol) was added to a mixture of 3-(3-chloro-benzoyl)-1H-pyrazole-1-sulfonic acid dimethylamide (1.68 g, 5.35 mmol) and 2-methyl-2-propanesulfinamide (0.71 g, 5.89 mmol) in toluene (32 mL) under nitrogen. The mixture was stirred at 110° C. for 24 hours. The mixture was cooled and poured into brine while rapidly stirring. The mixture was filtered through diatomaceous earth and the filter cake was washed with AcOEt. The filtrate was transferred to a separation funnel where the organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; AcOEt in DCM 0/100 to 10/90). The desired fractions were collected and concentrated in vacuo to yield 3-[(3-chloro-phenyl)-(2-methyl-propane-2-sulfinylimino)-methyl]-pyrazole-1-sulfonic acid dimethylamide (2.17 g, 97% yield) as a yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11].[F:12][C:13]([F:27])([F:26])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38]>C(O)CCC.C(O)C>[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38].[F:26][C:13]([F:12])([F:27])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([N:20]2[CH2:21][CH2:22][N:23]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[CH2:10][CH2:9][CH2:8][C:7]3=[O:11])[CH2:24][CH2:25]2)[CH:15]=1
Reactant: O=C1CCCN1CCCCBr
Reactant: FC(F)(F)c1ccnc(N2CCNCC2)c1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Solvent: CCO
Product: O=C1CCCN1CCCCN1CCN(c2cc(C(F)(F)F)ccn2)CC1
Yield: 52 %

Procedure:
2 7 g of 1-(4-bromobutyl)-2-pyrrolidinone were mixed with 2.2 g of 1-[4-(trifluoromethyl)-2-pyridinyl]piperazine dissolved in 30 ml of butanol, after which 1.3 g of sodium carbonate were added. The mixture was refluxed for 2 hours, after which the precipitate was filtered and washed with butanol. The solvent was evaporated and the residue was dissolved in dichloromethane, washed with water, and dried over anhydrous magnesium sulfate. After evaporation of the solvent 3.4 g of 1-[4-[4-[4-(trifluoromethyl)-2-pyridinyl]-1-piperazinyl]butyl]-2-pyrrolidinone were obtained. To make the monofumarate, 1 g of fumaric acid dissolved in absolute ethanol was mixed with the free base. The resulting compound was recrystallized twice from acetonitrile, after which 2.4 g (52% yield) of 1-[4-[4-[4-(trifluoromethyl)-2-pyridinyl]-1-piperazinyl]butyl]-2pyrrolidinone (E)-2-butenedioate (1:1) salt were obtained with a melting point of 140° C.
Reaction SMILES: [C:1]([C:5]1[C:6]([CH3:34])([CH3:33])[CH2:7][O:8][C:9]=1[C:10]1[CH:24]=[C:23]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:16][C:12]=2[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[Na].[O:39]=[O:40]>>[C:1]([C:5]12[O:40][O:39][C:9]1([C:10]1[CH:24]=[C:23]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])[C:13]3[N:14]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[O:16][C:12]=3[CH:11]=1)[O:8][CH2:7][C:6]2([CH3:34])[CH3:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1=C(c2cc(O[Si](C)(C)C(C)(C)C)c3nc(-c4ccccc4)oc3c2)OCC1(C)C
Reactant: O=O
Agent: [Na]
Solvent: ClCCl
Product: CC(C)(C)C12OOC1(c1cc(O[Si](C)(C)C(C)(C)C)c3nc(-c4ccccc4)oc3c1)OCC2(C)C
Yield: 85.1 %

Procedure:
Adding 1 mg of TPP and 27.9 mg (0.058 mmol) of 4-t-butyl-5-[4-(t-butyldimethylsiloxy)-2-phenylbenzo[d]oxazol-6-yl]-3,3-dimethyl-2,3-dihydrofuran (Compound [65]) to 5 ml of methylene chloride, the mixture was externally irritated with a 940 W sodium lamp for 30 minutes in oxygen atmosphere. After concentrated, the resulting mixture was applied to a silica gel column and the elution was carried out the mixture of hexane and ethyl acetate (hexane:ethyl acetate=15:1) to obtain 25.3 mg of 5-t-butyl-1-[4-(t-butyldimethylsiloxy)-2-phenylbenzo[d]oxazol-6-yl]-4,4-dimethyl-2,6,7-trioxabicyclo[3.2.0]heptane (Compound [66]) as a purple oil. Yield 85.1%.
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37](O)(=[O:48])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH:46]=[CH2:47]>CN(C)C1C=CN=CC=1.ClCCl>[C:37]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])(=[O:48])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH:46]=[CH2:47]
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reactant: C=CCCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCCCCCCCCC(=O)OC(CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 37.8 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 184 mg (1 mmole) of undecylenic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedures as described in Example 1 to obtain 172 mg (Yield: 38%) of the title compound having the following structure as a red oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:1][C:2]2[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=2)=[O:16])=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Nc1cccc(C=O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=Cc1cccc(NC(=O)c2ccc(Cl)cc2)c1
Yield: 129 %

Procedure:
to a solution of 242 mg of 3-aminobenzaldehyde (2 mmoles) and 250 μl of 4-chlorobenzoyl chloride (2 mmoles) in 5 ml of DMF is added 700 μl of DIEA (4 mmoles). The reaction is irradiated in under microwaves at 110° C. for 10 minutes. The precipitate formed is filtrated and washed with methanol. 670 mg of 4-Chloro-N-(3-formyl-phenyl)-benzamide are isolated as a white solid (yield=85%). Analytical LC/MS method A: ([M+H]+): 260
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15].ClC1C=CC(F)=C(C=1)C#N.N1CCCC1=O.[H-].[Na+]>CN(C=O)C>[Cl:9][C:7]1[CH:6]=[CH:5][C:4]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])=[C:3]([CH:8]=1)[C:2]#[N:1]
Reactant: NCc1cc(Cl)ccc1N1CCCC1=O
Agent: N#Cc1cc(Cl)ccc1F
Agent: O=C1CCCN1
Agent: [H-]
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)ccc1N1CCCC1=O
Reaction time: 8 h

Procedure:
1-(2-Aminomethyl-4-chloro-phenyl)-pyrrolidin-2-one: To 5-chloro-2-fluorobenzonitrile (0.3 g, 1.929 mmol) and pyrrolidin-2-one (0.246 g, 2.89 mmol) in DMF (5 mL) was added NaH (0.116 g, 2.89 mmol) and the reaction was stirred overnight. The reaction mixture was partitioned with EtOAc/water/brine and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (MgSO4), and evaporated to give 5-Chloro-2-(2-oxo-pyrrolidin-1-yl)-benzonitrile (0.42 g). LCMS m/z 221.2 (M+H)+. This intermediate was converted to 125A following the procedure described for 102B. LCMS m/z 207.2 (M+H−NH3)+. 1HNMR (400 MHz, CHLOROFORM-D) δ: 2.08-2.20 (m, 2H) 2.57 (t, J=7.71 Hz, 2H) 3.56 (t, J=6.69 Hz, 2H) 4.61 (s, 2H) 6.50 (d, J=8.34 Hz, 1H) 6.97 (d, J=2.27 Hz, 1H) 7.11 (dd, J=8.34, 2.27 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Br)=[CH:4][CH:3]=1.COC1C=CC(CCCCCCBr)=CC=1.B(Br)(Br)Br.[I-].[K+].[CH3:36][CH2:37][C:38](=[O:44])[CH2:39][C:40](=[O:43])[CH2:41][CH3:42].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CC(C)=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:39]([C:38](=[O:44])[CH2:37][CH3:36])[C:40](=[O:43])[CH2:41][CH3:42])=[CH:4][CH:3]=1
Reactant: Oc1ccc(CCCCCCBr)cc1
Reactant: CCC(=O)CC(=O)CC
Agent: BrB(Br)Br
Agent: COc1ccc(CCCCCCBr)cc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCC(=O)C(CCCCCCc1ccc(O)cc1)C(=O)CC

Procedure:
A suspension of 0.5 mole of 6-(4-hydroxyphenyl)hexyl bromide [pepared from 6-(4-methoxyphenyl)hexyl bromide and boron tribromide in methylene dichloride according to the procedure of Example 42f], 0.125 mole of potassium iodide, 1.15 moles of 3,5-heptanedione and 1.05 moles of powdered anhydrous potassium carbonate (dried in vacuo for two hours) in 2 liters of acetone is stirred at reflux for 24 hours. One liter of solvent is distilled off and the remainder of the reaction mixture is poured with stirring into a solution of 4 liters of ice-water containing 160 ml. of concentrated hydrochloric acid. The separated product is extracted with ether and the ether extracts washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The ether is distilled off in vacuo and the excess 3,5-heptanedione removed at 70° C. (0.8 mm.) in a rotary evaporator. The residual product is crystallized from isopropyl alcohol-pentane to give 4-[6-(4-hydroxyphenyl)hexyl]-3,5-heptanedione.