Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.O.[CH:12]([CH:14]=O)=[O:13]>C(O)(=O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]/[N:10]=[CH:14]/[CH:12]=[O:13])=[CH:5][CH:4]=1
Reactant: O=CC=O
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C/C=N/Nc1ccc(F)cc1
Reaction time: 2 h
Yield: 97.9 %

Procedure:
A mixture of 1-(4-fluorophenyl)hydrazine hydrochloride (5.0 g, 30.75 mmol), water (20 mL), and acetic acid (20 mL) was added with stirring to a 40% aqueous solution of glyoxal (17.6 mL, 153.8 mmol) over 20 minutes. Stirring was continued for 2 hours and the mixture was then filtered. The precipitate washed with water and dried to afford 5.0 g (98%) of the desired product. 1H NMR (400 MHz, CDCl3) δ 9.56 (d, 1H), 8.63 (br s, 1H), 7.24 (m, 1H), 7.16 (m, 2H), 7.06 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −120.3. LRMS (ESI pos) m/e 151.1 (M−16).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH2:11][CH2:10]1.[CH3:28][NH2:29]>>[CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13]([NH:29][CH3:28])[C:12]=2[CH2:11][CH2:10]1
Reactant: CN
Reactant: Cc1cc(F)ccc1N1CCc2c(Cl)nc3c(OC(F)(F)F)cccc3c21
Product: CNc1nc2c(OC(F)(F)F)cccc2c2c1CCN2c1ccc(F)cc1C
Temperature: 190 °C

Procedure:
1-(2-Methyl-4-fluorophenyl)-4-chloro-6-trifluoromethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(500 mg, 1.3 mmol) was dissolved in aqueous solution of methylamine(40%, 10 ml) in the pressure tube, and the reaction mixture was refluxed at 190° C. for 3 hours. The solvent was removed by distillation under reduced pressure, and the residue was diluted in dichloromethane(20 ml), then washed with water(15 ml) for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate as eluent to obtain 380 mg of desired compound as solid in 72% of yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].I[CH2:13][CH2:14][O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18]>>[CH3:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([O:7][CH2:13][CH2:14][O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])=[O:6])=[CH:3][C:2]=1[O:1][CH2:13][CH2:14][O:15][Si:16]([CH:20]([CH3:21])[CH3:22])([CH:17]([CH3:19])[CH3:18])[CH:23]([CH3:24])[CH3:25]
Reactant: Cc1ccc(C(=O)O)cc1O
Reactant: CC(C)[Si](OCCI)(C(C)C)C(C)C
Product: Cc1ccc(C(=O)OCCO[Si](C(C)C)(C(C)C)C(C)C)cc1OCCO[Si](C(C)C)(C(C)C)C(C)C

Procedure:
Analogously to Example 12d, 5.0 g of 3-hydroxy-4-methylbenzoic acid and 24.3 g of (2-iodoethoxy)triisopropylsilane are reacted. The title compound is obtained as a yellowish oil. Rf=0.66 (1:4 EtOAc-heptane); Rt=6.30.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][NH2:7].C(=O)([O-])[O-].[Na+].[Na+].Br[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[N+:25]([O-:27])=[O:26])[C:17](=O)[O:16]1.O>CN(C=O)C>[N+:25]([C:23]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:24]=1[CH:15]=[N:6][NH:7][C:17]2=[O:16])([O-:27])=[O:26]
Reactant: NN
Reactant: O=C1OC(Br)c2c1cccc2[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]ncc2c([N+](=O)[O-])cccc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 43.8 %

Procedure:
18.25 g of hydrazine sulfate and 14.88 g of sodium carbonate are stirred in 300 ml of DMF at 100° C. for 1 hour. Then, 7.24 g of 3-bromo-4-nitro-phthalide in 100 ml of DMF is added, and it is stirred for another 4 hours at 100° C. It is added to water, extracted several times with ethyl acetate, and the organic phase is washed with water and brine. It is dried, and the solvent is removed in a vacuum. After recrystallization from ethyl acetate, 2.35 g of 5-nitro-phthalazin-1-one is obtained as a solid.
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[H-].[Na+].Cl[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1>CN(C)C=O>[C:1]1([CH2:7][O:8][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: OCC1=CCCCC1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COCC2=CCCCC2)cc1
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
To a mixture of cyclohexenylmethanol (2.50 g, 22.3 mmol) in N,N-dimethylformamide (40 mL) and sodium hydride (60% dispersion in mineral oil, 0.89 g, 22.3 mmol) was added in portions at 0° C. The reaction mixture was stirred for 0.5 hour, then added 1-(chloromethyl)-4-methoxybenzene (3.49 g, 22.3 mmol). The reaction mixture was stirred for another 0.5 hour and quenched with slow addition of water (50 mL). The organic layer was extracted with ethyl acetate (80 mL) and concentrated in vacuo to dryness. The residue was purified by column chromatography with ethyl acetate in hexanes (10%) to afford the title compound as a colorless liquid (3.50 g, 68%).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].CCN(CC)CC.[Br:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1/[C:23](=[CH:33]\OC)/[C:24](=[O:32])[NH:25][C:26]2=[O:31].O>CN(C)C=O>[Br:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1/[C:23](=[CH:33]/[NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([OH:2])[CH:4]=1)/[C:24](=[O:32])[NH:25][C:26]2=[O:31]
Reactant: COc1ccc(CN)cc1O
Reactant: CO/C=C1/C(=O)NC(=O)c2cccc(Br)c21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN/C=C2\C(=O)NC(=O)c3cccc(Br)c32)cc1O
Reaction time: 3.5 h
Yield: 86.4 %

Procedure:
A solution of 88.5 mg (0.468 mmol) of 3-hydroxy-4-methoxy-benzylamine hydrogen chloride in 1.8 mL of N,N-dimethylformamide (DMF) at RT under N2 is treated with 94.5 mg (0.936 mmol) of Et3N. (4E)-5-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (132 mg, 0.468 mmol) is added and the mixture is stirred for 3.5 h. Water is added and the product is collected, washed with H2O and Et2O and dried to give 163 mg (86%) of pale yellow amorphous solid: mp 204-206° C.; 1H NMR (DMSO-d6) δ 11.11 (s, 1H), 10.56 (m, 1H), 9.08 (s, 1H), 8.93 (d, 1H, J=13.6 Hz), 8.05 (d, 1H, J=6.9 Hz), 7.87 (d, 1H, J=6.9 Hz), 7.09 (m, 1H), 6.91 (d, 1H, J=8.07 Hz), 6.78 (m, 2H), 4.49 (d, 2H, J=5.37 Hz), 3.75 (s, 3H); HRMS (ESI) m/z calcd for C18H15BrN2O4 403.02880. found 403.02840 (M+H)+1.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][NH2:5].N#N.[OH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](OC)=[O:22]>C[O-].[Na+].C1COCC1>[NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][NH:5][C:10](=[O:9])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22]
Reactant: COC(=O)CCCCCCCCCCCO
Reactant: NCC(O)CN
Agent: C[O-]
Agent: N#N
Agent: [Na+]
Solvent: C1CCOC1
Product: NCC(O)CNC(=O)CCCCCCCCCCCO
Yield: 75.7 %

Procedure:
A 100-ml two-necked flask equipped with a stirrer and dropping funnel was charged with 9.39 g (104 mmol) of 1,3-diamino-2-propanol and 0.047 g (0.87 mmol) of sodium methoxide. While heating and stirring the contents at 80° C. in an N2 atmosphere, a THF solution of 4.00 g (17.4 mmol) of methyl 12-hydroxydodecanate was added dropwise over 2.5 hours. Precipitate formed was washed with water and recrystallized from ethyl acetate-methanol (4:1 v/v), thereby obtaining 3.80 g (yield: 75%) of the title compound (IIh-12) as colorless powder.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[NH:13][C:7]2=[N:8][CH:9]=[CH:10][C:11]([CH3:12])=[C:6]2[N:5]=1.I[CH3:15].O>CN(C)C=O>[CH3:12][C:11]1[CH:10]=[CH:9][N:8]=[C:7]2[NH:13][C:4]([S:3][CH3:15])=[N:5][C:6]=12
Reactant: Cc1ccnc2[nH]c(S)nc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc2c(C)ccnc2[nH]1
Reaction time: 0.17 h

Procedure:
130 mg of sodium hydride was dropwise added at room temperature to a solution of 500 mg of 2-mercapto-7-methyl-3H-imidazo[4,5-b]pyridine in dimethylformamide. The mixture was stirred for 10 min, and 0.21 ml of iodomethane was added thereto, followed by reaction for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was distilled off in vacuo. The resultant solid was washed with a small amount of ethyl acetate to prepare 210 mg of 7-methyl-2-methylthio-3H-imidazo[4,5-b]pyridine as a mud yellow solid.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=[O:3].[Cl:9][C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=1.[Mg].O1CCCC1>C(OCC)C>[CH2:7]([O:6][C:1](=[O:5])[C:2]([C:13]1[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=1)([OH:3])[CH3:4])[CH3:8]
Reactant: CCOC(=O)C(C)=O
Reactant: Clc1ccc(I)cc1
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 11.5 g ethyl pyruvate in 20 ml diethylether is slowly added under cooling (0° C.), a freshly prepared Grignard solution (from 23.9 g 4-chloro-iodobenzene and 3 g magnesium turnings). Some tetrahydrofurane is added to prevent the formation of viscous suspension. After stirring for 2 hours at room temperature the reaction is quenched by pouring it onto a mixture of ice and 2N sulfuric acid. Extraction of the suspension with diethyl ether followed by washing with brine, drying over sodium sulfate and evaporation leads to a residue which is purified on silicagel (hexane-ethyl acetate) to obtain 2-(4-chlorophenyl)-2-hydroxy propionic acid ethyl ester as yellowish oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.C[O:8][C:9]([C:11]1[C:15]([NH:16][C:17]([C:19]2[C:24]([NH:25][C:26]3[CH:27]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:23][CH:22]=[C:21]([CH:32]3[CH2:34][CH2:33]3)[N:20]=2)=[O:18])=[CH:14][N:13]([CH3:35])[N:12]=1)=O>>[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:9]([C:11]2[C:15]([NH:16][C:17]([C:19]3[C:24]([NH:25][C:26]4[CH:27]=[N:28][CH:29]=[N:30][CH:31]=4)=[CH:23][CH:22]=[C:21]([CH:32]4[CH2:34][CH2:33]4)[N:20]=3)=[O:18])=[CH:14][N:13]([CH3:35])[N:12]=2)=[O:8])[CH2:3]1
Reactant: OC1CCNC1
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: Cn1cc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)N2CCC(O)C2)n1
Yield: 15 %

Procedure:
According to the general method described in step 5 of example 27, reaction of 3-hydroxy-pyrrolidine with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (15%) as sticky yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]2[N:9]([C:12]3[S:16][C:15]([C:17]([NH2:19])=[O:18])=[C:14]([O:20][C@@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH3:22])[CH:13]=3)[CH:10]=[N:11][C:5]=2[CH:4]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[CH3:40][S:41]([NH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]2[N:9]([C:12]3[S:16][C:15]([C:17]([NH2:19])=[O:18])=[C:14]([O:20][C@@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:30])([F:31])[F:32])[CH3:22])[CH:13]=3)[CH:10]=[N:11][C:5]=2[CH:4]=1)(=[O:43])=[O:42]
Reactant: C[C@@H](Oc1cc(-n2cnc3cc(CN)ncc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-n2cnc3cc(CNS(C)(=O)=O)ncc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Temperature: 25 °C

Procedure:
A mixture of 48.7 mg of 5-[6-(aminomethyl)-3H-imidazo[4,5-c]pyridin-3-yl]-3-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide and 26.1 mg triethylamine in 1 ml anhydrous dichloromethane is stirred at room temperature. Under nitrogen atmosphere, 14 mg methanesulfonyl chloride is added. The reaction mixture is stirred at room temperature for 14 h. The solvent is removed under pressure and the residue is purified by preparative HPLC (ammonium formate buffer/acetonitrile, elution gradient 97/3 to 0/100 (v/v)) to obtain the title product.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][N:10]=[C:9]2[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[CH:29])[CH:23]=1.[C:30]([O-:33])(=[O:32])[CH3:31].[Cs+]>CN(C=O)C>[C:30]([O:33][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][N:10]=[C:9]2[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[CH:29])[CH:23]=1)(=[O:32])[CH3:31]
Reactant: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCCl)cc23)c1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC(C)=O)cc23)c1
Yield: 183.8 %

Procedure:
The title product of Example 30 (160 mg, 0.368 mmol); was treated with cesium acetate (707 mg, 3.68 mmol) in DMF (3 mL) at 120° C. under an atmosphere of N2 for 16 hours. The reaction mixture was partitioned between brine and CHCl3, and the organic extract was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford a residue (285 mg) which was recrystallized from ethylacetate/hexane. (134 mg; M.P. 84°-87° C.; LC-MS: 422 (MH+); anal. RP18-HPLC RT: 4.38 min.).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH:19]=[C:18]2[CH2:36][C:37]2[O:41][C:40]([C:42]([O:44][CH:45]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[O:43])=[CH:39][CH:38]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(#N)C.ClC1C=CC=C(C(OO)=[O:69])C=1>C(O)(C)C>[C:15]([O:14][CH3:7])(=[O:16])[CH3:17].[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20](=[O:69])[CH2:19][C:18]=2[CH2:36][C:37]2[O:41][C:40]([C:42]([O:44][CH:45]([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[O:43])=[CH:39][CH:38]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(Cc3ccc(C(=O)OC(c4ccccc4)c4ccccc4)o3)=CS[C@H]12
Solvent: CC#N
Solvent: CC(C)O
Product: COC(C)=O
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Cc3ccc(C(=O)OC(c4ccccc4)c4ccccc4)o3)CS(=O)[C@H]12
Reaction time: 2 h

Procedure:
A solution of 2.5 g of 3-(5-diphenylmethoxycarbonylfurfuryl)-7β-phenylacetylamino-ceph-2-em-4ξ-carboxylic acid diphenylmethyl ester in 10 ml of a 1:1-mixture of acetonitrile and isopropanol is treated at 0°-5° with 0.7 g of 3-chloroperbenzoic acid and stirred for 2 hours. The reaction product is worked up as usual (see Example 71) and the crude product is purified by column chromatography (silica gel; elution with a 4:1-mixture of methylene chloride and methyl acetate), to yield the colourless, foamy 3-(5-diphenylmethoxycarbonyl-furfuryl)-7β-phenylacetylamino-ceph-3-em-4-carboxylic acid diphenylmethyl ester 1-oxide; thin-layer chromatogram (silica gel); Rf = 0.43 (system: toluene/acetone 4:1) and Rf = 0.53 (system: toluene/ethyl acetate 4:1); ultraviolet absorption spectrum (in 95% aqueous ethanol): λmax = 269-273 mμ (ε = 21000).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:6]=[CH:7][CH:8]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].CC(C)([O-])C.[K+]>CC(N(C)C)=O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][O:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COc1cccc(CCc2ccccc2O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cccc(CCc2ccccc2OCCC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 87.2 %

Procedure:
Following a procedure similar to that described in Example 40(a), 1.20 g of 2-[2-(3-methoxyphenyl) ethyl]phenol (prepared as described in Preparation 20), 2.00 g of 1-t-butoxycarbonyl-4-[2-(p-toluenesulfonyloxy)ethyl]piperidine and 0.590 g of potassium t-butoxide were reacted in 20 ml of dimethylacetamide. The mixture was then worked up as described in Example 40(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 2.00 g (yield 86%) of the title compound as a colorless oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[NH4+].[Cl-]>O1CCCC1.C(OCC)(=O)C>[CH2:23]([O:22][C:20](=[O:21])[CH:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:24]
Reactant: CCOC(=O)Cc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C(=O)c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 35.5 %

Procedure:
To 2.5 mL (0.033 mol) of diisopropylamine dissolved in 50 mL of anhydrous tetrahydrofuran at 0° C. under argon was added dropwise 11.1 mL (0.028 mol) of a 2.5 M solution of n-butyllithium in hexanes over 30 min. After the mixture was stirred at 0° C. for 20 min and cooled to −78° C., 2 mL (0.0126 mol) of ethyl phenylacetate was added followed by stirring for 30 min. The resulting solution was treated with 1.61 mL (0.014 mol) of benzoyl chloride at −78° C. After being stirred at −78° C. for 1 h, the reaction mixture was added to 10 mL of saturated NH4Cl solution. The mixture was then diluted with ethyl acetate and washed with saturated NH4Cl solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water (1×) and then with saturated aqueous sodium chloride solution (1×). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel and eluted with 5-10% ethyl acetate/hexanes to give 1.2 g (36%) of 3-oxo-2,3-diphenylpropionic acid ethyl ester.
Reaction SMILES: N1C=CC=CC=1.[Si:7]([O:14][CH2:15][CH:16]([CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[OH:17])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[C:36](Cl)(=[O:58])[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=[CH:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57].O>C1(C)C=CC=CC=1>[Si:7]([O:14][CH2:15][CH:16]([CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[O:17][C:36](=[O:58])[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=[CH:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)Cl
Reactant: CCCCCCCCCCCCCCCCOCC(O)CO[Si](C)(C)C(C)(C)C
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)OC(COCCCCCCCCCCCCCCCC)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 81.3 %

Procedure:
Anhydrous pyridine (0.15 mL) and toluene (10 mL) were added to 3a (249.0 mg, 0.578 mmol) and stirred at RT under dry argon. Docosahexaenoyl chloride (200.0 mg, 0.578 mmol) in toluene (5 mL) was then added dropwise to the reaction mixture over a period of 20 min and stirred at RT for 96 hours. The reaction mixture was poured into water (100 mL), extracted with diethyl ether (100 mL, 3×), washed successively with 0.25 M H2SO4 solution (100 mL), saturated aqueous NaHCO3 (100 mL) and water (100 mL), and dried over anhydrous Na2SO4. After removal of solvent, the crude product was chromatographed on silica gel using hexane-dichloromethane to obtain product 4a (348.4 mg, 81.4% yield). 1H NMR (in CDCl3): δ in ppm 0.89 (18H, m), 1.24 (29H, m), 1.53 (2H, m), 2.06 (2H, m), 2.40 (4H, m), 2.83 (10H, m), 3.40 (3H, m), 3.55 (2H, m), 3.71 (2H, m), 5.36 (12H, m); 13C NMR (in CDCl3): δ in ppm 14.2, 14.4, 20.7, 22.2, 25.7 (2), 25.8, 26.0, 26.1, 26.3, 29.5, 29.7, 29.8, 29.9, 32.0, 35.3, 65.4, 71.7, 72.9 (2), 127.1, 127.9, 128.0, 128.1, 128.2, 128.4, 128.5, 128.7, 129.2, 129.3, 130.1, 132.1, 168.8.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12](=[N:18]O)[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N=C=NCCCN(C)C)C.C(OCC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[NH2:18][C:12](=[N:11][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=C(O)c1ccc(F)cc1
Reactant: CCOC(=O)C(N)=NO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C(N)=NOC(=O)c1ccc(F)cc1
Yield: 88.2 %

Procedure:
To a mixture of 4-fluorobenzoic acid (2.0 g), ethyl 2-amino-2-hydroxyiminoacetate (2.07 g) and 4-dimethylaminopyridine (0.52 g) in methylene chloride (30 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.87 ml) at 0° C. under stirring. After stirring at ambient temperature for 1 hour, diethyl ether (10 ml) was added thereto and the resulting precipitate was filtered off, washed with diethyl ether, and dried in vacuo to give ethyl 2-amino-2-(4-fluorobenzoyloxyimino)acetate (3.2 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.Cl.[CH3:13]O>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: Cl
Product: COC(=O)Cc1ccc(O)cc1
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To 200 mL of methanol, was added 6.3 g of p-hydroxyphenylacetic acid. Ten droplets of concentrated hydrochloric acid was added to the resulting mixture by a Pasteur pipet and reaction proceeded at 80° C. for 1 hour. The mixture was concentrated, mixed with 100 mL of ethyl acetate, and washed twice with 50 mL of distilled water. The resultant was dried over sodium sulfate, filtered, concentrated, and dried under reduced pressure. As a result, 6.5 g (95.1%) of methyl p-hydroxyphenylacetate was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:20])[CH:16]=3)[CH:11]2[CH3:21])=[N:4][C:5]([Cl:9])=[N:6][C:7]=1[CH3:8].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[ClH:9].[CH3:1][C:2]1[C:3]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:20])[CH:16]=3)[CH:11]2[CH3:21])=[N:4][C:5]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(Cl)nc(N2CCc3cc(Cl)ccc3C2C)c1C
Reactant: Nc1ccccc1
Product: Cc1nc(Nc2ccccc2)nc(N2CCc3cc(Cl)ccc3C2C)c1C
Product: Cl
Yield: 56.7 %

Procedure:
The same procedures as in Step 2 of Example 3 above were repeated using 5,6-dimethyl-2-chloro-4-(1-methyl-6-chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine (0.1 g, 0.31 mmol) prepared in Step 1 of Example 33 and aniline (0.74 mmol) to afford 73 mg (54.3%) of the titled compound