Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Br[C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH:23]=1)[C:19]([O:21][CH3:22])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C.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>[CH3:22][O:21][C:19](=[O:20])[C:18]1[CH:23]=[C:14]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=2)[CH:15]=[N:16][CH:17]=1
Reactant: COc1ccc(B(O)O)cc1Cl
Reactant: COC(=O)c1cncc(Br)c1
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: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cncc(-c2ccc(OC)c(Cl)c2)c1
Yield: 37.3 %

Procedure:
6.5 g of 3-chloro-4-methoxyphenylboronic acid, 5.0 g of methyl 5-bromonicotinate, 1.3 g of tetrakis(triphenylphosphine)palladium(0), and 22.6 g of Cs2CO3 were stirred in 325 ml of DMF and 65 ml of water for 3 h at 45° C. The reaction mixture was then poured into 750 ml of water and extracted three times using 300 ml of EA each. The combined organic layers were then washed twice using 150 ml of water each. The organic layer was then dried using MgSO4 and evaporated. Chromatography on silica gel using EA/HEP (gradient) yielded 2.4 g of the title compound, colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[CH:13]1[CH:14]=[CH:15][C:16]([C@H:19]2O[C@@H:20]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:18]=1.B(F)(F)F.CCOCC>O1CCOCC1>[C:16]1([C:19]([C:3]2[C:4](=[O:12])[O:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:20][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=c1oc2ccccc2c(O)c1C(=Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a flame-dried flask containing a mixture of 650 mg of 4-hydroxycoumarin and 1.0 g of commercially available trans-stilbene oxide in 20 mL of dioxane under an argon atmosphere is added 2.5 mL of boron trifluoride etherate. The resulting yellow solution is left to stir at room temperature overnight. The volatiles are removed and the residue is partioned between diethyl ether and 1N sodium hydroxide. The basic aqueous phase is washed with diethyl ether and acidified to pH=1 with 6N hydrochloric acid. The resulting precipitant is repeatedly extracted with dichloromethane (methanol-chloroform co-solvents). The combined dichloromethane extracts are washed once with dilute sodium bicarbonate to remove most of the unreacted 4-hydroxycoumarin, then brine, dried (magnesium sulfate), and finally concentrated under reduced pressure. The residue is flash column chromatographed with 50% to 66% ethyl acetate in hexane to yield 880 mg of the title product as a white solid.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][N:6](C(OCC2C=CC=CC=2)=O)[CH:5]([C:18]2([O:21][CH3:22])[CH2:20][CH2:19]2)[CH2:4]1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][CH:3]1[CH2:7][NH:6][CH:5]([C:18]2([O:21][CH3:22])[CH2:20][CH2:19]2)[CH2:4]1
Reactant: [H][H]
Reactant: COC1CC(C2(OC)CC2)N(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC1CNC(C2(OC)CC2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To benzyl 4-methoxy-2-(1-methoxycyclopropyl)pyrrolidine-1-carboxylate (141 mg, 0.462 mmol) dissolved in ethyl acetate (3.1 mL) was added palladium on carbon (49.1 mg, 0.05 mmol). Hydrogen gas was added via balloon and the reaction was stirred at room temperature for 3 hours. The mixture was filtered over celite and concentrated under reduced pressure to afford 4-methoxy-2-(1-methoxycyclopropyl)pyrrolidine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][N:13]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Li+].CC([N-]C(C)C)C.CN([CH:34]=[O:35])C>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH:34]=[O:35])[N:13]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc([N+](=O)[O-])cc2)c1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: C[Si](C)(C)CCOCn1cc(-c2ccc([N+](=O)[O-])cc2)nc1C=O
Yield: 29.9 %

Procedure:
Reaction of 4-(4-nitro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (170 mg, 0.53 mmol), 0.53 M LDA (1 mL, 0.53 mmol), and DMF (232 uL, 1.60 mmol) for 4 h at −40° C. followed by column chromatography on silica gel (EtOAc/hexane 9:1) gave the title compound (55 mg, 30%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ0.00 (s, 9H), 0.95 (t, 2H, J=9.0 Hz), 3.63 (t, 2H, J=9.0 Hz), 5.82 (s, 2H), 7.79 (s, 1H), 7.98 (d, 2H, J=9.0 Hz), 8.27 (d, 2H, J=9 Hz), 9.89 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([NH:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])(=[O:25])=[O:24]
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(NS(C)(=O)=O)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of dimethyl 5-aminoisophthalate (2.09 g, 10 mmol) in dichloromethane (30 mL), pyridine (2.43 mL, 30 mmol) was added at room temperature. At 0° C., methanesulfonyl chloride (0.86 mL, 11 mmol) was added and the resulting mixture was stirred overnight at room temperature. The reaction mixture was then concentrated under reduced pressure and ethyl acetate (50 mL) was added. The resulting white precipitate was filtered and washed with hexanes to give dimethyl 5-(methylsulfonamido)isophthalate in 95% (2.715 g) yield as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4](OCC)=[O:5].C(O)(=O)C.[CH:17](N)=[NH:18]>COC(O)C>[N:1]1[C:2]2[C:3](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:4]([OH:5])=[N:18][CH:17]=1
Reactant: CCOC(=O)c1ccccc1N
Reactant: N=CN
Agent: COC(C)O
Solvent: CC(=O)O
Product: Oc1ncnc2ccccc12
Yield: 110.4 %

Procedure:
A solution of ethyl 2-aminobenzoate (5.0 g, 30 mmol) in methoxyethanol (20 mL) was treated with formamidine acetate (8 g, 77 mmol) under reflux for 17 h. A second portion of formamidine acetate (8 g, 77 mmol) was then added, and the reflux was continued for 7 more hours. The mixture was cooled, and the solvent was removed under vacuum. The residue was taken in saturated NaHCO3 and extracted with ethyl acetate. The organic layers were combined, washed with saturated NaHCO3, and dried with magnesium sulfate, and the solvent was removed under vacuum to give the desired compound (4.84 g, 91%), which was used for the next step without further purification. LC-MS: m/z 147.7 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[N:15]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:35])[O:32][CH2:33][CH3:34]>O1CCCC1>[CH2:33]([O:32][C:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[N:15]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1)=[O:35])[CH3:34]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3ccc(N)cc3)cs2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Nc1ccc(-c2csc(Cn3cc(C(=O)OCC)cn3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
In an ice-bath, to a solution (4 mL) of the crude compound (0.84 mmol) obtained in Example 36b in tetrahydrofuran were added triethylamine (0.15 ml, 1.1 mmol) and ethyl chlorocarbonate (79 ml, 1.0 mmol), and the mixture was stirred at room temperature overnight. After confirmation of the termination of the reaction by TLC, the resulting salt was removed. The solvent was evaporated under reduced pressure. The resulting crude title compound was recrystallized (hexane-ethyl acetate) to give the title compound (180 mg, 54% in 2 steps) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][NH2:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:13](=O)C1C=CC=CC=1.CI>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][NH:12][CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(CN)cc1OC
Solvent: CCO
Solvent: CI
Product: CNCc1ccc(OC)c(OC)c1
Yield: 63.7 %

Procedure:
3,4-Dimethoxybenzenemethanamine (100 g) was mixed with benzaldehyde (64 g), and rotoevaporated to give an oil. Methyl iodide (75 ml) was then added and the mixture was heated for 48 h at 40° and then boiled with 80% ethanol (800 ml) for 3 h. After half of the ethanol had evaporated, the solution was treated with ether (1 liter) to give a solid that was filtered, washed with ether, treated with dilute sodium hydroxide and extracted with ether to give the title compound (69 g) as an oil that was distilled under reduced pressure, b.p. 0.03 mm; 91°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:13][C:14](=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1>>[F:1][C:2]1[CH:3]=[C:4]([NH:13][C:14](=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:27]3[CH:28]=[N:23][CH:24]=[N:25][CH:26]=3)[CH:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10]
Reactant: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cccc(I)c1
Reactant: OB(O)c1cncnc1
Product: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cccc(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described infashion to that described in Example 1 using N-(3-fluoro-4-(trifluoromethoxy)phenyl)-3-iodobenzamide (Stage 9.1) and pyrimidin-5-ylboronic acid to afford the title compound as a white solid. UPLC-MS (Condition 1) tR=2.63 min, m/z=378.0 [M+H]+, m/z=376.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.56-7.64 (m, 1H) 7.66 (dd, J=9.0, 1.2 Hz, 1H) 7.70-7.76 (m, 1H) 7.97-8.11 (m, 3H) 8.36 (s, 1H) 9.25 (s, 1H) 9.26 (s, 2H) 10.67 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[NH:16][N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:28][C:27]([F:29])([F:30])[C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:16]2[C:15](=[O:18])[N:4]3[CH:5]=[CH:6][C:7]([C:8]4[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=4)=[C:2]([Cl:1])[C:3]3=[N:17]2)=[CH:22][CH:23]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: Cc1ccc(-c2ccn3c(=O)[nH]nc3c2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(-c2ccn3c(=O)n(Cc4ccc(C(F)(F)F)cc4)nc3c2Cl)cc1
Temperature: 25 °C
Yield: 62.6 %

Procedure:
To a stirred solution of 8-chloro-7-p-tolyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (100 mg, 0.39 mmol) in acetone (10 mL) at room temperature under argon was added 1-(bromomethyl)-4-(trifluoromethyl)benzene (111 mg, 0.46 mmol), followed by K2CO3 (107 mg, 0.77 mmol). The resulting suspension was heated at reflux overnight. Analysis by HPLC/MS indicated that starting material had been consumed. After cooling the reaction mixture to room temperature, most of the solvent was removed under reduced pressure. Water (15 mL) and EtOAc (15 mL) were added. The layers were separated. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by automated silica gel chromatography (eluted with ethyl acetate-hexanes) to obtain 102 mg of the title compound as a white solid. HPLC/MS: retention time=4.03 min, [M+H]+=418. 1H NMR (CDCl3): δ 7.77 (d, J=7.0 Hz, 1H), 7.61-7.45 (m, 4H), 7.38 (d, J=8.1 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H), 6.58 (d, J=7.0 Hz, 1H), 5.31 (s, 2H), 2.46 (s, 3H). N-alkylation, rather than O-alkylation, was demonstrated by the presence of a 13C NMR resonance at 49.6 ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14]C2CCCCO2)=[CH:6][C:5]=1[CH:21]=[C:22]1[NH:26][C:25](=[O:27])[NH:24][C:23]1=O)([O-])=O.CO.II>CN(C)C=O.[Pd]>[OH:14][CH2:13][CH2:12][CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]2[N:1]=[C:23]3[NH:24][C:25](=[O:27])[NH:26][C:22]3=[CH:21][C:5]=2[CH:6]=1
Reactant: O=C1NC(=O)C(=Cc2cc(OCCCOC3CCCCO3)ccc2[N+](=O)[O-])N1
Agent: [Pd]
Agent: II
Solvent: CO
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc3cc(OCCCO)ccc3nc2[nH]1
Reaction time: 23 h
Yield: 33.2 %

Procedure:
A solution of 5-[[2-nitro-5-[3-[(tetrahydro-2H-pyran-2-yl)oxy]propoxy]phenyl]methylene]-2,4-imidazolidinedione (19.14 g, 49 mmol) in dimethylformamide (150 mL) was hydrogenated over 10% palladium on charcoal (2 g) at 55 p.s.i. in a low pressure hydrogenation apparatus. After 23 hours, the mixture was filtered through kieselguhr and concentrated in vacuo. The resultant yellow solid was dissolved in refluxing methanol (300 mL) and iodine (11.74 g, 49 mmol) added portionwise. After 15 minutes, the mixture was concentrated to dryness and the residue diluted with 10% sodium thiosulfate solution and 10% sodium carbonate solution. The solid was filtered off, washed with water and dried in air. Crystallization from aqueous dimethylformamide afforded 1,3-dihydro-7-(3-hydroxypropoxy)-2H-imidazo[4,5-b]quinolin-2-one (4.22 g, 33%), m.p. 343°-345° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[C:20]([O:27][CH3:28])(=[O:26])[CH2:21][C:22]([O:24][CH3:25])=[O:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:21]([C:20]([O:27][CH3:28])=[O:26])[C:22]([O:24][CH3:25])=[O:23])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH3:19])=[CH:16][CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: CCc1ccc(C(=O)C=Cc2ccc(Cl)cc2)cc1
Reactant: COC(=O)CC(=O)OC
Product: CCc1ccc(C(=O)CC(c2ccc(Cl)cc2)C(C(=O)OC)C(=O)OC)cc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 3-(4-chlorophenyl)-1-(4-ethylphenyl)prop-2-en-1-one and dimethyl malonate, dimethyl 2-(1-(4-chlorophenyl)-3-(4-ethylphenyl)-3-oxopropyl)malonate was obtained as pale yellowish solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[C:18]=4[CH3:24])=[N:15][N:14]=[C:13]([C:25]([O:27]C)=O)[C:9]=3[NH:10][C:11]=2[CH:12]=1)(=[O:3])[CH3:2].[NH3:29].CO>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[C:18]=4[CH3:24])=[N:15][N:14]=[C:13]([C:25]([NH2:29])=[O:27])[C:9]=3[NH:10][C:11]=2[CH:12]=1)(=[O:3])[CH3:2]
Reactant: N
Reactant: COC(=O)c1nnc(-c2cccc(N)c2C)c2c1[nH]c1cc(C(C)=O)ccc12
Solvent: CO
Product: CC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)nnc(-c3cccc(N)c3C)c12
Temperature: 100 °C

Procedure:
A mixture of methyl 7-acetyl-1-(3-amino-2-methylphenyl)-5H-pyridazino[4,5-b]indole-4-carboxylate (0.520 g, 1.389 mmol) and ammonia in methanol (30 ml, 210 mmol) was heated in a sealed bottle at 100° C. for 2 hr. Removal of the volatiles under vacuum gave a crude product (0.501 g) as a tan solid. This crude was 82% pure, but was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[C:9]([O:11]C)=O.[NH2:13][C:14]1[NH:18][N:17]=[CH:16][CH:15]=1>C(O)(=O)C>[Cl:8][C:6]1[N:5]=[CH:4][C:3]2[C:9](=[O:11])[N:18]3[N:17]=[CH:16][CH:15]=[C:14]3[NH:13][C:2]=2[CH:7]=1
Reactant: COC(=O)c1cnc(Cl)cc1Cl
Reactant: Nc1ccn[nH]1
Solvent: CC(=O)O
Product: O=c1c2cnc(Cl)cc2[nH]c2ccnn12

Procedure:
205 g. of 4,6-dichloropyridine-3-carboxylic acid, methyl ester and 166 g. of 5-aminopyrazole are refluxed together in 300 ml. of acetic acid for 10 hours with stirring. The crystalline 6-chloropyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one is filtered off, washed with water and recrystallized from dimethylformamide, yield: 185 g. (84%); m.p. > 300°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[O:22][CH2:23][C:24]([CH3:27])([CH3:26])[N:25]=1>>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[O:22][CH2:23][C:24]([CH3:27])([CH3:26])[N:25]=2)([OH:13])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)COC(c2ccccc2Br)=N1
Reactant: O=C1CCN(Cc2ccccc2)C1
Product: CC1(C)COC(c2ccccc2C2(O)CCN(Cc3ccccc3)C2)=N1

Procedure:
Reaction of 1-benzyl-3-pyrrolidone and 2-(2-bromophenyl)-4,4-dimethyl-2-oxazoline by the method described in Example 1c provides 1-benzyl-3-[2-(4,4-dimethyl-2-oxazolin-2-yl)phenyl]-3-hydroxypyrrolidine as an oil.
Reaction SMILES: [CH3:1][O:2][CH:3](Cl)[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].C(=O)([O-])[O-:15].[Na+].[Na+].CN1CCCC1=O>O>[CH3:1][O:2][CH:3]([OH:15])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: COC(Cl)C(=O)Nc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(O)C(=O)Nc1ccccc1
Yield: 70 %

Procedure:
In a 250 ml flask, 10 g (0.05 mol) of 2-methoxy-chloroacetanilide (prepared from chloroacetyl chloride and 2-methoxyaniline) and 6 g (0.55 mol) of sodium carbonate are heated at 100° C. in a solvent mixture of 100 ml of N-methylpyrrolidone and 70 ml of water. A GC check after a reaction time of 6 hours reveals a yield of 70% of 2-methoxy-hydroxyacetanilide and 5.5% of 2-methoxydiglycolanilide.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7](/[CH:11]=[CH:12]/[CH2:13][C@H:14](O)[CH3:15])[CH:8]=[N:9][CH:10]=1)([CH3:3])[CH3:2].[CH3:17][NH2:18]>C(O)C>[CH3:17][NH:18][C@H:14]([CH2:13]/[CH:12]=[CH:11]/[C:7]1[CH:8]=[N:9][CH:10]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=1)[CH3:15]
Reactant: CN
Reactant: CC(C)Oc1cncc(/C=C/C[C@@H](C)O)c1
Solvent: CCO
Product: CN[C@@H](C)C/C=C/c1cncc(OC(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31 %

Procedure:
A mixture of (2R)-(4E)-5-(5-isopropoxy-3-pyridyl)-4-penten-2-ol ptoluenesulfonate (11.00 g, 29.33 mmol), methylamine (200 mL, 40% solution in water), and ethyl alcohol (10 mL) was stirred at ambient temperature for 18 h. The resulting solution was extracted with chloroform (3×100 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product was purified by column chromatography over aluminum oxide, eluting with ethyl acetate-methanol (7:3, v/v). Selected fractions were combined and concentrated by rotary evaporation, producing an oil. Further purification by vacuum distillation furnished 2.10 g (31.0%) of a colorless oil, bp 90-100° C. at 0.5 mm Hg.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][CH2:33][CH2:34][OH:35].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:32][CH2:33][CH2:34][OH:35])=[O:5]
Reactant: NCCO
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NCCO)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 21.7 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 130 mg, 0.3 mmol) was dissolved in DMF (2 mL) and cooled to 0° C. prior to the addition of 2-aminoethanol (27.6 mg, 0.452 mmol), 4-methylmorpholine (0.133 mL, 1.206 mmol), and HATU (149 mg, 0.392 mmol). This was stirred overnight and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 15 mL/min, 220 nM, product retention=33.8 min) to give (R/S)-2-hydroxy-N-(2-hydroxyethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (34 mg, 0.065 mmol, 21.3% yield): LCMS [M+H]+=475.1; 1H NMR (400 MHz, methanol-d4) δ ppm 8.16 (2 H, dd, J=8.35, 4.39 Hz), 7.64-7.77 (4 H, m), 7.47-7.64 (3 H, m), 5.10-5.21 (1 H, m), 4.46 (2 H, t, J=5.49 Hz), 3.55-3.69 (2 H, m), 3.37 (1 H, m). HPLC Peak RT=8.6 min (Analytical Method A).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][OH:11])/[CH3:8])[CH3:3].[CH3:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][C:31](O)=[O:32].CCCCCC>C(CC(C)(C)C)(C)C>[C:31]([O:11][CH2:10]/[CH:9]=[C:7](/[CH2:6][CH2:5][CH:4]=[C:2]([CH3:1])[CH3:3])\[CH3:8])(=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Solvent: CCCCCC
Solvent: CC(C)CC(C)(C)C
Product: CCCCCCCCCC=CC=CC=CC=CC=CC(=O)OC/C=C(\C)CCC=C(C)C
Temperature: 60 °C
Reaction time: 24 h

Procedure:
There were dissolved, in 1 g of isooctane, 100 mg of geraniol and 900 mg of ethyl ester of eicosapentaenoic acid, followed by the addition of lipase in an amount of 1% relative to the total amount of the resulting solution and then stirring the mixture at 60° C. for 24 hours. After confirming whether the reaction system reached its equilibrium state or not by the GC technique, the reaction solution was diluted by the addition of hexane to the solution in an amount of 10 times the volume thereof, followed by the removal of the lipase from the reaction solution through filtration and then the removal of the hexane through distillation to thus give a crude reaction product. The crude product was purified by silica gel column chromatography to give 122 mg of geranyl eicosapentaenoate.
Reaction SMILES: [O:1]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:13].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[OH:20][C:14]1[CH:19]=[CH:18][C:17]([C:2](=[O:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:1])=[O:12])=[CH:16][CH:15]=1
Reactant: O=C1CCCCCCCCC(=O)O1
Reactant: Oc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C(O)CCCCCCCCC(=O)c1ccc(O)cc1
Reaction time: 72 h

Procedure:
To a 500 mL flask, equipped with mechanical stirrer and under inert atmosphere, was added Oxacycloundecane-2,11-dione (20 g, 108.5 mmol), phenol (10.22 g, 108.5 mmol), and 200 mL carbon disulfide. Aluminum (III) trichloride (72.34 g, 542 mmol) was added and the reaction was stirred for 72 hours. Carbon disulfide was decanted away, and ice was carefully added until most of mixture was dissolved. The insoluble material was collect by suction filtration and washed with 2×100 mL of water. The solid was then dissolved in 100 mL of 1 M aqueous sodium hydroxide and then carefully acidified with 1 M aqueous hydrochloric acid until pH=7.5 The solids that formed were removed by filtration and the parent solution was continued to be acidified until pH 2.5. The crude product precipitate was collected by filtration and was washed with 1×100 mL water. The crude product was dissolved in 100 mL of 1 M aqueous sodium hydroxide and then carefully acidified with 1 M aqueous hydrochloric acid until pH=7.5 and the impurities that precipitated were filtered off. The parent solution was further acidified until pH 2. The crude product was collected by filtration and washed with 2×50 mL water. The product was recrystallized form acetone. The isolated product (1.2 g, 4%) was collected by filtration. Found: C, 69.00; H, 7.81%; C16H22O4 requires C, 69.04; H, 7.97%; 1H NMR (d6-DMSO): δ 12.0, bs, 1H (COOH); δ 10.3, bs, 1H (aryl-hydroxyl); δ 7.8 d, 2H (aryl H's); δ 6.8, d, 2H, (aryl H's); δ 2.9, t, 2H (CH2 α to carbonyl); δ 2.2, t, 2H (CH2 α to COOH); δ 1.5, multiplet, 4H (CH2's β to carbonyl & β to COOH), δ 1.3, multiplet, 8H (rest of CH2's).