Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:19]=[C:18]([CH2:20][CH3:21])[O:17][N:16]=3)[N:4]2[N:3]=1.ClC1C2[C:27](=[CH:28]C=CC=2)[C:26]2=NN=[C:35]([C:36]3C=C(CC)O[N:37]=3)[N:25]2N=1.ClCC1C=NC=CN=1>>[CH2:20]([C:18]1[O:17][N:16]=[C:15]([C:14]2[N:4]3[N:3]=[C:2]([O:1][CH2:28][C:27]4[CH:26]=[N:25][CH:35]=[CH:36][N:37]=4)[C:11]4[C:6]([C:5]3=[N:12][N:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:19]=1)[CH3:21]
Reactant: CCc1cc(-c2nnc3c4ccccc4c(Cl)nn23)no1
Reactant: CCc1cc(-c2nnc3c4ccccc4c(O)nn23)no1
Agent: ClCc1cnccn1
Product: CCc1cc(-c2nnc3c4ccccc4c(OCc4cnccn4)nn23)no1

Procedure:
The title-compound was prepared from 6-hydroxy-3-(5-ethylisoxazol-3-yl)-1,2,4-triazolo[3,4-a]phthalazine (prepared from 6-chloro-3-(5-ethylisoxazol-3-yl)-1,2,4-triazolo[3,4-a]phthalazine, Example 105 part c, using conditions described for the preparation of Intermediate 2) and 2-chloromethylpyrazine (prepared as described in Example 15 part a) using the procedure described in Example 15 part b, 1H NMR (360 MHz, CDCl3) δ 1.42 (3H, t, J=7.6 Hz, CH3), 2.94 (2H, q, J=7.6 Hz, CH2), 5.83 (2H, s, CH2), 6.84 (1H, s, Ar—H), 7.84 (1H, m, Ar—H), 7.98 (1H, m, Ar—H), 8.30 (1H, d, J=7.9 Hz, Ar—H), 8.60-8.64 (2H, m, 2 of Ar—H), 8.70 (1H, m, Ar—H), 9.15 (1H, d, J=1.3 Hz, Ar—H); MS (ES30) m/e 374 [MH]+; Anal. Found. C, 61.16; H, 3.79; N, 26.19. C19H15N7O2 requires C, 61.12; H, 4.05; N, 26.26%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:8][C:9](=[O:16])[C:10](=[CH:14][CH:15]=2)[C:11](O)=O)=[CH:3][CH:2]=1.S(Cl)([Cl:19])=O>CCCCCC>[ClH:19].[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:8][C:9](=[O:16])[C:10](=[CH:14][CH:15]=2)[CH2:11][Cl:19])=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(-c2ccncc2)[nH]c1=O
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Product: Cl
Product: O=c1[nH]c(-c2ccncc2)ccc1CCl

Procedure:
A mixture of 13 g. of 6-(4-pyridyl)-1,2-dihydro-2-oxonicotinic acid (U.S. Pat. No. 3,873,523) and 90 ml. of thionyl chloride is stirred at room temperature for 16 hours, then diluted with 250 ml. of hexane. The resulting precipitate of 6-(4-pyridyl)-1,2-dihydro-2-oxonicotinyl chloride hydrochloride is collected by filtration, washed with hexane and dried.
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:14][CH3:15])[C:8](=[O:13])[CH2:9][CH2:10][NH:11][CH3:12])=[CH:5][N:4]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.N1C=CC=CC=1.[F:28][C:29]([F:35])([F:34])[CH2:30][C:31](Cl)=[O:32]>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[Cl:1][C:2]1[C:6]([N:7]([CH2:14][CH3:15])[C:8](=[O:13])[CH2:9][CH2:10][N:11]([CH3:12])[C:31](=[O:32])[CH2:30][C:29]([F:35])([F:34])[F:28])=[CH:5][N:4]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1
Reactant: CCN(C(=O)CCNC)c1cn(-c2cccnc2)nc1Cl
Reactant: O=C(Cl)CC(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CCN(C(=O)CCN(C)C(=O)CC(F)(F)F)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-(methyl amino)propanamide (0.070 g, 0.23 mmol) in dry CH2Cl2 (0.76 mL) was cooled to a temperature of about 0° C. under N2. To the solution, DMAP (0.014 g, 0.11 mmol), pyridine (0.028 mL, 0.34 mmol), and 3,3,3-trifluoropropanoyl chloride (0.026 mL, 0.25 mmol) were added sequentially. The reaction was slowly warmed up to room temperature under N2, then stirred at room temperature overnight. The reaction was diluted with water (2 mL) and stirred for five minutes. Layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×2 mL). The combined organic extracts were dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0%-5% MeOH/CH2Cl2 to afford the title compound F102 as a white semi-solid (0.062 g, 63%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:13]2[N:14]=[C:15](SC)[N:16]=[CH:17][C:12]=2[CH:11]=[C:10]1[C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:21].O[O:30][S:31]([O-:33])=O.[K+].S([O-])(O[O-])(=O)=O.[K+].[K+].[C:43]([O-])(O)=O.[Na+]>C1COCC1.O.CO>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:13]2[N:14]=[C:15]([S:31]([CH3:43])(=[O:33])=[O:30])[N:16]=[CH:17][C:12]=2[CH:11]=[C:10]1[C:20]([C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)=[O:21]
Reactant: O=C([O-])O
Reactant: CSc1ncc2cc(C(=O)c3ccc(F)cc3)n(-c3c(F)cccc3F)c2n1
Reactant: O=S([O-])OO
Agent: O=S(=O)([O-])O[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ncc2cc(C(=O)c3ccc(F)cc3)n(-c3c(F)cccc3F)c2n1

Procedure:
To a solution of [7-(2,6-difluoro-phenyl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluoro-phenyl)-methanone, 3, (4.6 g, 11.5 mmol) in THF:methanol (108 mL of 1:1 mixture) is added dropwise a solution of Oxone® (potassium peroxymonosulfate) (28.4 g, 46.1 mmol) in H2O (83 mL). After stirring the reaction for 1 hour at room temperature, the solution is poured into aqueous saturated NaHCO3. The aqueous phase is extracted three times with EtOAc and the combined organic phases are dried (MgSO4), filtered and concentrated in vacuo to afford 4.5 g of the desired product which is used without further purification.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[C:23]([C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[C:29]([O:35][CH2:36][CH3:37])[CH:28]=1)([CH3:26])([CH3:25])[CH3:24].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[C:23]([C:27]1[CH:34]=[CH:33][C:30]([C:31]2[N:2]([CH3:1])[N:3]=[C:4]([C:5]3[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=3[Cl:12])[N:32]=2)=[C:29]([O:35][CH2:36][CH3:37])[CH:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CN(N=C(Cl)c1c(F)cccc1Cl)S(=O)(=O)c1ccccc1
Reactant: CCOc1cc(C(C)(C)C)ccc1C#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: CCOc1cc(C(C)(C)C)ccc1-c1nc(-c2c(F)cccc2Cl)nn1C
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 11.6 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (1.60 g), 4-t-butyl-2-ethoxybenzonitrile (1.00 g), anhydrous aluminum chloride (0.60 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, the reaction mixture is dissolved in chloroform (100 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.20 g of desired compound (melting point: 108.0°-111.0° C.).
Reaction SMILES: CN([CH:4]=[C:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10])C.[CH2:11]([SH:15])[CH2:12][CH2:13][CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:11]([S:15][CH:4]=[C:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCS
Reactant: CN(C)C=C1CCOC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCSC=C1CCOC1=O

Procedure:
A mixture of γ-butyrolactone (1 mol) and tris(dimethylamino)methane (1.5 mol) is stirred under dry nitrogen at 75° C. for 2 days to give 3-[(dimethylamino)methylene]dihydro-2(3H)-furanone. A solution containing 3-[(dimethylamino)methylene]dihydro-2(3H)-furanone (1 mol), n-butanethiol (1.1 mol) and para-toluenesulfonic acid (1 mol) in benzene is heated at reflux overnight to give upon aqueous work-up 3-[(butylthio)methylene]dihydro-2(3H)-furanone. After a solution of 3-[(butylthio)methylene]dihydro-2(3H)-furanone (1 mol) in anhydrous diethyl ether is added to a solution of lithium di-n-butylcuprate (1.1 mol) in diethyl ether at -78° C., the resulting mixture is stirred at -78° C. for an additional 0.5 hours and then quenched with methanol. Work-up affords 3-ethylidenedihydro-2(3H)-furanone. Freshly prepared W-2 Raney nickel (about 3 parts) is deactivated by refluxing in benzene for 1 hour, whereupon 3-ethylidenedihydro-2(3H)-furanone is added and the mixture is heated at reflux under nitrogen for 24-48 hours; the reaction is monitored by thin layer chromatography. After complete washing of the Raney nickel with hot benzene, the title compound is obtained.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.Cl.[CH2:14]([O:21][NH2:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:22][O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:4]
Reactant: NOCc1ccccc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccccc1C(=O)NOCc1ccccc1
Yield: 67 %

Procedure:
Reaction with isatoic anhydride: A mixture of isatoic anhydride (3.3 g, 20 mmol), O-benzylhydroxylamine hydrochloride (4.4 g, 27 mmol) and K2CO3 (6.9 g, 50 mmol) in 20 mL of DMF was stirred at rt until all the anhydride was consumed (ca. 2 days) by thin layer chromatographic analysis. The mixture was diluted with MTBE and washed with water and brine. After removal of solvent, the crude product was recrystallized from EtOAc/heptane to give 2-amino-N-benzyloxylbenzamide as a white solid (3.25 g, 67% yield).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:37])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:37])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[CH:31]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(Cl)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(Cl)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (5-chloro-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M75) (0.34 g, 0.62 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (222 mg, 83%).
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1.CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:19]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCCCCCCCCCO
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCCCCCCCCCO)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.4 %

Procedure:
To a stirred solution of 51.2 grams (0.320 mole) of 1,9-nonanediol in 500 ml of tetrahydrofuran was added one crystal of p-dimethylaminopyridine, and then 8.9 grams (0.088 mole) of triethylamine was added. To this mixture was added dropwise a solution of 11.2 grams (0.08 mole) of benzoyl chloride in 40 ml of methylene chloride. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to a residue. The residue was dissolved in 200 ml of methylene chloride and was washed with five 75 ml portions of water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. Volatile materials were removed by distillation leaving 11.5 grams of 9-hydroxynonyl benzoate. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Na].[CH2:2]1[O:12][C:11]2[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][C:4]=2[O:3]1.[Br:13][CH2:14][C:15]([CH3:19])=[CH:16][CH2:17]Br>COCCOC>[Br:13][CH2:14][C:15]([CH3:19])=[CH:16][CH2:17][O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:11]2[O:12][CH2:2][O:3][C:4]=2[CH:5]=1
Reactant: CC(=CCBr)CBr
Reactant: OCc1ccc2c(c1)OCO2
Agent: [Na]
Solvent: COCCOC
Product: CC(=CCOCc1ccc2c(c1)OCO2)CBr
Reaction time: 0.25 h

Procedure:
8.7 g (0.05 mol) of sodium salt of the 3,4-methylendioxybenzylalcohol are added at 0° during the course of 15 minutes and while stirring to 12.5 g (0.055 mol) of 1,4-dibromo-2-methyl-2-butene which is dissolved in 100 cc of 1,2-dimethoxyethane. The mixture is stirred at 20°-25° for 16 hours and at 50° for 15 minutes. The solvent is then distilled off at reduced pressure and 100 cc amounts of water and ether are added to the residue. The aqueous phase is separated in a separatory funnel, the ether phase is extracted with saturated salt solution, is dried with sodium sulphate and evaporated. The residue is chromatographed on silica gel with hexane/ethyl acetate 9:1, whereby the 5-[(4-bromo-3-methyl-2-butenyloxy)-methyl]-1,3-benzodioxol is obtained as uniform colourless oil.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:6])#[N:2].C(S)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:6])#[N:2]
Reactant: SCCc1ccccc1
Reactant: CSc1ccc(S(=O)(=O)C[C@@H]2CCCC[C@H]2C(=O)NCC#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCNC(=O)[C@@H]1CCCC[C@H]1CS(=O)(=O)c1ccc(SCCc2ccccc2)cc1
Temperature: 100 °C

Procedure:
A mixture of trans-N-cyanomethyl-2-(4-methylsulfanylbenzenesulfonylmethyl)-cyclohexanecarboxamide (0.1 g, 0.298 mmol), phenethyl mercaptan (0.103 mL, 0.764 mmol) and cesium carbonate (0.25 g, 0.764 mmol) was dissolved in dimethylformamide (1.5 mL) and heated at 100° C. for 4 h. The reaction mixture was diluted with ethyl acetate (30 mL), filtered through Celite, evaporated to dryness, and purified on a short plug of silica gel (2040% ethyl acetate/CHCl3), yielding the desired product. NMR (DMSO-d6): 1.1 (3H, m); 1.3 (1H, m) 1.6-1.7 (3H, m); 2.03 (2H, m); 2.16 (1H, d): 2.92 (3H, m); 3.15 (1H, dd); 3.36 (2H, m); 4.03 (2H, d); 7.1 (1H, d); 7.25 (4H, m); 7.47 (2H, d); 7.68 (2H, d); 8.56 (1H, t). MS [ESI, (M+Na)+] m/z=479 amu.
Reaction SMILES: [CH2:1]([N:8](C)[C@H:9]([C:11]([C@:13]([CH3:23])([OH:22])[C:14]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15])=[O:12])[CH3:10])C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2].[C]>[CH3:1][NH:8][C@H:9]([C:11]([C@:13]([CH3:23])([OH:22])[C:14]([N:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)=[O:15])=[O:12])[CH3:10]
Reactant: C[C@@H](C(=O)[C@](C)(O)C(=O)N1CCCCC1)N(C)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CN[C@@H](C)C(=O)[C@](C)(O)C(=O)N1CCCCC1
Yield: 100 %

Procedure:
3.3 g (9.9 mmol) of N-benzyl-N-methyl-L-alanyl-D-lactic acid piperidide are hydrogenated in 100 ml of ethanol in the presence of 0.35 g of Pd(OH)2-carbon [20% Pd content] until absorption of hydrogen is complete (about 4 hours). After filtering off the catalyst, the entire reaction solution is concentrated in vacuo. 2.4 g (100% of theory) of N-methyl-L-alanyl-D-lactic acid piperidide are obtained.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH:12](OCC)(OCC)[O:13][CH2:14][CH3:15].C(OC(=O)C)(=O)C>>[C:1]([C:6](=[CH:12][O:13][CH2:14][CH3:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)C(C)C

Procedure:
A mixture of ethyl isobutyrylacetate (60.5 g, 0.38 mol), triethyl orthoformate (126 ml, 0.76 mol) and acetic anhydride (36 ml, 0.38 mol) was heated at reflux for 24 hours, then the volatile components removed in vacuo, finally at 100°/0.5 mm. The residue consisted mainly of ethyl 2-isobutyryl-3-ethoxyacrylate as a mixture of E/Z isomers, and was used without further purification.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([C:16]2[C:17]([CH3:32])=[N:18][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)[CH3:15])=[CH:9][C:8]=1[CH3:33])C.ClC(C1C(C)=NC(C2C=CC(C(F)(F)F)=CC=2)=CC=1)C.ClC(C1C(C)=NC(C2C=CC(C(F)(F)F)=CC=2)=CC=1)CC>>[CH3:33][C:8]1[CH:9]=[C:10]([O:13][CH:14]([C:16]2[C:17]([CH3:32])=[N:18][C:19]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[CH3:15])[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:34])=[O:3]
Reactant: CCOC(=O)COc1ccc(OC(C)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: CCC(Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(C)Cl
Product: Cc1cc(OC(C)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCC(=O)O

Procedure:
A] The title compound was prepared in analogy to example 49, via [rac]-(2-methyl-4-{1-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-phenoxy)-acetic acid ethyl ester, but using in step A] [rac]-3-(1-chloro-ethyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example 17C]) instead of [rac]-3-(1-chloro-propyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine as off-white foam.
Reaction SMILES: BrC1N(C)N=CC=1[C:8](O)=[O:9].[NH:11]1[CH:20]2[CH:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:14][CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl.CN(C)C=O>[N:11]1([CH:8]=[O:9])[CH:20]2[CH:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:14][CH2:13][CH2:12]1
Reactant: Cn1ncc(C(=O)O)c1Br
Reactant: C1CCC2NCCCC2C1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=CN1CCCC2CCCCC21
Temperature: 25 °C
Reaction time: 8 h
Yield: 159.6 %

Procedure:
5-Bromo-1-methyl-1H-pyrazole-4-carboxylic acid (29.6 mmol), decahydro-quinoline (Aldrich Chemical Company, Inc., Milwaukee, Wis.; 4.9 g, 35.5 mmol), diisopropylethylamine (11 mL, 59.2 mmol), and PyBrop (bromo-tris-pyrrolidino-phophonium hexafluorophosphate) (Chem-Impex International, Inc., Wood Dale, Ill.; 16.6 g, 35.5 mmol) were mixed together in dry dichloromethane (70 mL) and dry dimethylformamide (20 mL). The mixture was stirred overnight at room temperature. At this time, the mixture was diluted with dichloromethane and extracted three times with water. The combined dichloromethane extracts were evaporated, and the residue was purified by flash chromatography, eluting with 0-10% ethyl acetate/hexanes to give 5-bromo-1-methyl-1H-pyrazol-4-yl)-(octahydro-quinolin-1-yl)-methanone (7.9 g, 82% yield).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10](/[C:13](/[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([O:28][CH3:29])[N:22]=2)=[CH:14]\[C@@H:15]2[NH:19][C:18](=[O:20])[CH2:17][CH2:16]2)=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[CH3:30]I.O>O1CCCC1.C(OCC)(=O)C>[C:3]([C:7]1[CH:8]=[CH:9][C:10](/[C:13](/[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([O:28][CH3:29])[N:22]=2)=[CH:14]\[C@@H:15]2[N:19]([CH3:30])[C:18](=[O:20])[CH2:17][CH2:16]2)=[CH:11][CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)ccc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(/C(=C/[C@H]2CCC(=O)N2C)c2ccc(C(C)(C)C)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
60% sodium hydride (27 mg) was added to a solution of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(5-chloro-6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one (185 mg) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 20 minutes. Methyl iodide (60 μL) was then added and the mixture was stirred at room temperature for 4.5 hours. Water and ethyl acetate were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, after which the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (hexane:ethyl acetate=80:20) to give (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(5-chloro-6-methoxypyridin-2-yl)ethenyl]-1-methylpyrrolidin-2-one as a colorless powder (180 mg).
Reaction SMILES: [CH:1]1([N:7]2[CH2:15][C:14]3[C:9](=[CH:10][C:11]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)=[CH:12][CH:13]=3)[C:8]2=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:23]([N:19]1[CH2:18][CH2:17][N:16]([C:11]2[CH:10]=[C:9]3[C:14]([CH2:15][N:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[C:8]3=[O:22])=[CH:13][CH:12]=2)[CH2:21][CH2:20]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1c2cc(N3CCNCC3)ccc2CN1C1CCCCC1
Product: O=C(c1ccccc1)N1CCN(c2ccc3c(c2)C(=O)N(C2CCCCC2)C3)CC1

Procedure:
In the same manner as in Example 28, the title compound was prepared from the compound obtained in step (e) of Example 1 and benzoyl chloride.
Reaction SMILES: C([O:4][CH:5]([C:7]1[CH:8]=[N:9][C:10]([C:17]2[NH:18][C:19](=[O:26])[C:20]([CH:23]([CH3:25])[CH3:24])([CH3:22])[N:21]=2)=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13])[CH3:6])(=O)C.C[O-].[Na+].C(O)(=O)C>CO>[OH:4][CH:5]([C:7]1[CH:8]=[N:9][C:10]([C:17]2[NH:18][C:19](=[O:26])[C:20]([CH:23]([CH3:25])[CH3:24])([CH3:22])[N:21]=2)=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13])[CH3:6]
Reactant: COC(=O)c1cc(C(C)OC(C)=O)cnc1C1=NC(C)(C(C)C)C(=O)N1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(C(C)O)cnc1C1=NC(C)(C(C)C)C(=O)N1

Procedure:
A solution of 16 g of methyl 5-(1-acetoxyethyl)-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinate and 0.5 g sodium methoxide in 150 mL methanol is stirred at room temperature under nitrogen for 5 days. The reaction is acidified to pH 5 with acetic acid and concentrated in vacuo. The residue is partitioned between methylene chloride and water, the aqueous layer is further extracted with methylene chloride, and the combined organic phases are dried over sodium sulfate and concentrated in vacuo to an orange oil. Column chromatography of this oil using ether-hexane as eluent affords the desired product as a white foam.
Reaction SMILES: [O-:1][OH:2].[C:3]1([CH:9]([CH3:11])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:12][CH:13]([CH3:22])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20]O)[CH:15]=1.C1(C(C)C)C=CC=CC=1>>[C:9]([O:1][O:2][C:15]1[C:16]([CH3:20])=[CH:17][CH:18]=[CH:19][C:14]=1[CH:13]([CH3:22])[CH3:12])([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)([CH3:11])[CH3:10]
Reactant: CC(C)c1cccc(CO)c1
Reactant: CC(C)c1ccccc1
Reactant: [O-]O
Product: Cc1cccc(C(C)C)c1OOC(C)(C)c1ccccc1
Reaction time: 3 h
Yield: 90 %

Procedure:
To a mixture of 76 g (0.5 mole) of cumene hydroperoxide, 75 g (0.5 mole) of α,α-dimethyl-m-tolylcarbinol and 15 g of cumene was added 2 g of synthetic silica-alumina, and reaction was carried out at 60° C. for 3 hours while blowing nitrogen, to obtain cumyl-m-cymylperoxide in a yield of 90%.