Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[CH:14]([N:12]([CH3:13])[C:11]1[C:2]([C:27]2[CH:26]=[CH:25][C:24]([O:23][C:22]([F:21])([F:33])[F:34])=[CH:29][CH:28]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2)([CH3:16])[CH3:15]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc(OC(F)(F)F)cc3)c(N(C)C(C)C)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (200 mg, 0.68 mmol, 1.00 equiv), 4-(trifluoromethoxy)phenylboronic acid (280 mg, 1.36 mmol, 1.99 equiv), Pd(PPh3)4 (157 mg, 0.14 mmol, 0.20 equiv), K3PO4 (577 mg, 2.73 mmol, 4.01 equiv), 1,4-dioxane (4 mL). The resulting solution was stirred for overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:40). This resulted in 120 mg (42%) of methyl 3-(isopropyl(methyl)amino)-2-(4-(trifluoromethoxy)phenyl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][N:18]3C(=O)C4C(=CC=CC=4)C3=O)[C:11]=2[S:10][C:9]=1[NH2:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][NH2:18])[C:11]=2[S:10][C:9]=1[NH2:29])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2CN
Yield: 72.8 %

Procedure:
To a mixture of 2-amino-7-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (6.0 g, 0.014 mol) in ethanol (100 ml) was added hydrazine hydrate (1.4 ml, 0.028 mol). The reaction mixture was heated at reflux for 1 h, cooled and the precipitate filtered off. The filtrate was evaporated in vacuo and to the residue was added water (100 ml) and the resulting mixture was extracted with diethyl ether (2×100 ml). The combined organic extracts were washed with brine (100 ml), dried (Na2SO4), filtered and the solvent evaporated in vacuo affording 2.9 g (71%) of 2-amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: Br[C:2]1[C:3]([NH:8][C:9](=[O:11])[CH3:10])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:12]([Sn](CCCC)(CCCC)C=C)[CH2:13]CC>C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:12]([C:2]1[C:3]([NH:8][C:9](=[O:11])[CH3:10])=[N:4][CH:5]=[CH:6][CH:7]=1)=[CH2:13]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(=O)Nc1ncccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=Cc1cccnc1NC(C)=O
Temperature: 95 °C
Yield: 46.4 %

Procedure:
To a stirred mixture of N-(3-Bromo-pyridin-2-yl)-acetamide (1.20 g, 5.58 mmol) in anhydrous toluene (40 mL) under argon was added Tri-n-butyl(vinyl)tin (3.25 mL, 11.1 mmol) and Bis(triphenylphosphine)Palladium dichloride (0.40g, 0.57 mmol). This mixture was heated at 95° C. for 30 minutes and cooled to room temperature. This mixture was then diluted with saturated NaHCO3 solution (100 mL) and extracted with EtOAc (3×120 mL). The combined EtOAc extracts were dried (MgSO4), filtered and concentrated in vacuo. This was purified by a ISCO auto CombiFlash with a RediSep 35 g column, eluted with CH2Cl2-EtOAc, detected at 220 nM to give 420 mg of N-(3-Vinyl-pyridin-2-yl)-acetamide 78C in 46% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[O:9])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Reactant: NCc1ccncc1
Product: COc1ccc(C(=O)NCc2ccncc2)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and 4-(aminomethyl)pyridine in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26]([OH:28])=O)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:30]=[C:31]([NH2:36])[CH2:32][CH2:33][O:34][CH3:35]>>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=3)[CH2:13][CH:12]([C:26]3[O:28][N:36]=[C:31]([CH2:32][CH2:33][O:34][CH3:35])[N:30]=3)[CH2:11]2)=[O:9])[CH2:6][CH2:7]1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: COCCC(N)=NO
Product: COCCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCC(O)CC3)C2)n1
Yield: 18.3 %

Procedure:
250 mg (0.624 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 99A) and 108 mg (0.687 mmol, 75% pure) of N′-hydroxy-3-methoxypropanimidamide (Example 64A) were reacted according to the General Method 1. Enantiomer separation of the racemate according to Method 16D gave 56.0 mg of the title compound from Example 275 and 55.0 mg of the title compound from Example 276 (36% of theory).
Reaction SMILES: C(OC(=O)NCC([N:11]1[CH2:16][CH2:15][C:14]([CH2:25][NH2:26])([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)=O)(C)(C)C.[NH2:28][C:29]1[C:30]([C:37]([NH:39][C:40](=[NH:43])SC)=[O:38])=[N:31][C:32]([Cl:36])=[C:33]([NH2:35])[N:34]=1>O1CCCC1>[NH2:31][CH2:30][C:37]([N:26]([CH2:25][C:14]1([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1)[C:40]([NH:39][C:37]([C:30]1[C:29]([NH2:28])=[N:34][C:33]([NH2:35])=[C:32]([Cl:36])[N:31]=1)=[O:38])=[NH:43])=[O:38]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC(CN)(CCc2ccccc2)CC1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Solvent: C1CCOC1
Product: N=C(NC(=O)c1nc(Cl)c(N)nc1N)N(CC1(CCc2ccccc2)CCNCC1)C(=O)CN
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 130 mg (0.35 mmol) [2-(4-aminomethyl-4-phenethyl-piperidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (A.50) and 80 mg (0.3 mmol) 1-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea in 5 ml tetrahydrofuran is stirred at 70° C. overnight. Then the reaction mixture is concentrated under reduced pressure and the residue is purified via preparative reverse phase HPLC (gradient of acetonitrile and water+0.2% trifluoroacetic acid, 25° C.). Fractions containing the title compound were concentrated under reduced pressure. Then the residue is co-evaporated with methanolic hydrochloric acid in order to remove the protecting group.
Reaction SMILES: [Cl:1][C:2]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][C:5]1[C:6]([O:21][CH3:22])=[N:7][NH:8][C:9]=1[N:10]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C1COCC1>[Cl:1][C:2]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][C:5]1[C:9]([NH2:10])=[N:8][NH:7][C:6]=1[O:21][CH3:22]
Reactant: COc1n[nH]c(N2C(=O)c3ccccc3C2=O)c1Cc1cccc(Cl)c1Cl
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: COc1[nH]nc(N)c1Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a solution of 2-(4-(2,3-dichlorobenzyl)-3-methoxy-1H-pyrazol-5-yl)isoindoline-1,3-dione (620 mg, 1.54 mmol) in THF (20 mL) was added hydrazine hydrate (1.0 g, 20 mmol) dropwise with stirring at room temperature. Then, the mixture was stirred at room temperature for 2 hours and 50° C. for another 2 hours. Then the reaction mixture was concentrated under vacuo and the residue was purified by silica gel chromatography eluted with EA to give the titled compound (301 mg, 72%) as a colorless viscous liquid. LC/MS: MS (ES+) m/e 272 (MH+); 1H NMR (300 MHz, CDCl3) δ ppm 3.71 (s, 2H), 3.86 (s, 3H), 7.07-7.14 (m, 2H), 7.29-7.32 (m, 1H).
Reaction SMILES: [N+:1]([CH2:4][C:5]([S-:7])=S)([O-:3])=[O:2].[K+].[K+].[N+]([CH2:13]C([S-])=S)([O-])=O.[CH3:17][NH:18][CH3:19].S(OC)(OC)(=O)=O>O.[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[CH3:17][N:18]([CH3:19])[C:5]([S:7][CH3:13])=[CH:4][N+:1]([O-:3])=[O:2]
Reactant: CNC
Reactant: O=[N+]([O-])CC(=S)[S-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CSC(=C[N+](=O)[O-])N(C)C
Reaction time: 6 h

Procedure:
To a solution of dipotassium nitrodithioacetate (118 g) dissolved in water (630 ml), dimethylamine (1.1 equivalents) was added as a 40% w/w solution in water. After stirring for 6 hours at 20°-25° C., benzyltrimethylammonium chloride (7 g ) was charged followed by dimethyl sulphate (175 g ) over one hour. After stirring overnight, the reaction mixture was extracted three times with 100 ml aliquots of dichloromethane. After drying over MgSO4, the combined organic phases were concentrated to a red oil which was chromatographed on a silica gel column, using ethyl acetate as eluant to give, after recrystallisation from isopropanol, 36 g (40%) of the title compound, m.p. 60° C.
Reaction SMILES: Cl[CH:2]1[C:6]([CH3:8])([CH3:7])[C:5]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:4]=2[O:3]1.[S-:15][C:16]#[N:17].[K+].O>CN(C)C=O>[C:13]([C:10]1[CH:11]=[CH:12][C:4]2[O:3][CH:2]([N:17]=[C:16]=[S:15])[C:6]([CH3:8])([CH3:7])[C:5]=2[CH:9]=1)#[N:14]
Reactant: CC1(C)c2cc(C#N)ccc2OC1Cl
Reactant: N#C[S-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)c2cc(C#N)ccc2OC1N=C=S
Yield: 21.6 %

Procedure:
2-Chloro-5-cyano-2,3-dihydro-3,3-dimethylbenzofuran (5 g) from Example 15 and potassium thiocyanate (4.6 g) were heated in dimethylformamide (30 ml) at 110° C. for 7 hours. The mixture, after cooling, was added to water and the product extracted into diethyl ether. The ether solution was washed with water (twice), dried over magnesium sulphate and run down under vacuum yielding 4 g of crude product. Purification by silica gel chromatography in toluene yielded 1.2 g of title product, mp 52° C.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:6]=1)[OH:4])#[CH:2].O[C:23]1[CH:32]=[C:31](I)[CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]>>[OH:4][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:7]([C:18]([CH3:20])([CH3:19])[CH3:21])[CH:6]=1)[C:1]#[C:2][C:31]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:32]=1
Reactant: C#CC(O)c1ccc(OCCCCCC)c(C(C)(C)C)c1
Reactant: COC(=O)c1ccc(I)cc1O
Product: CCCCCCOc1ccc(C(O)C#Cc2ccc(C(=O)OC)cc2)cc1C(C)(C)C
Yield: 71.7 %

Procedure:
Following the basic procedure of Example 11(d), by reacting 3.8 g (13.2 mmol) of α-ethynyl-3-tert-butyl-4-(hexyloxy)benzenemethanol with 3.7 g (13.7 mmol) of methyl 2-hydroxy-4-iodobenzoate, 4 g (69%) of methyl 4-[3-hydroxy-3-(3-tert-butyl-4-hexyloxyphenyl)-1-propynyl]benzoate were obtained in the form of a dark brown oil.
Reaction SMILES: [C:1]([C:4]([CH3:35])([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]([NH:18][N:19]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[C:20]([NH:22]CCC)=[O:21])=O)=[CH:9][CH:8]=1)[CH3:5])([OH:3])=[O:2].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1>[Cl:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[Cl:33])[CH2:26][N:19]1[C:20](=[O:21])[NH:22][C:16]([CH2:15][CH2:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][C:4]([CH3:35])([CH3:5])[C:1]([OH:3])=[O:2])=[CH:8][CH:9]=2)=[N:18]1
Reactant: CCCNC(=O)N(Cc1ccc(Cl)c(Cl)c1)NC(=O)CCCc1ccc(OC(C)(C)C(=O)O)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: CC(C)(Oc1ccc(CCCc2nn(Cc3ccc(Cl)c(Cl)c3)c(=O)[nH]2)cc1)C(=O)O
Temperature: 90 °C
Yield: 67.9 %

Procedure:
To substrate 1-[4-[4-(1-Carboxy-1-methylethoxy)-phenyl]butyryl]-2-(3,4-dichlorophenylmethyl)-4-(propyl)semicarbazide (0.3658 g, 0.697 mmol) and camphorsulfonic acid (0.1658 g, 0.714 mmol) was added toluene (10 mL) and the resulting solution heated to 90° C. for 1 h. The solution was concentrated to an oil, and chromatographed on silica gel (7:3 ethyl acetate:hexanes) to afford title compound as an oil (0.2397 g, 0.473 mmol, 68%): 1H NMR (DMSO-d6) δ 12.95 (br s, 1 H), 7.58 (d, 2 H, J=8 Hz), 7.46 (d, 1 H, J=1.5 Hz), 7.19 (dd, 1 H, J=8, 1.5 Hz), 7.03 (d, 2 H, J=8.5 Hz), 6.72 (d, 2 H, J=8.5 Hz), 4.85 (s, 2 H), 3.47 (t, 2 H, J=7 Hz), 2.54 (t, 2 H, J=7.5 Hz), 1.83 (m, 2 H), 1.52 (q, 2 H, J=7 Hz), 1.45 (s, 6 H), 0.79 (t, 3 H, J=7 Hz); 13C NMR (DMSO-d6) δ 175.8, 154.1, 147.3, 139.2, 135.2, 131.7, 131.5, 130.8, 130.1, 129.7, 128.4, 119.3, 79.0, 47.3, 42.9, 34.0, 27.8, 25.7, 24.8, 22.5, 11.5; IR (CHCl3) 3028, 3005, 2939, 2878, 1696, 1574, 1509, 1472 cm−1; Anal. Calcd. for C25H29Cl2N3O4: C, 59.29; H, 5.77; N, 8.30. Found: C, 59.33; H, 5.63; N, 8.10.
Reaction SMILES: [Na].Cl.[NH2:3][OH:4].[F:5][C:6]([F:30])([F:29])[C:7]1[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[N:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10]>C(O)C>[OH:4][NH:3][C:23]([C:20]1[N:21]=[N:22][C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:9](=[O:10])[C:8]3[CH:25]=[CH:26][CH:27]=[CH:28][C:7]=3[C:6]([F:30])([F:29])[F:5])[CH2:16][CH2:15]2)=[CH:18][CH:19]=1)=[NH:24]
Reactant: N#Cc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: NO
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: N=C(NO)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
Sodium metal (0.116 g, 4.98 mmol) was added to ice cold ethanol (10 mL). When all the sodium metal dissolved, hydroxylamine hydrochloride (0.346 g, 4.98 mmol) was introduced in one portion. The suspension was stirred at room temperature for 15 minutes and a solution of 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]-pyridazine-3-carbonitrile (0.900 g, 2.49 mmol) in ethanol (2 mL) was then added. The mixture was further stirred at room temperature overnight. The solvent was removed in vacuo and the residue was suspended in ethyl acetate (10 mL) and filtered through celite. The filtrate was concentrated and the product was purified by column chromatography. The title compound was obtained as a pale yellow syrup in 55% yield (0.54 g). 1H NMR (300 MHz, CDCl3) δ 7.82 (d, J=9.6 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.70-7.52 (m, 2H), 7.35 (d, J=7.4 Hz, 1H), 6.95 (d, J=9.5 Hz, 1H), 5.53 (s, 2H), 4.10-3.95 (m, 1H), 3.98-3.82 (m, 1H), 3.82-3.60 (m, 4H), 3.32 (t, J=5.1 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 157.5, 147.5, 142.1, 132.2, 130.2, 127.3, 125.1, 123.2, 110.8, 44.2, 42.6, 42.3, 39.1 MS (ES+) m/z 395.3 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH2:9][CH2:8][CH2:7]2)(=[O:3])[CH3:2].[N:14]1([C:19]2[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1.[OH-].[Na+]>C(O)C>[N:14]1([C:19]2[CH:26]=[CH:25][C:22]([CH:23]=[CH:2][C:1]([C:4]3[CH:13]=[CH:12][C:11]4[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=4[CH:5]=3)=[O:3])=[CH:21][CH:20]=2)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CC(=O)c1ccc2c(c1)CCCC2
Reactant: O=Cc1ccc(N2CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=Cc1ccc(N2CCCC2)cc1)c1ccc2c(c1)CCCC2

Procedure:
A solution of 2.6 g of 1 (15 mmol), 2.6 g of p-pyrrolidinylbenzaldehyde (15 mmol), and 0.66 g of sodium hydroxide in 100 ml of ethanol was stirred under nitrogen at 50° for 24 hr. The reaction mixture was cooled in an ice bath, and the precipitated yellow solid 3-[4-(1-pyrrolidinyl)phenyl]-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-2-propen-1-one was collected by filtration and washed with cold ethanol. Yield: 3.2 g (64%); m.p. 167° to 169°. λmax (CHCl3): 420 nm (ε=36,800); 330 nm (4,300); 276 nm (16,400). Calcd for C23H25NO: C, 83.34; H, 7.60; N, 4.23. Found: C, 82.68, 82.67; H, 7.57, 7.55; N, 4.03, 4.15.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][CH3:10])[CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:21][CH2:22][N:23]([CH2:34][CH2:35]Cl)[S:24]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)(=[O:26])=[O:25]>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH2:35][CH2:34][N:23]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)(=[O:26])=[O:25])[CH2:22][CH2:21]2)=[C:4]([CH2:9][CH3:10])[CH:3]=1
Reactant: CCc1cc(Br)ccc1N
Reactant: Cc1ccc(S(=O)(=O)N(CCCl)CCCl)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(Br)ccc1N1CCN(S(=O)(=O)c2ccc(C)cc2)CC1

Procedure:
A mixture of 4-bromo-2-ethylaniline (1.4 mL), diisopropylethylamine (4.4 mL) and N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide (3 g) was refluxed for 5 hr. After cooling, the solvent was evaporated, and the residue was purified by column chromatography (chloroform) to give 1-(4-bromo-2-ethylphenyl)-4-(toluene-4-sulfonyl)piperazine (3 g). To a mixture of 1-(4-bromo-2-ethylphenyl)-4-(toluene-4-sulfonyl)piperazine (3 g), methylboronic acid (1.2 g), palladium acetate (112 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (411 mg) and potassium fluoride (2.3 g) was added tetrahydrofuran (30 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give 1-(2-ethyl-4-methylphenyl)-4-(toluene-4-sulfonyl)piperazine (2.9 g). A mixture of 1-(2-ethyl-4-methylphenyl)-4-(toluene-4-sulfonyl)piperazine (2.9 g), hydrobromic acid (16 mL) and acetic acid (16 mL) was refluxed for 8 hr. After cooling, the reaction mixture was alkalified with 1N aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. 4N hydrogen chloride/ethyl acetate (3 mL) was added and the mixture was filtered to give 1-(2-ethyl-4-methylphenyl)piperazine hydrochloride (1.7 g). To a mixture of 4-bromo-2-methanesulfonylbenzoic acid (1.1 g), 1-(2-ethyl-4-methylphenyl)piperazine hydrochloride (963 mg) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (1.5 g) were added chloroform (6 mL), methanol (6 mL) and N-methylmorpholine (440 μL), and the mixture was stirred at room temperature overnight. After evaporation of the solvent, the residue was purified by column chromatography (chloroform) to give the title compound (1.8 g).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:13](=[O:18])[NH:14][NH:15][C:16]=2[CH3:17])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH3:19][C:20]([O:22][CH2:23][C@H:24]1[O:29][C@H:28](Br)[C@H:27]([O:31][C:32]([CH3:34])=[O:33])[C@@H:26]([O:35][C:36]([CH3:38])=[O:37])[C@@H:25]1[O:39][C:40]([CH3:42])=[O:41])=[O:21]>O1CCCC1.C(=O)([O-])[O-].[Ag+2]>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]2[C:13]([O:18][C@@H:28]3[O:29][C@H:24]([CH2:23][O:22][C:20](=[O:21])[CH3:19])[C@@H:25]([O:39][C:40](=[O:41])[CH3:42])[C@H:26]([O:35][C:36](=[O:37])[CH3:38])[C@H:27]3[O:31][C:32](=[O:33])[CH3:34])=[N:14][NH:15][C:16]=2[CH3:17])=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: Cc1[nH][nH]c(=O)c1Cc1ccc(OC(C)C)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C)c2Cc2ccc(OC(C)C)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 39 %

Procedure:
To a suspension of 1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one (46 mg), acetobromo-α-D-glucose (99 mg) and 4A molecular sieves in tetrahydrofuran (3 mL) was added silver carbonate (66 mg), and the mixture was stirred under shading the light at 65° C. overnight. The reaction mixture was purified by column chromatography on aminopropyl silica gel (eluent: tetrahydrofuran). Further purification by preparative thin layer chromatography on silica gel (developing solvent: ethyl acetate/hexane=2/1) afforded 4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (42 mg).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:14]2[S:15][CH:16]=[C:17]([CH:19]([CH3:21])[CH3:20])[N:18]=2)[N:3]=1.ClC1N=C(O[CH:36]2[CH2:53][CH:52]3[N:38]([C:39](=[O:59])[N:40]([CH3:58])[CH2:41][CH2:42][CH2:43][CH2:44][CH:45]=[CH:46][CH:47]4[C:49]([C:55]([OH:57])=[O:56])([NH:50][C:51]3=[O:54])[CH2:48]4)[CH2:37]2)C2C(C=1)=CC(OC)=CC=2>>[CH:19]([C:17]1[N:18]=[C:14]([C:4]2[N:3]=[C:2]([O:1][CH:36]3[CH2:53][CH:52]4[N:38]([C:39](=[O:59])[N:40]([CH3:58])[CH2:41][CH2:42][CH2:43][CH2:44][CH:45]=[CH:46][CH:47]5[C:49]([C:55]([OH:57])=[O:56])([NH:50][C:51]4=[O:54])[CH2:48]5)[CH2:37]3)[C:11]3[C:6]([CH:5]=2)=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[S:15][CH:16]=1)([CH3:21])[CH3:20]
Reactant: COc1ccc2c(O)nc(-c3nc(C(C)C)cs3)cc2c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(Cl)cc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3nc(C(C)C)cs3)cc2c1

Procedure:
The title product 69 was prepared from 1-hydroxy-3-(4-isopropylthiazol-2-yl)-6-methoxyisoquinoline (6) following the same procedures described for the preparation of 17-(3-chloro-6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (42, Example 10): m/z=634 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH:15]([OH:16])[C:14]([CH3:18])([CH3:17])[CH2:13][C:12](=[O:19])[C:11]([CH3:20])=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:28](OC(=O)C)(=[O:30])[CH3:29]>O1CCCC1>[C:28]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]1[CH:15]([OH:16])[C:14]([CH3:17])([CH3:18])[CH2:13][C:12](=[O:19])[C:11]([CH3:20])=[CH:10]1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CC1=CC(NCc2ccccc2)C(O)C(C)(C)CC1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N(Cc1ccccc1)C1C=C(C)C(=O)CC(C)(C)C1O
Temperature: 50 °C
Yield: 95 %

Procedure:
The 4-benzylamino-5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one obtained in Example 1 (17.3 g, 63.4 millimoles) was dissolved in tetrahydrofuran (100 ml), triethylamine (19.2 g, 190 millimoles) was added, and acetic anhydride (12.9 g, 127 millimoles) was added dropwise while stirring on ice. After heating the reaction solution at 50° C. for 3 hours, it was poured into ice water (300 ml). After 30 minutes the aqueous solution was subjected to extraction with benzene, washed with water, and then dried over anhydrous magnesium sulfate. The benzene was distilled off, and the resulting residue was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain 19.0 g (95%) of 4-(N-acetylbenzylamino)-5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one.