Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[CH:6]=[N+:5]([O-])[C:4]=2[CH:3]=[CH:2]1.[CH2:15]([Mg]Br)[CH3:16]>O1CCCC1.C(Cl)Cl>[CH2:15]([C:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[S:1][CH:2]=[CH:3][C:4]=2[N:5]=1)[CH3:16]
Reactant: CC[Mg]Br
Reactant: [O-][n+]1cc2ccccc2c2sccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1nc2ccsc2c2ccccc12
Reaction time: 0.17 h
Yield: 80.5 %

Procedure:
A suspension of Thieno[3,2-c]isoquinoline 4-oxide (20 g, 99 mmol) in dry tetrahydrofuran (ca. 400 mL) was treated dropwise at −78° C. with an ethereal solution of ethylmagnesium bromide (3.0 M, 40 mL, 120 mmol) during 10 min. After 6 h the reaction mixture was quenched with 2 N aqueous hydrochloride acid (75 mL) and stirred for ca. 10 min. At this time the solution was treated with 2.5 N aqueous sodium hydroxide (65 mL). The resulting gelatinous residue was diluted with water (400 mL), filtered through Celite, and the filtrate was extracted with ethyl acetate (3×500 mL). The combined extracts were washed with water and brine (1.5 L each), dried (K3CO3) and concentrated in vacuo to give the crude product (19 g) as an orange oil which was taken up in methylene chloride (ca. 60 mL) and pre-adsorbed on silica gel (60 g). Flash chromatography on silica gel (740 g) eluting 2.5-, then 5-, and then 10% ethyl acetate-hexane provided the title compound (17 g, 81%, m.p. 39-41° C.) as a clear, pale yellow oil which crystallized on standing.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([CH3:28])=[C:11]([CH3:27])[C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:30]([C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[C:35]([OH:42])[CH:34]=1)(=[O:32])=[O:31]>>[CH2:1]([C:8]1[O:9][C:10]([CH3:28])=[C:11]([CH3:27])[C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][S:30]([C:33]2[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[C:35]([OH:42])[CH:34]=2)(=[O:32])=[O:31])=[C:17]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:16]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1oc(Cc2ccccc2)c(C(=O)c2ccc(O)c(C3CCCC3)c2)c1C
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: Cc1oc(Cc2ccccc2)c(C(=O)c2ccc(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C3CCCC3)c2)c1C
Yield: 55 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using (2-benzyl-4,5-dimethyl-furan-3-yl)-(3-cyclopentyl-4-hydroxy-phenyl)-methanone (0.509 g, 1.36 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.645 g, 2.72 mmol). Purification on 2% H3PO4/MeOH treated silica gel, eluting with 20% EtOAc/hexane gave 0.430 g (55%) of the title compound a pale yellow solid, mp 80-85° C. 1H NMR (DMSO-d6) δ 1.23-1.34 (m, 2H), 1.45-1.59 (m, 2H), 1.61-1.74 (m, 4H), 1.76 (s, 3H), 2.16 (s, 3H), 2.95 (quintet, 1H), 3.78 (s, 2H), 6.98 (d, 2H), 7.13-7.25 (m, 4H), 7.36-7.38 (m, 2H), 7.44-7.57 (m, 2H), 7.97 (d, 1H). IR (KBr) 3400, 2950, 1690, 1580, 1480 and 1190 cm−1. mass spectrum (−ESI) m/z 573 (M−H). Anal. Calcd. for C32H30O8S.0.2H2O: C, 66.88; H, 5.26; N, 0.00. Found: C., 66.53; H, 5.40; N, 0.07.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:7][CH:6]([C:8]#[N:9])[CH2:5]1)#[N:2].[NH:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1.C(#N)C.N12CCCN=C1CCCCC2>>[C:1]([CH2:3][C:4]1([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7][CH:6]([C:8]#[N:9])[CH2:5]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: N#CC=C1CC(C#N)C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(C#N)C4)c3)ncnc21
Temperature: 25 °C

Procedure:
3-(Cyanomethylene)cyclobutanecarbonitrile (120 mg, 0.0010 mol) was combined with 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (0.1 g, 0.0003 mol) in acetonitrile (2 mL, 0.04 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (6 μL, 0.00004 mol) under nitrogen. The mixture was stirred at room temperature over the weekend. After evaporation to dryness, the crude mixture was purified by flash column, eluting with 0 to 10% MeOH in dichloromethane, to give the desired product. LCMS (M+H) 434.4.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[S:19](Cl)([CH3:22])(=[O:21])=[O:20]>ClCCl>[CH3:22][S:19]([O:9][CH2:8][CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: OCCN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A flask was charged with 2-morpholinoethanol (1.0 g, 7.1 mmol), DIEA (2.4 mL, 14 mmol) and dichloromethane (100 mL). Mesylchloride (0.64 mL, 8.3 mmol) was added in a dropwise fashion to the dichloromethane mixture and the reaction mixture was stirred at room temperature for 15 hours. Concentration of the reaction mixture gave rise to a quantitative yield of 2-morpholinoethyl methanesulfonate, which was used in the next step without any without further purification. EI (MS); 210 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([S:16][CH3:17])[C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([S:16][CH3:17])[C:4]=1[C:5]([Cl:20])=[O:6]
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)Cl
Temperature: 80 °C

Procedure:
A mixture of 51 mg (0.191 mmol) 2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoic acid (CAS 1208984-79-5) and 140 ul (1.91 mmol) thionylchloride in toluene (0.5 ml) was heated in a 80° C. oil bath for 4 hours. The solvent was removed in vacuo to provide the title compound.
Reaction SMILES: [C:1]1([C:7]2[C:16]([NH:17][C@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:26]([O:28]C)=[O:27])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:32]I.Cl>C1COCC1>[CH3:32][N:17]([C@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[C:16]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:26]([OH:28])=[O:27])=[CH:11][CH:10]=2
Reactant: CI
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N[C@@H](C)c3ccccc3)nc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (S)-methyl 2-phenyl-3-(1-phenylethylamino)quinoxaline-6-carboxylate (110 mg, 0.29 mmol, 1.00 equiv) in THF (9 mL), sodium hydride (137.9 mg, 5.74 mmol, 20.00 equiv, 60%). The resulting solution was stirred for 1 h at room temperature in an ice/salt bath. This was followed by the addition of a solution of CH3I (407.8 mg, 2.87 mmol, 10.00 equiv) THF (1 mL) dropwise with stiffing at 0° C. The resulting solution was stirred for overnight at 20° C. in an ice/salt bath. The pH value of the solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). This resulted in 40 mg (36%) of (S)-3-(methyl(1-phenylethyl)amino)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:2]1=[O:3].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[C:12]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[NH:1][C:2](=[O:3])[CH2:4][CH2:5]2)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1CCc2ccccc2N1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C1CCc2cc(C(=O)c3ccccc3)ccc2N1

Procedure:
A mixture of 2.2 g of 3,4-dihydrocarbostyril, 3.21 g of benzoyl chloride and 13 g of aluminum chloride in 50 ml of carbon disulfide was refluxed for 2 days. The reaction mixture was poured onto ice water and the resulting solid filtered off, washed with water and dried under reduced pressure to yield 6-benzoyl-3,4-dihydrocarbostyril, m.p. 205°-207° C.
Reaction SMILES: [OH-].[NH4+].[NH2:3][C:4]([CH3:9])([CH3:8])[C:5]([OH:7])=[O:6].[Br:10][CH:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12](Cl)=[O:13]>C(#N)C>[Br:10][CH:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12]([NH:3][C:4]([CH3:9])([CH3:8])[C:5]([OH:7])=[O:6])=[O:13]
Reactant: O=C(Cl)C(Br)c1ccccc1
Reactant: CC(C)(N)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Product: CC(C)(NC(=O)C(Br)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
Ammonium hydroxide (1.6 g) aqueous solution (40 mL) was added to aminoisobutyric acid (2.1 g). The solution was cooled to 0° C., to which a solution of a-bromophenylacetyl chloride (6 g) in acetonitrile (5 mL) was slowly added dropwise. After the addition was completed, the mixture was warmed to room temperature and stirred overnight. The precipitate was filtered off and washed with water to give 3.4 g of 2-(α-bromophenylacetylamino)isobutyric acid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[CH:11]=O.C([O-])(=O)C.[NH4+].[N+:18]([CH2:21][CH3:22])([O-:20])=[O:19]>CO>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[CH:11]=[C:21]([N+:18]([O-:20])=[O:19])[CH3:22]
Reactant: CC[N+](=O)[O-]
Reactant: Cc1c(C=O)[nH]c2ccccc12
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(=Cc1[nH]c2ccccc2c1C)[N+](=O)[O-]

Procedure:
A mixture of 3-methyl-2-indolecarbaldehyde (7.0 g), ammonium acetate (1.4 g) and nitroethane (10.5 ml) in methanol [35 ml) was refluxed for an hour. After the solvent was removed, the residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was pulverized with isopropyl ether to give 3-methyl-2-[2-nitro-1-propenyl)indole (4.29 g).
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([NH:20][C:21]([C:23]2[CH:43]=[CH:42][C:26]([CH2:27][NH:28][C:29](=[O:41])[O:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=3)=[CH:25][CH:24]=2)=[O:22])=[N:11][N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1)=O)(C)(C)C.Cl>C(OCC)(=O)C.O1CCOCC1>[NH2:8][C:9]1[C:10]([NH:20][C:21]([C:23]2[CH:43]=[CH:42][C:26]([CH2:27][NH:28][C:29](=[O:41])[O:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=3)=[CH:25][CH:24]=2)=[O:22])=[N:11][N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cn(-c2ccccc2)nc1NC(=O)c1ccc(CNC(=O)Oc2ccc3ccccc3c2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1cn(-c2ccccc2)nc1NC(=O)c1ccc(CNC(=O)Oc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-naphthyl {4-[({4-[(tert-butoxycarbonyl)amino]-1-phenyl-1H-pyrazol-3-yl}amino)carbonyl]benzyl}carbamate (approximately 5 mg) in ethyl acetate (1 mL) was added 4M HCl in dioxane (1 mL). The reaction was stirred at ambient temperature for 16 hours. Evaporation in vacuo gave the title compound as a white solid. 1H NMR (600 MHz, CD3OD) δ 8.44 (s, 1H), 8.07 (d, J=8.2 Hz, 2H), 7.87 (t, J=8.5 Hz, 2H), 7.82 (d, J=7.9 Hz, 1H), 7.79 (d, J=8.8 Hz, 2H), 7.52 (m, 7H), 7.37 (t, J=7.3 Hz, 1H), 7.28 (dd, J=8.8, 2.1 Hz, 1H), 4.50 (s, 2H); ESIMS calcd 478.2 (M++H), found 478.1 (M++H).
Reaction SMILES: [CH:1]1([C:4]([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:11][C:10]=3[N:9]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:8]=2)=[N:5][OH:6])[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:39][CH2:40][O:41][CH3:42].O>O1CCCC1>[CH3:42][O:41][CH2:40][CH2:39][O:6][N:5]=[C:4]([CH:1]1[CH2:2][CH2:3]1)[C:7]1[C:15]2[CH:14]=[CH:13][C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:11][C:10]=2[N:9]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:8]=1
Reactant: COCCBr
Reactant: C[Si](C)(C)CCOCn1nc(C(=NO)C2CC2)c2c1CC(c1ccccc1)(c1ccccc1)C=C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCON=C(c1nn(COCC[Si](C)(C)C)c2c1C=CC(c1ccccc1)(c1ccccc1)C2)C1CC1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of 0.35 g of the E isomer of cyclopropyl(6,6-diphenyl-1-(2-trimethylsilanylethoxymethyl)-6,7-dihydro-1H-indazol-3-yl)methanone oxime in 10 cm3 of tetrahydrofuran is added dropwise to a suspension of 0.036 g of sodium hydride (at 60% in oil) in 7 cm3 of tetrahydrofuran. After stirring the reaction mixture for about 2 hours in the region of 20° C., a solution of 0.16 g of 1-bromo-2-methoxyethane in 5 cm3 of tetrahydrofuran is poured into the solution obtained. After stirring in the region of 20° C. for about two and a half hours, 5 cm3 of water are added and the solution is concentrated to dryness under reduced pressure (13 kPa). The residue is taken up in 20 cm3 of water and extracted with three times 40 cm3 of dichloromethane. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated. After flash chromatography on a column of silica [eluent: dichloromethane/ethyl acetate (99/1 by volume)], 0.32 g of the E isomer of cyclopropyl(6,6-diphenyl-1-(2-trimethylsilanylethoxymethyl)-6,7-dihydro-1H-indazol-3-yl)methanone O-(2-methoxyethyl)oxime is thus obtained in the form of a resin, the characteristics of which are as follows:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH:9]=O)[CH3:8].[CH:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15].C([O-])([O-])=O.[K+].[K+].CNC>ClCCCl>[CH3:8][N:7]([CH:9]=[C:12]([CH2:13][CH2:14][CH3:15])[CH:11]=[O:16])[CH3:6]
Reactant: CN(C)C=O
Reactant: CCCCC=O
Agent: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCCC(C=O)=CN(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 5.7 %

Procedure:
To a solution of phosphorus oxychloride (2.330 mL, 25.00 mmol, Aldrich) in 1,2-dichloroethane (5.0 mL) at 0° C. was added DMF (7.74 mL, 100 mmol, EMD) in 1,2-dichloroethane (10.0 mL) during the course of 10 min. The mixture was stirred at 0° C. for 20 min and then warmed up to room temperature. After stirring at room temperature for 3 hrs, valeraldehyde (2.66 mL, 25.0 mmol, Aldrich) in 1,2-dichloroethane (5.0 mL) was added dropwise (5 min) and the resulting mixture was stirred at room temperature for 50 min and at 85° C. for 50 min. The cooled reaction mixture was poured into a mixture of ice and K2CO3 (7.5 g) followed by addition of saturated K2CO3 aqueous solution until the pH of the mixture was around 10. To the above mixture, dimethyl amine (8.0 mL, 40 wt. % solution in water, Aldrich) was added and the reaction mixture was heated at 80° C. for 1 hr, cooled and evaporated under reduced pressure to remove 1,2-dichloroethane. The resulting mixture was then heated at 95° C. for 1 hr, cooled to room temperature and extracted with EtOAc (3×). The combined extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was distilled under reduced pressure (1 torr at 145-155° C. of oil bath) to yield the title compound (200 mg, 5.7%) as an orange oil. 1H NMR (500 MHz, CDCl3) δ 8.85 (s, 1 H), 6.48 (s, 1 H), 3.13 (s, 6 H), 2.30-2.45 (m, 2 H), 1.32-1.53 (m, 2 H), 0.93 (t, J=7.42 Hz, 3 H).
Reaction SMILES: [C:1]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:28][C:29]1([CH3:45])[O:34][CH:33]([C:35]([NH:37][CH2:38][CH2:39][C:40](O)=[O:41])=[O:36])[C:32]([CH3:44])([CH3:43])[CH2:31][O:30]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH3:28][C:29]1([CH3:45])[O:34][CH:33]([C:35]([NH:37][CH2:38][CH2:39][C:40]([O:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[NH:20][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:41])=[O:36])[C:32]([CH3:44])([CH3:43])[CH2:31][O:30]1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1ccccc1O
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1ccccc1OC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 72 %

Procedure:
A solution of 303 mg of 2-oleoylaminophenol, mg of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid, 227 mg of dicyclohexylcarbodiimide and 122 mg of 4-dimethylamino pyridine in 15 ml of toluene was heated under reflux for 2 hours. After cooling the reaction mixture, the crystals formed were filtered. The filtrate was concentrated and the residue obtained was subjected to silica gel column chromatography to obtain 445 mg of the title compound (yield: 72%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[O:21])[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=1.C[Si]([C:26]([F:29])([F:28])[F:27])(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>C1COCC1>[F:27][C:26]([F:29])([F:28])[CH:20]([C:5]1[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)=[CH:8][C:7]=2[CH:19]=[C:3]([O:2][CH3:1])[CH:4]=1)[OH:21]
Reactant: COc1ccc(-c2cc3cc(OC)cc(C=O)c3o2)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3cc(OC)cc(C(O)C(F)(F)F)c3o2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
To a solution of 2 (1.2 g, 4.3 mmol) and Trimethylsilyltrifluoromethane (20 ml of 0.5M in THF, 10 mmol) in THF (20 ml) was added TBAF (10 ml of 1.0M in THF, 10 mmol) and the reaction was stirred at rt. After 30 min, the rextion was poured into 2N HCl and extracted with ether. The ether was dried, concentrated and the product was purified by column chromatography (eluent 10% EtOAc/Hex) to give 139 as a solid (1.2 g, 80%); Mp=120-122° C.; 1H NMR(CDCl3) δ 7.75 (d, 2 H, J=8.8 Hz), 7.15-6.95 (m, 4 H), 6.84 (s, 1 H), 5.59 (m, 1 H), 3.86 (s, 6 H); MS 353 (M+H)+
Reaction SMILES: [N+](C1C=CC(C([O:10][CH:11]2[CH2:16][CH2:15][C:14]([N:18]3[CH2:22][CH2:21][CH:20]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=4[Cl:31])[C:19]3=[O:32])([CH3:17])[CH2:13][CH2:12]2)=O)=CC=1)([O-])=O.C([O-])([O-])=O.[K+].[K+]>CO>[Cl:31][C:25]1[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:24]=1[CH2:23][CH:20]1[CH2:21][CH2:22][N:18]([C:14]2([CH3:17])[CH2:15][CH2:16][CH:11]([OH:10])[CH2:12][CH2:13]2)[C:19]1=[O:32]
Reactant: CC1(N2CCC(Cc3ccc(Cl)cc3Cl)C2=O)CCC(OC(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC1(N2CCC(Cc3ccc(Cl)cc3Cl)C2=O)CCC(O)CC1
Yield: 88.6 %

Procedure:
Dissolve 4-(3-(2,4-dichlorobenzyl)-2-oxopyrrolidin-1-yl)-4-methylcyclohexyl 4-nitrobenzoate (Preparation 57) (0.38 g, 0.76 mmol) in MeOH (50 mL). Add K2CO3 (0.21 g, 1.52 mmol) and stir the reaction overnight at room temperature. Add water (50 mL) and extract the aqueous with EtOAc (3×100 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 50-80% of EtOAc/Hexane) to give 0.24 g (91%) of the title compound as a white solid. MS (APCI-pos mode) m/z (rel intensity) 356.0 (100), 358.0 (60).
Reaction SMILES: [O:1]=[C:2]1[N:8]2[C@H:4]([O:5][C:6]([CH:9]=[CH2:10])=[CH:7]2)[CH2:3]1.[SH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([S:11][CH2:10]/[CH:9]=[C:6]2/[CH2:7][N:8]3[C@H:4]([O:5]/2)[CH2:3][C:2]3=[O:1])=[CH:13][CH:14]=1
Reactant: Oc1ccc(S)cc1
Reactant: C=CC1=CN2C(=O)C[C@H]2O1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1C[C@H]2O/C(=C\CSc3ccc(O)cc3)CN12

Procedure:
(5R)-7-Oxo-3-vinyl-4-oxa-1-azabicyclo[3.2.0] hept-2-ene (2.5 mmole) in dry tetrahydrofuran (20 ml) was treated with p-mercaptophenol (650 mg) and benzoyl peroxide (10 mg). The resulting solution was stirred under dry nitrogen while being irradiated using a 200 W bulb placed 1" from the reaction vessel for 1 hour. (The temperature of the solution was 25°-30° during this period). The mixture was diluted with ethyl acetate (100 ml) and was washed with water (3×30 ml) and saturated brine (30 ml). The solution was dried (magnesium sulphate) and the solvent was evaporated under reduced pressure to yield a pale yellow gum. The gum was chromatographed on silica gel using ethyl acetate/petroleum ether (b.p. 60°-80°) to give the title compound as a colourless waxy solid (125 mg), [α]D20 =+138.5° (c 1.0, CHCl3), (Found: M+, 263.0585; C13H 13 NO3S requires 263.0616). νmax (CHCl3): 3200, 1790, 1695, 1600, 1580, 1495 cm-1. δ (CDCl3): 2.62 (1H, d, J 16 Hz), 3.10-3.65 (4H, complex), 4.24 (1H, d, J 14 Hz), 4.39 (1H, t, J 7 Hz), 5.25 (1H, d, J 2 Hz), 6.5-6.8 (3H, m), 7.15-7.35 (2H, m). m/e: 263 (M+, 9%), 138 (100), 126 (25), 125 (23), 96 (42).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:16][C:17]([NH2:19])=[O:18])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([CH2:12][N:13]([CH3:15])[CH3:14])=[CH:5]2.C[O:21][C:22](=O)[C:23]([C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH3:34])[CH:26]=1)=O.[K].CC([O-])(C)C.[K+]>C1COCC1>[Cl:1][C:2]1[C:3]([C:16]2[C:17](=[O:18])[NH:19][C:22](=[O:21])[C:23]=2[C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH3:34])[CH:26]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([CH2:12][N:13]([CH3:14])[CH3:15])=[CH:5]2
Reactant: CN(C)Cc1cc2c(CC(N)=O)c(Cl)ccc2cn1
Reactant: COC(=O)C(=O)c1cn(C)c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [K]
Solvent: C1CCOC1
Product: CN(C)Cc1cc2c(C3=C(c4cn(C)c5ccccc45)C(=O)NC3=O)c(Cl)ccc2cn1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(6-chloro-3-dimethylaminomethyl-isoquinolin-5-yl)-acetamide (47 mg, 0.17 mmol) and (1-methyl-1H-indol-3-yl)-oxo-acetic acid methyl ester (56 mg, 0.26 mmol) in anhydrous THF was added dropwise a 1 M solution of potassium t-BuOK in THF (1.8 mL) under an argon atmosphere at 0° C. The resulting deep red reaction mixture was stirred for 1.5 h at 0° C., quenched with a saturated aqueous NH4Cl solution and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated at reduced pressure. Purification by flash column chromatography (silica gel, EtOAc/water/acetic acid 7:1:1) afforded the title compound as its acetate salt (61 mg, 0.12 mmol, 70%). MS (ES+): 445 (M(C25H2135ClN4O2)+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([C@H:13]1[C@:17]([CH3:22])([CH2:18][C:19]([OH:21])=[O:20])[C@@H:16]([OH:23])[CH2:15][CH2:14]1)[CH2:7][CH2:6]2.[CH3:24]OC(OC)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([C@H:13]1[C@:17]([CH3:22])([CH2:18][C:19]([O:21][CH3:24])=[O:20])[C@@H:16]([OH:23])[CH2:15][CH2:14]1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC([C@@H]1CC[C@H](O)[C@@]1(C)CC(=O)O)C2
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)C[C@]1(C)[C@@H](O)CC[C@H]1C1CCc2cc(OC)ccc2C1

Procedure:
A solution of 2.19 g of (1S,2S,5S)-5-(1,2,3,4-tetrahydro-6-methoxy-2-naphthyl)-2-hydroxy-1-methylcyclo-pentaneacetic acid and 5 ml of 2,2-dimethoxypropane in 40 ml of methanol containing 0.05 g of p-toluenesulfonic acid monohydrate is refluxed for 18 hours. The resultant solution is partitioned between aqueous 5% sodium bicarbonate and ether. The ether phase is separated, dried over magnesium sulfate, and stripped of solvent by vacuum distillation. The residue is crystallized from a mixture of acetone and hexane to give methyl (1S,2S,5S)-5-(1,2,3,4-tetrahydro-6-methoxy-2-naphthyl)-2-hydroxy-1-methylcyclopentaneacetate melting at approximately 86°-87°.