Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][S:43]([CH:46]=[CH2:47])(=[O:45])=[O:44])[CH2:4][CH2:3]2.[OH-:48].[Na+]>O1CCOCC1>[OH:48][CH2:47][CH2:46][S:43]([CH2:42][CH2:41][NH:40][C@:5]12[CH2:36][CH2:35][C@@H:34]([C:37]([CH3:39])=[CH2:38])[C@@H:6]1[C@@H:7]1[C@@:2]([CH3:1])([CH2:3][CH2:4]2)[C@@:19]2([CH3:20])[C@@H:10]([C@:11]3([CH3:33])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]2[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1)(=[O:45])=[O:44]
Reactant: [OH-]
Reactant: C=CS(=O)(=O)CCN[C@]12CC[C@@H](C(=C)C)[C@@H]1[C@H]1CC[C@@H]3[C@@]4(C)CC=C(c5ccc(C(=O)OC)cc5)C(C)(C)[C@@H]4CC[C@@]3(C)[C@]1(C)CC2
Agent: [Na+]
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCCS(=O)(=O)CCO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 78 °C
Yield: 55.3 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(vinylsulfonyl)ethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (25 mg, 0.038 mmol) and sodium hydroxide (0.189 mL, 0.189 mmol) in dioxane (1 mL) was heated at 78° C. for 3 h. The reaction mixture was filtered and the clear solution was purified by prep HPLC to provide the title compound as a white solid (14 mg, 53%). LCMS: m/e 666.39 (M+H)+, 2.48 min (method 10). 1H NMR (500 MHz, Acetic acid d4) δ ppm 8.03 (d, J=8.24 Hz, 2H), 7.30 (d, J=8.24 Hz, 2H), 5.37 (d, J=4.27 Hz, 1H), 4.87 (s, 1H), 4.75 (s, 1H), 4.31-4.01 (m, 3H), 3.93-3.74 (m, 3H), 3.68-3.41 (m, 2H), 3.06-2.73 (m, 1H), 2.48-1.26 (m, 22H), 1.76 (s, 3H), 1.23 (s, 3H), 1.14 (s, 3H), 1.09 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([C:15]([O:17][CH3:18])=[O:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1.[H][H]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:19])[CH:4]([C:15]([O:17][CH3:18])=[O:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1
Reactant: COC(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)OC
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1ccc(N)cc1)C(=O)OC
Yield: 98.1 %

Procedure:
The compound 2-carbomethoxy-3-(4-nitrophenyl)propanoic acid methyl ester (p-nitrobenzylmalonate dimethyl ester) (2.00 g, 7.55 mmole) was dissolved in 70 ml of ethyl acetate containing 5 percent palladium on carbon (1.0 g--Aldrich Chemical Company) catalyst and was hydrogenated in a Parr shaker employing 50 psig of hydrogen at 22° C. Hydrogen uptake was rapid (15 minutes) and the mixture was maintained under hydrogen pressure for another three hours. The pressure vessel was vented and flushed with nitrogen (N2). The suspension was filtered through a pad of Celite™ and the solvent was removed in vacuo using a rotary evaporator to provide 3-(4-aminophenyl)-2-carbomethoxypropanoic acid methyl ester (p-aminobenzylmalonate dimethyl ester) (1.76 g, 7.41 mmole) as a light yellow oil in 98 percent yield. The structure was confirmed by 1H nuclear magnetic resonance (PMR) and 13C nuclear magnetic resonance (CMR) as well as mass spectroscopy (MS) spectral analysis.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][SH:5].C(#N)C.[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[C:13](F)[CH:12]=1.C(OCC)(=O)C>CCCCCC>[CH3:1][O:2][C:3]([C:4]1[S:5][C:13]2[CH:12]=[C:11]([Br:10])[CH:18]=[CH:17][C:14]=2[CH:15]=1)=[O:6]
Reactant: COC(=O)CS
Reactant: O=Cc1ccc(Br)cc1F
Solvent: CCCCCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2ccc(Br)cc2s1
Temperature: 85 °C
Yield: 89.8 %

Procedure:
TEA (1.29 g, 12.85 mmol) and mercapto-acetic acid methyl ester (1.14 g, 10.83 mmol) were added to acetonitrile (50 mL) previously purged with argon (10 minute). This was followed by the addition of 4-bromo-2-fluoro-benzaldehyde (2 g, 9.852 mmol) and the resulting mixture was heated to reflux at 85° C. overnight. The reaction was monitored by TLC (20% ethyl acetate in hexane). The reaction mixture was cooled, concentrated, basified with 10% NaOH solution and extracted with ethyl acetate to afford the crude product. Purification by column chromatography on silica gel (5% ethyl acetate in hexane) afforded 2.4 g of the product (90% yield).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]#[N:16])=[CH:12][CH:13]=2)[NH:8][N:7]=1>O.C(O)(=O)C>[C:15]([C:11]1[CH:10]=[C:9]2[C:14]([CH:6]=[N:7][NH:8]2)=[CH:13][CH:12]=1)#[N:16]
Reactant: N#Cc1ccc2c(N)n[nH]c2c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccc2cn[nH]c2c1
Temperature: 25 °C

Procedure:
A solution of sodium nitrite (218 mg, 3.16 mmol) in water (1 mL) was added dropwise over 2 min to a stirred suspension of 3-amino-6-cyanoindazole (250 mg, 1.58 mmol) in water (1 mL) and acetic acid (2 mL) at 0° C. The resulting thick suspension was warmed to rt. After 16 h the mixture was cooled to 0° C. and the solids were collected by filtration, washing with cold water. The solids were suspended in 0.1 M HCl (4 mL), DME (3 mL) was added and the resulting mixture was stirred and heated to 80° C. for 1.5 h. The reaction was cooled and concentrated to ⅓ the volume. The residue was neutralised with sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by chromatography on silica (5:1 chloroform/ethyl acetate) to give the title compound as a yellow solid:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].[CH3:15][N:16]=[C:17]=[S:18]>C(O)C>[CH3:15][NH:16][C:17]([NH:14][CH2:13][CH2:12][S:11][CH2:10][C:8]1[N:9]=[C:5]([CH2:4][N:2]([CH3:1])[CH3:3])[S:6][CH:7]=1)=[S:18]
Reactant: CN=C=S
Reactant: CN(C)Cc1nc(CSCCN)cs1
Solvent: CCO
Product: CNC(=S)NCCSCc1csc(CN(C)C)n1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution was prepared containing 0.80 g. of 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine and 0.29 g. of methylisothiocyanate in 10 ml. of ethanol. The solution was stirred at room temperature for about 17 hours after which time the solvent was removed by evaporation in vacuo. The residual gum, comprising N-methyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylthiourea formed in the above reaction, was purified by chromatography over silica using a gradient elution technique with ethyl acetate containing increasing quantities of methanol as the eluant. Fractions containing the above compound were combined and the solvent evaporated therefrom in vacuo, leaving as a residue 0.83 g. of a glassy solid.
Reaction SMILES: [N+]([N:4]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[N:6]=[CH:5]1)([O-])=O.C(=O)([O-])O.[Na+].[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[C:25][CH:26]=[C:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:19]=1>O.CC(C)=O>[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[C:25][CH:26]=[C:27]2[CH2:28][CH2:29][N:30]([C:8]3[NH:4][CH:5]=[N:6][C:7]=3[N+:9]([O-:11])=[O:10])[CH2:31][CH2:32]2)[N:19]=1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Reactant: O=[N+]([O-])c1cn([N+](=O)[O-])cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cccc(C#CC=C2CCN(c3[nH]cnc3[N+](=O)[O-])CC2)n1

Procedure:
To a solution of 1,4-dinitroimidazole (207 mg, 1.31 mmol) and sodium hydrogencarbonate (242 mg, 2.88 mmol) in 4 mL of water and 0.16 mL of acetone was added drop wise a solution of the compound of Example 3 (278 mg, 1.31 mmol) in acetone. The reaction mixture was refluxed for 2 h, poured into water and extracted with EtOAc. The crude residue was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with EtOAc-MeOH gradient from 1:0 to 92:8; affording the title compound not enough pure. So, it was purified again by preparative RP LC-MS chromatography, using MS-C18 XTerra column 30×50 mm eluting with ammonium bicarbonate 20 mM pH 8 buffer-acetonitrile gradient affording 4 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=O)[NH:6]2.[BH4-].[Na+].FC(F)(F)C(O)=O>O1CCOCC1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2
Reactant: O=C1Cc2c(Cl)cccc2N1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Clc1cccc2c1CCN2
Temperature: 25 °C
Yield: 77.4 %

Procedure:
5.5 g of 4-chlorooxindole was dissolved in 80 ml of dioxane and 6.2 g of sodium borohydride was suspended in the resulting solution. 12.7 ml of trifluoroacetic acid (d=1.48) was added thereto dropwise at room temperature while stirring. After heat-refluxing the mixture for 4.5 hours, the solvent was removed therefrom under reduced pressure. Water was added to the residue and the water-insoluble materials were removed by filtration and washed with diethyl ether. The filtrate was extracted with diethyl ether and the ether layer was dried over anhydrous sodium sulfate followed by removing the solvent. The residue was distilled under reduced pressure to obtain 3.9 g of 4-chloroindoline as a colorless oily product having a boiling point of 135° C. at 10 mm Hg.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:2]1.CO[C:16](=[O:32])[C:17]([C:19]1[C:29]2=[C:30]3[C:25](=[CH:26][CH:27]=[CH:28]2)[CH2:24][CH:23]([CH3:31])[CH2:22][N:21]3[CH:20]=1)=O>>[CH3:31][CH:23]1[CH2:24][C:25]2[C:30]3=[C:29]([C:19]([C:17]4[C:16](=[O:32])[NH:13][C:11](=[O:12])[C:10]=4[C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][CH:2]=4)=[CH:20][N:21]3[CH2:22]1)[CH:28]=[CH:27][CH:26]=2
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CC(C)C2
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Product: CC1Cc2cccc3c(C4=C(c5c[nH]c6ccccc56)C(=O)NC4=O)cn(c23)C1

Procedure:
Beginning with indole-3-acetamide and (5-methyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40]([O:42]C)=O)[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].OC(C1C=C2C(=CC=1)C=C(C(O)=O)C=C2)(C1N=C[N:52]([C:54]([C:67]2[CH:72]=[CH:71]C=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C(C)C.Cl.C1(N)CC1>>[CH:67]1([CH2:54][NH:52][C:40]([C:35]2[CH:34]=[CH:33][C:32]3[C:37](=[CH:38][CH:39]=[C:30]([C:2]([OH:1])([C:6]4[N:7]=[CH:8][NH:9][CH:10]=4)[CH:3]([CH3:5])[CH3:4])[CH:31]=3)[CH:36]=2)=[O:42])[CH2:72][CH2:71]1
Reactant: CC(C)C(O)(c1ccc2cc(C(=O)O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Agent: Cl
Agent: NC1CC1
Product: CC(C)C(O)(c1ccc2cc(C(=O)NCC3CC3)ccc2c1)c1c[nH]cn1

Procedure:
In a manner to that described in Example 9-(i), methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (1.78 g) was converted to 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid, which was reacted with cyclopropylamine hydrochloride (405 mg) in a similar manner as described in Example 24-(i) to give the titled compound (1.59 g) as a colorless powder.
Reaction SMILES: C(NC(C)C)(C)C.[Li][CH2:9][CH2:10][CH2:11][CH3:12].C([C:15]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:16]=1[C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[O:18])C.C(I)C>C1COCC1>[CH:10]([C:15]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:16]=1[C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[O:18])([CH2:11][CH3:12])[CH3:9]
Reactant: CCc1cc(OC)ccc1C(=O)N(CC)CC
Reactant: [Li]CCCC
Solvent: CCI
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCC(C)c1cc(OC)ccc1C(=O)N(CC)CC
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a mixture of diisopropylamine (40.7 mL, 290 mmol) in THF (800 mL) at -78° C. was added n-BuLi (100 ML, 255 mmol, 2.15M). The mixture was stirred for 1/4 hour, then 2-ethyl-4-methoxy-N,N-diethylbenzamide (235.3 g) in THF (300 mL) was added at -78° C. The mixture was stirred at -78° C. for 2.5 hours, then at 0° C. for 1 hour, and then ethyliodide (23.2 mL) in THF (150 mL) was added over 10 minutes at -78° C. The reaction mixture was stirred for about 1 hour, quenched with saturated NH4Cl (100 mL) and the solvent was removed in vacuo. Ether (500 mL) was added to the residue, the ether layer was washed with saturated NaHCO3 (50 mL), 1N HCl (50 mL), water, then brine, and then the ether layer was dried over Na2SO4 and the solvent was removed in vacuo. The residue was purified by distillation under high vacuum (2 mm Hg) to afford 46.6 g (76%) of 2-sec-butyl-4-methoxy-N,N-diethylbenzamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:22](=[O:23])[C:21]3[S:24][CH:25]=[CH:26][C:20]=3[NH:19][C:18]2=[O:27])[CH2:11][CH2:10]1.[CH3:28]N(C)C=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][N:17]2[C:22](=[O:23])[C:21]3[S:24][CH:25]=[CH:26][C:20]=3[N:19]([CH3:28])[C:18]2=[O:27])[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(CCn2c(=O)[nH]c3ccsc3c2=O)CC1
Reactant: CN(C)C=O
Product: COc1ccccc1N1CCN(CCn2c(=O)c3sccc3n(C)c2=O)CC1
Yield: 61 %

Procedure:
The title compound was produced following the procedure of Example 13 using dimethylformamide as the solvent and the thienopyrimidine-2,4-dione (1.82 g, 4.66 mmol) from Example 19. The title compound was isolated in 61% yield (1.13 g) after recrystallization from EtOH, mp 149°-151° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[C:15]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[N:14]=[C:13]3[CH2:30][CH2:31][CH2:32][C:12]=23)=[CH:6][CH:5]=1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:41]>>[ClH:41].[N:17]1([C:15]2[N:14]=[C:13]3[CH2:30][CH2:31][CH2:32][C:12]3=[C:11]([NH:10][C:7]3[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][OH:1])=[CH:9][CH:8]=3)[CH:16]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(Nc3ccc(CCO)cc3)c3c(n2)CCC3)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: OCCc1ccc(Nc2cc(N3CCNCC3)nc3c2CCC3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
To a solution of tert-butyl 4-(4-((4-(2-hydroxyethyl)phenyl)amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)piperazine-1-carboxylate (0.026 g, 0.059 mmol) in methylene chloride (5 mL) was added TFA (0.1 mL). The mixture stirred at rt for 16 h and purified by preparative HPLC (water/acetonitrile with 0.05% TFA), followed by formation of the hydrochloride salt to afford the title compound (0.010 g, 41%) as a yellow-brown solid. MW=411.37. 1H NMR (DMSO-d6, 500 MHz) δ 13.21 (s, 1H), 9.46-9.19 (m, 3H), 7.31 (d, J=8.0 Hz, 2H), 7.25 (d, J=8.0 Hz, 2H), 6.04 (s, 1H), 3.68-3.56 (m, 6H), 3.20 (br s, 4H), 3.05-2.96 (m, 2H), 2.81-2.72 (m, 4H), 2.19-2.10 (m, 2H); APCI MS m/z 339 [M+H]+.
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH:13]=[C:14]3[CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16][C@:15]3([CH3:21])[C@H:5]1[CH2:4][CH2:3]2.[C:22]([O:26]O)(C)(C)[CH3:23].Cl[O-:29].[Ca+2].Cl[O-]>C(OCC)(=O)C>[C:22]([O:20][C@H:18]1[CH2:17][CH2:16][C@@:15]2([CH3:21])[C:14](=[CH:13][C:12](=[O:29])[C@@H:6]3[C@@H:5]2[CH2:4][CH2:3][C@@:2]2([CH3:1])[C@H:7]3[CH2:8][CH2:9][C:10]2=[O:11])[CH2:19]1)(=[O:26])[CH3:23]
Reactant: [O-]Cl
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(C)(C)OO
Agent: [Ca+2]
Solvent: CCOC(C)=O
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC(=O)[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Temperature: 10 °C

Procedure:
DHEA-Ac (1.1 gm., 0.0033 mol.) was dissolved in a mixture of ethyl acetate (10 ml) and tert-butyl hydroperoxide (70% aqueous solution from Aldrich, 2.0 ml, 0.015 mol). The mixture was stirred at 10° C. and solid calcium hypochlorite (0.65 gm.) was added in small portions during a period of seven hours. The aqueous layer was then separated and the organic layer was stirred with sodium sulfite solution (3.0 gm in 10 ml of water) for 3 hours at 40-45° C. and filtered over celite. The aqueous yellow layer was removed and the organic layer was washed with half saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated on a rotary evaporator. The crude product, crystallized from methanol, afforded 3β-acetoxyandrost-5-en-7,17-dione (3) as a white solid, weight 0.42 gm.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[F:7][C:8]1[C:9]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][S:22][CH2:21]2)=[CH:10][C:11]2[O:15][C:14](=[O:16])[NH:13][C:12]=2[CH:17]=1>C(O)C.C1COCC1>[F:7][C:8]1[C:9]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][S:22](=[O:2])[CH2:21]2)=[CH:10][C:11]2[O:15][C:14](=[O:16])[NH:13][C:12]=2[CH:17]=1
Reactant: O=c1[nH]c2cc(F)c(NCC3CCCSC3)cc2o1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=c1[nH]c2cc(F)c(NCC3CCCS(=O)C3)cc2o1
Temperature: 25 °C
Reaction time: 20 h
Yield: 22.1 %

Procedure:
Alumina-supported sodium metaperiodate [K. T. Liu and Y. C. Tong, J.O.C. 43:2717 (1989)] (5.6 g) was added to a solution of 1.2 g (4.25 mmole) 5-fluoro-6-[(tetrahydrothiopyran-3-yl)methylamino]benzoxazolin-2-one in 200 ml ethanol and 50 ml THF. The mixture was stirred for 20 hours at room temperature. The alumina was filtered off and the solvent was removed in vacuo. The crude product was purified by silica gel column chromatography, eluting with ethyl acetate/THF/methanol (80:20:5), and recrystallized from methanol/diethyl ether to give the title compound (0.28 g, 22% yield).
Reaction SMILES: [SH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][N:10]2[C:14](=[O:15])[C:13]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:20])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[C:27]([O:31][C:32](=[O:37])[C:33](Br)([CH3:35])[CH3:34])([CH3:30])([CH3:29])[CH3:28]>CN(C)C=O>[C:27]([O:31][C:32](=[O:37])[C:33]([CH3:35])([S:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][N:10]2[C:11](=[O:20])[C:12]3=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]3[C:14]2=[O:15])[N:6]=1)[CH3:34])([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C1c2ccccc2C(=O)N1CCCc1csc(S)n1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCCN2C(=O)c3ccccc3C2=O)cs1
Temperature: 25 °C
Reaction time: 14 h
Yield: 96.5 %

Procedure:
2-Mercapto-4-(3-phthalimidopropyl)-1,3-thiazole (22.6 g) obtained in Example 31 was dissolved in N,N-dimethylformamide (200 mL), potassium carbonate (11.3 g) and 2-bromo-2-methylpropionic acid tert-butyl ester (17.4 g) were added, and the mixture was stirred at room temperature for 14 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added, and the mixture was stirred. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=7:3) to give the title compound (32.0 g) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[CH:4][CH:3]=1.[N+:10]([CH:13]([CH3:15])[CH3:14])([O-:12])=[O:11].CC(C)([O-])C.[K+]>COCCOCCOC>[CH3:14][C:13]([N+:10]([O-:12])=[O:11])([CH3:15])[CH2:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: OCc1ccc(O)cc1
Reactant: CC(C)[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOCCOC
Product: CC(C)(Cc1ccc(O)cc1)[N+](=O)[O-]
Temperature: 38 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
A mixture of 4-hydroxybenzyl alcohol (100.08 g, 806 mmol), 2-nitropropane (400 mL, 4.45 mol), and diglyme (800 mL) was heated to 38° C. Potassium t-butoxide (45.29 g, 403.6 mmol) was added, and the mixture was heated to reflux at 132° C. with a Dean-Stark trap. Water began collecting in the trap, and continued at a high rate for approximately 1.5 h. When water collection slowed (around 2.5 h) then aliquats of solvent (30–40 mL each) were removed every thirty minutes. During the water collection and solvent removal the temperature rose from 132° C. to 149° C. After 4 h less than 1% of the 4-hydroxybenzyl alcohol remained by HPLC analysis. The heating mantle was removed, and the reaction mixture was allowed to cool. When the temperature was 100° C. water (200 mL) was added, and the solution was allowed to cool to room temperature. The solvent was removed on a rotary evaporator under vacuum until 593 g of solution remained. Water (500 mL) and EtOAc (500 mL) were added and the layers were separated, and the aqueous layer was extracted with EtOAc (200 mL). The combined organic layers were extracted with 1N HCl (500 mL) and water (300 mL). The organic layer was distilled in vacuo to 261 g of oil to which EtOAc was added (160 mL). Heptane (3.4 L) was added rapidly with vigorous stirring for 30 min, and the product crystallized to yield a beige solid (112.36 g, 71% yield, >98% purity by HPLC analysis). Another crop of crystals may be obtained from the filtrate by concentrating and filtering the solids, or by concentrating more fully to a solution and adding heptane to crystallize. NMR, MS, and EA.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([SH:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1.[CH3:20][N:21]=[C:22]=[S:23]>ClCCl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([S:17][C:22](=[S:23])[NH:21][CH3:20])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1
Reactant: O=C1C2=C(CCCC2)C(S)N1c1ccc(Cl)cc1F
Reactant: CN=C=S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=S)SC1C2=C(CCCC2)C(=O)N1c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.7 %

Procedure:
In 20 ml of dichloromethane was dissolved 3.0 g of 2-(4-chloro-2-fluorophenyl)-2,3,4,5,6,7-hexahydro-3-mercapto-1H-isoindol-1-one, and 0.8 g of methyl isothiocyanate, together with one drop of triethylamine, was added to the solution, followed by stirring at room temperature for 5 hours. The dichloromethane was distilled off under reduced pressure, and the resulting crystals were washed with cold ethanol and dried, thereby producing 3.5 g (yield of 94%) of the subject compound. Recrystallization from ethanol yielded white crystals, 112°-114° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27]Cl>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2CCCN2)c1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(C2CCCN2Cc2ccccn2)c1
Reaction time: 65 h
Yield: 90.3 %

Procedure:
To a solution of 2-(3-methoxyphenyl)pyrrolidine (3.0 g) in dry acetonitrile (70 ml) was added milled potassium carbonate (6.1 g) followed by 2-picolyl chloride hydrochloride (3.1 g) at ambient temperature, under nitrogen, with stirring for 65 hrs. The reaction mixture was filtered through a pad of celite, and the filter cake was washed with ethyl acetate. The combined filtrates were concentrated and the residue was purified by flash column chromatography (silica gel, 5% methanol/ether). The appropriate fractions were collected and concentrated to give 4.1 g (91%) of 2-(3-methoxyphenyl)-1-(2-pyridinylmethyl)pyrrolidine.