Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)(=[O:14])=[O:13].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CO.C(Cl)Cl.O>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]2[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:2]=2[Cl:1])(=[O:13])=[O:14])=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(Cl)cc2Cl)cc1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Nc1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(Cl)cc2Cl)cc1

Procedure:
To a solution of the compound of Step 1 (2.12 g) in methanol (50 mL) and CH2Cl2 (50 mL) was added a solution of sodium metabisulfite (2.52 g) in water (50 mL) at room temperature. After 3 hrs the methanol was evaporated in vacuo. The residue was partitioned between sat. aq. Na2CO3 and EtOAc, Dried over MgSO4 and evaporated in vacuo. The resulting orange solid was absorbed onto silica gel (10 g) and purified by flash chromatography SiO2, 0-50% EtOAc Hexanes gradient elution to afford the title compound as a yellow solid. C18H14Cl2N2O3S MH+ requires 409.0175 found 409.0162.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:13])[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[CH:26][O:27][CH3:28])[C:23]([O-:25])=[O:24].[C:29](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:8][N:9]=[C:10]([O:13][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[CH:26][O:27][CH3:28])[C:23]([O:25][CH3:29])=[O:24])[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC=C(C(=O)[O-])c1ccccc1CBr
Reactant: O=C([O-])[O-]
Reactant: CCC(=O)NOCc1ccccc1
Agent: [K+]
Solvent: CC#N
Product: CCC(=NOCc1ccccc1)OCc1ccccc1C(=COC)C(=O)OC
Yield: 26.1 %

Procedure:
A mixture of N-benzyloxypropionamide (1.8 g, 10 mmol), 2-bromomethylphenyl-3-methoxypropenoate (2.85 g, 10 mmol), potassium carbonate (1.66 g, 12 mmol), 4-N,N-dimethyl-aminopyridine (0.1 g) and acetonitrile (20 ml) was heated with reflux for 7 hours. After completion of the reaction, the reaction solution was filtered, the solvent was removed by evaporation, and the residue was purified with silica gel chromatography to obtain methyl 2-[2-{(1-benzyloxyiminopropyl)oxymethyl}phenyl]-3-methoxypropenoate (1.00 g, yield: 26%). The proton NMR Spectra: 1.04 t (3H); 2.21 q (2H); 3.67 s (3H); 3.73 s (3H); 5.01 s (2H); 5.10 s (2H); 7.13-7.45 m (9H); 7.54 s (1H) (Solvent: CDCl3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25].C(N(CC)CC)C.O>C(#N)C>[C:14]([O:13][C:12](=[O:18])[NH:11][C@@H:9]1[CH2:10][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:24]([C:23]2[CH:27]=[CH:28][CH:29]=[C:21]([C:20]([F:19])([F:30])[F:31])[CH:22]=2)=[O:25])=[CH:3][CH:4]=1)([CH3:15])([CH3:17])[CH3:16]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl]carbamate (100 mg) described in a document (J. Am. Chem. Soc., 2010, 132, 6827.) in acetonitrile (4 mL) were added 3-(trifluoromethyl)benzoyl chloride (126 mg) and triethylamine (84 μL). The mixture was stirred at room temperature for 30 min and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was crystallized (hexane/ethyl acetate) to give the title compound (161 mg).
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][N:10]2[C:22]3[CH:21]=[C:20]([CH3:23])[CH:19]=[C:18]([OH:24])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:25](=[O:27])[NH2:26])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:29][C:30]([O:32][CH3:33])=[O:31]>CN(C=O)C.C1COCC1.C(OCC)(=O)C>[C:3]1([CH2:9][N:10]2[C:22]3[CH:21]=[C:20]([CH3:23])[CH:19]=[C:18]([O:24][CH2:29][C:30]([O:32][CH3:33])=[O:31])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:25](=[O:27])[NH2:26])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cc(O)c2c3c(C(N)=O)cccc3n(Cc3ccccc3)c2c1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)COc1cc(C)cc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1
Reaction time: 0.17 h
Yield: 75 %

Procedure:
60% Sodium hydride in mineral oil (30.4 mg, 0.76 mM) was added to a solution of 9-[(phenyl)methyl]-2-methyl-4-hydroxy-5-carbamoyl carbazole (202 mg, 0.61 mM) in 21 mL DMF and 4.6 ml THF. After 10 minutes, methyl bromoacetate (77 μl, 0.482 mM) was added and the resultant mixture stirred at room temperature for 1.25 hours. The mixture was diluted with ethyl acetate and washed with H2O. The aqueous layer was extracted with ethyl acetate. The combined organic layers were extracted with saturated brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 184 mg (75%) of {9-[(phenyl)methyl]-2-methyl-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester. 1H NMR (DMSO-d6) δ 7.55 (d, 1H, J=8 Hz), 7.5 (bs, 1H), 7.4-7.15 (m, 9H), 6.45 (s, 1H), 5.7 (s, 2H), 4.9 (s, 2H), 3.75 (s, 3H), 2.4 (s, 3H). MS (FD) m/e 386, 403.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][CH:15]([F:17])[F:16])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:18][C:19]1[CH:27]=[CH:26][C:25]([CH2:28][NH:29][C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])=[O:31])=[CH:24][C:20]=1[C:21](O)=[O:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(Cl)Cl.CCO>C1COCC1>[F:17][CH:15]([F:16])[CH2:14][O:13][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:21](=[O:22])[C:20]2[CH:24]=[C:25]([CH2:28][NH:29][C:30]([C:32]([CH3:33])([CH3:35])[CH3:34])=[O:31])[CH:26]=[CH:27][C:19]=2[Cl:18])=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Reactant: CCOC(=O)c1cc(N)ccc1OCC(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cc(NC(=O)c2cc(CNC(=O)C(C)(C)C)ccc2Cl)ccc1OCC(F)F

Procedure:
Prepared analogously to Example 4c from 2 ethyl 5-amino-2-(2,2-difluoroethyl)oxy-benzoate and 2-chloro-5-(tert-butylcarbonylamino)methyl-benzoic acid with TBTU and TEA in THF. Yield: (quantitative). MS [M+H]+=497 (Cl isotope pattern); TLC: Rf=0.35 (silica gel, DCM:EtOH 19:1).
Reaction SMILES: Br[C:2]([F:26])([F:25])[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])Br.[CH3:27][Si:28](Cl)([CH3:30])[CH3:29].[Mg].F[C]>C1COCC1>[CH3:27][Si:28]([CH3:30])([CH3:29])[C:2]([F:26])([F:25])[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[Si:28]([CH3:30])([CH3:29])[CH3:27]
Reactant: FC(F)(Br)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)Br
Reactant: C[Si](C)(C)Cl
Agent: [C]F
Agent: [Mg]
Solvent: C1CCOC1
Product: C[Si](C)(C)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
A mixture of 1,8-dibromohexadecafluorooctane (27.3 g) and the corresponding C10 derivative (4.4 g) (55.5 mmol) and trimethylsilyl chloride (54.9 g, 0.55 mol) was added to a slurry of magnesium turnings (4.11 g, 69 mmol) in THF (300 mL) over 25 minutes at -35° C. The mixture was stirred for 1.5 hours. The mixture was then allowed to warm slowly to 25° C. over 18 hours. Excess magnesium was removed by N2 pressure filtration, and most of the solvent was removed under reduced pressure. Petroleum ether (50 mL) was added, and the mixture was treated (twice) with 500 ml ice water. The organic layer was dried, stripped and kugelrohr distilled to provide 5.17 g (bp 50°-66° C., 0.05 mm; 55% of 1,8-bis(silyl) derivative, and a higher-boiling fraction, 21.4 g (bp 60°-80° C.; 82% 1,8-bis(silyl) derivative and 13% 1,10-bis(silyl) derivative; overall yield ca. 71%). 1H NMR (THF-d8): 0.30 (s). 19F NMR (THF-d8 /Freon® 11): -118.54 (s, 4F, CF2Si), -121.52 (s, 8F), -127.97 (s, 4F). GC analysis of the sample used for NMR showed a 92.4/7.6 ratio of C8 /C10 fluorocarbon products.
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7]([N:9]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][S:11][C@@H:10]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])=[O:8])(=[O:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.[NH2:39][C@H:40]([C:45]([OH:47])=[O:46])[CH2:41][CH:42]([CH3:44])[CH3:43]>C1COCC1.C(N(CC)CC)C>[C:1]([S:4][CH2:5][CH2:6][C:7]([N:9]1[C@H:13]([C:14]([NH:39][C@H:40]([C:45]([OH:47])=[O:46])[CH2:41][CH:42]([CH3:44])[CH3:43])=[O:16])[CH2:12][S:11][C@@H:10]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCCC(=O)N1[C@@H](c2ccccc2O)SC[C@H]1C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)SCCC(=O)N1[C@@H](c2ccccc2O)SC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)O
Yield: 76.7 %

Procedure:
The suspension of mixed anhydride in THF is prepared by using 1.78 g of (2R,4R)-3-(S-acetyl-3-mercaptopropanoyl)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid, 0.51 g of N-methylmorpholine and 0.68 g of isobutyl chlorocarbonate. To the suspension the aqueous solution of 1.31 g of L-leucine and 1.0 g of triethylamine is added, and treated in the same manner as Example 1 to give 1.8 g (77%) of the titled compound.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[O:13][CH3:14].C(N(CC)CC)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC(C)=O.C(OCC)(=O)C>CC(C)=O>[OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([O:9][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:8])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: BrCc1ccccc1
Reactant: COc1cc(C(O)C(=O)O)ccc1O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc(C(O)C(=O)OCc2ccccc2)ccc1O
Reaction time: 5 h
Yield: 277.5 %

Procedure:
To a mixture of 4.371 g (0.022 mole) of 4-hydroxy-3-methoxymandelic acid, 11 ml of triethylamine in 100 ml of acetone was added 3.13 ml (0.0265 mole) of benzyl bromide. The reaction mixture was stirred (magnetic stirring) and heated at reflux (oil bath) under a nitrogen atmosphere. After 5 minutes of heating the reaction mixture became cloudy. Thin layer chromatography (TLC) (silica gel, acetone/ethyl acetate 95:5) showed 50% of the starting material remaining after 5 hours. Additional triethylamine (2 ml) and benzyl bromide (1.5 ml) were added, and the mixture was heated at reflux for 4 hours. TLC still showed starting material present. Additional reagents were added (1.5 ml benzyl bromide and 2 ml triethylamine) and heating was continued for 14 hours. The triethylamine hydrobromide was removed by filtration, and the filter cake was washed with acetone (3×10 ml). The filtrate and washings were evaporated to give 17.6 g of a semi-solid residue. The residue was triturated with water (30 ml), and the product extracted with methylene chloride (4×15 ml) and dried (sodium sulfate). Evaporation of the solvent yielded 4.99 g of a light-brown oil which was triturated with hexanes (20 ml) to crystallize the product. The cream-colored solid was separated and washed with hexanes (3×10 ml) to give 3.351 g (53% yield) of the product. Estimated purity by TLC was 98% (hexanes/acetone 5:1).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:23][CH:22]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]4[CH2:31][CH2:32][CH2:33][CH2:34]4)=[CH:23][CH:22]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: COc1cccc([C@@H]2COc3cc(OC)ccc3[C@@H]2c2ccc(OCCN3CCCC3)cc2)c1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1cccc([C@@H]2COc3cc(O)ccc3[C@@H]2c2ccc(OCCN3CCCC3)cc2)c1

Procedure:
In an manner analogous to that described in step 5 for Example 10, (±)-cis-7-methoxy-3-(3-methoxyphenyl)-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane (0.345 g, 0.75 mmol) was de-methylated by heating with pyridine hydrochloride to give the title compound as an off-white foam.
Reaction SMILES: [CH2:1]([C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[C:12]([F:19])[C:11]=1[F:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[OH:21]O>>[CH2:1]([C:10]1[CH:15]=[CH:14][C:13]([OH:21])=[C:12]([F:19])[C:11]=1[F:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: OO
Reactant: CCCCCCCCCc1ccc(B(O)O)c(F)c1F
Product: CCCCCCCCCc1ccc(O)c(F)c1F

Procedure:
Quantities: compound from Example 32 (13.6 g, 60 mmol) and H2O2, (10%, 61 cm3). The experimental procedure was described in Example 37.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[C:32][CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:9]2[CH2:10][CH2:11][C:6]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[C:32][CH2:33][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[CH:25][CH:24]=3)(=[O:22])=[O:21])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OCC#CCN3CCCCC3)cc2)CCN(Cc2ccc(Br)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1(S(=O)(=O)c2ccc(OCC#CCN3CCCCC3)cc2)CCN(Cc2ccc(Br)cc2)CC1

Procedure:
1-(4-Bromo-benzyl)-4-[4-(4-piperidin-1-yl-but-2-ynyloxy)-benzenesulfonyl]-piperdine-4-carboxylic acid was prepared starting from 1-(4-bromo-benzyl)-4-[4-(4-piperidin-1-yl-but-2-ynyloxy)-benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester (4.64 g, 7.5 mmol) dissolved in THF:methanol (50:150 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in Example 1 (Step 7). Yield 3.35 g (76%); off white solid; mp 180° C.; MS: 295.9 (M+2H)2+ 590.9 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([Cl:11])[CH:3]=1.[CH2:12]([N:14](CC)[CH2:15][CH3:16])[CH3:13].N1CCCC1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:14]2[CH2:15][CH2:16][CH2:13][CH2:12]2)=[O:8])=[C:4]([Cl:11])[CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(Br)cc1Cl
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCNC1
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Br)cc1Cl)N1CCCC1
Reaction time: 1 h
Yield: 96.3 %

Procedure:
4-Bromo-2-chloro-benzoic acid (30 g, 127.4 mmol) was placed in a 3 L round bottom flask and 1.5 L of EtOAc was transferred into it. Triethylamine (25.8 g, 255 mmol), pyrrolidine (18 g, 255 mmol), and T3P (48.6 g, 152.9 mmol, 50 wt % in EtOAc) were then added. After 1 hr, the reaction was quenched with 200 mL of 1N NaOH and stirred for 10 min. The layers were separated and after 2 more extractions of the aqueous phase with EtOAc (2×500 ml), the combined organic extracts were dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to obtain a viscous oil. Flash chromatography using a 330 g ISCO™ column and 50%, 80% EtOAc/Hexanes yielded the title compound as a light yellow colored viscous oil (35.4 g, 96% yield). Rf=0.25 (50% EtOAc/Hexanes), LRMS m/z Calcd for C11H11BrClNO, 288.6, found, 289.9 (M+H) APCI; 1H-NMR (CDCl3) δ 7.56 (d, J=1.7 Hz, 1H), 7.43 (dd, J=1.7, 8.3 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 3.63 (b apt t, J=6.6 Hz, 2H), 3.17 (B apt t, J=6.6 Hz, 2H), 2.00-1.84 (m, 4H). 13C-NMR (CDCl3) δ 166.0, 136.6, 132.6, 131.3, 130.7, 128.9, 123.3, 48.0, 45.8, 26.1, 24.7.
Reaction SMILES: O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[CH:13]1([CH2:19][C@H:20]([NH:32][CH2:33]C(=O)NC(C)(C)C)[CH2:21][NH:22][C:23](=[O:31])[O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)C.CCOCC>[CH:13]1([CH2:19][C@H:20]([NH:32][CH3:33])[CH2:21][NH:22][C:23](=[O:31])[O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:28])[CH3:30])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CC(C)(C)NC(=O)CN[C@H](CNC(=O)OCC[Si](C)(C)C)CC1CCCCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: CN[C@H](CNC(=O)OCC[Si](C)(C)C)CC1CCCCC1
Reaction time: 2 h
Yield: 9.4 %

Procedure:
A solution of toluenesulfonic acid monohydrate (10 mg, 0.053 mmol) in absolute ethanol (1 mL) was added to a solution of 2-(trimethylsilyl)ethyl (S)-3-cyclohexyl-2-((tert-butyl-carbamoyl)methylamino)propylcarbamate (21.3 mg, 0.51 mmol) in Et2O (10 mL). This solution was placed in a flask on a rotary evaporator and the Et2O was removed at ambient temp. The flask was then lowered into a water bath (60° C.) and selective removal of the Boc group proceeded concurrently with removal of the solvent. The reaction was complete within 2 h. This material was taken up in CH2Cl2 (20 mL) and 1N aq NaOH (10 mL) and extracted with CH2Cl2 (2×10 mL). The combined organic layers were washed with brine (2×5 mL), dried over Na2SO4, decanted, and stripped to afford 2-(trimethylsilyl)ethyl (S)-3-cyclohexyl-2-(methylamino)propylcarbamate (15.0 mg, 94%) as a clear film. MS ESI+ve m/z 315 (M+1).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2.[Br:24][CH2:25][C:26]([NH:28][C:29]1[O:33][N:32]=[C:31]([CH3:34])[CH:30]=1)=[O:27].C(OCC)(=O)C.CCCC(C)C>C(#N)C>[Br-:24].[CH3:34][C:31]1[CH:30]=[C:29]([NH:28][C:26]([CH2:25][N+:1]23[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]2)[C@@H:3]([O:9][C:10]([C:12]2([C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:2]3)=[O:27])[O:33][N:32]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2cccs2)CCCCCC1
Reactant: Cc1cc(NC(=O)CBr)on1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCCC(C)C
Product: Cc1cc(NC(=O)C[N+]23CCC(CC2)[C@@H](OC(=O)C2(c4cccs4)CCCCCC2)C3)on1
Product: [Br-]
Reaction time: 8 h
Yield: 45.8 %

Procedure:
1-Thiophen-2-yl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 5d) (50 mg) and 2-bromo-N-(3-methylisoxazol-5-yl)acetamide (Example 7a) (32 mg) were dissolved in acetonitrile (2 mL) and left overnight. Ethyl acetate (10 mL) and isohexane (10 mL) were added and the crystals filtered off, washed with ethyl acetate and dried to afford the titled compound (37 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[C:3]1[C:10]([O:12]C)=[O:11].[OH-].[Na+]>C1COCC1.O.O>[CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[C:3]1[C:10]([OH:12])=[O:11]
Reactant: COC(=O)c1cc([N+](=O)[O-])cn1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc([N+](=O)[O-])cc1C(=O)O
Reaction time: 8 h
Yield: 87.8 %

Procedure:
Methyl 1-methyl-4-nitro-1H-pyrrole-2-carboxylate (5.0 g, 27.17 mmol) in 120 ml of 1:1 THF/H2O was added 8 g of NaOH in 30 ml of water. The mixture was stirred overnight, concentrated, diluted with water, extracted with EtAc/Hexane (1:1). The aqueous solution was adjusted to pH 3˜4 with 20% H3PO4 and extracted with EtAc (4×60 ml). The organic solutions were combined, dried over MgSO4, filtered, evaporated and crystallized with ethanol/EtAc/Hexane to afford 4.06 g (88%) of the title product. 1H NMR (DMSO) 13.12 (s, 1H), 8.21 (s, 1H), 7.25 (s, 1H), 3.91 (s, 3H); 13C NMR 160.97, 134.01, 129.16, 123.81, 111.38, 37.47; MS m/z−169.1 (M−H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=1[NH:18][C:19](=[O:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN>CCOC(C)=O.CCO.[Ni]>[NH2:15][C:13]1[CH:12]=[CH:11][C:10]([NH:18][C:19](=[O:21])[CH3:20])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cc1OCc1ccccc1
Agent: [Ni]
Agent: NN
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)Nc1ccc(N)cc1OCc1ccccc1
Yield: 85.1 %

Procedure:
N-(2-Benzyloxy-4-nitro-phenyl)-acetamide (418) (5 g, 17.5 mmol) was dissolved in a mixture of EtOAc (25 mL) and EtOH (25 mL). The solution was chilled on an ice bath. Raney Nickel (5 mL, 50% slurry in water) followed immediately by anhydrous hydrazine (10 mL) were added. Violent bubbling was observed. The ice bath was removed after 10 minutes and the slurry continued to stir until all bubbling had ceased (˜30 minutes). LC-MS and TLC (Rf: 0.15 compared to Rf: 0.5 for compound 418 in 1:1 hexane/EtOAc) indicated complete reduction at this point. The reaction mixture was passed through a plug of silica gel, concentrated, dissolved in EtOAc (250 mL), washed with water (2×75 mL), brine (2×75 mL), dried over MgSO4 and concentrated to give the desired product (419) as a beige solid (3.82 g, 14.9 mmol, 85.3% yield). LC-MS (ESI): (exact mass: 256.12) m/e=257.1 [M+1]+ (100%), 513.2 [2M+1]+ (15%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C:19]2(SC2C=CC=CC=2)[S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:15]2[C@@:6]1([F:39])[C@:7]1([CH3:38])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:37])[CH:9]=[CH:8]1)(=[O:3])[CH3:2]>C(C1C=CC=CC=1CC)C>[C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH:18]=[C:19]2[S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:15]2[C@@:6]1([F:39])[C@:7]1([CH3:38])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:37])[CH:9]=[CH:8]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1C[C@@]2(C)[C@@H](CCC2(Sc2ccccc2)Sc2ccccc2)[C@@H]2CCC3=CC(=O)C=C[C@]3(C)[C@@]12F
Agent: CCc1ccccc1CC
Product: CC(=O)O[C@H]1C[C@]2(C)C(Sc3ccccc3)=CC[C@H]2[C@@H]2CCC3=CC(=O)C=C[C@]3(C)[C@@]12F
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
A suspension of 1.5 g of 11β-acetyloxy-17,17-bis(phenylthio)-9-fluoroandrosta-1,4-dien-3-one in 25 ml of dry diethylbenzene is stirred at 185°-190° C. (oil bath temperature) for 1.0 hour. The suspension gradually becomes a homogeneous solution during the heating and the resulting solution is cooled to 0° C. The solid that precipitates is filtered and dried in vacuo to give 0.9 g of the title compound, melting point 228°-229° C., with consistent spectral data.
Reaction SMILES: [CH3:1][C:2]([CH2:10][CH3:11])([CH2:6][C:7]([OH:9])=O)[C:3]([OH:5])=O.[N+:12]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18])([O-:14])=[O:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[N+:12]([C:15]1[CH:16]=[C:17]([N:18]2[C:7](=[O:9])[CH2:6][C:2]([CH3:1])([CH2:10][CH3:11])[C:3]2=[O:5])[CH:19]=[CH:20][CH:21]=1)([O-:14])=[O:13]
Reactant: CCC(C)(CC(=O)O)C(=O)O
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: CCC1(C)CC(=O)N(c2cccc([N+](=O)[O-])c2)C1=O

Procedure:
Sixty-four g. of 2-methyl-2-ethylsuccinic acid was combined with 55.2 g. of m-nitro aniline in 250 ml. of xylene. One-half g. of p-toluene sulfonic acid was added and the mixture heated to reflux under a modified Dean Stark apparatus. After 15-16 ml. of water was removed, the mixture was cooled and the product recovered by filtration. Yield was 78 g. of a product having a m.p. of 88°-89° C. The product was identified as the title compound by analysis of infrared spectra.