Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9]([O-:11])=[O:10].O.[C@:22]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9]([O:11][CH3:22])=[O:10]
Reactant: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Reactant: O=C([O-])C(c1ccccc1Cl)N1CCc2sccc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1
Temperature: -2.5 °C
Reaction time: 0.17 h

Procedure:
2 g (0.0173 mole) Methyl (2-chlorophenyl(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate (where ee was 95%) was dissolved in 10 ml acetone and the reaction mixture was stirred for 10 min, followed by reflux. To the reaction mixture, 1.49 g (1S)-(+)-camphor-10-sulfonic acid hydrate in 0.8 mL water was added followed by 1 mL acetone. Then whole reaction mixture was refluxed for 1 hrs and cooled gradually. This was later stirred overnight at room temperature. The clear solution was cooled further at 0 to −5° C., wherein precipitate was obtained. The salt formed was added to ethyl acetate and water, which was later basified with NaHCO3, the organic layer was washed with water, concentrated under reduced pressure, to give free base 0.386 g with chiral purity=99.85% (+)-isomer (ee=99.7%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH3:11])[C:6]=2[C:5]([F:12])=[C:4]([F:13])[CH:3]=1.C1C(=O)N([Br:21])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH2:11][Br:21])[C:6]=2[C:5]([F:12])=[C:4]([F:13])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1coc2c(Br)cc(F)c(F)c12
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(Br)c2occ(CBr)c2c1F
Yield: 43 %

Procedure:
the compound (2.6 g, 10.5 mmol) of Step 1 of Example 21, NBS (2.06 g, 11.58 mmol), BPO (catalytic amount), and carbon tetrachloride (120 mL) were added, and heated under reflux overnight. After cooling, the solvent was distilled away. After diluted with ethyl acetate, the resultant was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away, and the resulting residue was purified by silica gel chromatography (hexane/ethyl acetate) to thus obtain the title compound.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([NH2:18])[CH2:15][CH2:16][CH3:17])[CH2:3][CH2:4][CH3:5].[CH2:19](C1CC=CCCC=CCC(CCC)N=N1)[CH2:20]C.[CH3:37][CH2:38]C(N1CCCCCCCCC(C(CC)CC)NC1)CC>>[NH2:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([NH2:18])[CH:15]([CH2:37][CH3:38])[CH2:16][CH3:17])[CH:3]([CH2:19][CH3:20])[CH2:4][CH3:5]
Reactant: CCCC(N)CCCCCCCCC(N)CCC
Reactant: CCCC1CC=CCCC=CCC(CCC)N=N1
Reactant: CCC(CC)C1CCCCCCCCN(C(CC)CC)CN1
Product: CCC(CC)C(N)CCCCCCCCC(N)C(CC)CC

Procedure:
If there are used in the manner described under (a), instead of 942 g (3.79 mols) of 3,12-dipropyl-1,2-diaza-1,5,9-cyclododecatriene, 49 g (0.159 mol) of 3,12-di-(3-pentyl)-1,3-diazacyclododecane and correspondingly reduced amounts of catalyst and solvent, there is obtained, after chromatographic purification and distillation, 26.8 g (54% of theory) of 4,13-diamino-3,14-diethylhexadecane as colourless oil [b.p. 141°-143° C./0.004 Torr; nD° =1.4666; IR (liquid) inter alia bands at 3378, 3278 and 1613 cm-1 ].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[S:20]([N:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][C@H:24]3[CH3:36])(=[O:22])=[O:21])=[CH:10][C:9]=2[F:37])=[CH:4][N:3]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[F:37][C:9]1[CH:10]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]2[CH3:36])(=[O:22])=[O:21])[CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CNCCN1S(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
The title compound was prepared by dissolving (R)-tert-butyl 4-((4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)-3-methylpiperazine-1-carboxylate (42 mg, 0.08 mmol) in a 50/50 mixture of DCM/TFA (1 mL) and allowing it to stir at rt for 2 h. The reaction mixture was concentrated to dryness and the residue subjected to HPLC purification to give the title compound (29 mg, 85%). MS (ESI): mass calcd. for C21H22FN5O2S, 427.15; m/z found, 428.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J=1.4, 2H), 8.16 (dd, J=8.0, 1.4, 1H), 7.65-7.58 (m, 1H), 7.56-7.49 (m, 1H), 7.48-7.39 (m, 1H), 7.38-7.31 (m, 3H), 5.18 (s, 2H), 3.64-3.52 (m, 1H), 2.99-2.87 (m, 2H), 2.81-2.69 (m, 1H), 2.61-2.41 (m, 4H), 1.18 (d, J=6.8, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([S:20]([N:23]1[CH2:28][C@H:27]([CH3:29])[NH:26][C@H:25]([CH3:30])[CH2:24]1)(=[O:22])=[O:21])=[CH:5]2.C(N(C(C)C)CC)(C)C.[Br:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][CH:42]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Br:40][C:41]1[CH:49]=[CH:48][C:44]([C:45]([N:26]2[CH:27]([CH3:29])[CH2:28][N:23]([S:20]([C:6]3[N:7]([S:11]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)(=[O:13])=[O:12])[C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=4)(=[O:21])=[O:22])[CH2:24][CH:25]2[CH3:30])=[O:46])=[CH:43][CH:42]=1
Reactant: C[C@@H]1CN(S(=O)(=O)c2cc3cc(Cl)ccc3n2S(=O)(=O)c2ccccc2)C[C@H](C)N1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CN(S(=O)(=O)c2cc3cc(Cl)ccc3n2S(=O)(=O)c2ccccc2)CC(C)N1C(=O)c1ccc(Br)cc1
Reaction time: 3 h

Procedure:
In dichloromethane (40 ml), cis-1-[(5-chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-3,5-dimethylpiperazine (1.30 g) was dissolved. To the resulting suspension, diisopropylethylamine (645 μl) was added under ice cooling, followed by the dropwise addition of a solution of 4-bromobenzoyl chloride (0.74 g) in dichloromethane (5 ml). Stirring was then effected at room temperature for 3 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture. The organic layer thus separated was washed with 0.5N hydrochloric acid and saturated aqueous NaCl solution, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=2:1 to 1:1), whereby the title compound (1.8 g, 97%) was obtained as a pale yellow amorphous.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][CH:11]=[N:12][C:5]=2[NH:4][C:3]1=[S:13].[H-].[Na+].[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1>CN(C=O)C.C([O-])(O)=O.[Na+]>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][S:13][C:3]3[N:2]([CH3:1])[C:7](=[O:8])[C:6]4[CH:9]=[CH:10][CH:11]=[N:12][C:5]=4[N:4]=3)=[CH:25][CH:24]=2)=[O:22])=[CH:31][CH:32]=1
Reactant: Cn1c(=S)[nH]c2ncccc2c1=O
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(SCc2ccc(C(=O)c3ccc(Cl)cc3)cc2)nc2ncccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
To a solution of 3-methylpyrido[2,3-d]pyrimidin-4-one-2-thione (193 mg) in DMF (5 ml) were added sodium hydride (60 mg) and 4-(4-chlorobenzoyl)benzyl bromide (310 mg) and the mixture was stirred at room temperature for 30 minutes. The reaction mixtrue was then diluted with saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate and the solvent was then distilled off. The residue was recrystallized (ethyl acetate-ether-hexane) to provide the title compound as white powder (162 mg, 38%). 1H-NMR (CDCl3) δ: 3.62(3H,s), 4.73(2H,s), 7.26-7.79(9H,m), 8.54-8.61(1H,m), 8.90-8.95(1H,m).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]2[CH2:9][CH2:10][CH2:11][C:4]=2[N:3]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>C(O)(C)C>[C:12]([NH:16][C:6]1[C:5]2[CH2:9][CH2:10][CH2:11][C:4]=2[N:3]=[C:2]([Cl:1])[N:7]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: Clc1nc(Cl)c2c(n1)CCC2
Reactant: CC(C)(C)N
Solvent: CC(C)O
Product: CC(C)(C)Nc1nc(Cl)nc2c1CCC2
Yield: 63.8 %

Procedure:
A mixture of 2,4-dichloro-6,7-dihydro-5H-cyclopentapyrimidine (0.47 g, 2.5 mmol), tert-butylamine (1.25 ml, 11.8 mmol) and isopropanol (5 ml) was heated at reflux for 8 to 18 hours. After evaporation of volatiles the mixture was purified by flash chromatography over silica gel to afford the title compound as a white solid (0.36 g, 64% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][CH2:7][CH2:6]2.[CH3:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][Cl:21])=[CH:18][CH:17]=1>C(Cl)CCl>[Cl-:21].[CH3:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N+:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)=[CH:18][CH:17]=1
Reactant: COc1cc2c(cc1OC)CCN=C2
Reactant: Cc1ccc(CCl)cc1
Solvent: ClCCCl
Product: COc1cc2c(cc1OC)CC[N+](Cc1ccc(C)cc1)=C2
Product: [Cl-]

Procedure:
The title compound is prepared analogously to Example A from 6,7-dimethoxy-3,4-dihydro-isoquinoline and 4-methylbenzyl chloride in ethylene chloride. Melting point: 181°-183° C. (Decomp.)
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][CH2:6][CH:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]1.Br[CH:15]([CH2:23][CH3:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[H-].[Na+]>C(#N)C>[C:19]([O:18][C:16]([CH:15]([N:8]1[C:2](=[O:1])[CH2:3][CH2:4][CH:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:7]1)[CH2:23][CH3:24])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCC(Br)C(=O)OC(C)(C)C
Reactant: CCOC(=O)C1CCNC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)C1CCC(=O)N(C(CC)C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Yield: 94.4 %

Procedure:
In a 150 ml three necked flask fitted with reflux condenser, magnetic stirrer and dropping funnel under inert atmosphere, 5.09 g (27.5 mmoles, 1 eq) of ethyl 7-oxo-4-azepanecarboxylate 28 and 12.27 g (55 mmoles, 2 eq) of tert-butyl 2-bromobutanoate were dissolved in 70 ml of acetonitrile. The temperature was raised to 50° C. and 1.32 g (55 mmoles, 2 eq) of sodium hydride were added portionwise (exothermicl). The mixture was stirred one more hour at 50° C. and concentrated to dryness, the residue was poured on ice/water and neutralised with solid ammonium chloride. The mixture was extracted three times with CH2Cl2, the combined organic phases were dried over magnesium sulfate, filtered and concentrated to dryness. The residue was purified by PrepLC (1 kg SiO2, CH2Cl2/MTBE, 85/15) to give 8.5 g of pure diester 29, 69% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1S(O)(=O)=O.[CH2:13]([NH2:16])[CH2:14][NH2:15].[C:17](#[N:19])C>>[CH:6]1[CH:7]=[C:2]([Cl:1])[C:3]([NH:19][C:17]2[NH:16][CH2:13][CH2:14][N:15]=2)=[C:4]([Cl:8])[CH:5]=1
Reactant: NCCN
Reactant: CC#N
Reactant: O=S(=O)(O)c1c(Cl)cccc1Cl
Product: Clc1cccc(Cl)c1NC1=NCCN1
Temperature: 65 °C

Procedure:
2,6-dichlorophenylsulfonic acid (1.0 g, 0.0037 m) was added to ethylenediamine (0.5 g, 0.008 m) in the absence of solvent. The reaction exothermed to 35° C. and was diluted with acetonitrile and heated at 65° C. for 7.25 hr. The reaction was concentrated, treated with sodium hydroxide and extracted with methylene chloride. The organic phase was dried and concentrated to yield 0.5 g of clonidine. The product was identified by spectroscopic methods.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH2:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:26][CH3:27])=[C:5]([CH3:28])[O:4][N:3]=1.[N:29]([CH2:32][CH2:33][NH:34]C(=O)OC(C)(C)C)=[C:30]=S.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:26][CH3:27])=[CH:9][C:10]3[C:11]4[N:18]([CH2:19][CH:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)[C:30]([NH:29][CH2:32][CH2:33][NH2:34])=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: CC(C)(C)OC(=O)NCCN=C=S
Reactant: COc1cc2c(NCC3CCOCC3)c(N)cnc2cc1-c1c(C)noc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(NCCN)n(CC3CCOCC3)c12
Reaction time: 1 h
Yield: 31 %

Procedure:
From 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-((tetrahydro-2H-pyran-4-yl)methyl)quinoline-3,4-diamine (for a preparation see Intermediate 17) (70 mg) and 1,1-dimethylethyl (2-isothiocyanatoethyl)carbamate (50 mg). The crude product isolated was treated with TFA (2 ml) in DCM (10 ml), the mixture stirred for 1 h, then evaporated in vacuo. The residue was dissolved in DMSO (1 ml) and purified by MDAP (HpH method) to give the title compound as a beige solid (26 mg, 31%). LCMS (HpH) Rt 0.73 min, MH+ 451
Reaction SMILES: Cl.[F:2][CH2:3][C:4]([C:8]1[CH:9]=[C:10]([NH:20][C:21]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([O:34][CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)=[N:26][CH:25]=2)=[O:22])[N:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:12]=1)([CH2:6][F:7])[CH3:5].[F:41][C:42]1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:43]=1[C:44](Cl)=[O:45].C(N(CC)CC)C.O>ClCCl>[F:41][C:42]1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:43]=1[C:44]([N:38]1[CH2:39][CH2:40][CH:35]([O:34][C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]([NH:23][C:21]([NH:20][C:10]3[N:11]([C:13]4[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=4)[N:12]=[C:8]([C:4]([CH2:6][F:7])([CH3:5])[CH2:3][F:2])[CH:9]=3)=[O:22])=[CH:25][N:26]=2)[CH2:36][CH2:37]1)=[O:45]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Cc1ccc(-n2nc(C(C)(CF)CF)cc2NC(=O)Nc2cnc(OC3CCNCC3)c3ccccc23)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(-n2nc(C(C)(CF)CF)cc2NC(=O)Nc2cnc(OC3CCN(C(=O)c4c(F)cccc4F)CC3)c3ccccc23)cc1

Procedure:
Stir 1-[5-(2-fluoro-1-fluoromethyl-1-methyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]-3-[1-(piperidin-4-yloxy)-isoquinolin-4-yl]-urea hydrochloride (Preparation 37, 0.6 mmol, 0.3 g), 2,6-difluorobenzoyl chloride (0.6 mmol, 0.07 mL) and triethylamine (1.7 mmol, 0.2 mL) in 5 mL of dichloromethane at room temperature overnight. Add some water and extract in dichloromethane. Wash organic layer with saturated aq. sodium chloride. Dry over anhydrous sodium sulfate and concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with hexanes/ethyl acetate as eluent (30%-70%). LCMS ES+(m/z) 675 [M+H].
Reaction SMILES: [CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]=2[CH:6]=[CH:5]1)([CH3:3])[CH3:2].OS(O)(=O)=O.[CH3:23]O>>[CH3:23][O:16][C:15]([C:8]1[C:7]2[CH:6]=[CH:5][N:4]([CH:1]([CH3:3])[CH3:2])[C:12]=2[CH:11]=[C:10]([O:13][CH3:14])[CH:9]=1)=[O:17]
Reactant: COc1cc(C(=O)O)c2ccn(C(C)C)c2c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(OC)cc2c1ccn2C(C)C
Yield: 32.4 %

Procedure:
To a stirred suspension of 1-isopropyl-6-methoxy-1H-indole-4-carboxylic acid (700 mg, 3.00 mmol) in MeOH was added H2SO4 (440 mg, 4.50 mmol) and then heated at reflux for 3 h. Methanol was distilled off completely under reduced pressure and the residue basified with saturated aqueous NaHCO3 solution and extracted with ethyl acetate (2×5 mL). The combined organic layers were dried over anhyrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, 100-200) by eluting 5% ethyl acetate in petroleum ether to afford 1-isopropyl-6-methoxy-1H-indole-4-carboxylic acid methyl ester (240 mg, 32.4%) as white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.45 (d, J=6.8 Hz, 6H), 3.84 (s, 3H), 3.88 (s, 3H), 4.81-4.78 (m, 1H), 6.86 (d, J=3.2 Hz, 1H), 7.34 (d, J=2.4 Hz, 1H), 7.39 (d, J=2 Hz, 1H), 7.54 (d, J=3.6 Hz, 1H). LCMS (ES+): m/z=248.16[M+H].
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[NH2:22][C:23]1[C:32](Br)=[N:31][C:30]([Br:34])=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]>>[NH2:22][C:23]1[C:32]([C:10]2[CH:11]=[CH:12][C:7]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])=[CH:8][CH:9]=2)=[N:31][C:30]([Br:34])=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: CC(C)OC(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(Br)nc(Br)c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1cc(Br)nc(-c2ccc(C(=O)OC(C)C)cc2)c1N
Temperature: 110 °C
Reaction time: 16 h
Yield: 43.2 %

Procedure:
A mixture of 4-isopropoxycarbonylphenylboronic acid (0.98 g, 4 7 mmol), sodium carbonate (1.02 g, 9.58 mmol), tetrakistriphenylphosphine palladium (0) (0.205 g, 0.177 mmol), and methyl 3-amino-2,6-dibromoisonicotinate (1.1 g, 3 6 mmol) in a vial was flushed with nitrogen. Toluene (12 mL) and methanol (4 mL) were added and the reaction stirred at 110° C. for 16 h. The reaction mixture was partitioned between EtOAc and sat. aq. sodium bicarbonate solution. The organic phase was washed with sat. aq. sodium bicarbonate solution, brine, and dried with sodium sulfate. Removal of the solvents followed by silica gel chromatography (step gradient elution with hexane containing 0 to 20% EtOAc afforded methyl 3-amino-6-bromo-2-(4-(isopropoxycarbonyl)phenyl)isonicotinate (1.04 g, 2.59 mmol, 73% yield). MS (ESI) m/z 393.00 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 8.14 (2H, d, J=8.24 Hz), 7.84 (1H, s), 7.69 (2H, d, J=8.24 Hz), 5.94 (2H, br. s.), 5.27 (1H, dt, J=12.51, 6.26 Hz), 3.93 (3H, s), 1.38 (6H, d, J=6.10 Hz).
Reaction SMILES: [ClH:1].[C:2]1([C@:8]2([OH:36])[CH2:16][CH2:15][C:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@@H:13]3[C@H:9]2[CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1>[ClH:1].[C:2]1([C@:8]2([OH:36])[CH2:16][CH2:15][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C@@H:13]3[C@H:9]2[CH2:10][NH:11][CH2:12]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2[C@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@]2(O)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: O[C@@]1(c2ccccc2)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Reaction time: 2 h

Procedure:
115 cm3 of a 6.3N solution of hydrochloric acid in dioxane are added to a solution of 6.8 g of (3aS,4S,7aS)-4,7,7-triphenyl-2-tert-butoxycarbonylperhydroisoindol-4-ol in 60 cm3 of dioxane at room temperature. The reaction mixture is stirred at this temperature for 2 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is washed with acetonitrile, filtered off and then dried. 4 g of (3aS,4S,7aS)-4,7,7-triphenylperhydroisoindol-4-ol hydrochloride are obtained in the form of a white foam.
Reaction SMILES: [CH2:1]1COCC1.[C:6]([CH:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)([CH3:9])([CH3:8])[CH3:7]>C(Cl)Cl.CCCCCC>[C:6]([CH:10]1[CH2:15][CH2:14][C:13](=[CH2:1])[CH2:12][CH2:11]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: C1CCOC1
Reactant: CC(C)(C)C1CCC(=O)CC1
Solvent: ClCCl
Solvent: CCCCCC
Product: C=C1CCC(C(C)(C)C)CC1
Reaction time: 8 h
Yield: 70 %

Procedure:
BDAM (3.00 grams) was suspended in 40 milliliters of methylene chloride and 2 molar equivalents of THF were added at 0° C. After a homogeneous solution was formed, 1 molar equivalent of TEAL in 10 milliliters of hexane was added followed by 2.20 grams of 4-tert-butylcyclohexanone. After overnight stirring, reaction mixture was hydrolyzed and worked up as described in Example 1. A total of 1.50 grams of 4-tert-butyl-1-methylenecyclohexane was isolated (70% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([CH2:54][O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])([CH2:34][O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].CO.[BH4-].[Na+].Cl>C1COCC1.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([CH2:54][O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])([CH2:34][O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:8]=[CH:7][C:4]=1[CH2:5][OH:6]
Reactant: CCCCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCCCC)(COCCCCCCCCCCCCCCCCCC)COc1ccc(C=O)c(OC)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCCCC)(COCCCCCCCCCCCCCCCCCC)COc1ccc(CO)c(OC)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
2-Methoxy-4-(2′,2′,2′-tris(octadecyloxymethyl)ethoxy)benzaldehyde (288 mg, 280 μmol) was dissolved in THF (3 ml), methanol (0.3 ml) and sodium borohydride (31.8 mg, 841 μmol) were added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was cooled to room temperature, 1N hydrochloric acid (5 ml) and chloroform (5 ml) were added, and the mixture was stirred. The aqueous layer was removed, and the organic layer was further washed twice with purified water (5 ml). The organic layer was evaporated under reduced pressure, and the residue was azeotropically distilled with acetonitrile and dried in vacuo to give 2-methoxy-4-(2′,2′,2′-tris(octadecyloxymethyl)ethoxy)benzyl alcohol.
Reaction SMILES: [FH:1].[NH:2]([C:6]1[C:23](=[O:24])[C@@H:22]2O[CH:21]2[C@@:20]2([CH3:26])[C:7]=1[CH:8]=[CH:9][C@@H:10]1[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]1[CH2:12][CH2:13][C:14]2=[O:27])[C:3]([CH3:5])=[O:4].F.O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(Cl)(Cl)Cl>[C:3]([NH:2][C:6]1[C:23](=[O:24])[C:22]([F:1])=[CH:21][C@@:20]2([CH3:26])[C:7]=1[CH:8]=[CH:9][C@@H:10]1[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]1[CH2:12][CH2:13][C:14]2=[O:27])(=[O:4])[CH3:5]
Reactant: F
Reactant: CC(=O)NC1=C2C=C[C@H]3[C@@H]4CCC(=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)C2O[C@H]2C1=O
Agent: *CC*
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(=O)NC1=C2C=C[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)C=C(F)C1=O
Temperature: -60 °C
Yield: 70 %

Procedure:
To a solution of anhydrous hydrogen fluoride (6 g) in tetrahydrofuran (11.8 g) and chloroform (6 ml) contained in a screw-capped polyethylene bottle chilled to about -60° C. was added a solution of 4-acetamino-1,2α-epoxy-androsta-4,6-diene-3,17-dione (3.554 g, 10 mmol) in chloroform (30 ml) likewise chilled to about -60° C. The hydrogen fluoride-tetrahydrofuran reagent was immersed in an acetone-dry ice bath while the steroid was being added. Additional chloroform (6 ml) was used to aid the transfer of the epoxide. Subsequently the reaction mixture was maintained at -30° C. for 4 h and then added gradually to a well agitated mixture of an aqueous solution of potassium carbonate, chloroform and ice. The organic layer was separated, the alkaline aqueous layer back-extracted twice with chloroform and the combined organic layers were evaporated to dryness. The residue was submitted to flash chromatography with ethyl acetate-ethanol to give pure 4-acetylamino-2-fluoroandrosta-1,4,6-triene-3,17-dione in 70% yield (2.502 g).