Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]([CH2:14]Cl)=[CH:4][N:3]=1.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:16]([CH2:14][C:5]1[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)CNc1nc(Cl)ncc1CCl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)CNc1nc(Cl)ncc1CN=[N+]=[N-]
Temperature: 30 °C
Reaction time: 2.5 h

Procedure:
A solution of 1.47 g (5.92 mmol) of (2-chloro-5-chloromethyl-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine and 0.46 g (7.1 mmol) NaN3 is dissolved in 6 ml of DMF and was stirred at 30° C. for 2.5 hours. Then the reaction mixture is cooled to rt., diluted with ethyl acetate and twice extracted with H2O. The organic layer is separated and dried over Na2SO4. Evaporation of the ethyl acetate yielded (5-azidomethyl-2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine as white crystalls.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[C:16]=1[NH2:22].FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[NH2:22][C:16]1[C:17]([NH:21][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)=[CH:18][CH:19]=[CH:20][N:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1cccnc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccnc2N)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 883.8 %

Procedure:
A 50 mL 3-necked round bottom flask fitted with a thermometer and an overhead stirrer was charged with tert-butyl 4-oxopiperidine-1-carboxylate (3.00 g, 15.1 mmol) and acetonitrile (25 mL, HPLC grade). The reaction mixture was stirred at room temperature for 10 minutes to ensure complete dissolution of all solid material. Pyridine-2,3-diamine (1.50 g, 13.7 mmol) was added, the slurry was stirred for an additional 30 minutes, and resulted in the formation of a dark brown solution. The reaction mixture was cooled to 5° C. and trifluoroacetic acid (2 mL) was added over a period of 20 minutes. During the course of the addition, fuming was observed, accompanied by a slight temperature rise to 10-15° C. The reaction mixture was stirred for an additional 30 minutes at 5-10° C., and sodium triacetoxyborohydride (4.37 g, 20.6 mmol) was added over a period of 20 minutes. The ice bath was removed and the reaction mixture was stirred for an additional 30 minutes. The flask was placed back in an ice bath and aqueous 4M sodium hydroxide was added to the reaction in small portions to adjust the reaction mixture to pH 8. The solution was stirred for an additional 30 minutes, cooled to 5° C., and diluted with ice cold water (80 mL), and resulted in the formation of a brown precipitate. The resulting slurry was stirred overnight at room temperature. The solids were collected by vacuum filtration, washed with cold water (3×5 mL) and dried to constant weight to give 35.4 g (88% yield) of tert-butyl 4-(2-aminopyridin-3-ylamino)piperidine-1-carboxylate. This material was submitted to the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ 7.25 (dd, 1H), 6.64 (d, 1H), 6.17 (dd, 1H), 5.43 (broad s, 2H), 4.48 (d, 1H), 3.88 (d, 2H), 3.38 (broad s, 1H), 2.87 (broad s, 2.87), 1.87 (d, 2H), 1.38 (s, 9H), 1.19 (m, 2H). MS (EI) for C15H24N4O2: 293 (MH+)
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH3:6][N:7]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[F:14][C:15]1[C:21](F)=[CH:20][C:18]([NH2:19])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=1.O>CN(C=O)C>[F:14][C:15]1[C:21]([N:10]2[CH2:11][CH2:12][CH2:13][N:7]([CH3:6])[CH2:8][CH2:9]2)=[CH:20][C:18]([NH2:19])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: CN1CCCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCCN(c2cc(N)c([N+](=O)[O-])cc2F)CC1
Temperature: 80 °C
Yield: 90.9 %

Procedure:
36.2 g of sodium bicarbonate and 29.5 g of N-methyl-homopiperazine are added to a solution of 15 g of 4,5-difluoro-2-nitroaniline in 120 mL of anhydrous DMF. The reaction medium is heated at 80° C. using an oil bath for 2H30. The reaction medium is cooled to ambient temperature, and then poured into 400 mL of water. The mixture is cooled using an ice bath and stirred, and precipitation occurs. The precipitate is filtered off through sintered glass. The yellow solid is rinsed with water. The solid is dried in an oven at 40° C. 21 g of 4-fluoro-5-(4-methylperhydro-1,4-diazepin-1-yl)-2-nitrophenylamine are obtained in the form of a yellow solid. 1H NMR (300 MHz, DMSO-d6, δ in ppm): 1.90 (m, 2H); 2.27 (s, 3H); 2.50 (m masked, 2H); 2.64 (m, 2H); 3.46 (m, 2H); 3.52 (m, 2H); 6.21 (d, J=9.0 Hz, 1H); 7.24 (broad s, 2H); 7.59 (d, J=16.0 Hz, 1H). EI mass spectrum: m/z=268: M+. (base peak)—m/z=253: (M−CH3)+—m/z=198: (M−C4H8N)+—m/z=70: C4H8N+—m/z=57: C3H7N+.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1B(O)O>>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[N:15]1[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:17]=[CH:16]1
Reactant: OB(O)c1c(Cl)cccc1Cl
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Product: Oc1ccc2ncn(-c3c(Cl)cccc3Cl)c2n1

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 2,6-dichlorophenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=279.9 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:15])[CH:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]=[N:11][C:10]=2[CH:14]=1)[CH3:5].O[Li].O.C(O)(=O)C>C1COCC1.O>[O:13]1[C:9]2[CH:8]=[CH:7][C:6]([CH:4]([CH3:5])[C:3]([OH:15])=[O:2])=[CH:14][C:10]=2[N:11]=[CH:12]1
Reactant: COC(=O)C(C)c1ccc2ocnc2c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc2ocnc2c1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
Methyl-2-(benzo[d]oxazol-5-yl)propanoate (425 mg, 2.07 mmol) was dissolved in THF (8 ml) and water (8 ml). LiOH.H2O (93 mg, 2.21 mmol) was added thereto at RT. The reaction mixture was stirred for 40 h at RT, combined with water (25 ml) and adjusted with acetic acid to a pH value of 3. The reaction mixture was extracted with DC M and the combined organic phases were dried over MgSO4 and filtered. The solvent was removed under a vacuum and the residue purified by means of column chromatography (n-hexane/MeOH=15:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.[CH3:12][C:13](=O)[CH3:14].N1CCCC1>C1C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([C:8](=[O:10])[CH2:9][C:13]([CH3:14])([CH3:12])[O:11]2)=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: CC(=O)c1ccc(F)cc1O
Solvent: c1ccccc1
Solvent: C1CCNC1
Solvent: CCOC(C)=O
Product: CC1(C)CC(=O)c2ccc(F)cc2O1
Temperature: 80 °C
Yield: 70.7 %

Procedure:
To 1-(4-fluoro-2-hydroxyphenyl)ethanone (5.75 g, 37.3 mmol) and propan-2-one (12 mL, 37.3 mmol) in benzene (50 mL) was added pyrrolidine (3.11 mL, 37.3 mmol) and the reaction heated at 80° C. for 3 hours. The reaction was diluted with ethyl acetate (50 mL), washed with 1N HCl (50 mL), brine (50 mL), dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of 5% ethyl acetate/hexanes to 50% ethyl acetate, to provide the title compound (5.12 g, 70.7% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[CH2:17]([OH:20])[CH:18]=[CH2:19].[H-].[Na+]>CN(C)C=O>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=[C:2]([O:20][CH2:17][CH:18]=[CH2:19])[CH:7]=1
Reactant: C=CCO
Reactant: Clc1cc(Cl)nc(OCc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(Cl)nc(OCc2ccccc2)n1
Temperature: 25 °C

Procedure:
4,6-Dichloro-2-(phenylmethoxy)pyrimidine (Compound I-173) (1.5 g, 5.9 mmol) and allyl alcohol (0.342 g, 5.9×1.0 mmol) were introduced into a 50 ml eggplant type flask, to which dimethylformamide (20 ml) was added to form a solution. While cooling with ice, 60% sodium hydride (0.247 g, 5.9×1.05 mmol) which had been washed with hexane was added. After stirred for one night at room temperature, the reaction solution was poured into iced water and extracted with toluene (40 ml). The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and thereafter, the solvent was distilled off to afford an oily product, which was then purified on silica gel column chromatography (Wakogel C300, 300 ml, hexane/ethyl acetate=25/1000(v/v)) to obtain the compound (I-343).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[F:19][C:20]1[C:25]([F:26])=[CH:24][C:23]([F:27])=[C:22]([F:28])[C:21]=1[N:29]=[C:30]=[S:31]>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])=[CH:3][C:2]=1[NH:1][C:30]([NH:29][C:21]1[C:22]([F:28])=[C:23]([F:27])[CH:24]=[C:25]([F:26])[C:20]=1[F:19])=[S:31]
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: Fc1cc(F)c(F)c(N=C=S)c1F
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1c(F)c(F)cc(F)c1F
Yield: 88.6 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.243 g, 1.0 mmol) and 2,3,5,6-tetrafluorophenyl isothiocyanate (0.224 g, 1.1 mmol) to give the product (0.398 g); m.p. 170-174° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.C([Li])CCC.CN(C)CCN(C)C.[CH2:20]([Sn:24](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23]>C1COCC1>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[Sn:24]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1cccc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Temperature: -35 °C
Reaction time: 1.5 h

Procedure:
1-Methylpyrrole (0.065 g) was added to a cooled (-35° C.), stirred solution of butyllithium (2.5M, 0.32 mL) in dry THF (5 mL). N,N,N',N'-Tetramethylethylenediamine (0.090 g) was then added and the mixture was stirred for 90 min at -10° to -15° C. Tributyltin chloride (0.26 g) was then slowly added, and the mixture was allowed to warm to room temperature and stirred for 15 min. The solvent was evaporated to provide (1-methylpyrrol-2-yl)tributyltin, suitable for use in the next reaction.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:33]=[CH:32][C:11]2[CH2:12][C@@H:13]3[C@@H:18]([CH3:19])[C@:17]([CH3:20])([C:10]=2[CH:9]=1)[CH2:16][CH2:15][N:14]3[C:21]([C:23]1[CH:31]=[CH:30][C:26]2[N:27]=[CH:28][NH:29][C:25]=2[CH:24]=1)=[O:22])=[O:7])C.Cl>C(O)C>[N:27]1[C:26]2[CH:30]=[CH:31][C:23]([C:21]([N:14]3[CH2:15][CH2:16][C@:17]4([CH3:20])[C@H:18]([CH3:19])[C@H:13]3[CH2:12][C:11]3[CH:32]=[CH:33][C:8]([C:6]([OH:7])=[O:5])=[CH:9][C:10]=34)=[O:22])=[CH:24][C:25]=2[NH:29][CH:28]=1
Reactant: CCOC(=O)c1ccc2c(c1)[C@]1(C)CCN(C(=O)c3ccc4nc[nH]c4c3)[C@H](C2)[C@H]1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H]1[C@H]2Cc3ccc(C(=O)O)cc3[C@]1(C)CCN2C(=O)c1ccc2nc[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Aqueous 4 M NaOH solution (1 mL) is added to a solution of (2R,6R,11S)-3-(3H-benzoimidazole-5-carbonyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8-carboxylic acid ethyl ester (0.60 g) in ethanol (3 mL). The resulting solution is stirred at ambient temperature for 3 h. Then, the solution is slightly acidified (pH ca. 5) using 1 M hydrochloric acid and the resulting solution is extracted with ethyl acetate. The combined organic extracts are washed with brine and dried (MgSO4). The solvent is evaporated under reduced pressure to give the product as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH:9][C:10]([C:12]2[C:13]([S:18][CH2:19][CH3:20])=[N:14][CH:15]=[N:16][CH:17]=2)=O)=[CH:7][C:6]([C:21]([F:24])([F:23])[F:22])=[CH:5][N:4]=1.C(=O)(O)[O-].[Na+]>CN1C(=O)CCC1>[CH2:19]([S:18][C:13]1[C:12]([C:10]2[N:2]([CH3:1])[C:3]3=[N:4][CH:5]=[C:6]([C:21]([F:24])([F:23])[F:22])[CH:7]=[C:8]3[N:9]=2)=[CH:17][N:16]=[CH:15][N:14]=1)[CH3:20]
Reactant: CCSc1ncncc1C(=O)Nc1cc(C(F)(F)F)cnc1NC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCSc1ncncc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 150 °C
Reaction time: 2 h
Yield: 7.1 %

Procedure:
A mixture of 1.94 g of 4-ethylsulfanylpyrimidine-5-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide, 2.07 g of p-toluenesolufonic acid-hydrate and 5 ml of NMP was heated and stirred at 150° C. for 2 hours. A saturated aqueous sodium bicarbonate solution was poured to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 130 mg of 2-(4-ethylsulfanylpyrimidin-5-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as Compound of Present Invention 14).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH2:7][S:6][C:5]1=[O:10].[CH3:11][NH:12][CH3:13].O>CN(C=O)C>[CH3:11][N:12]([CH3:13])[CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH2:7][S:6][C:5]1=[O:10]
Reactant: O=C1CSC(=O)N1CCBr
Reactant: CNC
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCN1C(=O)CSC1=O
Temperature: 50 °C
Yield: 23.8 %

Procedure:
To a 35 ml seal tube, 3-(2-bromoethyl)thiazolidine-2,4-dione (1.5 g, 0.6.69 mmole) was taken in DMF (1 mL) under N2 atmosphere and dimethyl amine (2M solution in THF) (11 mL, 20.0 mmole) was added. The reaction mixture was heated to 50° C. for 16 hrs. After completion of the reaction, water was added to the reaction mixture and product was extracted with ethyl acetate. The combined organic layer was dried over Na2SO4 and evaporated to get the crude product which was purified using column purification using 60-120 mesh size neutral silica by eluting the compound with 2% MeOH in CH2Cl2 to yield 0.3 g of 3-(2-(dimethylamino)ethyl)thiazolidine-2,4-dione which was converted to 3-(2-(dimethylamino)-ethyl)-5-(4-(7-pivaloyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)benzylidene)-thiazolidine-2,4-dione as described in Example 6 above.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:20]([OH:22])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH2:24][CH2:25][CH3:26]>>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:24][CH2:25][CH3:26])[CH:12]=1)[C:20]([OH:22])=[O:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CCCI
Product: CCCn1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Yield: 97.5 %

Procedure:
The procedure of Referential Example 1(a) was repeated, except that N-tert-butoxycarbonyl-D-tryptophan (1.0 g) and 1-iodopropane (838 mg) were used, whereby the title compound (1.11 g) was yielded.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH:15]([F:17])[F:16])=[N:12][CH:13]=1)=[CH2:7])CCC.[Br:18]N1C(=O)CCC1=O>C1COCC1.O.O>[Br:18][CH2:5][C:6]([C:8]1[CH:13]=[N:12][C:11]([O:14][CH:15]([F:17])[F:16])=[CH:10][CH:9]=1)=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(OCCCC)c1ccc(OC(F)F)nc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(CBr)c1ccc(OC(F)F)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
A solution of 100 mg (0.41 mmol) of 5-(1-butoxyvinyl)-2-difluoromethoxypyridine in 4 mL of THF/H2O (3/1: v/v) is cooled to 0° C. 74 mg (0.41 mmol) of N-bromosuccinimide are then added in a single portion. The yellow solution is stirred at 0° C. for 1 hour and then taken up in water and extracted with EtOAc. The organic phase is washed with saturated aqueous NaHCO3 solution and then with saturated NaCl solution, dried over magnesium sulfate and then evaporated to dryness. The crude product is purified by chromatography on silica gel (eluent: 20/80 EtOAc/heptane to 40/60 EtOAc/heptane over 15 minutes) to give 82 mg of 2-bromo-1-(6-difluoromethoxypyrid-3-yl)ethanone, corresponding to the following characteristics:
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C:19]2([S:26][CH2:27][CH2:28][CH2:29][CH3:30])[S:23][CH2:24][CH3:25])[C@H:15]2[C@@:6]1([F:33])[C@:7]1([CH3:32])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:31])[CH:9]=[CH:8]1)(=O)C>CO.O1CCCC1>[CH2:27]([S:26][C:19]1([S:23][CH2:24][CH3:25])[CH2:18][CH2:17][C@H:16]2[C@H:15]3[C@:6]([F:33])([C@@H:5]([OH:4])[CH2:22][C@:20]12[CH3:21])[C@:7]1([CH3:32])[C:12](=[CH:11][C:10](=[O:31])[CH:9]=[CH:8]1)[CH2:13][CH2:14]3)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCSC1(SCC)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@@]21C
Solvent: C1CCOC1
Solvent: CO
Product: CCCCSC1(SCC)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Yield: 102.8 %

Procedure:
11β-Acetyloxy-17-(butylthio)-17-(ethylthio)-9-fluoroandrosta-1,4-diene-3-one (925 mg) is dissolved in a mixture of methanol (20 ml) and tetrahydrofuran (20 ml). The solution is stirred, purged with nitrogen and 3.0 M sodium hydroxide (3.0 ml) is added. After 2 hours a slight excess of acetic acid is added and the mixture is then concentrated in vacuo. It is diluted with water (150 ml) and extracted with chloroform. The chloroform extract is washed with water, dried (MgSO4 anh.) and evaporated to afford the title compound (870 mg). Examinations of the nmr spectrum and tlc behavior of this compound show the presence of some 17-(ethylthio)-9-fluoro-11β-hydroxyandrosta-1,4,16-triene-3-one and two 17-stereoisomers of the title compound. The material is applied on four 2.0 mm Merck silica gel plates and the plates are developed twice with chloroform-ethyl acetate (7:3). The products from the upper 1/3 and lower 2/3 of the broad band are isolated separately by extraction with chloroform-methanol (3:1 ) to afford respectively 340 and 527 mg of solids. One crystallization of the 340 mg of solid from ethyl acetate-hexane (1:1) and drying (100° C., 0.3 mm of Hg, 20 hours) gives the analytical specimen of the title compound (281 mg) melting point 118°-125° C. with consistent spectral data.
Reaction SMILES: [CH:1]1([C:6]([OH:19])([C:17]#[CH:18])[CH2:7][C:8]2[O:13][C:12]([CH3:15])([CH3:14])[O:11][C:10](=[O:16])[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:21]1[S:22][CH:23]=[CH:24][N:25]=1.C(NC(C)C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH:1]1([C:6]([OH:19])([C:17]#[C:18][C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[CH2:7][C:8]2[O:13][C:12]([CH3:15])([CH3:14])[O:11][C:10](=[O:16])[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#CC(O)(CC1=CC(=O)OC(C)(C)O1)C1CCCC1
Reactant: Brc1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC1(C)OC(=O)C=C(CC(O)(C#Cc2nccs2)C2CCCC2)O1
Yield: 81 %

Procedure:
To a degassed solution of 6-(2-cyclopentyl-2-hydroxy-but-3-ynyl)-2,2-dimethyl-[1,3]dioxin-4-one (264.1 mg, 1.0; prepared as described in Example 1, Step 2), 2-bromothiazole (99.1 μL, 1.1 mmol), diisopropylamine (1.5 mL), and DMF (0.5 mL), under argon, was added Pd(PPh3)2Cl2 (28.1 mg, 0.04 mmol) and Cul (15.2 mg, 0.08 mmol). The resulting mixture was vacuum-flushed with argon (3×), then placed in 100° C. oil bath for 5 minutes, during which time the reaction becomes black/brown in color. The mixture was filtered through a plug of silica eluted with ethylacetate, concentrated, and purified by flash chromatography using 30% EtOAc/Hex as the eluent. The yield of product was 280 mg (81% yield). 1H NMR (CDCl3): δ 1.63 (m, 4H), 1.72 (s, 3H), 1.73 (s, 3H), 2.23 (pentet, 1H, J=8.0 Hz), 2.54 (s, 1H), 2.65 (s, 2H), 3.81 (s, 3H), 5.47 (s, 1H), 6.83 (d, 2H, J=8.7 Hz), 7.31(d, 2H, J=8.1 Hz), ESIMS (M+Na+): 393.2.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([S:19]([NH:22][Si](C(C)(C)C)(C)C)(=[O:21])=[O:20])[CH:18]=3)=[O:12])=[CH:8][CH:9]=2)[N:4]([Si](C(C)(C)C)(C)C)[CH:3]=1.C(Cl)Cl.CO.[OH-].[NH4+:43]>>[CH3:8][C:7]1[CH:6]=[C:5]([C:2]2[C:10]3[C:5](=[CH:6][C:7]([C:11]([C:13]4[CH:18]=[C:17]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:16]=[CH:15][CH:14]=4)=[O:12])=[CH:8][CH:9]=3)[NH:4][CH:3]=2)[CH:10]=[CH:9][N:43]=1
Reactant: [NH4+]
Reactant: CC(C)(C)[Si](C)(C)NS(=O)(=O)c1cccc(C(=O)c2ccc3c(Br)cn([Si](C)(C)C(C)(C)C)c3c2)c1
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(-c2c[nH]c3cc(C(=O)c4cccc(S(N)(=O)=O)c4)ccc23)ccn1

Procedure:
3-[3-(2-Methyl-pyridin-4-yl)-1H-indole-6-carbonyl]-benzenesulfonamide is prepared from 0.25 g of 5-[3-bromo-1-(tert-butyl-dimethyl-silyl)-1H-indole-6-carbonyl]-N-(tert-butyl-dimethyl-silyl)-benzenesulfonamide according to the procedure described in Example 6 (microwave irradiation at 150° C. for 5 min). MS (m/z): 390 (M−1); Rf 0.19 (90:10:1 methylene chloride/methanol/ammonium hydroxide)
Reaction SMILES: [Cl-:1].[Li+].C1(C)C=CC(S([O:12][CH2:13][CH2:14][CH:15]([CH3:35])[CH:16]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:17]([NH:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:18])(=O)=O)=CC=1.O.C(OCC)(=O)C>CN(C=O)C>[Cl:1][CH:13]([OH:12])[CH2:14][CH:15]([CH3:35])[CH:16]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[C:17]([NH:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:18]
Reactant: [Cl-]
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)C(C(=O)NNC(=O)OC(C)(C)C)c2ccc(F)cc2)cc1
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(CC(O)Cl)C(C(=O)NNC(=O)OC(C)(C)C)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
Lithium chloride (283 mg) was added to a solution of 5-(N′-tert-butoxycarbonylhydrazino)-4-(4-fluorophenyl)-3-methyl-5-oxo-1-pentyl toluene-4-sulfonate (330 mg) in DMF (5 mL). The reaction solution was stirred at 80° C. for three hours and then left to cool to room temperature. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 170 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15](OC)=[O:16])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[K+]>C(OCC)C>[Si:1]([O:8][CH:9]1[CH2:10][CH2:11][CH:12]([CH2:15][OH:16])[CH2:13][CH2:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OC1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
200 mg (0.59 mmol) of the crude product from Example 9A (80% pure) are dissolved in 1.5 ml of diethyl ether. At RT, this solution is added dropwise to a suspension of 13.4 mg (0.35 mmol) of lithium aluminum hydride in 1.5 ml of diethyl ether. The mixture is stirred at RT for 20 h. 12 μl of water, 12 μl of 15% strength aqueous potassium hydroxide solution and 3 ml of diethyl ether are then added, and the mixture is stirred at RT for 30 min. The reaction mixture is then filtered through a cartridge charged with 2.4 g of silica gel and 2.4 g of Extrelut (mobile phase: dichloromethane/ethanol 10:1). The solvent is removed on a rotary evaporator and the residue is purified chromatographically on silica gel 60 (mobile phase: gradient cyclohexane/ethyl acetate 20:1→10:1).