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]([CH3:12])[C:9]([OH:11])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCN2C(=NCCC2)CC1.[NH2:36][C:37]1[O:41][N:40]=[C:39]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[C:38]=1[C:49]1[CH:54]=[CH:53][N:52]=[CH:51][N:50]=1>C1COCC1>[F:48][C:45]1[CH:46]=[CH:47][C:42]([C:39]2[C:38]([C:49]3[CH:54]=[CH:53][N:52]=[CH:51][N:50]=3)=[C:37]([NH:36][C:9](=[O:11])[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:12])[O:41][N:40]=2)=[CH:43][CH:44]=1
Reactant: CC(C(=O)O)c1ccccc1Cl
Reactant: Nc1onc(-c2ccc(F)cc2)c1-c1ccncn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C(=O)Nc1onc(-c2ccc(F)cc2)c1-c1ccncn1)c1ccccc1Cl
Temperature: 25 °C
Yield: 71.5 %

Procedure:
In 5 mL of THF, 0.144 g of 2-(2-chlorophenyl)propionic acid and 0.126 g of CDI were dissolved and stirred at room temperature for an hour. Then 5 mL of THF solution containing 0.237 g of DBU and 0.1 g of 5-amino-3 (4-fluorophenyl)-4-4-pyrimidinyl isoxazole was added and stirred at room temperature for 3 hours. The solvent was distilled off from the reaction solution under reduced pressure, and water was added to the residue which was then extracted with ethyl acetate. The ethyl acetate extract was dried over anhydrous magnesium sulfate, removed of the solvent by distillation under reduced pressure, and the residue was purified on 20 g silica gel chromatography (eluent, chloroform:methanol=50:1). Washing the residue with ether, 0.118 g (yield: 72%) of the title compound was obtained.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([S:10]([O-:12])=[O:11])[CH:7]=[CH:8][CH:9]=1.[Na+].Br[C:17]1[CH:25]=[C:24]([CH3:26])[C:23]2[N:22]([CH3:27])[C:21]3[CH2:28][CH:29]4[NH:33][CH:32]([C:20]=3[C:19]=2[C:18]=1[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31][CH2:30]4>>[F:14][C:2]([F:1])([F:13])[O:3][C:4]1[CH:5]=[C:6]([S:10]([C:17]2[CH:25]=[C:24]([CH3:26])[C:23]3[N:22]([CH3:27])[C:21]4[CH2:28][CH:29]5[NH:33][CH:32]([C:20]=4[C:19]=3[C:18]=2[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31][CH2:30]5)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cc(Br)c(C(=O)OC(C)(C)C)c2c3c(n(C)c12)CC1CCC3N1
Reactant: O=S([O-])c1cccc(OC(F)(F)F)c1
Agent: [Na+]
Product: Cc1cc(S(=O)(=O)c2cccc(OC(F)(F)F)c2)c(C(=O)OC(C)(C)C)c2c3c(n(C)c12)CC1CCC3N1
Yield: 26 %

Procedure:
Intermediate 3 was coupled to the product of Example 71, step C following the procedure of Example 71, step D. The crude product was purified by flash column chromatography (SiO2, 8:2 hexanes/ethyl acetate) to give tert-butyl 2-(3-trifluoromethoxy-phenyl)sulfonyl-4,5-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (58 mg, 26%) as a light-yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.02 (br s, 1H), 7.85-7.90 (m, 1H), 7.81 (br s, 1H), 7.50 (t, J=8.1 Hz, 1H), 7.31-7.37 (m, 2H), 5.21 (br s, 1H), 4.72 (br s, 1H), 3.85 (s, 3H), 3.35 (br s, 1H), 2.76 (s, 3H), 2.45 (d, J=15.6 Hz, 1H), 2.24-2.49 (m, 1H), 2.12-2.24 (m, 1H), 1.85-1.96 (m, 1H), 1.57-1.66 (m, 1H), 1.37 (br s, 9H).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[O:12][CH:13]=[C:14]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]4[CH:32]=[CH:31][N:30]=[C:29]4[CH2:33][CH2:34][C:35](O)=[O:36])=[CH:20][CH:19]=3)[N:15]=2)=[CH:5][CH:4]=1.[NH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1.P(C#N)(OCC)(OCC)=O>C(N(CC)CC)C>[F:38][C:2]([F:39])([F:1])[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11]2[O:12][CH:13]=[C:14]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]4[CH:32]=[CH:31][N:30]=[C:29]4[CH2:33][CH2:34][C:35]([N:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)=[O:36])=[CH:20][CH:19]=3)[N:15]=2)=[CH:7][CH:8]=1
Reactant: O=C(O)CCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Reactant: C1CCNC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Product: O=C(CCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1)N1CCCC1

Procedure:
Using 3-[1-[4-[4-[(2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl)methoxy]phenyl]butyl]-1H-imidazol-2-yl]propionic acid (200 mg), pyrrolidine (0.174 ml), diethyl cyanophosphate (0.303 ml) and triethylamine (0.310 ml), the same reaction as Example 5-(ii) was carried out to yield the titled compound (86 mg).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].C1COCC1.[CH2:26]([O:28][C:29](=[O:34])[C:30](=O)[CH2:31]Br)[CH3:27].FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[CH2:26]([O:28][C:29]([C:30]1[N:13]=[C:11]([CH:10]=[CH:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:14])([F:15])[F:1])=[CH:8][CH:7]=2)[O:12][CH:31]=1)=[O:34])[CH3:27]
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=O)C=Cc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCOC(=O)c1coc(C=Cc2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of 3-(4-trifluoromethyl-phenyl)-acrylamide (5.0 g, 23.2 mmol) and NaHCO3 (7.80 g, 92.9 mmol) in THF (90 ml) 3-bromo-2-oxo-propionic acid ethyl ester (5.53 g, 25.6 mmol) is added under an argon atmosphere. The mixture is heated to reflux for 15 h when another portion of 3-bromo-2-oxo-propionic acid ethyl ester (5.53 g, 25.6 mmol) is added and stirring continued for 5 h. After cooling to r.t. the mixture is filtered, concentrated in vacuo and the resulting residue suspended in THF (20 ml). At 0° C. trifluoroacetic acid anhydride (16.3 g, 77.9 mmol) is added and the mixture stirred at room temperature for 16 h. The mixture is neutralized with sat. NaHCO3, the aqueous layer extracted with ethyl acetate (2×200 ml) and the combined organic phases dried over Na2SO4 and concentrated in vacuo. The crude product is purified by flash column chromatography (ethyl acetate/heptane 4:1) yielding 2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazole-4-carboxylic acid ethyl ester as a colorless solid. Yield 5.84 g (81%)
Reaction SMILES: [C:1]([CH2:4][CH2:5][S:6][CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][O:10][C:9]2[CH:18]=[CH:19][C:20]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][C:28]([Cl:34])=[CH:29][CH:30]=4)[N:25]=3)=[CH:21][C:8]1=2)(O)=[O:2].[CH3:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42]([NH2:45])(=[O:44])=[O:43]>>[Cl:34][C:28]1[CH:27]=[C:26]2[C:31]([CH:32]=[CH:33][C:24]([CH2:23][O:22][C:20]3[CH:19]=[CH:18][C:9]4[O:10][CH2:11][C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=5[CH:7]([S:6][CH2:5][CH2:4][C:1]([NH:45][S:42]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=5[CH3:35])(=[O:44])=[O:43])=[O:2])[C:8]=4[CH:21]=3)=[N:25]2)=[CH:30][CH:29]=1
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: O=C(O)CCSC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Product: Cc1ccccc1S(=O)(=O)NC(=O)CCSC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21

Procedure:
11-(2-Carboxyethylthio)-2-(7-chloroquinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine and 2-methylbenzenesulfonamide were used and reacted in the same manner as in Example 39 to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:5][C:6](=[O:9])[C:7]=1[CH3:8])=[O:4].[K].Cl[CH2:12][CH2:13][CH2:14][Si:15]([O:20][CH3:21])([O:18][CH3:19])[O:16][CH3:17]>CN(C)C=O>[CH3:1][C:2]1[C:3]([N:5]([CH2:12][CH2:13][CH2:14][Si:15]([O:20][CH3:21])([O:18][CH3:19])[O:16][CH3:17])[C:6](=[O:9])[C:7]=1[CH3:8])=[O:4]
Reactant: CC1=C(C)C(=O)NC1=O
Reactant: CO[Si](CCCCl)(OC)OC
Agent: [K]
Solvent: CN(C)C=O
Product: CO[Si](CCCN1C(=O)C(C)=C(C)C1=O)(OC)OC
Temperature: 70 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
A mixture of 16.3 g (0.1 mol) of potassium 2,3-dimethylmaleimide (prepared by reacting 2,3-dimethylmaleimide with potassium methylate in methanol) and 150 ml of dry N,N-dimethylformamide is heated to 70° C. At this temperature, 19.8 g (0.1 mol) of 3-chloropropyltrimethoxysilane are added dropwise. After the exothermic reaction has subsided, the reaction mixture is kept at 70° C. for a further 2 hours, and after cooling to room temperature (20°-25° C.) the salt which has precipitated is filtered off. The N,N-dimethylformamide is distilled off under a high vacuum, under 13.333 Pa. The residue is taken up in a little dry diethyl ether, filtered again and, after removing the solvent, fractionated under a high vacuum. 16 g (56% of theory) of 3-(2,3-dimethylmaleimido)-propyl-trimethoxysilane are obtained; boiling point 112° C. (0.133 Pa).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:5]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[C:6]2[N:11]([CH:12]=1)[N:10]=[CH:9][N:8]=[C:7]2[NH2:13].[CH3:23]O>>[CH2:1]([O:2][CH2:3][C:4]1[C:5]([C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[C:6]2[N:11]([CH:12]=1)[N:10]=[CH:9][N:8]=[C:7]2[NH2:13])[CH3:23]
Reactant: CO
Reactant: COCc1cn2ncnc(N)c2c1-c1ccc([N+](=O)[O-])cc1
Product: CCOCc1cn2ncnc(N)c2c1-c1ccc([N+](=O)[O-])cc1

Procedure:
The method used in the preparation of Intermediate U was used to prepare the title compounds by substituting ethanol for methanol. MS [M+H]+=284.1; LCMS RT=0.35 min.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH:16]=[CH2:17])[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([O:5][C:6](=[O:7])[C:8]([CH2:13][OH:12])([CH2:9][OH:10])[CH:16]=[CH2:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC1(C(=O)OC(C)(C)C)COC(C)(C)OC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: C=CC(CO)(CO)C(=O)OC(C)(C)C
Yield: 81.6 %

Procedure:
A solution of 2,2-dimethyl-5-vinyl-[1,3]dioxane-5-carboxylic acid tert-butyl ester (969 mg, 4 mmol) and 4-toluenesulfonic acid hydrate (76 mg, 0.4 mmol) in methanol (10 mL) was stirred at room temperature for 30 min. The solvent was evaporated and the residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 4:1 to 1:1 to afford the title compound (660 mg, 82%) as a white solid. 1H NMR (300 MHz, d6-DMSO): δ 1.38 (s, 9H), 3.54-3.68 (m, 4H), 4.56 (t, J=5.4 Hz, 2H), 5.12 (d, J=10.5 Hz, 1H), 5.14 (d, J=18.3 Hz, 1H), 5.80 (dd, J=18.3, 10.5 Hz, 1H). LCMS (m/z) 225.2 [M+Na], Tr=1.47 min.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.[CH3:17][N:18]1C(=O)CCC1>[C-]#N.[C-]#N.[Zn+2]>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:2]([C:17]#[N:18])[C:3]=2[CH:4]=[N:5]1
Reactant: CN1CCCC1=O
Reactant: Brc1cccc2c1cnn2C1CCCCO1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cccc2c1cnn2C1CCCCO1
Temperature: 85 °C
Yield: 75 %

Procedure:
To a mixture of 196 (0.57 g, 2.05 mmol), Zn(CN)2 (264 mg, 2.25 mmol) in NMP (6 mL) under an argon atmosphere was added (Ph3P)4Pd(0) (356 mg, 0.31 mmol). The mixture was heated at 85° C. overnight, cooled, and partitioned between EtOAc (300 mL) and H2O (50 mL). The organic layer was separated and washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with 1% MeOH/DCM to afford 430 mg (75%) of 1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonitrile (198) as yellow solid: MS (ESI) m/z=228 [M+1]+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]#[CH:6])[CH3:3].C(NC(C)C)(C)C.I[C:15]1[CH:20]=[CH:19][C:18](/[C:21](/[C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)=[CH:22]\[CH2:23][O:24][C:25]2[CH:36]=[CH:35][C:28]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[C:27]([CH3:37])[CH:26]=2)=[CH:17][CH:16]=1>O1CCCC1.[Cu]I.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>[CH3:37][C:27]1[CH:26]=[C:25]([O:24][CH2:23]/[CH:22]=[C:21](\[C:18]2[CH:17]=[CH:16][C:15]([C:6]#[C:5][CH2:4][N:2]([CH3:3])[CH3:1])=[CH:20][CH:19]=2)/[C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)[CH:36]=[CH:35][C:28]=1[O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN(C)C)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
N,N-Dimethylpropargylamine (0.11 mL, 1.03 mmol) and diisopropylamine (0.34 mL, 2.42 mmol) were added to a solution of methyl (Z)-[4-[3-(4-iodophenyl)-3-(4-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetate (300 mg, 0.515 mmol; example 4) in tetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide (8 mg, 0.042 mmol) and bis(triphenylphosphine)palladium(II) dichloride (18 mg, 0.026 mmol) were added. The reaction mixture was stirred at ambient temperature for 20 h and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, dichloromethane/methanol 98:2) yielding methyl (E)-[2-methyl-4-[3-[4-[3-(N,N-dimethylamino)propynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]phenoxy]acetate as brown oil.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].[C:13](O)([CH3:16])([CH3:15])[CH3:14].[OH-].[Na+]>FC(F)(F)C(O)=O>[C:1]([C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:11]=1)([CH2:4][CH3:5])([CH3:2])[CH3:3]
Reactant: CCC(C)(C)c1ccc(O)cc1
Reactant: CC(C)(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Yield: 39 %

Procedure:
4-t-amylphenol (80 g, 0.49 mole) was dissolved in 200 ml anhydrous trifluoroacetic acid (TFA). T-butyl alcohol (39 g, 0.53 mole) was added with stirring. The mixture was stoppered and stirred for 19 hours at ambient (~22° C.) temperature. The solution was then poured into 400 ml of 1M NaOH, and the resulting upper organic layer was isolated in a separatory funnel. The crude product was dried over anhydrous magnesium sulfate. The product, 4-t-amyl-2-t-butylphenol, was purified by eluting 35 g of the mixture the mixture with 60:40 hexanes:dichloromethane (v/v) in a 5×20 cm silica column and eluted with 300 to 700 ml of solvent and collected in aliquots of 50 ml. Aliquots showing a single spot by Thin Layer Chromatography (TLC) (on silica eluted with 60:40 hexanes:dichloromethane (v/v)) were combined and rotoevaporated to a thick syrup. The yield was 39%.
Reaction SMILES: Br[C:2]1[C:3]([N:9]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH3:11])=[N:4][CH:5]=[C:6](C)[CH:7]=1.[CH2:18]1N2CCN(CC2)C1.Cl>CN(C)C=O>[CH3:18][C:7]1[CH:6]=[CH:5][N:4]=[C:3]2[NH:9][C:10]([C:12]3[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=3)=[CH:11][C:2]=12
Reactant: CC(=Nc1ncc(C)cc1Br)c1ccncc1
Reactant: C1CN2CCN1CC2
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ccnc2[nH]c(-c3ccncc3)cc12
Temperature: 120 °C
Reaction time: 36 h

Procedure:
To a solution of (3-bromo-5-methylpyridin-2-yl)-(1-pyridin-4-ylethylidene)amine (4.25 g, 14.65 mmol) in dimethylformamide (75 ml) was added DABCO® (4.93 g, 43.96 mmol) and], bis-dichlorotriphenylphosphine palladium (0.52 g, 0.73 mmol). The reaction mixture was heated at 120° C. under argon atmosphere. After 1.5 days, the reaction mixture was cooled into room temperature and poured into 10% hydrochloric acid (100 ml). The solution was filtered through Celite® and the filtrate was neutralized to pH 7 with 10% sodium hydroxide and the solid was filtered off to give 4-methyl-2-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine (1.57 g) as a brown solid.
Reaction SMILES: [F:1][CH:2]([F:29])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][C:21]([CH:24]([OH:26])[CH3:25])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:28])[CH3:27])=[O:4].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39].C(=O)(O)[O-]>C(Cl)Cl>[F:29][CH:2]([F:1])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]([O:26][S:38]([CH3:37])(=[O:40])=[O:39])[CH3:25])=[N:20][CH:19]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:28])[CH3:27])=[O:4]
Reactant: CC(O)c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
To a stirred solution of 2,2-Difluoro-1-((4S,5R)-4-fluoromethyl-5-{4-[6-(1-hydroxy-ethyl)-pyridin-3-yl]-phenyl}-2,2-dimethyl-oxazolidin-3-yl)-ethanone (2.2 g, 5.39 mmol) in CH2Cl2 (25 mL) is added triethylamine (1.51 mL, 10.78 mmol) and methane sulfonyl chloride (0.527 mL, 6.47 mmol). Reaction mixture is stirred at 0° C. for 30 minutes then diluted using saturated bicarbonate solution and extracted with CH2Cl2 (30 mL) Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by combiflash using 45% ethyl acetate in hexane as an eluent to afford the title compound (1.8 g). 1H NMR (400 MHz, DMSO-d6) δ: 1.53 (s, 3H), 1.60 (s, 3H), 1.68 (d, J=6.56 Hz, 3H), 3.21 (s, 3H), 4.54-4.58 (m, 0.5H), 4.66-4.71 (m, 1H), 4.81-4.84 (m, 0.5H), 4.90-4.95 (m, 1H), 5.27 (d, J=3.92 Hz, 1H), 5.79-5.84 (m, 1H), 6.64 (t, J=52.24, 1 H), 7.60-7.63 (m, 3H), 7.81 (d, J=8.2 Hz, 2H), 8.17-8.20 (dd, J1=8.08 Hz, J2=2.24 Hz, 1H), 8.92 (d, J=2.00 Hz, 1H). LC-Ms (m/z): 487.1 [M+H].
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4](Cl)[N:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([NH2:41])[C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[CH:28][CH:27]=1>C1COCC1>[CH3:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([CH:32]([NH:41][C:4]2[N:3]=[C:2]([Cl:1])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])[C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[CH:38][CH:37]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: COc1ccc(C(N)c2ccc(OC)cc2)cc1
Solvent: C1CCOC1
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NC(c4ccc(OC)cc4)c4ccc(OC)cc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 50 °C

Procedure:
To a solution of N-[(1S,2R,3S,4R)-4-(2,6-dichloro-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-propionamide (Intermediate J7) (2.6 g, 7.22 mmol) in dry THF (26 ml) is added C,C-Bis-(4-methoxy-phenyl)-methylamine (Intermediate Y) (3.5 g, 14.44 mmol). The mixture is heated at 50° C. for 12 hours and then concentrated in vacuo. The residue is dissolved in chloroform and washed sequentially with 1.5N HCl, water and saturated aqueous brine solution. The organic phase is dried over anhydrous sodium sulphate and concentrated in vacuo. The crude product is purified by chromatography on silica (60-120 mesh) eluting with 2% methanol in chloroform to afford the title product. LC-MS (0.1% formic acid, acetonitrile): (MH+ 567)
Reaction SMILES: C1(S(N2C3=NC=CC=C3C=C2C([C:26]2[CH:38]=[CH:37][C:29]([C:30]([NH:32]C(C)(C)C)=[O:31])=[CH:28][CH:27]=2)=CC2CCCC2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[C:30]([NH2:32])(=[O:31])[C:29]1[CH:37]=[CH:38][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)NC(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1ccccc1
Yield: 318.6 %

Procedure:
A solution of 4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-N-tert-butyl-benzamide (300 mg, 0.57 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 5 mL, 5 mmol) was stirred at room temperature for 12 h. The mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous ammonium chloride solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford N-tert-butyl-4-[2-cyclopentyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-benzamide (220 mg, quant.) as a white solid: LC/MS m/e calcd for C25H29N3O [M+H]+ 388.53, observed 388.2.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[C:10]1[S:11][C:12]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:13]=2[N:14]=1>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[S:11][C:12]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: Nc1ccc(Br)cc1
Product: Clc1ccc2nc(Nc3ccc(Br)cc3)sc2c1
Temperature: 25 °C
Yield: 100 %

Procedure:
Solid 4-bromoaniline (1.00 g, 5.81 mmol) and 2,6-dichlorobenzothiazole (1.18 g, 5.81 mmol) were heated at 140° C. for 3 days in a flask equipped with an air condenser (fusion occurred within a few minutes to give a clear liquid which solidified over the course of 3 days). The reaction mixture was allowed to cooled to ambient temperature to give N-(4-bromophenyl)-N-(6-chloro-1,3-benzothiazol-2-yl)amine (1.97 g, 5.81 mmol): RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 14.65 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=3)[C:19]([O:21]C)=[O:20])=[N:9][C@@H:8]3[CH2:26][CH2:27][S:28][CH2:29][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].[OH-].[Na+].Cl>O1CCOCC1>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=3)[C:19]([OH:21])=[O:20])=[N:9][C@@H:8]3[CH2:26][CH2:27][S:28][CH2:29][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)OC)c1)=N[C@@H]1CCSC[C@H]21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)O)c1)=N[C@@H]1CCSC[C@H]21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of methyl 3-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoate (0.5 g; compound C7) in 1,4-dioxane (8 ml) is added an 2 M aqueous solution of sodium hydroxide (1.3 ml) and the reaction mixture is stirred at RT for 12 h. An aqueous solution of hydrogen chloride (1.3 ml, 2.0 M) is added under stirring. The reaction mixture is evaporated to dryness in vacuo and the resulting residue is used for the next step without further purification.
Reaction SMILES: C([O:4][C:5]1[C:22]([I:23])=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14](=[O:24])[CH2:13][CH2:12]4)[C@@H:9]([O:25]C(=O)C)[CH2:8][C:7]=2[CH:6]=1)(=O)C.C[O-].[Na+]>CO>[OH:4][C:5]1[C:22]([I:23])=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14](=[O:24])[CH2:13][CH2:12]4)[C@@H:9]([OH:25])[CH2:8][C:7]=2[CH:6]=1
Reactant: CC(=O)Oc1cc2c(cc1I)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1[C@@H](OC(C)=O)C2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@]12CC[C@@H]3c4cc(I)c(O)cc4C[C@H](O)[C@H]3[C@@H]1CCC2=O
Reaction time: 8 h
Yield: 68.6 %

Procedure:
For the removal of both acetyl protective groups, 700 mg (1.4 mmol) of 3,7β-diacetoxy-2-iodo-estra-1,3,5(10)-trien-17-one, dissolved in 20 ml of methanol, was mixed with 200 mg of sodium methanolate, and the solution was stirred overnight. Then, it was mixed with 2.5 g of Amberlite IR-120, stirred for 30 minutes, filtered, and the solution was concentrated by evaporation in a rotary evaporator. Flash chromatography (cyclohexane/ethyl acetate) yielded 396 mg (68%) of colorless crystals.
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1>CS(C)=O>[C:1]([CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)#[N:2]
Reactant: [C-]#N
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55 %

Procedure:
A solution of sodium cyanide (20 g, 0.41 mol) in dimethylsulfoxide at 40° C. was treated dropwise with a solution of methyl 4-(bromomethyl)benzoate (52 g, 0.227 mol) in dimethylsulfoxide, stirred for 90 min., cooled to room temperature, quenched with saturated aqueous sodium chloride and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. Purification of the concentrate via column chromatography (silica, hexanes:ethyl acetate 0→5%) provided methyl 4-(cyanomethyl)benzoate (55%). 1H NMR (400 MHz, CDCl3): 8.05 (d, J=8 Hz, 2H); 7.42 (d, J=8 Hz, 2H); 3.93 (s, 3H); 3.81 (s, 2H). [M+H] 176