Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:17][CH3:18])=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.O1CCCC1.C([Li])CCC.[CH2:29]([O:31][C:32]([CH:34]1[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][CH2:35]1)=[O:33])[CH3:30].Cl>C1(C)C=CC=CC=1>[CH2:29]([O:31][C:32]([CH:34]1[CH2:39][CH2:38][C:37]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH2:17][CH3:18])=[N:7][N:8]3[CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:4][CH:3]=2)([OH:40])[CH2:36][CH2:35]1)=[O:33])[CH3:30]
Reactant: CCc1nn(C2CCCCC2)c2cc(Br)ccc12
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCC(O)(c2ccc3c(CC)nn(C4CCCCC4)c3c2)CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
To a solution of 6bromo-1-cyclohexyl-3-ethyl-1H-indazole (12.7 g, 41.3 mmol) in toluene (64 mL) was added tetrahydrofuran (6.70 mL, 82.6 mmol). The solution was cooled to -78° C. and n-butyllithium (17.3 mL of a 2.5M solution in hexanes, 43.4 mmol) was added dropwise. The solution was stirred 10 minutes and added to a solution of 4-oxo-cyclohexanecarboxylic acid ethyl ester (8.80 g, 51.7 mmol) in toluene (127 mL) at -78° C. The reaction mixture was stirred for 15 minutes and poured into 1N aqueous hydrochloric acid (200 mL). The layers were separated and the aqueous layer was reextracted with toluene (60 mL). The organic extracts were combined and dried over magnesium sulfate, filtered, and concentrated to an oil which was purified by filtration through a pad of silica gel eluting with 4:1 hexanes/ethyl acetate. The product-rich fractions were concentrated to yield 4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-hydroxy-cyclohexanecarboxylic acid ethyl ester (13.5 g, 82%) as a mixture of diastereoisomers. Upon standing, one of the diastereoisomers crystallized and was isolated by trituration with hexanes. 1H NMR (400 MHz, CDCl3) δ 1.25-1.40 (m, 4), 1.27 (t, 3, J=7.1), 1.35 (t, 3, J=7.7), 1.65-2.07 (m, 15), 2.37-2.44 (m, 1), 2.96 (q, 2, J=7.7), 4.15 (q, 2, J=7.1), 4.30-4.38 (m, 1), 7.13 (d, 1, J=8.5), 7.58 (s, 1), 7.63 (d, 1, J=8.5). 13C NMR (100 MHz, CDCl3) δ 14.16, 14.26, 20.69, 24.60, 25.39, 25.91, 32.54, 38.22, 42.57, 57.59, 60.34, 72.80, 104.49, 116.80, 120.28, 121.26, 139.84, 146.09, 146.93, 175.63. Analysis calculated for C24H34N2O3 : C, 72.33; H, 8.60; N, 7.03. Found: C, 72.11; H, 8.55; N, 6.92.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:9][C:8]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:16][C:7]=2[N:6]2[CH:17]=[C:18]([C:20]([O:22]CC)=[O:21])[N:19]=[C:5]12.[N:25](OCCC(C)C)=[O:26].O>CS(C)=O.C(O)(=O)C>[OH:26][N:25]=[C:16]1[C:7]2[N:6]3[CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=[C:5]3[C:4](=[O:3])[NH:9][C:8]=2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]1=2
Reactant: CC(C)CCON=O
Reactant: CCOC(=O)c1cn2c3c([nH]c(=O)c2n1)-c1ccccc1C3
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cn2c3c([nH]c(=O)c2n1)-c1ccccc1C3=NO
Reaction time: 18 h

Procedure:
0.34 g of sodium hydride is added to 1 g of ethyl 4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylate in solution in 20 ml of anhydrous dimethyl sulphoxide, while the temperature of the reaction mixture is maintained below 20° C. 0.44 ml of isoamyl nitrite is then added and stirring is continued for 18 hours at the same temperature. The reaction mixture is then poured into iced water and the solution is acidified with 15 ml of acetic acid. The precipitate formed is filtered off, washed with water, with acetone and then with methanol and finally dried under reduced pressure (1 mm Hg; 0.13 kPa) to produce 0.25 g of 10-hydroxyimino-4,5-dihydro-4-oxo-imidazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylic acid in the form of a brown powder whose melting point is higher than 260° C. (1H spectrum in DMSO, T=300K, δ in ppm (200 MHz), mixture of the syn and anti isomers: Major isomer: between 7.30 and 7.50 (2H, m, CH arom.), 7.62 (1H, s, CH arom.), 7.82 (1H, d, J=7 Hz, CH arom.), 8.00 (1H, s, CH arom.), 8.20 (1H, d, J=7 Hz, CH arom.), 12.7 (1H, s, NH), 13.0 (1H, s, OH), Minor isomer: between 7.30 and 7.50 (2H, m, CH arom.), 7.51 (1H, s, CH arom.), 7.70 (1H, d, J=7 Hz, CH arom.), 7.88 (1H, d, J=7 Hz, CH arom.), 8.58 (1H, s, CH arom.), 12.7 (1H, s, NH), 13.2 (1H, s, OH)).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]=1.CO.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][C:14]1[CH:13]=[N+:12]([O-:9])[CH:17]=[CH:16][CH:15]=1)[CH3:23]
Reactant: CCOC(=O)Cc1cccnc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)Cc1ccc[n+]([O-])c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 124.9 %

Procedure:
m-Chloro perbenzoic acid (6.2 g, 36.06 mmol) in CHCl3 (30 mL) was added drop wise to a solution of ethyl 2-(pyridin-3-yl)acetate (3.5 g, 21.21 mmol) in CHCl3 (30 mL) at room temperature under nitrogen atmosphere and the resulting reaction mass was stirred at room temperature for 5 hours. The reaction was monitored by TLC (10% methanol in chloroform). The reaction mass was basified using aqueous NaHCO3 solution to pH 7 and extracted using CHCl3. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford 4.8 g of the crude product. LCMS: 60.09%, m/z=182.0 (M+1)
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[S:15][C:14](C=O)=[CH:13][CH:12]=1)(C(C)(C)C)(C)C.[Cl-].[NH4+].[CH:20]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])OCC>C(O)C>[CH2:28]([O:27][CH:20]([O:24][CH2:25][CH3:26])[C:14]1[S:15][C:11]([CH2:10][CH2:9][OH:8])=[CH:12][CH:13]=1)[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(C=O)s1
Reactant: CCOC(OCC)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(OCC)c1ccc(CCO)s1
Reaction time: 0.5 h

Procedure:
A mixture of 5-(2-(tert-butyldimethylsilyloxy)ethyl)thiophene-2-carbaldehyde (example 21, step a) (1.37 g) and ammonium chloride (0.135 g) and triethyl orthoformate (0.928 mL) in ethanol (15 mL) was heated at reflux under nitrogen for 3 hours. Most of the ethanol was removed under reduced pressure and the remaining mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution, the organic layer was dried over sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was dissolved in THF (20 mL) and tetrabutylammonium fluoride (1M in THF, 5.07 mL) was added dropwise over 1 minute. The mixture was allowed to stand at room temperature for 30 minutes. The solvent was removed under reduced pressure and the residue was purified by flash silica chromatography eluting with 25% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.940 g.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21]([CH3:23])C)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl.O1CC[CH2:36][CH2:35]1>O>[O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([NH:19][CH:20]([CH2:35][CH3:36])[CH2:21][CH3:23])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: C1CCOC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Product: CCC(CC)Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.08 g, 0.18 mmol) in tetrahydrofuran (7 mL) and methanol (0.015 mL, 0.36 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.135 mL, 0.27 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid a pH of approximately 2-4, diluted with water (10 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 98:2 dichloromethane/methanol to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.87 (m, 6 H) 1.29 (m, 4 H) 3.03 (m, 1 H) 5.76 (d, J=3.68 Hz, 1 H) 7.12 (d, J=5.52 Hz, 1 H) 7.19 (d, J=8.46 Hz, 1 H) 7.26 (t, J=6.99 Hz, 1 H) 7.54 (m, 1 H) 7.65 (d, J=7.72 Hz, 1 H) 7.74 (d, J=5.15 Hz, 1 H) 15.95 (s, 1 H). MS (ESI−) m/z 431 (M−H)−.
Reaction SMILES: [OH:1][C@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]4[O:21][CH2:22][O:23][C:17]=4[CH:16]=3)=[CH:13][C:5]=2[S:4][C@H:3]1[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1.Cl.[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36]Cl>>[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36][N:7]1[C:6]2[CH:10]=[CH:11][C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]4[O:21][CH2:22][O:23][C:17]=4[CH:16]=3)=[CH:13][C:5]=2[S:4][C@@H:3]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C@@H:2]([OH:1])[C:8]1=[O:9]
Reactant: CN(C)CCCl
Reactant: COc1ccc([C@@H]2Sc3cc(Oc4ccc5c(c4)OCO5)ccc3NC(=O)[C@@H]2O)cc1
Agent: Cl
Product: COc1ccc([C@@H]2Sc3cc(Oc4ccc5c(c4)OCO5)ccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1

Procedure:
Following a procedure similar to that described in Example 11(d). 0.68 g of (2S, 3S)-2,3-dihydro-3-hydroxy- 2-(4-methoxyphenyl)-8-(3,4-methylenedioxyphenoxy)-1,5- benzothiazepin-4(5H)-one [prepared as described in step (c) above] was alkylated with 2-dimethylaminoethyl chloride hydrochloride to afford 0.72 g of the title compound as a gum.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=O)(C)(C)C.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(Cl)Cl>[OH:33][C:27]([C:29]([F:32])([F:31])[F:30])=[O:28].[NH2:8][C@@H:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccccn1)C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
To (S)-benzyl 2-((tert-butoxycarbonyl)amino)-3-(pyridin-2-yl)propanoate (0.558 g, 1.57 mmol) was added DCM (2 mL) followed by TFA (2 mL). The reaction mixture was allowed to stand for 1 h at which time it was concentrated to provide (S)-benzyl 2-amino-3-(pyridin-2-yl)propanoate TFA salt (quant. yield) as a yellow oil. MS (EI) for C17H16F3N2O3, found 257.2 [M-TFA]+.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:23]C(=O)OC(C)(C)C)[C:11](=[O:22])[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)=[CH:6][CH:5]=1>CO>[NH2:23][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=1)[CH:11]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[CH:17]2)[OH:22]
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1cccc2cccnc12)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(c1ccc(F)cc1)C(O)c1cccc2cccnc12
Reaction time: 1 h
Yield: 40.9 %

Procedure:
0.48 g (13 mmol) of sodium borohydride was added to a solution of 4.9 g (13 mmol) of tert-butyl [1-(4-fluorophenyl)-2-oxo-2-quinolin-8-ylethyl]carbamate in 75 ml of methanol at 0-5° C. After 1 h, the reaction mixture was concentrated and diluted with ethyl acetate and water, and the organic phase was washed with saturated ammonium chloride and sodium bicarbonate solutions. The residue after drying of the organic phase and concentration was dissolved in 40 ml of methylene chloride, and 9 ml of trifluoroacetic acid were added. After 2 h, ice-water was added and the product was extracted into the aqueous phase. The aqueous phase was made alkaline, the product was extracted with methylene chloride, and 1.5 g of 2-amino-2-(4-fluorophenyl)-1-quinolin-8-ylethanol were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19](=[O:35])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:22][CH:21]=1)=[C:14](OS(C(F)(F)F)(=O)=O)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B1(B2OCC(C)(C)CO2)OCC(C)(C)CO1.[F-].[Cs+].Br[C:63]1[CH:68]=[CH:67][C:66]([F:69])=[CH:65][C:64]=1[F:70]>C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[Pd].C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:24][CH:25]=1)=[O:35])=[C:14]([C:63]1[CH:68]=[CH:67][C:66]([F:69])=[CH:65][C:64]=1[F:70])[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(Br)c(F)c1
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(OS(=O)(=O)C(F)(F)F)ccc2cc(OCc3ccccc3)ccc12
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Solvent: CC#N
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(F)cc2F)ccc2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 58.1 %

Procedure:
Add trifluoromethanesulfonic acid 6-benzyloxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (0.45 g, 0.73 mmol), bis(neopentyl glycolato)diboron (0.18 g, 0.81 mmol), bis(tricyclohexylphosphine)palladium(0) (0.098 g, 0.15 mmol) and acetonitrile (7.5 mL) to a round bottom flask. Stir at ambient temperature for approximately 5 minutes to dissolve most of the reagents. Add cesium fluoride (1.00 g, 6.61 mmol), place the flask in a 90° C. oil bath, and stir under nitrogen for 2-3 minutes. Now add 1-bromo-2,4-difluorobenzene (0.174 mL, 1.54 mmol) and stir for 20 minutes. At this time add more 1-bromo-2,4-difluorobenzene (0.06 mL, 0.53 mmol) and continue stirring the reaction for 2 hours at 90° C. At this time add more 1-bromo-2,4-difluorobenzene (0.05 mL, 0.44 mmol) and continue stirring for another 2 hours. Cool the reaction to ambient temperature and then filter it through a pad of Celite. Rinse the pad with ample, hot ethyl acetate. Wash the filtrate in a separatory funnel with 50% aqueous sodium carbonate, saturated aqueous ammonium chloride, H2O and brine; then dry (sodium sulfate) and evaporate it in vacuo. Load resulting material onto an SCX column, wash with dichloromethane, 50% dichloromethane/methanol, elute with ammonia solution (2N NH3 in methanol) and remove solvent under vacuum. Purify the resulting residue by flash chromatography (silica gel; 1.5%-3% methanol gradient in dichloromethane) to provide 0.245 g (58%) of the title compound: mass spectrum (ion spray) m/z=578 (M+H).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]4[C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[NH:19][C:18]5[N:26]=[CH:27][CH:28]=[CH:29][C:17]=5[N:16]4[C:30]=3[C:31]3[CH:36]=[CH:35][C:34]([C:37]4([NH:41]C(=O)OC(C)(C)C)[CH2:40][CH2:39][CH2:38]4)=[CH:33][CH:32]=3)=[CH:9][CH:8]=2)=[O:5])[CH2:3][CH2:2]1.[ClH:49].O1CCOCC1>C(Cl)Cl>[ClH:49].[ClH:49].[ClH:49].[NH2:41][C:37]1([C:34]2[CH:33]=[CH:32][C:31]([C:30]3[N:16]4[C:17]5[CH:29]=[CH:28][CH:27]=[N:26][C:18]=5[NH:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[C:15]4=[N:14][C:13]=3[C:10]3[CH:9]=[CH:8][C:7]([NH:6][C:4]([CH:1]4[CH2:3][CH2:2]4)=[O:5])=[CH:12][CH:11]=3)=[CH:36][CH:35]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(NC(=O)C5CC5)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC1(c2ccc(-c3c(-c4ccc(NC(=O)C5CC5)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 78.1 %

Procedure:
tert-Butyl {1-[4-(2-{4-[(cyclopropylcarbonyl)amino]phenyl}-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (53.9 mg, 0.0965 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 19 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (48.8 mg, 78.1%) as yellow solid. 1HNMR (DMSO-d6) 500 MHz δ: 10.36 (s, 1H), 8.71-8.63 (m, 3H), 8.13-8.10 (m, 1H), 7.97-7.93 (m, 1H), 7.58-7.52 (m, 4H), 7.43-7.37 (m, 3H), 7.34-7.29 (m, 3H), 7.17-7.12 (m, 1H), 6.92-6.88 (m, 1H), 6.75 (dd, J=8.3, 4.9 Hz, 1H), 2.63-2.40 (m, 4H), 2.25-2.12 (m, 1H), 1.86-1.76 (m, 2H), 0.81-0.75 (m, 4H); LCMS: 539 [M+H].
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:10]=[C:5]2[N:4]=[CH:3]1.Br[C:19]1[CH:24]=[CH:23][C:22]([S:25][C:26]([F:29])([F:28])[F:27])=[CH:21][C:20]=1[S:30][CH2:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(OCC)(=O)C>[CH2:31]([S:30][C:20]1[CH:21]=[C:22]([S:25][C:26]([F:29])([F:27])[F:28])[CH:23]=[CH:24][C:19]=1[C:3]1[N:2]([CH3:1])[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:10]=[C:5]2[N:4]=1)[CH3:32]
Reactant: Cn1cnc2cc(C(F)(F)C(F)(F)F)cnc21
Reactant: CCSc1cc(SC(F)(F)F)ccc1Br
Agent: [Cu+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCSc1cc(SC(F)(F)F)ccc1-c1nc2cc(C(F)(F)C(F)(F)F)cnc2n1C
Yield: 82.4 %

Procedure:
A mixture of 0.12 g of 3-methyl-6-pentafluoroethyl-3H-imidazo[4,5-b]pyridine, 0.15 g of 1-bromo-2-ethylsulfanyl-4-trifluoromethylsulfanylbenzene, 0.01 g of palladium(II) acetate, 0.01 g of triphenylphosphine, 0.02 g of copper(II) acetate monohydrate, 0.13 g of potassium carbonate and 3 ml of toluene was stirred under heating and refluxing for 2 hours. Ethyl acetate and water were added to the cooled reaction mixture, and the mixture was filtered. The filtrate was extracted with ethyl acetate, and then dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.19 g of 2-(2-ethylsulfanyl-4-trifluoromethylsulfanylphenyl)3-methyl-6-pentafluoroethyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as Compound 8).
Reaction SMILES: [OH-].[K+].[CH3:3][C@@:4]12[C:20](=[O:21])[CH2:19][CH2:18][C@H:17]1[C@H:16]1[C@@H:7]([C:8]3[CH:9]=[CH:10][C:11]([OH:22])=[CH:12][C:13]=3[CH2:14][CH2:15]1)[CH2:6][CH2:5]2.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[CH:28]=O.C(O)(=O)C>C(O)C>[OH:22][C:11]1[CH:10]=[CH:9][C:8]2[CH:7]3[CH:16]([CH2:15][CH2:14][C:13]=2[CH:12]=1)[CH:17]1[C:4]([CH3:3])([C:20](=[O:21])[C:19](=[CH:28][C:27]2[CH:30]=[C:31]([O:35][CH3:36])[C:32]([O:33][CH3:34])=[C:25]([O:24][CH3:23])[CH:26]=2)[CH2:18]1)[CH2:5][CH2:6]3
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(C=C2CC3C4CCc5cc(O)ccc5C4CCC3(C)C2=O)cc(OC)c1OC
Reaction time: 4 h

Procedure:
Potassium hydroxide (1.0 g) was added to a solution of estrone (1.350 g, 2.0 mmol) and 3,4,5-trimethoxybenzaldehyde (1.00 g, 5.10 mmol) in ethanol (50 ml) at room temperature. The resulting dark brown solution was stirred at this temperature for 4 h, then glacial acetic acid (ca. 2.5 ml) was added with stirring. The colour changed to yellow and a white solid precipitated. The solid was filtered off and washed with water (50 ml), ethanol (20 ml), diethyl ether (50 ml) and hexane and recrystallised from ethanol. Yield: 2.063 g (92%) light yellow crystals. 1H-NMR (CDCl3, 400 MHz), δ: 1.00 (s, 3H), 1.40-1.78 (m, 5H), 2.00-2.11 (m, 2H), 2.26-2.34 (m, 1H), 2.38-2.56 (m, 2H), 2.84-3.04 (m, 3H), 3.90 (s, 3H), 3.91 (s, 6H), 4.93 (s, 1H, —OH), 6.60 (d, J=2.3 Hz, 1H), 6.66 (dd, J=8.2, 2.3 Hz, 1H), 6.80 (s, 2H), 7.17 (d, J=8.2 Hz, 1H), 7.40 (s, 1H). 13C-NMR (CDCl3, 100 MHz), δ: 15.0, 26.4, 27.2, 29.4, 32.1, 38.4, 44.4, 48.2, 49.0, 56.6, 61.3, 108.2, 113.2, 115.6, 126.6, 131.3, 131.9, 133.9, 135.2, 137.9, 139.7, 153.4, 154.0, 209.9. LRMS (FAB+): 449.3 (100, [M+H]+). LRMS (FAB−): 447.3 (100, [M−H]−). HRMS (FAB+): 448.223763.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:21][CH2:22][OH:23])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C@H](C(O)=O)CC(O)=O.CCN(C(C)C)C(C)C.CS(C)=O>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Si:1]([O:18][CH2:19][C@@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:21][CH:22]=[O:23])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: N[C@@H](CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CC=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (S)-tert-butyl (1-((tert-butyldiphenylsilyl)oxy)-4-hydroxybutan-2-yl)carbamate (prepared according to the procedure described in WO2013124826 A1 using L-aspartic acid) (15.0 g, 33.8 mmol) and DIPEA (29.5 mL, 169 mmol) in DCM (50 mL) at 0° C. was added a slurry of DMSO (7.20 mL, 101 mmol) and sulfurtrioxide pyridine complex (16.14 g, 101 mmol) in DCM (50 mL). After stirring at rt for 1.5 h, the mixture was diluted with saturated NaHCO3 (aq) and the layers were separated. The aqueous layer was extracted with DCM and the combined organic portions were dried over Na2SO4 and concentrated in vacuo to afford the title compound (16.9 g, assumed quantitative) as a ight brown oil. It was used as such without further purification. LCMS: Rt=1.20 min, m/z=442.2 (M+1) Method 2m_acidic.
Reaction SMILES: [H-].[Na+].[OH:3][N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]([OH:12])[CH2:6][C:5]1([CH3:14])[CH3:13].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>O1CCCC1>[OH:3][N:4]1[C:9]([CH3:10])([CH3:11])[CH2:8][CH:7]([O:12][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:6][C:5]1([CH3:14])[CH3:13]
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COC1CC(C)(C)N(O)C(C)(C)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.48 g (20 mmol) of sodium hydride is added to a solution of 3.0 g (17 mmol) of 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine in 25 mL of anhydrous tetrahydrofuran. The reaction mixture is stirred under a blanket of nitrogen for one hour. The mixture is chilled to 0° C. and 2.9 g (17 mmol) of ethyl bromoacetate is added dropwise. After the addition is complete, the reaction is stirred for an additional 30 minutes during which time a white precipitate forms. The mixture is filtered and the solvent is removed under reduced pressure. The title compound is isolated as an orange solid after column chromatography and melts at 41-43° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4].S(Cl)(Cl)=O.O[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH:27][C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=2)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCOc1ccc(C(=O)O)cc1
Reactant: COC(=O)C=Cc1ccc(O)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCOc1ccc(C(=O)Oc2ccc(/C=C/C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
8.7 g (0.045 mol) of 4-(but-3-enyloxy)-benzoic acid were treated with 76 ml of thionyl chloride and 2 drops of DMF and boiled under reflux for 3.5 hours. The excess thionyl chloride was completely removed firstly in a water-jet vacuum and subsequently in a high vacuum. The residual acid chloride was taken up in 10 ml of dichloromethane and slowly added dropwise at 0° C. to a mixture of 7.59 g (0,042 mol) of methyl 3-(4-hydroxyphenyl)-acrylate (Example 1) and 6 ml of triethylamine in 40 ml of dichloromethane. The batch was stirred at room temperature overnight. The white precipitate in the reaction mixture was dissolved by the addition of dichloromethane. The organic phase was washed repeatedly with water, dried over Na2SO4 and evaporated to dryness. For purification, the residue was chromatographed on silica gel with dichloromethane and subsequently recrystallized from ethanol. 12.65 g of 4-[(E)-2-methoxycarbonyl-vinyl]-phenyl 4-(but-3-enyloxy)-benzoate were isolated as a white powder; phase succession (° C.): C 103 N138 I.