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                            The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
 
                
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    							Batch number can be found on the product's label following the word 'Batch'.
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Search for reports by entering the product batch number.
    							Batch number can be found on the product's label following the word 'Batch'.
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| CAS No. : | 2605-68-7 | 
| Formula : | C22H21O2P | 
| M.W : | 348.38 | 
| SMILES Code : | COC(=O)C(C)=P(C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1 | 
| MDL No. : | MFCD08062441 | 
| InChI Key : | WCXPAYJKBTVUBC-UHFFFAOYSA-N | 
| Pubchem ID : | 10569721 | 
| GHS Pictogram: |   | 
| Signal Word: | Warning | 
| Hazard Statements: | H302-H315-H319-H335 | 
| Precautionary Statements: | P261-P305+P351+P338 | 
| Num. heavy atoms | 25 | 
| Num. arom. heavy atoms | 18 | 
| Fraction Csp3 | 0.09 | 
| Num. rotatable bonds | 5 | 
| Num. H-bond acceptors | 2.0 | 
| Num. H-bond donors | 0.0 | 
| Molar Refractivity | 107.97 | 
| TPSA ? Topological Polar Surface Area: Calculated from  | 36.11 Ų | 
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from  | 0.0 | 
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by  | 3.96 | 
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from  | 3.35 | 
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from  | 4.73 | 
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by  | 5.42 | 
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions | 3.49 | 
| Log S (ESOL):? ESOL: Topological method implemented from  | -4.7 | 
| Solubility | 0.00699 mg/ml ; 0.0000201 mol/l | 
| Class? Solubility class: Log S scale  | Moderately soluble | 
| Log S (Ali)? Ali: Topological method implemented from  | -4.42 | 
| Solubility | 0.0133 mg/ml ; 0.0000381 mol/l | 
| Class? Solubility class: Log S scale  | Moderately soluble | 
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by  | -8.02 | 
| Solubility | 0.00000337 mg/ml ; 0.0000000097 mol/l | 
| Class? Solubility class: Log S scale  | Poorly soluble | 
| GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg | High | 
| BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg | Yes | 
| P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set)  | No | 
| CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) | No | 
| CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) | No | 
| CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) | No | 
| CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) | No | 
| CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) | No | 
| Log Kp (skin permeation)? Skin permeation: QSPR model implemented from  | -5.61 cm/s | 
| Lipinski? Lipinski (Pfizer) filter: implemented from  | 1.0 | 
| Ghose? Ghose filter: implemented from  | None | 
| Veber? Veber (GSK) filter: implemented from  | 0.0 | 
| Egan? Egan (Pharmacia) filter: implemented from  | 0.0 | 
| Muegge? Muegge (Bayer) filter: implemented from  | 0.0 | 
| Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat  | 0.55 | 
| PAINS? Pan Assay Interference Structures: implemented from  | 0.0 alert | 
| Brenk? Structural Alert: implemented from  | 1.0 alert: heavy_metal | 
| Leadlikeness? Leadlikeness: implemented from  | No; 1 violation:MW<1.0 | 
| Synthetic accessibility? Synthetic accessibility score:  from 1 (very easy) to 10 (very difficult) | 3.97 | 
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 97% | A mixture of methyl-2-bromopropionate (S7) (2.00 mL, 17.9 mmol, 1.10 eq) and triphenylphosphine (4.27 g,16.3 mmol, 1.00 eq) in water (18.0 mL) was stirred at 70 C for 2.5 h. Both the aqueousand the organic layer still contained PPh3. The temperature was raised to 80 C and themixture was stirred for further 2 h. According to TLC, there was still a considerableamount of PPh3. Therefore, the mixture was stirred at 75 C overnight. After totally 23 hthe mixture was allowed to cool to rt. Afterwards aqueous NaOH (38 mL 1 M, 2.3 eq) wasadded, which led to the immediate precipitation of a yellow solid. The suspension wasstirred for 5 min, then CH2Cl2 (50 mL) was added and the layers were separated. Theaqueous phase was extracted with CH2Cl2 (2×50 mL), washed with brine, dried overMgSO4 and concentrated under reduced pressure. The crude was obtained as a yellow oil,which turned into a solid upon addition of pentane. The solid was washed with hexane(3×20 mL) and dried in vacuo to afford phosphonium ylide 17 (5.48 g, 97%) as a slightlyyellow powder. | |
| 91% | With potassium iodide; In water; toluene; at 70℃; for 20h; | After dissolving 5 g (19.06 mmol) of triphenylphosphine in 15 ml of toluene, an aqueous solution of 0.32 g (1.90 mmol) of potassium iodide in 15 ml of distilled water and 3.2 ml (28.6 mmol) of methyl 2-bromopropionate were added thereto. And the mixture was stirred at 70 C for 20 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, basified (pH 9) with 10 N aqueous sodium hydroxide solution, and extracted with dichloromethane. The obtained organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The obtained solid was washed with hexane and then filtered under reduced pressure and dried under reduced pressure to give 6.0 g (yield: 91%) of the title compound. | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| With sodium hydroxide; In dichloromethane; water; at 20℃; for 0.25h;Inert atmosphere; | Sodium hydroxideaq. (2 M, 85 mL, 170mmol) was added to a solution ofcarbomethoxy methyl triphenylphosphonium bromide (5.15 g,12.0mmol) and CH2Cl2 (20 mL) at room temperature. Afterstirring for 15min at room temperature, the solution wasextracted with CHCl3 (2 15 mL), washed with brine (15 mL),dried over Na2SO4 and concentrated. The resulting ylide wasused without further purification. A solution of the ylide and CH2Cl2 (30 mL) was added to asolution of lactol 36 (1.00 g, 5.98mmol) and CH2Cl2 (30 mL) atroom temperature. After maintaining for 19 h at room temperature,diisopropylethylamine (5.2 mL, 30mmol) and BOMCl(3.3 mL, 24mmol) were added to the yellow solution at roomtemperature. The solution was maintained for 2 d at roomtemperature, quenched with H2O (40 mL) and extracted withCHCl3 (3 30 mL). The combined organic extracts werewashed with brine (30 mL), dried over Na2SO4 and concentrated.The residue was purified by silica gel column chromatography(EtOAc/hexane 1:24 to 1:7) to give 2.27 g of a mixtureof the unsaturated methylester 37 and benzyl alcohol, whichwas used in the next step without further purification. Foran analytical sample, the mixture was purified by HPLC(PEGASIL Silica 1205250 20 mm, UV 254 nm, EtOAc/hexane 1:3, 10mL/min, TR = 12min) to afford the pureunsaturated methylester 37 | 
 [ 375-00-8 ]
                                                    
                                                    [ 375-00-8 ]
 [ 2605-68-7 ]
                                                    
                                                    [ 2605-68-7 ]
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 70% | In dichloromethane; at 47℃; for 3h; | To a solution of the phosphonium ylide17 (62.1 g, 178 mmol, 1.00 eq) in CH2Cl2 (230 mL) was added acrolein (18) (11.9 mL,178 mmol, 1.00 eq) dropwise at rt. The addition was ceased from time to time due toexcessive boiling of the mixture. After the addition, the yellow solution was heated (47 Coil bath) to maintain a gentle reflux. After 3 h, the mixture was allowed to cool to rt andstored overnight. Then it was concentrated under reduced pressure (Vigreux, short pathdistillation, “Hausvakuum”, 55 C oil bath), which took several hours. The concentrate wasthen cooled to 0 C, pentane was added, the resulting suspension was filtered and the filtercake was washed with pentane. The combined filtrates were concentrated (Vigreux, shortpath distillation, 50 C oil bath) and the crude was purified by distillation (75-77 oil bath, 20 mbar, bp = 59-60 C) to afford 19 as a colourless liquid (70%).1H-NMR (CDCl3, 400.1 MHz): δ = 7.17 (mc, 1H), 6.66 (ddd, J = 10.1 Hz, J = 11.3 Hz, J = 16.8 Hz, 1H), 5.56 (mc, 1H), 5.45 (mc, 1H), 3.77 (s, 3H), 1.96 (mc, 3H). | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 96% | In tetrahydrofuran; at 70℃; for 3h; | Preparation of polyene 43, (E)-9-phenyl-2,6-dimethyl-2,6-nonadienyl]-l-oxy-(feri'.- butyl)diphenyldimethyl-silane[0159] The synthesis route used in this example is shown schematically in Fig. 24 (see the appended figures). Hydrocinnamaldehyde (5.0 mmol, 1.0 eq, compound 81) in THF solution was subject to prop-l-en-2-ylmagnesium bromide (7.5 mmol, 1.5 eq) in THF solution at 0 C. The reaction was allowed to proceed 12 hours before quenching by pouring into water. The aqueous layer was extracted with dichloromethane (2 x 30 mL), and the <n="58"/>combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residual crude product was purified by column chromatography to afford the desired allylic alcohol product 82.[0160] The obtained 2-methyl-5-phenyl-l-penten-3-ol (5.0 mmol, 1.0 eq, compound 82) was subsequently mixed with triethyl orthoacetate (35.0 mmol, 7.0 eq) and catalytic amount of propionic acid (0.30 mmol, 0.06 eq) at room temperature. The mixture was refluxed at 150 0C for 12 hours, whereafter EtOH was distilled off from reaction mixture. The residual crude product was purified by column chromatography to afford the desired product ester 83. [0161] (E)-4-methyl-7-phenyl-4-heptenoic acid ethyl ester (compound 83, 2.0 mmol,1.0 eq.) was dissolved in toluene and cooled down to -78 C. Diisobutylaluminium hydride (DIBAL-H, 1.0 M in hexane, 3.0 mmol, 1.5 eq.) was added by means of a dry syringe. The reaction was allowed to proceed for 12 hours before quenching by adding MeOH at -78 C. A saturated aqueous solution of potassium sodium tartrate was added and warmed up to room temperature (rt). The aqueous layer was extracted with dichloromethane (2 x 30 mL), and the combined organic extracts were washed with water (30 mL) and brine (30 mL) and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residual crude product was purified by column chromatography to afford the desired product aldehyde 84.[0162] The obtained (4E)-4-methyl-7-phenyl-4-heptenal (compound 84, 2.0 mmol, 1.0 eq) was mixed together with ylide (6.0 mmol, 3.0eq) in THF. After refluxing for 4 hours, the solvent was removed in vacuo. The residual crude product was purified by column chromatography to afford (E)-2,6-dimethyl-9-phenyl-2,6-nonadienoic acid methyl ester (compound 85).[0163] Ester 85 (2.0 mmol, 1.0 eq) was dissolved in toluene and cooled down to -78 C. Diisobutylaluminium hydride (DIBAL-H5LO M in hexane, 4.0 mmol, 2.0 eq) was added by means of a dry syringe. The reaction was warmed upto room temperature and allowed to proceed for 12 hours before quenching by adding methanol at room temperature. Saturated potassium sodium tartrate aqueous solution was added and the mixture stirred for 1 hour. The aqueous layer was extracted with dichloromethane (2 x 30 mL), and the combined organic extracts were washed with water (30 mL) and brine (30 mL) and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residual crude product was purified by column chromatography to afford the desired product alcohol 86.[0164] (2E,6E)-2,6-dimethyl-9-phenyl-2,6-nonadien-l-ol (compound 86, 1.0 mmol, 1.0 eq ) was dissolved in THF together with imidazole (1.5 mmol, 1.5 eq) at room teperature. <n="59"/>(tert.-butyl)dimethyl-silylchloride (TBSCl, 1.2 mmol, 1.2 eq) was added. The reaction was allowed to proceed for 24 hours before quenching with water. The aqueous layer was extracted with dichloromethane (2 x 30 mL), and the combined organic extracts were washed with water (30 mL) and brine (30 mL) and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residual crude product was purified by column chromatography to afford (E)-9-phenyl-2,6-dimethyl-2,6-nonadienyl]-l-oxy-(fert.-butyl)dimethyl-silane (compound 43). | 
 [ 5370-25-2 ]
                                                    
                                                    [ 5370-25-2 ]
 [ 2605-68-7 ]
                                                    
                                                    [ 2605-68-7 ]

| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| In toluene; at 150℃; for 48h; | EXAMPLE 58; A mixture of the commercially available ketone (1.64 g), methyl triphenylphosphoranylidene acetate (2.8 g), and 20 mL of toluene was heated at 150 0C for 2 days. The mixture was purified by Biotage (5% ethyl acetate in hexane) to afford the enoate (cis:trans=l:l) as a white solid. The hydrolysis of this enoate, and the subsequent amide formation, followed the procedures described in the Examples above to provide a yellow oil. A solution of the bromide (1.24 g), hexamethyl ditin (1.6 g) in 10 mL of THF was degassed with argon, and to this solution was added Pd(PPh3)4 (151 mg). The mixture was heated at 80 0C overnight. The resulting stannane mixture was used directly for the subsequent Stille coupling, following procedures described in the above Examples. Following similar procedures as described in EXAMPLE 54, after hydrogenation, conversion of the amino group to the hydroxyl group, and hydrolysis, the desired product was obtained as a brown oil. 1H NMR (acetone-d6, 500 MHz) δ 11.3 (IH, s), 8.75 (IH, d), 8.13 (IH, d), 8.10 (IH, d), 7.63 (IH, d), 7.60 (IH, t), 7.33 (IH, d), 7.25 (IH, dd), 7.16 (IH, t), 6.91 (IH, d), 3.68 (IH, m), 2.83 (IH, dd), 2.75 (IH, dd), 1.45 (3H, d); LCMS m/z 383 (M++l). | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| In xylenes; at 170℃; for 4h;Heating / reflux; | EXAMPLE 7; To a xylenes solution of 6-methoxy-2-naphthaldehyde (0.855g, 4.585 mmol) was added the stabilized ylide shown in Scheme 2 (2.16g, 5.96 mmol, 1.3 eq.) at room temperature. The solution was heated to reflux for 4 h. The solvent was removed under vacuum, and the residue was chromatographed with AcOEt/Hexanes (4 to 1) to obtain the ethyl enoate intermediate. To a methanol solution of this intermediate (5.73 g) was added Pd/C (0-3 g), and the mixture was subjected to <n="33"/>hydrogenation under a balloon atmosphere of H2 gas, at room temperature for 16 h. The solution was filtered, and the solvent was removed in vacuo to obtain the saturated ester. The methoxy naphthyl ester (5.73 g) was treated with NCS (0.82g, 6.11 mmol, 1.1 eq) in DMF solvent at room temperature, and the solution was stirred for 16 h. Removal of the DMF in vacuo provided a residue which was recrystalized from methanol/methylene chloride to obtain the chlorinated intermediate. The racemic mixture of this chloride (1.5 g, 3.69 mmol) was separated into its single enantiomers using chiral HPLC with a Chiralcel OJ column, and isocratic elution with 35% isopropanol-heptane. The ethyl ester intermediate (65 mg, 0.21 mmol) was dissolved in (1:1) acetic acid-HCl (2 mL) and heated to 110 0C for 10 min. Then 5 mL of water was added, and the solution cooled to 0 0C to obtain the acid intermediate after filtration. Oxalyl chloride (0.3 mmol) was then added to a CH2CI2 (2 mL) solution of this acid intermediate (45 mg, 0.1 mmol), and one drop of DMF was added at 0 0C. The solvent was removed in vacuo after the solution was sirred for 1 h at room temperature. The residue was dissolved in THF (2 mL), and this solution was added to a THF (2 mL) solution of 3-amino-2-carboxylthiophene (0.11 mmol) and Et3N (0.3 mmol) at 0 0C. The pure thiophene methyl ester intermediate was obtained after HPLC purification. Potassium trimethylsilanolate (4 eq, 0.4 mmol) was added to a THF solution of this methyl ester intermediate (0.09 mmol) at 0 0C. The solution was stirred at room temperature for 2 h, and the desired product was obtained by preparative RPHPLC purification. 1H NMR (CD3OD, 500 MHz) δ 8.07 (d, IH), 7.99 (d, IH), 7.74 (d,lH), 7.66 (s, IH), 7.64(d, IH), 7.47 (dd IH), 7.40(d, IH), 4.00 (s, 3H), 3.17(m, IH), 2.97 (m, 2H), 1.30 (d, 3H); LCMS m/z 402 (M-I). | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 94% | In dichloromethane; at 20℃; for 24h; | To a solution of lactol 18 (1.04 g, 4.29 mmol) in CH2Cl2 (10 mL, 0.43 M) was added <strong>[2605-68-7]methyl 2-(triphenylphosphoranylidene)propionate</strong> (4.48 g, 12.87 mmol) at room temperature. After being stirred at the same temperature for 24 h, the reaction mixture was diluted with a small amount of hexanes. This mixture was purified by column chromatography (silica gel, hexanes/ethyl acetate, 1:1) to give the mixture of α,β-unsaturated ester 19 as a colorless oil (1.26 g, E:Z = 95:5, total 94%) |