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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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| CAS No. : | 269409-73-6 | 
| Formula : | C13H17BO4 | 
| M.W : | 248.08 | 
| SMILES Code : | C1=C(C=CC=C1B2OC(C(O2)(C)C)(C)C)C(=O)O | 
| MDL No. : | MFCD03411930 | 
| InChI Key : | OPWAPCOSDAFWFB-UHFFFAOYSA-N | 
| Pubchem ID : | 2734653 | 
| GHS Pictogram: |   | 
| Signal Word: | Warning | 
| Hazard Statements: | H315-H319-H335 | 
| Precautionary Statements: | P261-P305+P351+P338 | 
| Num. heavy atoms | 18 | 
| Num. arom. heavy atoms | 6 | 
| Fraction Csp3 | 0.46 | 
| Num. rotatable bonds | 2 | 
| Num. H-bond acceptors | 4.0 | 
| Num. H-bond donors | 1.0 | 
| Molar Refractivity | 69.88 | 
| TPSA ? Topological Polar Surface Area: Calculated from  | 55.76 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  | 2.43 | 
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from  | 1.68 | 
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from  | 1.27 | 
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by  | 1.25 | 
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions | 1.33 | 
| Log S (ESOL):? ESOL: Topological method implemented from  | -3.02 | 
| Solubility | 0.235 mg/ml ; 0.000947 mol/l | 
| Class? Solubility class: Log S scale  | Soluble | 
| Log S (Ali)? Ali: Topological method implemented from  | -3.24 | 
| Solubility | 0.142 mg/ml ; 0.00057 mol/l | 
| Class? Solubility class: Log S scale  | Soluble | 
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by  | -3.38 | 
| Solubility | 0.104 mg/ml ; 0.000421 mol/l | 
| Class? Solubility class: Log S scale  | 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)  | Yes | 
| 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  | -6.09 cm/s | 
| Lipinski? Lipinski (Pfizer) filter: implemented from  | 0.0 | 
| 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  | 0.56 | 
| 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) | 2.87 | 
* 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 | 
|---|---|---|
| To a solution of 3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-benzoic acid (1.15 g, 4.63 mmol) and HBTU (1.52 g, 4.03 mmol) in anhydrous DMF (20 ml) was added N,N-diisopropylethylamine (1.2 ml, 6.71 mmol). The resultant solution was stirred at room temperature for 45 min. Ethanolamine (0.29 ml, 4.84 mmol) was added slowly to the solution, and the stirring was continued for another 25 h. After evaporation of solvent, the residue was subjected to flash column chromatography on silica gel (elution with CH2C12-EtOAC) to yield N-(2-hydroxyethyl)-3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-benzamide as white crystals (398 mg). ESI-MS: m/z 292 (M+l); IH NMR (600 MHz, CDC13): δ 8.11 (IH, s), 7.98 (IH, d, J= 7.2 Hz), 7.94 (IH, d, J= 7.2 Hz), 7.46 (IH, t, J= 7.2 Hz), 3.85 (2H, t, J= 4.8 Hz), 3.64 (2H, dd, J= 4.8, 10.2 Hz); 13C NMR (150.9 MHz, CDC13): δ 168.69, 138.00, 133.42, 132.39, 130.52, 128.21, 84.19, 62.47, 42.97, 24.88. | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 24h; | A mixture of 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoic acid (0.8 g, 3.22 mmol), <strong>[6274-22-2]4-amino-N-methylbenzamide</strong> (0.58 g, 3.86 mmol), HATU (1.47 g, 3.8 mmol) and DIEA (1 g, 7.7 mmol) in DMF (10 mL) was stirred at room temperature for 24 h. The solvent was evaporated at 70C under reduced pressure to give a crude product. It was filtered through a plug of silica gel and the filter cake washed with ethyl acetate / petroleum ether (1: 1, v/v). The combined filtrates were concentrated to give crude N-(4- (methylcarbamoyl)phenyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide (0.56 g, 45.9 %) as a white solid that was used directly without further purification.LC/MS: 381.1 [M+H]+. | 
 [ 269409-73-6 ]
                                                    
                                                    [ 269409-73-6 ]
 [ 49851-36-7 ]
                                                    
                                                    [ 49851-36-7 ]
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| TEA (1.685 mL, 12.09 mmol) was added to a mixture of 3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzoic acid (CAS 269409-73-6) (1 g, 4.03 mmol) and HATU (1.686 g, 4.43 mmol) in DMF (4.5 mL). After 30 min, <strong>[49851-36-7]methyl 2-(2-aminophenyl)acetate hydrochloride</strong> (CAS 49851-36-7) (0.666 g, 4.03 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction was diluted with a 4:1 EtOAc/heptanes mixture and water. The aqueous phase was extracted with 4:1 EtOAc/heptanes. The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (heptane/EtOAc with 10% MeOH, 100:0 to 0:100) to give the title compound. MS (ESI+) m/z 396.4 (M+H). | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 75% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In water; N,N-dimethyl-formamide; at 110℃;Inert atmosphere; | To a degassed souton of DMF:H20 (10:1 raUo) (0.3 M), under an atmosphere of nitrogen, was added the pnaco ester (1 mmo), 2-bromopyrdne or 2-choropyrmdne (1 .5 eq.), and Cs2CO3 (4.4 eq.). The whoe mxture was degassed once agan and then Pd(PPh3)4 (5mo%) was added. The resutng souton was heated to 110C overnght. The sovent was removed in vacuo to give a dark gummy residue, which was taken up nto EtOAc and H20, then acdfied with 2 M HC to pH 2. The organic ayer was separated and the aqueous ayer was further extracted with EtOAc (2x). The combined organic ayers were dried over MgSO4 and concentrated in vacuo to gve a back ofly residue. The residue was dry oaded ontosWca ge in vacuo then purfied by flash coumn chromatography, eutng with 10-30% EtOAc/petroeum benzne and 1% acetic acid to afford the tWe compound.The foHowng compounds were made by Suzuk CoupUng F:P1B1Off white soUd (75% yed). 1H NMR (400 MHz,DMSO) 6 8.71 8.68 (m, 1 H), 8.67 (s, 1 H), 8.29 (d,J = 7.8 Hz, 1 H), 8.01 (t, J = 8.4 Hz, 2H), 7.91 (td, J =7.8, 1.8 Hz, 1 H), 7.61 (t, J = 7.7 Hz, 1 H), 7.42 7.37(m, 1H). LCMS B rt3.17, m/z200.1 [M + H]. | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 78% | With bis-triphenylphosphine-palladium(II) chloride; potassium phosphate; In 1,4-dioxane; water; at 95℃;Inert atmosphere; | General procedure: The halo aryl (1.0 equiv) was dissolved in a mixture of water:dioxane (1:1). The boronic acid or ester(1.5 equiv) and potassium phosphate (5.0 equiv) were added. The solution was degassed byvacuum/argon cycles (10 times) before addition of PdCl2(PPh3)2 (10 mol%) and further degassed (5times). The resulting mixture was stirred at 95 C under argon atmosphere for 16-20 hours. Thereaction mixture was filtered through Celite and diluted with water (approx. 30 mL) before washingwith chloroform (3 x 30 mL). If not stated otherwise, the aqueous phase was concentrated underreduced pressure and applied to a C18 precolumn before purification on a 10g or 60 g C18 column witha gradient of acetonitrile in water (10-100%) to yield the desired product. | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 67% | With bis-triphenylphosphine-palladium(II) chloride; potassium phosphate; In 1,4-dioxane; water; at 95℃;Inert atmosphere; | General procedure: The halo aryl (1.0 equiv) was dissolved in a mixture of water:dioxane (1:1). The boronic acid or ester(1.5 equiv) and potassium phosphate (5.0 equiv) were added. The solution was degassed byvacuum/argon cycles (10 times) before addition of PdCl2(PPh3)2 (10 molpercent) and further degassed (5times). The resulting mixture was stirred at 95 °C under argon atmosphere for 16-20 hours. Thereaction mixture was filtered through Celite and diluted with water (approx. 30 mL) before washingwith chloroform (3 x 30 mL). If not stated otherwise, the aqueous phase was concentrated underreduced pressure and applied to a C18 precolumn before purification on a 10g or 60 g C18 column witha gradient of acetonitrile in water (10-100percent) to yield the desired product. | 

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