Structure of 338454-45-8
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CAS No. : | 338454-45-8 |
Formula : | C5H7BO3S |
M.W : | 157.98 |
SMILES Code : | OCC1=CC=C(S1)B(O)O |
MDL No. : | MFCD03095370 |
InChI Key : | IVBZNXLSUVVBCY-UHFFFAOYSA-N |
Pubchem ID : | 4374265 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 5 |
Fraction Csp3 | 0.2 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 3.0 |
Molar Refractivity | 40.27 |
TPSA ? Topological Polar Surface Area: Calculated from |
88.93 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 |
-0.31 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-1.23 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-1.35 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.15 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
-0.61 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.86 |
Solubility | 21.7 mg/ml ; 0.137 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.1 |
Solubility | 12.6 mg/ml ; 0.08 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.37 |
Solubility | 66.8 mg/ml ; 0.423 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 |
No |
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 |
-7.48 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 |
1.0 |
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) |
2.47 |
* 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 |
---|---|---|
36% | 2-Hydroxymethyl-thiophene (2.28 g; 20 mmol) is dissolved in tetrahydrofuran (40 ml, dried over a molecular sieve) and the solution is cooled to -78 C. while gassing with argon. A 1.6 M n-butyllithium solution in n-hexane (25 ml; 40 mmol) is slowly added dropwise. The reaction mixture is then allowed to warm to -30 C. and cooled again to -78 C., and a solution of trimethyl borate (6.69 ml; 60 mmol) in tetrahydrofuran (20 ml) is added dropwise in the course of 15 minutes at between -78 and -70 C. After stirring at -78 C. for 2 hours, the mixture is allowed to warm to room temperature and is poured on to water (50 ml), the pH is brought to 3 by addition of a 2 N aqueous hydrochloric acid solution (28 ml), the mixture is extracted with diethyl ether and the extract is washed with a saturated aqueous sodium chloride solution, dried with sodium sulphate, filtered with suction and concentrated. [00267] Yield: 1.1 g (36%) (5-hydroxymethyl-thiophen-2-yl)-boron acid as a brown oil. [00268] MS: 158 (M) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tetrahydroborate; isopropyl alcohol; at 0℃; for 1.25h; | Example 20a; 7V-(2-Amino-5-(5-((2-hydroxyethylamino)methyl)thiophen-2-yl)phenyl)-4- methoxybenzamide (193); <n="122"/>Scheme 20; Step 1 : 5-(Hvdroxymethyl)thiophen-2-ylboronic acid (186); [0782] A suspension of 5-formylthiophen-2-ylboronic acid 185 (1.096 g, 7.03 mmol) in isopropanol (10 mL), stirred at 0 0C, was treated with solid sodium borohydride (0.336 g, 8.88 mmol) added portion-wise at 0 0C then stirred for 75 min. The reaction was quenched with acetone and concentrated to give compound 186 (used directly in Step 2).[0783] LRMS: 158.0 (calc) 159.1 (obs). | |
With sodium tetrahydroborate; In methanol; at 20℃; for 1.0h; | To a solution of (5-formyl-2-thienyl) boronic acid (31 mg, 0.20 mmol) in MeOH (1 ml) was added NaBH4 (7.8 mg, 0. 20mol).). The resulting mixture was stirred at rt for 1 hr and filtered through celite. The solution was concentrated and the residue was purified by FCC to give 10 mg product. | |
With methanol; sodium tetrahydroborate; | The thiphene-5- al-2-boronic acid (0.47 g, 2.97 mmol) was reduced with NaBH4 (0.15 g, 3.95 mmol) in MeOH (3 ml) and solvent was evaporated to dryness. The residue was taken in 1 ,4-dioxane (12 ml) and 4-bromobenzaldehyde (0.65 g, 3.5 mmol) was added. To this Pd(PPh3J4 (0.05 g) was added with stirring at 80 9C, followed by the addition of a solution of NaHCO3 (0.6 g) in H2O (2 ml). The mixture was stirred at reflux for 1 h and the solvents were evaporated to dryness under reduced pressure. The residue was diluted to 100 ml with EtOAc and washed with H2O. The organic layer was separated, dried over MgSO4 and filtered. Tthe filtrate was evaporatedto dryness and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.61 g, 80%), as creamy paste. 1H- NMR (CDCI3) 9.98 (s, 1 H, CHO); 7.87 (d, 2H, J = 8.3 Hz); 7.72 (d, 2H, J = 8.31 Hz); 7.31 (d, 1 H, J = 3.74 Hz); 7.0 (d, 2H, J = 3.7 Hz); 4.84 (s, 2H). |
With methanol; sodium tetrahydroborate; at 20℃; for 2.0h; | To a solution of 5-formylthiophen-2-ylboronic acid (15.6 mg, 0.1 mmol) in MeOH (0.5 mL) was added excess amount of NaBH4. The mixture was stirred at room temperature for 2 hours and evaporated under reduced pressure to afford crude 5-(hydroxymethyl)thiophen-2-ylboronic acid, which was used in step E without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With cesium fluoride;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In methanol; at 120℃; for 0.333333h;microwave radiation; | A mixture of 2-[3-(l-ter^butoxycarbonylpiperidin-4-ylcarbonylammo)phenyl]-4-chloro-6-morpholinopyrimidine (0.054 g), 5-hydroxymethylthien-2-ylboronic acid (0.021 g),caesium fluoride (0.046 g), a [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(n)1:1 complex with methylene chloride (3 mg), and methanol (2 ml) was stirred and heated to120C using microwave radiation for 20 minutes under an atmosphere of nitrogen in a sealedglass tube. The resultant reaction mixture was evaporated and the residue was partitionedbetween methylene chloride and water. The organic solution was dried over magnesiumsulphate and evaporated. The residue was purified by column chromatography on silica usingan increasingly polar gradient of 0% to 5% methanol in methylene chloride as eluent. Therewas thus obtained 2-[3-(A^fe/t-butoxycarbonylpiperidin-4-ylcarbonylamino)phenyl]-4-(5-hydroxymethylthien-2-yl)-6-morpholinopyrimidine as a gum. Trifluoroacetic acid (2 ml)was added to the material so obtained and the mixture was stirred at ambient temperature for30 minutes. The mixture was evaporated and the residue was purified by HPLC usinga Waters 'Xterra' preparative reversed-phase column (5 microns silica, 19 mm diameter,100 mm length) using decreasingly polar mixtures of water (containing 1% of a concentrated(d=0.88) aqueous ammonium hydroxide solution) and acetonitrile as eluent. There was thusobtained the title compound as a solid (0.015 g); NMR Spectrum: (DMSOde) 1.55-1.66(m, 2H), 3.04 (d, 2H), 3.77 (d, 8H), 4.69 (d, 2H), 5.57 (t, 1H), 7.05 (d, 1H), 7.19 (s, 1H), 7.4(t, 1H), 7.9-7.95 (m, 2H), 8.07 (d, 1H), 8.48 (s, 1H), 10.01 (s, 1H); Mass Spectrum: M+H+480. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 150℃; for 0.25h;Microwave irradiation; | [0123] To a solution of 2 (1.0 g, 5.2 mmol), <strong>[338454-45-8]5-hydroxymethylthiophene-2-boronic acid</strong> (0.82 g, 5.2 mmol), and Pd(PPh3)4 (0.60 g, 0.078 mmol) in DMF (16 mL) was added Na2CO3 (2.0 M, 4.6 mL). The reaction mixture was heated for 15 min at 150 0C in a Biotage microwave reactor. The resulting mixture was filtered through a pad of silica gel, concentrated and purified by silica gel chromatography (hexanes/EtOAc 100:0 to 0:100 gradient) to afford the title compound as a yellow solid (0.93 g, 66 %).[0124] MS (ES+): m/z 270 (M +H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine)palladium (0); In 1,4-dioxane; water; | Intermediate 17: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-2-thienyl)-1H-indole-7-carboxamide To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (200 mg, 0.49 mmol) in dioxane (4.5 mL) and H2O (1.5 mL) was added <strong>[338454-45-8][5-(hydroxymethyl)-2-thienyl]boronic acid</strong> (232 mg, 1.47 mmol), potassium carbonate (406 mg, 2.94 mmol) and tetrakis(triphenylphosphine)palladium (0) (57 mg, 0.049 mmol). Reaction was run in the microwave at 150 C. for 20 min. Aqueous work-up with EtOAc/H2O gave 447 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(hydroxymethyl)-2-thienyl]-1H-indole-7-carboxamide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 140℃; for 0.25h;sealed tube; microwave irradiation; | [0163] To a microwave reaction tube was charged with 2,4-dichloro-5-methyl-pyrimidine (0.50 g, 3.1 mmol), <strong>[338454-45-8]5-hydroxymethylthiophene-2-boronic acid</strong> (0.60 g, 3.8 mmol) and Pd(PPh3 )4 (0.20 g, 0.17 mmol). DMF (6 mL) was added to the above mixture followed by aqueous sodium carbonate (2 M; 3.0 mL, 6.0 mmol). The reaction tube was sealed and the suspension irradiated with microwave at 140 0C for 15 min. After cooling to room temperature, the mixture was filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by column chromatography on silica gel (hexanes to 70% EtOAc/hexanes) to afford the title compound as an off white solid (0.16 g, 22%). MS (ES+): m/z 241 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; water; at 110℃; for 0.333333h;Microwave irradiation; | To a solution of 2,4-dichloro-7H-pyrrolo[2,3-J]pyrimidine (188 mg, 1.0 mmol) in dimethoxyethane (DME, 10 mL) was added a solution of benzo[b]thiophen-2-yl-2-boronic acid (174 mg, 1.1 mmol) in EtOH (5 mL), 2.0 M Na2CO3 (2 mL), and tetrakis(triphenylphosphine)palladium (0) (Pd(PPh3)4, 115 mg, 0.1 mmol). The reaction mixture was heated at 110 0C for 20 min under mu-wave. The hot solution was filtered and the solid was washed with EtOAc. The filtrate was washed with brine (50 mL). The aqueous was extracted with EtOAc (3 x 30 mL). Combined organic layer was dried (Na2SO4). The solvent was removed in vacuo. The residue was added MeOH and sonicated. The solid was collected by filtration. The title compound (165 mg, 62%) was afforded as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 140℃; for 0.333333h;Microwave irradiation; | To a microwave reaction tube was charged with 7 (85 mg, 0.24 mmol), 5- hydroxymethyl-2-boronic acid (50 mg, 0.32 mmol) and Pd(PPh3)4 (30 mg, 0.026 mmol).DMF (3 mL) was added to the above mixture followed by 2 M of sodium carbonate (0.5 mL). The reaction tube was sealed and the suspension irradiated with microwave at 140 0C for 20 min. After cooling to room temperature, the mixture was filtered, the filtered solid washed with DCM and the filtrate concentrated. The crude product was purified by etaPLC, the fractions combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue re-dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a yellow solid (50 mg, 48%).[0135] 1H NMR (500 MHz, DMSO-d6): delta 1.68-1.72 (m, 4H), 2.50-2.60 (m, 4H), 2.78- 2.84 (m, 2H), 4.04 (t, J = 4.9 Hz, 2H), 4.71 (d, J= 5.9 Hz, 2H), 5.61 (t, J= 5.8 Hz, IH), 6.79 (dd, J = 3.6, 1.8 Hz, IH), 6.88 (d, J= 9.1 Hz, 2H), 7.09 (d, J= 3.7 Hz, IH), 7.23 (dd, J= 3.5, 2.4 Hz, IH), 7.76 (d, J = 9.1 Hz, 2H), 7.91 (d, J = 3.8 Hz, IH), 8.98 (s, IH), 11.5 (s, IH) MS (ES+): m/z 436 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 80℃; for 1.0h;Reflux; | The thiphene-5- al-2-boronic acid (0.47 g, 2.97 mmol) was reduced with NaBH4 (0.15 g, 3.95 mmol) in MeOH (3 ml) and solvent was evaporated to dryness. The residue was taken in 1 ,4-dioxane (12 ml) and 4-bromobenzaldehyde (0.65 g, 3.5 mmol) was added. To this Pd(PPh3J4 (0.05 g) was added with stirring at 80 9C, followed by the addition of a solution of NaHCO3 (0.6 g) in H2O (2 ml). The mixture was stirred at reflux for 1 h and the solvents were evaporated to dryness under reduced pressure. The residue was diluted to 100 ml with EtOAc and washed with H2O. The organic layer was separated, dried over MgSO4 and filtered. Tthe filtrate was evaporatedto dryness and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.61 g, 80%), as creamy paste. 1H- NMR (CDCI3) 9.98 (s, 1 H, CHO); 7.87 (d, 2H, J = 8.3 Hz); 7.72 (d, 2H, J = 8.31 Hz); 7.31 (d, 1 H, J = 3.74 Hz); 7.0 (d, 2H, J = 3.7 Hz); 4.84 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 140℃; for 0.25h;Microwave irradiation; Inert atmosphere; | To a solution of 5-chloro-3-methyl-7-(4-morpholinophenyl)pyrido[4,3-<i]pyrimidin-4(3H)-one(6.0 mg, 0.017 mmol) in 1,4-dioxane (0.5 mL) were added crude <strong>[338454-45-8]5-(hydroxymethyl)thiophen-2-ylboronic acid</strong> from Step A, 2M aqueous Na2CO3 solution (0.1 mL, 0.2 mmol), and a catalytic amount of Pd(PPh3)4. The reaction mixture was purged with N2 and heated at 140 0C by a microwave reactor for 15 minutes. The mixture was then cooled, quenched with H2O, extracted with EtOAc, and purified by preparatory LC/MS to provide the title compound; ESI-MS mlz 435.1 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18.7% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 15.0h;Inert atmosphere; | 5-(4-(5-cyclopropyl-lH-pyrazol-3-ylamino)-5-fluoropyrimidin-2-yl)thiophen- 2-yl)methanol (Compound 26)A mixture of 2-chloro-N-(5-cyclopropyl-lH-pyrazol-3-yl)pyrimidin-4-amine (170 mg, 0.57 mmol, 1.0 equiv.), <strong>[338454-45-8]5-(hydroxymethyl)thiophen-2-ylboronic acid</strong> (117 mg, 0.74 mmol, 1.3 equiv.), Pd(PPh3)4 (132.6 mg, 0.114 mmol, 0.2 equiv.), Na2CO3 (211 mg, 2 mmol, 3.5 equiv.), dioxane (5 ml) and water (1 ml) was added to the filtrate. The reaction mixture was heated to 100 0C for 15h under nitrogen atmosphere. The residue was purified by silica gel chromatography (CH2Cl2 / methanol 500:1 to 40:1) to afford title compound (5-(4-(5-cyclopropyl-lH-pyrazol-3- ylamino)-5-fluoropyrimidin-2-yl)thiophen-2-yl)methanol (Compound 26) (35.3 mg, 18.7%) as solid. LC-MS (m/z) =332.1 [M+H]+; 1H NMR (400 MHz, OMSO-d6): delta 0.73 (d, J=4Hz, 2H), 0.94 (d, J=6.8Hz, 2H), 1.94 (m, IH), 4.64 (d, J=5.2Hz, 2H), 5.59 (t, J=5.2Hz, IH), 6.55 (s, IH), 6.98 (d, J=3.6Hz, IH), 7.59 (d, J=2.8Hz, IH), 8.26 (d, J=3.2Hz, IH), 10.04 (s, IH), 12.19 (s, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
984 mg | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; at 90℃; for 2.0h;Inert atmosphere; | Note: DME and 2M Na 2CO 3 were degassed with a stream of N 2 in separate flasks prior to addition. Tert-butyl 5-chloro-3-formylpyrazolo[1,5-a]pyrimidine-7-yl)(cyclopropyl)carbamate (1.5 g, 4.45 mmol) was dissolved in DME (40 mL). Crude 5-(hydroxymethyl)thiophen-3-boronic acid (1.4 g, 8.9 mmol) was added, followed by Pd(PPh 3) 4 (510 mg, 0.45 mmol) and finally 2M Na 2CO 3 (6.7 mL, 13.3 mmol). The reaction was heated to 90 C. for 2 h. The solution was partitioned between EtOAc (100 mL) and 0.5N HCl (100 mL). The aqueous layer was extracted with EtOAc (2×75 mL). The organics were washed with brine (250 mL), dried over MgSO 4, filtered and concentrated in vacuo. The residue was purified via flash column chromatography (30-45% EtOAc/hexanes) and then triturated with hexanes (3×10 mL) to yield tert-butyl cyclopropyl(3-formyl-5-(5-(hydroxymethyl)thiophen-2-yl)pyrazolo[1,5-a]pyrimidine-7-yl)carbamate (984 mg, 53%) as an off white solid. |
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