Structure of 1028252-13-2
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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. : | 1028252-13-2 |
| Formula : | C9H5BrClNO |
| M.W : | 258.50 |
| SMILES Code : | ClC1=CC2=C(C=C1)C(Br)=CNC2=O |
| English Name : | 4-Bromo-7-chloroisoquinolin-1(2H)-one |
| MDL No. : | MFCD13193317 |
| InChI Key : | DNIKNSRKTYSIMS-UHFFFAOYSA-N |
| Pubchem ID : | 59423588 |
| Num. heavy atoms | 13 |
| Num. arom. heavy atoms | 10 |
| Fraction Csp3 | 0.0 |
| Num. rotatable bonds | 0 |
| Num. H-bond acceptors | 1.0 |
| Num. H-bond donors | 1.0 |
| Molar Refractivity | 57.28 |
| TPSA ? Topological Polar Surface Area: Calculated from |
32.86 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.98 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.37 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.94 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.92 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.87 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.82 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-3.51 |
| Solubility | 0.0808 mg/ml ; 0.000313 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-2.7 |
| Solubility | 0.515 mg/ml ; 0.00199 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-5.08 |
| Solubility | 0.00216 mg/ml ; 0.00000834 mol/l |
| Class? Solubility class: Log S scale |
Moderately 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) |
Yes |
| 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 |
-6.19 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 |
0.55 |
| PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
| Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
| Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<0.0 |
| Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.7 |
* 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 |
|---|---|---|
| 90% | With N-Bromosuccinimide In acetonitrile for 3.5h; Reflux; Inert atmosphere; | |
| With N-Bromosuccinimide In acetonitrile for 3.5h; Reflux; | 6.1.5 A slurry of the product of Step 4 and NBS (39.747 g, 223.3 mmol) in MeCN (500 mL, anhydrous) was slowly heated to a gentle reflux over a period of approximately 2 h and maintained at a gentle reflux for 1.5 h. (This reaction can be monitored by LC/MS). The reaction mixture was then slowly cooled to room temperature over a period of 3 h and the observed solid was removed by simple filtration. The collected solid was washed with MeCN (100 mL×3) to provide 47 g of the desired product. This material was used in the next step without further purification.1H NMR (400 MHz, CD3OD) δ ppm 7.46(s, 1H), 7.81 (dd, J=8.40, 2.00 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 8.27(d, J=2.00 Hz, 1H); 13C NMR (100 MHz, DMSO-D6) δ ppm 96.68, 126.34, 127.58, 127.71, 130.73, 132.20, 133.47, 134.46, 159.88; LC-MS, MS m/z 258 (M++H). | |
| With N-Bromosuccinimide In acetonitrile at 20℃; Reflux; | 2.5 Step 5: A slurry of the product of Step 4, Example 2 and NBS (39.747 g, 223.3 mmol) in MeCN (500 mL, anhydrous) was slowly heated to a gentle reflux over a period of approximately 2 h and maintained at a gentle reflux for 1.5 h. (This reaction can be monitored by LC/MS). The reaction mixture was then slowly cooled to room temperature over a period of 3 h and the observed solid was removed by simple filtration. The collected solid was washed with MeCN (100 mL×3) to provide 47 g of the desired product. This material was used in the next step without further purification. 1H NMR (400 MHz, CD3OD) δ ppm 7.46(s, 1H), 7.81 (dd, J=8.40, 2.00 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 8.27(d, J=2.00 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ ppm 96.68, 126.34, 127.58, 127.71, 130.73, 132.20, 133.47, 134.46, 159.88; LC-MS, MS m/z 258. |
| With N-Bromosuccinimide In acetonitrile at 20℃; for 6.5h; Heating / reflux; | 22.5 Step 5:; A slurry of the product of Step 4 and NBS (39.747 g, 223.3 mmol) in MeCN (500 mL, anhydrous) was slowly heated to a gentle reflux over a period of approximately 2 h and maintained at a gentle reflux for 1.5 h (This reaction can be monitored by LC/MS). The reaction mixture was then slowly cooled to room temperature over a period of 3 h and the observed solid was removed by simple filtration. The collected solid was washed with MeCN (100 mL×3) to provide 47 g of the desired product. This material was used in the next step without further purification.1H NMR (400 MHz, CD3OD) δ ppm 7.46 (s, 1H), 7.81 (dd, J=8.40, 2.00 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 8.27 (d, J=2.00 Hz, 1H); 13C NMR (100 MHz, DMSO-D6) δ ppm 96.68, 126.34, 127.58, 127.71, 130.73, 132.20, 133.47, 134.46, 159.88; LC-MS, MS m/z 258. |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 73% | With trichlorophosphate for 5h; Reflux; Inert atmosphere; | |
| Stage #1: 4-bromo-7-chloroisoquinolin-1-ol With trichlorophosphate for 5h; Reflux; Stage #2: With sodium hydroxide In dichloromethane; water at -35℃; | 6.1.6 A heterogeneous solution of the product of Step 5 (47 g, 182 mmol) in POCl3 (200 mL, 2.15 mol) was slowly heated to reflux over a period of 1 h. The reaction mixture was maintained at reflux for 4 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo to remove excess POCl3. The resulting residue was then taken up into 600 mL of CH2Cl2, cooled to at -35° C., then slowly treated with 1 N NaOH (400 mL) until the mixture was slightly basic (pH=8). The resulting organic layer was separated, washed with water, dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was crystallized from EtOAc (approximately 50 mL) to give 32 g of desired product. The collected solid was washed with 10% EtOAc/Hexanes (3×50 mL).The mother liquors were concentrated and purified by flash column chromatography (SiO2, eluted with 16% EtOAc in hexanes) to give 4 g of the desired product as a solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.80 (dd, J=8.81, 2.01 Hz, 1H), 8.14 (d, J=9.06 Hz, 1H), 8.34 (d, J=1.76 Hz, 1H), 8.48 (s, 1H); 13C NMR (100 MHz, DMSO-D6) δ ppm 118.39, 125.06, 127.59, 128.71, 133.89, 134.14, 134.93, 143.18, 148.98; LC-MS, MS m/z 275 (M++H). | |
| Stage #1: 4-bromo-7-chloroisoquinolin-1-ol With trichlorophosphate for 5h; Reflux; Stage #2: With sodium hydroxide In dichloromethane; water | 2.6 Step 6:A heterogeneous solution of the product of Step 5, Example 2 (47 g, 182 mmol) in POCl3 (200 mL, 2.15 mol) slowly heated to reflux over a period of 1 h. The reaction mixture was maintained at reflux for 4 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo to remove excess POCl3. The resulting residue was then taken-up into 600 mL of CH2Cl2, cooled to at -35° C., then neutralized carefully with 1 N NaOH (400 mL) until the mixture was slightly basic (pH=8). The resulting organic layer was separated, washed with water, dried over MgSO4 and concentrated in vacuo. The resulting residue was crystallized from EtOAc (approximately 50 mL) to give 32 g of desired product. The collected solid was washed with 10% EtOAc/Hexanes (3×50 ml). The mother liquid was concentrated and purified by Biotage (elution with 16% EtOAc in hexanes) to give 4 g of the desired product as a solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.80 (dd, J=8.81, 2.01 Hz, 1H), 8.14 (d, J=9.06 Hz, 1H), 8.34 (d, J=1.76 Hz, 1H), 8.48 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ ppm 118.39, 125.06, 127.59, 128.71, 133.89, 134.14, 134.93, 143.18, 148.98; LC-MS, MS m/z 275. |
| Stage #1: 4-bromo-7-chloroisoquinolin-1-ol With trichlorophosphate for 5h; Heating / reflux; Stage #2: With sodium hydroxide In dichloromethane; water at -35℃; | 22.6 Step 6:; A heterogeneous solution of the product of Step 5 (47 g, 182 mmol) in POCl3 (200 mL, 2.15 mol) slowly heated to reflux over a period of 1 h. The reaction mixture was maintained at reflux for 4 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo to remove excess POCl3. The resulting residue was then taken-up into 600 mL of CH2Cl2, cooled to at -35° C., then neutralized carefully with 1 N NaOH (400 mL) until the mixture was slightly basic (pH=8). The resulting organic layer was separated, washed with water, dried over MgSO4 and concentrated in vacuo. The resulting residue was crystallized from EtOAc (approximately 50 mL) to give 32 g of desired product. The collected solid was washed with 10% EtOAc/Hexanes (3×50 ml).The mother liquid was concentrated and purified by Biotage (elution with 16% EtOAc in hexanes) to give 4 g of the desired product as a solid.1H NMR (400 MHz, CDCl3) δ ppm 7.80 (dd, J=8.81, 2.01 Hz, 1H), 8.14 (d, J=9.06 Hz, 1H), 8.34 (d, J=1.76 Hz, 1H), 8.48 (s, 1H); 13C NMR (100 MHz, DMSO-D6) δ ppm 118.39, 125.06, 127.59, 128.71, 133.89, 134.14, 134.93, 143.18, 148.98; LC-MS, MS m/z 275. |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With N-Bromosuccinimide In acetonitrile Reflux; | 1001.2 Step 2A slurry of the product of Step 1, Example 1001, 7-chloroisoquinolin-l(2H)- one (36.33 g, 203 mmol) and N-bromosuccinimide (39.74 g, 223.3 mmol) in anhydrous CH3CN (500 mL) was slowly heated to a gentle reflux over a period of approximately 2 h and maintained at a gentle reflux for 1.5 h. The reaction was monitored by LC/MS and, when complete, the slurry, was slowly cooled to room temperature over a period of 3 h. The precipitated solid was collected by filtration and washed with CH3CN (100 mL x 3) to provide 47 g (90%) of 4-bromo-7- chloroisoquinolin-l(2H)-one. This material was used in the next step without further purification. ¾ NMR (400 MHz, CD3OD) δ ppm 7.46(s, 1H), 7.81 (dd, J=8.40, 2.00 Hz, 1 H), 7.88 (d, J=8.8 Hz, 1 H), 8.27(d, J=2.00 Hz, 1 H); 13C NMR (101 MHz, DMSO-D6) δ ppm 96.68, 126.34, 127.58, 127.71, 130.73, 132.20, 133.47, 134.46, 159.88; LC/MS, MS m/z (M+H)+ 258. | |
| With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1.1: trichlorophosphate / 5 h / Reflux 1.2: -35 °C / pH 8 2.1: n-butyllithium; Triisopropyl borate / hexane; tetrahydrofuran / 0.75 h / -78 - -65 °C 2.2: 1.17 h / -60 - 20 °C 2.3: 0 °C / pH 6 3.1: diazomethyl-trimethyl-silane / hexane; acetonitrile / 14 h / 0 - 20 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Stage #1: 4-bromo-7-chloro-2H-isoquinolin-1-one With trichlorophosphate for 5h; Reflux; Stage #2: With sodium hydroxide In dichloromethane at -35℃; | 1001.3 Step 3A heterogeneous solution of the product of Step 2, Example 1001, 4-bromo-7- chloroisoquinolin-l(2H)-one (47 g, 182 mmol) in POCl3 (200 mL, 2.15 mol) was slowly heated to reflux over a period of 1 h. It should be noted that during this heating process, the reaction mixture became homogeneous. The reaction mixture was maintained at reflux for 4 h before being cooled to room temperature and concentrated in vacuo to remove excess POCl3. To ensure complete removal of residual POCl3, the residue was dissolved in CH2CI2 or, alternatively, toluene and concentrated in vacuo. This process was repeated as necessary. (Note that POCl3 was properly disposed of in glass bottles which were labeled accordingly). The residue was taken-up into 600 mL of CH2CI2, cooled to -35 °C, neutralized and subsequently basified carefully with IN NaOH (400 mL) until the mixture was slightly basic (pH = 8). The organic layer was separated, washed with H20, dried over MgS04 and concentrated in vacuo. The residual solid was crystallized from EtOAc (approximately 50 mL) to give 32 g of 4-bromo-l,7-dichloroisoquinoline. The mother liquor from the crystallization process was concentrated and purified by Biotage (16% EtOAc in hexanes) to provide an additional 4 g of 4-bromo-l,7- dichloroisoquinoline as a solid. In total 36 g (73 %) of 4-bromo-l,7- dichloroisoquinoline was obtained. XH NMR (400 MHz, CDC13) δ ppm 7.80 (dd, J=8.81, 2.01 Hz, 1 H), 8.14 (d, J=9.06 Hz, 1 H), 8.34 (d, J=1.76 Hz, 1 H), 8.48 (s, 1 H); 13C NMR (101 MHz, DMSO-D6) δ ppm 1 18.39, 125.06, 127.59, 128.71, 133.89, 134.14, 134.93, 143.18, 148.98; LC/MS, MS m/z (M+H)+ 275. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1: diphenyl phosphoryl azide; triethylamine / benzene / 2 h / Inert atmosphere 2: Diphenylmethane / 3.5 h / 90 °C / Inert atmosphere 3: N-Bromosuccinimide / acetonitrile / 3.5 h / Reflux; Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: Diphenylmethane / 3.5 h / 90 °C / Inert atmosphere 2: N-Bromosuccinimide / acetonitrile / 3.5 h / Reflux; Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 6 steps 1.1: trichlorophosphate / 5 h / Reflux; Inert atmosphere 2.1: n-butyllithium / hexane; tetrahydrofuran / 0.75 h / 65 °C / Inert atmosphere 2.2: 0.75 h / 65 °C / Inert atmosphere 2.3: 0.5 h / -60 - -40 °C 3.1: diazomethyl-trimethyl-silane / hexane; acetonitrile / 14 h / 0 - 20 °C / Inert atmosphere 4.1: potassium <i>tert</i>-butylate / dimethyl sulfoxide / 3.5 h / 10 - 20 °C / Sonication; Inert atmosphere 5.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h / Inert atmosphere 6.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h / 20 °C / Inert atmosphere | ||
| Multi-step reaction with 6 steps 1.1: trichlorophosphate / 5 h / Reflux; Inert atmosphere 2.1: n-butyllithium / hexane; tetrahydrofuran / 0.75 h / 65 °C / Inert atmosphere 2.2: 0.75 h / 65 °C / Inert atmosphere 2.3: 0.5 h / -60 - -40 °C 3.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 4 °C / Inert atmosphere 4.1: potassium <i>tert</i>-butylate / dimethyl sulfoxide / 3.5 h / 10 - 20 °C / Sonication; Inert atmosphere 5.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h / Inert atmosphere 6.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h / 20 °C / Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 7 steps 1.1: trichlorophosphate / 5 h / Reflux; Inert atmosphere 2.1: n-butyllithium / hexane; tetrahydrofuran / 0.75 h / 65 °C / Inert atmosphere 2.2: 0.75 h / 65 °C / Inert atmosphere 2.3: 0.5 h / -60 - -40 °C 3.1: diazomethyl-trimethyl-silane / hexane; acetonitrile / 14 h / 0 - 20 °C / Inert atmosphere 4.1: potassium <i>tert</i>-butylate / dimethyl sulfoxide / 3.5 h / 10 - 20 °C / Sonication; Inert atmosphere 5.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h / Inert atmosphere 6.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h / 20 °C / Inert atmosphere 7.1: hydrogen; platinum on carbon / ethyl acetate / 0.5 h / 1551.49 Torr / Inert atmosphere | ||
| Multi-step reaction with 7 steps 1.1: trichlorophosphate / 5 h / Reflux; Inert atmosphere 2.1: n-butyllithium / hexane; tetrahydrofuran / 0.75 h / 65 °C / Inert atmosphere 2.2: 0.75 h / 65 °C / Inert atmosphere 2.3: 0.5 h / -60 - -40 °C 3.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 4 °C / Inert atmosphere 4.1: potassium <i>tert</i>-butylate / dimethyl sulfoxide / 3.5 h / 10 - 20 °C / Sonication; Inert atmosphere 5.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h / Inert atmosphere 6.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h / 20 °C / Inert atmosphere 7.1: hydrogen; platinum on carbon / ethyl acetate / 0.5 h / 1551.49 Torr / Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 8 steps 1.1: trichlorophosphate / 5 h / Reflux; Inert atmosphere 2.1: n-butyllithium / hexane; tetrahydrofuran / 0.75 h / 65 °C / Inert atmosphere 2.2: 0.75 h / 65 °C / Inert atmosphere 2.3: 0.5 h / -60 - -40 °C 3.1: diazomethyl-trimethyl-silane / hexane; acetonitrile / 14 h / 0 - 20 °C / Inert atmosphere 4.1: potassium <i>tert</i>-butylate / dimethyl sulfoxide / 3.5 h / 10 - 20 °C / Sonication; Inert atmosphere 5.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h / Inert atmosphere 6.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h / 20 °C / Inert atmosphere 7.1: hydrogenchloride / methanol / 1 h / Reflux; Inert atmosphere 7.2: 2 h / 50 °C / Inert atmosphere 8.1: hydrogen; platinum on carbon / ethyl acetate / 0.6 h / 1551.49 Torr / Inert atmosphere | ||
| Multi-step reaction with 8 steps 1.1: trichlorophosphate / 5 h / Reflux; Inert atmosphere 2.1: n-butyllithium / hexane; tetrahydrofuran / 0.75 h / 65 °C / Inert atmosphere 2.2: 0.75 h / 65 °C / Inert atmosphere 2.3: 0.5 h / -60 - -40 °C 3.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 4 °C / Inert atmosphere 4.1: potassium <i>tert</i>-butylate / dimethyl sulfoxide / 3.5 h / 10 - 20 °C / Sonication; Inert atmosphere 5.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h / Inert atmosphere 6.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h / 20 °C / Inert atmosphere 7.1: hydrogenchloride / methanol / 1 h / Reflux; Inert atmosphere 7.2: 2 h / 50 °C / Inert atmosphere 8.1: hydrogen; platinum on carbon / ethyl acetate / 0.6 h / 1551.49 Torr / Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 4 steps 1.1: trichlorophosphate / 5 h / Reflux; Inert atmosphere 2.1: n-butyllithium / hexane; tetrahydrofuran / 0.75 h / 65 °C / Inert atmosphere 2.2: 0.75 h / 65 °C / Inert atmosphere 2.3: 0.5 h / -60 - -40 °C 3.1: diazomethyl-trimethyl-silane / hexane; acetonitrile / 14 h / 0 - 20 °C / Inert atmosphere 4.1: potassium <i>tert</i>-butylate / dimethyl sulfoxide / 3.5 h / 10 - 20 °C / Sonication; Inert atmosphere | ||
| Multi-step reaction with 4 steps 1.1: trichlorophosphate / 5 h / Reflux; Inert atmosphere 2.1: n-butyllithium / hexane; tetrahydrofuran / 0.75 h / 65 °C / Inert atmosphere 2.2: 0.75 h / 65 °C / Inert atmosphere 2.3: 0.5 h / -60 - -40 °C 3.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 4 °C / Inert atmosphere 4.1: potassium <i>tert</i>-butylate / dimethyl sulfoxide / 3.5 h / 10 - 20 °C / Sonication; Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1.1: trichlorophosphate / 5 h / Reflux; Inert atmosphere 2.1: n-butyllithium / hexane; tetrahydrofuran / 0.75 h / 65 °C / Inert atmosphere 2.2: 0.75 h / 65 °C / Inert atmosphere 2.3: 0.5 h / -60 - -40 °C | ||
| Multi-step reaction with 2 steps 1.1: trichlorophosphate / 5 h / Heating / reflux 1.2: -35 °C / pH 8 2.1: n-butyllithium / tetrahydrofuran; hexanes / 0.75 h / -78 - -65 °C 2.2: 0.67 h / -78 - -65 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1.1: trichlorophosphate / 5 h / Reflux; Inert atmosphere 2.1: n-butyllithium / hexane; tetrahydrofuran / 0.75 h / 65 °C / Inert atmosphere 2.2: 0.75 h / 65 °C / Inert atmosphere 2.3: 0.5 h / -60 - -40 °C 3.1: diazomethyl-trimethyl-silane / hexane; acetonitrile / 14 h / 0 - 20 °C / Inert atmosphere | ||
| Multi-step reaction with 3 steps 1.1: trichlorophosphate / 5 h / Reflux; Inert atmosphere 2.1: n-butyllithium / hexane; tetrahydrofuran / 0.75 h / 65 °C / Inert atmosphere 2.2: 0.75 h / 65 °C / Inert atmosphere 2.3: 0.5 h / -60 - -40 °C 3.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 4 °C / Inert atmosphere | ||
| Multi-step reaction with 3 steps 1.1: trichlorophosphate / 5 h / Heating / reflux 1.2: -35 °C / pH 8 2.1: n-butyllithium / tetrahydrofuran; hexanes / 0.75 h / -78 - -65 °C 2.2: 0.67 h / -78 - -65 °C 3.1: methanol; hexanes; acetonitrile / 14 h / 0 - 20 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 5 steps 1.1: trichlorophosphate / 5 h / Reflux; Inert atmosphere 2.1: n-butyllithium / hexane; tetrahydrofuran / 0.75 h / 65 °C / Inert atmosphere 2.2: 0.75 h / 65 °C / Inert atmosphere 2.3: 0.5 h / -60 - -40 °C 3.1: diazomethyl-trimethyl-silane / hexane; acetonitrile / 14 h / 0 - 20 °C / Inert atmosphere 4.1: potassium <i>tert</i>-butylate / dimethyl sulfoxide / 3.5 h / 10 - 20 °C / Sonication; Inert atmosphere 5.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h / Inert atmosphere | ||
| Multi-step reaction with 5 steps 1.1: trichlorophosphate / 5 h / Reflux; Inert atmosphere 2.1: n-butyllithium / hexane; tetrahydrofuran / 0.75 h / 65 °C / Inert atmosphere 2.2: 0.75 h / 65 °C / Inert atmosphere 2.3: 0.5 h / -60 - -40 °C 3.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 4 °C / Inert atmosphere 4.1: potassium <i>tert</i>-butylate / dimethyl sulfoxide / 3.5 h / 10 - 20 °C / Sonication; Inert atmosphere 5.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h / Inert atmosphere |

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