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[ CAS No. 1513857-77-6 ] {[proInfo.proName]}

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Chemical Structure| 1513857-77-6
Chemical Structure| 1513857-77-6
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Product Details of [ 1513857-77-6 ]

CAS No. :1513857-77-6 MDL No. :MFCD31706227
Formula : C24H27F2N5O4 Boiling Point : -
Linear Structure Formula :- InChI Key :HCDMJFOHIXMBOV-UHFFFAOYSA-N
M.W : 487.50 Pubchem ID :86705695
Synonyms :
INCB054828

Safety of [ 1513857-77-6 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 1513857-77-6 ]

* 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.

  • Downstream synthetic route of [ 1513857-77-6 ]

[ 1513857-77-6 ] Synthesis Path-Downstream   1~41

YieldReaction ConditionsOperation in experiment
With tetrabutyl ammonium fluoride In tetrahydrofuran at 50℃; for 1.5h; 221 Step 4: 3-(2, 6-difluoro-3 , 5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1, 3,4,7-tetrahydro-2H-pyrrolo[3 ‘,2 ‘:5, 6Jpyrido[4, 3-dJpyrimidin-2-one General procedure: Step 4: 3-(2, 6-difluoro-3 , 5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1, 3,4,7-tetrahydro-2H-pyrrolo[3 ‘,2 ‘:5, 6Jpyrido[4, 3-dJpyrimidin-2-one To a solution of 3 -(2,6-difluoro-3 ,5 -dimethoxyphenyl)- 1 -ethyl-8-(morpholin-4- ylmethyl)-7-(phenylsulfonyl)- 1,3 ,4,7-tetrahydro-2H-pyrrolo [3 ‘,2’: 5 ,6]pyrido[4,3 -d]pyrimidin2-one (1.5 g, 2.4 mmol) in tetrahydrofuran (40 mL) was added tetra-n-butylammonium fluoride (1M in THF, 7.2 mL, 7.2 mmol). The resulting solution was stirred at 50 °C for 1.5 hthen cooled to room temperature and quenched with water. The mixture was extracted with dichloromethane (DCM) and the organic extracts were combined then washed with water and brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography eluted with 0 to 10 % MeOH in DCM to give the desired product as a white solid, which was further purified by prep HPLC (pH = 2, acetonitrile/H20). LC-MScalculated for C24H28F2N504 (M+H) mlz: 488.2; found: 488.0. ‘H NMR (500 MHz, DMSO)ö 12.09 (s, 1H), 8.06 (s, 1H), 7.05 (t, J= 8.1 Hz, 1H), 6.87 (s, 1H), 4.78 (s, 2H), 4.50 (s, 2H),4.17 (q, J= 6.8 Hz, 2H), 3.97 (br, 2H), 3.89 (s, 6H), 3.65 (br, 2H), 3.37 (br, 2H), 3.15 (br,2H), 1.37 (t, J= 6.8 Hz, 3H).
  • 2
  • [ 1513857-72-1 ]
  • [ 1513857-77-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: sodium hydride / mineral oil; N,N-dimethyl-formamide / 0.5 h / 0 °C 1.2: 1.5 h / 0 °C 2.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C 2.2: 0.5 h / -78 °C 3.1: acetic acid / dichloromethane / 20 °C 3.2: 3 h / 20 °C 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 1.5 h / 50 °C
Multi-step reaction with 4 steps 1.1: sodium hydride / mineral oil; N,N-dimethyl-formamide / 0.5 h / 0 °C 1.2: 1.5 h / 0 °C 2.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C 2.2: 0.5 h / -78 °C 3.1: acetic acid / dichloromethane / 20 °C 3.2: 3 h / 20 °C 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 1.5 h / 50 °C
Multi-step reaction with 4 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C / Inert atmosphere 1.2: 1.5 h / 0 °C 2.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 2.2: 0.5 h / -78 °C 3.1: acetic acid / dichloromethane / 20 °C / Inert atmosphere 3.2: 3 h / 20 °C 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 1.5 h / 50 °C / Inert atmosphere
Multi-step reaction with 4 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C 1.2: 1.5 h / 0 °C 2.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C 2.2: 0.5 h / -78 °C 3.1: acetic acid / dichloromethane / 20 °C 3.2: 3 h / 20 °C 4.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating

  • 3
  • [ 958230-19-8 ]
  • [ 1513857-77-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: 2-methoxy-ethanol; water / 130 °C 2.1: (1S)-(+)-10-camphorsulfonic acid / 5,5-dimethyl-1,3-cyclohexadiene / 48 h / Reflux; Dean-Stark 2.2: 3 h / 50 °C 3.1: tetrahydrofuran / 6 h / 0 - 20 °C 4.1: sodium hydride / mineral oil; N,N-dimethyl-formamide / 0.5 h / 0 °C 4.2: 1.5 h / 0 °C 5.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C 5.2: 0.5 h / -78 °C 6.1: acetic acid / dichloromethane / 20 °C 6.2: 3 h / 20 °C 7.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 1.5 h / 50 °C
Multi-step reaction with 9 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 0.33 h / 0 - 5 °C / Large scale 1.2: 1 h / 10 °C / Large scale 2.1: p-toluenesulfonic acid monohydrate / toluene / 9 h / 20 °C / Reflux; Large scale 3.1: lithium diisopropyl amide / ethylbenzene; tetrahydrofuran; n-heptane / 1 h / -70 °C / Inert atmosphere 3.2: 0.5 h 4.1: acetic acid / 0 - 18 °C 4.2: 0.5 h / 20 - 32 °C 5.1: hydrogenchloride / water; dichloromethane / 0.12 h / 20 °C 6.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 0.25 h / 20 - 23 °C 6.2: 4.5 h / 0 - 5 °C 7.1: methanesulfonic acid / acetonitrile / 24.58 h / 0 - 20 °C 8.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 9.1: sodium hydroxide / water; 1,4-dioxane / 18 h / 75 °C
Multi-step reaction with 7 steps 1.1: 2-methoxy-ethanol; water / 130 °C 2.1: [(1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid / 5,5-dimethyl-1,3-cyclohexadiene / 48 h / Reflux; Dean-Stark 2.2: 3 h / 50 °C 3.1: tetrahydrofuran / 6 h / 0 - 20 °C 3.2: 0 - 20 °C 4.1: sodium hydride / mineral oil; N,N-dimethyl-formamide / 0.5 h / 0 °C 4.2: 1.5 h / 0 °C 5.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C 5.2: 0.5 h / -78 °C 6.1: acetic acid / dichloromethane / 20 °C 6.2: 3 h / 20 °C 7.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 1.5 h / 50 °C
Multi-step reaction with 7 steps 1.1: water; 2-methoxy-ethanol / 130 °C / Inert atmosphere 2.1: [(1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid / 5,5-dimethyl-1,3-cyclohexadiene / 48 h / Reflux; Dean-Stark 2.2: 3 h / 20 - 50 °C 3.1: tetrahydrofuran / 6 h / 0 - 20 °C / Inert atmosphere 3.2: 0 - 20 °C 4.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C / Inert atmosphere 4.2: 1.5 h / 0 °C 5.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 5.2: 0.5 h / -78 °C 6.1: acetic acid / dichloromethane / 20 °C / Inert atmosphere 6.2: 3 h / 20 °C 7.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 1.5 h / 50 °C / Inert atmosphere
Multi-step reaction with 7 steps 1.1: water; 2-methoxy-ethanol / 130 °C 2.1: (1S)-10-camphorsulfonic acid / 5,5-dimethyl-1,3-cyclohexadiene / 48 h / Reflux; Dean-Stark 2.2: 3 h / 50 °C 3.1: tetrahydrofuran / 6 h / 0 - 20 °C 4.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C 4.2: 1.5 h / 0 °C 5.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C 5.2: 0.5 h / -78 °C 6.1: acetic acid / dichloromethane / 20 °C 6.2: 3 h / 20 °C 7.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating
Multi-step reaction with 9 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 0 h / Cooling; Large scale 1.2: Cooling; Large scale 2.1: toluene-4-sulfonic acid / toluene / 9 h / Reflux; Large scale 3.1: lithium diisopropyl amide / tetrahydrofuran; n-heptane; ethylbenzene / 1 h / -70 °C / Inert atmosphere 3.2: 0.5 h 4.1: acetic acid / tetrahydrofuran; n-heptane; ethylbenzene / 0 - 18 °C 4.2: 0.5 h / 20 - 32 °C 5.1: hydrogenchloride / water; dichloromethane / 23 h / 20 °C 6.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 1.75 h / 20 - 23 °C 6.2: 4.5 h / 0 - 5 °C 7.1: methanesulfonic acid / acetonitrile / 24 h / 0 - 20 °C 8.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 9.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating

  • 4
  • [ 915403-16-6 ]
  • [ 1513857-77-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: (1S)-(+)-10-camphorsulfonic acid / 5,5-dimethyl-1,3-cyclohexadiene / 48 h / Reflux; Dean-Stark 1.2: 3 h / 50 °C 2.1: tetrahydrofuran / 6 h / 0 - 20 °C 3.1: sodium hydride / mineral oil; N,N-dimethyl-formamide / 0.5 h / 0 °C 3.2: 1.5 h / 0 °C 4.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C 4.2: 0.5 h / -78 °C 5.1: acetic acid / dichloromethane / 20 °C 5.2: 3 h / 20 °C 6.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 1.5 h / 50 °C
Multi-step reaction with 6 steps 1.1: [(1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid / 5,5-dimethyl-1,3-cyclohexadiene / 48 h / Reflux; Dean-Stark 1.2: 3 h / 50 °C 2.1: tetrahydrofuran / 6 h / 0 - 20 °C 2.2: 0 - 20 °C 3.1: sodium hydride / mineral oil; N,N-dimethyl-formamide / 0.5 h / 0 °C 3.2: 1.5 h / 0 °C 4.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C 4.2: 0.5 h / -78 °C 5.1: acetic acid / dichloromethane / 20 °C 5.2: 3 h / 20 °C 6.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 1.5 h / 50 °C
Multi-step reaction with 6 steps 1.1: [(1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid / 5,5-dimethyl-1,3-cyclohexadiene / 48 h / Reflux; Dean-Stark 1.2: 3 h / 20 - 50 °C 2.1: tetrahydrofuran / 6 h / 0 - 20 °C / Inert atmosphere 2.2: 0 - 20 °C 3.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C / Inert atmosphere 3.2: 1.5 h / 0 °C 4.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 4.2: 0.5 h / -78 °C 5.1: acetic acid / dichloromethane / 20 °C / Inert atmosphere 5.2: 3 h / 20 °C 6.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 1.5 h / 50 °C / Inert atmosphere
Multi-step reaction with 6 steps 1.1: (1S)-10-camphorsulfonic acid / 5,5-dimethyl-1,3-cyclohexadiene / 48 h / Reflux; Dean-Stark 1.2: 3 h / 50 °C 2.1: tetrahydrofuran / 6 h / 0 - 20 °C 3.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C 3.2: 1.5 h / 0 °C 4.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C 4.2: 0.5 h / -78 °C 5.1: acetic acid / dichloromethane / 20 °C 5.2: 3 h / 20 °C 6.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating

  • 5
  • [ 1513859-26-1 ]
  • [ 1513857-77-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: tetrahydrofuran / 6 h / 0 - 20 °C 2.1: sodium hydride / mineral oil; N,N-dimethyl-formamide / 0.5 h / 0 °C 2.2: 1.5 h / 0 °C 3.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C 3.2: 0.5 h / -78 °C 4.1: acetic acid / dichloromethane / 20 °C 4.2: 3 h / 20 °C 5.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 1.5 h / 50 °C
Multi-step reaction with 5 steps 1.1: tetrahydrofuran / 6 h / 0 - 20 °C 1.2: 0 - 20 °C 2.1: sodium hydride / mineral oil; N,N-dimethyl-formamide / 0.5 h / 0 °C 2.2: 1.5 h / 0 °C 3.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C 3.2: 0.5 h / -78 °C 4.1: acetic acid / dichloromethane / 20 °C 4.2: 3 h / 20 °C 5.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 1.5 h / 50 °C
Multi-step reaction with 5 steps 1.1: tetrahydrofuran / 6 h / 0 - 20 °C / Inert atmosphere 1.2: 0 - 20 °C 2.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C / Inert atmosphere 2.2: 1.5 h / 0 °C 3.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 3.2: 0.5 h / -78 °C 4.1: acetic acid / dichloromethane / 20 °C / Inert atmosphere 4.2: 3 h / 20 °C 5.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 1.5 h / 50 °C / Inert atmosphere
Multi-step reaction with 5 steps 1.1: tetrahydrofuran / 6 h / 0 - 20 °C 2.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C 2.2: 1.5 h / 0 °C 3.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C 3.2: 0.5 h / -78 °C 4.1: acetic acid / dichloromethane / 20 °C 4.2: 3 h / 20 °C 5.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating

  • 6
  • [ 1513860-01-9 ]
  • [ 1513857-77-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C 1.2: 0.5 h / -78 °C 2.1: acetic acid / dichloromethane / 20 °C 2.2: 3 h / 20 °C 3.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 1.5 h / 50 °C
Multi-step reaction with 3 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C 1.2: 0.5 h / -78 °C 2.1: acetic acid / dichloromethane / 20 °C 2.2: 3 h / 20 °C 3.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 1.5 h / 50 °C
Multi-step reaction with 3 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 1.2: 0.5 h / -78 °C 2.1: acetic acid / dichloromethane / 20 °C / Inert atmosphere 2.2: 3 h / 20 °C 3.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 1.5 h / 50 °C / Inert atmosphere
Multi-step reaction with 3 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C 1.2: 0.5 h / -78 °C 2.1: acetic acid / dichloromethane / 20 °C 2.2: 3 h / 20 °C 3.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating

  • 7
  • 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo-[3′,2’:5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde [ No CAS ]
  • [ 1513857-77-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: acetic acid / dichloromethane / 20 °C 1.2: 3 h / 20 °C 2.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 1.5 h / 50 °C
Multi-step reaction with 2 steps 1.1: acetic acid / dichloromethane / 20 °C / Inert atmosphere 1.2: 3 h / 20 °C 2.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 1.5 h / 50 °C / Inert atmosphere
Multi-step reaction with 2 steps 1.1: acetic acid / dichloromethane / 20 °C 1.2: 3 h / 20 °C 2.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating
  • 8
  • [ 1513860-02-0 ]
  • [ 1513857-77-6 ]
YieldReaction ConditionsOperation in experiment
87.6% With sodium hydroxide In 1,4-dioxane; water at 75℃; for 18h; 1.6 Step 6: Synthesis of 3-( 2, 6-difluoro-3, 5-dimethoxyphenyl)-l-ethyl-8-(morpholin-4-ylmethyl)- 1,3, 4, 7 -tetrahydro-2H-pyrrolo [ 3 ', 2 5, 6 ]pyrido[ 4, 3-dJpyrimidin-2-one To a stirring suspension of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-l-ethyl-8- (morpholinomethyl)-7-(phenylsulfonyl)-l,3,4,7-tetrahydro-2i/-pyrrolo[3',2':5,6]pyrido[4,3- d]pyrimidin-2-one (10.0 g, 15.93 mmol) in l,4-dioxane (100 ml, 103 g) in a 500 mL flask equipped with a nitrogen inlet, a condenser, a thermocouple and a heating mantle was added 1 M aqueous sodium hydroxide (63.7 ml, 66.3 g, 63.7 mmol). The reaction mixture was heated at 75 °C for 18 h. LCMS showed the reaction was complete. Water (100 mL, 100 g) was added to give a thick suspension. This slurry was stirred at room temperature for 1 h and filtered. The cake was washed with water (3 x 10 mL, 3 x 10 g) and heptane (2 x 10 mL, 2 x 6.84 g). The cake was dried overnight by pulling a vacuum through the filter cake and then dried in an oven at 50 °C under vacuum overnight to give 3-(2,6-difluoro-3,5- dimethoxyphenyl)-l-ethyl-8-(morpholin-4-ylmethyl)-l,3,4,7-tetrahydro-2H-pyrrolo[3',2':5, 6]pyrido[4,3-d]pyrimidin-2-one (6.8 g, 87.6% yield): LCMS calculated for C24H28F2N5O4 [M+H]+: 488.20; Found: 488.2.
With tetrabutyl ammonium fluoride In tetrahydrofuran at 50℃; for 1.5h; 126.4 Step 4: 3-(2, 6-difluoro-3 , 5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1, 3,4,7-tetrahydro-2H-pyrrolo[3 ‘,2 ‘:5, 6Jpyrido[4, 3-dJpyrimidin-2-one Step 4: 3-(2, 6-difluoro-3 , 5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1, 3,4,7-tetrahydro-2H-pyrrolo[3 ‘,2 ‘:5, 6Jpyrido[4, 3-dJpyrimidin-2-one To a solution of 3 -(2,6-difluoro-3 ,5 -dimethoxyphenyl)- 1 -ethyl-8-(morpholin-4- ylmethyl)-7-(phenylsulfonyl)- 1,3 ,4,7-tetrahydro-2H-pyrrolo [3 ‘,2’: 5 ,6]pyrido[4,3 -d]pyrimidin2-one (1.5 g, 2.4 mmol) in tetrahydrofuran (40 mL) was added tetra-n-butylammonium fluoride (1M in THF, 7.2 mL, 7.2 mmol). The resulting solution was stirred at 50 °C for 1.5 hthen cooled to room temperature and quenched with water. The mixture was extracted with dichloromethane (DCM) and the organic extracts were combined then washed with water and brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography eluted with 0 to 10 % MeOH in DCM to give the desired product as a white solid, which was further purified by prep HPLC (pH = 2, acetonitrile/H20). LC-MScalculated for C24H28F2N504 (M+H) mlz: 488.2; found: 488.0. ‘H NMR (500 MHz, DMSO)ö 12.09 (s, 1H), 8.06 (s, 1H), 7.05 (t, J= 8.1 Hz, 1H), 6.87 (s, 1H), 4.78 (s, 2H), 4.50 (s, 2H),4.17 (q, J= 6.8 Hz, 2H), 3.97 (br, 2H), 3.89 (s, 6H), 3.65 (br, 2H), 3.37 (br, 2H), 3.15 (br,2H), 1.37 (t, J= 6.8 Hz, 3H).
With tetrabutyl ammonium fluoride In tetrahydrofuran at 50℃; for 1.5h; 1.7 Step 7:
3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2': 5,6]pyrido[4,3-d]pyrimidin-2-one (pemigatinib) To a solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2': 5,6]pyrido[4,3-d]pyrimidin-2-one (1.5 g, 2.4 mmol) in tetrahydrofuran (40 mL) was added tetra-n-butylammonium fluoride (1M in THF, 7.2 mL, 7.2 mmol). The resulting solution was stirred at 50° C. for 1.5 h then cooled to room temperature and quenched with water. The mixture was extracted with dichloromethane (DCM) and the organic extracts were combined then washed with water and brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography eluted with 0 to 10% MeOH in DCM to give the desired product as a white solid, which was further purified by prep HPLC (pH=2, acetonitrile/H2O). LC-MS calculated for C24H28F2N5O4 (M+H)+ m/z: 488.2; found: 488.0. 1H NMR (500 MHz, DMSO) δ 12.09 (s, 1H), 8.06 (s, 1H), 7.05 (t, J=8.1 Hz, 1H), 6.87 (s, 1H), 4.78 (s, 2H), 4.50 (s, 2H), 4.17 (q, J=6.8 Hz, 2H), 3.97 (br, 2H), 3.89 (s, 6H), 3.65 (br, 2H), 3.37 (br, 2H), 3.15 (br, 2H), 1.37 (t, J=6.8 Hz, 3H).
With tetrabutyl ammonium fluoride In tetrahydrofuran at 50℃; for 1.5h; Inert atmosphere;
6.8 g With water; sodium hydroxide In 1,4-dioxane for 18h; Heating; 1.6; 5.7 Step 6:
Synthesis of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one To a stirring suspension of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholinomethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one (10.0 g, 15.93 mmol) in 1,4-dioxane (100 ml, 103 g) in a 500 mL flask equipped with a nitrogen inlet, a condenser, a thermocouple and a heating mantle was added 1 M aqueous sodium hydroxide (63.7 ml, 66.3 g, 63.7 mmol). The reaction mixture was heated at 75° C. for 18 h. LCMS showed the reaction was complete. Water (100 mL, 100 g) was added to give a thick suspension. This slurry was stirred at room temperature for 1 h and filtered. The cake was washed with water (3*10 mL, 3*10 g) and heptane (2*10 mL, 2*6.84 g). The cake was dried overnight by pulling a vacuum through the filter cake and then dried in an oven at 50° C. under vacuum overnight to give 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one (6.8 g, 87.6% yield): LCMS calculated for C24H28F2N5O4 [M+H]+: 488.20; Found: 488.2.

  • 9
  • [ 1513857-77-6 ]
  • 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one hydrobromide [ No CAS ]
YieldReaction ConditionsOperation in experiment
91.4% With hydrogen bromide In methanol; dichloromethane; water at 20 - 50℃; for 2.5h; 6 Example 6 Preparation of the Hydrobromic Acid Salt Hydrobromic acid (48% in water, 0.084 mL, 1.2 equiv) was added to a solution of Compound 1 (0.3 g) in a mixture of dichloromethane (3.6 mL) and methanol (4.0 mL). The reaction was heated to 50 °C, distilling off the dichloromethane. The mixture was stirred at 50 °C for about 1 h. The mixture was cooled to room temperature and stirred for another 1.5 h. The reaction was filtered and the solids were washed with methyl t-butyl ether (1.5 mL). The solid was dried at 40 °C under vacuum overnight to provide Compound 1 hydrobromic acid salt (0.32 g, 91.4% yield). Figure 16 shows the NMR of Compound 1 hydrobromic acid salt. The crystallinity of Compound 1 hydrobromic acid salt was confirmed by XRPD (Figure 17). Figure 18 shows the DSC thermogram of Compound 1 hydrobromic acid salt. Figure 19 shows the TGA thermogram of Compound 1 hydrobromic acid salt. Analytical data collected on the product, including characterization by XRPD and DSC were performed as described in Example 1. The hydrobromic acid salt exhibits a DSC thermogram having endothermic peaks at temperatures of about 84 °C and about 235 °C. Table 5. XRPD Peak Data for the Hydrobromic Acid Salt
  • 10
  • [ 1513857-77-6 ]
  • 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one phosphate [ No CAS ]
YieldReaction ConditionsOperation in experiment
97.2% With phosphoric acid In methanol; dichloromethane; water at 20 - 50℃; for 2.5h; 8 Example 8 Preparation of the Phosphoric Acid Salt Phosphoric acid (85% in water, 0.051 mL, 1.2 equiv) was added to a solution of Compound 1 (0.3 g) in a mixture of dichloromethane (3.6 mL) and methanol (4.0 mL). The reaction was heated to 50 °C, distilling off the dichloromethane. The mixture was stirred at 50 °C for about 1 h. The mixture was cooled to room temperature and stirred for another 1.5 h. The reaction was filtered and the solids were washed with methyl t-butyl ether (1.5 mL). The solid was dried at 40 °C under vacuum overnight to provide Compound 1 phosphoric acid salt (0.35 g, 97.2% yield). Figure 24 shows the 'H NMR of Compound 1 phosphoric acid salt. Figure 25 shows the XRPD pattern of Compound 1 phosphoric acid salt. Figure 26 shows the DSC thermogram of Compound 1 phosphoric acid salt. Figure 27 shows the TGA thermogram of Compound 1 phosphoric acid salt. Analytical data collected on the product, including characterization by XRPD and DSC were performed as described in Example 1. The phosphoric acid salt exhibits a DSC thermogram having endothermic peaks at temperatures of about 215 °C and about 221 °C. Table 7. XRPD Peak Data for the Phosphoric Acid Salt
  • 11
  • [ 1513857-77-6 ]
  • 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
87% With hydrogenchloride In methanol; dichloromethane; water; isopropyl alcohol at 20 - 50℃; 5 Example 5 Preparation of the Hydrochloric Acid Salt Hydrochloric acid (0.25 mL, 1 M in 2-propanol/water, 0.25 mmol, 1.25 eq.) was added to a solution of Compound 1 (94.49 mg, 0.194 mmol) in a mixture of dichloromethane (1.5 mL) and methanol (1.0 mL). The reaction mixture was stirred to give a clear solution. The solution was evaporated to remove dichloromethane to give a slurry. The slurry was stirred for 50 min at 50 °C, and then cooled to room temperature and stirred overnight. The slurry was filtered and the solids washed with methyl t-butyl ether. The solids were dried under vacuum at 36-40 °C overnight (16 h) to provide Compound 1 hydrochloric acid salt (88.2 mg, 87% yield). The crystallinity of Compound 1 hydrochloride was confirmed by XRPD (Figure 13) and further supported by DSC (Figure 14). Figure 15 shows the result of TGA. Analytical data collected on the product, including characterization by XRPD, DSC, and TGA were performed as described in Example 1. The hydrochloric acid salt exhibits a DSC thermogram having endothermic peaks at temperatures of about 120 °C, 189 °C, and 274 °C.
  • 12
  • [ 1513857-77-6 ]
  • [ 110-17-8 ]
  • 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one fumarate [ No CAS ]
YieldReaction ConditionsOperation in experiment
91.6% In methanol; dichloromethane at 20 - 50℃; for 2.5h; 7 Example 7 Preparation of the Fumaric Acid Salt Fumaric acid (.086 g, 1.2 equiv) was added to a solution of Compound 1 (0.3 g) in a mixture of dichloro methane (3.6 mL) and methanol (4.0 mL). The reaction was heated to 50 °C, distilling off the dichloromethane. The mixture was stirred at 50 °C for about 1 h. The mixture was cooled to room temperature and stirred for another 1.5 h. The reaction was filtered and the solids were washed with methyl t-butyl ether (1.5 mL). The solid was dried at 40 °C under vacuum overnight to provide Compound 1 fumaric acid salt (0.34 g, 91.6% yield). Figure 20 shows the 'H NMR of Compound 1 fumaric acid salt. Figure 21 shows the XRPD pattern of Compound 1 fumaric acid salt. Figure 22 shows the DSC thermogram of Compound 1 fumaric acid salt. Figure 23 shows the TGA thermogram of Compound 1 fumaric acid salt. Analytical data collected on the product, including characterization by XRPD and DSC were performed as described in Example 1. The fumaric acid salt exhibits a DSC thermogram having an endothermic peak at a temperature of about 214 °C. Table 6. XRPD Peak Data for the Fumaric Acid Salt
  • 13
  • [ 1513857-77-6 ]
  • [ 98-11-3 ]
  • 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one besylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
70.5% In methanol; dichloromethane at 20 - 50℃; for 2.5h; 9 Example 9 Preparation of the Benzenesulfonic Acid Salt Benzenesulfonic acid (94%, 0.124 g, 1.2 equiv) was added to a solution of Compound 1 (0.3 g) in a mixture of dichloromethane (3.6 mL) and methanol (4.0 mL). The reaction was heated to 50 °C, distilling off the dichloromethane. The mixture was stirred at 50 °C for about 1 h. The mixture was cooled to room temperature and stirred for another 1.5 h. The reaction was filtered and the solids were washed with methyl t-butyl ether (1.5 mL). The solid was dried at 40 °C under vacuum overnight to provide Compound 1 benzenesulfonic acid salt (0.28 g, 70.5% yield). Figure 28 shows the 'H NMR of Compound 1 benzenesulfonic acid salt. Figure 29 shows the XRPD pattern of a solid form of Compound 1 benzenesulfonic acid salt. Figure 30 shows the DSC thermogram of a solid form of Compound 1 benzenesulfonic acid salt. Figure 31 shows the TGA thermogram of a solid form of Compound 1 benzenesulfonic acid salt. Analytical data collected on the product, including characterization by XRPD, DSC, and TGA were performed as described in Example 1. The benzenesulfonic acid salt exhibits a DSC thermogram having endothermic peaks at temperatures of about 105 °C, about 190 °C, about 222 °C, and about 241 °C. Table 8. XRPD Peak Data for the Benzenesulfonic Acid Salt
  • 14
  • [ 594-45-6 ]
  • [ 1513857-77-6 ]
  • 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one esylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
73.4% In methanol; dichloromethane; isopropyl alcohol at 20 - 50℃; for 2.5h; 10 Example 10 Preparation of the Ethanesulfonic Acid Salt Ethanesulfonic acid (95%, 0.063 mL, 1.2 equiv) was added to a solution of Compound 1 (0.3 g) in a mixture of dichloromethane (3.6 mL) and methanol (4.0 mL). The reaction was heated to 50 °C, distilling off the dichloromethane. Isopropyl alcohol (3 mL) was added. The mixture was stirred at 50 °C for about 1 h. The mixture was cooled to room temperature and stirred for another 1.5 h. The reaction was filtered and the solids were washed with methyl t-butyl ether (1.5 mL). The solid was dried at 40 °C under vacuum overnight to provide Compound 1 ethanesulfonic acid salt (0.27 g, 73.4% yield). Figure 32 shows the 'H NMR of Compound 1 ethanesulfonic acid salt. Figure 33 shows the XRPD pattern of Compound 1 ethanesulfonic acid salt. Figure 34 shows the DSC thermogram of a solid form of Compound 1 ethanesulfonic acid salt. Figure 35 shows the TGA thermogram of a solid form of Compound 1 ethanesulfonic acid salt. Analytical data collected on the product, including characterization by XRPD, DSC, and TGA were performed as described in Example 1. The ethanesulfonic acid salt exhibits a DSC thermogram having an endothermic peak at a temperature of about 227 °C. Table 9: XRPD of the Ethanesulfonic Acid Salt
  • 15
  • [ 1513857-77-6 ]
  • [ 110-16-7 ]
  • 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one maleate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In methanol; dichloromethane at 20 - 50℃; for 2.5h; 11 Example 11 Preparation of the Maleic Acid Salt Maleic acid (0.086 g, 1.2 equiv) was added to a solution of Compound 1 (0.3 g) in a mixture of dichloro methane (3.6 mL) and methanol (4.0 mL). The reaction was heated to 50 °C, distilling off the dichloromethane. The mixture was stirred at 50 °C for about 1 h. The mixture was cooled to room temperature and stirred for another 1.5 h. The reaction was filtered and the solids were washed with methyl t-butyl ether (1.5 mL). The solid was dried at 40 °C under vacuum overnight to provide Compound 1 maleic acid salt (0.38 g, 102.7% yield [product may contain residual solvent]). Figure 36 shows the 'H NMR of Compound 1 maleic acid salt. Figure 37 shows the XRPD pattern of Compound 1 maleic acid salt. Figure 38 shows the DSC thermogram of Compound 1 maleic acid salt. Figure 39 shows the TGA thermogram of Compound 1 maleic acid salt. Analytical data collected on the product, including characterization by XRPD, DSC, and TGA were performed as described in Example 1. The maleic acid salt exhibits a DSC thermogram having endothermic peaks at temperatures of about 205 °C and 280 °C. Table 10. XRPD Peak Data for the Maleic Acid Salt
  • 16
  • [ 147-71-7 ]
  • [ 1513857-77-6 ]
  • 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one D-(-)-tartrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
84% In methanol; dichloromethane at 20 - 50℃; 2 Example 2 Preparation of the D-(-)-Tartaric Acid Salt -(-)-tartaric acid (32.55 mg, 0.217 mmol, 1.12 eq.) was added to a solution of Compound 1 (94.55 mg, 0.194 mmol) in a 1 :1 v/v mixture of methanol and dichloromethane (2.4 mL). The reaction mixture was stirred to give a thick slurry. The slurry was stirred for 1.5 h at 50 °C for 65 min, and then cooled to room temperature and stirred overnight. The slurry was filtered, and the solids were dried under vacuum at 36-40 °C overnight (16 h) to provide Compound 1 //-(-)-tartaric acid salt (104.6 mg, 84% yield). The stoichiometric ratio between Compound 1 and //-(-)-tartaric acid was determined as 1 :1 by NMR (Figure 1). The crystallinity of the Compound 1 D-(-)- tartrate was confirmed by XRPD (Figure 2) and further supported by DSC (Figure 3) and TGA (Figure 4). Analytical data collected on the product, including characterization by XRPD, DSC, and TGA were performed as described in Example 1. The //-(-(-tartaric acid salt exhibits a DSC thermogram having an endothermic peak at a temperature of about 276 °C. Table 1. XRPD Peak Data for the D-(-)-Tartaric Acid Salt
  • 17
  • [ 87-69-4 ]
  • [ 1513857-77-6 ]
  • 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one L-(+)-tartrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
84% In methanol; dichloromethane at 20 - 50℃; 3 Example 3 Preparation of the T-(+)-Tartaric Acid Salt -(-)-tartaric acid (32.85 mg, 0.218 mmol, 1.25 eq.) was added to a solution of Compound 1 (85.01 mg, 0.174 mmol) in a 1 : 1 mixture of methanol and dichloromethane (2.4 mL). The reaction mixture was stirred to give a slurry. The slurry was stirred for 50 min at 50 °C for 65 min, and then cooled to room temperature and stirred overnight. The slurry was filtered, and the solids were washed with methyl t-butyl ether, and dried under vacuum at 36- 40 °C overnight (16 h) to provide Compound 1 Z-(-)- tartaric acid salt (104.6 mg, 84% yield). The stoichiometric ratio between Compound 1 and Z-(+)-tartaric acid was 1 : 1 by 1 H NMR (Figure 5). The crystallinity of Compound 1 /.-(+)-tartrate was confirmed by XRPD (Figure 6) and further supported by DSC (Figure 7). TGA of the salt is provided in Figure 8. Analytical data collected on the product, including characterization by XRPD, DSC, and TGA were performed as described in Example 1. The /.-(+)-tartaric acid salt exhibits a DSC thermogram having endothermic peaks at temperatures of about 90 °C, 211 °C, and 266 °C. Table 2. XRPD Peak Data for the f-(+)-Tartaric Acid Salt
  • 18
  • [ 1513857-77-6 ]
  • [ 69-72-7 ]
  • 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one salicylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
92% In methanol; dichloromethane at 20 - 50℃; 4 Example 4 Preparation of the Salicylic Acid Salt Salicylic acid (33.8, 0.245 mmol, 1.26 eq.) was added to a solution of Compound 1 (94.42 mg, 0.193 mmol) in a mixture of dichloromethane (1.5 mL) and methanol (1.0 mL). The reaction mixture was stirred to give a clear solution. The solution was evaporated to remove dichloromethane to give a slurry. The slurry was stirred for 50 min at 50 °C, and then cooled to room temperature and stirred overnight. The slurry was filtered and the solids washed with methyl t-butyl ether. The solids were dried under vacuum at 36-40 °C overnight (16 h) to provide Compound 1 salicylic acid salt (111.7 mg, 92% yield). The stoichiometric ratio between Compound 1 and salicylic acid was determined by 'H NMR (Figure 9) as 1 :1. The crystallinity of the Compound 1 salicylate was confirmed by XRPD (Figure 10) and further supported by DSC (Figure 11). TGA of the salicylic acid salt is provided in Figure 12. Analytical data collected on the product, including characterization by XRPD, DSC, and TGA were performed as described in Example 1. The salicylic acid salt exhibits a DSC thermogram having an endothermic peak at a temperatures of about 212 °C. Table 3. XRPD Peak Data for the Salicylic Acid Salt
  • 19
  • 4-((4-chloro-5-(1,3-dioxolan-2-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b] pyridin-2-yl)methyl) morpholine [ No CAS ]
  • [ 1513857-77-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: hydrogenchloride / water; dichloromethane / 0.12 h / 20 °C 2.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 0.25 h / 20 - 23 °C 2.2: 4.5 h / 0 - 5 °C 3.1: methanesulfonic acid / acetonitrile / 24.58 h / 0 - 20 °C 4.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 5.1: sodium hydroxide / water; 1,4-dioxane / 18 h / 75 °C
Multi-step reaction with 5 steps 1.1: hydrogenchloride / water; dichloromethane / 23 h / 20 °C 2.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 1.75 h / 20 - 23 °C 2.2: 4.5 h / 0 - 5 °C 3.1: methanesulfonic acid / acetonitrile / 24 h / 0 - 20 °C 4.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 5.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating
  • 20
  • 4-chloro-2-(morpholinomethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde [ No CAS ]
  • [ 1513857-77-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 0.25 h / 20 - 23 °C 1.2: 4.5 h / 0 - 5 °C 2.1: methanesulfonic acid / acetonitrile / 24.58 h / 0 - 20 °C 3.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 4.1: sodium hydroxide / water; 1,4-dioxane / 18 h / 75 °C
Multi-step reaction with 4 steps 1.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 1.75 h / 20 - 23 °C 1.2: 4.5 h / 0 - 5 °C 2.1: methanesulfonic acid / acetonitrile / 24 h / 0 - 20 °C 3.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 4.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating
  • 21
  • N-((4-chloro-2-(morpholinomethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2,6-difluoro-3,5-dimethoxyaniline [ No CAS ]
  • [ 1513857-77-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: methanesulfonic acid / acetonitrile / 24.58 h / 0 - 20 °C 2: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 3: sodium hydroxide / water; 1,4-dioxane / 18 h / 75 °C
Multi-step reaction with 3 steps 1: methanesulfonic acid / acetonitrile / 24 h / 0 - 20 °C 2: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 3: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating
  • 22
  • 1-((4-chloro-2-(morpholinomethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-1-(2,6-difluoro-3,5-dimethoxyphenyl)-3-ethylurea [ No CAS ]
  • [ 1513857-77-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 2: sodium hydroxide / water; 1,4-dioxane / 18 h / 75 °C
Multi-step reaction with 2 steps 1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 2: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating
  • 23
  • [ 271-63-6 ]
  • [ 1513857-77-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 13 steps 1.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 8 h / 0 - 10 °C / Large scale 2.1: methanesulfonyl chloride / N,N-dimethyl-formamide / 2 h / 50 - 90 °C / Large scale 3.1: sodium hydride / mineral oil; tetrahydrofuran / 1 h / 0 - 20 °C / Inert atmosphere 3.2: 20 h / 25 °C 4.1: sec.-butyllithium / cyclohexane; tetrahydrofuran / 8 h / -75 - -60 °C / Inert atmosphere; Large scale 4.2: 2 h / -75 - -65 °C / Large scale 5.1: caesium carbonate / N,N-dimethyl-formamide / 0.33 h / 0 - 5 °C / Large scale 5.2: 1 h / 10 °C / Large scale 6.1: p-toluenesulfonic acid monohydrate / toluene / 9 h / 20 °C / Reflux; Large scale 7.1: lithium diisopropyl amide / ethylbenzene; tetrahydrofuran; n-heptane / 1 h / -70 °C / Inert atmosphere 7.2: 0.5 h 8.1: acetic acid / 0 - 18 °C 8.2: 0.5 h / 20 - 32 °C 9.1: hydrogenchloride / water; dichloromethane / 0.12 h / 20 °C 10.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 0.25 h / 20 - 23 °C 10.2: 4.5 h / 0 - 5 °C 11.1: methanesulfonic acid / acetonitrile / 24.58 h / 0 - 20 °C 12.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 13.1: sodium hydroxide / water; 1,4-dioxane / 18 h / 75 °C
Multi-step reaction with 11 steps 1.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 8 h / 0 - 10 °C / Large scale 2.1: methanesulfonyl chloride / N,N-dimethyl-formamide / 50 - 90 °C / Large scale 3.1: sodium hydride; pyridine / mineral oil / 1 h / 0 - 20 °C / Inert atmosphere; Large scale 3.2: 20 h / 20 - 25 °C / Large scale 4.1: sec.-butyllithium / cyclohexane / 0.8 h / -75 - -60 °C / Inert atmosphere; Large scale 4.2: 0.5 h / -75 - -65 °C / Large scale 4.3: 20 - 25 °C / Large scale 5.1: water; 2-methoxy-ethanol / 130 °C 6.1: (1S)-10-camphorsulfonic acid / 5,5-dimethyl-1,3-cyclohexadiene / 48 h / Reflux; Dean-Stark 6.2: 3 h / 50 °C 7.1: tetrahydrofuran / 6 h / 0 - 20 °C 8.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C 8.2: 1.5 h / 0 °C 9.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C 9.2: 0.5 h / -78 °C 10.1: acetic acid / dichloromethane / 20 °C 10.2: 3 h / 20 °C 11.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating
Multi-step reaction with 13 steps 1.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 8 h / 0 - 10 °C / Large scale 2.1: methanesulfonyl chloride / N,N-dimethyl-formamide / 50 - 90 °C / Large scale 3.1: sodium hydride; pyridine / mineral oil / 1 h / 0 - 20 °C / Inert atmosphere; Large scale 3.2: 20 h / 20 - 25 °C / Large scale 4.1: sec.-butyllithium / cyclohexane / 0.8 h / -75 - -60 °C / Inert atmosphere; Large scale 4.2: 0.5 h / -75 - -65 °C / Large scale 4.3: 20 - 25 °C / Large scale 5.1: caesium carbonate / N,N-dimethyl-formamide / 0 h / Cooling; Large scale 5.2: Cooling; Large scale 6.1: toluene-4-sulfonic acid / toluene / 9 h / Reflux; Large scale 7.1: lithium diisopropyl amide / tetrahydrofuran; n-heptane; ethylbenzene / 1 h / -70 °C / Inert atmosphere 7.2: 0.5 h 8.1: acetic acid / tetrahydrofuran; n-heptane; ethylbenzene / 0 - 18 °C 8.2: 0.5 h / 20 - 32 °C 9.1: hydrogenchloride / water; dichloromethane / 23 h / 20 °C 10.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 1.75 h / 20 - 23 °C 10.2: 4.5 h / 0 - 5 °C 11.1: methanesulfonic acid / acetonitrile / 24 h / 0 - 20 °C 12.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 13.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating
  • 24
  • [ 55052-24-9 ]
  • [ 1513857-77-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 12 steps 1.1: methanesulfonyl chloride / N,N-dimethyl-formamide / 2 h / 50 - 90 °C / Large scale 2.1: sodium hydride / mineral oil; tetrahydrofuran / 1 h / 0 - 20 °C / Inert atmosphere 2.2: 20 h / 25 °C 3.1: sec.-butyllithium / cyclohexane; tetrahydrofuran / 8 h / -75 - -60 °C / Inert atmosphere; Large scale 3.2: 2 h / -75 - -65 °C / Large scale 4.1: caesium carbonate / N,N-dimethyl-formamide / 0.33 h / 0 - 5 °C / Large scale 4.2: 1 h / 10 °C / Large scale 5.1: p-toluenesulfonic acid monohydrate / toluene / 9 h / 20 °C / Reflux; Large scale 6.1: lithium diisopropyl amide / ethylbenzene; tetrahydrofuran; n-heptane / 1 h / -70 °C / Inert atmosphere 6.2: 0.5 h 7.1: acetic acid / 0 - 18 °C 7.2: 0.5 h / 20 - 32 °C 8.1: hydrogenchloride / water; dichloromethane / 0.12 h / 20 °C 9.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 0.25 h / 20 - 23 °C 9.2: 4.5 h / 0 - 5 °C 10.1: methanesulfonic acid / acetonitrile / 24.58 h / 0 - 20 °C 11.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 12.1: sodium hydroxide / water; 1,4-dioxane / 18 h / 75 °C
Multi-step reaction with 10 steps 1.1: methanesulfonyl chloride / N,N-dimethyl-formamide / 50 - 90 °C / Large scale 2.1: sodium hydride; pyridine / mineral oil / 1 h / 0 - 20 °C / Inert atmosphere; Large scale 2.2: 20 h / 20 - 25 °C / Large scale 3.1: sec.-butyllithium / cyclohexane / 0.8 h / -75 - -60 °C / Inert atmosphere; Large scale 3.2: 0.5 h / -75 - -65 °C / Large scale 3.3: 20 - 25 °C / Large scale 4.1: water; 2-methoxy-ethanol / 130 °C 5.1: (1S)-10-camphorsulfonic acid / 5,5-dimethyl-1,3-cyclohexadiene / 48 h / Reflux; Dean-Stark 5.2: 3 h / 50 °C 6.1: tetrahydrofuran / 6 h / 0 - 20 °C 7.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C 7.2: 1.5 h / 0 °C 8.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C 8.2: 0.5 h / -78 °C 9.1: acetic acid / dichloromethane / 20 °C 9.2: 3 h / 20 °C 10.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating
Multi-step reaction with 12 steps 1.1: methanesulfonyl chloride / N,N-dimethyl-formamide / 50 - 90 °C / Large scale 2.1: sodium hydride; pyridine / mineral oil / 1 h / 0 - 20 °C / Inert atmosphere; Large scale 2.2: 20 h / 20 - 25 °C / Large scale 3.1: sec.-butyllithium / cyclohexane / 0.8 h / -75 - -60 °C / Inert atmosphere; Large scale 3.2: 0.5 h / -75 - -65 °C / Large scale 3.3: 20 - 25 °C / Large scale 4.1: caesium carbonate / N,N-dimethyl-formamide / 0 h / Cooling; Large scale 4.2: Cooling; Large scale 5.1: toluene-4-sulfonic acid / toluene / 9 h / Reflux; Large scale 6.1: lithium diisopropyl amide / tetrahydrofuran; n-heptane; ethylbenzene / 1 h / -70 °C / Inert atmosphere 6.2: 0.5 h 7.1: acetic acid / tetrahydrofuran; n-heptane; ethylbenzene / 0 - 18 °C 7.2: 0.5 h / 20 - 32 °C 8.1: hydrogenchloride / water; dichloromethane / 23 h / 20 °C 9.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 1.75 h / 20 - 23 °C 9.2: 4.5 h / 0 - 5 °C 10.1: methanesulfonic acid / acetonitrile / 24 h / 0 - 20 °C 11.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 12.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating
  • 25
  • [ 55052-28-3 ]
  • [ 1513857-77-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 11 steps 1.1: sodium hydride / mineral oil; tetrahydrofuran / 1 h / 0 - 20 °C / Inert atmosphere 1.2: 20 h / 25 °C 2.1: sec.-butyllithium / cyclohexane; tetrahydrofuran / 8 h / -75 - -60 °C / Inert atmosphere; Large scale 2.2: 2 h / -75 - -65 °C / Large scale 3.1: caesium carbonate / N,N-dimethyl-formamide / 0.33 h / 0 - 5 °C / Large scale 3.2: 1 h / 10 °C / Large scale 4.1: p-toluenesulfonic acid monohydrate / toluene / 9 h / 20 °C / Reflux; Large scale 5.1: lithium diisopropyl amide / ethylbenzene; tetrahydrofuran; n-heptane / 1 h / -70 °C / Inert atmosphere 5.2: 0.5 h 6.1: acetic acid / 0 - 18 °C 6.2: 0.5 h / 20 - 32 °C 7.1: hydrogenchloride / water; dichloromethane / 0.12 h / 20 °C 8.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 0.25 h / 20 - 23 °C 8.2: 4.5 h / 0 - 5 °C 9.1: methanesulfonic acid / acetonitrile / 24.58 h / 0 - 20 °C 10.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 11.1: sodium hydroxide / water; 1,4-dioxane / 18 h / 75 °C
Multi-step reaction with 11 steps 1.1: sodium hydride; pyridine / mineral oil / 1 h / 0 - 20 °C / Inert atmosphere; Large scale 1.2: 20 h / 20 - 25 °C / Large scale 2.1: sec.-butyllithium / cyclohexane / 0.8 h / -75 - -60 °C / Inert atmosphere; Large scale 2.2: 0.5 h / -75 - -65 °C / Large scale 2.3: 20 - 25 °C / Large scale 3.1: caesium carbonate / N,N-dimethyl-formamide / 0 h / Cooling; Large scale 3.2: Cooling; Large scale 4.1: toluene-4-sulfonic acid / toluene / 9 h / Reflux; Large scale 5.1: lithium diisopropyl amide / tetrahydrofuran; n-heptane; ethylbenzene / 1 h / -70 °C / Inert atmosphere 5.2: 0.5 h 6.1: acetic acid / tetrahydrofuran; n-heptane; ethylbenzene / 0 - 18 °C 6.2: 0.5 h / 20 - 32 °C 7.1: hydrogenchloride / water; dichloromethane / 23 h / 20 °C 8.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 1.75 h / 20 - 23 °C 8.2: 4.5 h / 0 - 5 °C 9.1: methanesulfonic acid / acetonitrile / 24 h / 0 - 20 °C 10.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 11.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating
Multi-step reaction with 9 steps 1.1: sodium hydride; pyridine / mineral oil / 1 h / 0 - 20 °C / Inert atmosphere; Large scale 1.2: 20 h / 20 - 25 °C / Large scale 2.1: sec.-butyllithium / cyclohexane / 0.8 h / -75 - -60 °C / Inert atmosphere; Large scale 2.2: 0.5 h / -75 - -65 °C / Large scale 2.3: 20 - 25 °C / Large scale 3.1: water; 2-methoxy-ethanol / 130 °C 4.1: (1S)-10-camphorsulfonic acid / 5,5-dimethyl-1,3-cyclohexadiene / 48 h / Reflux; Dean-Stark 4.2: 3 h / 50 °C 5.1: tetrahydrofuran / 6 h / 0 - 20 °C 6.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C 6.2: 1.5 h / 0 °C 7.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C 7.2: 0.5 h / -78 °C 8.1: acetic acid / dichloromethane / 20 °C 8.2: 3 h / 20 °C 9.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating
  • 26
  • [ 651744-48-8 ]
  • [ 1513857-77-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 10 steps 1.1: sec.-butyllithium / cyclohexane; tetrahydrofuran / 8 h / -75 - -60 °C / Inert atmosphere; Large scale 1.2: 2 h / -75 - -65 °C / Large scale 2.1: caesium carbonate / N,N-dimethyl-formamide / 0.33 h / 0 - 5 °C / Large scale 2.2: 1 h / 10 °C / Large scale 3.1: p-toluenesulfonic acid monohydrate / toluene / 9 h / 20 °C / Reflux; Large scale 4.1: lithium diisopropyl amide / ethylbenzene; tetrahydrofuran; n-heptane / 1 h / -70 °C / Inert atmosphere 4.2: 0.5 h 5.1: acetic acid / 0 - 18 °C 5.2: 0.5 h / 20 - 32 °C 6.1: hydrogenchloride / water; dichloromethane / 0.12 h / 20 °C 7.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 0.25 h / 20 - 23 °C 7.2: 4.5 h / 0 - 5 °C 8.1: methanesulfonic acid / acetonitrile / 24.58 h / 0 - 20 °C 9.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 10.1: sodium hydroxide / water; 1,4-dioxane / 18 h / 75 °C
Multi-step reaction with 10 steps 1.1: sec.-butyllithium / cyclohexane / 0.8 h / -75 - -60 °C / Inert atmosphere; Large scale 1.2: 0.5 h / -75 - -65 °C / Large scale 1.3: 20 - 25 °C / Large scale 2.1: caesium carbonate / N,N-dimethyl-formamide / 0 h / Cooling; Large scale 2.2: Cooling; Large scale 3.1: toluene-4-sulfonic acid / toluene / 9 h / Reflux; Large scale 4.1: lithium diisopropyl amide / tetrahydrofuran; n-heptane; ethylbenzene / 1 h / -70 °C / Inert atmosphere 4.2: 0.5 h 5.1: acetic acid / tetrahydrofuran; n-heptane; ethylbenzene / 0 - 18 °C 5.2: 0.5 h / 20 - 32 °C 6.1: hydrogenchloride / water; dichloromethane / 23 h / 20 °C 7.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 1.75 h / 20 - 23 °C 7.2: 4.5 h / 0 - 5 °C 8.1: methanesulfonic acid / acetonitrile / 24 h / 0 - 20 °C 9.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 10.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating
Multi-step reaction with 8 steps 1.1: sec.-butyllithium / cyclohexane / 0.8 h / -75 - -60 °C / Inert atmosphere; Large scale 1.2: 0.5 h / -75 - -65 °C / Large scale 1.3: 20 - 25 °C / Large scale 2.1: water; 2-methoxy-ethanol / 130 °C 3.1: (1S)-10-camphorsulfonic acid / 5,5-dimethyl-1,3-cyclohexadiene / 48 h / Reflux; Dean-Stark 3.2: 3 h / 50 °C 4.1: tetrahydrofuran / 6 h / 0 - 20 °C 5.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C 5.2: 1.5 h / 0 °C 6.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C 6.2: 0.5 h / -78 °C 7.1: acetic acid / dichloromethane / 20 °C 7.2: 3 h / 20 °C 8.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating
  • 27
  • [ 1032815-07-8 ]
  • [ 1513857-77-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 8 steps 1.1: p-toluenesulfonic acid monohydrate / toluene / 9 h / 20 °C / Reflux; Large scale 2.1: lithium diisopropyl amide / ethylbenzene; tetrahydrofuran; n-heptane / 1 h / -70 °C / Inert atmosphere 2.2: 0.5 h 3.1: acetic acid / 0 - 18 °C 3.2: 0.5 h / 20 - 32 °C 4.1: hydrogenchloride / water; dichloromethane / 0.12 h / 20 °C 5.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 0.25 h / 20 - 23 °C 5.2: 4.5 h / 0 - 5 °C 6.1: methanesulfonic acid / acetonitrile / 24.58 h / 0 - 20 °C 7.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 8.1: sodium hydroxide / water; 1,4-dioxane / 18 h / 75 °C
Multi-step reaction with 8 steps 1.1: toluene-4-sulfonic acid / toluene / 9 h / Reflux; Large scale 2.1: lithium diisopropyl amide / tetrahydrofuran; n-heptane; ethylbenzene / 1 h / -70 °C / Inert atmosphere 2.2: 0.5 h 3.1: acetic acid / tetrahydrofuran; n-heptane; ethylbenzene / 0 - 18 °C 3.2: 0.5 h / 20 - 32 °C 4.1: hydrogenchloride / water; dichloromethane / 23 h / 20 °C 5.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 1.75 h / 20 - 23 °C 5.2: 4.5 h / 0 - 5 °C 6.1: methanesulfonic acid / acetonitrile / 24 h / 0 - 20 °C 7.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 8.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating
  • 28
  • [ 1032815-08-9 ]
  • [ 1513857-77-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: lithium diisopropyl amide / ethylbenzene; tetrahydrofuran; n-heptane / 1 h / -70 °C / Inert atmosphere 1.2: 0.5 h 2.1: acetic acid / 0 - 18 °C 2.2: 0.5 h / 20 - 32 °C 3.1: hydrogenchloride / water; dichloromethane / 0.12 h / 20 °C 4.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 0.25 h / 20 - 23 °C 4.2: 4.5 h / 0 - 5 °C 5.1: methanesulfonic acid / acetonitrile / 24.58 h / 0 - 20 °C 6.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 7.1: sodium hydroxide / water; 1,4-dioxane / 18 h / 75 °C
Multi-step reaction with 7 steps 1.1: lithium diisopropyl amide / tetrahydrofuran; n-heptane; ethylbenzene / 1 h / -70 °C / Inert atmosphere 1.2: 0.5 h 2.1: acetic acid / tetrahydrofuran; n-heptane; ethylbenzene / 0 - 18 °C 2.2: 0.5 h / 20 - 32 °C 3.1: hydrogenchloride / water; dichloromethane / 23 h / 20 °C 4.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 1.75 h / 20 - 23 °C 4.2: 4.5 h / 0 - 5 °C 5.1: methanesulfonic acid / acetonitrile / 24 h / 0 - 20 °C 6.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 7.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating
  • 29
  • [ 602-94-8 ]
  • [ 1513857-77-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 9 steps 1.1: thionyl chloride / 21 h / 20 - 50 °C / Reflux; Large scale 2.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 4.5 h / 50 - 65 °C / Large scale 3.1: methanol / 21 h / 20 - 70 °C / Inert atmosphere; Large scale 4.1: sodium hydroxide / water; tert-butyl methyl ether / 0.5 h / 20 - 85 °C / Inert atmosphere; Large scale 5.1: ammonium formate; palladium on activated charcoal; acetic acid / ethanol / 50 °C / Large scale 5.2: 3 h / Reflux; Large scale 6.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 0.25 h / 20 - 23 °C 6.2: 4.5 h / 0 - 5 °C 7.1: methanesulfonic acid / acetonitrile / 24.58 h / 0 - 20 °C 8.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 9.1: sodium hydroxide / water; 1,4-dioxane / 18 h / 75 °C
Multi-step reaction with 11 steps 1.1: thionyl chloride / 21 h / 20 °C / Reflux; Large scale 2.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 4.5 h / 50 - 65 °C / Large scale 3.1: methanol / 21 h / 20 - 70 °C / Inert atmosphere; Large scale 3.2: 1 h / Large scale 4.1: 75 - 85 °C / Inert atmosphere; Large scale 5.1: palladium on activated charcoal; ammonium formate; acetic acid / ethanol / 50 °C / Large scale 6.1: (1S)-10-camphorsulfonic acid / 5,5-dimethyl-1,3-cyclohexadiene / 48 h / Reflux; Dean-Stark 6.2: 3 h / 50 °C 7.1: tetrahydrofuran / 6 h / 0 - 20 °C 8.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C 8.2: 1.5 h / 0 °C 9.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C 9.2: 0.5 h / -78 °C 10.1: acetic acid / dichloromethane / 20 °C 10.2: 3 h / 20 °C 11.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating
Multi-step reaction with 9 steps 1.1: thionyl chloride / 21 h / 20 °C / Reflux; Large scale 2.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 4.5 h / 50 - 65 °C / Large scale 3.1: methanol / 21 h / 20 - 70 °C / Inert atmosphere; Large scale 3.2: 1 h / Large scale 4.1: 75 - 85 °C / Inert atmosphere; Large scale 5.1: palladium on activated charcoal; ammonium formate; acetic acid / ethanol / 50 °C / Large scale 6.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 1.75 h / 20 - 23 °C 6.2: 4.5 h / 0 - 5 °C 7.1: methanesulfonic acid / acetonitrile / 24 h / 0 - 20 °C 8.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 9.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating
  • 30
  • [ 36629-42-2 ]
  • [ 1513857-77-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 8 steps 1.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 4.5 h / 50 - 65 °C / Large scale 2.1: methanol / 21 h / 20 - 70 °C / Inert atmosphere; Large scale 3.1: sodium hydroxide / water; tert-butyl methyl ether / 0.5 h / 20 - 85 °C / Inert atmosphere; Large scale 4.1: ammonium formate; palladium on activated charcoal; acetic acid / ethanol / 50 °C / Large scale 4.2: 3 h / Reflux; Large scale 5.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 0.25 h / 20 - 23 °C 5.2: 4.5 h / 0 - 5 °C 6.1: methanesulfonic acid / acetonitrile / 24.58 h / 0 - 20 °C 7.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 8.1: sodium hydroxide / water; 1,4-dioxane / 18 h / 75 °C
Multi-step reaction with 10 steps 1.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 4.5 h / 50 - 65 °C / Large scale 2.1: methanol / 21 h / 20 - 70 °C / Inert atmosphere; Large scale 2.2: 1 h / Large scale 3.1: 75 - 85 °C / Inert atmosphere; Large scale 4.1: palladium on activated charcoal; ammonium formate; acetic acid / ethanol / 50 °C / Large scale 5.1: (1S)-10-camphorsulfonic acid / 5,5-dimethyl-1,3-cyclohexadiene / 48 h / Reflux; Dean-Stark 5.2: 3 h / 50 °C 6.1: tetrahydrofuran / 6 h / 0 - 20 °C 7.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C 7.2: 1.5 h / 0 °C 8.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C 8.2: 0.5 h / -78 °C 9.1: acetic acid / dichloromethane / 20 °C 9.2: 3 h / 20 °C 10.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating
Multi-step reaction with 8 steps 1.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 4.5 h / 50 - 65 °C / Large scale 2.1: methanol / 21 h / 20 - 70 °C / Inert atmosphere; Large scale 2.2: 1 h / Large scale 3.1: 75 - 85 °C / Inert atmosphere; Large scale 4.1: palladium on activated charcoal; ammonium formate; acetic acid / ethanol / 50 °C / Large scale 5.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 1.75 h / 20 - 23 °C 5.2: 4.5 h / 0 - 5 °C 6.1: methanesulfonic acid / acetonitrile / 24 h / 0 - 20 °C 7.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 8.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating
  • 31
  • [ 122590-82-3 ]
  • [ 1513857-77-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: methanol / 21 h / 20 - 70 °C / Inert atmosphere; Large scale 2.1: sodium hydroxide / water; tert-butyl methyl ether / 0.5 h / 20 - 85 °C / Inert atmosphere; Large scale 3.1: ammonium formate; palladium on activated charcoal; acetic acid / ethanol / 50 °C / Large scale 3.2: 3 h / Reflux; Large scale 4.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 0.25 h / 20 - 23 °C 4.2: 4.5 h / 0 - 5 °C 5.1: methanesulfonic acid / acetonitrile / 24.58 h / 0 - 20 °C 6.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 7.1: sodium hydroxide / water; 1,4-dioxane / 18 h / 75 °C
Multi-step reaction with 7 steps 1.1: methanol / 21 h / 20 - 70 °C / Inert atmosphere; Large scale 1.2: 1 h / Large scale 2.1: 75 - 85 °C / Inert atmosphere; Large scale 3.1: palladium on activated charcoal; ammonium formate; acetic acid / ethanol / 50 °C / Large scale 4.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 1.75 h / 20 - 23 °C 4.2: 4.5 h / 0 - 5 °C 5.1: methanesulfonic acid / acetonitrile / 24 h / 0 - 20 °C 6.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 7.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating
Multi-step reaction with 9 steps 1.1: methanol / 21 h / 20 - 70 °C / Inert atmosphere; Large scale 1.2: 1 h / Large scale 2.1: 75 - 85 °C / Inert atmosphere; Large scale 3.1: palladium on activated charcoal; ammonium formate; acetic acid / ethanol / 50 °C / Large scale 4.1: (1S)-10-camphorsulfonic acid / 5,5-dimethyl-1,3-cyclohexadiene / 48 h / Reflux; Dean-Stark 4.2: 3 h / 50 °C 5.1: tetrahydrofuran / 6 h / 0 - 20 °C 6.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C 6.2: 1.5 h / 0 °C 7.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C 7.2: 0.5 h / -78 °C 8.1: acetic acid / dichloromethane / 20 °C 8.2: 3 h / 20 °C 9.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating
  • 32
  • [ 651734-52-0 ]
  • [ 1513857-77-6 ]
  • 33
  • n-benzyl-2,6-difluoro-3,5-dimethoxyaniline [ No CAS ]
  • [ 1513857-77-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: ammonium formate; palladium on activated charcoal; acetic acid / ethanol / 50 °C / Large scale 1.2: 3 h / Reflux; Large scale 2.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 0.25 h / 20 - 23 °C 2.2: 4.5 h / 0 - 5 °C 3.1: methanesulfonic acid / acetonitrile / 24.58 h / 0 - 20 °C 4.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 5.1: sodium hydroxide / water; 1,4-dioxane / 18 h / 75 °C
Multi-step reaction with 5 steps 1.1: palladium on activated charcoal; ammonium formate; acetic acid / ethanol / 50 °C / Large scale 2.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 1.75 h / 20 - 23 °C 2.2: 4.5 h / 0 - 5 °C 3.1: methanesulfonic acid / acetonitrile / 24 h / 0 - 20 °C 4.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 5.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating
Multi-step reaction with 7 steps 1.1: palladium on activated charcoal; ammonium formate; acetic acid / ethanol / 50 °C / Large scale 2.1: (1S)-10-camphorsulfonic acid / 5,5-dimethyl-1,3-cyclohexadiene / 48 h / Reflux; Dean-Stark 2.2: 3 h / 50 °C 3.1: tetrahydrofuran / 6 h / 0 - 20 °C 4.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C 4.2: 1.5 h / 0 °C 5.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C 5.2: 0.5 h / -78 °C 6.1: acetic acid / dichloromethane / 20 °C 6.2: 3 h / 20 °C 7.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating
  • 34
  • 4-chloro-5-(1,3-dioxolan-2-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde [ No CAS ]
  • [ 1513857-77-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: acetic acid / 0 - 18 °C 1.2: 0.5 h / 20 - 32 °C 2.1: hydrogenchloride / water; dichloromethane / 0.12 h / 20 °C 3.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 0.25 h / 20 - 23 °C 3.2: 4.5 h / 0 - 5 °C 4.1: methanesulfonic acid / acetonitrile / 24.58 h / 0 - 20 °C 5.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 6.1: sodium hydroxide / water; 1,4-dioxane / 18 h / 75 °C
Multi-step reaction with 6 steps 1.1: acetic acid / tetrahydrofuran; n-heptane; ethylbenzene / 0 - 18 °C 1.2: 0.5 h / 20 - 32 °C 2.1: hydrogenchloride / water; dichloromethane / 23 h / 20 °C 3.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 1.75 h / 20 - 23 °C 3.2: 4.5 h / 0 - 5 °C 4.1: methanesulfonic acid / acetonitrile / 24 h / 0 - 20 °C 5.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 6.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating
  • 35
  • [ 651734-54-2 ]
  • [ 1513857-77-6 ]
  • 36
  • 4-((5-bromo-4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)morpholine [ No CAS ]
  • [ 1513857-77-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 2 h / -10 - 0 °C 1.2: 2.5 h / -5 - 23 °C 2.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 1.75 h / 20 - 23 °C 2.2: 4.5 h / 0 - 5 °C 3.1: methanesulfonic acid / acetonitrile / 24 h / 0 - 20 °C 4.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 5.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating
  • 37
  • [ 19798-80-2 ]
  • [ 1513857-77-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 10 steps 1.1: N-Bromosuccinimide / acetonitrile / 2.75 h / 15 - 20 °C 2.1: sulfuric acid; iodine; periodic acid / 75 - 85 °C 3.1: copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); diisopropylamine / toluene / 17 h / 50 °C / Inert atmosphere 4.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 3 h / 30 - 35 °C 5.1: sodium hydride / tetrahydrofuran; mineral oil / 0 - 5 °C 6.1: isopropylmagnesium chloride / tetrahydrofuran / 2 h / -10 - 0 °C 6.2: 2.5 h / -5 - 23 °C 7.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 1.75 h / 20 - 23 °C 7.2: 4.5 h / 0 - 5 °C 8.1: methanesulfonic acid / acetonitrile / 24 h / 0 - 20 °C 9.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 10.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating
  • 38
  • [ 942947-94-6 ]
  • [ 1513857-77-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 9 steps 1.1: sulfuric acid; iodine; periodic acid / 75 - 85 °C 2.1: copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); diisopropylamine / toluene / 17 h / 50 °C / Inert atmosphere 3.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 3 h / 30 - 35 °C 4.1: sodium hydride / tetrahydrofuran; mineral oil / 0 - 5 °C 5.1: isopropylmagnesium chloride / tetrahydrofuran / 2 h / -10 - 0 °C 5.2: 2.5 h / -5 - 23 °C 6.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 1.75 h / 20 - 23 °C 6.2: 4.5 h / 0 - 5 °C 7.1: methanesulfonic acid / acetonitrile / 24 h / 0 - 20 °C 8.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 9.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating
  • 39
  • 2-amino-5-bromo-4-chloro-3-iodopyridine [ No CAS ]
  • [ 1513857-77-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 8 steps 1.1: copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); diisopropylamine / toluene / 17 h / 50 °C / Inert atmosphere 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 3 h / 30 - 35 °C 3.1: sodium hydride / tetrahydrofuran; mineral oil / 0 - 5 °C 4.1: isopropylmagnesium chloride / tetrahydrofuran / 2 h / -10 - 0 °C 4.2: 2.5 h / -5 - 23 °C 5.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 1.75 h / 20 - 23 °C 5.2: 4.5 h / 0 - 5 °C 6.1: methanesulfonic acid / acetonitrile / 24 h / 0 - 20 °C 7.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 8.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating
  • 40
  • 5-bromo-4-chloro-3-(3-morpholinoprop-1-yn-1-yl)pyridin-2-amine [ No CAS ]
  • [ 1513857-77-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 3 h / 30 - 35 °C 2.1: sodium hydride / tetrahydrofuran; mineral oil / 0 - 5 °C 3.1: isopropylmagnesium chloride / tetrahydrofuran / 2 h / -10 - 0 °C 3.2: 2.5 h / -5 - 23 °C 4.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 1.75 h / 20 - 23 °C 4.2: 4.5 h / 0 - 5 °C 5.1: methanesulfonic acid / acetonitrile / 24 h / 0 - 20 °C 6.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 7.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating
  • 41
  • 4-((5-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)morpholine [ No CAS ]
  • [ 1513857-77-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: sodium hydride / tetrahydrofuran; mineral oil / 0 - 5 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 2 h / -10 - 0 °C 2.2: 2.5 h / -5 - 23 °C 3.1: chloro-trimethyl-silane / N,N-dimethyl-formamide / 1.75 h / 20 - 23 °C 3.2: 4.5 h / 0 - 5 °C 4.1: methanesulfonic acid / acetonitrile / 24 h / 0 - 20 °C 5.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 20 °C 6.1: sodium hydroxide; water / 1,4-dioxane / 18 h / Heating
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