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[ CAS No. 861905-94-4 ] {[proInfo.proName]}

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3d Animation Molecule Structure of 861905-94-4
Chemical Structure| 861905-94-4
Chemical Structure| 861905-94-4
Structure of 861905-94-4 * Storage: {[proInfo.prStorage]}
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Product Details of [ 861905-94-4 ]

CAS No. :861905-94-4 MDL No. :MFCD16622791
Formula : C8H6FIO2 Boiling Point : -
Linear Structure Formula :- InChI Key :PODTVAOVOKWNDI-UHFFFAOYSA-N
M.W : 280.03 Pubchem ID :44479445
Synonyms :

Calculated chemistry of [ 861905-94-4 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.12
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 51.04
TPSA : 37.3 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.19 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.78
Log Po/w (XLOGP3) : 2.56
Log Po/w (WLOGP) : 2.86
Log Po/w (MLOGP) : 3.24
Log Po/w (SILICOS-IT) : 3.06
Consensus Log Po/w : 2.7

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.85

Water Solubility

Log S (ESOL) : -3.49
Solubility : 0.09 mg/ml ; 0.000321 mol/l
Class : Soluble
Log S (Ali) : -2.99
Solubility : 0.286 mg/ml ; 0.00102 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.38
Solubility : 0.115 mg/ml ; 0.000412 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 1.9

Safety of [ 861905-94-4 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P264-P270-P271-P280-P301+P312+P330-P302+P352+P312-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P362-P363-P403+P233-P405-P501 UN#:N/A
Hazard Statements:H302+H312+H332-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 861905-94-4 ]

* 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 [ 861905-94-4 ]

[ 861905-94-4 ] Synthesis Path-Downstream   1~97

  • 1
  • [ 65-85-0 ]
  • [ 861905-94-4 ]
YieldReaction ConditionsOperation in experiment
With N-iodo-succinimide; trifluorormethanesulfonic acid at 0℃; for 6h; 18.18a The benzoic acid (1.54 g, 0.01 mol) is dissolved in trifluoromethanesulfonic acid (10 mL) and cooled to about 0 0C. NIS (2.25 g. 0.01 mol) is added in several portions over a 6 h period while maintaining the reaction temperature at about 0 0C. The mixture is allowed to warm to rt. overnight. The reaction mixture is then poured over ice and extracted with ethyl acetate (3x). The organic layers are washed (Na2S2Os) and concentrated. The material is carried on crude.
  • 2
  • [ 861905-94-4 ]
  • [ 585544-31-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: thionyl chloride / 2.5 h / 100 °C 2: sodium carbonate / dichloromethane / 72 h / 20 °C
Multi-step reaction with 2 steps 1: thionyl chloride / 20 - 80 °C 2: sodium carbonate / dichloromethane
With thionyl chloride at 80℃; for 2h; 18.18b The crude acid from Example 18a (~1.5 g) is dissolved in thionyl chloride (75 mL) and heated to 80 0C for about 2 h. The mixture is then cooled to room temperature and stirred under N2 overnight. The mixture is concentrated in vacuo and dissolved in 15 mL DCM. Na2CO3 (3g) is added along with the cyclopropyl amine (0.69 mL, 0.01 moles (hereinafter "mol")). The mixture is allowed to stir overnight and purified via flash chromatography (5% MeOH / CH2Cl2) to afford 0.904g of the title compound.
Multi-step reaction with 2 steps 1: thionyl chloride / 2.5 h / 100 °C 2: sodium carbonate / dichloromethane / 72 h / 20 °C

  • 3
  • [ 350-28-7 ]
  • [ 861905-94-4 ]
YieldReaction ConditionsOperation in experiment
82% With N-iodo-succinimide; trifluorormethanesulfonic acid; at 0 - 20℃; EXAMPLE 32; 5-(Cyclopropylaminocarbonyl)-3-fluoro-2-methylboronic acid; a) 3-Fluoro-5-iodo-4-methylbenzoic acid; To a mixture of <strong>[350-28-7]3-fluoro-4-methylbenzoic acid</strong> (1.54g, 10.0 mmol) in trifluoromethanesulfonic acid (10 ml_), cooled to 0 0C, Lambda/-iodosuccinimide (2.25 g, 10.0 mmol) was added in portions. The mixture was stirred at 0 0C for 3h and then at room temperature overnight. The crude was poured over 40 ml_ of icy water. The solid that precipitated was filtered and washed with water. This crude solid was dissolved in EtOAc and washed with brine. The organic phase was dried over Na2SO4 and the solvent was evaporated to afford 2.3 g of the title compound (yield: 82%). LC-MS (method 2): tR = 4.17 min; m/z = 279.2 [M-H]-.
66% To <strong>[350-28-7]3-fluoro-4-methylbenzoic acid</strong> (60 g, 389 mmol, 1.0 eq.)Concentrated sulfuric acid (210 ml, 3.5 rel vol) was added.The mixture was stirred at ambient temperature for about 15 minutes.It is then cooled to between -5 C and -10 C.A solution of N-iodosuccinimide (NIS, 140.1 g, 623 mmol, 1.6 eq.) in concentrated sulfuric acid (360 mL) was slowly added.The internal temperature was maintained in the range of -5 C to -10 C.The mixture was stirred at this temperature for an additional 2 h and complete conversion was monitored.The reaction mixture was added to water (1.8 L, 30 relative volume),Maintain the temperature below 30 C. Filter the resulting suspension,The filter cake was slurried in 5% aqueous Na2SO3 solution (600 mL, 10 vol.).After filtration and recrystallization from toluene (90 mL, 1.5 rel vol),3-Fluoro-5-iodo-4-methyl-benzoic acid (71.9 g, 66% yield) was isolated as a white solid.
62% With N-iodo-succinimide; methanesulfonic acid; potassium chloride; at -20 - 20℃; for 16.5h;Product distribution / selectivity; Preparation of 3-Fluoro-5-iodo-4-methyIbenzoic acid; 3-Fluoro-4-methylbenzoic acid (1 eqv) and potassium chloride (0.01 eqv) were added to trifluoromethanesulphonic acid (7 vol), then the resulting solution was cooled to -20C. EPO <DP n="28"/>N-iodosuccinimide (1.3 eqv) was added portionwise over 3n, then the mixture stirred at - 2O0C for 11h. The mixture was then warmed to 2O0C over 1.5h, then held at this temperature for 1 h. The resulting reaction mixture was added over 1 J5h to a mixture of water (22 vol) and sodium sulfite 10% aq. soln. (7.5 vol) at 5 to +15C.The resulting suspension was filtered and the cake washed with water (3 x 3 vol). After drying the solid product under a stream of nitrogen, the solid was dissolved in ethyl acetate (13.6 vol), then the resulting solution was washed with 10% aqueous sodium sulphate (2 x 4 vol), with the aqueous washed then back-extracted with ethyl acetate (5 vol). The combined ethyl acetate solutions were washed with brine (4.9 vol), then concentrated to about 3.5 vol. The resulting suspension was cooled to 0 - 5C over 1h. The solid was collected on a filter, then dried under vacuum at 45 - 500C to give the title compound.A second crop of product was obtained by added methylcyclohexane (2 vol) to the crystallisation liquors, concentrating to a volume of 3.3 vol, then adding further methylcyclohexane (3.3 vol). The resulting suspension was cooled to -30C over 1h, and the solid was collected on a filter, then dried on the filter. Total recovery: 62% th.
59% With N-iodo-succinimide; trifluorormethanesulfonic acid; at 20℃; N-lodosuccinimide (3.31 g, 14.7 mmol) was added in portions over a 3-hour period to a stirred solution of <strong>[350-28-7]3-fluoro-4-methylbenzoic acid</strong> (2.27 g, 14.7 mmol) in trifluoromethanesulphonic acid (15 mL) at 0 C. The mixture was warmed to room temperature, stirred overnight and then poured into an ice-water mixture and the precipitate that formed was collected by filtration and washed with water. The solid was dissolved in ethyl acetate, washed with aqueous sodium thiosulphate and brine, dried (MgSO4) and dried to give the title compound (3.45 g, 59%) as a solid. LRMS (m/z): 279 (M-1)-. 1H-NMR delta (CDCl3): 2.41 (s, 3H), 2.86 (m, 1H), 6.30 (brs, 1H), 7.72 (m, 1H), 8.34 (m, 1H).
59% With N-iodo-succinimide; trifluorormethanesulfonic acid; at 0 - 20℃; a) 3-Fluoro-5-iodo-4-methylbenzoic acid N-lodosuccinimide (3.31 g, 14.70 mmol) was added in portions over a 3-hour period to a stirred solution of <strong>[350-28-7]3-fluoro-4-methylbenzoic acid</strong> (2.27 g, 14.70 mmol) in trifluoromethanesulphonic acid (15 mL) at 0 C. The mixture was warmed to room temperature, stirred overnight and then poured into an ice-water mixture and the precipitate that formed was collected by filtration and washed with water. The solid was dissolved in ethyl acetate, washed with aqueous sodium thiosulphate and brine, dried (MgSO4 and dried to give the title compound (3.45 g, 59%) as a solid. LRMS (m/z): 279 (M-1)-.1H NMR (300 MHz, CHLOROFORM-d) delta ppm 2.41 (s, 3 H), 2.86 (m, 1 H), 6.30 (br. s , 1 H), 7.72 (m, 1 H), 8.34 (m, 1 H)
59% With N-iodo-succinimide; trifluorormethanesulfonic acid; at 0 - 20℃;Product distribution / selectivity; INTERMEDIATE 9; 3-(3-Fluoro-5-iodo-4-methylpheny -5-methyl-4 -1,2,4-triazole; a) 3-Fluoro-5-iodo-4-methylbenzoic acid; /V-lodosuccinimide (3.31 g, 14.70 mmol) was added in portions over a 3-hour period to a stirred solution of <strong>[350-28-7]3-fluoro-4-methylbenzoic acid</strong> (2.27 g, 14.70 mmol) in trifluoromethanesulphonic acid (15 mL) at 0 C. The mixture was warmed to room temperature, stirred overnight and then poured into an ice-water mixture and the precipitate that formed was collected by filtration and washed with water. The solid was dissolved in ethyl acetate, washed with aqueous sodium thiosulphate and brine, dried (MgS04) and dried to give the title compound (3.45 g, 59%) as a solid.LRMS (m/z): 279 (M-1)".1 H NMR (300 MHz, CHLOROFORM-d) delta ppm 2.41 (s, 3 H), 2.86 (m, 1 H), 6.30 (br. s , 1 H), 7.72 (m, 1 H), 8.34 (m, 1 H)
53% 10c) 3-fluoro-5-iodo-4-methylbenzoic acid3-Fluoro-4-methyl benzoic acid (120 g, 0.78 mol) was added to triflic acid (830 mL) at O0C and the resultant mixture was cooled to -150C. N- lodosuccinimide (157 g, 0.70mol) was then added in five portions over 30 min, EPO <DP n="66"/>while the temperature of the reaction mixture was kept below -100C, and the resultant mixture was stirred at 00C for 3 h. A further portion of Lambda/-iodosuccinimide (58 g, 0.20mol) was added and after being left to stand in the fridge for 24 h, a final portion (35 g, 0.16 mol) was added, and the reaction was left to stand in the fridge for a further 3 days. The reaction mixture was then poured into a mixture of ice (2.3 kg) and 10% aqueous sodium thiosulphate (1.2 L) and allowed to warm to room temperature. The resultant solid was collected by filtration, washed with water, air-dried, and taken up in ethyl acetate (4.0 L). The organic solution was then washed with 10% aqueous sodium thiosulphate (2 x 1.0 L) and saturated aqueous sodium chloride, and the aqueous phase was further extracted with ethyl acetate (2 x 1.0 L). The combined organic fractions were then dried (MgSO4) and concentrated to a volume of about 320 mL, and the resultant solid was collected by filtration, washed with hexane, and air-dried to afford 3-fluoro-5- iodo-4-methylbenzoic acid (116 g, 53%) as an off-white solid. 26a) 3-fluoro-5-iodo-4-methylbenzoic acid3-Fluoro-4-methyl benzoic acid (120 g, 0.78 mol) was added to triflic acid (830 mL) at 00C and the resultant mixture was cooled to -150C. N- lodosuccinimide (157 g, 0.70mol) was then added in five portions over 30 min, while the temperature of the reaction mixture was kept below -100C, and the resultant mixture was stirred at O0C for 3 h. A further portion of N- iodosuccinimide (58 g, 0.20mol) was added and after being left to stand in the fridge for 24 h, a final portion (35 g, 0.16 mol) was added, and the reaction EPO <DP n="78"/>was left to stand in the fridge for a further 3 days. The reaction mixture was then poured into a mixture of ice (2.3 kg) and 10% aqueous sodium thiosulphate (1.2 L) and allowed to warm to room temperature. The resultant solid was collected by filtration, washed with water, air-dried, and taken up in ethyl acetate (4.0 L). The organic solution was then washed with 10% aqueous sodium thiosulphate (2 x 1.0 L) and saturated aqueous sodium chloride, and the aqueous phase was further extracted with ethyl acetate (2 x 1.0 L). The combined organic fractions were then dried (MgSO4) and concentrated to a volume of about 320 mL, and the resultant solid was collected by filtration, washed with hexane, and air-dried to afford the title compound (116 g, 53%) as an off-white solid.
With N-iodo-succinimide; trifluorormethanesulfonic acid; at -20 - -10℃; for 64.67h; A stirred mixture of <strong>[350-28-7]3-fluoro-4-methylbenzoic acid</strong> (10.3g) in trifluoromethane sulfonic acid (50ml) at -20C was treated with N-iodosuccinimide in portions over 40min. The reaction was stirred at -10C for 44h when a further amount of N-iodosuccinimide (6.0g) was added. After 20h the reaction mixture was added to ice/water and extracted with ethyl acetate. The organic solution was washed with aqueous sodium metabisulfite and dried over sodium sulfate. The residue was dissolved in methanol (50ml), the solution was treated with concentrated sulfuric acid (91ml) and the mixture was heated at reflux for 6h. The solvent was evaporated and the residue was dissolved in ethyl acetate. This solution was washed with aqueous sodium bicarbonate and dried with brine and over magnesium sulfate. Purification by biotage chromatography (x2), firstly using cyclohexane/ethyl acetate (100/1) and secondly cyclohexane/toluene (6/1) as eluents gave the title compound (9.31 g). LC-MS: Rt 3.55min.
With N-iodo-succinimide; trifluorormethanesulfonic acid; at -22 - -20℃; for 48.25h; A solution of <strong>[350-28-7]3-fluoro-4-methylbenzoic acid</strong> (149.7g) in trifluoromethanesulphonic acid (1050ml) at -22C under nitrogen was treated portionwise over 1.25h with iodosuccinimide (203.5g). The mixture was stirred at -20C for and further portions of iodosuccinimide were added after 2.5h (46.5g) and 20.5h (30g). The mixture was stirred at -20C for a further 24h then added slowly to a mixture of aqueous sodium thiosulphate (10%, 1.5L) and ice (3kg). The resultant precipitate was collected by filtration and stirred with ethyl acetate (5L) and aqueous sodium thiosulphate (10%, 1.5L). The organic phase was dried (MgSO4) and concentrated to -1.5L then left overnight. The precipitate was collected by filtration and further material was obtained through concentration of the filtrate to give the title compound as a white solid (133.9g). LC-MS: Rt 3.60, MH+ 281.
With N-iodo-succinimide; trifluorormethanesulfonic acid; at 0 - 20℃; Example 49; iV-cyclopropyl-3-(8-(2,6-difluorophenyl)-2-[2-hydroxy-l-(hydroxymethv?ethyl1amino|-7-oxo-7,8-dihydropyrido["2.3-cr|pyrimidin-4-ylV5- fluoro-4-rnethylbenzamide EPO <DP n="78"/>3-Fluoro-4-methylbenzoic acid (1.54 g, 0.01 mol) is dissolved in trifluoromethanesulfonic acid (10 mL) and cooled to about 0 0C. NIS (2.25 g. 0.01 mol) is added in several portions over a 6 h period while maintaining the reaction temperature at about 00C. The mixture is allowed to warm to rt. overnight. The reaction mixture is then poured over ice and extracted with ethyl acetate (3x). The organic layers are washed (Na2S2O5) and concentrated. The material is carried on crude.The crude acid from above (~1.5 g) is dissolved in thionyl chloride (75 mL) and heated to 80 0C for about 2 h. The mixture is then cooled to room temperature and stirred under N2 overnight. The mixture is concentrated in vacuo and dissolved in 15 mL DCM. Na2CO3 (3g) is added along with the cyclopropyl amine (0.69 mL, 0.01 moles (hereinafter "mol")). The mixture is allowed to stir overnight and purified via flash chromatography (5% MeOH / CH2Cl2) to afford 0.904g of N-cyclopropyl-3- fluoro-5-iodo-4-methylbenzamide iV-cyclopropyl-3-fluoro-5-iodo-4-methylbenzamide (0.904 g, 2.83 mmol) is dissolved in DMF (30 mL). Bis-pinicalato-diborane (1.44 g, 2.83 mmol) is added followed by PdCl2. dppf (55 mg) and potassium acetate (1.38 g, 14.15 mmol). The mixture are stirred for about 18 h, concentrated in vacuo and purified via flash chromatography to afford N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)benzamide (60 mg).4-Chloro-8-(2,6-difluorophenyl)-2-[2-hydroxy-l-(hydroxymethyl)ethyl]- amino}pyrido[253-<^pyrimidin-7(8H)-one (0.056 g, 0.17 mmol), N-cyclopropyl-3- fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)benzamide (0.065 g, 0.17 mmol), K2CO3 (0.07 g, 0.51 mmol) and tetrakis triphenyl phosphine palladium (10 mg, 0.05eq) are dissolved in dioxane / water (3:1, 10 mL) and heated to about 100 0C for about 3 h. The mixture is concentrated and purified via reverse phase HPLC to afford the title compound (9 mg, yellow powder, mp 214.2-217.5): LC-MS m/z 540 (M+H)+, 1.69 min (ret time). HPLC indicates 96% pure.
With N-iodo-succinimide; trifluorormethanesulfonic acid; at -22 - -18℃;Product distribution / selectivity; 3-Fluoro-4-methylbenzoic acid (182g) was added to trifluoromethanesulphonic acid (1.121) and the solution cooled to -200C under nitrogen, lodosuccinimide (266g) was added in portions over 75min, maintaining a reaction temperature of -18 to -19C, and the reaction was then stirred at -200C for 4hours. lodosuccinimide (54.8g) was added portionwise and the reaction stirred at -200C overnight, lodosuccinimide (19g) added before stirring at - 200C for a further 24hours. The reaction was warmed to -5C and the suspension poured into a stirred mixture of ice (3kg) and sodium thiosulphate solution (10%). The mixture was filtered and the solid partially dried on the sinter. The solid was partitioned between ethyl acetate (5I) and sodium thiosulphate solution (10%, 1.51), the organic washed with sodium thiosulphate solution (10%) and dried (sodium sulphate), before concentrating in vacuo to ca. 600ml. The resulting slurry was allowed to stand for 4hours, filtered, the residue washed with ethyl acetate and dried, to give 3-fluoro-5-iodo-4-methylbenzoic acid (215g). LCMS: [M-H]" 279, retention time 3.75min.; 3-Fluoro-4-methylbenzoic acid (150.3g) was added to trifluoromethanesulphonic acid (1.051) and the solution cooled to -22C under nitrogen, lodosuccinimide (200.8g) was added in portions over 60min, maintaining a reaction temperature of -19 to -22C, and the reaction was then stirred at -200C for 2.5hours. lodosuccinimide (51.0) was added portionwise over 30min and the reaction stirred at -200C overnight, lodosuccinimide (19g) added before stirring at -200C for a further 17hours. A further portion of iodosuccinimide (28.2g) and stirring continued at -200C for a further 24hours. The reaction was poured into a stirred mixture of ice (3kg) and 10% sodium thiosulphate solution (1.5L). The mixture was filtered, washed with water and the solid dried on the sinter. The solid was partitioned between ethyl acetate (5I) and sodium thiosulphate solution (10%, 1.51). The organic layer was washed with sodium thiosulphate solution (10%, 1.51) and the aqueous phases back extracted with ethyl acetate. The organic phases were combined and drwashed with brine and dried (magnesium sulphate), before concentrating in vacuo to approximately 750ml. The resulting mixture was allowed to stand for 24hours, filtered, the residue washed with ethyl acetate and dried, to give 3-fluoro-5-iodo-4-methylbenzoic acid (126.5g). LCMS: [M-H]" 279, retention time 3.6min.
With N-iodo-succinimide; trifluorormethanesulfonic acid; at -22 - -5℃;Product distribution / selectivity; Intermediate 1 : 3-Fluoro-5-iodo-4-methylbenzoic acid - preparation 1; 3-Fluoro-4-methylbenzoic acid (182g) was added to trifluoromethanesulphonic acid (1.121) and the solution cooled to -200C under nitrogen, lodosuccinimide (266g) was added in portions over 75min, maintaining a reaction temperature of -18 to -19C, and the reaction was then stirred at -200C for 4hours. lodosuccinimide (54.8g) was added portionwise and the reaction stirred at -200C overnight, lodosuccinimide (19g) added before stirring at - 200C for a further 24hours. The reaction was warmed to -5C and the suspension poured into a stirred mixture of ice (3kg) and sodium thiosulphate solution (10%). The mixture was filtered and the solid partially dried on the sinter. The solid was partitioned between ethyl acetate (5I) and sodium thiosulphate solution (10%, 1.51), the organic washed with sodium thiosulphate solution (10%) and dried (sodium sulphate), before concentrating in vacuo to ca. 600ml. The resulting slurry was allowed to stand for 4hours, filtered, the residue washed with ethyl acetate and dried, to give 3-fluoro-5-iodo-4-methylbenzoic acid (215g). LCMS: [M-H]" 279, retention time 3.75min.; Intermediate 1 : 3-Fluoro-5-iodo-4-methylbenzoic acid - preparation 2; 3-Fluoro-4-methylbenzoic acid (150.3g) was added to trifluoromethanesulphonic acid (1.051) and the solution cooled to -22C under nitrogen, lodosuccinimide (200.8g) was added in portions over 60min, maintaining a reaction temperature of -19 to -22C, and the reaction was then stirred at -200C for 2.5hours. lodosuccinimide (51.0) was added portionwise over 30min and the reaction stirred at -200C overnight, lodosuccinimide (19g) added before stirring at -200C for a further 17hours. A further portion of iodosuccinimide <n="21"/>(28.2g) and stirring continued at -200C for a further 24hours. The reaction was poured into a stirred mixture of ice (3kg) and 10% sodium thiosulphate solution (1.5L). The mixture was filtered, washed with water and the solid dried on the sinter. The solid was partitioned between ethyl acetate (5I) and sodium thiosulphate solution (10%, 1.51). The organic layer was washed with sodium thiosulphate solution (10%, 1.51) and the aqueous phases back extracted with ethyl acetate. The organic phases were combined and drwashed with brine and dried (magnesium sulphate), before concentrating in vacuo to approximately 750ml. The resulting mixture was allowed to stand for 24hours, filtered, the residue washed with ethyl acetate and dried, to give 3-fluoro-5-iodo-4-methylbenzoic acid (126.5g). LCMS: [M-H]" 279, retention time 3.6min.
With N-iodo-succinimide; trifluorormethanesulfonic acid; at 0 - 20℃; N-Iodosuccinimide (22. 5g) was added in portions to a solution of 3-fluoro-4- methylbenzoic acid (15.4g) in trifluoromethanesulphonic acid (100ml) at 0C over 3hours and the reaction then allowed to warm to room temperature overnight. The reaction mixture was poured into ice/water (400ml) and the precipitate filtered off and washed with water. The solid remaining was dissolved in ethyl acetate, washed with aqueous sodium thiosulphate (x2), then brine, dried (magnesium sulphate) and the solvent evaporated under vacuum. The residue was mixed with thionyl chloride (30ml) and heated at 100C for 2. 5hours. The excess thionyl chloride was removed from the cooled reaction under vacuum and the residue dissolved in DCM (100ml). Sodium carbonate (25g) and cyclopropylamine (13ml) were added to the solution and the reaction stirred at room temperature for 72hours. The reaction was filtered and the residue washed with DCM and ethyl acetate. The solvent was evaporated from the combined filtrate and washings under vacuum. The residue was absorbed onto silica and chromatographed on a flash silica column eluting with an ethyl acetate/cyclohexane gradient (22-28% ethyl acetate). Appropriate fractions were reduced to dryness under vacuum to give N- cyclopropyl-5-fluoro-3-iodo-4-methylbenzamide. LCMS; MH+ 320, retention time 3. 16minutes.
With N-iodo-succinimide; trifluoroacetic acid; at 0 - 20℃; Intermediate 7: N-CVCLOPROPVL-5-FLUORO-3-IODO-4-METHVLBENZAMIDE; N-LODOSUCCINIMIDE (22.5g) was added in portions to a solution of <strong>[350-28-7]3-fluoro-4-methylbenzoic acid</strong> (15. 4g) in TRIFLUOROMETHANESULPHONIC acid (100MOL) at 0C over 3hours and the reaction then allowed to warm to room temperature overnight. The reaction mixture was poured into ice/water (400ML) and the precipitate filtered off and washed with water. The solid remaining was dissolved in ethyl acetate, washed with aqueous sodium thiosulphate (x2), then brine, dried (magnesium sulphate) and the solvent evaporated under vacuum. The residue was mixed with thionyl CHLORIDE (30M1) and heated at 100C for 2.5hours. The excess thionyl chloride was removed from the cooled reaction under vacuum and the residue dissolved in DCM (100ML). Sodium carbonate (25g) and CYCLOPROPYLAMINE (13ML) were added to the solution and the reaction stirred at room temperature for 72hours. The reaction was filtered and the residue washed with DCM and ethyl acetate. The solvent was evaporated from the combined filtrate and washings under vacuum. The residue was absorbed onto silica and chromatographed on a flash silica column eluting with an ethyl acetate/cyclohexane gradient (22-28% ethyl acetate). Appropriate fractions were reduced to dryness under vacuum to give N-cyclopropyl-5-fluoro-3-iodo-4- methylbenzamide. LCMS; MH+ 320, retention time 3.16minutes
With N-iodo-succinimide; trifluorormethanesulfonic acid; at -22 - -20℃; for 48.25h; Intermediate 11 : 3-Fluoro-5-iodo-4-methylbenzoic acid; A solution of <strong>[350-28-7]3-fluoro-4-methylbenzoic acid</strong> (149.7g) in trifluoromethanesulphonic acid (1050m1) at-22C under nitrogen was treated portionwise over 1.25h with iodosuccinimide (203.5g). The mixture was stirred at-20C for and further portions of iodosuccinimide were added after 2.5h (46.5g) and 20.5h (30g). The mixture was stirred at-20C for a further 24h then added slowly to a mixture of aqueous sodium thiosulphate (10%, 1.5L) and ice (3kg). The resultant precipitate was collected by filtration and stirred with ethyl acetate (5L) and aqueous sodium thiosulphate (10%, 1.5L). The organic phase was dried (MgS04) and concentrated to-1.5L then left overnight. The precipitate was collected by filtration and further material was obtained through concentration of the filtrate to give the title compound as a white solid (133. 9g). LC-MS: Rt 3. 60, MH+ 281
With N-iodo-succinimide; trifluorormethanesulfonic acid; at -22 - -20℃; for 48.25h; Intermediate 29: 3-Fluoro-5-iodo-4-methvlbenzoic acid; A solution of <strong>[350-28-7]3-fluoro-4-methylbenzoic acid</strong> (149.7g) in trifluoromethanesulphonic acid (1050ml) at-22C under nitrogen was treated portionwise over 1.25h with iodosuccinimide (203.5g). The mixture was stirred at-20C for and further portions of iodosuccinimide were added after 2.5h (46.5g) and 20.5h (30g). The mixture was stirred at-20C for a further 24h then added slowly to a mixture of aqueous sodium thiosulphate (10%, 1.5L) and ice (3kg). The resultant precipitate was collected by filtration and stirred with ethyl acetate (5L) and aqueous sodium thiosulphate (10%, 1.5L). The organic phase was dried (MgS04) and concentrated to-1.5L then left overnight. The precipitate was collected by filtration and further material was obtained through concentration of the filtrate to give the title compound as a white solid (133. 9g). LC-MS : Rt 3. 60, MH+ 281
With N-iodo-succinimide; trifluorormethanesulfonic acid; at 0 - 20℃; Example 18; N-cyclopropyl-3-f 8-(2,6-difluorophenyl)-2- (["2-hvdroxy-l -QivdroxLambdamiethyl)ethyl1amino}-7-oxo-7,8-dihvdropyridor2.l3--(f|pyrimidin-4-y?-5- fluoro-4-methylbenzarnideThe benzoic acid (1.54 g, 0.01 mol) is dissolved in trifluoroniethanesulfonic acid (10 mL) and cooled to about 00C. NIS (2.25 g. 0.01 mol) is added in several portions over a 6 h period while maintaining the reaction temperature at about 0 0C. The mixture is allowed to warm to rt. overnight. The reaction mixture is then poured over ice and extracted with ethyl acetate (3x). The organic layers are washed (Na2SaO5) and concentrated. The material is carried on crude.
With N-iodo-succinimide; In trifluorormethanesulfonic acid; at 0 - 20℃; 3-Fluoro-4-methylbenzoic acid (1.54 g, 0.01 mol) is dissolved in trifluoromethanesulfonic acid (10 mL) and cooled to about 0 0C. NIS (2.25 g. 0.01 mol) is added in several portions over a 6 h period while maintaining the reaction temperature at about 0 0C. The mixture is allowed to warm to rt. overnight. The reaction mixture is then poured over ice and extracted with ethyl acetate (3x). The organic layers are washed (Na2S2Os) and concentrated. The material is carried on crude.The crude acid from above (~1.5 g) is dissolved in thionyl chloride (75 mL) and heated to 80 0C for about 2 h. The mixture is then cooled to room temperature and stirred under N2 overnight. The mixture is concentrated in vacuo and dissolved in 15 mL DCM. Na2CO3 (3g) is added along with the cyclopropyl amine (0.69 mL, 0.01 moles (hereinafter "mol")). The mixture is allowed to stir overnight and purified via flash chromatography (5% MeOH / CH2Cl2) to afford 0.904g of N-cyclopropyl-3-fluoro-5-iodo-4-methylbenzamidelambda/-cyclopropyl-3-fluoro-5-iodo-4-methylbenzamide (0.904 g, 2.83 mmol) is dissolved in DMF (30 mL). Bis-pinicalato-diborane (1.44 g, 2.83 mmol) is added followed by PdCl2. dppf (55 mg) and potassium acetate (1.38 g, 14.15 mmol). The mixture are stirred for about 18 h, concentrated in vacuo and purified via flash chromatography to afford N- cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide (60 mg).4-Chloro-8-(2,6-difluorophenyl)-2-[2-hydroxy-l-(hydroxymethyl)ethyl]- amino}pyrido[2,3-(i]pyrimidin-7(8H)-one (0.056 g, 0.17 mmol), iV-cyclopropyl-3-fluoro-4- methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide (0.065 g, 0.17 mmol), K2CO3 (0.07 g, 0.51 mmol) and tetrakis triphenyl phosphine palladium (10 mg, 0.05eq) are dissolved in dioxane / water (3:1, 10 mL) and heated to about 100 0C for about 3 h. The <n="76"/>mixture is concentrated and purified via reverse phase HPLC to afford the title compound (9 mg, yellow powder, mp 214.2-217.5): LC-MS m/z 540 (M+H)+, 1.69 min (ret time). HPLC indicates 96% pure.
With N-iodo-succinimide; trifluorormethanesulfonic acid; at 0℃; lambda/-lodosuccinimide (3.31 g) was added in portions to a solution of <strong>[350-28-7]3-fluoro-4-methylbenzoic acid</strong> (2.27 g) in trifluoromethanesulphonic acid (15 mL) at 0c over 3 hours and the mixture was allowed to warm to room temperature overnight. The reaction mixture was poured into ice/water and the precipitate was collected by filtration and rinsed with water. The solid was dissolved in ethyl acetate, washed with aqueous sodium thiosulphate and brine, dried over anhydrous magnesium sulphate and the solvent was removed under vacuum. The residue obtained was treated with thionyl chloride (20 mL) and heated at 1000C for 2.5 hours. Excess thionyl chloride was removed under vacuum and the residue was dissolved in dichloromethane (20 mL). Sodium carbonate (3.7 g) and cyclopropylamine (1.9 mL) were added to the solution and the mixture was stirred at room temperature for 72 hours. The mixture was filtered and the residue was rinsed with dichloromethane and ethyl acetate. The combined filtrates and washings were concentrated under vacuum.The residue was purified by flash chromatography eluting with hexanes:ethyl acetate (10:1 to 5:1) to give 2.13 g (45%) of lambda/-cyclopropyl-3-fluoro-5-iodo-4-methylbenzamide.
With N-iodo-succinimide; methanesulfonic acid; at -20 - -18℃;Product distribution / selectivity; Intermediate 1: 3-Fluoro-5-iodo-4-methylbenzoic acid; 3-Fluoro-4-methylbenzoic acid (182g) was added to trifluoromethanesulphonic acid (1.12L) and the solution cooled to -200C under nitrogen, lodosuccinimide (266g) was added in portions over 75min, maintaining a reaction temperature of -18 to -19C, and the reaction was then stirred at -200C for 4h. lodosuccinimide (54.8g) was added portionwise and the reaction stirred at -2O0C overnight, lodosuccinimide (19g) added before stirring at -200C for a further 24h. The reaction was warmed to -5C and the suspension poured into a stirred mixture of ice (3kg) and sodium thiosulphate solution (10%). The mixture was filtered and the solid partially dried on the sinter. The solid was partitioned between ethyl acetate (5L) and aqueous sodium thiosulphate solution (10%, 1.5L) and the organic phase was washed with sodium thiosulphate solution (10%) dried (sodium sulphate) and concentrated under vacuum to ca. 600ml. The resulting slurry was allowed to stand for 4h and the solid was collected by filtration, washed with ethyl acetate and dried, to give the title compound (215g). LC-MS: Rt 3.75min.

Reference: [1]Patent: WO2007/339,2007,A1 .Location in patent: Page/Page column 53
[2]Patent: CN108884057,2018,A .Location in patent: Paragraph 0139; 0203; 0204; 0210-0214
[3]Journal of Medicinal Chemistry,2009,vol. 52,p. 6257 - 6269
[4]Patent: WO2006/134382,2006,A1 .Location in patent: Page/Page column 26-27
[5]Patent: EP2108641,2009,A1 .Location in patent: Page/Page column 58
[6]Patent: EP2322176,2011,A1 .Location in patent: Page/Page column 22
[7]Patent: WO2011/57757,2011,A1 .Location in patent: Page/Page column 38
[8]Patent: WO2006/110173,2006,A2 .Location in patent: Page/Page column 64-65; 76-77
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[21]Patent: WO2006/134382,2006,A1 .Location in patent: Page/Page column 21
  • 4
  • [ 861905-94-4 ]
  • [ 918331-98-3 ]
YieldReaction ConditionsOperation in experiment
With thionyl chloride at 110℃; for 1h; 3-Fluoro-5-iodo-4-methylbenzoic acid (Intermediate 69, 20g) in thionyl chloride (20ml)was heated at 110°C for 1h. The excess thionyl chloride was evaporated under vacuum and the residual oil was dissolved in DCM (100ml). Potassium carbonate (21 g) was added to the solution followed by the slow addition of ethylamine (2M in THF, 70ml). The reaction was left25 at room temperature overnight, filtered and the residue was washed with ethyl acetate. The combined filtrate a nd washings were reduced to d ryness u nder vacuum a nd the resulting solid was washed with ether/cyclohexane (1:1) to give the title compound as a pale beige solid (18.5g). NMR: [5H d6-DMSO] 8.58(1 H, b), 8.15(1H, s), 7.64(1H, d), 3.26(2H, quin), 2.3330 (3H,s), 1.11(3H,t).
With thionyl chloride at 100℃; for 2.5h; 32.b b) 3-Fluoro-5-iodo-4-methylbenzoyl chloride; A mixture of 3-fluoro-5-iodo-4-methylbenzoic acid (2.3 g, 8.2 mmol, obtained in section a) in thionyl chloride (3mL) was heated at 100 0C for 2.5h. The solvent was ditilled off to afford the title compound as a crude product that was directly used in the following step.
With thionyl chloride for 2.5 - 3h; Heating / reflux; 2 Intermediate 2: Methyl 3-fluoro-5-iodo-4-methylbenzoate; A mixture of 3-fluoro-5-iodo-4-methylbenzoic acid (28g) and thionyl chloride (40ml) was heated at reflux under nitrogen for 3 hours, before the reaction was allowed to cool and the excess thionyl chloride evaporated in vacuo, azeotroping with DCM (3x50ml). The remaining oil was dissolved in DCM (50ml) and added dropwise with stirring to a solution of dry methanol (30ml) and triethylamine (20ml) in DCM (150ml) with ice/water cooling. The reaction was stirred under nitrogen at room temperature overnight, diluted with DCM (100ml), then washed with water (200ml), hydrochloric acid (2M, 2x 200ml), water (200ml) and brine (100ml). The organic phase was dried (magnesium sulphate) and reduced to dryness under vacuum. The residual oil was purified by chromatography on a silica gel column eluting with DCM / hexane (10-20% DCM) to give, after evaporation of the solvent in vacuo, methyl 3-fluoro-5-iodo-4-methylbenzoate.NMR: CDCI3 δH 8.27,(1 H, s), 7.65,(1 H, dd), 3.92,(3H, s), 2.41 , (3H, d).; Intermediate 7: 3-fluoro-5-iodo-4-methyl-λ/-(1-methyl-1H-pyrazol-5-yl)benzamide - preparation 2; A mixture of 3-fluoro-5-iodo-4-methylbenzoic acid (28.9g) and thionyl chloride (30ml) was heated under nitrogen at 1000C for 2.5 hours. The reaction mixture was a pale yellow solution with a small quantity of floating solid. Thionyl chloride was evaporated in vacuo and the residual oil azeotroped with toluene. The oil was dissolved in DCM (60ml), filtered and added over approximately 5 minutes to a mixture of 2-methyl-3-aminopyrazole (10g), potassium carbonate (20.4g) in DCM (100ml). The reaction mixture was stirred at room temperature overnight. The solvent had evaporated so the residue was resuspended in DCM (150ml) and diisopropylethylamine (18ml) added. The reaction mixture was stirred for 45 minutes to give a yellow solution. It was then partitioned between ethyl acetate and water. An aqueous suspension was formed and this was extracted four times with ethyl acetate; the combined organic fractions washed with water, 2N hydrochloric acid, water and twice with brine. The organic solution was dried with anhydrous magnesium sulphate, concentrated to dryness in vacuo and the resulting solid triturated with diethyl ether and dried at 4O0C under vacuum to give 3-fluoro-5-iodo-4-methyl-λ/-(1 -methyl-1 H-pyrazol-5- yl)benzamide (28.33g). LCMS MH+ 360, retention time 3.13 min.
With thionyl chloride at 100℃; for 2.5h; 48 N-Iodosuccinimide (22. 5g) was added in portions to a solution of 3-fluoro-4- methylbenzoic acid (15.4g) in trifluoromethanesulphonic acid (100ml) at 0°C over 3hours and the reaction then allowed to warm to room temperature overnight. The reaction mixture was poured into ice/water (400ml) and the precipitate filtered off and washed with water. The solid remaining was dissolved in ethyl acetate, washed with aqueous sodium thiosulphate (x2), then brine, dried (magnesium sulphate) and the solvent evaporated under vacuum. The residue was mixed with thionyl chloride (30ml) and heated at 100°C for 2. 5hours. The excess thionyl chloride was removed from the cooled reaction under vacuum and the residue dissolved in DCM (100ml). Sodium carbonate (25g) and cyclopropylamine (13ml) were added to the solution and the reaction stirred at room temperature for 72hours. The reaction was filtered and the residue washed with DCM and ethyl acetate. The solvent was evaporated from the combined filtrate and washings under vacuum. The residue was absorbed onto silica and chromatographed on a flash silica column eluting with an ethyl acetate/cyclohexane gradient (22-28% ethyl acetate). Appropriate fractions were reduced to dryness under vacuum to give N- cyclopropyl-5-fluoro-3-iodo-4-methylbenzamide. LCMS; MH+ 320, retention time 3. 16minutes.
With thionyl chloride at 100℃; for 2.5h; Intermediate 7: N-CVCLOPROPVL-5-FLUORO-3-IODO-4-METHVLBENZAMIDE; N-LODOSUCCINIMIDE (22.5g) was added in portions to a solution of 3-fluoro-4-methylbenzoic acid (15. 4g) in TRIFLUOROMETHANESULPHONIC acid (100MOL) at 0°C over 3hours and the reaction then allowed to warm to room temperature overnight. The reaction mixture was poured into ice/water (400ML) and the precipitate filtered off and washed with water. The solid remaining was dissolved in ethyl acetate, washed with aqueous sodium thiosulphate (x2), then brine, dried (magnesium sulphate) and the solvent evaporated under vacuum. The residue was mixed with thionyl CHLORIDE (30M1) and heated at 100°C for 2.5hours. The excess thionyl chloride was removed from the cooled reaction under vacuum and the residue dissolved in DCM (100ML). Sodium carbonate (25g) and CYCLOPROPYLAMINE (13ML) were added to the solution and the reaction stirred at room temperature for 72hours. The reaction was filtered and the residue washed with DCM and ethyl acetate. The solvent was evaporated from the combined filtrate and washings under vacuum. The residue was absorbed onto silica and chromatographed on a flash silica column eluting with an ethyl acetate/cyclohexane gradient (22-28% ethyl acetate). Appropriate fractions were reduced to dryness under vacuum to give N-cyclopropyl-5-fluoro-3-iodo-4- methylbenzamide. LCMS; MH+ 320, retention time 3.16minutes
With thionyl chloride at 100℃; for 3h; Inert atmosphere;
With thionyl chloride at 100℃; for 2.5h; 2.a INTERMEDIATE 2; /V-Cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide; a) A -Cyclopropyl-3-fluoro-5-iodo-4-methylbenzamide; /V-lodosuccinimide (3.31 g, 14.71 mmol) was added in portions to a solution of 3-fluoro-4- methylbenzoic acid (2.27 g, 14.77 mmol) in trifluoromethanesulphonic acid (15 mL) at 0° C over 3 hours and the mixture was allowed to warm to room temperature overnight. The reaction mixture was poured into ice/water and the precipitate was collected by filtration and washed with water. The solid was dissolved in ethyl acetate, washed with aqueous sodium thiosulphate (x2) and brine, dried (Na2S04) and the solvent was removed under vacuum. The residue obtained was treated with thionyl chloride (20 mL) and heated at 100° C for 2.5 hours. Excess thionyl chloride was removed under vacuum and the residue was dissolved in dichloromethane (20 ml_). Sodium carbonate (3.7 g, 34.90 mmol) and cyclopropylamine (1.9 ml_, 27.42 mmol) were added to the solution and the mixture was stirred at room temperature for 72 hours. The mixture was filtered and the residue was washed with dichloromethane and ethyl acetate. The combined filtrate and washings were concentrated under vacuum. The residue was purified by flash chromatography (10:1 hexanes/ethyl acetate to 5:1 hexanes/ethyl acetate) to give the title compound (2.13 g, 45%).LRMS (m/z): 320 (M+1)+.
With thionyl chloride at 80℃; for 6h; 1 Step (1): Preparation of N-cyclopropyl-3-fluoro-5-iodo-4-methylbenzamide (compound II-b) 3-fluoro-5-iodo-4-methylbenzoic acid (compound II-a, 36 mmol) and 7 thionyl chloride (50 mL) were added into a reaction flask and heated to reflux for 6 hours at 80°C. The excess of thionyl chloride was evaporated under reduced pressure to obtain a pale yellow oil, dichloromethane(30mL)was added thereinto and the resulting product was used for the subsequent reaction.
With thionyl chloride at 20 - 80℃; 18.18b The crude acid from Example 18a (~ 1.5 g) is dissolved in thionyl chloride (75 mL) and heated to 80 0C for about 2 h. The mixture is then cooled to room temperature and stirred under N2 overnight. The mixture is concentrated in vacuo and dissolved in 15 mL DCM. Na2CO3 (3g) is added along with the cyclopropyl amine (0.69 mL, 0.01 moles (hereinafter "mol")). The mixture is allowed to stir overnight and purified via flash chromatography (5% MeOH / CH2Cl2) to afford 0.904g of the title compound.
With thionyl chloride at 100℃; for 2.5h; 12.a λ/-lodosuccinimide (3.31 g) was added in portions to a solution of 3-fluoro-4-methylbenzoic acid (2.27 g) in trifluoromethanesulphonic acid (15 mL) at 0°c over 3 hours and the mixture was allowed to warm to room temperature overnight. The reaction mixture was poured into ice/water and the precipitate was collected by filtration and rinsed with water. The solid was dissolved in ethyl acetate, washed with aqueous sodium thiosulphate and brine, dried over anhydrous magnesium sulphate and the solvent was removed under vacuum. The residue obtained was treated with thionyl chloride (20 mL) and heated at 1000C for 2.5 hours. Excess thionyl chloride was removed under vacuum and the residue was dissolved in dichloromethane (20 mL). Sodium carbonate (3.7 g) and cyclopropylamine (1.9 mL) were added to the solution and the mixture was stirred at room temperature for 72 hours. The mixture was filtered and the residue was rinsed with dichloromethane and ethyl acetate. The combined filtrates and washings were concentrated under vacuum.The residue was purified by flash chromatography eluting with hexanes:ethyl acetate (10:1 to 5:1) to give 2.13 g (45%) of λ/-cyclopropyl-3-fluoro-5-iodo-4-methylbenzamide.
With thionyl chloride at 95℃; for 1.75 - 3h; Heating / reflux; 2; 6 Intermediate 2: Methyl 3-fluoro-5-iodo-4-methvlbenzoate; A mixture of 3-fluoro-5-iodo-4-methylbenzoic acid (Intermediate 1 , 28g) and thionyl chloride (40ml) was heated at reflux for 3h, before the reaction was allowed to cool and the excess thionyl chloride was removed under vacuum, azeotroping with DCM (3x50ml). The remaining oil was dissolved in DCM (50ml) and added dropwise with stirring to a solution of dry methanol (30ml) and triethylamine (20ml) in DCM (150ml) with ice/water cooling. The reaction was stirred at room temperature overnight, diluted with DCM (100ml) then washed with water (200ml), hydrochloric acid (2M, 2x 200ml), water (200ml) and brine (100ml). The organic phase was dried (magnesium sulphate) and reduced to dryness under vacuum. The residual oil was purified by chromatography on a silica gel column eluting with DCM / hexane (10-20% DCM) to give the title compound (30.3g). NMR: CDCI3 δH 8.27, (1H, s) 7.65,(1 H, dd) 3.92,(3H, s) 2.41 ,(3H, d).; Intermediate 6: 3-Fluoro-5-iodo-/V-3-isoxazolyl-4-methylbenzamide;Thionyl chloride (10.4ml) was added to 3-fluoro-5-iodo-4-methylbenzoic acid (Intermediate 1 , 1Og) and the mixture was stirred at 95°C for 1.75h. The thionyl chloride was removed under vacuum, the residue was azeotroped with toluene and the residue was dissolved in dry dichloromethane (100ml). A solution of 3-isoxazolamine (3.6g) N, N- diisopropylethylamine (12.4ml) and 4-dimethylaminopyridine (4.36g) in dry dichloromethane (250ml) was stirred at room temperature for 45min then the acid chloride solution was added over a period of about 20min. The reaction mixture was stirred at room temperature for 3h, water was added and the mixture was partitioned between ethyl acetate and hydrochloric acid (1M). The organic layer was separated, the aqueous layer was re-extracted with ethyl acetate and the combined organic extracts were washed with aqueous sodium hydrogen carbonate (1 M) and brine, dried and concentrated under vacuum to give the title compound as a cream solid (11.9g). LC-MS: Rt 1.80min.

  • 5
  • [ 861905-94-4 ]
  • [ 1820-80-0 ]
  • [ 861905-52-4 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; HATU In DMF (N,N-dimethyl-formamide) at 20℃; N,N-Diisopropylethlamine (3.8ml) and HATU (3.32g) were added to a solution of 3-fluoro-5-iodo-4-methylbenzoic acid (Intermediate 69, 2.07g) in DMF (80ml) and the reaction mixture was stirred for 10min at room temperature. 3-Aminopyrazole (0.9ml) was added and stirring was continued at room temperature overnight. The reaction mixture was absorbed onto silica, applied to a silica column (100g) and eluted with an ethyl acetate/cyclohexane20 gradient to give the title compound as a pale yellow solid (555mg). LC-MS: Rt 3.07min, MH+ 346.
  • 6
  • [ 67-56-1 ]
  • [ 861905-94-4 ]
  • [ 861905-21-7 ]
YieldReaction ConditionsOperation in experiment
100% With sulfuric acid In water at 20 - 50℃; for 15h; 1.3 Preparation of methyl 3-fluoro-5-iodo-4-methylbenzoate; 3-Fluoro-5-iodo-4-methylbenzoic acid (1 eqv) was dissolved in methanol (6.6 vol) and treated with 98% sulphuric acid (0.375 vol) at 2O0C. The solution was heated to 50°C and stirred for 15h at this temperature then the solution cooled to 20°C.The volume of the solution was reduced to 25% of the initial volume by vacuum distillation. After cooling to 2O0C, TBME (5.5 vol) was added, followed by 8% aqueous NaHCO3 solution (9.4 vol) over 15 min to a pH of 7-8. After stirring for 10 min, the layers were separated and the aqueous layer was extracted with further TBME (5.5 vol). After stirring for 10 min, the layers were separated and the combined organic layers were stirred and washed with water (4.6 vol). After stirring for 10 min, the layers were separated and the organic layer was concentrated and dried at 45 - 500C to give the title compound. Yield: ca. 100% th.
77% With sulfuric acid at 50℃; Inert atmosphere; Large scale;
With sulfuric acid for 6h; Heating / reflux; A stirred mixture of 3-fluoro-4-methylbenzoic acid (10.3g) in trifluoromethane sulfonic acid (50ml) at -20°C was treated with N-iodosuccinimide in portions over 40min. The reaction was stirred at -10°C for 44h when a further amount of N-iodosuccinimide (6.0g) was added. After 20h the reaction mixture was added to ice/water and extracted with ethyl acetate. The organic solution was washed with aqueous sodium metabisulfite and dried over sodium sulfate. The residue was dissolved in methanol (50ml), the solution was treated with concentrated sulfuric acid (91ml) and the mixture was heated at reflux for 6h. The solvent was evaporated and the residue was dissolved in ethyl acetate. This solution was washed with aqueous sodium bicarbonate and dried with brine and over magnesium sulfate. Purification by biotage chromatography (x2), firstly using cyclohexane/ethyl acetate (100/1) and secondly cyclohexane/toluene (6/1) as eluents gave the title compound (9.31 g). LC-MS: Rt 3.55min.
  • 7
  • [ 861905-94-4 ]
  • [ 1192-21-8 ]
  • [ 861905-50-2 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 3-fluoro-5-iodo-4-methylbenzoic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 5-Amino-1-methylpyrazole In N,N-dimethyl-formamide 3; 1.ii DIPEA (9.3ml) and HATU (8.17g) were added to a solution of 3-fluoro-5-iodo-4- methylbenzoic acid (5.08g) in DMF (95ml) and the mixture stirred for 10min at room temperature. 1 -Methyl-1 H-pyrazol-5-amine (2.23g) was added to the reaction and stirring continued overnight. The solvent was evaporated from the reaction mixture in vacuo, the residue applied to an SPE cartridge (Si, 5Og) and eluted with an ethyl acetate / cyclohexane gradient (0-100% ethyl acetate), then methanol and acetone. The pure product fractions were combined, reduced to dryness in vacuo. The less pure fractions were combined, evaporated and dissolved in methanol. Pure 3-fluoro-5-iodo-4-methyl-/V- (1 -methyl-1 H-pyrazol-5-yl)benzamide remained as undissolved white solid; the solution was filtered through two SPE cartdridges (aminopropyl 10g) and cartdriges washed with methanol. The filtrate and washings were evaporated and combined the 'pure' prduct fractions and this micture recrystallised from methanol to give further amounts of 3-fluoro- 5-iodo-4-methyl-λ/-(1 -methyl-1 H-pyrazol-5-yl)benzamide The methanolic and acetone fraction from the silica SPE purification above were spartely filtered through an SPE (aminopropyl, 20and 10g), reduced to dryness in vacuo and the residue triturated with methanol to give 3-fluoro-5-iodo-4-methyl-λ/-( 1 -methyl-1 H-pyrazol-5-yl)benzamide. The second and third batches of the required compound were combined to give 3-fluoro-5- iodo-4-methyl-λ/-(1 -methyl-1 H-pyrazol-5-yl)benzamide as an off-white solid (5.16g).NMR: D6-DMSO δH 10.41 , (1 H, s), 8.28,(1 H, s), 7.78,(1 H, d), 7.39,(1 H, s), 6.23,(1 H, s), 3.69,(3H, s), 3.33,(3H, s)
Stage #1: 3-fluoro-5-iodo-4-methylbenzoic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 5-Amino-1-methylpyrazole In N,N-dimethyl-formamide 1 Intermediate 7: 3-Fluoro-5-iodo-4-methyl-λ/-(1-methyl-1H-pyrazol-5-yl)benzamide - preparation 1; DIPEA (9.3ml) and HATU (8.17g) were added to a solution of 3-fluoro-5-iodo-4- methylbenzoic acid (5.08g) in DMF (95ml) and the mixture stirred for 10min at room temperature. 2-methyl-3-aminopyrazole (2.23g) was added to the reaction and stirring continued overnight. The solvent was evaporated from the reaction mixture in vacuo, the residue applied to an SPE cartridge (Si, 5Og) and eluted with an ethyl acetate / cyclohexane gradient (0-100% ethyl acetate), then methanol and acetone. The pure product fractions were combined, reduced to dryness in vacuo The less pure fractions were combined, evaporated and dissolved in methanol. Pure 3-fluoro-5-iodo-4-methyl-/V- (1-methyl-1 H-pyrazol-5-yl)benzamide remained as undissolved white solid; the solution was filtered through two SPE cartridges (aminopropyl 10g) and cartdriges washed with methanol. The filtrate and washings were evaporated and combined the 'pure' prduct fractions and this mixture recrystallised from methanol to give further amounts of 3-fluoro- 5-iodo-4-methyl-λ/-(1-methyl-1 H-pyrazol-5-yl)benzamide The methanolic and acetone fraction from the silica SPE purification above were filtered through an SPE (aminopropyl, 2Og and 10g), reduced to dryness in vacuo and the residue triturated with methanol to give 3-fluoro-5-iodo-4-methyl-λ/-(1-methyl-1 /-/-pyrazol-5-yl)benzamide. The second and third batches of the required compound were combined to give 3-fluoro-5-iodo-4-methyl- λ/-(1-methyl-1 H-pyrazol-5-yl)benzamide as an off-white solid (5.16g).NMR: D6-DMSO δH 10.41 , (1 H, s), 8.28,(1 H, s), 7.78,(1 H, d), 7.39,(1 H, s), 6.23,(1 H, s), 3.69,(3H, s), 3.33,(3H, s).
Stage #1: 3-fluoro-5-iodo-4-methylbenzoic acid With thionyl chloride at 110℃; for 2.5h; Stage #2: 5-Amino-1-methylpyrazole With potassium carbonate In dichloromethane Intermediate 23: 3-Fluoro-5-iodo-4-methvl-N- (1-methvl-1H-pvrazol-5-vl) benzamide; 3-Fluoro-5-iodo-4-methylbenzoic acid (Intermediate 29,6. 27g) in thionyl chloride (10ml) was heated at 110°C for 2.5h. The reaction was left to cool to room temperature overnight and the excess thionyl chloride was removed under vacuum. A portion (2.18g) of the crude acid chloride in DCM (10ml) was treated with potassium carbonate (1.7g) followed by a solution of 5-amino-1-methylpyrazole (0.94g) in DCM (10mut). The mixture was stirred overnight then concentrated under vacuum. The residue was washed with water then triturated with cyclohexane to give the title compound as a cream solid (1.44g). LC-MS: Rt 3.08min, MH+ 360
  • 8
  • [ 861905-94-4 ]
  • [ 1190862-88-4 ]
YieldReaction ConditionsOperation in experiment
89% With ammonium hydroxide; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In water; N,N-dimethyl-formamide at 20℃; 9b b) 3-Fluoro-5-iodo-4-methylbenzamide N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (2.01 g, 10.49 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (1.59 g, 10.52 mmol) and 32% aqueous ammonium hydroxide solution (0.55 mL, 13.97 mmol) were sequentially added to a stirred solution of 3-fluoro-5-iodo-4-methylbenzoic acid (Intermediate 9a, 1.96 g, 7.00 mmol) in N,N'-dimethylformamide (11 mL) at room temperature. After stirring overnight, the mixture was concentrated in vacuo and then water was added to the crude. The solid that formed was filtered, washed with water, 1 M aqueous sodium hydroxide solution, 1 M aqueous hydrogen chloride solution and water, and dried in vacuo to give the title compound (1.74 g, 89%) as a white solid. LRMS (m/z): 280 (M+1)+.1H NMR (300 MHz, DMSO-d6) δ ppm 2.34 (s, 3 H) 7.56 (br. s., 1 H) 7.67 (d, J=10.44 Hz, 1 H) 8.09 (br. s., 1 H) 8.18 (s, 1 H)
89% With ammonium hydroxide; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In water; N,N-dimethyl-formamide at 20℃; 9.b b) 3-Fluoro-5-iodo-4-methylbenzamide; /V-iS-dimethylaminopropyl^/V-ethylcarbodiimide hydrochloride (2.01 g, 10.49 mmol), 1 H- benzo[d][1 ,2,3]triazol-1-ol hydrate (1.59 g, 10.52 mmol) and 32% aqueous ammonium hydroxide solution (0.55 mL, 13.97 mmol) were sequentially added to a stirred solution of 3- fluoro-5-iodo-4-methylbenzoic acid (Intermediate 9a, 1.96 g, 7.00 mmol) in Ν,Ν'- dimethylformamide (11 ml_) at room temperature. After stirring overnight, the mixture was concentrated in vacuo and then water was added to the crude. The solid that formed was filtered, washed with water, 1 M aqueous sodium hydroxide solution, 1 M aqueous hydrogen chloride solution and water, and dried in vacuo to give the title compound (1.74 g, 89%) as a white solid.LRMS (m/z): 280 (M+1)+.1 H NMR (300 MHz, DMSO-d6) δ ppm 2.34 (s, 3 H) 7.56 (br. s., 1 H) 7.67 (d, j=10.44 Hz, 1 H) 8.09 (br. s., 1 H) 8.18 (s, 1 H)
  • 9
  • [ 861905-94-4 ]
  • [ 75-04-7 ]
  • [ 861905-38-6 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 3-fluoro-5-iodo-4-methylbenzoic acid With thionyl chloride at 110℃; for 1h; Stage #2: ethylamine With potassium carbonate In tetrahydrofuran; dichloromethane at 20℃; Intermediate 4: N-Ethvl-3-fluoro-5-iodo-4-methvibenzamide; 3-Fluoro-5-iodo-4-methylbenzoic acid (Intermediate 11,20g) in thionyl chloride (20ml) was heated at 110°C for 1 h. The excess thionyl chloride was evaporated under vacuum and the residual oil was dissolved in DCM (100ml). Potassium carbonate (21g) was added to the solution followed by the slow addition of ethylamin (2M in THF, 70ml). The reaction was left at room temperature overnight, filtered and the residue was washed with ethyl acetate. The combined filtrate andwashingswerereduced todrynessundervacuumand the resulting solid was washed with ether/cyclohexane (1: 1) to give the title compound as a pale beige solid (18.5g). NMR: [8H d6-DMSO] 8.58 (1 H, b), 8.15 (1 H, s), 7.64 (1 H, d), 3.26 (2H, quin), 2.33 (3H, s), 1.11 (3H, t)
Stage #1: 3-fluoro-5-iodo-4-methylbenzoic acid With thionyl chloride at 110℃; for 1h; Stage #2: ethylamine With potassium carbonate In tetrahydrofuran; dichloromethane at 20℃; Intermediate 11 : de 3-Fluoro-5-iodo-4-methylbenzoic acid; (Intermediate 29,20g) in thionyl chloride (20mi) was heated at 110°C for 1h. The excess thionyl chloride was evaporated under vacuum and the residual oil was dissolved in DCM (100ml). Potassium carbonate (21g) was added to the solution followed by the slow addition of ethylamin (2M in THF, 70moi). The reaction was left at room temperature overnight, filtered and the residue was washed with ethyl acetate. The combined filtrate and washings were reduced to dryness under vacuum and the resulting solid was washed with ether/cyclohexane (1: 1) to give the title compound as a pale beige solid (18.5g). NMR: [5H d6-DMSO] 8.58 (1H, b), 8.15 (1H, s), 7.64 (1 H, d), 3.26 (2H, quin), 2.33 (3H, s), 1.11 (3H, t)
  • 10
  • [ 861905-94-4 ]
  • [ 765-30-0 ]
  • [ 585544-31-6 ]
YieldReaction ConditionsOperation in experiment
82% With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;
54% Stage #1: 3-fluoro-5-iodo-4-methylbenzoic acid With oxalyl dichloride In dichloromethane at 0 - 20℃; for 2h; Stage #2: Cyclopropylamine With triethylamine In dichloromethane at 0 - 20℃; for 3h; 26.b 26b) N-cvclopropyl-3-fluoro-5-iodo-4-methylbenzamideTo a suspension of 3-fluoro-5-iodo-4-methylbenzoic acid (28g, 100 mmol) in DCM (200 ml) cooled to 00C an ice bath, was slowly added oxalyl chloride (10.5ml, 1.1 equivs). The solid dissolved and the resultant solution was stirred to ambient temperature over two hours and then concentrated. DCM (200 ml) was added to the residue and the resultant solution cooled in an ice bath. A solution of cyclopropylamine (5.7g, 1 equiv) and triethylamine (20ml) in DCM (50 ml) was added at O0C. Once addition was complete, the mixture was stirred to RT over three hours and quenched by the addition of water (100 ml). Layers were separated and the organic washed with water 100ml). The aqueous was re-extracted with ethyl acetate (50 ml) and the combined organics dried (MgSO4) and concentrated. The residue was purified by flash chromatography (silica, 1 :2 EtOAc : hexanes) to afford the title compound (18g, 54%) as a pale yellow solid; mp=112-114°C.
  • 11
  • [ 861905-94-4 ]
  • [ 865-47-4 ]
  • [ 861905-85-3 ]
YieldReaction ConditionsOperation in experiment
69% Stage #1: 3-fluoro-5-iodo-4-methylbenzoic acid With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran at 0 - 20℃; for 1 - 2h; Stage #2: potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃; for 1h; 10.d 1Od) 1 ,1-dimethylethyl 3-fluoro-5-iodo-4-methylbenzoateOxalyl chloride (7.6 mL, 87.1 mmol) was added to a solution of 3-fluoro-5- iodo-4-methylbenzoic acid (20 g, 71.4 mmol) in tetrahydrofuran (100 mL) and a drop of Λ/,Λ/-dimethylformamide at 00C, and the resultant reaction mixture was allowed to warm to room temperature over 1-2 h. The excess oxalyl chloride was removed under reduced pressure, tetrahydrofuran (100 mL) was added to the residue, the resultant solution was cooled to 00C, and potassium te/t-butoxide (8.0 g, 71.3 mmol) was added. The reaction mixture was then stirred at room temperature for 1 h, the majority of the solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried (MgSO4), and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (silica, 5-20% ethyl acetate in hexane) to afford the title compound (16.6 g, 69%) as an off-white solid, m.p. 77-800C.
  • 12
  • [ 861905-94-4 ]
  • [ 1190862-92-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; ammonium hydroxide / N,N-dimethyl-formamide; water / 20 °C 2: 2 h / 120 °C 3: acetic acid; hydrazine hydrate / 2 h / 90 °C
Multi-step reaction with 3 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; ammonium hydroxide / N,N-dimethyl-formamide; water / 20 °C 2: 2 h / 120 °C / sealed tube 3: hydrazine hydrate; acetic acid / 2 h / 90 °C
  • 13
  • [ 861905-94-4 ]
  • [ 1190862-90-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; ammonium hydroxide / N,N-dimethyl-formamide; water / 20 °C 2: 2 h / 120 °C
Multi-step reaction with 2 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; ammonium hydroxide / N,N-dimethyl-formamide; water / 20 °C 2: 2 h / 120 °C / sealed tube
  • 14
  • [ 861905-94-4 ]
  • [ 585544-29-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: thionyl chloride / 2.5 h / 100 °C 2: sodium carbonate / dichloromethane / 72 h / 20 °C 3: potassium acetate / dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / N,N-dimethyl-formamide / 18 h / 110 °C
Multi-step reaction with 3 steps 1: thionyl chloride / 6 h / 80 °C 2: sodium carbonate / dichloromethane / 1 h / 0 - 20 °C 3: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 12 h / 80 °C
Multi-step reaction with 3 steps 1: thionyl chloride / 20 - 80 °C 2: sodium carbonate / dichloromethane 3: potassium acetate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 18 h
Multi-step reaction with 2 steps 1: thionyl chloride / 2 h / 80 °C 2: potassium acetate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 18 h
Multi-step reaction with 3 steps 1: thionyl chloride / 2.5 h / 100 °C 2: sodium carbonate / dichloromethane / 72 h / 20 °C 3: potassium acetate / dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / N,N-dimethyl-formamide / 18 h / 110 °C
Multi-step reaction with 2 steps 1.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 3 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide / 4 h / 90 °C
Multi-step reaction with 2 steps 1: benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C 2: potassium acetate; palladium bis[bis(diphenylphosphino)ferrocene] dichloride / N,N-dimethyl-formamide / 90 °C

  • 15
  • [ 861905-94-4 ]
  • N-cyclopropyl-3-fluoro-4-methyl-5-(3-oxo-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-7-yl)benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: thionyl chloride / 2.5 h / 100 °C 2: sodium carbonate / dichloromethane / 72 h / 20 °C 3: potassium acetate / dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / N,N-dimethyl-formamide / 18 h / 110 °C 4: caesium carbonate / dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane; water / 17 h / 90 °C / Inert atmosphere
  • 16
  • [ 861905-94-4 ]
  • 3-[2-(2-Chlorophenyl)-3-oxo-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-7-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: thionyl chloride / 2.5 h / 100 °C 2: sodium carbonate / dichloromethane / 72 h / 20 °C 3: potassium acetate / dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / N,N-dimethyl-formamide / 18 h / 110 °C 4: caesium carbonate / dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane; water / 17 h / 90 °C / Inert atmosphere 5: potassium carbonate / copper(l) iodide; trans-N,N'-dimethyl-1,2-cyclohexyldiamine / dimethyl sulfoxide / 6 h / 160 °C / Inert atmosphere; microwave irradiation
  • 17
  • [ 861905-94-4 ]
  • [ 73183-34-3 ]
  • 3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
70.5% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In N,N-dimethyl-formamide at 100℃; for 18h; 1 Preparation of 3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid(compound II-c) Compound II-a(14.0g, 50.0mmol) and 15 bis(pinacolato)diboron(19.0g, 75.0mmol) were suspended in 300mL 16 DMF, 17 potassium acetate(14.7g, 150mmol) and Pd(dppf)Cl2(3.65g, 5.0mmol) were added respectively and reacted at 100°C for 18 hours. After completion of the reaction, the resulting substance was cooled to room temperature and filtered, 500mL 11 water was added thereinto, 18 ethyl acetate (300mL×3) was added to extract. The organic phase was combined, washed with IN diluted 19 hydrochloric acid (200mL×2) and concentrated under reduced pressure to dryness. The residue was recrystallized with 100mL 20 isopropyl ether to give a white 21 solid (9.87g, yield: 70.5%), which is compound II-c.
  • 18
  • [ 861905-94-4 ]
  • 6-(5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl)-N-butyl-N-methylpyridazin-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: thionyl chloride / 6 h / 80 °C 2: sodium carbonate / dichloromethane / 1 h / 0 - 20 °C 3: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 12 h / 80 °C 4: sodium hydrogencarbonate; tetrakis(triphenylphosphine) palladium(0) / isopropyl alcohol / 10 h / 90 °C
  • 19
  • [ 861905-94-4 ]
  • 6-(5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl)-N-isobutylpyridazin-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: thionyl chloride / 6 h / 80 °C 2: sodium carbonate / dichloromethane / 1 h / 0 - 20 °C 3: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 12 h / 80 °C 4: sodium hydrogencarbonate; tetrakis(triphenylphosphine) palladium(0) / isopropyl alcohol / 10 h / 90 °C
  • 20
  • [ 861905-94-4 ]
  • N-(azetidin-3-yl)-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 18 h / 100 °C 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / dichloromethane / 0.5 h / 20 °C 2.2: 8 h / 20 °C 3.1: palladium 10% on activated carbon; hydrogen / methanol / 5 h / 20 °C
  • 21
  • [ 861905-94-4 ]
  • 3-fluoro-N-(2-hydroxyethyl)-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 18 h / 100 °C 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / dichloromethane / 0.5 h / 20 °C 2.2: 8 h / 20 °C
  • 22
  • [ 861905-94-4 ]
  • N-allyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 18 h / 100 °C 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / dichloromethane / 0.5 h / 20 °C 2.2: 8 h / 20 °C
  • 23
  • [ 861905-94-4 ]
  • N-(1-benzylazetidin-3-yl)-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 18 h / 100 °C 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / dichloromethane / 0.5 h / 20 °C 2.2: 8 h / 20 °C
  • 24
  • [ 861905-94-4 ]
  • Losmapimod [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: thionyl chloride / 6 h / 80 °C 2: sodium carbonate / dichloromethane / 1 h / 0 - 20 °C 3: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 12 h / 80 °C 4: sodium hydrogencarbonate; tetrakis(triphenylphosphine) palladium(0) / isopropyl alcohol / 10 h / 90 °C
  • 25
  • [ 861905-94-4 ]
  • N-cyclopropyl-3-(8-(2,6-difluorophenyl)-2-[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-5-fluoro-4-methylbenzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: thionyl chloride / 20 - 80 °C 2: sodium carbonate / dichloromethane 3: potassium acetate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 18 h 4: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 3 h / 100 °C
Multi-step reaction with 3 steps 1: thionyl chloride / 2 h / 80 °C 2: potassium acetate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 18 h 3: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 3 h / 100 °C
  • 26
  • [ 861905-94-4 ]
  • N-cyclopropyl-3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: thionyl chloride / 2 h / 80 °C 2: potassium acetate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 18 h 3: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 4 h / Heating / reflux
  • 27
  • [ 861905-94-4 ]
  • 2'-amino-N3-cyclopropyl-N4'-(2,2-dimethylpropyl)-5-fluoro-6-methyl-3,4'-biphenyldicarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 3 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide / 4 h / 90 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 0.5 h / 150 °C / Irradiation
  • 28
  • [ 861905-94-4 ]
  • [ 913002-80-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 3 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide / 4 h / 90 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 7 h / 90 °C 4.1: sodium chlorite; potassium dihydrogenphosphate; dihydrogen peroxide; sodium sulfite / water; acetonitrile / 0.5 h / 0 - 20 °C 5.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 48 h / 20 °C 6.1: lithium hydroxide; water / tetrahydrofuran / 18 h / 20 °C
  • 29
  • [ 861905-94-4 ]
  • N4-(2,2-dimethylpropyl)-5'-fluoro-N3'-(2-hydroxyethyl)-6'-methyl-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 1.67 h / -10 - 0 °C 2.2: 0.08 h / 0 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 0.25 h / 150 °C / Irradiation 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: chloroformic acid ethyl ester; triethylamine / tetrahydrofuran / 0.25 h / 0 °C 5.2: 1 h / 0 °C 6.1: triethylsilane; trifluoroacetic acid / dichloromethane / -20 - 20 °C 7.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 20 °C
Multi-step reaction with 7 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 16 h / Heating / reflux 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: chloroformic acid ethyl ester; triethylamine / tetrahydrofuran / 0.25 h / 0 °C 5.2: 1 h / 0 °C 6.1: triethylsilane; trifluoroacetic acid / dichloromethane / -20 - 20 °C 7.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 20 °C
  • 30
  • [ 861905-94-4 ]
  • N3'-cyclopropyl-5'-fluoro-N4,6'-dimethyl-N2-1,3-thiazol-2-yl-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 3 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide / 4 h / 90 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 7 h / 90 °C 4.1: sodium chlorite; potassium dihydrogenphosphate; dihydrogen peroxide; sodium sulfite / water; acetonitrile / 0.5 h / 0 - 20 °C 5.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 48 h / 20 °C 6.1: lithium hydroxide; water / tetrahydrofuran / 18 h / 20 °C 7.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 120 h / 20 °C
  • 31
  • [ 861905-94-4 ]
  • N4-(2,2-dimethylpropyl)-5'-fluoro-6'-methyl-N3'-3-pyridinyl-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 1.67 h / -10 - 0 °C 2.2: 0.08 h / 0 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 0.25 h / 150 °C / Irradiation 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: chloroformic acid ethyl ester; triethylamine / tetrahydrofuran / 0.25 h / 0 °C 5.2: 1 h / 0 °C 6.1: triethylsilane; trifluoroacetic acid / dichloromethane / -20 - 20 °C 7.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 20 °C
Multi-step reaction with 7 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 16 h / Heating / reflux 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: chloroformic acid ethyl ester; triethylamine / tetrahydrofuran / 0.25 h / 0 °C 5.2: 1 h / 0 °C 6.1: triethylsilane; trifluoroacetic acid / dichloromethane / -20 - 20 °C 7.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 20 °C
  • 32
  • [ 861905-94-4 ]
  • N4-(2,2-dimethylpropyl)-5'-fluoro-N3'-[(2S)-2-hydroxypropyl]-6'-methyl-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 1.67 h / -10 - 0 °C 2.2: 0.08 h / 0 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 0.25 h / 150 °C / Irradiation 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: chloroformic acid ethyl ester; triethylamine / tetrahydrofuran / 0.25 h / 0 °C 5.2: 1 h / 0 °C 6.1: triethylsilane; trifluoroacetic acid / dichloromethane / -20 - 20 °C 7.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 20 °C
Multi-step reaction with 7 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 16 h / Heating / reflux 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: chloroformic acid ethyl ester; triethylamine / tetrahydrofuran / 0.25 h / 0 °C 5.2: 1 h / 0 °C 6.1: triethylsilane; trifluoroacetic acid / dichloromethane / -20 - 20 °C 7.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 20 °C
  • 33
  • [ 861905-94-4 ]
  • N4-(2,2-dimethylpropyl)-5'-fluoro-N3'-[(2R)-2-hydroxypropyl]-6'-methyl-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 1.67 h / -10 - 0 °C 2.2: 0.08 h / 0 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 0.25 h / 150 °C / Irradiation 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: chloroformic acid ethyl ester; triethylamine / tetrahydrofuran / 0.25 h / 0 °C 5.2: 1 h / 0 °C 6.1: triethylsilane; trifluoroacetic acid / dichloromethane / -20 - 20 °C 7.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 20 °C
Multi-step reaction with 7 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 16 h / Heating / reflux 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: chloroformic acid ethyl ester; triethylamine / tetrahydrofuran / 0.25 h / 0 °C 5.2: 1 h / 0 °C 6.1: triethylsilane; trifluoroacetic acid / dichloromethane / -20 - 20 °C 7.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 20 °C
  • 34
  • [ 861905-94-4 ]
  • N4-(2,2-dimethylpropyl)-5'-fluoro-N3'-[(1R)-2-hydroxy-1-methylethyl]-6'-methyl-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 1.67 h / -10 - 0 °C 2.2: 0.08 h / 0 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 0.25 h / 150 °C / Irradiation 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: chloroformic acid ethyl ester; triethylamine / tetrahydrofuran / 0.25 h / 0 °C 5.2: 1 h / 0 °C 6.1: triethylsilane; trifluoroacetic acid / dichloromethane / -20 - 20 °C 7.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 20 °C
Multi-step reaction with 7 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 16 h / Heating / reflux 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: chloroformic acid ethyl ester; triethylamine / tetrahydrofuran / 0.25 h / 0 °C 5.2: 1 h / 0 °C 6.1: triethylsilane; trifluoroacetic acid / dichloromethane / -20 - 20 °C 7.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 20 °C
  • 35
  • [ 861905-94-4 ]
  • N4-(2,2-dimethylpropyl)-5'-fluoro-N3'-[(1S)-2-hydroxy-1-methylethyl]-6'-methyl-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 1.67 h / -10 - 0 °C 2.2: 0.08 h / 0 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 0.25 h / 150 °C / Irradiation 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: chloroformic acid ethyl ester; triethylamine / tetrahydrofuran / 0.25 h / 0 °C 5.2: 1 h / 0 °C 6.1: triethylsilane; trifluoroacetic acid / dichloromethane / -20 - 20 °C 7.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 20 °C
Multi-step reaction with 7 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 16 h / Heating / reflux 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: chloroformic acid ethyl ester; triethylamine / tetrahydrofuran / 0.25 h / 0 °C 5.2: 1 h / 0 °C 6.1: triethylsilane; trifluoroacetic acid / dichloromethane / -20 - 20 °C 7.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 20 °C
  • 36
  • [ 861905-94-4 ]
  • N4-(2,2-dimethylpropyl)-5'-fluoro-N3'-(3-hydroxypropyl)-6'-methyl-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 1.67 h / -10 - 0 °C 2.2: 0.08 h / 0 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 0.25 h / 150 °C / Irradiation 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: chloroformic acid ethyl ester; triethylamine / tetrahydrofuran / 0.25 h / 0 °C 5.2: 1 h / 0 °C 6.1: triethylsilane; trifluoroacetic acid / dichloromethane / -20 - 20 °C 7.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 20 °C
Multi-step reaction with 7 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 16 h / Heating / reflux 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: chloroformic acid ethyl ester; triethylamine / tetrahydrofuran / 0.25 h / 0 °C 5.2: 1 h / 0 °C 6.1: triethylsilane; trifluoroacetic acid / dichloromethane / -20 - 20 °C 7.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 20 °C
  • 37
  • [ 861905-94-4 ]
  • N3'-cyclopropyl-5'-fluoro-6'-methyl-N4-(2-methylpropyl)-N2-1,3-thiazol-2-yl-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 3 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide / 4 h / 90 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 7 h / 90 °C 4.1: sodium chlorite; potassium dihydrogenphosphate; dihydrogen peroxide; sodium sulfite / water; acetonitrile / 0.5 h / 0 - 20 °C 5.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 48 h / 20 °C 6.1: lithium hydroxide; water / tetrahydrofuran / 18 h / 20 °C 7.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 120 h / 20 °C
  • 38
  • [ 861905-94-4 ]
  • N3'-cyclopropyl-5'-fluoro-6'-methyl-N4-phenyl-N2-1,3-thiazol-2-yl-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 3 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide / 4 h / 90 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 7 h / 90 °C 4.1: sodium chlorite; potassium dihydrogenphosphate; dihydrogen peroxide; sodium sulfite / water; acetonitrile / 0.5 h / 0 - 20 °C 5.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 48 h / 20 °C 6.1: lithium hydroxide; water / tetrahydrofuran / 18 h / 20 °C 7.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 18 h / 20 °C
  • 39
  • [ 861905-94-4 ]
  • N3'-cyclopropyl-N4,N4-diethyl-5'-fluoro-6'-methyl-N2-1,3-thiazol-2-yl-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 3 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide / 4 h / 90 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 7 h / 90 °C 4.1: sodium chlorite; potassium dihydrogenphosphate; dihydrogen peroxide; sodium sulfite / water; acetonitrile / 0.5 h / 0 - 20 °C 5.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 48 h / 20 °C 6.1: lithium hydroxide; water / tetrahydrofuran / 18 h / 20 °C 7.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 16 h / 20 °C
  • 40
  • [ 861905-94-4 ]
  • N3'-cyclopropyl-N4-[(1R)-1,2-dimethylpropyl]-5'-fluoro-6'-methyl-N2-1,3-thiazol-2-yl-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 3 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide / 4 h / 90 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 7 h / 90 °C 4.1: sodium chlorite; potassium dihydrogenphosphate; dihydrogen peroxide; sodium sulfite / water; acetonitrile / 0.5 h / 0 - 20 °C 5.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 48 h / 20 °C 6.1: lithium hydroxide; water / tetrahydrofuran / 18 h / 20 °C 7.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 120 h / 20 °C
  • 41
  • [ 861905-94-4 ]
  • N3'-cyclopropyl-N4-[(1S)-1,2-dimethylpropyl]-5'-fluoro-6'-methyl-N2-1,3-thiazol-2-yl-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 3 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide / 4 h / 90 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 7 h / 90 °C 4.1: sodium chlorite; potassium dihydrogenphosphate; dihydrogen peroxide; sodium sulfite / water; acetonitrile / 0.5 h / 0 - 20 °C 5.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 48 h / 20 °C 6.1: lithium hydroxide; water / tetrahydrofuran / 18 h / 20 °C 7.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 120 h / 20 °C
  • 42
  • [ 861905-94-4 ]
  • N3'-cyclopropyl-5'-fluoro-6'-methyl-N4-1,2,4-thiadiazol-5-yl-N2-1,3-thiazol-2-yl-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 3 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide / 4 h / 90 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 7 h / 90 °C 4.1: sodium chlorite; potassium dihydrogenphosphate; dihydrogen peroxide; sodium sulfite / water; acetonitrile / 0.5 h / 0 - 20 °C 5.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 48 h / 20 °C 6.1: lithium hydroxide; water / tetrahydrofuran / 18 h / 20 °C 7.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 336 h / 20 °C
  • 43
  • [ 861905-94-4 ]
  • N3'-cyclopropyl-N4-(1-ethylpropyl)-5'-fluoro-6'-methyl-N2-1,3-thiazol-2-yl-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 3 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide / 4 h / 90 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 7 h / 90 °C 4.1: sodium chlorite; potassium dihydrogenphosphate; dihydrogen peroxide; sodium sulfite / water; acetonitrile / 0.5 h / 0 - 20 °C 5.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 48 h / 20 °C 6.1: lithium hydroxide; water / tetrahydrofuran / 18 h / 20 °C 7.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 120 h / 20 °C
  • 44
  • [ 861905-94-4 ]
  • N3'-cyclopropyl-5'-fluoro-6'-methyl-N2,N4-di-1,3-thiazol-2-yl-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 3 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide / 4 h / 90 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 7 h / 90 °C 4.1: sodium chlorite; potassium dihydrogenphosphate; dihydrogen peroxide; sodium sulfite / water; acetonitrile / 0.5 h / 0 - 20 °C 5.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 48 h / 20 °C 6.1: lithium hydroxide; water / tetrahydrofuran / 18 h / 20 °C 7.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 16 h / 20 °C
  • 45
  • [ 861905-94-4 ]
  • N3'-cyclopropyl-N4-(cyclopropylmethyl)-5'-fluoro-6'-methyl-N2-1,3-thiazol-2-yl-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 3 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide / 4 h / 90 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 7 h / 90 °C 4.1: sodium chlorite; potassium dihydrogenphosphate; dihydrogen peroxide; sodium sulfite / water; acetonitrile / 0.5 h / 0 - 20 °C 5.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 48 h / 20 °C 6.1: lithium hydroxide; water / tetrahydrofuran / 18 h / 20 °C 7.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 120 h / 20 °C
  • 46
  • [ 861905-94-4 ]
  • N3'-cyclopropyl-5'-fluoro-6'-methyl-N2-1,3-thiazol-2-yl-N4-[(1R)-1,2,2-trimethylpropyl]-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 3 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide / 4 h / 90 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 7 h / 90 °C 4.1: sodium chlorite; potassium dihydrogenphosphate; dihydrogen peroxide; sodium sulfite / water; acetonitrile / 0.5 h / 0 - 20 °C 5.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 48 h / 20 °C 6.1: lithium hydroxide; water / tetrahydrofuran / 18 h / 20 °C 7.1: 6-chloro-3-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazol-3-ium-1-olatehexafluorophosphate(V); triethylamine / dichloromethane / 144 h / 20 °C
  • 47
  • [ 861905-94-4 ]
  • N3'-cyclopropyl-5'-fluoro-6'-methyl-N2-1,3-thiazol-2-yl-N4-[(1S)-1,2,2-trimethylpropyl]-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 3 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide / 4 h / 90 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 7 h / 90 °C 4.1: sodium chlorite; potassium dihydrogenphosphate; dihydrogen peroxide; sodium sulfite / water; acetonitrile / 0.5 h / 0 - 20 °C 5.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 48 h / 20 °C 6.1: lithium hydroxide; water / tetrahydrofuran / 18 h / 20 °C 7.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 18 h / 20 °C
  • 48
  • [ 861905-94-4 ]
  • N4-(2,2-dimethylpropyl)-5'-fluoro-6'-methyl-N3'-phenyl-N2-1,3-thiazol-2-yl-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 1.67 h / -10 - 0 °C 2.2: 0.08 h / 0 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 0.25 h / 150 °C / Irradiation 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 16.08 h / 20 °C 6.1: hydrogenchloride / 1,4-dioxane; water / 0.5 h / Heating / reflux 7.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 72 h / 20 °C
Multi-step reaction with 7 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 16 h / Heating / reflux 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 16.08 h / 20 °C 6.1: hydrogenchloride / 1,4-dioxane; water / 0.5 h / Heating / reflux 7.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 72 h / 20 °C
  • 49
  • [ 861905-94-4 ]
  • N4-(2,2-dimethylpropyl)-5'-fluoro-N3'-[(4-fluorophenyl)methyl]-6'-methyl-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 1.67 h / -10 - 0 °C 2.2: 0.08 h / 0 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 0.25 h / 150 °C / Irradiation 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: chloroformic acid ethyl ester; triethylamine / tetrahydrofuran / 0.25 h / 0 °C 5.2: 1 h / 0 °C 6.1: triethylsilane; trifluoroacetic acid / dichloromethane / -20 - 20 °C 7.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 20 °C
Multi-step reaction with 7 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 16 h / Heating / reflux 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: chloroformic acid ethyl ester; triethylamine / tetrahydrofuran / 0.25 h / 0 °C 5.2: 1 h / 0 °C 6.1: triethylsilane; trifluoroacetic acid / dichloromethane / -20 - 20 °C 7.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 20 °C
  • 50
  • [ 861905-94-4 ]
  • N4-(2,2-dimethylpropyl)-5'-fluoro-6'-methyl-N2,N3'-di-1,3-thiazol-2-yl-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 1.67 h / -10 - 0 °C 2.2: 0.08 h / 0 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 0.25 h / 150 °C / Irradiation 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 16.08 h / 20 °C 6.1: hydrogenchloride / 1,4-dioxane; water / 0.5 h / Heating / reflux 7.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 72 h / 20 °C
Multi-step reaction with 7 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 16 h / Heating / reflux 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 16.08 h / 20 °C 6.1: hydrogenchloride / 1,4-dioxane; water / 0.5 h / Heating / reflux 7.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 72 h / 20 °C
  • 51
  • [ 861905-94-4 ]
  • N3'-cyclopropyl-5'-fluoro-6'-methyl-N4-1H-pyrazol-5-yl-N2-1,3-thiazol-2-yl-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 3 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide / 4 h / 90 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 7 h / 90 °C 4.1: sodium chlorite; potassium dihydrogenphosphate; dihydrogen peroxide; sodium sulfite / water; acetonitrile / 0.5 h / 0 - 20 °C 5.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 48 h / 20 °C 6.1: lithium hydroxide; water / tetrahydrofuran / 18 h / 20 °C 7.1: 6-chloro-3-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazol-3-ium-1-olatehexafluorophosphate(V); triethylamine / dichloromethane / 144 h / 20 °C
  • 52
  • [ 861905-94-4 ]
  • N3'-cyclopropyl-5'-fluoro-6'-methyl-N4-(3-methylbutyl)-N2-1,3-thiazol-2-yl-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 3 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide / 4 h / 90 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 7 h / 90 °C 4.1: sodium chlorite; potassium dihydrogenphosphate; dihydrogen peroxide; sodium sulfite / water; acetonitrile / 0.5 h / 0 - 20 °C 5.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 48 h / 20 °C 6.1: lithium hydroxide; water / tetrahydrofuran / 18 h / 20 °C 7.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 120 h / 20 °C
  • 53
  • [ 861905-94-4 ]
  • N3'-cyclopropyl-5'-fluoro-6'-methyl-N4-(phenylmethyl)-N2-1,3-thiazol-2-yl-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 3 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide / 4 h / 90 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 7 h / 90 °C 4.1: sodium chlorite; potassium dihydrogenphosphate; dihydrogen peroxide; sodium sulfite / water; acetonitrile / 0.5 h / 0 - 20 °C 5.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 48 h / 20 °C 6.1: lithium hydroxide; water / tetrahydrofuran / 18 h / 20 °C 7.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 336 h / 20 °C
  • 54
  • [ 861905-94-4 ]
  • N3'-cyclopropyl-5'-fluoro-6'-methyl-N2-1,3-thiazol-2-yl-N4-(2,2,2-trifluoroethyl)-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 3 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide / 4 h / 90 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 7 h / 90 °C 4.1: sodium chlorite; potassium dihydrogenphosphate; dihydrogen peroxide; sodium sulfite / water; acetonitrile / 0.5 h / 0 - 20 °C 5.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 48 h / 20 °C 6.1: lithium hydroxide; water / tetrahydrofuran / 18 h / 20 °C 7.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 120 h / 20 °C
  • 55
  • [ 861905-94-4 ]
  • N4-(2,2-dimethylpropyl)-5'-fluoro-6'-methyl-N2-1,3-thiazol-2-yl-N3'-[(1R)-1,2,2-trimethylpropyl]-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 1.67 h / -10 - 0 °C 2.2: 0.08 h / 0 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 0.25 h / 150 °C / Irradiation 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 16.08 h / 20 °C 6.1: hydrogenchloride / 1,4-dioxane; water / 0.5 h / Heating / reflux 7.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 16 h / 20 °C
Multi-step reaction with 7 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 16 h / Heating / reflux 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 16.08 h / 20 °C 6.1: hydrogenchloride / 1,4-dioxane; water / 0.5 h / Heating / reflux 7.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 16 h / 20 °C
  • 56
  • [ 861905-94-4 ]
  • N4-(2,2-dimethylpropyl)-5'-fluoro-6'-methyl-N2-1,3-thiazol-2-yl-N3'-[(1S)-1,2,2-trimethylpropyl]-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 1.67 h / -10 - 0 °C 2.2: 0.08 h / 0 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 0.25 h / 150 °C / Irradiation 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 16.08 h / 20 °C 6.1: hydrogenchloride / 1,4-dioxane; water / 0.5 h / Heating / reflux 7.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 16 h / 20 °C
Multi-step reaction with 7 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 16 h / Heating / reflux 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 16.08 h / 20 °C 6.1: hydrogenchloride / 1,4-dioxane; water / 0.5 h / Heating / reflux 7.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 16 h / 20 °C
  • 57
  • [ 861905-94-4 ]
  • N3'-cyclopropyl-5'-fluoro-6'-methyl-4-[(4-methyl-1-piperazinyl)carbonyl]-N2-1,3-thiazol-2-yl-2,3'-biphenyldicarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 3 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide / 4 h / 90 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 7 h / 90 °C 4.1: sodium chlorite; potassium dihydrogenphosphate; dihydrogen peroxide; sodium sulfite / water; acetonitrile / 0.5 h / 0 - 20 °C 5.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 48 h / 20 °C 6.1: lithium hydroxide; water / tetrahydrofuran / 18 h / 20 °C 7.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 32 h / 20 °C
  • 58
  • [ 861905-94-4 ]
  • N4-cyclohexyl-N3'-cyclopropyl-5'-fluoro-6'-methyl-N2-1,3-thiazol-2-yl-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 3 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide / 4 h / 90 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 7 h / 90 °C 4.1: sodium chlorite; potassium dihydrogenphosphate; dihydrogen peroxide; sodium sulfite / water; acetonitrile / 0.5 h / 0 - 20 °C 5.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 48 h / 20 °C 6.1: lithium hydroxide; water / tetrahydrofuran / 18 h / 20 °C 7.1: 6-chloro-3-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazol-3-ium-1-olatehexafluorophosphate(V); N-ethyl-N,N-diisopropylamine / dichloromethane / 72 h / 20 °C
  • 59
  • [ 861905-94-4 ]
  • N3'-cyclopropyl-N4-(3,5-dimethyl-1H-pyrazol-4-yl)-5'-fluoro-6'-methyl-N2-1,3-thiazol-2-yl-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 3 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide / 4 h / 90 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 7 h / 90 °C 4.1: sodium chlorite; potassium dihydrogenphosphate; dihydrogen peroxide; sodium sulfite / water; acetonitrile / 0.5 h / 0 - 20 °C 5.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 48 h / 20 °C 6.1: lithium hydroxide; water / tetrahydrofuran / 18 h / 20 °C 7.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 336 h / 20 °C
  • 60
  • [ 861905-94-4 ]
  • N3'-cyclohexyl-N4-(2,2-dimethylpropyl)-5'-fluoro-6'-methyl-N2-1,3-thiazol-2-yl-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 1.67 h / -10 - 0 °C 2.2: 0.08 h / 0 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 0.25 h / 150 °C / Irradiation 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 16.08 h / 20 °C 6.1: hydrogenchloride / 1,4-dioxane; water / 0.5 h / Heating / reflux 7.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 72 h / 20 °C
Multi-step reaction with 7 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 16 h / Heating / reflux 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 16.08 h / 20 °C 6.1: hydrogenchloride / 1,4-dioxane; water / 0.5 h / Heating / reflux 7.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 72 h / 20 °C
  • 61
  • [ 861905-94-4 ]
  • N3'-cyclopropyl-N4-[(3,4-dimethylphenyl)methyl]-5'-fluoro-6'-methyl-N2-1,3-thiazol-2-yl-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 3 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide / 4 h / 90 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 7 h / 90 °C 4.1: sodium chlorite; potassium dihydrogenphosphate; dihydrogen peroxide; sodium sulfite / water; acetonitrile / 0.5 h / 0 - 20 °C 5.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 48 h / 20 °C 6.1: lithium hydroxide; water / tetrahydrofuran / 18 h / 20 °C 7.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 120 h / 20 °C
  • 62
  • [ 861905-94-4 ]
  • N4-(cyclohexylmethyl)-N3'-cyclopropyl-5'-fluoro-6'-methyl-N2-1,3-thiazol-2-yl-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 3 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide / 4 h / 90 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 7 h / 90 °C 4.1: sodium chlorite; potassium dihydrogenphosphate; dihydrogen peroxide; sodium sulfite / water; acetonitrile / 0.5 h / 0 - 20 °C 5.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 48 h / 20 °C 6.1: lithium hydroxide; water / tetrahydrofuran / 18 h / 20 °C 7.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 120 h / 20 °C
  • 63
  • [ 861905-94-4 ]
  • N3'-cyclopropyl-5'-fluoro-6'-methyl-N4-[2-(1-pyrrolidinyl)ethyl]-N2-1,3-thiazol-2-yl-2,3',4-biphenyltricarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 3 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide / 4 h / 90 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 7 h / 90 °C 4.1: sodium chlorite; potassium dihydrogenphosphate; dihydrogen peroxide; sodium sulfite / water; acetonitrile / 0.5 h / 0 - 20 °C 5.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 48 h / 20 °C 6.1: lithium hydroxide; water / tetrahydrofuran / 18 h / 20 °C 7.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 336 h / 20 °C
  • 64
  • [ 861905-94-4 ]
  • [ 911370-56-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide
  • 65
  • [ 861905-94-4 ]
  • [ 913002-77-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 3 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide / 4 h / 90 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 7 h / 90 °C
  • 66
  • [ 861905-94-4 ]
  • [ 913002-78-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 3 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide / 4 h / 90 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 7 h / 90 °C 4.1: sodium chlorite; potassium dihydrogenphosphate; dihydrogen peroxide; sodium sulfite / water; acetonitrile / 0.5 h / 0 - 20 °C
  • 67
  • [ 861905-94-4 ]
  • [ 913002-82-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 1.67 h / -10 - 0 °C 2.2: 0.08 h / 0 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 0.25 h / 150 °C / Irradiation 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: chloroformic acid ethyl ester; triethylamine / tetrahydrofuran / 0.25 h / 0 °C 5.2: 1 h / 0 °C 6.1: triethylsilane; trifluoroacetic acid / dichloromethane / -20 - 20 °C
Multi-step reaction with 6 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 16 h / Heating / reflux 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: chloroformic acid ethyl ester; triethylamine / tetrahydrofuran / 0.25 h / 0 °C 5.2: 1 h / 0 °C 6.1: triethylsilane; trifluoroacetic acid / dichloromethane / -20 - 20 °C
  • 68
  • [ 861905-94-4 ]
  • [ 913002-72-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 1.67 h / -10 - 0 °C 2.2: 0.08 h / 0 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 0.25 h / 150 °C / Irradiation
Multi-step reaction with 3 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 16 h / Heating / reflux
  • 69
  • [ 861905-94-4 ]
  • [ 913002-81-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 1.67 h / -10 - 0 °C 2.2: 0.08 h / 0 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 0.25 h / 150 °C / Irradiation 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: chloroformic acid ethyl ester; triethylamine / tetrahydrofuran / 0.25 h / 0 °C 5.2: 1 h / 0 °C
Multi-step reaction with 5 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 16 h / Heating / reflux 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: chloroformic acid ethyl ester; triethylamine / tetrahydrofuran / 0.25 h / 0 °C 5.2: 1 h / 0 °C
  • 70
  • [ 861905-94-4 ]
  • [ 913002-73-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 1.67 h / -10 - 0 °C 2.2: 0.08 h / 0 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 0.25 h / 150 °C / Irradiation 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation
Multi-step reaction with 4 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 16 h / Heating / reflux 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation
  • 71
  • [ 861905-94-4 ]
  • [ 913002-79-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 3 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide / 4 h / 90 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 7 h / 90 °C 4.1: sodium chlorite; potassium dihydrogenphosphate; dihydrogen peroxide; sodium sulfite / water; acetonitrile / 0.5 h / 0 - 20 °C 5.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 48 h / 20 °C
  • 72
  • [ 861905-94-4 ]
  • [ 913002-75-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 1.67 h / -10 - 0 °C 2.2: 0.08 h / 0 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 0.25 h / 150 °C / Irradiation 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 16.08 h / 20 °C 6.1: hydrogenchloride / 1,4-dioxane; water / 0.5 h / Heating / reflux
Multi-step reaction with 6 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 16 h / Heating / reflux 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 16.08 h / 20 °C 6.1: hydrogenchloride / 1,4-dioxane; water / 0.5 h / Heating / reflux
  • 73
  • [ 861905-94-4 ]
  • [ 913002-74-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 1.67 h / -10 - 0 °C 2.2: 0.08 h / 0 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 0.25 h / 150 °C / Irradiation 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 16.08 h / 20 °C
Multi-step reaction with 5 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 1 - 2 h / 0 - 20 °C 1.2: 1 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 16 h / Heating / reflux 4.1: methanol; potassium hydroxide; water / 0.17 h / 80 °C / Irradiation 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 16.08 h / 20 °C
  • 74
  • [ 861905-94-4 ]
  • [ 913002-18-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 3 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide / 4 h / 90 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 7 h / 90 °C 4.1: sodium chlorite; potassium dihydrogenphosphate; dihydrogen peroxide; sodium sulfite / water; acetonitrile / 0.5 h / 0 - 20 °C 5.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 48 h / 20 °C 6.1: lithium hydroxide; water / tetrahydrofuran / 18 h / 20 °C 7.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 120 h / 20 °C
  • 75
  • [ 861905-94-4 ]
  • [ 913002-23-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 3 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide / 4 h / 90 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 7 h / 90 °C 4.1: sodium chlorite; potassium dihydrogenphosphate; dihydrogen peroxide; sodium sulfite / water; acetonitrile / 0.5 h / 0 - 20 °C 5.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 48 h / 20 °C 6.1: lithium hydroxide; water / tetrahydrofuran / 18 h / 20 °C 7.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 336 h / 20 °C
  • 76
  • [ 861905-94-4 ]
  • [ 913002-54-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 3 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide / 4 h / 90 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 0.5 h / 150 °C / Irradiation 4.1: triethylamine / N,N-dimethyl-formamide / 20 °C
  • 77
  • [ 861905-94-4 ]
  • [ 913002-22-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 3 h / 0 - 20 °C 2.1: potassium acetate / 1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride / N,N-dimethyl-formamide / 4 h / 90 °C 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 7 h / 90 °C 4.1: sodium chlorite; potassium dihydrogenphosphate; dihydrogen peroxide; sodium sulfite / water; acetonitrile / 0.5 h / 0 - 20 °C 5.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 48 h / 20 °C 6.1: lithium hydroxide; water / tetrahydrofuran / 18 h / 20 °C 7.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 120 h / 20 °C
  • 78
  • [ 861905-94-4 ]
  • [ 911370-71-3 ]
  • 79
  • [ 861905-94-4 ]
  • [ 861905-21-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: thionyl chloride / 1.75 - 3 h / 95 °C / Heating / reflux 2: triethylamine / dichloromethane / 0 - 20 °C
  • 80
  • [ 861905-94-4 ]
  • [ 861905-22-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: sulfuric acid / water / 15 h / 20 - 50 °C 2: potassium acetate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 18 h / 80 - 85 °C
Multi-step reaction with 3 steps 1: thionyl chloride / 1.75 - 3 h / 95 °C / Heating / reflux 2: triethylamine / dichloromethane / 0 - 20 °C 3: potassium acetate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 18 h / 80 - 85 °C
  • 81
  • [ 861905-94-4 ]
  • {3-fluoro-2-methyl-5-[(methyloxy)carbonyl]phenyl}boronic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: sulfuric acid / water / 15 h / 20 - 50 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 1.42 h / -25 °C 2.2: 3.17 h / -25 - 20 °C 2.3: 1 h / 0 - 20 °C / pH < 3
Multi-step reaction with 3 steps 1.1: thionyl chloride / 1.75 - 3 h / 95 °C / Heating / reflux 2.1: triethylamine / dichloromethane / 0 - 20 °C 3.1: isopropylmagnesium chloride / tetrahydrofuran / 1.42 h / -25 °C 3.2: 3.17 h / -25 - 20 °C 3.3: 1 h / 0 - 20 °C / pH < 3
  • 82
  • [ 861905-94-4 ]
  • [ 917223-84-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: thionyl chloride / 1.75 - 3 h / 95 °C / Heating / reflux 2: dmap; N-ethyl-N,N-diisopropylamine / dichloromethane / 3.33 h / 20 °C
  • 83
  • [ 861905-94-4 ]
  • [ 917223-86-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: thionyl chloride / 1.75 - 3 h / 95 °C / Heating / reflux 2.1: dmap; N-ethyl-N,N-diisopropylamine / dichloromethane / 3.33 h / 20 °C 3.1: isopropylmagnesium chloride / tetrahydrofuran / 1.9 h / -12 - 0 °C 3.2: -10 - 20 °C 3.3: pH 1
  • 84
  • [ 861905-94-4 ]
  • [ 917223-88-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: sulfuric acid / water / 15 h / 20 - 50 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 1.42 h / -25 °C 2.2: 3.17 h / -25 - 20 °C 2.3: 1 h / 0 - 20 °C / pH < 3 3.1: sodium hydrogencarbonate / tetrakis(triphenylphosphine) palladium(0) / water; isopropyl alcohol / 18 h / 20 - 80 °C
Multi-step reaction with 3 steps 1: sulfuric acid / water / 15 h / 20 - 50 °C 2: potassium acetate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 18 h / 80 - 85 °C 3: sodium hydrogencarbonate / tetrakis(triphenylphosphine) palladium(0) / water; isopropyl alcohol / 20 - 85 °C
Multi-step reaction with 4 steps 1.1: thionyl chloride / 1.75 - 3 h / 95 °C / Heating / reflux 2.1: triethylamine / dichloromethane / 0 - 20 °C 3.1: isopropylmagnesium chloride / tetrahydrofuran / 1.42 h / -25 °C 3.2: 3.17 h / -25 - 20 °C 3.3: 1 h / 0 - 20 °C / pH < 3 4.1: sodium hydrogencarbonate / tetrakis(triphenylphosphine) palladium(0) / water; isopropyl alcohol / 18 h / 20 - 80 °C
Multi-step reaction with 4 steps 1: thionyl chloride / 1.75 - 3 h / 95 °C / Heating / reflux 2: triethylamine / dichloromethane / 0 - 20 °C 3: potassium acetate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 18 h / 80 - 85 °C 4: sodium hydrogencarbonate / tetrakis(triphenylphosphine) palladium(0) / water; isopropyl alcohol / 20 - 85 °C

  • 85
  • [ 861905-94-4 ]
  • [ 917223-81-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: sulfuric acid / water / 15 h / 20 - 50 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 1.42 h / -25 °C 2.2: 3.17 h / -25 - 20 °C 2.3: 1 h / 0 - 20 °C / pH < 3 3.1: sodium hydrogencarbonate / tetrakis(triphenylphosphine) palladium(0) / water; isopropyl alcohol / 18 h / 20 - 80 °C 4.1: methanol; sodium hydroxide; water / 20 °C 4.2: pH ~ 5
Multi-step reaction with 4 steps 1.1: sulfuric acid / water / 15 h / 20 - 50 °C 2.1: potassium acetate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 18 h / 80 - 85 °C 3.1: sodium hydrogencarbonate / tetrakis(triphenylphosphine) palladium(0) / water; isopropyl alcohol / 20 - 85 °C 4.1: methanol; sodium hydroxide; water / 20 °C 4.2: pH ~ 5
Multi-step reaction with 5 steps 1.1: thionyl chloride / 1.75 - 3 h / 95 °C / Heating / reflux 2.1: triethylamine / dichloromethane / 0 - 20 °C 3.1: isopropylmagnesium chloride / tetrahydrofuran / 1.42 h / -25 °C 3.2: 3.17 h / -25 - 20 °C 3.3: 1 h / 0 - 20 °C / pH < 3 4.1: sodium hydrogencarbonate / tetrakis(triphenylphosphine) palladium(0) / water; isopropyl alcohol / 18 h / 20 - 80 °C 5.1: methanol; sodium hydroxide; water / 20 °C 5.2: pH ~ 5
Multi-step reaction with 5 steps 1.1: thionyl chloride / 1.75 - 3 h / 95 °C / Heating / reflux 2.1: triethylamine / dichloromethane / 0 - 20 °C 3.1: potassium acetate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 18 h / 80 - 85 °C 4.1: sodium hydrogencarbonate / tetrakis(triphenylphosphine) palladium(0) / water; isopropyl alcohol / 20 - 85 °C 5.1: methanol; sodium hydroxide; water / 20 °C 5.2: pH ~ 5

  • 86
  • [ 861905-94-4 ]
  • [ 917223-75-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: thionyl chloride / 1.75 - 3 h / 95 °C / Heating / reflux 2.1: dmap; N-ethyl-N,N-diisopropylamine / dichloromethane / 3.33 h / 20 °C 3.1: isopropylmagnesium chloride / tetrahydrofuran / 1.9 h / -12 - 0 °C 3.2: -10 - 20 °C 3.3: pH 1 4.1: sodium hydrogencarbonate / tetrakis(triphenylphosphine) palladium(0) / water; isopropyl alcohol / 3 h / 80 °C
Multi-step reaction with 5 steps 1.1: sulfuric acid / water / 15 h / 20 - 50 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 1.42 h / -25 °C 2.2: 3.17 h / -25 - 20 °C 2.3: 1 h / 0 - 20 °C / pH < 3 3.1: sodium hydrogencarbonate / tetrakis(triphenylphosphine) palladium(0) / water; isopropyl alcohol / 18 h / 20 - 80 °C 4.1: methanol; sodium hydroxide; water / 20 °C 4.2: pH ~ 5 5.1: thionyl chloride / N,N-dimethyl-formamide / dichloromethane / 15.17 h / 0 - 50 °C 5.2: 17 h / 0 - 20 °C
Multi-step reaction with 5 steps 1.1: sulfuric acid / water / 15 h / 20 - 50 °C 2.1: potassium acetate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 18 h / 80 - 85 °C 3.1: sodium hydrogencarbonate / tetrakis(triphenylphosphine) palladium(0) / water; isopropyl alcohol / 20 - 85 °C 4.1: methanol; sodium hydroxide; water / 20 °C 4.2: pH ~ 5 5.1: thionyl chloride / N,N-dimethyl-formamide / dichloromethane / 15.17 h / 0 - 50 °C 5.2: 17 h / 0 - 20 °C
Multi-step reaction with 6 steps 1.1: thionyl chloride / 1.75 - 3 h / 95 °C / Heating / reflux 2.1: triethylamine / dichloromethane / 0 - 20 °C 3.1: isopropylmagnesium chloride / tetrahydrofuran / 1.42 h / -25 °C 3.2: 3.17 h / -25 - 20 °C 3.3: 1 h / 0 - 20 °C / pH < 3 4.1: sodium hydrogencarbonate / tetrakis(triphenylphosphine) palladium(0) / water; isopropyl alcohol / 18 h / 20 - 80 °C 5.1: methanol; sodium hydroxide; water / 20 °C 5.2: pH ~ 5 6.1: thionyl chloride / N,N-dimethyl-formamide / dichloromethane / 15.17 h / 0 - 50 °C 6.2: 17 h / 0 - 20 °C
Multi-step reaction with 6 steps 1.1: thionyl chloride / 1.75 - 3 h / 95 °C / Heating / reflux 2.1: triethylamine / dichloromethane / 0 - 20 °C 3.1: potassium acetate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 18 h / 80 - 85 °C 4.1: sodium hydrogencarbonate / tetrakis(triphenylphosphine) palladium(0) / water; isopropyl alcohol / 20 - 85 °C 5.1: methanol; sodium hydroxide; water / 20 °C 5.2: pH ~ 5 6.1: thionyl chloride / N,N-dimethyl-formamide / dichloromethane / 15.17 h / 0 - 50 °C 6.2: 17 h / 0 - 20 °C

  • 87
  • [ 861905-94-4 ]
  • [ 68797-27-3 ]
  • 3-[[2-(2,2-dimethoxyethylamino)-2-oxoacetyl]amino]-5-fluoro-4-methylbenzoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% With copper(l) iodide; potassium carbonate; trans-N,N'-dimethylcyclohexane-1,2-diamine In N,N-dimethyl-formamide at 50 - 110℃; for 19h; Inert atmosphere; 4.3 Step 3: 3-[[2-(2,2-Dimethoxyethylamino)-2-oxo-acetyl]amino]-5-fluoro-4-methyl-benzoic acid 3-Fluoro-5-iodo-4-methyl-benzoic acid (40 g, 141.41 mmol, 1.0 eq.),N'-(2,2-dimethoxyethyl) oxalic acid amide (30.2 g, 170 mmol, 1.2 eq.)And potassium carbonate (39.1 g, 283 mmol, 2.0 equivalents)Placed in a condenser,Nitrogen/vacuum inlet and overhead mixer in a 500 mL jacketed vessel.Add DMF (320 mL, 8 relative volumes)The mixture was stirred vigorously to keep all solids suspended.Loading trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanecarboxamide(7.04mL, 42.4mmol, 0.3 equivalents)The mixture was degassed by a needle through a subsurface.The mixture was heated to 50 ° C,Cuprous iodide (8.24 g, 42.4 mmol, 0.3 eq.) was then charged to the suspension.The mixture was stirred at 110 ° C for 19 h under a nitrogen atmosphere.It is then cooled to ambient temperature.The dark green suspension was charged with 20 ° C ethanol (80 mL, 2 rel vols) and the contents of the vessel was slowly drained to a 2 L beaker containing 1 M citric acid (640 mL, 16 rel vol).The resulting slurry was diluted with water (200 mL, 5 EtOAc) and filtered.The filter cake was washed with water (4 x 200 mL) and dried in a vacuum oven at 60 ° C overnight to give a white solid.3-[[2-(2,2-dimethoxyethylamino)-2-oxo-acetyl]ammonium5-fluoro-4-methyl-benzoic acid (36.42 g, 98.9% purity, 77% yield).
  • 88
  • [ 861905-94-4 ]
  • 3-(2,3-dioxo-1H-pyrazin-4-yl)-5-fluoro-4-methylbenzoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium carbonate; copper(l) iodide; trans-N,N'-dimethylcyclohexane-1,2-diamine / N,N-dimethyl-formamide / 19 h / 50 - 110 °C / Inert atmosphere 2: acetic acid; methanesulfonic acid / 15 h / 17 - 110 °C
  • 89
  • [ 861905-94-4 ]
  • 3-(3-bromo-2-oxopyrazine-1-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: potassium carbonate; copper(l) iodide; trans-N,N'-dimethylcyclohexane-1,2-diamine / N,N-dimethyl-formamide / 19 h / 50 - 110 °C / Inert atmosphere 2.1: acetic acid; methanesulfonic acid / 15 h / 17 - 110 °C 3.1: triethylamine; phosphorus tribromide / acetonitrile / 1.33 h / 80 °C 3.2: 0.5 h / -9 - 0 °C
  • 90
  • [ 861905-94-4 ]
  • AZD7624*HBr [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 8 steps 1.1: sulfuric acid / 50 °C / Inert atmosphere; Large scale 2.1: tris-(dibenzylideneacetone)dipalladium(0); 1,1'-bis-(diphenylphosphino)ferrocene; caesium carbonate / toluene / Reflux; Inert atmosphere; Large scale 3.1: sulfuric acid / tert-butyl methyl ether; toluene; methanol / Inert atmosphere; Large scale 4.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / Reflux; Inert atmosphere; Large scale 5.1: dichloromethane / 0.57 h / 2 °C / Inert atmosphere; Large scale 5.2: 19.25 h / 5 - 32 °C / Inert atmosphere; Large scale 6.1: N-ethyl-N,N-diisopropylamine / toluene / 3.25 h / 95 °C / Inert atmosphere; Large scale 7.1: sodium methylate / toluene; methanol / 5 h / Large scale 8.1: 5%-palladium/activated carbon; ammonium formate; formic acid / water; ethanol / 1 h / 50 °C / Large scale
  • 91
  • [ 861905-94-4 ]
  • [ 1095004-78-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 9 steps 1.1: sulfuric acid / 50 °C / Inert atmosphere; Large scale 2.1: tris-(dibenzylideneacetone)dipalladium(0); 1,1'-bis-(diphenylphosphino)ferrocene; caesium carbonate / toluene / Reflux; Inert atmosphere; Large scale 3.1: sulfuric acid / tert-butyl methyl ether; toluene; methanol / Inert atmosphere; Large scale 4.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / Reflux; Inert atmosphere; Large scale 5.1: dichloromethane / 0.57 h / 2 °C / Inert atmosphere; Large scale 5.2: 19.25 h / 5 - 32 °C / Inert atmosphere; Large scale 6.1: N-ethyl-N,N-diisopropylamine / toluene / 3.25 h / 95 °C / Inert atmosphere; Large scale 7.1: sodium methylate / toluene; methanol / 5 h / Large scale 8.1: 5%-palladium/activated carbon; ammonium formate; formic acid / water; ethanol / 1 h / 50 °C / Large scale 9.1: sodium hydroxide / water; ethyl acetate / 0.5 h / Inert atmosphere; Large scale
  • 92
  • [ 861905-94-4 ]
  • [ 1095006-00-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: sulfuric acid / 50 °C / Inert atmosphere; Large scale 2: tris-(dibenzylideneacetone)dipalladium(0); 1,1'-bis-(diphenylphosphino)ferrocene; caesium carbonate / toluene / Reflux; Inert atmosphere; Large scale 3: sulfuric acid / tert-butyl methyl ether; toluene; methanol / Inert atmosphere; Large scale 4: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / Reflux; Inert atmosphere; Large scale
  • 93
  • [ 861905-94-4 ]
  • [ 1232287-18-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: sulfuric acid / 50 °C / Inert atmosphere; Large scale 2: tris-(dibenzylideneacetone)dipalladium(0); 1,1'-bis-(diphenylphosphino)ferrocene; caesium carbonate / toluene / Reflux; Inert atmosphere; Large scale
  • 94
  • [ 861905-94-4 ]
  • [ 1232287-16-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: sulfuric acid / 50 °C / Inert atmosphere; Large scale 2: tris-(dibenzylideneacetone)dipalladium(0); 1,1'-bis-(diphenylphosphino)ferrocene; caesium carbonate / toluene / Reflux; Inert atmosphere; Large scale 3: sulfuric acid / tert-butyl methyl ether; toluene; methanol / Inert atmosphere; Large scale
  • 95
  • [ 861905-94-4 ]
  • [ 1095006-01-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: sulfuric acid / 50 °C / Inert atmosphere; Large scale 2.1: tris-(dibenzylideneacetone)dipalladium(0); 1,1'-bis-(diphenylphosphino)ferrocene; caesium carbonate / toluene / Reflux; Inert atmosphere; Large scale 3.1: sulfuric acid / tert-butyl methyl ether; toluene; methanol / Inert atmosphere; Large scale 4.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / Reflux; Inert atmosphere; Large scale 5.1: dichloromethane / 0.57 h / 2 °C / Inert atmosphere; Large scale 5.2: 19.25 h / 5 - 32 °C / Inert atmosphere; Large scale
  • 96
  • [ 861905-94-4 ]
  • [ 1232287-20-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: sulfuric acid / 50 °C / Inert atmosphere; Large scale 2.1: tris-(dibenzylideneacetone)dipalladium(0); 1,1'-bis-(diphenylphosphino)ferrocene; caesium carbonate / toluene / Reflux; Inert atmosphere; Large scale 3.1: sulfuric acid / tert-butyl methyl ether; toluene; methanol / Inert atmosphere; Large scale 4.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / Reflux; Inert atmosphere; Large scale 5.1: dichloromethane / 0.57 h / 2 °C / Inert atmosphere; Large scale 5.2: 19.25 h / 5 - 32 °C / Inert atmosphere; Large scale 6.1: N-ethyl-N,N-diisopropylamine / toluene / 3.25 h / 95 °C / Inert atmosphere; Large scale
  • 97
  • [ 861905-94-4 ]
  • [ 1232287-22-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: sulfuric acid / 50 °C / Inert atmosphere; Large scale 2.1: tris-(dibenzylideneacetone)dipalladium(0); 1,1'-bis-(diphenylphosphino)ferrocene; caesium carbonate / toluene / Reflux; Inert atmosphere; Large scale 3.1: sulfuric acid / tert-butyl methyl ether; toluene; methanol / Inert atmosphere; Large scale 4.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / Reflux; Inert atmosphere; Large scale 5.1: dichloromethane / 0.57 h / 2 °C / Inert atmosphere; Large scale 5.2: 19.25 h / 5 - 32 °C / Inert atmosphere; Large scale 6.1: N-ethyl-N,N-diisopropylamine / toluene / 3.25 h / 95 °C / Inert atmosphere; Large scale 7.1: sodium methylate / toluene; methanol / 5 h / Large scale
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