[ CAS No. 75151-82-5 ] {[proInfo.proName]}

Name: 75151-82-5|N-(3-Hydroxyphenyl)pivalamide|97%
Brand: Ambeed
SKU: A1005983
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Quality Control of [ 75151-82-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 75151-82-5 ]

Product Details of [ 75151-82-5 ]

CAS No. :	75151-82-5	MDL No. :	MFCD02673565
Formula :	C₁₁H₁₅NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ICMIOUKQLCKMHC-UHFFFAOYSA-N
M.W :	193.24	Pubchem ID :	4186956
Synonyms :

Calculated chemistry of [ 75151-82-5 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.36
Num. rotatable bonds :	3
Num. H-bond acceptors :	2.0
Num. H-bond donors :	2.0
Molar Refractivity :	56.94
TPSA :	49.33 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.97 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.93
Log Po/w (XLOGP3) :	2.13
Log Po/w (WLOGP) :	2.19
Log Po/w (MLOGP) :	1.83
Log Po/w (SILICOS-IT) :	1.63
Consensus Log Po/w :	1.94

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.5
Solubility :	0.612 mg/ml ; 0.00317 mol/l
Class :	Soluble
Log S (Ali) :	-2.8
Solubility :	0.308 mg/ml ; 0.00159 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.04
Solubility :	0.178 mg/ml ; 0.00092 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.36

Safety of [ 75151-82-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P305+P351+P338-P280	UN#:	N/A
Hazard Statements:	H317-H319	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 75151-82-5 ]

* 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.

Upstream synthesis route of [ 75151-82-5 ]
Downstream synthetic route of [ 75151-82-5 ]

[ 75151-82-5 ] Synthesis Path-Upstream 1~1

1
[ 75151-82-5 ]
[ 74-88-4 ]
[ 56619-93-3 ]

Yield	Reaction Conditions	Operation in experiment
91%	With potassium carbonate In acetone for 3 h; Heating / reflux	Synthesis of N-(3-methoxyphenyl)pivalamide Into a 1000 mL round-bottom flask, was placed a solution of N-(3-hydroxyphenyl)pivalamide (13.4 g, 69.43 mmol, 1.00 equiv) in acetone (500 mL). To this was added K₂CO₃ (28.5 g, 206.52 mmol, 3.00 equiv). To the mixture was added MeI (39.4 g, 277.46 mmol, 4.00 equiv). The resulting solution was allowed to react, with stirring, for 3 h while the temperature was maintained at reflux in a bath of oil. The reaction progress was monitored by TLC (EtOAc/PE=1:2). A filtration was performed. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. The resulting mixture was washed with hexane. A filtration was performed. This resulted in 13.9 g (91percent) of N-(3-methoxyphenyl)pivalamide as a white solid.
91%	With potassium carbonate In acetone for 3 h; Heating / reflux	Methyl iodide (277 mmol) was added to a suspension of N-(3-hydroxyphenyl)pivalamide (69.4 mmol) and potassium carbonate (207 mmol) in acetone (500 mL) and the reaction mixture was heated at reflux for 3 h. The insoluble solids were removed by filtration and the filtrate was concentrated. The residue was extracted with hexane (3 x 300 mL) and the combined extracts were concentrated to provide N-(3-methoxyphenyl)pivalamide in 91percent yield as a white solid.
91%	With potassium carbonate In acetone for 3 h; Heating / reflux	Synthesis of N-(3-methoxyphenyl)pivalamide Into a 1000 mL round-bottom flask, was placed a solution of N-(3-hydroxyphenyl)pivalamide (13.4 g, 69.43 mmol, 1.00 equiv) in acetone (500 mL). To this was added K₂CO₃ (28.5 g, 206.52 mmol, 3.00 equiv). To the mixture was added MeI (39.4 g, 277.46 mmol, 4.00 equiv). The resulting solution was allowed to react, with stirring, for 3 h while the temperature was maintained at reflux in a bath of oil. The reaction progress was monitored by TLC (EtOAc/PE=1.2). A filtration was performed. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. The resulting mixture was washed with hexane. A filtration was performed. This resulted in 13.9 g (91percent) of N-(3-methoxyphenyl)pivalamide as a white solid.

91%	With potassium carbonate In acetone for 3 h; Reflux	2. Synthesis of N-(3-methoxyphenyl)pivalamide; Methyl iodide (277 mmol) was added to a suspension of N-(3-hydroxyphenyl)pivalamide (69.4 mmol) and potassium carbonate (207 mmol) in acetone (500 mL) and the reaction mixture was heated at reflux for 3 h. The insoluble solids were removed by filtration and the filtrate was concentrated. The residue was extracted with hexane (3.x.300 mL) and the combined extracts were concentrated to provide N-(3-methoxyphenyl)pivalamide in 91percent yield as a white solid.
91%	With potassium carbonate In acetone for 3 h; Reflux	2. Synthesis of 7V-(3-methoxyphenyl)pivalamide.Methyl iodide (277 mmol) was added to a suspension of 7V-(3 -hydro xyphenyl)pivalamide (69.4 mmol) and potassium carbonate (207 mmol) in acetone (500 mL) and the reaction mixture was heated at reflux for 3 h. The insoluble solids were removed by filtration and the filtrate was concentrated. The residue was extracted with hexane (3 x 300 mL) and the combined extracts were concentrated to provide 7V-(3-methoxyphenyl)pivalamide in 91percent yield as a white solid.
91%	With potassium carbonate In acetone for 3 h; Reflux	Methyl iodide (277 mmol) was added to a suspension of N-(3-hydroxyphenyl)pivalamide (69.4 mmol) and potassium carbonate (207 mmol) in acetone (500 mL) and the reaction mixture was heated at reflux for 3 h. The insoluble solids were removed by filtration and the filtrate was concentrated. The residue was extracted with hexane (3.x.300 mL) and the combined extracts were concentrated to provide N-(3-methoxyphenyl)pivalamide in 91percent yield as a white solid
91%	With potassium carbonate In acetone for 3 h; Reflux	2. Synthesis of 7V-(3-methoxyphenyl)pivalamide. Methyl iodide (277 mmol) was added to a suspension of 7V-(3-hydroxyphenyl)pivalamide(69.4 mmol) and potassium carbonate (207 mmol) in acetone (500 mL) and the reaction mixture was heated at reflux for 3 h. The insoluble solids were removed by filtration and the filtrate was concentrated. The residue was extracted with hexane (3 x 300 mL) and the combined extracts were concentrated to provide N-(3-methoxyphenyl)pivalamide in 91percent yield as a white solid. 3. Synthesis of iV-(2-(2-hvdroxyethv0-3-methoxyphenyl)pivalamide.
91%	With potassium carbonate In acetone for 3 h; Reflux	Methyl iodide (277 mmol) was added to a suspension of N-(3-hydroxyphenyl)pivalamide (69.4 mmol) and potassium carbonate (207 mmol) in acetone (500 mL) and the reaction mixture was heated at reflux for 3 h. The insoluble solids were removed by filtration and the filtrate was concentrated. The residue was extracted with hexane (3*300 mL) and the combined extracts were concentrated to provide N-(3-methoxyphenyl)pivalamide in 91percent yield as a white solid.

Reference： [1] Tetrahedron, 1995, vol. 51, # 45, p. 12263 - 12276
[2] Patent: US2008/318941, 2008, A1, . Location in patent: Page/Page column 38-39
[3] Patent: WO2009/23844, 2009, A2, . Location in patent: Page/Page column 127-128
[4] Patent: US2008/200471, 2008, A1, . Location in patent: Page/Page column 60; 61
[5] Patent: US2010/16297, 2010, A1, . Location in patent: Page/Page column 35
[6] Patent: WO2010/21797, 2010, A1, . Location in patent: Page/Page column 92
[7] Patent: US2010/29629, 2010, A1, . Location in patent: Page/Page column 61
[8] Patent: WO2010/24980, 2010, A1, . Location in patent: Page/Page column 110
[9] Patent: US2010/22581, 2010, A1, . Location in patent: Page/Page column 45; 46

[ 75151-82-5 ] Synthesis Path-Downstream 1~50

1
[ 3282-30-2 ]
[ 591-27-5 ]
[ 75151-82-5 ]

Yield	Reaction Conditions	Operation in experiment
95.4%	With sodium hydrogencarbonate In water; ethyl acetate for 2h;
90%	With sodium carbonate In water; ethyl acetate at 0℃; for 1h;	24 Synthesis of N-(3-hydroxphenyl)pivalamide Synthesis of N-(3-hydroxphenyl)pivalamide Into a 500 mL 3-necked round-bottom flask, was placed a solution of 3-aminophenol (3.98 g, 36.51 mmol, 1.00 equiv) in EtOAc (125 mL). This was followed by the addition of a solution of Na2CO3 (9.2 g, 86.79 mmol, 3.00 equiv) in H2O (150 mL). To the above was added pivaloyl chloride (4.62 g, 38.31 mmol, 1.10 equiv) dropwise with stirring while the temperature was maintained at 0° C. in a bath of H2O/ice. The resulting solution was allowed to react, with stirring, for 1 h. The reaction progress was monitored by TLC (EtOAc/PE=1:2). The resulting organic phase was washed with HCl(1N), H2O and brine. The organic phase was dried over Na2SO4 and concentrated by evaporation under vacuum using a rotary evaporator. This resulted in 6.7 g (90%) of N-(3-hydroxyphenyl)pivalamide as a gray solid.
90%	With sodium carbonate In water; ethyl acetate at 0℃; for 1h;	37.1 Pivaloyl chloride (38.3 mmol) was added dropwise to a biphasic mixture of 3-aminophenol (36.5 mmol) and sodium carbonate (86.8 mmol) in ethyl acetate (125 mL) and water (150 mL) at 0 °C. The resulting solution was stirred vigorously for 1 h and the layers were separated. The organic phase was washed with 1 N hydrochloric acid, water, and brine, was dried (sodium sulfate), and was concentrated to provide N-(3-hydroxyphenyl)pivalamide in 90% yield as a gray solid.

90%	With sodium carbonate In water; ethyl acetate at 0℃; for 1h;	21 Synthesis of N-(3-hydroxyphenyl)pivalamide Into a 500 mL 3-necked round-bottom flask, was placed a solution of 3-aminophenol (3.98 g, 36.51 mmol, 1.00 equiv) in EtOAc (125 mL). This was followed by the addition of a solution of Na2CO3 (9.2 g, 86.79 mmol, 3.00 equiv) in H2O (150 mL). To the above was added pivaloyl chloride (4.62 g, 38.31 mmol, 1.10 equiv) dropwise with stirring while the temperature was maintained at 0° C. in a bath of H2O/ice. The resulting solution was allowed to react, with stirring, for 1 h. The reaction progress was monitored by TLC (EtOAc/PE=1:2). The resulting organic phase was washed with HCl(1N), H2O and brine. The organic phase was dried over Na2SO4 and concentrated by evaporation under vacuum using a rotary evaporator. This resulted in 6.7 g (90%) of N-(3-hydroxyphenyl)pivalamide as a gray solid.
90%	Stage #1: pivaloyl chloride; m-Hydroxyaniline With sodium carbonate In water; ethyl acetate at 0℃; Stage #2: With hydrogenchloride In water; ethyl acetate	I.28.1 Intermediate 28: Synthesis of 2,3-dihydrobenzofuran-4-sulfonyl Chloride; 1. Synthesis of N-(3-hydroxyphenyl)pivalamide; Pivaloyl chloride (38.3 mmol) was added dropwise to a biphasic mixture of 3-aminophenol (36.5 mmol) and sodium carbonate (86.8 mmol) in ethyl acetate (125 mL) and water (150 mL) at 0° C. The resulting solution was stirred vigorously for 1 h and the layers were separated. The organic phase was washed with 1 N hydrochloric acid, water, and brine, was dried (sodium sulfate), and was concentrated to provide N-(3-hydroxyphenyl)pivalamide in 90% yield as a gray solid.
90%	Stage #1: pivaloyl chloride; m-Hydroxyaniline With sodium carbonate In water; ethyl acetate at 0℃; Stage #2: With hydrogenchloride In water; ethyl acetate	37.1 Intermediate 37: Synthesis of 2,3-dihydrobenzofuran-4-sulfonyl chloride.1. Synthesis of Λ/-(3-hydroxyphenyl)pivalamide.Pivaloyl chloride (38.3 mmol) was added dropwise to a biphasic mixture of 3- aminophenol (36.5 mmol) and sodium carbonate (86.8 mmol) in ethyl acetate (125 mL) and water (150 mL) at O 0C. The resulting solution was stirred vigorously for 1 h and the layers were separated. The organic phase was washed with 1 N hydrochloric acid, water, and brine, was dried (sodium sulfate), and was concentrated to provide iV-(3-hydroxyphenyl)pivalamide in 90% yield as a gray solid.
90%	With sodium carbonate In water; ethyl acetate	1 Pivaloyl chloride (38.3 mmol) was added dropwise to a biphasic mixture of 3-aminophenol (36.5 mmol) and sodium carbonate (86.8 mmol) in ethyl acetate (125 mL) and water (150 mL) at 0° C. The resulting solution was stirred vigorously for 1 h and the layers were separated. The organic phase was washed with 1 N hydrochloric acid, water, and brine, was dried (sodium sulfate), and was concentrated to provide N-(3-hydroxyphenyl)pivalamide in 90% yield as a gray solid.
90%	Stage #1: pivaloyl chloride; m-Hydroxyaniline With sodium carbonate In water; ethyl acetate at 0℃; Stage #2: With hydrogenchloride In water; ethyl acetate	1 Intermediate 37: Synthesis of 2,3-dihydrobenzofuran-4-sulfonyl chloride.1. Synthesis of AZ-Q-hydroxyphenvDpivalamide.Pivaloyl chloride (38.3 mmol) was added dropwise to a biphasic mixture of 3- aminophenol (36.5 mmol) and sodium carbonate (86.8 mmol) in ethyl acetate (125 mL) and water (150 mL) at 0 0C. The resulting solution was stirred vigorously for 1 h and the layers were separated. The organic phase was washed with 1 N hydrochloric acid, water, and brine, was dried (sodium sulfate), and was concentrated to provide Λ/-(3-hydroxyphenyl)pival amide in 90% yield as a gray solid.
90%	With sodium carbonate In water; ethyl acetate at 0℃;	28.1 1. Pivaloyl chloride (38.3 mmol) was added dropwise to a biphasic mixture of 3-aminophenol (36.5 mmol) and sodium carbonate (86.8 mmol) in ethyl acetate (125 mL) and water (150 mL) at 0° C. The resulting solution was stirred vigorously for 1 h and the layers were separated. The organic phase was washed with 1 N hydrochloric acid, water, and brine, was dried (sodium sulfate), and was concentrated to provide N-(3-hydroxyphenyl)pivalamide in 90% yield as a gray solid.
76%	With pyridine In tetrahydrofuran for 16.5h; Ambient temperature;
68%	Stage #1: pivaloyl chloride; m-Hydroxyaniline In tetrahydrofuran at -10 - -5℃; for 2h; Stage #2: With triethylamine In tetrahydrofuran at -5℃; for 2h;	1 Synthesis of 1 -(3-tert-l3utyl-4-hydroxy-3-oxo-2,3- dihydro-benzo[1 ,3]azaphosphol- 1 -yl)-2,2-dimethyl-propan-1 -one (III) A solution of 3-aminophenol (1110 (300 g, 2.75 mol) inTHF (2.4 L)was cooled to -10°C. Pivaloyl chloride (339 mE, 2.75 mol) was added while maintaining temperature below -5° C. Afier complete addition, the mixture was kept for 2 h. Triethylamine (113 mE, 0.825 mol) was added slowly while maintaining temperature below -5° C. and hold for another 2 h. Additional triethylamine (0.1 eq) was added to achieve complete conversion. The reaction mixture was warmed to 23°C. and acidifiedto pH=1 with conc. HC1. THF was removed by distillation. The solid was collected by filtration and then washed with water to give the product (lug) as a white solid (360 g, 68% yield). ‘H (400 MHz, CDC13) ö=8.19 (s, 1H), 7.96 (t, J=2.22, 1H), 7.41 (s, 1H), 7.15, (t, J=2.22, 1H), 6.66 (ddd, J=8.16, 2.40, 0.84 Hz, 1H),6.52 (ddd, J=7.96, 1.98, 0.82 Hz, 1H), 1.34 (s, 9H). ‘3C NMR (100 MHz, CDC13) ö=117.80, 157.77, 138.54, 129.65, 112.03, 110.52, 107.49, 39.82, 27.59.
54%	With triethylamine In ethyl acetate at 0℃; for 12h;
	Stage #1: pivaloyl chloride; m-Hydroxyaniline With sodium hydroxide In water; toluene at 0 - 25℃; for 16h; Stage #2: With hydrogenchloride In water; toluene	5.B To a solution of 3-amino-phenol (60 G, 6.55 mol) in 2 N NAOH (11), cooled to 10 °C, PIVALOYL chloride (68 ML, 0.55 mol) in toluene (200 ML) is added within 1 h. After stirring for 15 h at 25°C, the mixture is cooled to 0 °C and acidified to pH 1 with conc. HCI. Extraction with EtOAc washing with water, 10 % NaHCO3, water, and brine, followed by drying (Na2SO4), evaporation of volatiles, and crystallization (EtOAc/hexanes) gives N- (3-hydroxy-phenyl)-2, 2-dimethyl- propionamide. N- (3-HYDROXY-PHENYL)-2, 2-DIMETHYL-PROPIONAMIDE (49 g, 0.254 mol) in DICHLOROMETHANE (1 I) is treated with dihydropyrane (66 ML, 0.762 mol) and pyridinium p-toluenesulfonate (957 mg, 3.8 MMOL). After stirring for 6 days at 25°C, the solvent is removed and the residue crystallized from ETOAC/HEXANES to give 2, 2-DIMETHYL-N- [3- (TETRAHYDRO-PYRAN-2-YLOXY)-PHENYL]-PROPIONAMIDE. To a solution OF 2, 2-DIMETHYL-N- [3- (TETRAHYDRO-PYRAN-2-YLOXY)-PHENYL]-PROPIONAMIDE (57.7 g, 208 MMOL) in dry THF (500 ml) n-butyl lithium (325 ml, 1.6 M in hexanes, 521 MMOL) are added within 5 min at-55 to-20 °C (Argon). After stirring for 1 h dry ether (400 ml) is added, followed by liquid SO2 (100 G) AT-55 °C. The mixture is slowly warmed to 25°C and poured into an excess of diethyl. The precipitate is collected by filtration and washed with ether. This precipitate (84 g) is dissolved in water (440 ml). After the addition of NaOAc (85.5 g, 1.04 mol) and cooling to 15 °C, hydroxylamine-O-sulfonic acid (58.8 g, 0.52 mol) is added in portions within 20 min, keeping the temperature below 20 °C. Stirring at 25° for 15 h is followed by extraction with EtOAc. The organic layer is dried (NA2SO4) and evaporated. Chromatography (silica gel, HEXANES/ACOET, various ratios) gives 2, 2-DIMETHYL-N- [2-SULFAMOYL-3- (TETRAHYDRO-PYRAN-2-YLOXY)- PHENYL]-PROPIONAMIDE and N- (3-HYDROXY-2-SULFAMOYL-PHENYL)-2, 2-DIMETHYL-PROPIONAMIDE (CF below, cleavage OF TETRAHYDROPYRANYLOXY). To a solution OF 2, 2-DIMETHYL-N- [2-SULFAMOYL-3- (TETRAHYDRO-PYRAN-2-YLOXY)-PHENYL]-PROPIONAMIDE (21.9 g, 61.5 MMOL) in methanol (220 ml) a solution of methanesulfonic acid (11 mi) in methanol (10 ml) is added within 4 min at 25°C. After stirring for 1 h, the solvent is removed. The residue is partitioned between water and EtOAc. After washings with water, 10 % NAHCO3, and brine, evaporation of the dried (NA2SO4) organic phase gave N- (3-HYDROXY-2-SULFAMOYI-PHENYL)-2, 2- DIMETHYL-PROPIONAMIDE. A solution of N- (3-hydroxy-2-sulfamoyl-phenyl)-2, 2-dimethyl-propionamide (15.2 g, 55.9 MMOL) and N, N-DIMETHYLFORMAMIDE dimethylacetal (9.7 ml, 72.6 MMOL) in DMF (65 ml) is stirred at 60°C for 1 h. Volatiles are evaporated at reduced pressure. Chromatography of the residue (21. 8 G) dissolved in dichloromethane (silica gel, hexanes/EtOAc = 1 : 1) gives N- (2- { [L-DIMETHYLAMINO- meth-(E)-ylidene]-sulfamoyl}-3-hydroxy-phenyl)-2,3-dimethyl-propionamide. A solution of N- (2- { [L-DIMETHYLAMINO-METH- (E)-YLIDENE]-SULFAMOYL}-3-HYDROXY-PHENYL)-2, 2- dimethyl-propionamide (600 mg, 1.84 MMOL) in DMF (4 ml) is treated at 70 °C with allyl bromide (217 RI, 2.57 MMOL) and K2CO3 (380 mg) for 45 min with stirring. After evaporation of the solvent, the residue is partitioned between water and EtOAc. The organic layer is dried (Na2SO4) and evaporated yielding N- (3-ALLYLOXY-2- [1-DIMETHYLAMINO-METH- (E)-YLIDENE]- sulfamoyl}-phenyl)-2, 2-dimethyl-propionamide. A solution of N- (3-ALLYLOXY-2- { [1-DIMETHYLAMINO-METH- (E)-YLIDENE]-SULFAMOYL}-PHENYL)-2, 2- dimethyl-propionamide (387 mg, 1.05 MMOL) in ethanol (12 mi) and 12 drops of conc HCI (aprox. 0.2 mi) is refluxed for 36 h. After evaporation of the solvent, the residue is partitioned between ammonia (pH 10 to 11) and EtOAc. The organic layer is dried (NA2SO4) and evaporated. Chromatography (silica gel, EtOAc/hexanes = 2 : 1) afforded N-(3-allyloxy-2-sulfamoyl-phenyl)- 2, 2-DIMETHYL-PROPIONAMIDE containing some N-(3-allyloxy-2-sulfamoyl-phenyl)-2,2-dimethyl- propionamide. Treatment of this material with ethanol (20 ml) and conc. HCI (2 ML) for 30 h at reflux temperature and WORKUP as above gives N- (3-ALLYLOXY-2-SULFAMOYL-PHENYL)-2, 2-DIMETHYL- propionamide.
	Inert atmosphere; Schlenk technique; Alkaline conditions;

Reference： [1]Hillis, Larry R.; Gould, Steven J. [Journal of Organic Chemistry, 1985, vol. 50, # 5, p. 718 - 719]
[2]Current Patent Assignee: ROCHE HOLDING AG - US2008/318941, 2008, A1 Location in patent: Page/Page column 38
[3]Current Patent Assignee: ROCHE HOLDING AG - WO2009/23844, 2009, A2 Location in patent: Page/Page column 127-128
[4]Current Patent Assignee: ROCHE HOLDING AG - US2008/200471, 2008, A1 Location in patent: Page/Page column 60; 61
[5]Current Patent Assignee: ROCHE HOLDING AG - US2010/16297, 2010, A1 Location in patent: Page/Page column 34-35
[6]Current Patent Assignee: ROCHE HOLDING AG - WO2010/21797, 2010, A1 Location in patent: Page/Page column 92
[7]Current Patent Assignee: ROCHE HOLDING AG - US2010/29629, 2010, A1 Location in patent: Page/Page column 61
[8]Current Patent Assignee: ROCHE HOLDING AG - WO2010/24980, 2010, A1 Location in patent: Page/Page column 110
[9]Current Patent Assignee: ROCHE HOLDING AG - US2010/22581, 2010, A1 Location in patent: Page/Page column 45
[10]Dai, Wei-Min; Cheung, Yuk King; Tang, Kit Wan; Choi, Pui Yiu; Chung, Suet Lam [Tetrahedron, 1995, vol. 51, # 45, p. 12263 - 12276]
[11]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2018/155377, 2018, A1 Location in patent: Paragraph 0107; 0108
[12]Ueda, Satoshi; Nagasawa, Hideko [Journal of Organic Chemistry, 2009, vol. 74, # 11, p. 4272 - 4277]
[13]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2005/26158, 2005, A1 Location in patent: Page/Page column 15-17
[14]Aluri, Bhaskar R.; Shah, Kirti; Gupta, Neelima; Fomina, Olga S.; Yakhvarov, Dmitry G.; Ghalib, Mohammed; Jones, Peter G.; Schulzke, Carola; Heinicke, Joachim W. [European Journal of Inorganic Chemistry, 2014, vol. 2014, # 34, p. 5958 - 5968]

2
[ 75151-82-5 ]
[ 107-30-2 ]
[ 94596-98-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride 1.) THF, 0 deg C, 3 h, 2.) from 0 deg C to RT, overnight; Yield given. Multistep reaction;
	With potassium carbonate In acetone

Reference： [1]Hillis, Larry R.; Gould, Steven J. [Journal of Organic Chemistry, 1985, vol. 50, # 5, p. 718 - 719]
[2]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2014/44615, 2014, A1 Location in patent: Page/Page column 31

3
[ 3282-30-2 ]
[ 591-27-5 ]
[ 75151-82-5 ]
[ 173035-06-8 ]
2,2-Dimethyl-propionic acid 3-(2,2-dimethyl-propionylamino)-phenyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 9% 2: 16% 3: 63%	With sodium hydride In tetrahydrofuran for 4h; Ambient temperature;

Reference： [1]Dai, Wei-Min; Cheung, Yuk King; Tang, Kit Wan; Choi, Pui Yiu; Chung, Suet Lam [Tetrahedron, 1995, vol. 51, # 45, p. 12263 - 12276]

4
[ 75151-82-5 ]
[ 100-39-0 ]
3'-(benzyloxy)-2,2-dimethylpropionanilide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium carbonate In acetone at 40℃; for 24h;

Reference： [1]Dai, Wei-Min; Cheung, Yuk King; Tang, Kit Wan; Choi, Pui Yiu; Chung, Suet Lam [Tetrahedron, 1995, vol. 51, # 45, p. 12263 - 12276]

5
[ 1538-75-6 ]
[ 591-27-5 ]
[ 75151-82-5 ]

Yield	Reaction Conditions	Operation in experiment
89%	With pyridine In tetrahydrofuran for 24h; Ambient temperature;

Reference： [1]Dai, Wei-Min; Cheung, Yuk King; Tang, Kit Wan; Choi, Pui Yiu; Chung, Suet Lam [Tetrahedron, 1995, vol. 51, # 45, p. 12263 - 12276]

6
[ 138459-91-3 ]
[ 591-27-5 ]
[ 75151-82-5 ]

Yield	Reaction Conditions	Operation in experiment
83%	In tetrahydrofuran at 80℃; for 24h;

Reference： [1]Dai, Wei-Min; Cheung, Yuk King; Tang, Kit Wan; Choi, Pui Yiu; Chung, Suet Lam [Tetrahedron, 1995, vol. 51, # 45, p. 12263 - 12276]

7
[ 75151-82-5 ]
[ 74-88-4 ]
[ 56619-93-3 ]

Yield	Reaction Conditions	Operation in experiment
91%	With potassium carbonate; In acetone; for 3h;Heating / reflux;	Synthesis of N-(3-methoxyphenyl)pivalamide Into a 1000 mL round-bottom flask, was placed a solution of N-(3-hydroxyphenyl)pivalamide (13.4 g, 69.43 mmol, 1.00 equiv) in acetone (500 mL). To this was added K2CO3 (28.5 g, 206.52 mmol, 3.00 equiv). To the mixture was added MeI (39.4 g, 277.46 mmol, 4.00 equiv). The resulting solution was allowed to react, with stirring, for 3 h while the temperature was maintained at reflux in a bath of oil. The reaction progress was monitored by TLC (EtOAc/PE=1:2). A filtration was performed. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. The resulting mixture was washed with hexane. A filtration was performed. This resulted in 13.9 g (91%) of N-(3-methoxyphenyl)pivalamide as a white solid.
91%	With potassium carbonate; In acetone; for 3h;Heating / reflux;	Methyl iodide (277 mmol) was added to a suspension of N-(3-hydroxyphenyl)pivalamide (69.4 mmol) and potassium carbonate (207 mmol) in acetone (500 mL) and the reaction mixture was heated at reflux for 3 h. The insoluble solids were removed by filtration and the filtrate was concentrated. The residue was extracted with hexane (3 x 300 mL) and the combined extracts were concentrated to provide N-(3-methoxyphenyl)pivalamide in 91% yield as a white solid.
91%	With potassium carbonate; In acetone; for 3h;Heating / reflux;	Synthesis of N-(3-methoxyphenyl)pivalamide Into a 1000 mL round-bottom flask, was placed a solution of N-(3-hydroxyphenyl)pivalamide (13.4 g, 69.43 mmol, 1.00 equiv) in acetone (500 mL). To this was added K2CO3 (28.5 g, 206.52 mmol, 3.00 equiv). To the mixture was added MeI (39.4 g, 277.46 mmol, 4.00 equiv). The resulting solution was allowed to react, with stirring, for 3 h while the temperature was maintained at reflux in a bath of oil. The reaction progress was monitored by TLC (EtOAc/PE=1.2). A filtration was performed. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. The resulting mixture was washed with hexane. A filtration was performed. This resulted in 13.9 g (91%) of N-(3-methoxyphenyl)pivalamide as a white solid.

91%	With potassium carbonate; In acetone; for 3h;Reflux;	2. Synthesis of N-(3-methoxyphenyl)pivalamide; Methyl iodide (277 mmol) was added to a suspension of N-(3-hydroxyphenyl)pivalamide (69.4 mmol) and potassium carbonate (207 mmol) in acetone (500 mL) and the reaction mixture was heated at reflux for 3 h. The insoluble solids were removed by filtration and the filtrate was concentrated. The residue was extracted with hexane (3×300 mL) and the combined extracts were concentrated to provide N-(3-methoxyphenyl)pivalamide in 91% yield as a white solid.
91%	With potassium carbonate; In acetone; for 3h;Reflux;	2. Synthesis of 7V-(3-methoxyphenyl)pivalamide.Methyl iodide (277 mmol) was added to a suspension of 7V-(3 -hydro xyphenyl)pivalamide (69.4 mmol) and potassium carbonate (207 mmol) in acetone (500 mL) and the reaction mixture was heated at reflux for 3 h. The insoluble solids were removed by filtration and the filtrate was concentrated. The residue was extracted with hexane (3 x 300 mL) and the combined extracts were concentrated to provide 7V-(3-methoxyphenyl)pivalamide in 91% yield as a white solid.
91%	With potassium carbonate; In acetone; for 3h;Reflux;	Methyl iodide (277 mmol) was added to a suspension of N-(3-hydroxyphenyl)pivalamide (69.4 mmol) and potassium carbonate (207 mmol) in acetone (500 mL) and the reaction mixture was heated at reflux for 3 h. The insoluble solids were removed by filtration and the filtrate was concentrated. The residue was extracted with hexane (3×300 mL) and the combined extracts were concentrated to provide N-(3-methoxyphenyl)pivalamide in 91% yield as a white solid
91%	With potassium carbonate; In acetone; for 3h;Reflux;	2. Synthesis of 7V-(3-methoxyphenyl)pivalamide. Methyl iodide (277 mmol) was added to a suspension of 7V-(3-hydroxyphenyl)pivalamide(69.4 mmol) and potassium carbonate (207 mmol) in acetone (500 mL) and the reaction mixture was heated at reflux for 3 h. The insoluble solids were removed by filtration and the filtrate was concentrated. The residue was extracted with hexane (3 x 300 mL) and the combined extracts were concentrated to provide N-(3-methoxyphenyl)pivalamide in 91% yield as a white solid. 3. Synthesis of iV-(2-(2-hvdroxyethv0-3-methoxyphenyl)pivalamide.
91%	With potassium carbonate; In acetone; for 3h;Reflux;	Methyl iodide (277 mmol) was added to a suspension of N-(3-hydroxyphenyl)pivalamide (69.4 mmol) and potassium carbonate (207 mmol) in acetone (500 mL) and the reaction mixture was heated at reflux for 3 h. The insoluble solids were removed by filtration and the filtrate was concentrated. The residue was extracted with hexane (3*300 mL) and the combined extracts were concentrated to provide N-(3-methoxyphenyl)pivalamide in 91% yield as a white solid.

Reference： [1]Tetrahedron,1995,vol. 51,p. 12263 - 12276
[2]Patent: US2008/318941,2008,A1 .Location in patent: Page/Page column 38-39
[3]Patent: WO2009/23844,2009,A2 .Location in patent: Page/Page column 127-128
[4]Patent: US2008/200471,2008,A1 .Location in patent: Page/Page column 60; 61
[5]Patent: US2010/16297,2010,A1 .Location in patent: Page/Page column 35
[6]Patent: WO2010/21797,2010,A1 .Location in patent: Page/Page column 92
[7]Patent: US2010/29629,2010,A1 .Location in patent: Page/Page column 61
[8]Patent: WO2010/24980,2010,A1 .Location in patent: Page/Page column 110
[9]Patent: US2010/22581,2010,A1 .Location in patent: Page/Page column 45; 46

8
[ 6213-87-2 ]
[ 75151-82-5 ]
methyl (E)-3-(4-hydroxy-2-pivaloylaminophenyl)propenoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With silver trifluoromethanesulfonate; palladium dichloride In N,N-dimethyl-formamide at 90℃; for 1h;

Reference： [1]Zaitsev, Vladimir G.; Daugulis, Olafs [Journal of the American Chemical Society, 2005, vol. 127, # 12, p. 4156 - 4157]

9
[ 75151-82-5 ]
7-(2,2-Dimethyl-propionyl)-2-methoxy-7-aza-bicyclo[4.2.0]octa-1,3,5-trien-8-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 93 percent / K₂CO₃ / acetone / 24 h / 40 °C 2: 1.) n-BuLi / 1.) THF, 0 deg C, 3 h, 2.) THF, RT

Reference： [1]Dai, Wei-Min; Cheung, Yuk King; Tang, Kit Wan; Choi, Pui Yiu; Chung, Suet Lam [Tetrahedron, 1995, vol. 51, # 45, p. 12263 - 12276]

10
[ 75151-82-5 ]
2-[(2,2-Dimethyl-propionyl)-methoxycarbonyl-amino]-6-methoxy-benzoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 93 percent / K₂CO₃ / acetone / 24 h / 40 °C 2: 1.) n-BuLi / 1.) THF, 0 deg C, 3 h, 2.) THF, RT

Reference： [1]Dai, Wei-Min; Cheung, Yuk King; Tang, Kit Wan; Choi, Pui Yiu; Chung, Suet Lam [Tetrahedron, 1995, vol. 51, # 45, p. 12263 - 12276]

11
[ 75151-82-5 ]
[ 94596-96-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: sodium hydride / 1.) THF, 0 deg C, 3 h, 2.) from 0 deg C to RT, overnight 2: 1.) n-butyllithium / 1.) THF, hexane, 0 deg C, 2 h 3: HCl / H₂O 4: 72.4 percent / 6 N HCl, acetic acid / 96 h / 48 °C

Reference： [1]Hillis, Larry R.; Gould, Steven J. [Journal of Organic Chemistry, 1985, vol. 50, # 5, p. 718 - 719]

12
[ 75151-82-5 ]
[ 94596-99-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: sodium hydride / 1.) THF, 0 deg C, 3 h, 2.) from 0 deg C to RT, overnight 2: 1.) n-butyllithium / 1.) THF, hexane, 0 deg C, 2 h 3: HCl / H₂O

Reference： [1]Hillis, Larry R.; Gould, Steven J. [Journal of Organic Chemistry, 1985, vol. 50, # 5, p. 718 - 719]

13
[ 110-87-2 ]
[ 75151-82-5 ]
[ 103814-48-8 ]

Yield	Reaction Conditions	Operation in experiment
81%	With pyridinium p-toluenesulfonate In dichloromethane at 35℃;	1 To a solution of N-(3-hydroxyphenyl)pivalamide (lug) (360 g, 1.87 mol) and pyridinium p-toluenesulfonate (PPTS) (46.87 g, 0.187 mol) in CH2C12 (2 E) was added dihydropyran (485 mE, 5.60 mol). The reaction mixture was then heated at 35° C. overnight. Additional dihydropyran (1 eq) was added to push reaction to completion. The reaction was quenched with sat. NaHCO3 (400 mE) and then washed with water twice (400 mEx2). The organic layers were dried with anhydrous MgSO4 and concentrated. The crude product was purified by recrystallization in EtOAc/hexanes to produce the product N-(3-((tetrahydro-2H-pyran-2-yl)oxy)phe- nyl)pivalamide (md) as a white solid (420 g, 81% yield). ‘H (400 MHz, CDC13) ö=7.35 (t, J=2.2 Hz, 1H), 7.29 (bs, 1H), 7.21 (t, J=8.1 Hz, 1H), 7.12 (qd, J=0.9, 8.0 Hz, 1H), 6.80 (ddd, J=0.9, 2.5, 8.2, 1H), 5.44 (t, J=3.2, 1H) 3.90 (m, 1H), 3.61 (dtd, J=1.2, 4.1, 11.3 Hz, 1H), 1.99 (m, 1H), 1.84 (m, 2H), 1.55-1.75 (m, 3H), 1.31 (s, 9H). ‘3C NMR (100 MHz, CDC13) ö=176.5, 157.6, 139.1, 129.6, 113.1, 112.4, 108.3, 96.3, 61.9, 39.6, 30.3, 27.6, 25.2, 18.6.
	With pyridinium p-toluenesulfonate In dichloromethane at 25℃; for 144h;	5.B To a solution of 3-amino-phenol (60 G, 6.55 mol) in 2 N NAOH (11), cooled to 10 °C, PIVALOYL chloride (68 ML, 0.55 mol) in toluene (200 ML) is added within 1 h. After stirring for 15 h at 25°C, the mixture is cooled to 0 °C and acidified to pH 1 with conc. HCI. Extraction with EtOAc washing with water, 10 % NaHCO3, water, and brine, followed by drying (Na2SO4), evaporation of volatiles, and crystallization (EtOAc/hexanes) gives N- (3-hydroxy-phenyl)-2, 2-dimethyl- propionamide. N- (3-HYDROXY-PHENYL)-2, 2-DIMETHYL-PROPIONAMIDE (49 g, 0.254 mol) in DICHLOROMETHANE (1 I) is treated with dihydropyrane (66 ML, 0.762 mol) and pyridinium p-toluenesulfonate (957 mg, 3.8 MMOL). After stirring for 6 days at 25°C, the solvent is removed and the residue crystallized from ETOAC/HEXANES to give 2, 2-DIMETHYL-N- [3- (TETRAHYDRO-PYRAN-2-YLOXY)-PHENYL]-PROPIONAMIDE. To a solution OF 2, 2-DIMETHYL-N- [3- (TETRAHYDRO-PYRAN-2-YLOXY)-PHENYL]-PROPIONAMIDE (57.7 g, 208 MMOL) in dry THF (500 ml) n-butyl lithium (325 ml, 1.6 M in hexanes, 521 MMOL) are added within 5 min at-55 to-20 °C (Argon). After stirring for 1 h dry ether (400 ml) is added, followed by liquid SO2 (100 G) AT-55 °C. The mixture is slowly warmed to 25°C and poured into an excess of diethyl. The precipitate is collected by filtration and washed with ether. This precipitate (84 g) is dissolved in water (440 ml). After the addition of NaOAc (85.5 g, 1.04 mol) and cooling to 15 °C, hydroxylamine-O-sulfonic acid (58.8 g, 0.52 mol) is added in portions within 20 min, keeping the temperature below 20 °C. Stirring at 25° for 15 h is followed by extraction with EtOAc. The organic layer is dried (NA2SO4) and evaporated. Chromatography (silica gel, HEXANES/ACOET, various ratios) gives 2, 2-DIMETHYL-N- [2-SULFAMOYL-3- (TETRAHYDRO-PYRAN-2-YLOXY)- PHENYL]-PROPIONAMIDE and N- (3-HYDROXY-2-SULFAMOYL-PHENYL)-2, 2-DIMETHYL-PROPIONAMIDE (CF below, cleavage OF TETRAHYDROPYRANYLOXY). To a solution OF 2, 2-DIMETHYL-N- [2-SULFAMOYL-3- (TETRAHYDRO-PYRAN-2-YLOXY)-PHENYL]-PROPIONAMIDE (21.9 g, 61.5 MMOL) in methanol (220 ml) a solution of methanesulfonic acid (11 mi) in methanol (10 ml) is added within 4 min at 25°C. After stirring for 1 h, the solvent is removed. The residue is partitioned between water and EtOAc. After washings with water, 10 % NAHCO3, and brine, evaporation of the dried (NA2SO4) organic phase gave N- (3-HYDROXY-2-SULFAMOYI-PHENYL)-2, 2- DIMETHYL-PROPIONAMIDE. A solution of N- (3-hydroxy-2-sulfamoyl-phenyl)-2, 2-dimethyl-propionamide (15.2 g, 55.9 MMOL) and N, N-DIMETHYLFORMAMIDE dimethylacetal (9.7 ml, 72.6 MMOL) in DMF (65 ml) is stirred at 60°C for 1 h. Volatiles are evaporated at reduced pressure. Chromatography of the residue (21. 8 G) dissolved in dichloromethane (silica gel, hexanes/EtOAc = 1 : 1) gives N- (2- { [L-DIMETHYLAMINO- meth-(E)-ylidene]-sulfamoyl}-3-hydroxy-phenyl)-2,3-dimethyl-propionamide. A solution of N- (2- { [L-DIMETHYLAMINO-METH- (E)-YLIDENE]-SULFAMOYL}-3-HYDROXY-PHENYL)-2, 2- dimethyl-propionamide (600 mg, 1.84 MMOL) in DMF (4 ml) is treated at 70 °C with allyl bromide (217 RI, 2.57 MMOL) and K2CO3 (380 mg) for 45 min with stirring. After evaporation of the solvent, the residue is partitioned between water and EtOAc. The organic layer is dried (Na2SO4) and evaporated yielding N- (3-ALLYLOXY-2- [1-DIMETHYLAMINO-METH- (E)-YLIDENE]- sulfamoyl}-phenyl)-2, 2-dimethyl-propionamide. A solution of N- (3-ALLYLOXY-2- { [1-DIMETHYLAMINO-METH- (E)-YLIDENE]-SULFAMOYL}-PHENYL)-2, 2- dimethyl-propionamide (387 mg, 1.05 MMOL) in ethanol (12 mi) and 12 drops of conc HCI (aprox. 0.2 mi) is refluxed for 36 h. After evaporation of the solvent, the residue is partitioned between ammonia (pH 10 to 11) and EtOAc. The organic layer is dried (NA2SO4) and evaporated. Chromatography (silica gel, EtOAc/hexanes = 2 : 1) afforded N-(3-allyloxy-2-sulfamoyl-phenyl)- 2, 2-DIMETHYL-PROPIONAMIDE containing some N-(3-allyloxy-2-sulfamoyl-phenyl)-2,2-dimethyl- propionamide. Treatment of this material with ethanol (20 ml) and conc. HCI (2 ML) for 30 h at reflux temperature and WORKUP as above gives N- (3-ALLYLOXY-2-SULFAMOYL-PHENYL)-2, 2-DIMETHYL- propionamide.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2018/155377, 2018, A1 Location in patent: Paragraph 0107; 0109
[2]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2005/26158, 2005, A1 Location in patent: Page/Page column 15-17

14
[ 75151-82-5 ]
[ 79-44-7 ]
[ 36829-12-6 ]

Yield	Reaction Conditions	Operation in experiment
51%	With pyridine at 20 - 70℃; for 6h;

Reference： [1]Ueda, Satoshi; Nagasawa, Hideko [Journal of Organic Chemistry, 2009, vol. 74, # 11, p. 4272 - 4277]

15
[ 916811-87-5 ]
[ 75151-82-5 ]
N-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)pivalamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88.7%	With copper(l) iodide; caesium carbonate In N,N-dimethyl-formamide at 120℃;	1 Example 1: Preparation of -(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea [0189] To a solution of 4-(7-bromoquinoxalin-2-yl)morpholine (2.95 g, 0.01 mol, 1.0 eq.) and N- (3-hydroxyphenyl)pivalamide (2.3 g, 0.012 mol, 1.2eq.) in DMF (100 mL) were added Cs2C03 (9.78g, 0.03 mol, 3 eq.) and Cul (192 mg, 0.001 mol, O. leq.). The resulting mixture was stirred at 120 °C overnight, then cooled and concentrated. The resulting residue was dissolved in THF (100 mL) and the resulting precipitate was removed by filtration. The filtrate was concentrated and the resulting residue was purified by column chromatography (PE/EA=1 : 1 to EA, v/v) to afford N-(3-((3-morpholinoquinoxalin-6-yl)oxy) phenyl)pivalamide (3.6 g, 88.7%).

Reference： [1]Current Patent Assignee: NEUPHARMA INC - WO2013/112950, 2013, A2 Location in patent: Paragraph 0189

16
tert-butyl 4-(7-bromoquinoxalin-2-yl)piperazine-1-carboxylate [ No CAS ]
[ 75151-82-5 ]
tert-butyl tert-butyl 4-(7-(3-pivalamidophenoxy)quinoxalin-2-yl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	With copper(l) iodide; caesium carbonate In N,N-dimethyl-formamide at 120℃;	35 Example 35: Preparation of l-(3-fluorophenyl)-3-(3-((3-(piperazin-l-yl)quinoxalin-6- yl)oxy)phenyl)urea [0226] To a solution of teri-butyl 4-(7-bromoquinoxalin-2-yl)piperazine-l-carboxylate (3.63g, 15 mmol, 1.0 eq.) and N-(3-hydroxyphenyl)pivalamide (3.47 g, 18 mmol, 1.2 eq.) in DMF (200 mL) was added Cul (288 mg, 1.5 mmol, O. leq.) and Cs2C03 (14.7 g, 45 mmol, 3eq.). The resulting mixture was stirred at 120 °C overnight, then cooled to room temperature and concentrated. The resulting residue was dissolved in THF (300 mL) and the resulting solid was removed by filtration. The filtrate was concentrated and the resulting residue was purified by column chromatography (PE/EA=1 : 1 to EA, v/v) to afford tert-butyl tert-butyl 4-(7-(3-pivalamidophenoxy)quinoxalin-2-yl)piperazine-l- carboxylat(2.8g, 47%).

Reference： [1]Current Patent Assignee: NEUPHARMA INC - WO2013/112950, 2013, A2 Location in patent: Paragraph 0226

17
[ 75151-82-5 ]
[ 1584736-26-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: potassium carbonate / acetone 2: n-butyllithium / diethyl ether 3: manganese(IV) oxide 4: potassium hydroxide; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; water / 150 °C

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2014/44615, 2014, A1

18
[ 75151-82-5 ]
[ 1584736-24-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: potassium carbonate / acetone 2: n-butyllithium / diethyl ether 3: manganese(IV) oxide 4: potassium hydroxide; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; water / 150 °C 5: potassium hydroxide; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone / water

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2014/44615, 2014, A1

19
[ 75151-82-5 ]
[ 1584736-27-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: potassium carbonate / acetone 2: n-butyllithium / diethyl ether 3: manganese(IV) oxide 4: potassium hydroxide; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; water / 150 °C 5: potassium hydroxide; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone / water 6: toluene-4-sulfonic acid / methanol / Reflux

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2014/44615, 2014, A1

20
[ 75151-82-5 ]
[ 1584736-28-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: potassium carbonate / acetone 2: n-butyllithium / diethyl ether 3: manganese(IV) oxide 4: potassium hydroxide; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; water / 150 °C 5: potassium hydroxide; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone / water 6: toluene-4-sulfonic acid / methanol / Reflux 7: 1-methyl-pyrrolidin-2-one / toluene / 230 °C

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2014/44615, 2014, A1

21
[ 75151-82-5 ]
[ 1584736-29-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1: potassium carbonate / acetone 2: n-butyllithium / diethyl ether 3: manganese(IV) oxide 4: potassium hydroxide; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; water / 150 °C 5: potassium hydroxide; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone / water 6: toluene-4-sulfonic acid / methanol / Reflux 7: 1-methyl-pyrrolidin-2-one / toluene / 230 °C 8: sodium hydride / N,N-dimethyl-formamide

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2014/44615, 2014, A1

22
[ 75151-82-5 ]
[ 1584735-95-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 1: potassium carbonate / acetone 2: n-butyllithium / diethyl ether 3: manganese(IV) oxide 4: potassium hydroxide; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; water / 150 °C 5: potassium hydroxide; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone / water 6: toluene-4-sulfonic acid / methanol / Reflux 7: 1-methyl-pyrrolidin-2-one / toluene / 230 °C 8: sodium hydride / N,N-dimethyl-formamide 9: potassium <i>tert</i>-butylate / tetrahydrofuran

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2014/44615, 2014, A1

23
[ 75151-82-5 ]
[ 1584735-85-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 10 steps 1: potassium carbonate / acetone 2: n-butyllithium / diethyl ether 3: manganese(IV) oxide 4: potassium hydroxide; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; water / 150 °C 5: potassium hydroxide; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone / water 6: toluene-4-sulfonic acid / methanol / Reflux 7: 1-methyl-pyrrolidin-2-one / toluene / 230 °C 8: sodium hydride / N,N-dimethyl-formamide 9: potassium <i>tert</i>-butylate / tetrahydrofuran 10: ammonium formate; palladium on activated charcoal / ethanol / Reflux

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2014/44615, 2014, A1

24
[ 75151-82-5 ]
C₂₁H₂₇NO₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / acetone 2: n-butyllithium / diethyl ether

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2014/44615, 2014, A1

25
[ 75151-82-5 ]
C₂₁H₂₅NO₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: potassium carbonate / acetone 2: n-butyllithium / diethyl ether 3: manganese(IV) oxide

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2014/44615, 2014, A1

26
[ 75151-82-5 ]
[2-(2,2-dimethylpropionylamino)-6-hydroxy-phenyl]phosphonic acid diethyl ester [ No CAS ]
[4-(2,2-dimethylpropionylamino)-2-hydroxyphenyl]phosphonic acid diethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: tetrachloromethane; triethylamine / tetrahydrofuran / 24 h / 50 °C / Inert atmosphere; Schlenk technique 2.1: lithium diisopropyl amide / tetrahydrofuran / 4 h / -80 - -20 °C / Inert atmosphere; Schlenk technique 2.2: -80 - 20 °C / Inert atmosphere; Schlenk technique 2.3: Inert atmosphere; Schlenk technique

Reference： [1]Aluri, Bhaskar R.; Shah, Kirti; Gupta, Neelima; Fomina, Olga S.; Yakhvarov, Dmitry G.; Ghalib, Mohammed; Jones, Peter G.; Schulzke, Carola; Heinicke, Joachim W. [European Journal of Inorganic Chemistry, 2014, vol. 2014, # 34, p. 5958 - 5968]

27
[ 75151-82-5 ]
[ 762-04-9 ]
3-(2,2-dimethylpropanamido)phenyl diethyl phosphate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With tetrachloromethane; triethylamine In tetrahydrofuran at 50℃; for 24h; Inert atmosphere; Schlenk technique;

28
[ 75151-82-5 ]
C₁₇H₂₀N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: di-isopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 2.1: n-butyllithium / tetrahydrofuran; hexane / 6.5 h / -20 - 0 °C / Inert atmosphere 2.2: 0.75 h / -78 - 0 °C / Inert atmosphere 2.3: -78 - 20 °C / Inert atmosphere 3.1: potassium hydroxide; water / ethanol / 140 °C / Inert atmosphere; Sealed tube
	Multi-step reaction with 3 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran; water / 0 - 20 °C 2.1: n-butyllithium / tetrahydrofuran / 4.5 h / -20 - 0 °C 2.2: 0.75 h / -78 - 20 °C 2.3: -78 - 20 °C 3.1: potassium hydroxide / ethanol; water / 140 °C / Autoclave; Inert atmosphere

Reference： [1]Tan, Xuefeng; Gao, Shuang; Zeng, Weijun; Xin, Shan; Yin, Qin; Zhang, Xumu [Journal of the American Chemical Society, 2018, vol. 140, # 6, p. 2024 - 2027]
[2]Current Patent Assignee: SOUTHERN UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA - CN111499538, 2020, A

29
[ 75151-82-5 ]
C₁₇H₁₆I₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: di-isopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 2.1: n-butyllithium / tetrahydrofuran; hexane / 6.5 h / -20 - 0 °C / Inert atmosphere 2.2: 0.75 h / -78 - 0 °C / Inert atmosphere 2.3: -78 - 20 °C / Inert atmosphere 3.1: potassium hydroxide; water / ethanol / 140 °C / Inert atmosphere; Sealed tube 4.1: sodium nitrite; potassium iodide; hydrogenchloride / water; acetonitrile / 3.33 h / -20 - 80 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran; water / 0 - 20 °C 2.1: n-butyllithium / tetrahydrofuran / 4.5 h / -20 - 0 °C 2.2: 0.75 h / -78 - 20 °C 2.3: -78 - 20 °C 3.1: potassium hydroxide / ethanol; water / 140 °C / Autoclave; Inert atmosphere 4.1: hydrogenchloride; sodium nitrite; potassium iodide / water; acetonitrile / 3.33 h / -20 - 80 °C

30
[ 75151-82-5 ]
(R<SUB>ax</SUB>,S,S)-C<SUB>3</SUB>-TunePhos [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: di-isopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 2.1: n-butyllithium / tetrahydrofuran; hexane / 6.5 h / -20 - 0 °C / Inert atmosphere 2.2: 0.75 h / -78 - 0 °C / Inert atmosphere 2.3: -78 - 20 °C / Inert atmosphere 3.1: potassium hydroxide; water / ethanol / 140 °C / Inert atmosphere; Sealed tube 4.1: sodium nitrite; potassium iodide; hydrogenchloride / water; acetonitrile / 3.33 h / -20 - 80 °C / Inert atmosphere 5.1: n-butyllithium / diethyl ether / 0.33 h / -78 °C / Inert atmosphere 5.2: -78 - 20 °C / Inert atmosphere

Reference： [1]Tan, Xuefeng; Gao, Shuang; Zeng, Weijun; Xin, Shan; Yin, Qin; Zhang, Xumu [Journal of the American Chemical Society, 2018, vol. 140, # 6, p. 2024 - 2027]

31
[ 75151-82-5 ]
C₄₅H₄₄O₂P₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: di-isopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 2.1: n-butyllithium / tetrahydrofuran; hexane / 6.5 h / -20 - 0 °C / Inert atmosphere 2.2: 0.75 h / -78 - 0 °C / Inert atmosphere 2.3: -78 - 20 °C / Inert atmosphere 3.1: potassium hydroxide; water / ethanol / 140 °C / Inert atmosphere; Sealed tube 4.1: sodium nitrite; potassium iodide; hydrogenchloride / water; acetonitrile / 3.33 h / -20 - 80 °C / Inert atmosphere 5.1: n-butyllithium / diethyl ether / 0.33 h / -78 °C / Inert atmosphere 5.2: -78 - 20 °C / Inert atmosphere

Reference： [1]Tan, Xuefeng; Gao, Shuang; Zeng, Weijun; Xin, Shan; Yin, Qin; Zhang, Xumu [Journal of the American Chemical Society, 2018, vol. 140, # 6, p. 2024 - 2027]

32
[ 75151-82-5 ]
C₄₉H₅₂O₂P₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: di-isopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 2.1: n-butyllithium / tetrahydrofuran; hexane / 6.5 h / -20 - 0 °C / Inert atmosphere 2.2: 0.75 h / -78 - 0 °C / Inert atmosphere 2.3: -78 - 20 °C / Inert atmosphere 3.1: potassium hydroxide; water / ethanol / 140 °C / Inert atmosphere; Sealed tube 4.1: sodium nitrite; potassium iodide; hydrogenchloride / water; acetonitrile / 3.33 h / -20 - 80 °C / Inert atmosphere 5.1: n-butyllithium / diethyl ether / 0.33 h / -78 °C / Inert atmosphere 5.2: -78 - 20 °C / Inert atmosphere

Reference： [1]Tan, Xuefeng; Gao, Shuang; Zeng, Weijun; Xin, Shan; Yin, Qin; Zhang, Xumu [Journal of the American Chemical Society, 2018, vol. 140, # 6, p. 2024 - 2027]

33
[ 75151-82-5 ]
C₇₃H₁₀₀O₂P₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: di-isopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 2.1: n-butyllithium / tetrahydrofuran; hexane / 6.5 h / -20 - 0 °C / Inert atmosphere 2.2: 0.75 h / -78 - 0 °C / Inert atmosphere 2.3: -78 - 20 °C / Inert atmosphere 3.1: potassium hydroxide; water / ethanol / 140 °C / Inert atmosphere; Sealed tube 4.1: sodium nitrite; potassium iodide; hydrogenchloride / water; acetonitrile / 3.33 h / -20 - 80 °C / Inert atmosphere 5.1: n-butyllithium / diethyl ether / 0.33 h / -78 °C / Inert atmosphere 5.2: -78 - 20 °C / Inert atmosphere

Reference： [1]Tan, Xuefeng; Gao, Shuang; Zeng, Weijun; Xin, Shan; Yin, Qin; Zhang, Xumu [Journal of the American Chemical Society, 2018, vol. 140, # 6, p. 2024 - 2027]

34
[ 75151-82-5 ]
C₇₇H₁₀₈O₆P₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: di-isopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 2.1: n-butyllithium / tetrahydrofuran; hexane / 6.5 h / -20 - 0 °C / Inert atmosphere 2.2: 0.75 h / -78 - 0 °C / Inert atmosphere 2.3: -78 - 20 °C / Inert atmosphere 3.1: potassium hydroxide; water / ethanol / 140 °C / Inert atmosphere; Sealed tube 4.1: sodium nitrite; potassium iodide; hydrogenchloride / water; acetonitrile / 3.33 h / -20 - 80 °C / Inert atmosphere 5.1: n-butyllithium / diethyl ether / 0.33 h / -78 °C / Inert atmosphere 5.2: -78 - 20 °C / Inert atmosphere

Reference： [1]Tan, Xuefeng; Gao, Shuang; Zeng, Weijun; Xin, Shan; Yin, Qin; Zhang, Xumu [Journal of the American Chemical Society, 2018, vol. 140, # 6, p. 2024 - 2027]

35
[ 75151-82-5 ]
C₂₇H₃₆N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: di-isopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 2.1: n-butyllithium / tetrahydrofuran; hexane / 6.5 h / -20 - 0 °C / Inert atmosphere 2.2: 0.75 h / -78 - 0 °C / Inert atmosphere 2.3: -78 - 20 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran; water / 0 - 20 °C 2.1: n-butyllithium / tetrahydrofuran / 4.5 h / -20 - 0 °C 2.2: 0.75 h / -78 - 20 °C 2.3: -78 - 20 °C

36
[ 75151-82-5 ]
[ 42075-32-1 ]
C₂₇H₃₈N₂O₄ [ No CAS ]