[ CAS No. 285984-25-0 ] {[proInfo.proName]}

Name: 285984-25-0|3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-amine|97%
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SKU: A429531
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Quality Control of [ 285984-25-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 285984-25-0 ]

Product Details of [ 285984-25-0 ]

CAS No. :	285984-25-0	MDL No. :	MFCD04115090
Formula :	C₁₄H₁₉N₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ITHNHEWXIBNEDG-UHFFFAOYSA-N
M.W :	229.32	Pubchem ID :	2974132
Synonyms :

Calculated chemistry of [ 285984-25-0 ] Expand+

Physicochemical Properties

Num. heavy atoms :	17
Num. arom. heavy atoms :	11
Fraction Csp3 :	0.36
Num. rotatable bonds :	2
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	72.2
TPSA :	43.84 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.13 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.74
Log Po/w (XLOGP3) :	3.62
Log Po/w (WLOGP) :	3.07
Log Po/w (MLOGP) :	2.94
Log Po/w (SILICOS-IT) :	2.44
Consensus Log Po/w :	2.96

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.89
Solubility :	0.0296 mg/ml ; 0.000129 mol/l
Class :	Soluble
Log S (Ali) :	-4.23
Solubility :	0.0136 mg/ml ; 0.0000591 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-4.17
Solubility :	0.0154 mg/ml ; 0.0000671 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	2.28

Safety of [ 285984-25-0 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 285984-25-0 ]

* 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 [ 285984-25-0 ]
Downstream synthetic route of [ 285984-25-0 ]

[ 285984-25-0 ] Synthesis Path-Upstream 1~5

1
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Yield	Reaction Conditions	Operation in experiment
86%	With hydrogenchloride In ethanol for 48 h; Reflux	A solution of 4-tolyllhydrazine hydrochloride(5.20 g, 33 mmol) and pentylacyl acetonitrile (3.75 g, 30 mmol) in 0.4 M ethanolic solution of HCl(100 mL) was heated under reflux during 48 h. After cooling to room temperature, 1M NaOH wasadded to the mixture until the pH reached 10–11. The mixture was partitioned between water and ethylacetate. The water phase was extracted twice with dichloromethane. The organic phases werecombined and washed with water and brine, then dried with Na₂SO₄. Evaporation of the solvent invacuo afforded the crude product, which was subjected to recrystallization from ethyl acetate andpetroleum ether to produce compound 25a as a white solid (5.88 g, 86percent yield).
86.4%	With hydrogenchloride In ethanol at 80℃; for 8 h;	A solution of 4-tolyllhydrazine hydrochloride (5.20 g,33 mmol) and pentylacyl acetonitrile (3.75 g, 30 mmol) in 0.4 M ethanolic solution of HCl (100 mL)was heated under reflux during 8 h. After cooling to room temperature, 1 M NaOH was added to the mixture until the pH reached 10–11. The mixture was partitioned between water and ethyl acetate. The water phase was extracted twice with dichloromethane. The organic phases were combined and washed with water and brine, then dried with Na2SO4. Evaporation of the solvent in vacuo afforded the crude product, which was subjected to recrystallization from ethyl acetate and petroleum ether to produce compound 2a as a white solid (5.88 g,). Yield: 86.4percent. ¹H-NMR (CDCl3, 400 MHz), δ: 7.40 (d, 2H),7.25 (d, 2H), 5.50 (s, 1H), 4.72 (brs, 2H), 2.37 (s, 3H), 1.32 (s, 9H). ESI-MS (+Q, m/z): 230 [M + H]+,252 [M + Na]+.
52%	With hydrogenchloride In ethanol; waterReflux	Intermediate A: 3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-amine To a stirred solution of p-tolylhydrazine hydrochloride (100 g, 630 mmol) in EtOH (1251 mL) was added 4,4-dimethyl-3-oxopentanenitrile (88 g, 699 mmol) and HCl (62.5 mL, 750 mmol). The resulting mixture was stirred at reflux overnight. The reaction mixture was cooled to room temperature and concentrated in vacuo to c.a. 1/3 of the original volume. The reaction mixture was then cooled in an ice-bath and taken to c.a. pH 8-9 with 6M aq NaOH. The reaction mixture was extracted with diethyl ether (500 mL) and the organic phase washed with water (2*300 mL) before being dried over magnesium sulphate and concentrated in vacuo to afford an orange solid. The solid was suspended in iso-hexane and stirred at reflux for 2.5 h before being cooled and filtered whilst still hot to yield the subtitle product 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine as a pale brown solid (76.5 g, 52percent); R^t 1.31 min (Method 1); m/z 230 (M+H)⁺ (ES⁺); ¹H NMR δ: 1.20 (9H, s), 2.32 (3H, s), 5.10 (2H, br s), 5.35 (1H, s), 7.24 (2H, d), 7.42 (2H, m).

30 g

for 1.5 h;

Pivaloylacetonitrile (19.0 g) was refluxed with tolylhydrazine hydrochloride (24.0 g) in ethanol (190 ml) for 1.5 hr. The solution was cooled and volatiles removed in vacuo. The residue was extracted with ethyl acetate and 10percent aq. sodium carbonate, and the organic layer washed with water and brine. Drying over sodium sulfate and solvent removal afforded pyrazole 6 as an off-white solid (30 g).

Reference： [1] Patent: US2004/192653, 2004, A1,
[2] Molecules, 2014, vol. 19, # 2, p. 2004 - 2028
[3] Molecules, 2015, vol. 20, # 9, p. 16604 - 16619
[4] Organic Process Research and Development, 2010, vol. 14, # 3, p. 650 - 656
[5] Journal of the American Chemical Society, 2009, vol. 131, # 37, p. 13286 - 13296
[6] Organic Process Research and Development, 2011, vol. 15, # 4, p. 841 - 854
[7] Patent: US2015/232450, 2015, A1, . Location in patent: Paragraph 0205-0206
[8] Journal of Medicinal Chemistry, 2002, vol. 45, # 14, p. 2994 - 3008
[9] Patent: US2008/207647, 2008, A1, . Location in patent: Page/Page column 18
[10] Patent: US2015/183777, 2015, A1, . Location in patent: Paragraph 0191; 0192
[11] Molecules, 2016, vol. 21, # 5,

2
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Yield	Reaction Conditions	Operation in experiment
80.3%	With hydrogenchloride In ethanol for 8 h; Reflux	In a 250 mL pre-flask was added 100 mL of ethanol,(30 mmol) of pivaloylacetonitrile,(33. 63 mmol) of 4-methylphenylhydrazine,3. 6 mL of concentrated hydrochloric acid was added dropwise with stirring, heated under reflux for 8 hours,Cooled, concentrated, the residue adjusted with dilute sodium hydroxide PH10-11,Extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, concentrated,The resulting solid was recrystallized from ethyl acetate / petroleum ether to give white crystals C,Yield 80.3percent. 5-tert-butyl-2-p-methylphenyl-3-aminopyrazole (3. 5 mmolC) was placed in 100 ml three-necked flask and dissolved in 30 ml of tetrahydrofuran. The three-necked flask was allowed to cool to -20 ° C, stirring in batches by adding 2. 9g sodium bicarbonate, 15min, dropwise dropwise chloroformic acid trichloroethyl ester(3. 5 mmol),Control solution temperature does not exceed ° C,After completion of the dropwise addition, the mixture was stirred for 30 min and then heated to 0 ° C for 12 h. After completion of the reaction, the mixture was filtered and the residue was rinsed with ethyl acetate and the filtrate was concentrated to yield 85percent.
80.3%	With hydrogenchloride In ethanol; water for 8 h; Reflux	In a 250 mL round botom flask, 100 mL of ethanol was added, (30 mmol) of pivaloylacetonitrile, (33.63 mmol) of 4-methylphenylhydrazine, A solution of 3.6 mL of concentrated hydrochloric acid was added dropwise with stirring,Heated to reflux for 8 hours, cool down, concentrate, The residue was adjusted to pH 10-11 with dilute sodium hydroxide, Extracted three times with ethyl acetate, Dried over anhydrous sodium sulfate, concentrate, The resulting solid was recrystallized from ethyl acetate / petroleum ether to give white crystals C, Yield 80.3percent. 5-tert-butyl-2-p-methylphenyl-3-aminopyrazole (3.5 mmolC) was placed in a 100 ml three-Dissolved in 30 ml of tetrahydrofuran, Place the three-necked flask in a cryogenic tank to cool to -20 ° C, 2.9 g of sodium bicarbonate was added in portions with stirring, After 15 min, A solution of trichloroethyl chloroformate (3.5 mmol) was added dropwise, Control the solution temperature does not exceed 0 deg C, After dripping, Continue stirring for 30min, And then heated to 0 ° C for 12 h. After completion of the reaction, The mixture is filtered, The residue was washed with ethyl acetate, The filtrate was concentrated, Yield 85percent.
80.3%	for 8 h; Reflux	In 250 ml bottle eggplant adding 100 ml ethanol, (30mmol) special fifth heavenly stem acyl acetonitrile, (33.63mmol) 4 - methyl phenyl hydrazine, stirring next adds by drops 3.6 ml concentrated hydrochloric acid, heating reflux for 8 hours, cooling, concentrated, the residue with dilute sodium hydroxide to adjust the pH 10 - 11, ethyl acetate extraction three times, dried with anhydrous sodium sulfate, concentrated, the obtained solid ethyl acetate/petroleum ether recrystallization to obtain white crystal C, yield 80.3percent. 5 - tert-butyl -2 - methylphenyl -3 - amino pyrazole (3.5mmolC) in 100 ml in three-necked bottle, to 30 ml tetrahydrofuran is dissolved, the low temperature troughthree-necked bottle is lowering the temperature to -20 °C, stirring in batches under the adding 2.9g sodium bicarbonate, 15min after, little by chlorination formic acid trichloroethyl (3.5mmol), control solution at a temperature of not more than 0 °C, after dropping, continuing to stir 30min, then heating up to 0 °C reaction 12h. The completion of the reaction, the mixture filtration, the filter residue washed ethyl acetate, the filtrate is concentrated, yield 85percent.

Reference： [1] Patent: CN106518767, 2017, A, . Location in patent: Paragraph 0075; 0076; 0115
[2] Patent: CN106518766, 2017, A, . Location in patent: Paragraph 0098
[3] Patent: CN106518858, 2017, A, . Location in patent: Paragraph 0076
[4] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 6, p. 1772 - 1777
[5] Patent: US2009/131437, 2009, A1, . Location in patent: Page/Page column 15
[6] Patent: EP1698335, 2006, A1, . Location in patent: Page/Page column 42
[7] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 19, p. 5401 - 5409
[8] MedChemComm, 2016, vol. 7, # 7, p. 1421 - 1428

3
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Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 18, p. 4383 - 4388

4
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Reference： [1] Patent: US2003/232865, 2003, A1, . Location in patent: Page 34-35

5
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Reference： [1] Journal of Medicinal Chemistry, 2002, vol. 45, # 14, p. 2994 - 3008

[ 285984-25-0 ] Synthesis Path-Downstream 1~43

1
[ 59997-51-2 ]
[ 637-60-5 ]
[ 285984-25-0 ]

Yield	Reaction Conditions	Operation in experiment
99%	In methanol;	Step C: 5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-ylamine A solution of p-tolyl-hydrazine hydrochloride (15.86 g, 100 mmol) and pivaloylacetonitrile (17.9 g, 143 mmol) dissolved in MeOH (65 mL) was heated to reflux for 18 hours under N2 atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was triturated with ether and collected by filtration. The solid was dried under high vacuum to provide 26.6 g of white solid (99% yield).
86%	With hydrogenchloride; In ethanol; for 48h;Reflux;	A solution of 4-tolyllhydrazine hydrochloride(5.20 g, 33 mmol) and pentylacyl acetonitrile (3.75 g, 30 mmol) in 0.4 M ethanolic solution of HCl(100 mL) was heated under reflux during 48 h. After cooling to room temperature, 1M NaOH wasadded to the mixture until the pH reached 10-11. The mixture was partitioned between water and ethylacetate. The water phase was extracted twice with dichloromethane. The organic phases werecombined and washed with water and brine, then dried with Na2SO4. Evaporation of the solvent invacuo afforded the crude product, which was subjected to recrystallization from ethyl acetate andpetroleum ether to produce compound 25a as a white solid (5.88 g, 86% yield).
86.4%	With hydrogenchloride; In ethanol; at 80℃; for 8h;	A solution of 4-tolyllhydrazine hydrochloride (5.20 g,33 mmol) and pentylacyl acetonitrile (3.75 g, 30 mmol) in 0.4 M ethanolic solution of HCl (100 mL)was heated under reflux during 8 h. After cooling to room temperature, 1 M NaOH was added to the mixture until the pH reached 10-11. The mixture was partitioned between water and ethyl acetate. The water phase was extracted twice with dichloromethane. The organic phases were combined and washed with water and brine, then dried with Na2SO4. Evaporation of the solvent in vacuo afforded the crude product, which was subjected to recrystallization from ethyl acetate and petroleum ether to produce compound 2a as a white solid (5.88 g,). Yield: 86.4%. 1H-NMR (CDCl3, 400 MHz), delta: 7.40 (d, 2H),7.25 (d, 2H), 5.50 (s, 1H), 4.72 (brs, 2H), 2.37 (s, 3H), 1.32 (s, 9H). ESI-MS (+Q, m/z): 230 [M + H]+,252 [M + Na]+.

52%	With hydrogenchloride; In ethanol; water;Reflux;	Intermediate A: 3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-amine To a stirred solution of p-tolylhydrazine hydrochloride (100 g, 630 mmol) in EtOH (1251 mL) was added 4,4-dimethyl-3-oxopentanenitrile (88 g, 699 mmol) and HCl (62.5 mL, 750 mmol). The resulting mixture was stirred at reflux overnight. The reaction mixture was cooled to room temperature and concentrated in vacuo to c.a. 1/3 of the original volume. The reaction mixture was then cooled in an ice-bath and taken to c.a. pH 8-9 with 6M aq NaOH. The reaction mixture was extracted with diethyl ether (500 mL) and the organic phase washed with water (2*300 mL) before being dried over magnesium sulphate and concentrated in vacuo to afford an orange solid. The solid was suspended in iso-hexane and stirred at reflux for 2.5 h before being cooled and filtered whilst still hot to yield the subtitle product 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine as a pale brown solid (76.5 g, 52%); Rt 1.31 min (Method 1); m/z 230 (M+H)+ (ES+); 1H NMR delta: 1.20 (9H, s), 2.32 (3H, s), 5.10 (2H, br s), 5.35 (1H, s), 7.24 (2H, d), 7.42 (2H, m).
	In ethyl acetate; N,N-dimethyl-formamide; toluene;Heating / reflux;	1.4 Preparation of 5-tert-butyl-2p-tolyl-2H-pyrazol-3-ylamine ("1d") 5 g of p-tolylhydrazine hydrochloride and 3.8 g of 4,4-dimethyl-3-oxopentanenitrile are dissolved in 100 ml of toluene. The entire mixture is refluxed overnight. For work-up, the solvent is stripped off in a rotary evaporator. Water is added to the residue, which is then extracted with ethyl acetate. The organic phase is dried using Na2SO4, filtered. The filtrate is evaporated in a rotary evaporator and chromatographed (petroleum ether/ethyl acetate 1/1), giving 5.7 g of "1d", HPLC/MS [M+H+] 230.
30 g	In ethanol; for 1.5h;	Pivaloylacetonitrile (19.0 g) was refluxed with tolylhydrazine hydrochloride (24.0 g) in ethanol (190 ml) for 1.5 hr. The solution was cooled and volatiles removed in vacuo. The residue was extracted with ethyl acetate and 10% aq. sodium carbonate, and the organic layer washed with water and brine. Drying over sodium sulfate and solvent removal afforded pyrazole 6 as an off-white solid (30 g).
	In ethanol; at 80℃;	General procedure: A solution of the corresponding substituted phenylhydrazine hydrochloride (1 equiv.) and pivaloylacetonitrile (1.2 equiv.) was stirred overnight at 80 C in ethanol. The solution was extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), filtered, and evaporated to dryness. 3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-amine (2a). From p-tolylhydrazine hydrochloride (1.59 g, 10 mmol)and pivaloylacetonitrile (1.5 g, 12 mmol), after work-up and without further purification, compound 2a was obtained as a white solid (1.8 g, 80%). IR (KBr): 3345, 1598, 1578 cm-1; 1H-NMR (CDCl3) delta: 7.40 (d, 2H, J = 8.8 Hz), 7.25 (d, 2H, J = 8.8 Hz), 5.50 (s, 1H), 3.72 (brs, 2H, NH2), 2.37 (s, 3H), 1.32 (s,9H). MS (ESI): m/z 252.16 [M + Na]+. Mp 121.3-123.4 C.
3.6 g	In ethanol; for 1.5h;Reflux;	Pivaloylacetonitrile (1 ) (1.9 g, 15.1 mMol) was placed in a flask with tolylhydrazine hydrochloride (2.4 g, 15.1 mMol) in ethanol (19 mL) and the solution was heated to reflux for 1.5 hr. The solution was concentrated in vacuo until only a small amount of ethanol remained whereupon it was triturated with hexane, allowing it to stir for 1 hr before filtration of the white solid. Pyrazole 2 was isolated as its hydrochloride salt (3.6 g. 1.35 mMol) and was determined to be pure by LC-MS analysis (M+H=230.1).

Reference： [1]Patent: US2004/192653,2004,A1
[2]Molecules,2014,vol. 19,p. 2004 - 2028
[3]Molecules,2015,vol. 20,p. 16604 - 16619
[4]Organic Process Research and Development,2010,vol. 14,p. 650 - 656
[5]Journal of the American Chemical Society,2009,vol. 131,p. 13286 - 13296
[6]Organic Process Research and Development,2011,vol. 15,p. 841 - 854
[7]Patent: US2015/232450,2015,A1 .Location in patent: Paragraph 0205-0206
[8]Journal of Medicinal Chemistry,2002,vol. 45,p. 2994 - 3008
[9]Patent: US2008/207647,2008,A1 .Location in patent: Page/Page column 18
[10]Patent: US2015/183777,2015,A1 .Location in patent: Paragraph 0191; 0192
[11]Molecules,2016,vol. 21
[12]Patent: WO2019/232275,2019,A1 .Location in patent: Page/Page column 76

2
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[ 285984-47-6 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sodium hydroxide; In water; ethyl acetate; at 10.9 - 25.5℃; for 1h;	To a solution of 3-tert-butyl-l-p-tolyl-lH-pyrazol-5-amine (102.9 g, 448.9 mmol) in EtOAc (1 L) at 10.9 0C was added a NaOH solution (2.5 M5 269 mL), and the biphasic reaction mixture warmed to 15.9 and then stabilized. Phenyl chloroformate (98.4 g, <n="59"/>156.5 mmol) was added in one portion and the temperature rose to 25.5 and then stabilized. The ice bath was removed and the reaction was monitored by HPLC. After 1 hour an additional 25 mL of 2.5 M NaOH was added. The reaction mixture was stirred overnight, and then diluted with EtOAc (200 mL). The organic layer was washed with brine (1 L)5 dried over Na2SO4 (200 g) and concentrated to about 400 to 500 mL of EtOAc. The concentrated solution was warmed to 60 0C. After the solids had dissolved, heptane (2 L) was slowly added, during which solids formed. After stirring for 30 minutes the solid was collected via filtration and the cake was washed with 400-500 mL of heptane. The cake was dried in a vacuum oven at ambient temperature to yield 156.9 g (95.0%) of the title compound. 1H NMR (400 MHz3 CDCl3) delta 7.39 - 7.31 (m, 6H), 7.26-7.225 (m, 2H), 7.13 (br s, 2H)5 6.96 (br s. IH), 6.47 (br s, IH), 2.42 (s, 3H), 1.34 (s, 9H).
88%	With sodium carbonate; In Isopropyl acetate; water; at 20℃;	Intermediate B: Phenyl (3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)carbamate A solution of <strong>[285984-25-0]3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-amine</strong> (Intermediate A) (20 g, 87.0 mmol) in isopropyl acetate (240 mL) was added to a stirred solution of sodium carbonate (11.3 g, 106 mmol) in water (80 mL). After 10 min phenyl chloroformate (12.1 mL, 96 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with water (160 mL), the layers were separated and the organics were washed with water (2*80 mL), brine (80 mL), dried (MgSO4) and concentrated in vacuo. The resulting yellow solid was suspended in 10% ether/iso-hexane (320 mL) and stirred until a uniform suspension was obtained. The solid was collected by filtration and washed with iso-hexane to yield the subtitle compound phenyl (3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)carbamate as a white powder (27.3 g, 88%); Rt 2.65 min (Method 1); m/z 350 (M+H)+ (ES+); 1H NMR delta:1.29 (9H, s), 2.37 (3H, s), 6.35 (1H, s), 7.10-7.23 (3H, overlapping m), 7.33-7.46 (6H, overlapping m), 9.99 (1H, s).
70%		Example 2 1-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((2-oxoindolin-6-yl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea To a solution of Intermediate A1 (1.01 g, 4.30 mmol) in isopropyl acetate (40 mL) at RT was added a solution of Na2CO3 (552 mg, 5.21 mmol) in water (10 mL). After 5 min phenyl chloroformate (550 muL, 4.36 mmol) was added and the resulting biphasic reaction mixture was maintained at RT for 3 days. The layers were separated and the organic phase was washed with water (30 mL) and then dried and evaporated in vacuo to afford phenyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate as an off-white solid (1.36 g, 70% pure by HPLC, 63%); Rt 2.68 min (Method 2, acidic); m/z 350 (M+H)+, (ES+).

	With sodium carbonate; In Isopropyl acetate; water; at 20℃; for 4h;	Na2CO3 (3.84 g, 36 mmol) in water (42 mL) and Intermediate A1 (10.5 g, 45.7 mmol) in isopropyl acetate (130 mL, 1.082 mol) was stirred vigorously at RT for 5 min and was then treated with phenyl carbonochloridate (5.77 ml, 45.7 mmol). Stirring of the mixture was continued for a further 4 hr after which the layers were separated. The organic phase was added to a solution of Intermediate B1 (10.0 g, 30.5 mmol) and triethylamine (423 muL, 3.05 mmol) in ispropyl acetate (60 mL, 511 mmol). The reaction mixture was warmed to 48 C for 1 hr, then diluted with isopropyl acetate (190 mL) and cooled to RT for a further 18 hr, during which time a precipitate formed. The precipitate was isolated by filtration, washed with isopropyl acetate and then dried in vacuo at 40 C to afford the title compound, Example 1 as a white solid (16.5 g, 92 %); Rt2.74 min (Method 2); m/z 584 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) delta: 1.30 (9H, s), 2.41 (3H, s), 6.43 (1H, s), 6.58 (1H, d), 6.78 (1H, t), 6.97 (2H, t), 7.28 (2H, br m), 7.39 (2H, d), 7.40 (1H, d), 7.49 (2H, d), 7.56 (1H, m), 7.63 (1H, m), 7.82 (1H, dd), 7.95 (1H, d), 8.10 (1H, d), 8.40 (1H, d), 8.77 (1H, s), 9.16 (1H, br s), 9.50 (1H, br s).
1.36 g	With sodium carbonate; In Isopropyl acetate; water; at 20℃; for 72h;	To a solution of Intermediate A1 (1.01 g, 4.30 mmol) in isopropyl acetate (40 mL) at RT was added a solution of Na2C03 (552 mg, 5.21 mmol) in water (10 mL). After 5 min phenyl chloroformate (550 pL, 4.36 mmol) was added and the resulting biphasic reaction mixture was maintained at RT for 3 days. The layers were separated and the organic phase was washed with water (30 mL) and then dried and evaporated in vacuo to afford phenyl 3-tert- butyl-1-p-tolyl-1 H-pyrazol-5-ylcarbamate as an off-white solid (1.36g, 70% pure by HPLC, 63%); Rl 2.68 min (Method 2, acidic); m/z 350 (M+H)+, (ES+). This material was used directly in the subsequent synthetic step without additional purification.
16.9 g	With sodium hydrogencarbonate; In tetrahydrofuran; water; for 1h;	Pyrazole 6 (12.7 g), saturated aq. sodium bicarbonate (338 ml), and THF (200 ml) were cooled in an ice-bath. The rapidly stirring mixture was added phenyl chloroformate (13.0 g) drop-wise. After one additional hr of stirring the mixture was extracted with ether and the organic layer washed with water. Drying over sodium sulfate and solvent removal in vacuo afforded a white solid that was dissolved in DCM (80-100 ml) and hexane (350 ml) added wile rapidly stirring. The solids were filtered, washed with hexane, and dried to afford pyrazole 7 as a white solid (16.9 g). LC-MS retention time=5.35 min.
1.46 g	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 0.5h;	Pyrazole 2 (1.0 g, 4.4 mMol), diisopropylethylamine (684 mg, 5.3 mMol), and DCM (9 mL) were cooled to -10 C. and phenyl chloro formate (750 mg, 4.8 mMol) was added in a single portion. The solution was allowed to warm to 0 C. and stir for 30 min. The solution was partitioned between ether and aqueous sodium bicarbonate and the ether layer was washed with brine. The organic fraction was dried over anhydrous sodium sulfate and the solvent removed in vacuo. [Alternatively, for less reactive intermediates, the reaction with phenyl chloroformate was performed in DCM solvent in the presence of DIPEA as base.] After workup the residue purified using silica gel chromatography eluting with ethyl acetate (5%- 50%)/hexane. Solvent removal afforded the carbamate (3) as a brittle foam (1.46 g) which provided a single peak by LC-MS analysis (M+H=350.3). 1 H NMR (400 MHz, CDCb) d: 7.40-7.38 (m, 3H), 7.34 (dd, J=8.4, Hz, 2H). 7.25 (tt, J=7.6 Hz, 2H), 7.12 (d, J=6.6 Hz, 2H) 6.95 (br s, l H). 6.5 (s, 1 H), 2.43 (s, 3H), 1.36 (s, 9H).

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 2741 - 2756
[2]Patent: WO2007/89646,2007,A1 .Location in patent: Page/Page column 56-57
[3]Patent: US2015/232450,2015,A1 .Location in patent: Paragraph 0207-0208
[4]Patent: US2015/203475,2015,A1 .Location in patent: Paragraph 0557; 0558
[5]Journal of Medicinal Chemistry,2003,vol. 46,p. 4676 - 4686
[6]Patent: EP2578582,2013,A1 .Location in patent: Paragraph 0088; 0089
[7]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 5401 - 5409
[8]Patent: WO2014/33448,2014,A1 .Location in patent: Page/Page column 70
[9]Patent: US2015/183777,2015,A1 .Location in patent: Paragraph 0187; 0192
[10]Patent: WO2019/232275,2019,A1 .Location in patent: Page/Page column 76-77

3
[ 285984-25-0 ]
[ 285983-48-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sat. aq. NaHCO₃ / CH₂Cl₂; toluene / 0.25 h 2: 0.065 g / di-isopropylethylamine / tetrahydrofuran / 20 °C

Reference： [1]Regan, John; Moss, Neil; Pargellis, Chris; Pav, Sue; Proto, Alfred; Swinamer, Alan; Tong, Liang; Torcellini, Carol; Breitfelder, Steffen; Cirillo, Pier; Gilmore, Thomas; Graham, Anne G.; Hickey, Eugene; Klaus, Bernhard; Madwed, Jeffrey; Moriak, Monica [Journal of Medicinal Chemistry, 2002, vol. 45, # 14, p. 2994 - 3008]

4
[ 59997-51-2 ]
[ 539-44-6 ]
[ 285984-25-0 ]

Yield	Reaction Conditions	Operation in experiment
80.3%	With hydrogenchloride; In ethanol; for 8h;Reflux;	In a 250 mL pre-flask was added 100 mL of ethanol,(30 mmol) of pivaloylacetonitrile,(33. 63 mmol) of 4-methylphenylhydrazine,3. 6 mL of concentrated hydrochloric acid was added dropwise with stirring, heated under reflux for 8 hours,Cooled, concentrated, the residue adjusted with dilute sodium hydroxide PH10-11,Extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, concentrated,The resulting solid was recrystallized from ethyl acetate / petroleum ether to give white crystals C,Yield 80.3%. 5-tert-butyl-2-p-methylphenyl-3-aminopyrazole (3. 5 mmolC) was placed in 100 ml three-necked flask and dissolved in 30 ml of tetrahydrofuran. The three-necked flask was allowed to cool to -20 C, stirring in batches by adding 2. 9g sodium bicarbonate, 15min, dropwise dropwise chloroformic acid trichloroethyl ester(3. 5 mmol),Control solution temperature does not exceed C,After completion of the dropwise addition, the mixture was stirred for 30 min and then heated to 0 C for 12 h. After completion of the reaction, the mixture was filtered and the residue was rinsed with ethyl acetate and the filtrate was concentrated to yield 85%.
80.3%	With hydrogenchloride; In ethanol; water; for 8h;Reflux;	In a 250 mL round botom flask, 100 mL of ethanol was added, (30 mmol) of pivaloylacetonitrile, (33.63 mmol) of 4-methylphenylhydrazine, A solution of 3.6 mL of concentrated hydrochloric acid was added dropwise with stirring,Heated to reflux for 8 hours, cool down, concentrate, The residue was adjusted to pH 10-11 with dilute sodium hydroxide, Extracted three times with ethyl acetate, Dried over anhydrous sodium sulfate, concentrate, The resulting solid was recrystallized from ethyl acetate / petroleum ether to give white crystals C, Yield 80.3%. 5-tert-butyl-2-p-methylphenyl-3-aminopyrazole (3.5 mmolC) was placed in a 100 ml three-Dissolved in 30 ml of tetrahydrofuran, Place the three-necked flask in a cryogenic tank to cool to -20 C, 2.9 g of sodium bicarbonate was added in portions with stirring, After 15 min, A solution of trichloroethyl chloroformate (3.5 mmol) was added dropwise, Control the solution temperature does not exceed 0 deg C, After dripping, Continue stirring for 30min, And then heated to 0 C for 12 h. After completion of the reaction, The mixture is filtered, The residue was washed with ethyl acetate, The filtrate was concentrated, Yield 85%.
80.3%	With hydrogenchloride; for 8h;Reflux;	In 250 ml bottle eggplant adding 100 ml ethanol, (30mmol) special fifth heavenly stem acyl acetonitrile, (33.63mmol) 4 - methyl phenyl hydrazine, stirring next adds by drops 3.6 ml concentrated hydrochloric acid, heating reflux for 8 hours, cooling, concentrated, the residue with dilute sodium hydroxide to adjust the pH 10 - 11, ethyl acetate extraction three times, dried with anhydrous sodium sulfate, concentrated, the obtained solid ethyl acetate/petroleum ether recrystallization to obtain white crystal C, yield 80.3%. 5 - tert-butyl -2 - methylphenyl -3 - amino pyrazole (3.5mmolC) in 100 ml in three-necked bottle, to 30 ml tetrahydrofuran is dissolved, the low temperature troughthree-necked bottle is lowering the temperature to -20 C, stirring in batches under the adding 2.9g sodium bicarbonate, 15min after, little by chlorination formic acid trichloroethyl (3.5mmol), control solution at a temperature of not more than 0 C, after dropping, continuing to stir 30min, then heating up to 0 C reaction 12h. The completion of the reaction, the mixture filtration, the filter residue washed ethyl acetate, the filtrate is concentrated, yield 85%.

	In toluene; at 20℃; for 12h;Heating / reflux;	The title compound is prepared according to a published literature procedure (see J. Med. Chem. 2002, 45, 2994-3008.) 3.5 g (27.8 mMol) of pivaloylacetonitrile are added to a solution of 3.4 g (27.8 mMol) p-tolylhydrazine in 50 mL of toluene at rt, and the resulting yellow solution is heated to and kept under reflux for 12 h. After completion, the reaction mixture is concentrated, and the resulting crude product is purified by flash chromatography (SiO2, 100% CH2Cl2) to give the title compound as a yellow solid.
	In toluene;Heating / reflux;	A solution of 4-methylphenylhydrazine (0.90mL) and 4,4-dimethyl-3-oxopentanenitrile (1.0g) in toluene (3mL) was refluxed overnight. The reaction mixture was concentrated and the residue was purified by column to give the title compound (1.53g).

Reference： [1]Patent: CN106518767,2017,A .Location in patent: Paragraph 0075; 0076; 0115
[2]Patent: CN106518766,2017,A .Location in patent: Paragraph 0098
[3]Patent: CN106518858,2017,A .Location in patent: Paragraph 0076
[4]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 1772 - 1777
[5]Patent: US2009/131437,2009,A1 .Location in patent: Page/Page column 15
[6]Patent: EP1698335,2006,A1 .Location in patent: Page/Page column 42
[7]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 5401 - 5409
[8]MedChemComm,2016,vol. 7,p. 1421 - 1428

5
[ 285984-25-0 ]
[ 17341-93-4 ]
[ 317806-87-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	With sodium hydroxide; In water; ethyl acetate;	Step D: (5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloroethyl ester A cooled (0 C.) biphasic solution of 5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylamine (26.6 g, 100 mmol) in water (80 mL) and ethyl acetate (180 mL) was treated with NaOH (10 g, 250 mmol) followed by trichloroethylchloroformate (29.7 g, 140 mmol). The reaction mixture was warmed to room temperature and stirred for 1 hour. The layers were separated and the organic layer was washed with brine (100 mL), dried over MgSO4, filtered through Celite, and concentrated under reduced pressure to provide 40.3 g of pale yellow solid (99% yield).
85.2%	With sodium hydrogencarbonate; In tetrahydrofuran; at 0℃; for 12h;	The 2a (0.80 g, 3.5 mmol)was put in a 100 mL three-necked bottle and then dissolved in 30 mL THF . The bottle was cooled to 0 C and then put 2.9 g NaHCO3 into the bottle while stirring. Then drip the 2,2,2-trichloroethylcarbonochloridate into the bottle, keep the temp for 30 min, then 0 C for 12 h. The mixture was filtered and then extracted with ethyl acetate for 3 times. Dry the solution with sodium sulfate, concentrating then separate the production with column chromatograph. Yield: 85.2%. 1H-NMR (CDCl3, 400 MHz),delta: 9.10 (s, 1H), delta: 7.40 (d, 2H), 7.25 (d, 2H), 5.56 (s, 1H), 4.79 (s, 2H), 2.36 (s, 3H), 1.30 (s, 9H). ESI-MS(+Q, m/z): 404 [M + H]+, 426 [M + Na]+.
85%	With sodium hydrogencarbonate; In tetrahydrofuran; at -20 - 0℃; for 12.5h;	In a 250 mL pre-flask was added 100 mL of ethanol,(30 mmol) of pivaloylacetonitrile,(33. 63 mmol) of 4-methylphenylhydrazine,3. 6 mL of concentrated hydrochloric acid was added dropwise with stirring, heated under reflux for 8 hours,Cooled, concentrated, the residue adjusted with dilute sodium hydroxide PH10-11,Extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, concentrated,The resulting solid was recrystallized from ethyl acetate / petroleum ether to give white crystals C,Yield 80.3%. <strong>[285984-25-0]5-tert-butyl-2-p-methylphenyl-3-aminopyrazole</strong> (3. 5 mmolC) was placed in 100 ml three-necked flask and dissolved in 30 ml of tetrahydrofuran. The three-necked flask was allowed to cool to -20 C, stirring in batches by adding 2. 9g sodium bicarbonate, 15min, dropwise trichloroethyl chloroformate(3. 5 mmol),Control solution temperature does not exceed C,After completion of the dropwise addition, the mixture was stirred for 30 min and then heated to 0 C for 12 h. After completion of the reaction, the mixture was filtered and the residue was rinsed with ethyl acetate and the filtrate was concentrated to yield 85%

85%		In a 250 mL round botom flask, 100 mL of ethanol was added, (30 mmol) of pivaloylacetonitrile, (33.63 mmol) of 4-methylphenylhydrazine, A solution of 3.6 mL of concentrated hydrochloric acid was added dropwise with stirring,Heated to reflux for 8 hours, cool down, concentrate, The residue was adjusted to pH 10-11 with dilute sodium hydroxide, Extracted three times with ethyl acetate, Dried over anhydrous sodium sulfate, concentrate, The resulting solid was recrystallized from ethyl acetate / petroleum ether to give white crystals C, Yield 80.3%. <strong>[285984-25-0]5-tert-butyl-2-p-methylphenyl-3-aminopyrazole</strong> (3.5 mmolC) was placed in a 100 ml three-Dissolved in 30 ml of tetrahydrofuran, Place the three-necked flask in a cryogenic tank to cool to -20 C, 2.9 g of sodium bicarbonate was added in portions with stirring, After 15 min, A solution of trichloroethyl chloroformate (3.5 mmol) was added dropwise, Control the solution temperature does not exceed 0 deg C, After dripping, Continue stirring for 30min, And then heated to 0 C for 12 h. After completion of the reaction, The mixture is filtered, The residue was washed with ethyl acetate, The filtrate was concentrated, Yield 85%.
85%		In 250 ml bottle eggplant adding 100 ml ethanol, (30mmol) special fifth heavenly stem acyl acetonitrile, (33.63mmol) 4 - methyl phenyl hydrazine, stirring next adds by drops 3.6 ml concentrated hydrochloric acid, heating reflux for 8 hours, cooling, concentrated, the residue with dilute sodium hydroxide to adjust the pH 10 - 11, ethyl acetate extraction three times, dried with anhydrous sodium sulfate, concentrated, the obtained solid ethyl acetate/petroleum ether recrystallization to obtain white crystal C, yield 80.3%. 5 - tert-butyl -2 - methylphenyl -3 - amino pyrazole (3.5mmolC) in 100 ml in three-necked bottle, to 30 ml tetrahydrofuran is dissolved, the low temperature troughthree-necked bottle is lowering the temperature to -20 C, stirring in batches under the adding 2.9g sodium bicarbonate, 15min after, little by chlorination formic acid trichloroethyl (3.5mmol), control solution at a temperature of not more than 0 C, after dropping, continuing to stir 30min, then heating up to 0 C reaction 12h. The completion of the reaction, the mixture filtration, the filter residue washed ethyl acetate, the filtrate is concentrated, yield 85%.
83%	With sodium carbonate; In tetrahydrofuran; at 0℃; for 2h;	Preparation 17 l-(5-te^-Butyl-2-p-tolyl-2ff-pyrazol-3-ylVcarbamic acid 2.2.2-trichloro-ethyl ester To a solution of 5-te^-butyl-2-^-tolyl-2F-pyrazol-3-ylamine (Regan et al. J. Med. Chem. 2002, 45,2994-3008, 400 g, 1.74 mol) in THF (8L) add a saturated solution of sodium carbonate (2.4 L) and cool the mixture to 0 0C. Then add 2, 2, 2-trichloroethyl chloroformate (406.77 g, 1.92 mol) dropwise and stir mixture at 0 0C for 2 hours. Extract the reaction mixture with ethyl acetate (3 x 6.5L), dry over anhydrous magnesium sulfate and evaporate the solvent. Dissolve the solid in a minimum amount of ethyl acetate and <n="17"/>add an excess of hexanes to precipitate the solid. Collect the solid by filtration and dry to obtain the title compound as an off white solid (586 g, 83% yield). (ES+): m/z 406.1 (M+H).
83%	With sodium carbonate; In tetrahydrofuran; water; at 0℃; for 2h;	Preparation 38 5-fert-butyl-2- g-tolyl-2i7-pyrazol-3-ylVcarbamic acid. 2.2.2-trichloro-ethyl ester <n="28"/>Add a saturated solution OfNa2CO3 (2.4 L) to a solution of 5-tert-butyl-2-/>-tolyl-2.ff-pyrazol-3- ylamine (400 g, 1.74 mol) in THF (8L) and cool the mixture to 0 C. Then dropwise add 2, 2, 2- trichloroethyl chloroformate (406.77 g, 1.92 mol) and stir the mixture at 0 C for 2 hours. Extract the reaction mixture with ethyl acetate (3 x 6.5L), dry over anhydrous magnesium sulfate and concentrate. Dissolve the solid in a minimal amount of ethyl acetate and add an excess of hexanes to precipitate. Collect the solid by filtration and dry to obtain the title compound as an off white solid (586 g, 83% yield). 1H NMR (400 MHz, CDCl3) delta 7.34 (d, 2H), 7.29 (d, 2H), 6.78 (bs, IH), 6.41 (bs, IH), 4.81 (s, 2H), 2.41 (s, 3H), 1.34 (s, 9H). MS(ES+): m/? = 406.1 [M+H].
102 g	With sodium hydrogencarbonate; In tetrahydrofuran; at 5 - 20℃; for 4h;	To a stirred solution of 3-tert-butyl-l-(4-methylphenyl)-lH-pyrazol-5-amine (80gm, 349 mmol) (J. Med. Chem., 2002, 45, 2994-3008) and sodium bicarbonate (80gm, 952.38 mmol) in tetrahydrofuran (500 ml), 2,2,2-trichloroethyl chloroformate (57ml, 420mmol) was added at 5-10 C. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was poured into water and extracted by ethyl acetate. Ethyl acetate layer was separated, dried over sodium sulfate and evaporated under vacuum to get crude compound. The crude compound was suspended in hexane (500 ml), stirred at 0-5 C and separated solid was filtered and dried to get 102.0 gm of title compound as solid. 1H-NMR (400 MHz, DMSO-J6): delta 9.90 (1H, s), 7.35 (2H, d), 7.25 (2H, d), 6.26 (1H, s), 4.85 (2H, s), 2.33 (3H, s), 1.27 (9H, s). ESMS: 403.90, 405.91
	In tetrahydrofuran; at 0℃;	General procedure: A solution of the corresponding 2a-2i (1 equiv.) and 2,2,2-trichloroethyl carbonochloridate(1.1 equiv.) in THF was stirred 6 h at 0 C, then the mixture was filtered and extracted three times with ethyl acetate. The solution was dried with MgSO4 and concentrated to dryness. 2,2,2-Trichloroethyl(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)carbamate (3a). From 2a (2.30 g, 10 mmol) and2,2,2-trichloroethyl carbonochloridate (2.3 g, 11 mmol), after work-up and without further purification,3a was obtained as a white solid (3.02 g, 75%). IR (KBr): 3169, 1597, 1580 cm-1; 1H-NMR (DMSO-d6) :delta 9.47 (s, 1H), 7.41 (d, 2H, J = 8.8 Hz), 7.23 (d, 2H, J = 8.8 Hz), 5.51 (s, 1H), 4.85(s, 2H), 1.32 (s, 9H).MS (ESI): m/z 426.06 [M + Na]+. Mp 153.3-155.7 C.

Reference： [1]Patent: US2004/192653,2004,A1
[2]Synthetic Communications,2009,vol. 39,p. 3999 - 4009
[3]Molecules,2015,vol. 20,p. 16604 - 16619
[4]Patent: CN106518767,2017,A .Location in patent: Paragraph 0075; 0076; 0115
[5]Patent: CN106518766,2017,A .Location in patent: Paragraph 0098
[6]Patent: CN106518858,2017,A .Location in patent: Paragraph 0076
[7]Patent: WO2007/53346,2007,A1 .Location in patent: Page/Page column 15-16
[8]Patent: WO2007/53394,2007,A1 .Location in patent: Page/Page column 26-27
[9]Journal of the American Chemical Society,2009,vol. 131,p. 13286 - 13296
[10]Patent: WO2016/30852,2016,A1 .Location in patent: Page/Page column 31
[11]Molecules,2016,vol. 21

6
[ 60633-91-2 ]
[ 285984-25-0 ]
[ 945996-01-0 ]

Yield	Reaction Conditions	Operation in experiment
53%		Step 2: Synthesis of N-l-(2-(bromomethvnbenzyl>3-(3-tert-butyl-l-P-tolyl-lH- pyrazoI-S-vDnrea.2-(Bromomethyl)benzaldehyde (0.23 g, 1.15 mmol) was dissolved in toluene (30 mL). 3-te/t-Butyl-l-p-tolyl-lH-pyrazol-5-amine (0.158 g, 0.578 mmol), triethylsilane (0.37 mL, 0.269 g, 2.30 mmol), and trifluoroacetic acid (0.222 mL, 0.341 g, 2.99 mmol) were added. The reaction was stirred at 65 0C for five hours. It was allowed to cool to room temperature. Ethyl acetate (50 mL) was added and it was extracted with NaHCO3 (aq.) (50 mL) and H2O (50 mL). The organic phase was dried over MgSO4, filtered, and evaporated. The crude product was purified by flash column chromatography. The resulting solid was recrystallized from ethyl acetate / hexane. (0.140 g, 53 %). <n="285"/>IHNMR (400 MHz5 DMSO-J6) delta ppm 1.22 (s, 9H) 2.33 (s, 3H) 4.35 (d, J=5.64 Hz, 2H) 4.74 (s, 2H) 6.25 (s, IH) 6.95 (t, J=5.50 Hz, IH) 7.15-7.35 (m, 7H) 7.34-7.46 (m, IH) 8.21 (s, IH) HRMS (m/z) 455.1444. M+H, C23H27BrN4O requires 455.1441.

Reference： [1]Patent: WO2007/91176,2007,A1 .Location in patent: Page/Page column 282-283

7
[ 285984-25-0 ]
[ 503-38-8 ]
[ 499972-03-1 ]

Yield	Reaction Conditions	Operation in experiment
90%	With sodium hydrogencarbonate; In dichloromethane; water; at 0 - 20℃; for 1h;	To a solution of <strong>[285984-25-0]3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine</strong> (5) (1.00 g, 4.36 mmol) in DCM (90 mL) was added a saturated aq solution of NaHCO3 (60 mL). The mixture was stirred vigorously, cooled to 0 C. and diphosgene (2.1 mL, 17.4 mmol) was added in a single portion. After stirring for 1 hr at RT, the layers were separated and the organics dried and evaporated to give a brown oil. The oil was triturated with isohexane (5.0 mL) and the solid filtered. The filtrate was concentrated in vacuo to give 3-tert-butyl-5-isocyanato-1-p-tolyl-1H-pyrazole (28) as a light brown oil (1.00 g, 3.92 mmol, 90%). m/z 288 (in MeOH) (M+H+MeOH)+ (ES+).
83%	In toluene; at 0 - 20℃;	To a stirring solution of 5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-ylamine (250mg, leq) in dry toluene at0 C trichloromethylchloroformate(l. leq) was added dropwise. The reaction stirred at0 C and allowed to warm to room temperature overnight. The solvent was removed and the mixture was recrystallized in ethyl acetate. The solid was filtered off and <Desc/Clms Page number 164>washed with cold ethyl acetate. Yield: 242mg (83%).
	With sodium hydrogencarbonate; In dichloromethane; water; at 0℃; for 1.33333h;	A saturated aq. solution of NaHCO3 (H mL) was added to a solution of 3-terf-butyl-1 -p-tolyl-1 H- pyrazol-5-amine (WO 2000043384) (206 mg, 0.900 mmol) in DCM (20 mL) and the mixture was cooled to O0C and stirred vigorously whilst trichloromethylchloroformate (325 mul_, 2.70 mmol) was added in a single portion. The vigorous stirring was continued at O0C for a further 80 min. The organic layer was separated and dried and was then evaporated in vacuo to provide 3-te/f-butyl-5-isocyanato-1-p-tolyl-1 /-/-pyrazole, Intermediate B1 as orange oil. This material was pumped for 30 min under high vacuum and was then taken up into THF (6.0 ml.) and kept under nitrogen at O0C and used directly in the next step.

	With sodium hydrogencarbonate; In dichloromethane; water; at 0℃; for 1.33333h;	Intermediate D: 1 -(4-(2-Aminopyridin-4-yloxy)naphthalen-1 -yl)-3-(3-ieri-butyl-1 -p-tolyl-1 H- pyrazol-5-yl)urea To a stirred solution of 2-chloro-4-fluoropyridine (1 .26 g, 9.58 mmol) and 4-amino-1 -naphthol hydrochloride (750 mg, 3.83 mmol) in NMP (40 mL) at -20C was added potassium tert- butoxide (1 .29 g, 1 1.50 mmol) and the reaction mixture then warmed to RT for 2.5 hr. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL and 2 x 80 mL) and the combined organic extracts were washed with brine (150 mL), dried and evaporated in vacuo. The crude product was subjected to SCX capture and release and the volatiles were removed in vacuo to give 4-(2-chloropyridin-4-yloxy)naphthalen-1 -amine as a brown solid (1 .02 g, 92%): m/z 271 (M+H)+ (ES+).To a stirred solution of 4-(2-chloropyridin-4-yloxy)naphthalen-1 -amine (1 .02 g, 3.76 mmol) in THF (30 mL) at 0C was added DMAP (34 mg, 0.282 mmol) and then di-ie/f-butyl dicarbonate (904 mg, 4.14 mmol). The reaction mixture was stirred at 0C for 30 min and was then allowed to warm to RT. After 1 .5 hr the mixture was re-cooled to 0C and an additional aliquot of di-ie f- butyl dicarbonate (904 mg, 4.14 mmol) was added. The resulting mixture was stirred at 0C for 15 min and at RT for 16 hr and was diluted with water (40 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were washed with brine (75 mL), dried and evaporated in vacuo. The residue was purified by flash column chromatography (Si02, 80 g, 0-40% EtOAc in iso-hexane, gradient elution) to give 4-(2-chloropyridin-4-yloxy)naphthalen-1 -yV,yV-di-ieri- butylcarbamate as a purple solid (892 mg, 48%): m/z 471 (M+H)+ (ES+). A mixture of 4-(2-chloropyridin-4-yloxy)naphthalen-1 -/V,/V-di-ie f-butylcarbamate (892 mg, 1 .89 mmol), ie f-butyl carbamate (666 mg, 5.68 mmol), caesium carbonate (926 mg, 2.84 mmol), Pd2(dba)3 (43 mg, 0.047 mmol) and XantPhos (55 mg, 0.095 mmol) was suspended in THF (10.0 mL) and was purged thoroughly with nitrogen and then heated to reflux for 15 hr. The mixture was cooled to RT and diluted with water (35 mL) and was extracted with EtOAc (35 mL and 25 mL). The combined organic extracts were washed with brine (50 mL), dried and evaporated in vacuo. The residue was purified by flash column chromatography (Si02, 80 g, 0- 30% EtOAc in iso-hexane, gradient elution) to give ferf-butyl 4-(4-(/V,/V-di-(ferf-butyloxy carbonyl)amino)naphthalen-1 -yloxy)pyridin-2-yl carbamate, as a white solid (289 mg, 28%): m/z 552 (M+H)+ (ES+).To a stirred solution of ie f-butyl 4-(4-(/V,/V-di-(ie f-butyloxycarbonyl)amino)naphthalen-1 - yloxy)pyridin-2-yl carbamate (289 mg, 0.524 mmol) in DCM (8.0 mL), at 0C, was added TFA (4.0 mL) and the resulting mixture allowed to warm to RT. After 5 hr the volatiles were removed in vacuo and the residue was taken up in MeOH (5.0 mL) and subjected to SCX capture. The volatiles were removed in vacuo to provide 4-(4-aminonaphthalen-1 -yloxy)pyridin-2-amine, (1 16 mg, 85%) as a brown-orange oil: m/z 252 (M+H)+ (ES+). To a vigorously stirred mixture of Intermediate A (206 mg, 0.900 mmol) in DCM (20 mL) and saturated aq. NaHC03 (14 mL) at 0C was added trichloromethylchloroformate (325 mu, 2.70 mmol) in a single portion and the stirring continued at 0C for 80 min. The organic layer was separated and dried and was evaporated in vacuo to provide 3-ie f-butyl-5-isocyanato-1 -p-tolyl- 1 /-/-pyrazole, as an orange oil. This material was pumped under high vacuum for 30 min and was then taken up into THF (6.0 mL) and the resulting solution kept under nitrogen at 0C for use in the next step.To a stirred solution of 4-(4-aminonaphthalen-1 -yloxy)pyridin-2-amine, (1 16 mg, 0.462 mmol) and DIPEA (240 muIota, 1 .39 mmol) in THF (3.0 mL) at 0C was added an aliquot of the isocyanate solution prepared above (2.0 mL, 0.300 mmol) and the resulting mixture allowed to warm to RT. Additional aliquots of the isocyanate solution were added to the reaction mixture after 1 .5 hr, (1 .0 mL, 0.150 mmol) and after a further 3.5 hr (0.5 mL, 0.075 mmol). The mixture was maintained at RT for 20 hr and was then diluted with water (30 mL) and was extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with brine (50 mL), dried and then evaporated in vacuo. The residue was purified by flash column chromatography (Si02; 12 g, 25-100% [5% MeOH in EtOAc] in iso-hexane, gradient elution) to furnish the title compound Intermediate D, as a brown oil (127 mg, 49%): m/z 507 (M+H)+ (ES+).
	With sodium hydrogencarbonate; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran;	To a solution of <strong>[285984-25-0]3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine</strong> (5) (1.00 g, 4.36 mmol) in DCM (90 mL) was added a saturated aq solution of NaHCO3 (60 mL). The mixture was stirred vigorously, cooled to 0 C. and diphosgene (2.1 mL, 17.4 mmol) was added in a single portion. After stirring for 1 hr at RT, the layers were separated and the organics dried and evaporated to give a brown oil. The oil was triturated with isohexane (5.0 mL) and the solid filtered. The filtrate was concentrated in vacuo to give 3-tert-butyl-5-isocyanato-1-p-tolyl-1H-pyrazole (28) as a light brown oil (1.00 g, 3.92 mmol, 90%). m/z 288 (in MeOH) (M+H+MeOH)+ (ES+).

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 1727 - 1746
[2]Patent: US2016/45512,2016,A1 .Location in patent: Paragraph 0504; 0508
[3]Patent: WO2005/48948,2005,A2 .Location in patent: Page/Page column 163
[4]Patent: WO2010/67130,2010,A1 .Location in patent: Page/Page column 37-38
[5]Patent: WO2011/124923,2011,A2 .Location in patent: Page/Page column 31-32
[6]Patent: US2012/244120,2012,A1

8
[ 75-44-5 ]
[ 285984-25-0 ]
[ 317806-90-9 ]
[ 285983-48-4 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: phosgene; 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine With sodium hydrogencarbonate In dichloromethane; water; toluene at 0℃; for 0.25h; Stage #2: 4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-ylamine With N-ethyl-N,N-diisopropylamine In tetrahydrofuran	1 EXAMPLE 1; Synthesis of 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea A solution of the above 4-N-Boc-aminonaphthyl ether (0.511 g) and HCl (1 mL of a 4 M dioxane solution) in 5 mL dioxane was stirred at room temperature 20 hours. Removal of the volatiles in vacuo provided the desired 4-aminonaphthyl ether. To a solution of 5-amino-3-t-butyl-1-(4-methylphenyl)pyrazole (0.15 g), saturated NaHCO3 (15 mL), and dichloromethane (15 mL) at 0° C. was added phosgene (1.17 mL, 1.93M in toluene). The mixture was stirred for 15 minutes, the organic layer dried (MgSO4) and the volatiles removed in vacuo. The residue was added to a solution of the above 4-aminonaphthyl ether (0.15 g) and diisopropylethyl amine (0.32 mL) in 10 mL THF and the mixture stirred overnight. Ethyl acetate and water were added and the organic layer washed with water, brine and dried (MgSO4). Removal of the volatile in vacuo, purification of the residue by flash chromatography using ethyl acetate as the eluent and concentration in vacuo of the product-rich fractions, followed by recrystallization from hexanes and ethyl acetate provided the title compound.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2003/232865, 2003, A1 Location in patent: Page 34-35

9
[ 1023991-14-1 ]
[ 285984-25-0 ]
[ 848144-14-9 ]

Yield	Reaction Conditions	Operation in experiment
98%		N- (5-TERT-BUTVL-2-P-TOLVL-2H-PVRAZOL-3-VL)-2-F 4-F2-MORPHOLIN-4-VL-ETHOXV- naphthalen-1-yl]-2-oxo-acetamide, (13); Compound 12 (0. 224 g, 0. 653 mmol) was dissolved in THF (20 mL). To this solution was added 1 N LIOH (3 eq, 1. 96 mmol). The solution was allowed to stir for 2 hours then neutralized with 4 N HCl in dioxane and the solvent was evaporated providing a white solid. The residue was dried under high vacuum at 80C for 30 minutes and then suspended in CH2C12 (50 mL). To the suspension was added oxalyl chloride (0. 56 mL, 6. 53 mmol) and few drops of DMF. The suspension was stirred at room temperature for 2 hrs then the solvent evaporated. The resulting solid was suspended in ethyl acetate (20 mL) and added to 5-AMINO-3-T-BUTYL-L- (4-METHYLPHENYL) pyrazole (1) (0. 159 g, 0. 663 mmol) dissolved in ethyl acetate (20 mL) and a 50% NAHC03 solution (10 mL) and stirred overnight at 60C. The mixture was diluted with ethyl acetate and extracted with NaHCO3. The combined organic layers were washed with brine, dried over MGS04, filtered and the solvent removed leaving a brown oil. The material was purified by column chromatography (50-100% EtOAc/Hexanes) or (0-5% methanol/DCM) providing 0. 346 g (98%) of the desired compound as a yellow solid. LC-MS : Calculated mass= 540. Observed mass= 541.

Reference： [1]Patent: WO2005/23761,2005,A2 .Location in patent: Page/Page column 165

10
[ 79-04-9 ]
[ 285984-25-0 ]
[ 1241507-52-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With pyridine; In dichloromethane; at 20℃; for 2h;Inert atmosphere;	b. Lambda/-(5-fert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-chloro-acetamide; A solution of 5-ferf-butyl-2-p-tolyl-2/-/-pyrazol-3-ylamine (886 mg, 3.86 mmol), pyridine (465 muL, 5.80 mmol) and chloroacetyl chloride (462 mul_, 5.80 mmol) in DCM (5 ml_) was stirred at RT for 2 h. The reaction mixture was diluted with aq. sat. sodium bicarbonate and DCM and the resulting aqueous layer was extracted twice with DCM. The combined organic layers were dried (MgSO4) and concentrated in vacuo to afford the title compound (1.17g, 100%) as a yellow solid. LCMS (Method 5): Rt 4.41 min, m/z 306 [MH+].

Reference： [1]Patent: WO2010/94956,2010,A1 .Location in patent: Page/Page column 46

11
[ 75-44-5 ]
[ 883996-90-5 ]
[ 285984-25-0 ]
[3-(tert-butyl)-1-(4-methylphenyl)pyrazol-5-yl]amino}-N-[(2-[5-bromo-2-methyl-1-(methylethyl)-6-oxohydropyridin-4-yloxy]methyl}-5-fluorophenyl)methyl]carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57.2%		Example 127; [3-(tert-butyl)-l-(4-methylphenyl)pyrazol-5-yl]amino}-N-[(2-[5-bromo-2-methyl- l-(methylethyl)-6-oxohydropyridin-4-yloxy]methyl}-5- fluorophenyl)methyl]carboxamide; [0337] To a solution of 6-{ [2-(aminomethyl)-4-fluorophenyl]methoxy}-5-bromo- 2-methyl-3-(methylethyl)-3-hydropyrimidin-4-one (0.384g, 1.0 mmol) in dichloromethane (15 mL) and saturated solution Of NaHCO3 (15 mL), phosgene (20% in toluene, 1.042 mL, 1.97mmol) was added. The mixture was stirred for 15 min, the organic layer was dried over Na2SO4 and concentrated in vacuo, and the residue was treated with a solution of 3-(tert-butyl)-l-(4-methylphenyl)pyrazole-5-ylamine (0.229g) in dichloromethane (10 mL). The resulting mixture was stirred for 17 h at room temperature. After removal of the volatiles in vacuo the residue was purified by flash chromatography using dichloromethane/hexanes/acetone (5:5:1) as elution to give the title compound (0.366g, 57.2%) as a white solid: mp 133-135 0C; 1H NMR (CD3OD/400MHz) delta 7.44 (m, 1H),7.28 (m,lH), 6.97 (m, IH), 6.29 (s, IH), 5.44 (s, 2H), 4.60 (br.lH), 4.45 (s,2H), 2.57 (s, 3H), 2.37 (s, 3H), 1.54 (d, 6H, J = 6.8 Hz), 1.30 (s, 9H); Anal. Calcd for C31H36BrFN6O3: C, 58.22; H, 5.67; N, 13.14. Found: C, 57.72; H, 5.24; N, 12.76. ES-MS m/z 641.39 & 639.39

Reference： [1]Patent: WO2006/40666,2006,A1 .Location in patent: Page/Page column 185

12
[ 75-44-5 ]
[ 883996-93-8 ]
[ 285984-25-0 ]
[3-(tert-butyl)-1-(4-methylphenyl)pyrazol-5-yl]amino}-N-[(2-[5-chloro-2-methyl-1-(methylethyl)-6-oxohydropyridin-4-yloxy]methyl}-5-fluorophenyl)methyl]carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84.0%		Example 128; [3-(tert-butyI)-l-(4-methylphenyl)pyrazol-5-yl]amino}-N-[(2-[5-chloro-2-methyl- l-(methylethyI)-6-oxohydropyridin-4-yloxy]methyl}-5- fluorophenyl)methyl]carboxamide; [0338] To a solution of 3-(tert-butyl)-l-(4-methylphenyl)pyrazole-5-ylamine (0.229g, lmmol) and saturated solution of NaHCO3 (15 mL) in dichloromethane (10 mL), phosgene (20% in toluene, 1.042 mL,1.97mmol) was added. The mixture was stirred for 15 min and the organic layer was dried over Na2SO4. After removal of the volatiles in vacuo, the residue was treated with a solution of 6-{ [2-(aminomethyl)-4- fluorophenyl]methoxy}-5-chloro-2-methyl-3-(methylethyl)-3-hydropyrimidin-4-one (0.34Og, 1.0 mmol) in dichloromethane (15 mL) and the mixture was stirred for 17 h at room temperature. The reaction mixture was concentrated in vacuo and the residue which was purified by flash chromatography using dichloromethane/hexanes/acetone (5:5:1) as eluant to give the title compound (0.5Og, 84.0%) as a white solid: mp 153-155 0C; 1H NMR (CD3OD/400MHz) delta 7.46 (m, 1H),7.29 (m,lH), 6.98 (m, IH), 6.29 (s, IH), 5.46 (s, 2H), 4.60 (br,lH), 4.44 (s,2H), 2.59 (s, 3H), 2.38(s, 3H), 1.56 (d, 6H, J = 6.8 Hz), 1.30 (s, 9H); Anal. Calcd for C31H36ClFN6O3: C, 62.57; H, 6.10; N, 14.12. Found: C, 62.98; H, 6.56; N, 13.61. ES-MS m/z 597.45 & 595.46.

Reference： [1]Patent: WO2006/40666,2006,A1 .Location in patent: Page/Page column 186

13
[ 1229607-39-9 ]
[ 530-62-1 ]
[ 285984-25-0 ]
[ 1229606-73-8 ]

Yield	Reaction Conditions	Operation in experiment
78%		To a suspension of CDI (32.5 g, 200 mmol) in dry DCM (300 mL) was added Intermediate A1 (46.0 g, 200 mmol) portionwise over 1 hr and the mixture was stirred at RT for 2 hr, over which time a yellow solution was formed. An aliquot of this solution (220 mL, 147 mmol), was added dropwise over 20 min to a solution of /V-(4-(4-aminonaphthalen-1 -yloxy)pyridin-2-yl)-2- methoxyacetamide (40.0 g, 1 1 1 mmol) in DCM (600 mL) The reaction mixture was stirred at RT for 18 hr and ethanol (50.0 mL) was added. After a further 1 .5 hr the solvent was removed in vacuo to yield a purple oil which was taken up into EtOAc (1 .0 L) and was washed sequentially with sat. NaHC03 solution (2 x 250 mL), water (2 x 250 mL) and brine (2 x 200 mL) and was then dried. The solvent was removed in vacuo to yield a dark red viscous oil (75 g) which was purified through a silica plug (Si02, 500 g, EtOAc in isohexane, 20- 100%, gradient elution) to provide a brown solid (64.5 g). This material was combined with a second identically prepared batch (129 g in total) and re-crystallised (isohexane / EtOAc, 2:5, 4.0 L) to afford the title compound, Intermediate D1 , as a pale brown solid (101 g, 78%); m/z 579 (M+H)+ (ES+).
78%		To a suspension of CDI (32.5 g, 200 mmol) in dry DCM (300 mL) was added Intermediate A1 (46.0 g, 200 mmol) portionwise over 1 hr and the mixture was stirred at RT for 2 hr, over which time a yellow solution was formed. An aliquot of this solution (220 mL, 147 mmol), was added dropwise over 20 min to a solution of N-(4-(4-aminonaphthalen-1-yloxy)pyridin-2-yl)-2-methoxyacetamide (40.0 g, 111 mmol) in DCM (600 mL) The reaction mixture was stirred at RT for 18 hr and ethanol (50.0 mL) was added. After a further 1.5 hr the solvent was removed in vacuo to yield a purple oil which was taken up into EtOAc (1.0 L) and was washed sequentially with sat. NaHCO3 solution (2×250 mL), water (2×250 mL) and brine (2×200 mL) and was then dried. The solvent was removed in vacuo to yield a dark red viscous oil (75 g) which was purified through a silica plug (SiO2, 500 g, EtOAc in isohexane, 20-100%, gradient elution) to provide a brown solid (64.5 g). This material was combined with a second identically prepared batch (129 g in total) and re-crystallised (isohexane/EtOAc, 2:5, 4.0 L) to afford the title compound, Intermediate D1, as a pale brown solid (101 g, 78%); m/z 579 (M+H)+ (ES+).

Reference： [1]Patent: WO2011/121366,2011,A1 .Location in patent: Page/Page column 63-65
[2]Patent: US2013/29990,2013,A1 .Location in patent: Paragraph 0533

14
[ 1337932-17-8 ]
[ 530-62-1 ]
[ 285984-25-0 ]
[ 1337930-84-3 ]

Yield	Reaction Conditions	Operation in experiment
74%		To a suspension of CDI (973 mg, 6.00 mmol) in dry DCM (10.0 mL) under N2 was added Intermediate A1 (1 .38 g, 6.00 mmol) as a solid, in four equal portions, over 10 min and the resulting solution maintained at RT for 16 hr. An aliquot of this solution (247 muIota_, 0.148 mmol) was added to a suspension of Intermediate J3 (50 mg, 0.16 mmol) in dry DCM (5.0 mL) and the reaction mixture kept at RT for 5 hr. The resulting suspension was diluted with DCM (5.0 mL) and the solid was collected by filtration and then suspended in water (5.0 mL) and sonicated for 3 min. The solid was collected by filtration, washed with water (2 x 2.5 mL) and dried in vacuo at 45C for 16 hr to afford the title compound, Example 21 , as a white solid (70 mg, 74%); Rl 4.67 min (Method 1 basic); m/z 579 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-de) delta: 1.27 (9H, s), 2.39 (3H, s), 2.72 (3H, d), 5.31 (2H, s), 6.35 (1 H, s), 7.08 (1 H, dd), 7.20 (1 H, d), 7.36 (2H, m), 7.43-7.45 (3H, overlapping m), 7.60 (1 H, dd), 7.64 (1 H, d), 8.14 (1 H, br s), 8.19 (1 H, d), 8.27 (1 H, dd), 8.58 (1 H, br s), 8.89 (1 H, br s), 8.92 (1 H, dd), 9.33 (1 H, br s).
74%		To a suspension of CDI (973 mg, 6.0To a suspension of CDI (973 mg, 6.00 mmol) in dry DCM (10.0 mL) under N2 was added Intermediate A1 (1.38 g, 6.00 mmol) as a solid, in four equal portions, over 10 min and the resulting solution maintained at RT for 16 hr. An aliquot of this solution (247 muL, 0.148 mmol) was added to a suspension of Intermediate J3 (50 mg, 0.16 mmol) in dry DCM (5.0 mL) and the reaction mixture kept at RT for 5 hr. The resulting suspension was diluted with DCM (5.0 mL) and the solid was collected by filtration and then suspended in water (5.0 mL) and sonicated for 3 min. The solid was collected by filtration, washed with water (2×2.5 mL) and dried in vacuo at 45 C. for 16 hr to afford the title compound, Example 21, as a white solid (70 mg, 74%); Rt 4.67 min (Method 1 basic); m/z 579 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) delta: 1.27 (9H, s), 2.39 (3H, s), 2.72 (3H, d), 5.31 (2H, s), 6.35 (1H, s), 7.08 (1H, dd), 7.20 (1H, d), 7.36 (2H, m), 7.43-7.45 (3H, overlapping m), 7.60 (1H, dd), 7.64 (1H, d), 8.14 (1H, br s), 8.19 (1H, d), 8.27 (1H, dd), 8.58 (1H, br s), 8.89 (1H, br s), 8.92 (1H, dd), 9.33 (1H, br s).0 mmol) in dry DCM (10.0 mL) under N2 was added Intermediate A1 (1.38 g, 6.00 mmol) as a solid, in four equal portions, over 10 min and the resulting solution maintained at RT for 16 hr. An aliquot of this solution (247 muL, 0.148 mmol) was added to a suspension of Intermediate J3 (50 mg, 0.16 mmol) in dry DCM (5.0 mL) and the reaction mixture kept at RT for 5 hr. The resulting suspension was diluted with DCM (5.0 mL) and the solid was collected by filtration and then suspended in water (5.0 mL) and sonicated for 3 min. The solid was collected by filtration, washed with water (2×2.5 mL) and dried in vacuo at 45 C. for 16 hr to afford the title compound, Example 21, as a white solid (70 mg, 74%); Rt 4.67 min (Method 1 basic); m/z 579 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) delta: 1.27 (9H, s), 2.39 (3H, s), 2.72 (3H, d), 5.31 (2H, s), 6.35 (1H, s), 7.08 (1H, dd), 7.20 (1H, d), 7.36 (2H, m), 7.43-7.45 (3H, overlapping m), 7.60 (1H, dd), 7.64 (1H, d), 8.14 (1H, br s), 8.19 (1H, d), 8.27 (1H, dd), 8.58 (1H, br s), 8.89 (1H, br s), 8.92 (1H, dd), 9.33 (1H, br s).

Reference： [1]Patent: WO2011/121366,2011,A1 .Location in patent: Page/Page column 90
[2]Patent: US2013/29990,2013,A1 .Location in patent: Paragraph 0630-0631

15
[ 1337932-25-8 ]
[ 530-62-1 ]
[ 285984-25-0 ]
[ 1337930-87-6 ]

Yield	Reaction Conditions	Operation in experiment
37%		To a solution of CDI (510 mg, 3.15 mmol) in dry DCM (6.0 mL) at RT was added Intermediate A1 (722 mg, 3.15 mmol) portionwise over 15 min and the reaction mixture maintained at RT for 20 hr. An aliquot of the resulting solution (840 mu, 0.44 mmol) was added to a solution of Intermediate M1 , (81 mg, 0.21 mmol) in dry DCM (4.0 mL) and the reaction mixture was maintained at RT for 1 day and was then partitioned between saturated aq. NaHC03 (20 mL) and DCM (20 mL). The aq layer was separated and extracted with DCM (20 mL) and the combined organic extracts were dried and evaporated in vacuo. The residue was purified by flash column chromatography (Si02, 12 g, [1 % NH3 in MeOH] in DCM, 0-10%, gradient elution) to provide the title compound, Example 24, as a white solid (53 mg, 37 %); Rl 5.39 min (Method 1 basic); m/z 640/642 (M+H)+, (ES+); 1H NMR (400 MHz, DMSO-de) delta: 1.27 (9H, s), 2.16 (6H, s), 2.33 (2H, t), 2.34 (3H, s), 3.21 (2H, td), 6.38 (1 H, s), 7.23-7.28 (2H, overlapping m), 7.33-7.37 (3H, overlapping m), 7.41 (2H, m), 8.08 (1 H, d), 8.35 (1 H, d), 8.83 (1 H, br s), 9.17 (1 H, br s), 9.68 (1 H, br s).
37%		To a solution of CDI (510 mg, 3.15 mmol) in dry DCM (6.0 mL) at RT was added Intermediate A1 (722 mg, 3.15 mmol) portionwise over 15 min and the reaction mixture maintained at RT for 20 hr. An aliquot of the resulting solution (840 muL, 0.44 mmol) was added to a solution of Intermediate M1, (81 mg, 0.21 mmol) in dry DCM (4.0 mL) and the reaction mixture was maintained at RT for 1 day and was then partitioned between saturated aq. NaHCO3 (20 mL) and DCM (20 mL). The aq layer was separated and extracted with DCM (20 mL) and the combined organic extracts were dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 12 g, [1% NH3 in MeOH] in DCM, 0-10%, gradient elution) to provide the title compound, Example 24, as a white solid (53 mg, 37%); Rt 5.39 min (Method 1 basic); m/z 640/642 (M+H)+, (ES+); 1H NMR (400 MHz, DMSO-d6) delta: 1.27 (9H, s), 2.16 (6H, s), 2.33 (2H, t), 2.34 (3H, s), 3.21 (2H, td), 6.38 (1H, s), 7.23-7.28 (2H, overlapping m), 7.33-7.37 (3H, overlapping m), 7.41 (2H, m), 8.08 (1H, d), 8.35 (1H, d), 8.83 (1H, br s), 9.17 (1H, br s), 9.68 (1H, br s).

Reference： [1]Patent: WO2011/121366,2011,A1 .Location in patent: Page/Page column 92
[2]Patent: US2013/29990,2013,A1 .Location in patent: Paragraph 0637-0638

16
[ 1337931-85-7 ]
[ 530-62-1 ]
[ 285984-25-0 ]
[ 1337930-69-4 ]

Yield	Reaction Conditions	Operation in experiment
54%		To a solution of CDI (1.06 g, 6.54 mmol) in dry DCM (10.0 mL) under N2 was added Intermediate A1 (1 .50 g, 6.54 mmol) as a solid, in four equal portions, over 10 min and the resulting yellow solution was stirred at RT for 16 hr. An aliquot of this solution (1 .0 mL, 0.65 mmol) was added to a solution of Intermediate B5, (100 mg, 0.308 mmol) in dry DCM (2.0 mL) and the reaction mixture was maintained at RT for 20 hr. The reaction was quenched by the addition of MeOH (1 .0 mL) and after a further 5 min was evaporated in vacuo. The residue was purified twice by flash column chromatography (Si02, 12 g, EtOAc in isohexane, 0-100%, gradient elution and then Si02, 12 g, MeOH in DCM, 0-2%, gradient elution). The crude material so obtained was taken up in EtOAc (2.0 mL) and isohexane (10 mL) was added to give a precipitate which was collected by filtration to afford the title compound, Example 6, as an off-white solid (100 mg, 54 %); R' 4.78 min (Method 1 basic); m/z 580 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) delta: 1 .28 (9H, s), 2.40 (3H, s), 3.30 (3H, s), 3.97 (2H, s), 6.42 (1 H, s), 6.59 (1 H, dd), 7.38 (2H,d), 7.47 (2H,d), 7.53 (1 H, br s), 7.62 (2H, m), 8.02 (1 H, d), 8.1 1 (1 H, d), 8.45 (1 H, d), 8.78 (1 H, s), 8.84 (1 H, d), 9.25 (1 H, s), 9.96 (1 H, s).
54%		To a solution of CDI (1.06 g, 6.54 mmol) in dry DCM (10.0 mL) under N2 was added Intermediate A1 (1.50 g, 6.54 mmol) as a solid, in four equal portions, over 10 min and the resulting yellow solution was stirred at RT for 16 hr. An aliquot of this solution (1.0 mL, 0.65 mmol) was added to a solution of Intermediate B5, (100 mg, 0.308 mmol) in dry DCM (2.0 mL) and the reaction mixture was maintained at RT for 20 hr. The reaction was quenched by the addition of MeOH (1.0 mL) and after a further 5 min was evaporated in vacuo. The residue was purified twice by flash column chromatography (SiO2, 12 g, EtOAc in isohexane, 0-100%, gradient elution and then SiO2, 12 g, MeOH in DCM, 0-2%, gradient elution). The crude material so obtained was taken up in EtOAc (2.0 mL) and isohexane (10 mL) was added to give a precipitate which was collected by filtration to afford the title compound, Example 6, as an off-white solid (100 mg, 54%); Rt 4.78 min (Method 1 basic); m/z 580 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) delta: 1.28 (9H, s), 2.40 (3H, s), 3.30 (3H, s), 3.97 (2H, s), 6.42 (1H, s), 6.59 (1H, dd), 7.38 (2H, d), 7.47 (2H, d), 7.53 (1H, br s), 7.62 (2H, m), 8.02 (1H, d), 8.11 (1H, d), 8.45 (1H, d), 8.78 (1H, s), 8.84 (1H, d), 9.25 (1H, s), 9.96 (1H, s).

Reference： [1]Patent: WO2011/121366,2011,A1 .Location in patent: Page/Page column 81
[2]Patent: US2013/29990,2013,A1 .Location in patent: Paragraph 0598-0599

17
[ 1337932-08-7 ]
[ 530-62-1 ]
[ 285984-25-0 ]
[ 1337930-77-4 ]

Yield	Reaction Conditions	Operation in experiment
52%		To a stirred solution of CDI (223 mg, 1 .38 mmol) in dry DCM (3.5 mL) was added Intermediate A1 (315 mg, 1 .38 mmol) as a solid, portion-wise, over 12 min and the resulting solution maintained at RT for 4 hr. An aliquot of this solution (2.0 mL, 0.79 mmol) was added to a solution of Intermediate G1 , (140 mg, 0.39 mmol) in dry THF (5.0 mL), and the reaction mixture was kept at RT for 17 hr and was then partitioned between saturated aq. NaHC03 (30 mL) and DCM (30 mL). The aq. layer was extracted with DCM (30 mL) and the combined organic extracts were dried and evaporated in vacuo. The residue was purified by flash column chromatography (Si02, 12 g, [5% MeOH in EtOAc] in isohexane, 0-45%, gradient elution) to afford the title compound, Example 14, as an off white solid (127 mg, 52%); R' 5.40 min (Method 1 basic); m/z 61 1/613 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) delta: 1 .26 (9H, s), 2.37 (3H, s), 3.37 (3H, s), 4.07 (2H, s), 5.31 (2H, s), 6.34 (1 H, s), 7.18-7.23 (2H, overlapping m), 7.31 -7.34 (2H, overlapping m), 7.38-7.40 (2H, overlapping m), 7.85 (1 H, d), 8.21 (1 H, br s), 8.33 (1 H, dd), 8.60 (1 H, br s), 8.95 (1 H, br s), 10.01 (1 H, br s).
52%		To a stirred solution of CDI (223 mg, 1.38 mmol) in dry DCM (3.5 mL) was added Intermediate A1 (315 mg, 1.38 mmol) as a solid, portion-wise, over 12 min and the resulting solution maintained at RT for 4 hr. An aliquot of this solution (2.0 mL, 0.79 mmol) was added to a solution of Intermediate G1, (140 mg, 0.39 mmol) in dry THF (5.0 mL), and the reaction mixture was kept at RT for 17 hr and was then partitioned between saturated aq. NaHCO3 (30 mL) and DCM (30 mL). The aq. layer was extracted with DCM (30 mL) and the combined organic extracts were dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 12 g, [5% MeOH in EtOAc] in isohexane, 0-45%, gradient elution) to afford the title compound, Example 14, as an off white solid (127 mg, 52%); Rt 5.40 min (Method 1 basic); m/z 611/613 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) delta: 1.26 (9H, s), 2.37 (3H, s), 3.37 (3H, s), 4.07 (2H, s), 5.31 (2H, s), 6.34 (1H, s), 7.18-7.23 (2H, overlapping m), 7.31-7.34 (2H, overlapping m), 7.38-7.40 (2H, overlapping m), 7.85 (1H, d), 8.21 (1H, br s), 8.33 (1H, dd), 8.60 (1H, br s), 8.95 (1H, br s), 10.01 (1H, br s).

Reference： [1]Patent: WO2011/121366,2011,A1 .Location in patent: Page/Page column 86
[2]Patent: US2013/29990,2013,A1 .Location in patent: Paragraph 0616-0617

18
[ 1337932-10-1 ]
[ 530-62-1 ]
[ 285984-25-0 ]
[ 1337930-79-6 ]

Yield	Reaction Conditions	Operation in experiment
59%		To a suspension of CDI (973 mg, 6.00 mmol) in dry DCM (10.0 mL) under N2 was added Intermediate A1 (1 .38 g, 6.00 mmol) as a solid, in four equal portions, over 10 min and the resulting solution maintained at RT for 16 hr. An aliquot of this solution (473 muIota_, 0.284 mmol) was added to a suspension of Intermediate G2 (100 mg, 0.296 mmol) in anhydrous DCM (5.0 mL) and the reaction mixture kept at RT for 24 hr. The reaction mixture, in its entirety, was purified by flash column chromatography (Si02, 40 g, MeOH in DCM, 0-10 %, gradient elution) to afford the title compound, Example 16, as a yellow solid (108 mg, 59 %); R' 4.60 min (Method 1 basic); m/z 594 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) delta: 1 .27 (9H, s), 2.39 (3H, s), 3.36 (3H, s), 4.06 (2H, s), 5.39 (2H, s), 6.35 (1 H, s), 7.22 (1 H, d), 7.30 (1 H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.60 (1 H, dd), 7.64 (1 H, d), 8.24 (1 H, br s), 8.27 (1 H, dd), 8.34 (1 H, dd), 8.59 (1 H, br s), 8.89 (1 H, br s), 8.92 (1 H, dd), 10.04 (1 H, br s).
59%		To a suspension of CDI (973 mg, 6.00 mmol) in dry DCM (10.0 mL) under N2 was added Intermediate A1 (1.38 g, 6.00 mmol) as a solid, in four equal portions, over 10 min and the resulting solution maintained at RT for 16 hr. An aliquot of this solution (473 muL, 0.284 mmol) was added to a suspension of Intermediate G2 (100 mg, 0.296 mmol) in anhydrous DCM (5.0 mL) and the reaction mixture kept at RT for 24 hr. The reaction mixture, in its entirety, was purified by flash column chromatography (SiO2, 40 g, MeOH in DCM, 0-10%, gradient elution) to afford the title compound, Example 16, as a yellow solid (108 mg, 59%); Rt 4.60 min (Method 1 basic); m/z 594 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) delta: 1.27 (9H, s), 2.39 (3H, s), 3.36 (3H, s), 4.06 (2H, s), 5.39 (2H, s), 6.35 (1H, s), 7.22 (1H, d), 7.30 (1H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.60 (1H, dd), 7.64 (1H, d), 8.24 (1H, br s), 8.27 (1H, dd), 8.34 (1H, dd), 8.59 (1H, br s), 8.89 (1H, br s), 8.92 (1H, dd), 10.04 (1H, br s).

Reference： [1]Patent: WO2011/121366,2011,A1 .Location in patent: Page/Page column 87
[2]Patent: US2013/29990,2013,A1 .Location in patent: Paragraph 0620-0621

19
[ 1338053-36-3 ]
[ 530-62-1 ]
[ 285984-25-0 ]
[ 1338053-33-0 ]

Yield	Reaction Conditions	Operation in experiment
71%		Example 1To a suspension of CDI (416 mg, 2.57 mmol) in DCM (1 .0 mL) was added a solution of Intermediate A (589 mg, 2.57 mmol) in DCM (2.0 mL) over 1 .5 hr and after 1 hr a solution of Intermediate B (550 mg, 1 .71 1 mmol) in DCM (6.0 mL) was added and the reaction mixture maintained at RT for 16 hr. The reaction mixture was loaded directly on to silica and was purified by flash column chromatography (Si02, 40 g, EtOAc in isohexane, 50-100%, gradient elution) to afford the title compound, Example 1 , (700mg, 71 %): m/z 577 (M+H)+ (ES+). 1H NMR (400MHz, DMSO-d6) delta: 1 .26 (9 H, s), 2.08 (3 H, s), 2.38 (3 H, s), 3.20 (2H, t), 4.37 (2H, t), 6.34 (1 H, s), 6.95 (1 H, d), 7.15 (1 H, dd), 7.35 (2H, m), 7.45 (3H, overlapping m), 7.55 (1 H, m), 7.60 (1 H, m), 7.90 (1 H, d), 8.20 (3H, overlapping m), 8.57 (1 H, s), 8.77 (1 H, s) and 10.40 (1 H, s).

Reference： [1]Patent: WO2011/124923,2011,A2 .Location in patent: Page/Page column 32-33

20
[ 1220627-07-5 ]
[ 530-62-1 ]
[ 285984-25-0 ]
[ 1220627-08-6 ]

Yield	Reaction Conditions	Operation in experiment
63%		Intermediate C: 1 -(4-((2-aminopyridin-4-yl)methoxy)naphthalen-1 -yl)-3-(3-ferf-butyl-1 -p- tolyl-1 H-pyrazol-5-yl)urea To a solution of 4-nitronaphthol (5.17 g, 27.3 mmol), triphenylphosphine (10.75 g, 41 .0 mmol) and 2-aminopyridine-4-methanol (5.09g, 41.0 mmol) in THF (50 mL) at -15C was added dropwise DIAD (8.07 mL, 41.0 mmol) and the mixture then allowed to warm to RT and stirred overnight. The volatiles were removed in vacuo and the residue was triturated with EtOAc (150 mL), and the crude product was collected by filtration and washed with EtOAc (100 mL). A second trituration with MeOH (100 mL) gave 2-amino-4-((4-nitronaphthalen-1 - yloxy)methyl)pyridine (4.54 g, 56%) as a yellow solid: m/z 296 (M+H)+ (ES+).A solution of 2-amino-4-((4-nitronaphthalen-1 -yloxy)methyl)pyridine (4.50 g, 15.24 mmol) in MeOH (200 mL) and AcOH (200 mL) was passed through a Thales H-cube (2.0 mLmin"1, 40 C, 55 mm 10% Pt/C Cat-Cart, full hydrogen mode) and the volatiles were removed in vacuo. The crude product was subjected to SCX capture and release and the solvent was removed in vacuo to give 2-amino-4-((4-aminonaphthalen-1 -yloxy)methyl)pyridine, (3.82g, 94%) as a purple solid: m/z 266 (M+H)+ (ES+). A solution of CDI (4.18 g, 25.8 mmol) in DCM (15 mL) was added dropwise under nitrogen to a solution of Intermediate A (5.91 g, 25.8 mmol) in DCM (15 mL) over 40 min. The resulting solution was stirred at RT for 1 hr and was then added dropwise under nitrogen to a solution of 2-amino-4-((4-aminonaphthalen-1 -yloxy)methyl)pyridine (3.80 g, 12.9 mmol) in DCM and the mixture was stirred overnight. The volatiles were removed in vacuo.and the residue was purified by flash column chromatography (Si02, 120 g, MeOH in DCM, 0-6%, gradient elution) to give the tite compound, Intermediate C, as an off white solid (4.27 g, 63%): m/z 521 (M+H)+ (ES+).
63%		To a solution of CDI (4.18 g, 25.8 mmol) in DCM (15 mL) was added dropwise under nitrogen a solution of <strong>[285984-25-0]3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine</strong> (5) (WO 200/0043384) (5.91 g, 25.8 mmol) in DCM (15 mL) over 40 min. The resulting solution was stirred at RT for 1 hr then added dropwise under nitrogen to a solution of 2-amino-4-((4-aminonaphthalen-1-yloxy)methyl)pyridine (4) (3.80 g, 12.9 mmol). The mixture was stirred overnight and the volatiles were removed in vacuo. The crude material was purified by column chromatography (120 g); eluting with 0 to 6% MeOH in DCM to give the title compound, Intermediate A as an off white solid (4.27 g, 63%): m/z 521 (M+H)+ (ES+).

Reference： [1]Patent: WO2011/124923,2011,A2 .Location in patent: Page/Page column 30-31
[2]Journal of Medicinal Chemistry,2016,vol. 59,p. 1727 - 1746
[3]Patent: US2016/45512,2016,A1 .Location in patent: Paragraph 0397; 0400

21
[ 1220627-17-7 ]
[ 285984-25-0 ]
[ 1220627-18-8 ]

Yield	Reaction Conditions	Operation in experiment
80%	With CDI;SiO2; In methanol; 2-Methylpentane; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; ethyl acetate;	To a stirred suspension of CDI (3.00 g, 18.18 mmol) in DCM (15 mL) was added a solution of the pyrazole amine (5) (4.17 g, 18.18 mmol) in DCM (40 mL) over 1.5 hrs. After 2 hr at RT a solution of the naphthyl amine (22) (3.00 g, 7.91 mmol) in DCM (15 mL) was added. After stirring overnight, the solution was diluted with MeOH (10 mL) and absorbed onto silica gel (30 g) and subjected to column chromatography (SiO2, 330 g, 30% to 100% EtOAc in isohexane and then 0% to 6% MeOH in EtOAc) to give tert-butyl-4-(2-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)ethyl)pyridin-2-ylcarbamate (23) as a beige solid (4.20 g, 80%): m/z 635 (M+H)+ (ES+).

Reference： [1]Patent: US2012/244120,2012,A1

22
[ 1379401-24-7 ]
[ 1885-14-9 ]
[ 285984-25-0 ]
[ 1379397-83-7 ]

Yield	Reaction Conditions	Operation in experiment
92%		A heterogeneous mixture of a solution of Na2C03 (3.84 g, 36 mmol) in water (42 mL) and Intermediate A (10.5 g, 45.7 mmol) in isopropyl acetate (130 mL, 1 .082 mol) was stirred vigorously at RT for 5 min and was then treated with phenyl carbonochloridate (5.77 mL, 45.7 mmol). Stirring of the mixture was continued for a further 4 hr after which the layers were separated. The organic phase was added to a solution of Intermediate C (10.0 g, 30.5 mmol) and triethylamine (423 mu?, 3.05 mmol) in isopropyl acetate (60 mL, 51 1 mmol). The reaction mixture was warmed to 48 C for 1 hr, then diluted with isopropyl acetate (190 mL) and cooled to RT for a further 18 hr, during which time a precipitate formed. The precipitate was isolated by filtration, washed with isopropyl acetate and then dried in vacuo at 40 C to afford the title compound, Compound (1 ) as a white solid (anhydrous free base, polymorphic form A) (16.5 g, 92 %); R' 2.74 min (Method 2); m/z 584 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-de) delta: 1.30 (9H, s), 2.41 (3H, s), 6.43 (1 H, s), 6.58 (1 H, d), 6.78 (1 H, t), 6.97 (2H, t), 7.28 (2H, br m), 7.39 (2H, d), 7.40 (1 H, d), 7.49 (2H, d), 7.56 (1 H, m), 7.63 (1 H, m), 7.82 (1 H, dd), 7.95 (1 H, d), 8.10 (1 H, d), 8.40 (1 H, d), 8.77 (1 H, s), 9.16 (1 H, br s), 9.50 (1 H, br s).
92%		A heterogeneous mixture of a solution of Na2C03 (3.84 g, 36 mmol) in water (42 mL) and Intermediate A1 (10.5 g, 45.7 mmol) in isopropyl acetate (130 mL, 1.082 mol) was stirred vigorously at RT for 5 min and was then treated with phenyl carbonochloridate (5.77 ml, 45.7 mmol). Stirring of the mixture was continued for a further 4 hr after which the layers were separated. The organic phase was added to a solution of Intermediate B1 (10.0 g, 30.5 mmol) and triethylamine (423 muIota_, 3.05 mmol) in ispropyl acetate (60 mL, 511 mmol). The reaction mixture was warmed to 48 C for 1 hr, then diluted with isopropyl acetate (190 mL) and cooled to RT for a further 18 hr, during which time a precipitate formed. The precipitate was isolated by filtration, washed with isopropyl acetate and then dried in vacuo at 40 C to afford the title compound, Example 1 as a white solid (16.5 g, 92 %); R'2.74 min (Method 2); m/z 584 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-ds) delta: 1.30 (9H, s), 2.41 (3H, s), 6.43 (1 H, s), 6.58 (1 H, d), 6.78 (1 H, t), 6.97 (2H, t), 7.28 (2H, br m), 7.39 (2H, d), 7.40 (1 H, d), 7.49 (2H, d), 7.56 (1 H, m), 7.63 (1 H, m), 7.82 (1 H, dd), 7.95 (1 H, d), 8.10 (1 H, d), 8.40 (1 H, d), 8.77 (1 H, s), 9.16 (1 H, br s), 9.50 (1 H, br s).

Reference： [1]Patent: WO2013/50757,2013,A1 .Location in patent: Page/Page column 31
[2]Patent: WO2013/50756,2013,A1 .Location in patent: Page/Page column 21; 22

23
[ 476011-71-9 ]
[ 530-62-1 ]
[ 285984-25-0 ]
1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%		To a suspension of CDI (4.81 g, 29.7 mmol) in DCM (60 mL) was added Intermediate A1 (8.50 g, 29.7 mmol) portion-wise. After 3 hr an aliquot of this solution containing the activated CDI adduct, (30 mL, 15 mmol) was added to a solution of Intermediate D1 (3.01 g, 9.97 mmol) in DCM (60 mL) and the reaction mixture maintained at RT. After 2 hr a second aliquot of the CDI adduct solution (6.0 mL, 6.0 mmol) was added and the reaction mixture kept at RT for a further 16 hr. The resulting mixture was diluted with DCM (100 mL) and washed with saturated aq. NaHCC>3 (100 mL) and water (2 x 100 mLI) and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (Si02, [10% MeOH in DCM] in DCM, 0-100%, gradient elution then Si02, EtOAc in isohexane, 0-100%, gradient elution) to afford the title compound, Intermediate C1 as a yellow solid (3.07 g, 55%); R' 2.59 min (Method 2); m/z 527/529 (M+H)+ (ES+).
55%		To a suspension of CDI (4.81 g, 29.7 mmol) in DCM (60 mL) was added Intermediate A1 (8.50 g, 29.7 mmol) portion-wise. After 3 hr an aliquot of this solution containing the activated CDI adduct (30 mL, 15 mmol) was added to a solution of Intermediate E2 (3.01 g, 9.97 mmol) in DCM (60 mL) and the reaction mixture maintained at RT. After 2 hr a second aliquot of the CDI adduct solution (6.0 mL, 6.0 mmol) was added and the reaction mixture kept at RT for a further 16 hr. The resulting mixture was diluted with DCM (100 mL) and washed with saturated aq. NaHC03 (100 mL) and water (2 x 100 mLI) and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (Si02, [10% MeOH in DCM] in DCM, 0-100%, gradient elution then Si02, EtOAc in isohexane 0-100%, gradient elution) to afford the title compound, Intermediate C1 as a yellow solid (3.07 g, 55%); Rl 2.59 min (Method 2); m/z 527/529 (M+H)+ (ES+).
55%		Intermediate C1: 1-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)urea. To a suspension of CDI (4.81 g, 29.7 mmol) in DCM (60 mL) was added Intermediate A1 (8.50 g, 29.7 mmol) portion-wise. After 3 hr an aliquot of this solution containing the activated CDI adduct (30 mL, 15 mmol) was added to a solution of Intermediate E2 (3.01 g, 9.97 mmol) in DCM (60 mL) and the reaction mixture maintained at RT. After 2 hr a second aliquot of the CDI adduct solution (6.0 mL, 6.0 mmol) was added and the reaction mixture kept at RT for a further 16 hr. The resulting mixture was diluted with DCM (100 mL) and washed with saturated aq. NaHCO3 (100 mL) and water (2×100 mLl) and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, [10% MeOH in DCM] in DCM, 0-100%, gradient elution then SiO2, EtOAc in isohexane 0-100%, gradient elution) to afford the title compound, Intermediate C1 as a yellow solid (3.07 g, 55%); Rt 2.59 min (Method 2); m/z 527/529 (M+H)+ (ES+).

Reference： [1]Patent: WO2013/50756,2013,A1 .Location in patent: Page/Page column 21
[2]Patent: WO2014/33448,2014,A1 .Location in patent: Page/Page column 67
[3]Patent: US2015/203475,2015,A1 .Location in patent: Paragraph 0545; 0546

24
[ 1574358-67-0 ]
[ 530-62-1 ]
[ 285984-25-0 ]
[ 1574358-95-4 ]

Yield	Reaction Conditions	Operation in experiment
81%		To a solution of CDI (56 mg, 0.35 mmol) in DCM (3.0 mL) was added Intermediate A1 (68 mg, 0.24 mmol) and the reaction mixture maintained at RT for 23 hr. The resulting solution was added to a solution of Intermediate B5 (50 mg, 0.098 mmol) in THF (3.0 mL) and the reaction mixture was kept at RT for 2 hr and was then partitioned between EtOAc (30 mL) and saturated aq. NaHC03 (30 mL). The organic phase was separated and washed with saturated aq. NaHC03 (30 mL), water (2 x 30 mL) and brine (2 x 30 mL), and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (Si02, 12 g, 0-100% EtOAc in isohexane, gradient elution) to afford terf-butyl (5-((4-((4-(3-(3-(fenf-butyl)-1- (p-tolyl)-1 H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)benzo[d]isoxazol-3- yl)carbamate (62 mg, 81 %); R' 2.88 min (Method 2, acidic); m/z 740 (M+H)+, (ES+).
81%		Example 5 1-(4-((2-((3-Aminobenzo[d]isoxazol-5-yl)amino)pyrimidin-4-yl)oxy) naphthalen-1-yl)-3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea To a solution of CDI (56 mg, 0.35 mmol) in DCM (3.0 mL) was added Intermediate A1 (68 mg, 0.24 mmol) and the reaction mixture maintained at RT for 23 hr. The resulting solution was added to a solution of Intermediate B5 (50 mg, 0.098 mmol) in THF (3.0 mL) and the reaction mixture was kept at RT for 2 hr and was then partitioned between EtOAc (30 mL) and saturated aq. NaHCO3 (30 mL). The organic phase was separated and washed with saturated aq. NaHCO3 (30 mL), water (230 mL) and brine (230 mL), and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 12 g, 0-100% EtOAc in isohexane, gradient elution) to afford tert-butyl (5-((4-((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)benzo[d]isoxazol-3-yl)carbamate (62 mg, 81%); Rt 2.88 min (Method 2, acidic); m/z 740 (M+H)+, (ES+).

Reference： [1]Patent: WO2014/33448,2014,A1 .Location in patent: Page/Page column 72-73
[2]Patent: US2015/203475,2015,A1 .Location in patent: Paragraph 0567; 0568

25
[ 1574358-86-3 ]
[ 530-62-1 ]
[ 285984-25-0 ]
[ 1574358-59-0 ]

Yield	Reaction Conditions	Operation in experiment
57%		To a solution of CDI (91 mg, 0.56 mmol) in DCM (1.0 mL) was added Intermediate A1 (129 mg, 0.563 mmol) and the reaction mixture maintained at RT for 2 hr. A portion of this solution (500 pL, 0.28 mmol) was added to a solution of Intermediate B16 (80 mg, 0.19 mmol) in THF (2.0 mL) and the reaction mixture kept at RT for 3 hr and then quenched with the addition of MeOH (2.0 mL). The resulting mixture was evaporated in vacuo and the residue was purified by flash column chromatography (Si02, 12 g, 0-100% [10% MeOH in EtOAc] in isohexane, gradient elution) to afford methyl 5-((4-((4-(3-(3-(ierf-butyl)-1-(p-tolyl)-1 H-pyrazol- 5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-1 /-/-indazole-3-carboxylate as a pale tan solid (77 mg, 57 %); Rl 2.50 min (Method 2, acidic); m/z 680 (M-H)", (ES").
57%		Example 3 5-((4-((4-(3-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-N-(2-morpholinoethyl)-1H-indazole-3-carboxamide To a solution of CDI (91 mg, 0.56 mmol) in DCM (1.0 mL) was added Intermediate A1 (129 mg, 0.563 mmol) and the reaction mixture maintained at RT for 2 hr. A portion of this solution (500 muL, 0.28 mmol) was added to a solution of Intermediate B16 (80 mg, 0.19 mmol) in THF (2.0 mL) and the reaction mixture kept at RT for 3 hr and then quenched with the addition of MeOH (2.0 mL). The resulting mixture was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, 12 g, 0-100% [10% MeOH in EtOAc] in isohexane, gradient elution) to afford methyl 5-((4-((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-1H-indazole-3-carboxylate as a pale tan solid (77 mg, 57%); Rt 2.50 min (Method 2, acidic); m/z 680 (M-H)-, (ES-).

Reference： [1]Patent: WO2014/33448,2014,A1 .Location in patent: Page/Page column 71
[2]Patent: US2015/203475,2015,A1 .Location in patent: Paragraph 0560; 0561; 0562

26
[ 1071964-93-6 ]
[ 285984-25-0 ]
[ 1071964-41-4 ]

Yield	Reaction Conditions	Operation in experiment
27%	With bis(trichloromethyl) carbonate; triethylamine; In dichloromethane; at 25℃; for 3h;	General procedure: A solution of compounds 10a-d or compounds 17a-d (1.0 mmol) in dichloromethane (10 mL) was slowly added to a stirred solution of triphosgene (109 mg, 0.36 mmol) in dichloromethane (50 mL) over a period of 30 min using a syringe. After stirring for a further 30 min, a solution of compound 25a-r (0.6 mmol) and triethylamine (0.4 mL, 2.77 mmol) in dichloromethane (10 mL) was added in one portion. The reaction mixture was stirred for 2 h at room temperature. After completion of the reaction, the reaction was poured into water (50 mL) and extracted three times with dichloromethane. The organic layer was washed with water (5 mL), sat. NaCl solution (5 mL), anddried over Na2SO4. After evaporation of solvent under vacuum, the residue was purified by silica gel chromatography to give the desired chromanylurea or 2H-chromenyl urea compounds.