[ CAS No. 4835-90-9 ] {[proInfo.proName]}

Name: 4835-90-9|3-Hydroxy-2,2-dimethylpropanoic acid|97%
Brand: Ambeed
SKU: A128522
Price: 5.0 USD
Availability: InStock
Rating: 90 (30 reviews)

,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

HazMat Fee +

There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.

Type	HazMat fee for 500 gram (Estimated)
Excepted Quantity	USD 0.00
Limited Quantity	USD 15-60
Inaccessible (Haz class 6.1), Domestic	USD 80+
Inaccessible (Haz class 6.1), International	USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic	USD 100+
Accessible (Haz class 3, 4, 5 or 8), International	USD 200+

2D 3D

Structure of 4835-90-9 * Storage: {[proInfo.prStorage]}

Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

For Research Only 110K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 4835-90-9 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 4835-90-9 ]

SDS Specification

Alternatived Products of [ 4835-90-9 ]

Product Details of [ 4835-90-9 ]

CAS No. :	4835-90-9	MDL No. :	MFCD00059953
Formula :	C₅H₁₀O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	RDFQSFOGKVZWKF-UHFFFAOYSA-N
M.W :	118.13	Pubchem ID :	78548
Synonyms :

Calculated chemistry of [ 4835-90-9 ]

Physicochemical Properties

Num. heavy atoms :	8
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.8
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	2.0
Molar Refractivity :	28.82
TPSA :	57.53 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.04 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.8
Log Po/w (XLOGP3) :	-0.03
Log Po/w (WLOGP) :	0.09
Log Po/w (MLOGP) :	0.01
Log Po/w (SILICOS-IT) :	-0.29
Consensus Log Po/w :	0.12

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-0.42
Solubility :	44.8 mg/ml ; 0.379 mol/l
Class :	Very soluble
Log S (Ali) :	-0.73
Solubility :	22.1 mg/ml ; 0.187 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	0.14
Solubility :	165.0 mg/ml ; 1.4 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.23

Safety of [ 4835-90-9 ]

Signal Word:	Danger	Class:	9
Precautionary Statements:	P280-P301+P312+P330-P305+P351+P338+P310	UN#:	3077
Hazard Statements:	H302-H318	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 4835-90-9 ]

* 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 [ 4835-90-9 ]
Downstream synthetic route of [ 4835-90-9 ]

[ 4835-90-9 ] Synthesis Path-Upstream 1~9

1
[ 4835-90-9 ]
[ 324763-51-1 ]

Reference： [1] Patent: WO2012/10651, 2012, A2,

2
[ 67-56-1 ]
[ 4835-90-9 ]
[ 14002-80-3 ]

Yield	Reaction Conditions	Operation in experiment
57.2%	for 16 h; Reflux	3-Hydroxy-2,2-dimethylpropanoic acid (15.00 g, 127.0 mmol) was dissolved in a solution of MeOH (200 mL) and cone. H₂SO₄ (13.5 g, 254 mmol) and stirred at reflux for 16 h. The reaction mixture was concentrated in vacuo, diluted with EtOAc (100 mL), washed with water (2 x 50 mL), sat. NaHC0₃ (aq) (50 mL), water (50 mL), brine (1 x 50 mL), and dried ( a₂S0₄). Organic solvent was removed in vacuo to afford methyl 3-hydroxy-2,2- dimethylpropanoate (6.4 g, 57.2 percent) as a colorless liquid. H NMR (400 MHz, DMSO-i: δ 3.71 (s, 3 H), 3.56 (s, 2 H), 2.05-2.04 (m, 1 H), 1.19 (s, 6 H).

Reference： [1] Patent: WO2014/145023, 2014, A1, . Location in patent: Paragraph 0390
[2] Bulletin de la Societe Chimique de France, 1904, vol. <3>31, p. 129

3
[ 4835-90-9 ]
[ 14002-80-3 ]

Reference： [1] Patent: US5877317, 1999, A,

4
[ 67-56-1 ]
[ 126-30-7 ]
[ 4835-90-9 ]
[ 14002-80-3 ]

Reference： [1] Catalysis Letters, 2012, vol. 142, # 9, p. 1114 - 1120
[2] Chemistry - A European Journal, 2013, vol. 19, # 35, p. 11725 - 11732

5
[ 67-56-1 ]
[ 126-30-7 ]
[ 597-31-9 ]
[ 4835-90-9 ]
[ 14002-80-3 ]

Reference： [1] Catalysis Letters, 2012, vol. 142, # 9, p. 1114 - 1120

6
[ 4835-90-9 ]
[ 75-03-6 ]
[ 14002-73-4 ]

Yield	Reaction Conditions	Operation in experiment
68%	With caesium carbonate In N,N-dimethyl-formamide at 50 - 70℃;	A dry 500 mL round-bottomed flask equipped with a magnetic stirring bar, a reflux condenser, and a rubber septum was charged under an atmosphere of nitrogen with 7.09 g (60.0 mmol) of 3-hydroxy-2,2-dimethylpropanoic acid (hydroxypivalic acid, HPA) or 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoic acid (bis-hydroxypivalic acid, BHPA) and 19.55 g (60.0 mmol) of dried and freshly powdered cesium carbonate (Cs₂CO₃). 150 mL of anhydrous dimethylformamide (DMF) was added followed by 0.7-1.0 equivalents (40.0 to 60.0 mmol) of an appropriately substituted alkyl halide. The reaction mixture was heated under an atmosphere of nitrogen for overnight to ca. 50-70° C. (oil bath) (depending on the boiling point of the halide). The reaction mixture was diluted with ethyl acetate, precipitates were filtered off, and the filtrate was carefully diluted with a one molar (1.0 M) of hydrochloric acid (HCl). The aqueous phase was extracted several times with ethyl acetate and the combined organic extracts were washed with a saturated aqueous solution of sodium hydrogen carbonate (NaHCO₃). The organic solvents were removed under reduced pressure using a rotary evaporator and the residue was diluted in methyl tert-butyl ether (MTBE). The organic solution was washed five times with water (to remove residual DMF), then brine, dried over anhydrous magnesium sulfate (MgSO₄), filtered and the residual solvents removed under reduced pressure using a rotary evaporator. Generally, the products were of sufficient purity to be used directly in the next step without further purification or, optionally, were purified by fractional distillation under reduced pressure or silica gel column chromatography using ethyl acetate/hexane mixtures as eluent. Following the general procedure for the synthesis of hydroxypivalic ester derivatives of Description 2, 4.73 g (40.0 mmol) of 3-hydroxy-2,2-dimethylpropanoic acid (hydroxypivalic acid, HPA) was reacted with 3.23 mL (6.24 g, 40.0 mmol) of iodoethane in 80 mL of DMF in the presence of 13.03 g (40.0 mmol) of Cs₂CO₃. After work-up, 3.40 g (68percent yield) of the title compound (2) was obtained as a yellow liquid. The material was of sufficient purity to be used in the next step without further purification. ¹H NMR (400 MHz, CDCl₃): δ=1.20 (s, 6H), 1.28 (t, J=7.2 Hz, 3H), 2.50-2.55 (br. m, 1H), 3.52-3.57 (br. m, 2H), 4.16 (q, J=7.2 Hz, 2H) ppm.

Reference： [1] Patent: US2009/69419, 2009, A1, . Location in patent: Page/Page column 43-44

7
[ 64-17-5 ]
[ 4835-90-9 ]
[ 14002-73-4 ]

Reference： [1] Bulletin de la Societe Chimique de France, 1904, vol. <3>31, p. 129
[2] Journal of Organic Chemistry, 1973, vol. 38, p. 2346 - 2350
[3] Journal of the American Chemical Society, 1962, vol. 84, p. 3307 - 3319

8
[ 4835-90-9 ]
[ 100-39-0 ]
[ 17701-61-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium hydrogencarbonate In N,N-dimethyl-formamide at 20℃; for 16 h;	Reference Example 1 Benzyl 3-hydroxy-2,2-dimethylpropanoate [0391] [0392] 2,2-Dimethyl-3-hydroxypropanoic acid (10.0 g) was dissolved in N,N-dimethylformamide (150 mL). To this solution, potassium hydrogen carbonate (10.2 g) was added, and then, benzyl bromide (10.7 mL) was added thereto. The resulting solution was stirred at room temperature for 16 hours. To the reaction mixture, water (300 mL) was added, and extraction was performed with a mixed solution of n-hexane and ethyl acetate (1:4) (200 mL×2). The organic layers were combined and washed with a saturated aqueous solution of sodium chloride (200 mL), and then dried over magnesium sulfate. After magnesium sulfate was removed by filtration, the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (a medium-pressure preparative liquid chromatograph, W-prep 2XY manufactured by Yamazen Corporation (column: main column 4L, inject column 3L, n-hexane:ethyl acetate=1:0-1:1 (gradient time: 15 minutes), fractionation mode GR), whereby the title compound (17.6 g, 100percent) having the following physical properties was obtained. [0393] TLC (Rf value): 0.39 (n-hexane:ethyl acetate=3:1) [0394] NMR (CDCl₃): δ 7.29-7.41 (m, 5H), 5.15 (s, 2H), 3.57 (d, J=6.3 Hz, 2H), 1.22 (s, 6H)
3.04 g	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 5 h;	LiOH (15.9 g, 37.9 mmol) in THF/MeOH/H₂O (1:1:0.5, 62.5 mL) was added to a solution of 3-hydroxy-2,2-dimethylpropionate 14 (5 g, 37.9 mmol) in THF/MeOH (1:1, 25 mL) at 0 °C. The solution was warmed to rt and stirred for 1.5 h, the reaction mixture was adjusted to pH 2 by addition of H₂SO₄. The solution was concentrated under reduced pressure to remove THF and the residue washed with H₂O (10 mL), extracted with EtOAc (3 12 mL), dried over Na₂SO₄ and concentrated under reduced pressure to give the acid (3.3 g, 27.9 mmol, 73percent) as a white solid. Benzyl bromide (1.9 mL, 16.1 mmol) was added to a solution of crude acid (2.0 g, 16.9 mmol) and K₂CO₃ (2.57 g, 18.6 mmol) in DMF (20 mL). The reaction mixture was stirred for 5 h then quenched by the addition of H₂O (5 mL). The reaction mixture was extracted with Et₂O (3 10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na₂SO₄ and concentrated under reduced pressure. Purification by column chromatography using 9:1 to 3:2 hexanes/EtOAc as eluent gave the title compound 20 (3.04 g, 86percent) as a yellow oil. R_f: 0.48 (60percent hexanes/EtOAc); δ_H (400 MHz, CDCl₃): 7.39-7.29 (5H, m, Ph), 5.14 (2H, s, CH₂Ph), 3.57 (2H, d, J = 6.4 Hz, H-3), 2.54 (1H, br s, OH), 1.21 (6H, s, 2 CH₃); δ_C (100 MHz, CDCl₃): 176.9 (C=O, C-1), 135.8 (C, Ph), 128.3 (2 CH, Ph), 127.9 (CH, Ph), 127.5 (2 CH, Ph), 69.3 (CH₂, C-3), 66.1 (CH₂, CH₂Ph), 44.2 (C, C-2), 21.8 (2 CH₃). The spectroscopic data were in agreement with those reported in the literature.⁷

Reference： [1] Patent: US2013/245074, 2013, A1, . Location in patent: Paragraph 0391-0394
[2] Journal of the American Chemical Society, 2002, vol. 124, # 34, p. 9966 - 9967
[3] Patent: EP1544208, 2005, A1, . Location in patent: Page/Page column 43
[4] Patent: EP1452526, 2004, A1, . Location in patent: Page 55
[5] Tetrahedron, 2014, vol. 70, # 3, p. 590 - 596
[6] Patent: WO2017/96301, 2017, A1, . Location in patent: Page/Page column 165

9
[ 4835-90-9 ]
[ 7285-83-8 ]
[ 17701-61-0 ]

Reference： [1] European Journal of Organic Chemistry, 2015, vol. 2015, # 36, p. 7997 - 8002

[ 4835-90-9 ] Synthesis Path-Downstream 1~64

1
[ 64-17-5 ]
[ 4835-90-9 ]
[ 14002-73-4 ]

Reference： [1]Bulletin de la Societe Chimique de France,1904,vol. <3>31,p. 129
[2]Journal of Organic Chemistry,1973,vol. 38,p. 2346 - 2350
[3]Journal of the American Chemical Society,1962,vol. 84,p. 3307 - 3319

2
[ 19295-57-9 ]
[ 4835-90-9 ]

Reference： [1]Monatshefte fur Chemie,1906,vol. 27,p. 955

3
[ 4835-90-9 ]
[ 2843-17-6 ]

Yield	Reaction Conditions	Operation in experiment
66%	With hydrogen bromide; In water; at 100℃; for 19h;	Example 6 (Step F; )Hydroxy pivalic acid (6') (18.0 g, 152.4 mrnoi) was mixed with aqueous HBr (62%, 100 mL). The mixture was heated to 100 C and the temperature was kept for 19 h. The mixture was cooled to ambient temperature and diluted with 250 mL of water. The aqueous layer was extracted with diethyl ether (2 x 50 mL). The combined organic extracts were washed with water (3 x 25 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure to provide an oil which crystallized on standing. Bromo pivalic acid (7') was obtained in a yield of 66% (18.26 g, 100.9 mmol).1 H-NMR (300 MHz, CDCI3): delta = 1.34 (s, 6H, CH3), 1.99 (s, 2H, CH2) ppm.13C-NMR (75 MHz, CDCI3): delta = 24.3 (CH3), 40.8 (CH2), 44.2 (Cq), 181.5 (COOH) ppm.
		(a) Bromopivalic acid The title compound was prepared from hydroxypivalic acid (TCI America, 50.0 g, 423 mmol) using the procedure for Example 1(c). After removing the HBr under high vacuum the product was obtained (66.42 g, 367 mmol, 87%). 1 H NMR (DMSO-d6) delta 12.3 (br s); 3.57 (s, 2H); 1.19 (s, 6H). MS Da/e=181 (M), 183 (M+2). Calcd for C5 H9 O2 Br: C, 33.17; H, 5.01; Br, 44.13. Found: C, 34.07; H, 5.08; Br, 42.45.
	With sodium chloride; In hydrogen bromide;	Step B Synthesis of 3-bromo-2,2-dimethylpropionic acid A stirred solution of 4.5 grams (0.038 mole) of 3-hydroxy-2,2-dimethylpropionic acid in 45.0 grams of aqueous 48% hydrobromic acid was heated under reflux for 24 hours. The reaction mixture was cooled to ambient temperature and diluted with 100 ml of saturated aqueous solution of sodium chloride. The mixture was extracted with four portions of 50 ml each of methylene chloride and four portions each of diethyl ether. The combined extracts were washed with two portions of 50 ml each of distilled water then dried with sodium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure to a residual solid. The solid was recrystallized twice from cold pentane to give 4.0 grams of 3-bromo-2,2-dimethylpropionic acid; mp 46-48. The nmr and the ir spectra were consistent with the assigned structure. Analysis calc'd for C5 H9 BrO2: C 33.17; H 5.01; Found: C 34.68; H 4.93.

1.3 g

With carbon tetrabromide; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere;

To a solution of 3 -hydroxy-2, 2-dimethylpropanoic acid (3.5 g, 30 mmol) and CBr4(14.9 g, 45 mmol) in THF (50 mL) was added PPh3(11.8 g, 45 mmol) at 0C. The mixture was stirred at 0C for 30 min. The reaction was stirred at room temperature overnight under N2atmosphere. The reaction mixture was then quenched with water and extracted with DCM. The dichloromethane solution was dried over Na2S04, filtered and concentrated to give crude product. The crude product was purified by chromatography (silica gel, 1 to ~50 % AcOEt in PE) to give 3 -bromo-2, 2-dimethylpropanoic acid (1.3 g) as a colorless oil.

Reference： [1]Patent: WO2012/10651,2012,A2 .Location in patent: Page/Page column 20
[2]Bulletin de la Societe Chimique de France,1904,vol. <3>31,p. 155
[3]Monatshefte fur Chemie,1907,vol. 28,p. 1056
[4]Chemische Berichte,1959,vol. 92,p. 1329,1334
[5]Monatshefte fur Chemie,1907,vol. 28,p. 1056
[6]Canadian Journal of Chemistry,1971,vol. 49,p. 3866 - 3876
[7]Patent: US5998400,1999,A
[8]Patent: US4405357,1983,A
[9]Patent: WO2019/118612,2019,A1 .Location in patent: Paragraph 0252

4
[ 4835-90-9 ]
[ 75-36-5 ]
[ 2843-16-5 ]

Yield	Reaction Conditions	Operation in experiment
96%	at 0 - 20℃; for 16h;Inert atmosphere;	Step 7: Preparation of 3-acetoxy-2,2-dimethylpropanoic acid. [0627] <strong>[4835-90-9]3-Hydroxy-2,2-dimethylpropanoic acid</strong> (1.00 g, 8.47 mmol) was slowly added acetyl chloride (1.33 g, 16.9 mmol) at 0 C. The reaction mixture was then warmed to 20 C, stirred at 20 C for 16 h under N2 atmosphere. The colorless solution was formed gradually. Acetyl chloride was removed under reduced pressure to afford 3-acetoxy- 2,2-dimethylpropanoic acid (1.30 g, yield: 96%) as a white gum. 'H NMR (400 MHz, CDCh) d 1.26 (6H, s), 2.06 (3H, s), 4.12 (2H, s).
95.0%	With pyridine; at 0 - 20℃; for 3h;	Step A: 2.2-dimethyl-3-acetyloxypropionic acid; [512] 2,2-Dimethyl-3-hydroxypropionic acid (11.8 g, 100 mmol) was dissolved in pyridine (30 mL), and the reaction solution was cooled to 0C. Acetyl chloride (11.8 g, 15.0 mmol) was slowed added dropwise, the temperature was increased to rt, and the reaction solution was stirred at rt for 3 h. After the reaction finished, IN HCl (30 mL) was added, pH adjusted to 3-4, the reaction mixture was extracted with EtOAc. The organic extracts were washed with IN HCl for 4-5 times, dried over MgSO 4 , con- centrated in vacuo to give the title compound (15.2 g, 95.0 %).[513] MS[M+H] = 161(M+1)
95%	With pyridine; at 0 - 20℃;	Step A: 2,2-dimethyl-3-acetyloxypropionic acid 2,2-dimethyl-3-hydroxypropionic acid (11.8 g, 100 mmol) was dissolved in pyridine (30 mL), and the reaction solution was cooled to 0 C. Acetyl chloride (11.8 g, 15.0 mmol) was slowly added dropwise, the temperature was then raised to room temperature, and the reaction solution was stirred at room temperature for 3 hours. After the reaction was completed, 1 N HCl (30 mL) was added to adjust pH to 3-4, and then the reaction mixture was extracted with EtOAc. The organic extracts were washed with 1 N HCl, 4-5 times, dried over MgSO4, and concentrated in vacuo, give the title compound (15.2 g, 95.0%) MS[M+H]=161 (M+1)

95.0%		Preparation 10: 2,2-dimethyl-3-acetyloxypropionyl chloride[342] Step A: 2.2-dimethyl-3-acetyloxypropionic acid[343] 2,2-dimethyl-3-hydroxypropionic acid (11.8 g, 100 mmol) was dissolved in pyridine (30 mL), and the reaction solution was cooled to O0C. Acetyl chloride (11.8 g, 15.0 mmol) was slowly added dropwise, the temperature was then raised to room temperature, and the reaction solution was stirred at room temperature for 3 hours. After the reaction was completed, IN HCl (30 mL) was added to adjust pH to 3-4, and then the reaction mixture was extracted with EtOAc. The organic extracts were washed with IN HCl, 4-5 times, dried over MgSO4, and concentrated in vacuo, give the title compound (15.2 g, 95.0 %)[344] MS [M+H] = 161 (M+ 1 )
81%	at 80℃; for 2h;Inert atmosphere;	Step 1 : 3-Acetoxy-2,2-dimethyl-propionic acid A solution of 3-hydroxy-2,2-dimethyl-propionic acid (1.5 g, 12.69 mmol) in 5 ml of acetyl chloride was heated at 80C under nitrogen for 2 hours. The excess of acetyl chloride was evaporated under reduced pressure. The resulting residue was dissolved in dichloromethane and washed with water. The organic layer was separated, dried and evaporated to get the desired 3^ acetoxy-2,2-dimethyl-propionic acid (1.65 g, 81% yield) as a colorless liquid.
81%	In dichloromethane; at 80℃; for 2h;Inert atmosphere;	Step 1: 3-Acetoxy-2,2-dimethyl-propionic acid A solution of 3-hydroxy-2,2-dimethyl-propionic acid (1.5 g, 12.69 mmol) in 5 ml of acetyl chloride was heated at 80 C. under nitrogen for 2 hours. The excess of acetyl chloride was evaporated under reduced pressure. The resulting residue was dissolved in dichloromethane and washed with water. The organic layer was separated, dried and evaporated to get the desired 3-acetoxy-2,2-dimethyl-propionic acid (1.65 g, 81% yield) as a colorless liquid.
81%	In pyridine; at 0 - 20℃; for 4h;	2-Acetoxvmethyl-2-methyl-propionic acid 2,2-Dimethyl-3-hydroxypropionic acid (1.0 g, 8.48 mmol) was dissolved in pyridine (6 mL) at 0C and acetyl chloride (0.91 mL, 12.7 mmol) was added dropwise at this temperature. The mixture was warmed to room temperature and stirred for 4 h. After which a solution of 1NHC1 was added to adjust the pH (to 3-4). The mixture was extracted with EtOAc (3 x 30 mL) and the combined organic layer dried over anhydrous Na2SO4. Concentration under reduced pressure then gave 2-acetoxymethyl-2-methyl-propionic acid (1.1 g, 81 %) as an off-white crystallinesolid which was used directly in the next reaction without further purification.
	With pyridine; dmap;	(a) 3-Acetoxy-2,2-dimethylpropionic acid Acetyl chloride (4.52 g, 58.2 mmol) was added dropwise to a cold (0 C.) pyridine solution (10 ml) of 2,2-dimethyl-3-hydroxypropionic acid (5.5 g, 46.5 mmol) and 4-DMAP (0.57 g, 4.65 mmol). After stirring overnight at ambient temperature, the reaction was poured into ether (200 ml). This mixture was washed with 10% HCl (220 ml), and saturated brine (225 ml) and the resulting ethereal solution was dried (MgSO4). Evaporation gave the title compound as a pale yellow solid which was used in the next step without further purification. NMR (CDCl3) delta4.13 (2H, s), 2.08 (3H, s), 1.26 (6H, s).
	With pyridine; dmap;	(a) 3-Acetoxy-2,2-dimethylpropionic acid Acetyl chloride (4.52, 58.2 mmol) was added dropwise to a cold (0 C.) pyridine solution (10 ml) of 2,2-dimethyl-3-hydroxypropionic acid (5.5 g, 46.5 mmol) and 4-DMAP (0.57 g, 4.65 mmol). After stirring overnight at ambient temperature, the reaction was poured into ether (200 ml). This mixture was washed with 10% HCl (220 ml), and saturated brine (225 ml) and the resulting ethereal solution was dried (MgSO4). Evaporation gave the title compound as a pale yellow solid which was used in the next step without further purification. NMR (CDCl3) delta4.13 (2H, s), 2.08 (3H, s), 1.26 (6H, s).
	With pyridine; dmap;	(a) 3-Acetoxy-2,2-dimethylpropionic acid Acetyl chloride (4.52%, 58.2 mmol) was added dropwise to a cold (0C) pyridine solution (10 ml) of 2,2-dimethyl-3-hydroxypropionic acid (5.5 g, 46.5 mmol) and 4-DMAP (0.57 g, 4.65 mmol). After stirring overnight at ambient temperature, the reaction was poured into ether (200 ml). This mixture was washed with 10% HCl (2 x 20 ml), and saturated brine (2 x 25 ml) and the resulting ethereal solution was dried (MgSO4). Evaporation gave the title compound as a pale yellow solid which was used in the next step without further purification. NMR (CDCl3) delta 4.13 (2H, s), 2.08 (3H, s), 1.26 (6H, s).

Reference： [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 3896 - 3911
[2]Patent: WO2019/126731,2019,A1 .Location in patent: Paragraph 0627
[3]Patent: WO2008/7930,2008,A1 .Location in patent: Page/Page column 29
[4]Patent: US2010/120783,2010,A1 .Location in patent: Page/Page column 11
[5]Patent: WO2010/56022,2010,A2 .Location in patent: Page/Page column 24-25
[6]Patent: WO2011/73172,2011,A1 .Location in patent: Page/Page column 47-48
[7]Patent: US2011/152257,2011,A1 .Location in patent: Page/Page column 35
[8]Patent: WO2014/64134,2014,A1 .Location in patent: Page/Page column 89
[9]Bulletin de la Societe Chimique de France,1904,vol. <3>31,p. 129
[10]Patent: US4665091,1987,A
[11]Patent: US4668699,1987,A
[12]Patent: EP211416,1991,B1
[13]Chemistry - A European Journal,2014,vol. 20,p. 9530 - 9533

5
[ 4835-90-9 ]
[ 622-33-3 ]
[ 49640-44-0 ]

Reference： [1]Journal of the American Chemical Society,1980,vol. 102,p. 7026 - 7032
[2]Chemische Berichte,1973,vol. 106,p. 2246 - 2254

6
[ 4835-90-9 ]
[ 57497-39-9 ]
[ 60859-59-8 ]

Reference： [1]Archiv der Pharmazie,1976,vol. 309,p. 413 - 421

7
[ 4835-90-9 ]
[ 50632-53-6 ]
[ 60859-58-7 ]

Reference： [1]Archiv der Pharmazie,1976,vol. 309,p. 413 - 421

8
[ 19295-57-9 ]
hydrochloric acid <15 percent > [ No CAS ]
[ 4835-90-9 ]

Reference： [1]Monatshefte fur Chemie,1906,vol. 27,p. 955

9
[ 1115-20-4 ]
[ 4835-90-9 ]
[ 126-30-7 ]

Reference： [1]Franke; Kohn [Monatshefte fur Chemie, 1904, vol. 25, p. 866]

10
[ 597-31-9 ]
[ 4835-90-9 ]

Yield	Reaction Conditions	Operation in experiment
91%		The hydroxypivalaldehyde and sodium hydroxide solution obtained in the step (3) were added to a four-necked flask, heated and refluxed for 2 hours with stirring at 85 to 95 ° C,The weight ratio of the BaO / SiO2 core-shell microsphere catalyst was 27: 5: 270: 15, the weight ratio of the catalyst was 4: Stirring to 60 ° C while adding ammonia to keep the pH of the reaction solution 7-9, 8 hours after the stop reaction, the reaction solution suction filter, the filtrate concentration adjusted with concentrated hydrochloric acid ph value 3-4, extracted with acetone , After evaporation of acetone standing, precipitation crystallization is hydroxy pivalic acid, the yield was 91percent
85%	With phosphotungstic acid; dihydrogen peroxide; In water; at 55℃; for 2h;	2) Synthesis of Hydroxypivalic Acid: Add 40 ml of water to a 500 ml three-necked flask, start stirring, add 85 g of hydroxypivalaldehyde and 0.85 g of phosphotungstic acid catalyst, and then start heating. When the temperature rises to 55 ° C, Adding 123g of hydrogen peroxide, and adding for 2 hours; the oxidizing liquid is dehydrated under reduced pressure, filtering after dehydration to obtain the catalyst, taking out and reusing, and cooling and crystallizing the filtrate to obtain hydroxypivalic acid solution. 3) Drying: Hydroxypivalic acid solution was filtered to obtain wet products, the use of vacuum dryer for drying, temperature control at 58 , vacuum control in 0.085MPa, the final product hydroxypivalic acid, product yield of 85percent.

Reference： [1]Patent: CN105753684,2016,A .Location in patent: Paragraph 0052; 0053; 0057
[2]Patent: CN105753683,2016,A .Location in patent: Paragraph 0042; 0043
[3]Russian Journal of Applied Chemistry,2002,vol. 75,p. 942 - 945
[4]Monatshefte fur Chemie,1900,vol. 21,p. 220

11
[ 4835-90-9 ]
[ 824-94-2 ]
[ 238399-73-0 ]

Yield	Reaction Conditions	Operation in experiment
72.84%	With triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃;	To a stirred solution of 3-hydroxy-2,2-dimethylpropanoic acid (15.0 g, 126.978 mmol, 1.0 eq) in DMF (150 mL) at 0 °C was added TEA (53.16 mL, 380.936 mmol, 3.0 eq) and l-(chloromethyl)-4-methoxybenzene (21.693 mL, 152.37 mmol, 1.2 eq). The reaction mixture was allowed to stir at room temperature for overnight. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (2000 mL) and extracted with ethyl acetate (3x500 mL). The combined organic layers were washed with water (500 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 0-1percent methanol in DCM gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to obtain the title compound (22.0 g, yield: 72.84percent) as a colourless oil. 1H NMR (300 MHz, CDC13): delta ppm 7.27 (d, = 8.7 Hz, 2H), 6.88 (d, = 8.7 Hz, 2H), 5.07 (s, 3H), 3.80 (s, 3H), 3.55 (s, 2H), 1.18 (s, 6H).
72.84%	With triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃;	To a stirred solution of 3-hydroxy-2,2-dimethylpropanoic acid (15.0 g, 126.978mmol, 1.0 eq) in DMF (150 mL) at 0 °C was added triethylamine (53.16 mL, 380.936 mmol,3.0 eq) and 1-(chloromethyl)-4-methoxybenzene (21.693 mL, 152.37 mmol, 1.2 eq). The reaction mixture was allowed to stir at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water (2000 mL) and extracted with ethyl acetate (3x500 mL). Thecombined organic layers were washed with water (500 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 0-1percent methanol in DCM gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to obtain the title compound (22.0 g, yield: 72.84percent) as a colourless oil. ?H NMR (300 MHz, CDC13): ppm7.27 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 5.07 (s, 2H), 3.80 (s, 3H), 3.55 (s, 2H),1.18 (s, 6H).

Reference： [1]Patent: WO2018/29610,2018,A1 .Location in patent: Page/Page column 24; 25
[2]Patent: WO2018/69857,2018,A1 .Location in patent: Page/Page column 22
[3]Organic Letters,2003,vol. 5,p. 2473 - 2475

12
[ 4835-90-9 ]
[ 18162-48-6 ]
[ 528602-18-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	With 1H-imidazole; In dichloromethane;	A 2 L round bottomed flask equipped with a magnetic stir bar was charged with 11.8 g (100 mmol) of 3-hydroxy-2,2-dimethylpropanoic acid and the acid dissolved in 1 L of anhydrous dichloromethane (DCM). Tert-butyl dimethylchlorosilane (31.7 g, 210 mmol) and imidazole (14.3 g, 210 mmol) was added while stirring. The reaction was monitored by TLC. After the starting material was completely consumed the white precipitate was filtered off and the solvent removed under reduced pressure using a rotary evaporator. The residue was dissolved in 500 mL of diethyl ether (Et2O). The mixture was stirred for two hours and the colorless precipitate filtered off. After removing diethyl ether under reduced pressure using a rotary evaporator, the residue was dissolved in 600 mL of a mixture of water and acetonitrile (1:1). 8.0 g (200 mmol) of sodium hydroxide was added to the solution and the mixture was stirred overnight at room temperature. The reaction was acidified with a one normal (1N) aqueous solution of hydrogen chloride (HCl) and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over magnesium sulfate (MgSO4), filtered, and the solvents removed under reduced pressure using a rotary evaporator. The residue was purified by silica gel chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:4) as eluent to provide 23 g (quant.) of the title compound (18a) as a colorless liquid. Rf=0.58 (EtOAc/Hexane =1:4). 1H NMR (400 MHz, CDCl3): delta=0.07 (s, 6H), 0.90 (s, 9H), 1.19 (s, 6H), 3.60 (s, 2H) ppm. MS (ESI) m/z 233.01 (M+H)+.

Reference： [1]Patent: US2009/69419,2009,A1 .Location in patent: Page/Page column 47
[2]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 3231 - 3234

13
[ 14002-80-3 ]
[ 4835-90-9 ]

Yield	Reaction Conditions	Operation in experiment
73%	With water; lithium hydroxide; In tetrahydrofuran; methanol; at 0 - 20℃; for 1.5h;	LiOH (15.9 g, 37.9 mmol) in THF/MeOH/H2O (1:1:0.5, 62.5 mL) was added to a solution of 3-hydroxy-2,2-dimethylpropionate 14 (5 g, 37.9 mmol) in THF/MeOH (1:1, 25 mL) at 0 °C. The solution was warmed to rt and stirred for 1.5 h, the reaction mixture was adjusted to pH 2 by addition of H2SO4. The solution was concentrated under reduced pressure to remove THF and the residue washed with H2O (10 mL), extracted with EtOAc (3 12 mL), dried over Na2SO4 and concentrated under reduced pressure to give the acid (3.3 g, 27.9 mmol, 73percent) as a white solid. Benzyl bromide (1.9 mL, 16.1 mmol) was added to a solution of crude acid (2.0 g, 16.9 mmol) and K2CO3 (2.57 g, 18.6 mmol) in DMF (20 mL). The reaction mixture was stirred for 5 h then quenched by the addition of H2O (5 mL). The reaction mixture was extracted with Et2O (3 10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography using 9:1 to 3:2 hexanes/EtOAc as eluent gave the title compound 20 (3.04 g, 86percent) as a yellow oil.

Reference： [1]Tetrahedron,2014,vol. 70,p. 590 - 596
[2]Journal of the American Chemical Society,2002,vol. 124,p. 9966 - 9967

14
[ 4835-90-9 ]
[ 100-39-0 ]
[ 17701-61-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium hydrogencarbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;	Reference Example 1 Benzyl 3-hydroxy-2,2-dimethylpropanoate [0391] [0392] 2,2-Dimethyl-3-hydroxypropanoic acid (10.0 g) was dissolved in N,N-dimethylformamide (150 mL). To this solution, potassium hydrogen carbonate (10.2 g) was added, and then, benzyl bromide (10.7 mL) was added thereto. The resulting solution was stirred at room temperature for 16 hours. To the reaction mixture, water (300 mL) was added, and extraction was performed with a mixed solution of n-hexane and ethyl acetate (1:4) (200 mL×2). The organic layers were combined and washed with a saturated aqueous solution of sodium chloride (200 mL), and then dried over magnesium sulfate. After magnesium sulfate was removed by filtration, the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (a medium-pressure preparative liquid chromatograph, W-prep 2XY manufactured by Yamazen Corporation (column: main column 4L, inject column 3L, n-hexane:ethyl acetate=1:0-1:1 (gradient time: 15 minutes), fractionation mode GR), whereby the title compound (17.6 g, 100%) having the following physical properties was obtained. [0393] TLC (Rf value): 0.39 (n-hexane:ethyl acetate=3:1) [0394] NMR (CDCl3): delta 7.29-7.41 (m, 5H), 5.15 (s, 2H), 3.57 (d, J=6.3 Hz, 2H), 1.22 (s, 6H)
	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 5h;	To a suspension of hydroxypivalic acid (3 g) and potassium carbonate (3.9 g) in N,N-dimethylformamide (25 mL) was added benzyl bromide (2.9 mL), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with water twice and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (4.7 g).1H-NMR (CDCl3) delta ppm: 1.22 (6H, s), 2.33 (1H, t, J=6.7Hz), 3.58 (2H, d, J=6.7Hz), 5.15 (2H, s), 7.3-7.4 (5H, m)
	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 12h;	Hydroxypivalic acid (5.03 g) was dissolved in DMF (50 ml) and benzyl bromide (5.50 ml) and potassium carbonate (11.38 g) were successively added. The mixture was stirred at room temperature for 12 hr. Water (100 ml) was added to the reaction mixture and the mixture was extracted with ether (2×100 ml). The organic layer was washed successively with water (2×50 ml) and saturated aqueous sodium chloride solution (50 ml), dried and concentrated under reduced pressure. The obtained oily substance was purified by column chromatography to give the title compound (6.54 g) as a colorless oil.1H-NMR(delta, 300MHz, CDCl3) 1.22(6H,s),2.37(1H,t,J=6.8Hz),3.58(2H,d,J=6.8Hz),5.15(2H,s),7. 30-7.40(5H,m).

3.04 g	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 5h;	LiOH (15.9 g, 37.9 mmol) in THF/MeOH/H2O (1:1:0.5, 62.5 mL) was added to a solution of 3-hydroxy-2,2-dimethylpropionate 14 (5 g, 37.9 mmol) in THF/MeOH (1:1, 25 mL) at 0 C. The solution was warmed to rt and stirred for 1.5 h, the reaction mixture was adjusted to pH 2 by addition of H2SO4. The solution was concentrated under reduced pressure to remove THF and the residue washed with H2O (10 mL), extracted with EtOAc (3 12 mL), dried over Na2SO4 and concentrated under reduced pressure to give the acid (3.3 g, 27.9 mmol, 73%) as a white solid. Benzyl bromide (1.9 mL, 16.1 mmol) was added to a solution of crude acid (2.0 g, 16.9 mmol) and K2CO3 (2.57 g, 18.6 mmol) in DMF (20 mL). The reaction mixture was stirred for 5 h then quenched by the addition of H2O (5 mL). The reaction mixture was extracted with Et2O (3 10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography using 9:1 to 3:2 hexanes/EtOAc as eluent gave the title compound 20 (3.04 g, 86%) as a yellow oil. Rf: 0.48 (60% hexanes/EtOAc); deltaH (400 MHz, CDCl3): 7.39-7.29 (5H, m, Ph), 5.14 (2H, s, CH2Ph), 3.57 (2H, d, J = 6.4 Hz, H-3), 2.54 (1H, br s, OH), 1.21 (6H, s, 2 CH3); deltaC (100 MHz, CDCl3): 176.9 (C=O, C-1), 135.8 (C, Ph), 128.3 (2 CH, Ph), 127.9 (CH, Ph), 127.5 (2 CH, Ph), 69.3 (CH2, C-3), 66.1 (CH2, CH2Ph), 44.2 (C, C-2), 21.8 (2 CH3). The spectroscopic data were in agreement with those reported in the literature.7
		Take compound XIII-1 (12.403 g, 105 mmol) and dissolve it in N, N-dimethylformamide (124 mL, 0.805 M).Potassium carbonate (15.894 g, 115 mmol) was added sequentially,Benzyl bromide (11.877mL, 100mmol),The temperature was raised to 70 C.After 3.5 hours of reaction,TLC monitors the end of the reaction.Most of N, N-dimethylformamide was distilled off under reduced pressure,Add water (300mL),Ethyl acetate (50mL x 5) extraction,Combined organic phases,Washed with saturated saline (100mL x 2),Dry over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure,The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 20/1),A colorless oil was obtained. The obtained oil was dissolved in anhydrous tetrahydrofuran (150 mL),Triphenylphosphine (39.342 g, 150 mmol) was added sequentially,Pyridine (3.955 mL, 114 mmol).Under nitrogen protection and ice bath conditions,A solution of carbon tetrabromide (38.137 g, 115 mmol) in tetrahydrofuran (50 mL) was added dropwise.React overnight,TLC monitors the end of the reaction.Add n-hexane (50 mL),There is solid precipitation,Suction filtration,The filter cake was washed with tetrahydrofuran (5 mL x 2),The filtrate was concentrated,The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 300/1),Compound XIII-2 was obtained (yellow oil, 4.659 g, yield 17%).

Reference： [1]Patent: US2013/245074,2013,A1 .Location in patent: Paragraph 0391-0394
[2]Journal of the American Chemical Society,2002,vol. 124,p. 9966 - 9967
[3]Patent: EP1544208,2005,A1 .Location in patent: Page/Page column 43
[4]Patent: EP1452526,2004,A1 .Location in patent: Page 55
[5]Tetrahedron,2014,vol. 70,p. 590 - 596
[6]Patent: WO2017/96301,2017,A1 .Location in patent: Page/Page column 165
[7]Patent: CN110372638,2019,A .Location in patent: Paragraph 0642; 0644; 0645

15
[ 4835-90-9 ]
[ 19036-43-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: hydrobromic acid 2: alcohol; ammonia / 0 °C / im geschlossenen Rohr zunaechst bei gewoehnlicher Temp_. und dann bei 100grad
	Multi-step reaction with 2 steps 1: hydrogen bromide / water / 19 h / 100 °C 2: ammonia / 1,4-dioxane / 16 h / 60 °C / 2250.23 Torr / Autoclave

Reference： [1]Kohn; Schmidt [Monatshefte fur Chemie, 1907, vol. 28, p. 1056]
[2]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2012/10651, 2012, A2

16
2-methyl-1-{(1R,5S)-8-[2-(2-phenylmorpholin-2-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole trihydrochloride [ No CAS ]
[ 4835-90-9 ]
[ 716324-21-9 ]

Yield	Reaction Conditions	Operation in experiment
55%	With 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V); N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 24h;	To a stirred solution OF 2-METHYL-1-{(1R, 5S)-8-[2-(2-PHENYLMORPHOLIN-2- yl) ethyl]-8-azabicyclo [3.2. 1] oct-3-yl}-1H-benzimidazole trihyrdochloride (59.3 mg, 0.10 MMOL), 3-hydroxy-2, 2-DIMETHYLPROPANOIC acid (18 mg, 0.15 MMOL), and DIISOPROPYLETHYLAMINE (70P, L, 0.40 MMOL) in 1 mL DMF was added HATU (57 mg, 0.15 MMOL). The resulting mixture was stirred at ambient temperature for 24 h and then diluted with methylene chloride and washed with saturated aqueous NAHCO3. The organic phase was dried (NA2SO4), concentrated by evaporation, and purified by chromatography (5percent (2M NH3/MeOH) in CHCl3) to afford 2, 2-dimethyl-3- (2- {2- [ (1 R, 5S)-3- (2-METHYL-1 H-BENZIMIDAZOL-1-YL)-8-AZABICYCLO [3. 2.1] OCT-8-YL] ETHYL}-2- PHENYLMORPHOLIN-4-YL)-3-OXOPROPAN-1-OL (29.3 mg. 55percent) as amorphous SOLID.APOS;H NMR (400 MHz, CDCl3), 6 7.65 (m, 1H), 7.44-7. 26 (m, 6H), 7.19-7. 10 (m, 2H), 4.80 (br. , 1H), 4.69 (m, 1H), 3.75-3. 37 (m, 8H), 3.35-3. 16 (m, 3H), 2.58 (s, 3H), 2.46-2. 34 (m, 2H), 2.13-1. 84 (m, 8H), 1.68-1. 59 (m, 2H), 1.23 (s, 3H), 1.02 (s, 3H); ESI-MS 531 (M+H), 553 (M+Na).

Reference： [1]Patent: WO2004/55011,2004,A1 .Location in patent: Page 65-66

17
[ 195314-59-1 ]
[ 4835-90-9 ]
tert-butyl 4-[(3-hydroxy-2,2-dimethylpropanoyl)amino]cyclohexylcarbamate [ No CAS ]
tert-butyl 4-[(3-hydroxy-2,2-dimethylpropanoyl)amino]cyclohexylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 18h;	Preparation 45; TEFF-BUTYL 4-[(3-hydroxy-2,2-dimethylpropanoyl)amino]cyclohexylcarbamate (mixture of cis (major) and trans (minor)); tert-Butyl 4-aminocyclohexylcarbamate (4: 1 cis: trans mix of isomers, 1. 00g, 4. 67mmol), 3-HYDROXY-2, 2-DIMETHYLPROPANOIC acid (0.60g, 5. 13MMOL) and triethylamine (1. 30ml, 9. 33MMOL) were dissolved in DIMETHYLFORMAMIDE (20MUT) and 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (984mg, 5. 13mmol) and 1-HYDROXYBENZOTRIAZOLE (694mg, 5. 13MMOL) were added. The reaction was stirred under nitrogen at room temperature for 18h then partitioned between water and ethyl acetate. The organic phase was washed with water, dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting using dichloromethane : methanol : 0. 880AMMONIA (95: 5: 0.5) as eluant to give TERT-BUTYL 4- [ (3- HYDROXY-2, 2-DIMETHYLPROPANOYL) AMINO] CYCLOHEXYLCARBAMATE (840mg) as a white foam as a ca. 4: 1 mixture of diastereoisomers. 1H NMR (400MHZ, CDC13) : (peaks relating to major diastereoisomer) 9 = 6. 08-6.18 (1H, m), 4.48-4. 59 (1 H, m), 3.84-3. 94 (1H, m), 3.56 (3H, s), 1.46-1. 82 (8H, m), 1.44 (9H, s), 1.16 (6H, S) ppm. LRMS (electrospray) : m/z [M+Na] + 337

Reference： [1]Patent: WO2005/9966,2005,A1 .Location in patent: Page/Page column 86-87

18
[ 110-87-2 ]
[ 4835-90-9 ]
[ 162635-08-7 ]

Yield	Reaction Conditions	Operation in experiment
> 95%	With toluene-4-sulfonic acid; In dichloromethane; at 20℃; for 3h;	Example 60: 2, 2-Dimethyl-3- (tetrahydropyran-2-yloxy)-propionic acid (Intermediate) 2,2-Dimethyl-3-hydroxy propionic acid (100 mmol) and 3, 4-dihydro-2H-pyran (210 mmol) were dissolved in dichloromethane (50 ml), and para-toluenesulfonic acid (10 mg) was added and the reaction was stirred at ambient temperature for 3 hours. The reaction solvent was then removed and the residue was dissolved in ethanol (100 ml). A solution of KOH (120 mmol) in water (30 ml) was added and the reaction was heated at reflux for 18 hours. The reaction solvent was removed in vacuo and the residue was partitioned between water and diethyl ether. The aqueous layer was acidified with pH 2 buffer (0.5 M Na2SO4/0. 5 M NaHSO4) and then extracted with diethyl ether. The diethyl ether layer was then dried over Na2SO4 and the solvent was removed in vacuo to give 2, 2-dimethyl-3- (tetrahydropyran-2-yloxy)-propionic acid as an oil (20.0 g, >95percent); 5H (400 MHz, CDCl3) 4.62 (1H, t, J3. 5, CHO2), 3.82 (1H, ddd, J 12,9, 3, ring CH2O), 3.75 (1H, d, J 12, chain CH2O), 3.55-3. 46 (1H, m, ring CH2O), 3.40 (1H, d, J 12, chain CH2O), 1.90-1. 45 (6H, m, (CH2) 3), 1.25 (3H, s, CH3) and 1.23 (3H, s, CH3).

Reference： [1]Patent: WO2005/53702,2005,A2 .Location in patent: Page/Page column 47-48

19
[ 13511-38-1 ]
[ 4835-90-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In water;	Step A Synthesis of 3-hydroxy-2,2-dimethylpropionic acid To a stirred solution of 8.8 grams (0.219 mole) of sodium hydroxide in 50 ml of water was added 10.0 grams (0.073 mole) of <strong>[13511-38-1]3-chloro-2,2-dimethylpropionic acid</strong>. The resultant solution was heated under reflux for two hours. The reaction mixture was cooled to ambient temperature and acidified with concentrated hydrochloric acid. The mixture was saturated with solid sodium chloride and extracted with three portions of 50 ml each of methylene chloride then with three portions of 50 ml each of diethyl ether. The combined extracts were dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 5.9 grams of 3-hydroxy-2,2-dimethylpropionic acid; mp 123-124. The nmr and the ir spectra were consistent with the assigned structure. Analysis calc'd for C5 H10 O3: C 50.84; H 8.53; Found: C 50.40; H 8.26.

Reference： [1]Patent: US4405357,1983,A

20
C₂₆H₃₁BrN₄O₇S*ClH [ No CAS ]
[ 4835-90-9 ]
C₃₁H₃₉BrN₄O₉S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%	With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine; diisopropyl-carbodiimide; In N,N-dimethyl-formamide; at 20℃; for 12h;	EXAMPLE 4U - SYNTHESIS OF COMPOUND 1078 OFTABLE 1:; BrdrilCompound 1078To a solution of 2,2-dimethyl-3-hydroxypropionic acid (1.25 eq, 7.21 mg), amine 4d1(1 eq, 40 mg) and DIPEA (5 eq, 53 uL) in DMF (1 ml), was added the solution of DIC-HOAT (1.4 eq each, 13.3 uL and 11.6 mg respectively) in DMF (1 ml_). The reactionmixture was stirred at room temperature for 12 h, then was filtered through Millex filterand purified by preparative HPLC (Combiprep ODS-AQ, 20 x 50mm) to afford afterlyophilization compound 1078 as a white amorphous solid (14.5 mg, 37percent). ReversePhase HPLC Homogeneity (0.06 percent TFA; CH3CN: H2O): 96 percent 1H NMR (DMSO-d6,400MHz):10.49 (s, 1H); 8.77 (s, 1H); 7.89 (d, J= 9Hz, 1H); 7.31 (d, J= 9.2Hz, 1H);6.53 (s, 1H); 5.64-5.55 (m, 1H); 5.44 (broad s, 1H); 5.27 (d, J= 17Hz, 1H); 5.11 (d, J=10.4Hz, 1H); 4.55-4.47 (m, 3H); 4.39-4.34 (m, 1H); 4.28 (d, J= 12.1Hz, 1H); 4.03-3.94(m, 4H); 3.50 (d, J= 11 Hz, 1 H); 3.40 (d, J= 11 Hz, 1 H); 2.94-2.91 (m, 1 H); 2.42-2.37(m, 1H); 2.19-2.08 (m, 2H); 1.72 (dd, J= 5.1 Hz, J= 7.9Hz, 1H) ; 1.40 (t, J= 7.2Hz, 3H);1.27 (dd, J= 5.1Hz, J= 9.4Hz, 1H); 1.11-1.03 (m, 10H); MS: (M+H)+: 723; (MH+2)+:725.

Reference： [1]Patent: WO2006/7700,2006,A1 .Location in patent: Page/Page column 111

21
[ 4835-90-9 ]
[ 1049682-82-7 ]
C₂₁H₃₁NO₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	2,2-Dimethyl-3-hydroxypropionic acid (300 mg, 2.5 mmol), HOBT (583 mg, 3.8 mmol), EDC (487 mg, 2.5 mmol), and ethyl 4-(2-piperidin-4-yl-ethoxy)-benzoate (1.0 g of the TFA salt, <n="60"/>2.5 mmol) were suspended in DMF (2.5 ml) before DIPEA (0.44 ml, 2.5 mmol) was added. The reaction mixture was stirred at 20 0C overnight, concentrated in vacuo and purified by flash chromatography (EtOAc/heptane 30: 70 --> 50: 50) to give 0.71 g of the desired carboxamide.
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	Carboxamide formation; 2,2-Dimethyl-3-hydroxypropionic acid (300 mg, 2.5 mmol), HOBT (583 mg, 3.8 mmol), EDC (487 mg, 2.5 mmol), and ethyl 4-(2-piperidin-4-yl-ethoxy)-benzoate (1.0 g of the TFA salt, 2.5 mmol) were suspended in DMF (2.5 ml) before DIPEA (0.44 ml, 2.5 mmol) was added. The reaction mixture was stirred at 20 0C overnight, concentrated in vacuo and purified by flash chromatography (EtOAc/heptane 30: 70 --> 50: 50) to give 0.71 g of the desired carboxamide.

Reference： [1]Patent: WO2008/101885,2008,A1 .Location in patent: Page/Page column 58-59
[2]Patent: WO2008/101886,2008,A1 .Location in patent: Page/Page column 60

22
[ 4835-90-9 ]
[ 50893-36-2 ]
[ 1131569-68-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 70℃;	For the synthesis of acyloxyalkyl ester derivatives or alkoxy- and aryloxycarbonyloxyalkyl ester derivatives, a 100 mL round bottomed flask equipped with a magnetic stirring bar and a rubber septum was charged under a nitrogen atmosphere with 709 mg (6.0 mmol) of 3-hydroxy-2,2-dimethylpropanoic acid (hydroxypivalic acid, HPA) or 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoic acid (bis-hydroxypivalic acid, BHPA), and 2.0 equivalents (12.0 mmol) of an appropriately substituted 1-chloro- or 1-iodoalkyl carboxylate or an appropriately substituted 1-chloro- or 1-iodoalkyl alkyl- or arylcarbonate. 2.09 mL (1.55 g, 12.0 mmol) of diethylisopropylamine (DIEA, Huenigs base) were added neat. Optionally, 2 mL of anhydrous 1,2-dichloroethane was added to dissolve the reactants and to facilitate stirring. The reaction mixture was heated to ca. 70° C. and reacted overnight. Volatile reactants or solvents were removed under reduced pressure using a rotary evaporator. The residue was diluted with ethyl acetate (EtOAc) and water. After extraction, the combined extracts were washed with brine and dried over magnesium sulfate (MgSO4), filtered and the solvents removed under reduced pressure using a rotary evaporator. Optionally, the residues were used in the next step without further purification or were purified using silica gel column chromatography with ethyl acetate/hexane mixtures as eluent. Following the general procedure for the synthesis of acyloxyalkyl ester derivatives or alkoxy- and aryloxycarbonyloxyalkyl derivatives of Description 2, 709 mg (6.0 mmol) of 3-hydroxy-2,2-dimethylpropanoic acid (hydroxypivalic acid, HPA) was reacted with 1.83 g (12.0 mmol) of 1-chloroethyl ethyl carbonate in the presence of 2.09 mL (1.55 g, 12.0 mmol) of diethylisopropylamine (DIEA, Huenigs base). After work-up and isolation, ca. 1.4 g (quant.) of the title compound (7) was obtained as a colorless liquid. The material was of sufficient purity to be used in the next step without further purification. Rf=0.44 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): delta=1.18 (s, 3H), 1.21 (s, 3H), 1.32 (t, J=6.8 Hz, 3H), 1.53 (d, J=5.2 Hz, 3H), 2.35-2.52 (br. m, 1H), 3.48 (d, J=11.2 Hz, 1H), 3.60 (d, J=11.2 Hz, 1H), 4.22 (q, J=6.8 Hz, 2H), 6.70 (q, J=5.2 Hz, 1H) ppm. MS (ESI) m/z 257.00 (M+Na)+.

Reference： [1]Patent: US2009/69419,2009,A1 .Location in patent: Page/Page column 44-45

23
[ 4835-90-9 ]
[ 75-03-6 ]
[ 14002-73-4 ]

Yield	Reaction Conditions	Operation in experiment
68%	With caesium carbonate; In N,N-dimethyl-formamide; at 50 - 70℃;	A dry 500 mL round-bottomed flask equipped with a magnetic stirring bar, a reflux condenser, and a rubber septum was charged under an atmosphere of nitrogen with 7.09 g (60.0 mmol) of 3-hydroxy-2,2-dimethylpropanoic acid (hydroxypivalic acid, HPA) or 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoic acid (bis-hydroxypivalic acid, BHPA) and 19.55 g (60.0 mmol) of dried and freshly powdered cesium carbonate (Cs2CO3). 150 mL of anhydrous dimethylformamide (DMF) was added followed by 0.7-1.0 equivalents (40.0 to 60.0 mmol) of an appropriately substituted alkyl halide. The reaction mixture was heated under an atmosphere of nitrogen for overnight to ca. 50-70 C. (oil bath) (depending on the boiling point of the halide). The reaction mixture was diluted with ethyl acetate, precipitates were filtered off, and the filtrate was carefully diluted with a one molar (1.0 M) of hydrochloric acid (HCl). The aqueous phase was extracted several times with ethyl acetate and the combined organic extracts were washed with a saturated aqueous solution of sodium hydrogen carbonate (NaHCO3). The organic solvents were removed under reduced pressure using a rotary evaporator and the residue was diluted in methyl tert-butyl ether (MTBE). The organic solution was washed five times with water (to remove residual DMF), then brine, dried over anhydrous magnesium sulfate (MgSO4), filtered and the residual solvents removed under reduced pressure using a rotary evaporator. Generally, the products were of sufficient purity to be used directly in the next step without further purification or, optionally, were purified by fractional distillation under reduced pressure or silica gel column chromatography using ethyl acetate/hexane mixtures as eluent. Following the general procedure for the synthesis of hydroxypivalic ester derivatives of Description 2, 4.73 g (40.0 mmol) of 3-hydroxy-2,2-dimethylpropanoic acid (hydroxypivalic acid, HPA) was reacted with 3.23 mL (6.24 g, 40.0 mmol) of iodoethane in 80 mL of DMF in the presence of 13.03 g (40.0 mmol) of Cs2CO3. After work-up, 3.40 g (68% yield) of the title compound (2) was obtained as a yellow liquid. The material was of sufficient purity to be used in the next step without further purification. 1H NMR (400 MHz, CDCl3): delta=1.20 (s, 6H), 1.28 (t, J=7.2 Hz, 3H), 2.50-2.55 (br. m, 1H), 3.52-3.57 (br. m, 2H), 4.16 (q, J=7.2 Hz, 2H) ppm.

Reference： [1]Patent: US2009/69419,2009,A1 .Location in patent: Page/Page column 43-44

24
[ 4835-90-9 ]
[ 324763-51-1 ]

Reference： [1]Patent: WO2012/10651,2012,A2

25
[ 4835-90-9 ]
[ 38336-04-8 ]
[ 1093206-04-2 ]

Yield	Reaction Conditions	Operation in experiment
97%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;Inert atmosphere;	To a solution of 3-hydroxy-2,2-dimethylpropanoic acid (2.36 g, 20 mmol), 2-(benzyloxy)ethanamine (3.02 g, 20 mmol), and HOBt (2.71 g, 20 mmol) in dry dichloromethane (100 mL) was added EDCI (3.82 g, 20 mmol) at room temperature under nitrogen. The reaction mixture was then stirred at room temperature under nitrogen overnight. The reaction was quenched with brine, and extracted with EtOAc (3*). The combined organic layers were washed with saturated NaHCO3 solution, dilute HCl, brine, and dried over Na2SO4. After evaporation of the solvent, the residue was purified by chromatography on silica gel eluting with 40% EtOAc in hexanes to give the title compound as colorless oil (4.89 g) in 97% yield. MS 252 (MH+).
97%	With benzotriazol-1-ol; In dichloromethane;	Example 199c N-(2-(benzyloxy)ethyl)-3-hydroxy-2,2-dimethylpropanamide To a solution of 3-hydroxy-2,2-dimethylpropanoic acid (2.36 g, 20 mmol), 2-(benzyloxy)ethanamine (3.02 g, 20 mmol), and HOBt (2.71 g, 20 mmol) in dry dichloromethane (100 mL) was added EDCI (3.82 g, 20 mmol) at room temperature under nitrogen. The reaction mixture was then stirred at room temperature under nitrogen overnight. The reaction was quenched with brine, and extracted with EtOAc (3*). The combined organic layers were washed with saturated NaHCO3 solution, dilute HCl, brine, and dried over Na2SO4. After evaporation of the solvent, the residue was purified by chromatography on silica gel eluting with 40% EtOAc in hexanes to give the title compound as colorless oil (4.89 g) in 97% yield. MS 252 (MH+).

Reference： [1]Patent: US2015/245642,2015,A1 .Location in patent: Paragraph 1079
[2]Patent: US2012/41078,2012,A1

26
[ 1384980-61-3 ]
[ 4835-90-9 ]
[ 76456-06-9 ]

Reference： [1]Organic Letters,2012,vol. 14,p. 3724 - 3727

27
[ 4835-90-9 ]
[ 75-31-0 ]
[ 1359965-53-9 ]

Yield	Reaction Conditions	Operation in experiment
34%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;	to a solution of propan-2-amine (9.7 mL, 1 13.0 mmol) and 3-hydroxy-2,2- dimethylpropanoic acid (1 1.1 g, 94.2 mmol) in dichloromethane (500 mL) was added l-(3- dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (22.0 g, 113 mmol), 1- hydroxybenzotriazole monohydrate (17.3 g, 113 mmol), and triethylamine (16 mL, 113 mmol). The reaction was stirred at room temperature overnight. The crude mixture was concentrated on the rotovap. The residue was taken up in EtOAc and washed with saturated NaHC03, brine, and water. The organic layer was dried over Na2SC>4, filtered and evaporated under reduced pressure to afford the tile compound as a clear oil (5.12 g, 34percent). MS 160 (MH+)
34%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; water; at 20℃;	To a solution of propan-2-amine (9.7 mE, 113.0 mmol) and 3-hydroxy-2,2-dimethylpropanoic acid (11.1 g, 94.2 mmol) in dichioromethane (500 mE) was added 1-(3- dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (22.0 g, 113 mmol), 1 -hydroxybenzotriazole monohydrate (17.3 g, 113 mmol), and triethylamine (16 mE, 113 mmol). The reaction was stirred at room temperature overnight. The crude mixture was concentrated on the rotovap. The residue was taken up in EtOAc and washed with saturated NaHCO3, brine, and water. The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to afford the tile compound as a clear oil (5.12 g, 34percent). MS 160 (MHj.

Reference： [1]Patent: WO2013/25560,2013,A1 .Location in patent: Page/Page column 64; 65
[2]Patent: US2015/245642,2015,A1 .Location in patent: Paragraph 0796; 0797

28
[ 4835-90-9 ]
[ 1294496-86-8 ]
[ 1449737-61-4 ]

Yield	Reaction Conditions	Operation in experiment
700 mg	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 22 - 26℃; for 12h;	To a solution of ethyl 3-(aminomethyl)-6-chloro-2-fluorobenzoate (Intermediate-2, step-1, 800 mg, 3.45 mmol) and 3-hydroxy-2,2-dimethylpropanoic acid (591 mg, 5.00 mmol) in DMF (5 mL) were added (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (2.29 g, 5.18 mmol) and DIPEA (1.29 g, 10.0 mmol). Then reaction mixture was stirred at rt for 12 h and it was diluted with EtOAc, washed with H2O and brine. The organic layer was separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 700 mg of the title product. 1H NMR (400 MHz, DMSO d6): delta 8.09-8.06 (t, J=8.0 Hz, 1H), 7.45-7.38 (m, 2H), 4.91-4.88 (t, J=5.2 Hz, 1H), 4.42-4.37 (q, J=8.0 Hz, 2H), 4.29-4.28 (d, J=5.6 Hz, 2H), 3.48 (m, 2H), 1.33-1.29 (t, J=8.0 Hz, 3H), 1.05 (s, 6H).
700 mg	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 12h;	To a solution of ethyl 3-(aminomethyl)-6-chloro-2-fluorobenzoate (Intermediate-4, step-1 product, 800 mg, 3.45 mmol) and 3-hydroxy-2,2-dimethylpropanoic acid (591 mg, 5.00 mmol) in DMF (5 mL) were added (benzotriazol-1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (2.29 g, 5.18 mmol) and DIPEA (1.29 g, 10.0 mmol). Then reaction mixture was stirred at rt for 12 h and diluted with EtOAc and was washed with H20 and brine. The organic layer was separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 700 mg of the title product. 1H NMR (400 MHz, DMSO- d6): delta 8.09-8.06 (t, = 8.0 Hz, 1H), 7.45-7.38 (m, 2H), 4.91-4.88 (t, = 5.2 Hz, 1H), 4.42-4.37 (q, J = 8.0 Hz, 2H), 4.29-4.28 (d, J = 5.6 Hz, 2H), 3.48 (m, 2H), 1.33-1.29 (t, 7 = 8.0 Hz, 3H), 1.05 (s, 6H).

Reference： [1]Patent: US2013/210844,2013,A1 .Location in patent: Paragraph 0529; 0530
[2]Patent: WO2014/167444,2014,A1 .Location in patent: Page/Page column 41

29
[ 4835-90-9 ]
((S)-1-{(2S,5S)-2-[4-(5'-chloro-4'-[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2'-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-5-methyl-piperidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester trihydrochloride [ No CAS ]
[ 76-05-1 ]
[(S)-1-((2S,5S)-2-{4-[5'-chloro-4'-({6-[(R)-4-(3-hydroxy-2,2-dimethyl-propionyl)-2-methyl-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-2'-trifluoromethoxy-biphenyl-4-yl]-1H-imidazol-2-yl}-5-methyl-piperidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester di-trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%		(c) [(S)-1-((2S,5S)-2-{4-[5'-Chloro-4'-({6-[(R)-4-(3-hydroxy-2,2-dimethyl-propionyl)-2-methyl-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-2'-trifluoromethoxy-biphenyl-4-yl]-1H-imidazol-2-yl}-5-methyl-piperidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester To a solution of 2,2-dimethyl-3-hydroxypropionic acid (1.5 mg, 0.013 mmol) in DMA (1 mL) was added HATU (5.0 mg, 0.013 mmol). The reaction mixture was stirred at RT for 20 min and then the product of the previous step (10 mg, 0.011 mmol) was added followed by DIPEA (11.7 muL, 0.067 mmol). The reaction mixture was stirred at RT overnight, concentrated by rotary evaporation, dissolved in 1:1 acetic acid:water (1.5 mL) and purified by reverse phase HPLC to provide the di-TFA salt of the title compound (5.3 mg, 53percent yield). (m/z): [M+H]+ calcd for C45H54ClF3N8O7 911.38 found 911.8.

Reference： [1]Patent: US2013/287731,2013,A1 .Location in patent: Paragraph 0360

30
[ 4835-90-9 ]
[ 1477815-93-2 ]
[ 1477815-94-3 ]

Yield	Reaction Conditions	Operation in experiment
68%		A solution of 2,2-dimethyl-3-hydroxypropionic acid (15.9 mg, 0.13 mmol) and HATU (51.1 mg, 0.13 mmol) in DMA (3 mL) was stirred at 50° C. for 15 min and then a solution of the product of the previous step in DMA (2.63 mL) was added, followed by DIPEA (97.6 muL, 0.56 mmol). The solution was stirred at 50° C. for 4 hours, concentrated under vacuum, and purified by silica gel chromatography (0-5percent MeOH in DCM). The pure fractions were combined and concentrated under vacuum to provide the title intermediate (42 mg, 68percent yield) as a white foam. (m/z): [M+H]+ calcd for C22H30BrF3N4O4 551.14, 553.14 found 553.4.

Reference： [1]Patent: US2013/287730,2013,A1 .Location in patent: Paragraph 0329

31
[ 4835-90-9 ]
[ 97518-80-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 5 h / 20 °C 2.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 1 h 2.2: 20 °C
	Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: DMP / dichloromethane / 2 h / 20 °C / Inert atmosphere

Reference： [1]Finch, Orla C.; Furkert, Daniel P.; Brimble, Margaret A. [Tetrahedron, 2014, vol. 70, # 3, p. 590 - 596]
[2]Current Patent Assignee: DENALI THERAPEUTICS INC - WO2017/96301, 2017, A1

32
[ 4835-90-9 ]
[ 64241-78-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sulfuric acid / 16 h / Reflux 2.1: sodium hydride / tetrahydrofuran / 1.5 h / 0 - 20 °C 2.2: 16 h / 0 - 20 °C 2.3: 16 h / 20 °C

Reference： [1]Current Patent Assignee: DECIPHERA PHARMACEUTICALS LLC - WO2014/145023, 2014, A1

33
[ 4835-90-9 ]
[ 6638-79-5 ]
3-hydroxy-N-methoxy-N,2,2-trimethylpropanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 16h;	Step 1: 3-Hydroxy-N-methoxy-N,2,2-trimethylpropanamide The mixture of 3-hydroxy-2,2-dimethylpropanoic acid (10 g, 84.7 mmol), N,O-dimethylhydroxylamine hydrochloride (16.4 g, 101.7 mmol), EDCI (24.4 g, 127.1 mmol), HOBT (17.2 g, 127.1 mmol) and DIPEA (28 mL, 169.5 mmol) in DMF (200 mL) was stirred at rt for 16 hrs. The reaction mixture was extracted with EtOAc (200 mL3) and water (100 mL), combined the organic layers which washed with 1 N HCl (30 mL2), 1 N NaHCO3 (30 mL*2) and brine (50 mL), dried, concentrated to afford a residue which purified by chromatography (silica, ethyl acetate/petroleum ether=1/2) to afford 3-hydroxy-N-methoxy-N,2,2-trimethylpropanamide (6.9 g, 50percent) as a colorless oil. ESI-MS (EI+, m/z): 162.2 [M+H]+.
50%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 16h;	The mixture of 3-hydroxy-2,2-dimethylpropanoic acid (10 g, 84.7 mmol), N,Odimethylhydroxylamine hydrochloride (16.4 g, 101.7 mmol), EDCI (24.4 g, 127.1 mmol), HOBT (17.2 g, 127.1 mmol) and DIPEA (28 mL, 169.5 mmol) in DMF (200 mL) was stirred at rt for 16 hrs. The reaction mixture was extracted with EtOAc (200 mL x 3) and water (100 mL), combined the organic layers which washed with 1 NHC1 (30 mL*2), 1 N NaHCO3 (30 mL x 2) and brine (50 mL), dried, concentrated to afford a residue which purified by chromatography (silica, ethyl acetate/petroleum ether = 1/2) to afford 3 -hydroxy-N-methoxy-N,2,2- trimethylpropanamide(6.9 g, 50percent) as a corlorless oil. ESI-MS (EI, m/z): 162.2 [M+H]t

Reference： [1]Patent: US2017/114080,2017,A1 .Location in patent: Paragraph 0607
[2]Patent: WO2018/200625,2018,A1 .Location in patent: Paragraph 00527; 00528
[3]Advanced Synthesis and Catalysis,2015,vol. 357,p. 747 - 752

34
[ 107-10-8 ]
[ 4835-90-9 ]
[ 1093205-95-8 ]

Yield	Reaction Conditions	Operation in experiment
71%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;Inert atmosphere;	To a solution of 3-hydroxy-2,2-dimethylpropanoicacid (20.0 g, 0.169 mol), propylamine (15.3 mE, 0.186 mol), and HOBt (25.1 g, 0.186 mol) in dry dichloromethane (500 mE) was added EDCI (35.6 g, 0.186 mmol) at room temperature under nitrogen. The reaction mixture was then stirred at room temperature under nitrogen overnight. The reaction quenched with brine, and extracted EtOAc (8x). The combined organic layers were washed with saturated NaHCO3 solution, dilute HC1, brine, and dried over Na2504. Evaporation of the solvent under reduced pressure gave the title compound as colorless oil (19.2 g, 71percent). MS 160 (MW).

Reference： [1]Patent: US2015/245642,2015,A1 .Location in patent: Paragraph 1068; 1069

35
[ 4835-90-9 ]
[ 1620576-76-2 ]
1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-methyl-1,2,4-triazol-3-yl)piperidin-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h;Inert atmosphere;	General procedure: TBTU (201 mg, 0.63 mmol) was added to a stirred suspension of 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-(1-methyl-3-(piperidin-4-yl)-1,2,4-triazol-5-yl)pyrazin-2-amine 39a (200 mg, 0.52 mmol), DIPEA (0.27 mL, 1.6 mmol) and (R)-3-hydroxybutanoic acid (65 mg, 0.63 mmol) in DMF (3 mL). The resulting suspension was stirred at room temperature for 2 h. The resulting mixture was purified by preparative HPLC using a WatersX-Bridge reverse-phase column (C-18, 5 microns silica, 30 mm diameter, 150 mm length, flow rate of 60 mL/min) using an isocratic mixture of 31percent acetonitrile in water (containing ammonium carbonate (2 g/L). The fractions containing the desired compound were evaporated to dryness to afford a pale yellow solid. This solid was stirred in acetonitrile (3 mL) at room temperature. The resulting solid was filtered, washed with cold acetonitrile and dried to afford the title compound (125 mg, 51percent) as a pale yellow solid.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 5155 - 5162

36
[ 4835-90-9 ]
[ 7285-83-8 ]
[ 17701-61-0 ]

Reference： [1]European Journal of Organic Chemistry,2015,vol. 2015,p. 7997 - 8002

37
[ 4835-90-9 ]
[ 1031416-37-1 ]
1'-(3-hydroxy-2,2-dimethylpropanoyl)-7-methoxyspiro[chroman-2,4'-piperidin]-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%		Example 107A -(3-hydroxy-2,2-dimethylpropanoyl)-7-methoxyspiro[chroman-2,4'-piperidin]-4-one To 3-hydroxy-2,2-dimethylpropanoic acid (1 12 mg, 0.952 mmol) in DMF (4 mL) was added HATU (l-[bis(dimethylamino)methylene]-lH-l ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (543 mg, 1.427 mmol). The mixture was stirred for 5 minutes at room temperature, followed by the sequential addition of 7-methoxyspiro[chroman-2,4'-piperidin]-4- one, hydrochloric acid (CAS 1031416-37-1 , MFCD1 1973587) (270 mg, 0.952 mmol) and N- ethyl-N-isopropylpropan-2-amine (0.663 mL, 3.81 mmol). The mixture was stirred at room temperature for 2 hours. Purification by chromatography on silica gel, eluting with 5-50percent ethyl acetate in heptane provided the title compound (305 mg, 92 percent yield). LC/MS m/z 348 (M+H)+.

Reference： [1]Patent: WO2016/69757,2016,A1 .Location in patent: Page/Page column 204-205

38
[ 4835-90-9 ]
4-bromodeacetyl colchicine [ No CAS ]
4-bromo-N-(3-hydroxy-2,2-dimethylpropionyl)deacetyl colchicine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%		Hydroxypivalic acid (20 mg, 0.14x1.2 mmol) was dissolved in N.N-dimethylformamide (0.4 mL). 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (33 mg, 0.14x1.2 mmol) and 1-hydroxybenzotriazol monohydrate (23 mg, 0.14x1.2 mmol) were added, and stirred at room temperature for 30 minutes. 4-bromodeacetyl colchicine (62 mg, 0.14 mmol) was added, and stirred at the room temperature overnight. The solvent was distilled off after the reaction. The mixture was dissolved in chloroform and washed with 1 mol/L hydrochloric acid, 1 mol/L sodium hydroxide aqueous solution, and the saturated sodium chloride solution, dried with anhydrous magnesium sulfate and distilled off the solvent. The residue was purified by Silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform/methanol) to obtain title compound (a yellow solid, 79 mg, quant.) .

Reference： [1]Patent: JP5829520,2015,B2 .Location in patent: Paragraph 0288

39
[ 4835-90-9 ]
[ 51762-67-5 ]
3-(3,3-dimethyl-4-carboxypropoxy)phthalonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 96h;Inert atmosphere;	A mixture of 3-nitro-phthalonitrile (5mmol) and hydroxy pivalic acid (5mmol) was dissolved in DMSO (20ml), and reacted at room temperature under nitrogen, after 10min was added anhydrous potassium carbonate (10mmol), 24h and then adding hydroxypivalic acid (5mmol) and anhydrous potassium carbonate (10mmol), the reaction 72h, the end of the reaction monitored by thin layer chromatography.The reaction mixture was diluted with sand core funnel filtration, the filtrate was collected, and the filtrate was added to 500ml of ice water mixture, adjusted with 1M hydrochloric acid solution until the solution was acidic precipitation heavy precipitate, was allowed to stand, an organic microporous membrane, repeated washing more times until the solution was neutral, the solid was collected and lyophilized to give a white solid, further use DMF- water purified by recrystallization to give a white desired product, a yield of about 50percent.

Reference： [1]Patent: CN105622682,2016,A .Location in patent: Paragraph 0035; 0036

40
[ 4221-03-8 ]
[ 4835-90-9 ]

Yield	Reaction Conditions	Operation in experiment
	With aluminum oxide; bismuth(III) oxide; sodium hydroxide; In water; at 70℃; for 2h;	Step 2: Disproportionation and oxidation reactions. A mixture of 20 g of sodium hydroxide solution having a mass concentration of 50%, a mixture of oxidizing and alumina was added to the three-necked flask, and the weight ratio of oxidizing and alumina was 1 : 1; its specific surface area of 30-32m2 / g) lg stirring mixed evenly, the control temperature of 70 C reflux heating reaction 2h; reflux heating reaction after the temperature dropped to room temperature, add distilled water to adjust the pH to 8-9, open Slowly stirring the catalytic oxidation reaction 3h pumping to remove the catalyst bismuth oxide and alumina, the filtrate was concentrated to l0ml, add concentrated hydrochloric acid to adjust the pH value of 3 after extraction with ether and remove the ether to stand for crude 2,2_ dimethyl 3-hydroxypropionic acid, crude 2,2-dimethyl-3-hydroxypropionic acid was recrystallized from acetonitrile to give 2,2-dimethyl-3-hydroxypropionic acid

Reference： [1]Patent: CN105622414,2016,A .Location in patent: Paragraph 0030; 0031; 0034; 0035

41
[ 4835-90-9 ]
tert-butyl 3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-3-methylpiperidine-1-carboxylate [ No CAS ]
tert-butyl 3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-methylpiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32.9%		Example 6 - Preparation of Compound 4 The synthesis of Compound 4 followed the procedure of General Procedure 5b following. Compound 2 Compound 4 To a cold solution (0°C) of 3-hydroxy-2,2-dimethylpropanoic acid (0.576 g, 4.85 mmol, 2.0 eq) in THF (25 mL) was added 1-propanephosphonic anhydride (T3P, 1.551 g, 4.85 mmol, 2.0 eq), followed by diisopropylethylamine (DIPEA, 0.986 g, 9.75 mmol, 4.0 eq) under nitrogen. The reaction mixture was stirred for 1 hour, and to it was added tert-butyl 3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3- yl)-3-methylpiperidine-1-carboxylate (Compound 2, 1.0 g, 3.43 mmol, 1.0 eq). The reaction was stirred for 48 hours and monitored by TLC. After reaction completion, the mixture was poured into water (50 mL), extracted with ethyl acetate (2 x 20 mL), washed with water and then brine, then dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography using silica gel (60-120 mesh size) eluting with 10-20percent ethyl acetate in n-hexane, yielding tert-butyl 3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(3- hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-methylpiperidine-1-carboxylate (Compound 4, 0.410 g, yield: 32.9percent) m/z 511.8 [M+1]+ 1H NMR (400 MHz, DMSO) delta 7.63 (s, 1H), 6.92 (d, J = 37.7 Hz, 2H), 5.46 (s, 1H), 4.83 (t, J = 5.3 Hz, 1H), 4.41 (s, 2H), 3.87 (s, 2H), 3.42 (s, 2H), 3.19 (d, J = 5.2 Hz, 2H), 1.91 (s, 1H), 1.55 (s, 2H), 1.36 (s, 3H), 1.30 (s, 6H), 1.12 (s, 3H) ppm.

Reference： [1]Patent: WO2016/138532,2016,A1 .Location in patent: Paragraph 0241

42
[ 4835-90-9 ]
N-((5-chlorothiophen-2-yl)methyl)-3-(1-(2-morpholinoethyl)piperidin-4-yl)-1H-pyrazol-5-amine [ No CAS ]
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(1-(2-morpholinoethyl)piperidin-4-yl)-1H-pyrazol-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22%		Example 162- Preparation of Compound 113 The synthesis of Compound 113 followed the procedure of General Procedure 5a following: Compound 111 Compound 113 To a solution of hydroxypivalic acid (60.0 mg, 0.49 mmol, 1.0 eq.) in THF (10 mL) was added DIPEA (130.0 mg, 0.98 mmol, 2.0 eq.), HOBt (66.0 mg, 0.49 mmol, 1.0 eq.) and then EDCI-HCl (143.0 mg, 0.75 mmol, 1.5 eq.). The mixture was stirred at room temperature for 30 minutes. To it was added N-((5-chlorothiophen-2- yl)methyl)-3-(1-(2-morpholinoethyl)piperidin-4-yl)-1H-pyrazol-5-amine (Compound 111, 200.0 mg, 0.49 mmol, 1.0 eq.) and the mixture allowed to stir at room temperature for another 12 hours. After completion, the reaction mixture was concentrated and poured on to ice-cold water and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were concentrated under reduced pressure to give a residue, which was purified by preparative HPLC using 100percent MeCN and 0.1percent formic acid in water to give 1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(1-(2- morpholinoethyl)piperidin-4-yl)-1H-pyrazol-1-yl)-3-hydroxy-2,2-dimethylpropan-1- one (Compound 113, 55.0 mg, yield: 22percent) m/z 510.78 [M+1]+; 1H NMR (400 MHz, DMSO) delta 8.21 (s, 1H), 7.67 (t, J = 6.2 Hz, 1H), 6.97 (q, J = 3.8 Hz, 2H), 5.38 (s, 1H), 4.40 (d, J = 6.2 Hz, 2H), 3.86 (s, 2H), 3.59? 3.53 (m, 4H), 2.95 (d, J = 11.2 Hz, 2H), 2.43 (d, J = 6.7 Hz, 3H), 2.38 (s, 4H), 2.12 (t, J = 11.1 Hz, 2H), 1.83 (d, J = 11.8 Hz, 2H), 1.67? 1.51 (m, 2H), 1.30 (s, 6H), 1.03 (s, 1H) ppm.

Reference： [1]Patent: WO2016/138532,2016,A1 .Location in patent: Paragraph 0397

43
[ 4835-90-9 ]
1-(4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)piperidin-1-yl)-2-morpholinoethan-1-one [ No CAS ]
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(1-(2-morpholinoacetyl)piperidin-4-yl)-1H-pyrazol-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10%		Example 169- Preparation of Compound 117 The synthesis of Compound 117 followed the procedure of General Procedure 5a following: Compound 115 Compound 117 To a solution of hydroxypivalic acid (0.1 g, 0.9 mmol, 1.0 eq) in THF (6.0 mL) was added DIEA (0.18 mL, 1.0 mmol, 1.5 eq), HOBt (0.018 g, 0.14 mmol, 0.2 eq) and then EDCI.HCl (0.13 g, 1.0 mmol, 1.5 eq), and the mixture stirred at room temperature for 30 minutes. To the mixture was then added 1-(4-(5-(((5- chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)piperidin-1-yl)-2- morpholinoethan-1-one (Compound 115, 0.30 g, 0.7 mmol, 1.0 eq) and the reaction mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was concentrated and poured into ice-cold water (5.0 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were concentrated under reduced pressure to give a residue, which was purified by preparative HPLC using 100percent MeCN and water as mobile phase, to give 1-(5-(((5-chlorothiophen-2- yl)methyl)amino)-3-(1-(2-morpholinoacetyl)piperidin-4-yl)-1H-pyrazol-1-yl)-3- hydroxy-2,2-dimethylpropan-1-one (Compound 117, 38.0 mg, yield: 10percent) m/z 524.83 [M+H]+; 1HNMR (400 MHz, DMSO) delta 7.69 (t, J = 6.0 Hz, 1H), 6.96 (q, J = 3.7 Hz, 2H), 5.39 (s, 1H), 4.83 (t, J = 5.4 Hz, 1H), 4.41 (d, J = 6.1 Hz, 2H), 4.28 (d, J = 12.3 Hz, 1H), 4.03 (d, J = 13.0 Hz, 1H), 3.86 (d, J = 5.5 Hz, 2H), 3.56 (s, 4H), 3.24 (d, J = 13.3 Hz, 1H), 3.18? 3.01 (m, 2H), 2.73 (dd, J = 23.5, 12.4 Hz, 2H), 2.36 (d, J = 22.9 Hz, 4H), 1.87 (s, 2H), 1.60 (d, J = 12.5 Hz, 1H), 1.37 (d, J = 11.6 Hz, 1H), 1.31 (s, 6H) ppm.

Reference： [1]Patent: WO2016/138532,2016,A1 .Location in patent: Paragraph 0404

44
[ 4835-90-9 ]
(4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)piperidin-1-yl)(morpholino)methanone [ No CAS ]
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(1-(morpholine-4-carbonyl)piperidin-4-yl)-1H-pyrazol-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12%		Example 187- Preparation of Compound 135 The synthesis of Compound 135 followed the procedure of General Procedure 5a following: Compound 118 Compound 135 To a solution of hydroxypivalic acid (138 mg, 1.2 mmol, 1.2 eq) in THF (8 mL) was added DIEA (0.25 mL, 1.46 mmol, 1.5 eq), HOBt (26 mg.0.2 mmol, 0.2 eq) and then EDCI.HCl (282 mg, 1.5 mmol, 1.5 eq). After stirring for another 30 minutes, (4-(5- (((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)piperidin-1- yl)(morpholino)methanone (Compound 118, 400 mg, 0.98 mmol, 1.0 eq) was added and the mixture allowed to stir at room temperature for 16 hours. After completion, the reaction mixture was concentrated, poured into ice-cold water and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were concentrated under reduced pressure to give a residue which was purified by preparative HPLC using 100percent acetonitrile and 100percent water to give 1-(5-(((5-chlorothiophen-2- yl)methyl)amino)-3-(1-(morpholine-4-carbonyl)piperidin-4-yl)-1H-pyrazol-1-yl)-3- hydroxy-2,2-dimethylpropan-1-one (Compound 135, 58 mg, yield: 12percent) m/z 510.53 [M+1]+; 1H NMR (400 MHz, DMSO) delta 7.68 (t, J = 6.2 Hz, 1H), 6.96 (d, J = 3.8 Hz, 2H), 5.40 (s, 1H), 4.83 (t, J = 5.4 Hz, 1H), 4.41 (d, J = 6.1 Hz, 2H), 3.87 (d, J = 5.3 Hz, 2H), 3.61 (d, J = 13.5 Hz, 2H), 3.59? 3.53 (m, 4H), 3.15? 3.08 (m, 4H), 2.86 (t, J = 11.6 Hz, 2H), 2.66 (d, J = 11.5 Hz, 1H), 1.85 (d, J = 10.6 Hz, 2H), 1.50 (dd, J = 21.0, 11.8 Hz, 2H), 1.31 (s, 6H) ppm.

Reference： [1]Patent: WO2016/138532,2016,A1 .Location in patent: Paragraph 0425

45
[ 4835-90-9 ]
2-(4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)piperidine-1-yl)-1-morpholinoethan-1-one [ No CAS ]
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(1-(2-morpholino-2-oxoethyl)piperidin-4-yl)-1H-pyrazol-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12%		Example 173- Preparation of Compound 122 The synthesis of Compound 122 followed the procedure of General Procedure 5c following: Compound 120 Compound 122 To a solution of hydroxypivalic acid (92 mg, 0.78 mmol, 1.0 eq) in acetonitrile (10 mL) was added DIEA (301 mg, 2.3 mmol, 3.0 eq) and then TBTU (375 mg, 0.78 mmol, 1.0 eq), and then the mixture stirred at room temperature for 30 minutes. To this was added 2-(4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3- yl)piperidin-1-yl)-1-morpholinoethan-1-one (Compound 120, 0.33 g, 0.78 mmol, 1.0 eq) and the reaction was stirred at room temperature for 12 hours. After completion, the mixture was concentrated under reduced pressure to give a crude product, which was purified by preparative HPLC using 100percent MeCN and 0.1percent formic acid in water, to give 1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(1-(2-morpholino-2-oxoethyl) piperidin-4-yl)-1H-pyrazol-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one (Compound 122, 50 mg, yield: 12percent) m/z 524.63 [M+1]+; 1H NMR (400 MHz, DMSO) delta 7.74 (d, J = 6.1 Hz, 1H), 6.97 (s, 2H), 5.39 (s, 1H), 4.85 (t, J = 5.4 Hz, 1H), 4.42 (d, J = 6.2 Hz, 2H), 4.30? 4.06 (m, 1H), 3.87 (d, J = 5.4 Hz, 2H), 3.66? 3.54 (m, 4H), 3.50 (s, 2H), 3.38 (d, J = 17.7 Hz, 2H), 3.03 (s, 2H), 2.68 (s, 2H), 2.38? 1.74 (m, 6H), 1.32 (s, 6H) ppm.

Reference： [1]Patent: WO2016/138532,2016,A1 .Location in patent: Paragraph 0409

46
[ 4835-90-9 ]
N-((5-chlorothiophen-2-yl)methyl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-amine [ No CAS ]
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
16%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; ethyl acetate; at 20℃;	Example 176- Preparation of Compound 125 The synthesis of Compound 125 followed the procedure of General Procedure 5b following: Compound 123 Compound 125 To a solution of hydroxypivalic acid (0.119 g, 1.1 mmol, 1.5 eq.) in THF (8 mL) was added propylphosphonic anhydride (T3P in 50percent solution in ethyl acetate, 0.318 g, 1.0 mmol, 1.5 eq), DIEA (0.20 g, 2 mmol, 3eq) and then N-((5-chlorothiophen-2- yl)methyl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-amine (Compound 123, 0.25 g, 0.66 mmol, 1 eq). The reaction mixture was stirred at room temperature overnight. After reaction completion (as monitored by LC-MS), the mixture was poured into water (20 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic phases were washed with water, brine, and dried over sodium sulfate to give a residue, which was purified by preparative HPLC using water- acetonitrile as mobile phase, to give 1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3- (1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-1-yl)-3-hydroxy-2,2-dimethylpropan- 1-one Compound 125, 0.051 g, yield: 16percent) m/z 475.43 [M+]+ 1H NMR (400 MHz, DMSO) delta 7.70 (d, J = 6.0 Hz, 1H), 6.97 (t, J = 4.0 Hz, 2H), 5.43 (s, 1H), 4.83 (s, 1H), 4.41 (d, J = 6.4 Hz, 2H), 3.87 (d, J = 5.1 Hz, 2H), 3.56 (d, J = 11.2 Hz, 2H), 3.12? 2.74 (m, 5H), 2.64 (d, J = 27.0 Hz, 2H), 1.97 (d, J = 12.0 Hz, 2H), 1.62 (d, J = 9.3 Hz, 2H), 1.27 (d, J = 28.3 Hz, 6H) ppm.

Reference： [1]Patent: WO2016/138532,2016,A1 .Location in patent: Paragraph 0412

47
[ 4835-90-9 ]
N-((5-chlorothiophen-2-yl)methyl)-3-(1-(phenylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-amine [ No CAS ]
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(1-(phenylsulfonyl)piperidin-4-yl)-1H-pyrazol-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
16%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; ethyl acetate; at 20℃; for 16h;	Example 179- Preparation of Compound 128 The synthesis of Compound 128 followed the procedure of General Procedure 5b following: Compound 126 Compound 128 To a solution of hydroxypivalic acid (0.102 g, 0.85 mmol, 1.5 eq) in THF (6 mL) was added propylphosphonic anhydride (T3P in 50percent solution in ethyl acetate, 0.273 g, 0.85 mmol, 1.5 eq), DIEA (0.173 g, 1.7 mmol, 3 eq) followed by N-((5- chlorothiophen-2-yl)methyl)-3-(1-(phenylsulfonyl)piperidin-4-yl)-1H-pyrazol-5- amine (Compound 126, 0.27 g, 0.57 mmol, 1 eq). The reaction mixture was stirred at room temperature overnight. After completion (as monitored by LC-MS), the mixture was poured into water (20 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic phases were washed with water, brine, and dried over sodium sulfate, then filtered and evaporated under reduced pressure to give a residue. This was purified by preparative HPLC using water-acetonitrile as mobile phase to give 1- (5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(1-(phenylsulfonyl)piperidin-4-yl)-1H- pyrazol-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one (Compound 128, 0.054 g, yield: 16percent) m/z 537.54 [M+]+ 1H NMR (400 MHz, DMSO) delta 7.70 (ddd, J = 29.6, 11.6, 7.1 Hz, 5H), 6.95 (s, 2H), 5.33 (s, 1H), 4.79 (t, J = 5.3 Hz, 1H), 4.38 (d, J = 6.2 Hz, 2H), 3.81 (d, J = 5.2 Hz, 2H), 3.59 (d, J = 11.7 Hz, 2H), 1.91 (d, J = 10.8 Hz, 2H), 1.59 (dd, J = 21.2, 10.6 Hz, 2H), 1.25 (s, 6H) ppm.

Reference： [1]Patent: WO2016/138532,2016,A1 .Location in patent: Paragraph 0415

48
[ 4835-90-9 ]
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-N,N-dimethylpiperidine-1-carboxamide [ No CAS ]
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-N,N-dimethylpiperidine-1-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
11%		Example 181- Preparation of Compound 131 The synthesis of Compound 131 followed the procedure of General Procedure 5a following: Compound 129 Compound 131 To a solution of hydroxypivalic acid (154 mg, 1.3 mmol, 1.0 eq) in THF (10 mL) was added DIEA (280 mg, 1.6 mmol, 1.5 eq), HOBt (29 mg, 0.22 mmol, 0.2 eq) and finally EDCI.HCl (315 mg, 1.6 mmol, 1.5 eq). After stirring at room temperature for 30 minutes, 4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-N,N- dimethylpiperidine-1-carboxamide (Compound 129, 400 mg, 1.1 mmol, 1.0 eq) was added and the reaction mixture was stirred at room temperature for another 12 hours. After completion, the reaction mixture was concentrated under reduced pressure, poured into ice-cold water and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were concentrated under reduced pressure to give a residue, which was purified by preparative HPLC using 100percent acetonitrile and 0.1percent formic acid in water to give 4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(3-hydroxy-2,2- dimethylpropanoyl)-1H-pyrazol-3-yl)-N,N-dimethylpiperidine-1-carboxamide (Compound 131, 56 mg, yield: 11percent) m/z 468.63 [M+1]+; 1H NMR (400 MHz, DMSO) delta 7.68 (t, J = 6.2 Hz, 1H), 6.97 (q, J = 3.8 Hz, 2H), 5.40 (s, 1H), 4.83 (t, J = 5.3 Hz, 1H), 4.41 (d, J = 6.1 Hz, 2H), 3.87 (d, J = 5.2 Hz, 2H), 3.55 (d, J = 13.0 Hz, 2H), 2.80 (t, J = 11.4 Hz, 2H), 2.73 (s, 6H), 2.63 (t, J = 11.3 Hz, 1H), 1.85 (d, J = 11.3 Hz, 2H), 1.51 (dt, J = 15.0, 7.7 Hz, 2H), 1.31 (s, 6H) ppm.

Reference： [1]Patent: WO2016/138532,2016,A1 .Location in patent: Paragraph 0418

49
[ 4835-90-9 ]
N-((5-chlorothiophen-2-yl)methyl)-3-(1-(2,2-difluoro-2-(pyridin-2-yl)ethyl)piperidin-4-yl)-1H-pyrazol-5-amine [ No CAS ]
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(1-(2,2-difluoro-2-(pyridin-2-yl)ethyl)piperidin-4-yl)-1H-pyrazol-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%		Example 196- Preparation of Compound 145 The synthesis of Compound 145 followed the procedure of General Procedure 5a following: Compound 143 Compound 145 To a cooled solution (0oC) of hydroxypivalic acid (89 mg, 0.76 mmol, 1.1 eq) in THF (10 mL) was added DIPEA (221 mg, 1.7 mmol, 2.5 eq), HOBt (46 mg, 0.34 mmol, 0.5 eq) and then EDCI.HCl (197 mg, 1.0 mmol, 1.5 eq). After stirring at 0oC for 30 minutes, to the mixture was added N-((5-chlorothiophen-2-yl)methyl)-3-(1-(2,2- difluoro-2-(pyridin-2-yl)ethyl)piperidin-4-yl)-1H-pyrazol-5-amine (Compound 143, 300 mg, 0.68 mmol, 1.0 eq) and the mixture stirred at room temperature for another 12 hours. After completion, the reaction mixture was concentrated, poured into ice- cold water and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative HPLC using 100percent acetonitrile and 100percent water to give 1-(5-(((5-chlorothiophen-2- yl)methyl)amino)-3-(1-(2,2-difluoro-2-(pyridin-2-yl)ethyl)piperidin-4-yl)-1H- pyrazol-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one (Compound 145, 76 mg, yield: 21percent) m/z 540.63 [M+1]+; 1H NMR (400 MHz, DMSO) delta 8.68 (d, J = 4.4 Hz, 1H), 7.97 (td, J = 7.8, 1.7 Hz, 1H), 7.71 (s, 1H), 7.63 (d, J = 6.3 Hz, 1H), 7.54 (dd, J = 7.4, 4.8 Hz, 1H), 7.03? 6.89 (m, 2H), 5.35 (s, 1H), 4.81 (t, J = 5.4 Hz, 1H), 4.39 (d, J = 6.2 Hz, 2H), 3.84 (d, J = 5.4 Hz, 2H), 3.21 (t, J = 14.8 Hz, 2H), 2.82 (d, J = 11.5 Hz, 2H), 2.34 (dd, J = 23.2, 11.6 Hz, 4H), 1.72 (d, J = 11.4 Hz, 2H), 1.50? 1.35 (m, 2H), 1.29 (s, 6H) ppm.

Reference： [1]Patent: WO2016/138532,2016,A1 .Location in patent: Paragraph 0435

50
[ 4835-90-9 ]
(9H-fluoren-9-yl)methyl4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)piperidine-1-carboxylate [ No CAS ]
(9H-fluoren-9-yl)methyl 4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In chloroform; at 20℃; for 4h;Inert atmosphere;	Example 215 - Preparation of Compound 164 The synthesis of Compound 164 followed the procedure of General Procedure 5 following: Compound 161 Compound 164 To a solution of (9H-fluoren-9-yl)methyl 4-(5-(((5-chlorothiophen-2- yl)methyl)amino)-1H-pyrazol-3-yl)piperidine-1-carboxylate (Compound 161, 300 mg, 0.48 mmol) and 3-hydroxy-2,2-dimethylpropanoic acid (59 mg, 0.58 mmol) in chloroform (5 mL) under nitrogen at room temperature, was added O-(Benzotriazol- 1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU, 171 mg, 0.53 mmol), followed by triethylamine (TEA, 0.1 mL, 0.72 mmol). The reaction mixture was stirred at room temperature for 4 hr, diluted with water (50 mL) and extracted with dichloromethane (2 x 25 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (100-200 mesh), eluting with 20percent ethyl acetate/petroleum ether, to afford (9H-fluoren-9-yl)methyl 4-(5-(((5- chlorothiophen-2-yl)methyl)amino)-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H- pyrazol-3-yl)piperidine-1-carboxylate (Compound 164, 250 mg, yield: 71percent). m/z 620.19 [M+1]+; TLC System: 10percent Methanol in dichloromethane. Rf-0.85.

Reference： [1]Patent: WO2016/138532,2016,A1 .Location in patent: Paragraph 0454

51
[ 4835-90-9 ]
(9H-fluoren-9-yl)methyl-2-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)pyrrolidine-1-carboxylate [ No CAS ]
(9H-fluoren-9-yl)methyl 2-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In chloroform; at 20℃; for 4h;Inert atmosphere;	Example 260 - Preparation of Compound 204 The synthesis of Compound 204 followed the procedure of General Procedure 5 following: Compound 199 Compound 204 To a solution of (9H-fluoren-9-yl)methyl 2-(5-(((5-chlorothiophen-2- yl)methyl)amino)-1H-pyrazol-3-yl)pyrrolidine-1-carboxylate (Compound 199, 500 mg, 0.99 mmol) and 3-hydroxy-2,2-dimethylpropanoic acid (146 mg, 1.2 mmol) in chloroform (25 mL) under nitrogen at room temperature, was added O-(Benzotriazol- 1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU, 365 mg, 1.1 mmol), followed by diisopropylethylamine (DIEA, 0.3mL, 7.4 mmol). The reaction mixture was stirred at room temperature for 4 hr, diluted with water (50 mL) and extracted with chloroform (2 x 25 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by preparative HPLC using acetonitrile-water as mobile phase to give product (9H-fluoren-9-yl)methyl 2-(5-(((5-chlorothiophen-2-yl)methyl)amino)- 1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)pyrrolidine-1-carboxylate (Compound 204, 250 mg, yield: 42percent). m/z 605.19 [M+1]+; TLC System: 10percent Methanol in dichloromethane. Rf-0.9.

Reference： [1]Patent: WO2016/138532,2016,A1 .Location in patent: Paragraph 0499

52
[ 4835-90-9 ]
[ 83766-88-5 ]
[ 25307-76-0 ]

Yield	Reaction Conditions	Operation in experiment
84%	With boron trifluoride diethyl etherate; In toluene; at 20℃; for 2h;	Carboxylic acid (0.2 g, 1.64 mmol), tert-butoxypyridine (0.33 g, 2.21 mmol) and boron trifluoride diethyl etherate (0.31 g, 2.21 mmol) in dry PhCH3 (2 mL) were added to a 20-ml vial. The reaction mixture was then allowed to stir at room temperature for 30 min before quenching with anhydrous NaHCO3. The reaction mixture was diluted with ethyl acetate (30 mL), then washed with water (20 mL), followed by brine (20 mL). The organic layer was dried over anhydrous sodium sulfate and carefully concentrated under reduced pressure. The resulting residue was then purified by flash column chromatography on silica gel with 0:4 to 1:4 dichloromethane/hexane as eluent to yield the desired product 5a as a colorless oil.

Reference： [1]Tetrahedron,2018,vol. 74,p. 3748 - 3754

53
[ 4835-90-9 ]
[ 111-27-3 ]
[ 14002-75-6 ]

Yield	Reaction Conditions	Operation in experiment
61%	With sulfuric acid; at 80℃;	A mixture of 99 3-hydroxy-2,2-dimethylpropionic acid (4.7 g, 40 mmol), 109 1-hexanol (70 mL) and 101 concentrated sulfuric acid (or fuming sulfuric acid, 1 mL) was heated to 80° C. and stirred overnight. After allowing to cool, the mixture was concentrated under vacuum (high vacuum pump required) and the residue was then partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (100 mL). The aqueous phase was washed with H2O (50 mL), saturated NaHCO3 (50 mL) and brine (50 mL), and then dried over anhydrous Na2SO4, filtered and concentrated under vacuum to provide the product as an oil. The product was difficult to purify using silica gel chromatography; and therefore the product was distilled under high vacuum at 47° C. to provide 4.92 g of the pure ester product (111 39a) (yield 61percent). 1H-NMR (300 MHz, CDCl3) delta 4.10 (td, J=6.7, 1.3 Hz, 2H), 3.55 (d, J=5.1 Hz, 2H), 2.42 (s, 1H), 1.64 (s, 1H), 1.72-1.56 (m, 1H), 1.35 (s, 1H), 1.31 (s, 6H), 1.27-1.11 (m, 6H), 0.95-0.84 (m, 3H). MS (ESI) C11H22O3=203 (M+1)+.
	at 80℃;	Reference is made to German Application Publication No. DE3045373. A mixture of 3-hydroxy-2,2-dimethylpropionic acid (4.7 g, 40 mmol), 1-hexanol (70 mL) and concentrated sulfuric acid (or fuming sulfuric acid; 1 mL) was heated to 80 C. and stirred overnight. After allowing to cool, the mixture was concentrated under vacuum (high vacuum pump required) and the residue partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (100 mL). The aqueous mixture was washed with H2O (50 mL), saturated NaHCO3 (50 mL) and brine (50 mL), then dried (Na2SO4), filtered and concentrated under vacuum to provide the product (12a) as an oil. The product was used directly in the next step without further purification. 1H-NMR (300 MHz, CDCl3): delta 4.04-3.98 (m, 2H), 3.47-3.45 (m, 2H), 2.26 (s, 1H), 1.58-1.32 (m, 2H), 1.32-1.23 (m, 61-), 1.12 (s, 3H), 1.11 (s, 3H).

Reference： [1]Patent: US2019/100516,2019,A1 .Location in patent: Paragraph 1029; 1030; 1119; 1120; 1176; 1177
[2]Patent: US2020/102307,2020,A1 .Location in patent: Paragraph 1398-1400; 1455-1457; 1721-1723
[3]Patent: US10085999,2018,B1 .Location in patent: Page/Page column 99; 100

54
[ 111-70-6 ]
[ 4835-90-9 ]
heptyl 3-hydroxy-2,2-dimethylpropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With sulfuric acid; at 80℃;	A mixture of 3-hydroxy-2,2-dimethylpropionic acid (4.7 g, 40 mmol), 1-heptanol (70 mE) and concentrated sulfuric acid (1 mE) was heated to 80° C. and stirred overnight. Afier allowing to cool, the mixture was concentrated under vacuum (high vacuum pump required) and the residue partitioned between EtOAc (100 mE) and saturated aqueous NaHCO3 (100 mE). The aqueous phase was washed with H20 (50 mE), saturated NaHCO3 (50 mE) and brine (50 mE), and then dried (Na2504), filtered and concentrated under vacuum to provide the product as an oil. The product was distilled under high vacuum at 65° C. to provide the title compound (40a) as an oil (6.7 g, 77percent yield). ?H-NMR (300 MHz, CDC13) oe 4.09 (td, J=6.7, 0.9 Hz, 2H), 3.55 (d, J6.1 Hz, 2H), 2.43 (t, J6.7 Hz, 1H), 1.60 (d, J=22.8 Hz, 4H), 1.3-1.58 (m, 6H), 1.27-1.14 (m, 6H), 0.92-0.83 (m, 3H).
	at 80℃;	Reference is made to German Application Publication No. DE3045373. A mixture of 3-hydroxy-2,2-dimethylpropionic acid (4.7 g, 40 mmol), 1-heptanol (70 mL) and concentrated sulfuric acid (or fuming sulfuric acid; 1 mL) was heated to 80 C. and stirred overnight. After allowing the mixture to cool, the mixture was concentrated under vacuum (high vacuum pump required) and the residue partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (100 mL). The aqueous was washing with H2O (50 mL), saturated NaHCO3 (50 mL) and brine (50 mL), then dried (Na2SO4), filtered and concentrated under vacuum to provide the product (13a) as an oil. The product was used directly in the next step without further purification. 1H-NMR (300 MHz, CDCl3): delta 4.31 (t, J=6.5 Hz, 2H), 3.77 (s, 2H), 1.87-1.81 (m, 2H), 1.53-1.50 (m, 8H), 1.41 (s, 6H), 1.12-1.08 (m, 3H)

Reference： [1]Patent: US2019/100516,2019,A1 .Location in patent: Paragraph 1036; 1037; 1124; 1125; 1181; 1182
[2]Patent: US2020/102307,2020,A1 .Location in patent: Paragraph 1403-1405; 1460-1462; 1730-1732
[3]Patent: US10085999,2018,B1 .Location in patent: Page/Page column 101
[4]Journal of Medicinal Chemistry,2018,vol. 61,p. 10340 - 10344

55
[ 4835-90-9 ]
[ 6482-24-2 ]
2-methoxyethyl 3-hydroxy-2,2-dimethylpropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 23 - 70℃;	<strong>[4835-90-9]3-Hydroxy-2,2-dimethylpropanoic acid</strong> (1.2 g, 10.3 mmol) and Cs2CO3 (3.4 g, 10.4 mmol) were suspended in DMF (25 mL) at 23 C., then 2-bromoethyl methyl ether (1.0 mL, 10.4 mmol) was added. The resulting mixture was stirred at 70 C. overnight. After cooling, the mixture was filtered through a pad of Celite. The filtrate was diluted with EtOAc (150 mL), and the mixture washed with water (3×100 mL) and brine, then dried (Na2SO4), filtered and concentrated to leave a crude residue. The residue was purified by column chromatography on silica gel using EtOAc/hexanes (1:4 to 4:1) as eluent to provide the product (15a) (1.3 g, crude weight) as an oil. 1H-NMR (300 MHz, CDCl3): delta 4.28 (t, J=4.8 Hz, 2H), 3.62-3.55 (m, 4H), 3.38 (s, 3H), 2.65 (t, J=6.0 Hz, 1H), 1.21 (s, 6H).
	With caesium carbonate; In N,N-dimethyl-formamide; at 23 - 70℃;	<strong>[4835-90-9]3-Hydroxy-2,2-dimethylpropanoic acid</strong> (1.2 g, 10.3 mmol) and 142 Cs2CO3 (3.4 g, 10.4 mmol) were suspended in 143 DMF (25 mL) at 23° C., then 144 2-bromoethyl methyl ether (1.0 mL, 10.4 mmol) was added. The resulting mixture was stirred at 70° C. overnight. After cooling, the mixture was filtered through a pad of Celite®. The filtrate was diluted with EtOAc (150 mL), and the mixture washed with water (3×100 mL) and brine, then dried (Na2SO4), filtered and concentrated to leave a crude residue. The residue was purified by column chromatography on silica gel using 21 EtOAc/hexanes (1:4 to 4:1) as eluent to provide the 145 product (14a) (1.3 g, crude weight) as an oil. 1H-NMR (300 MHz, CDCl3): delta 4.28 (t, J=4.8 Hz, 2H), 3.62-3.55 (m, 4H), 3.38 (s, 3H), 2.65 (t, J=6.0 Hz, 1H), 1.21 (s, 6H).

Reference： [1]Patent: US10085999,2018,B1 .Location in patent: Page/Page column 105
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 10340 - 10344
[3]Patent: US2019/100516,2019,A1 .Location in patent: Paragraph 1051; 1052; 1192; 1193
[4]Patent: US2020/102307,2020,A1 .Location in patent: Paragraph 1471-1473

56
[ 26272-85-5 ]
[ 4835-90-9 ]
oxetan-3-yl 3-hydroxy-2,2-dimethylpropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	With caesium carbonate; In N,N-dimethyl-formamide; at 23 - 70℃;	<strong>[4835-90-9]3-Hydroxy-2,2-dimethylpropanoic acid</strong> (4.7 g, 40 mmol) and Cs2CO3 (13.0 g, 40 mmol) were suspended in DMF (100 mL) at 23 C., then 3-iodooxetane (7.4 g, 40 mmol) was added. The resulting mixture was stirred at 70 C. overnight. After cooling, the mixture was diluted with EtOAc (150 mL), and the mixture washed with water (3×100 mL) and brine, then dried (Na2SO4), filtered and concentrated to provide a crude residue. The residue was purified by column chromatography on silica gel using EtOAc/hexanes as eluent to give the product (16a) (3.6 g, 51%) as an oil.
51%	With caesium carbonate; In N,N-dimethyl-formamide; at 23 - 70℃;	<strong>[4835-90-9]3-Hydroxy-2,2-dimethylpropanoic acid</strong> (4.7 g, 40 mmol) and 142 Cs2CO3 (13.0 g, 40 mmol) were suspended in 143 DMF (100 mL) at 23° C., then 154 3-iodooxetane (7.4 g, 40 mmol) was added. The resulting mixture was stirred at 70° C. overnight. After cooling, the mixture was diluted with EtOAc (150 mL), and the mixture washed with water (3×100 mL) and brine, then dried (Na2SO4), filtered and concentrated to provide a crude residue. The residue was purified by column chromatography on silica gel using 21 EtOAc/hexanes as eluent to give the 155 product (15a) (3.6 g, 51percent) as an oil.

Reference： [1]Patent: US10085999,2018,B1 .Location in patent: Page/Page column 106; 107
[2]Patent: US2019/100516,2019,A1 .Location in patent: Paragraph 1058; 1059; 1197; 1198
[3]Patent: US2020/102307,2020,A1 .Location in patent: Paragraph 1476-1478

57
[ 4835-90-9 ]
[ 91526-18-0 ]
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-hydroxy-2,2-dimethylpropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%	With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃;	To a stirred solution of 3-hydroxy-2,2-dimethylpropanoic acid (4.0 g, 33.9 mmol) and potassium carbonate (4.68 g, 33.9 mmol) in DMF (45 mL) at 0 C. was added 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one (5.03 g, 33.9 mmol) in DMF (5 mL) dropwise over 1 h. The reaction was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to give a crude residue. The residue was purified by silica gel column chromatography using EtOAc/ hexane (1:4 to 2:3) as eluent to give the product (25a) as a yellow liquid (1.6 g, yield 21%). 1H NMR (300 MHz, CDCl3): delta 4.86 (s, 2H), 3.58 (s, 2H), 2.18 (s, 3H), 1.20 (s, 6H).
21%	With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃;	To a stirred solution of 99 3-hydroxy-2,2-dimethylpropanoic acid (4.0 g, 33.9 mmol) and 280 potassium carbonate (4.68 g, 33.9 mmol) in 143 DMF (45 mL) at 0° C. was added 281 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one (5.03 g, 33.9 mmol) in DMF (5 mL) dropwise over 1 h. The reaction was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to give a crude residue. The residue was purified by silica gel column chromatography using 21 EtOAc/282 hexane (1:4 to 2:3) as eluent to give the 283 product (42a) as a yellow liquid (1.6 g, yield 21percent). 1H-NMR (300 MHz, CDCl3): delta 4.86 (s, 2H), 3.58 (s, 2H), 2.18 (s, 3H), 1.20 (s, 6H).

Reference： [1]Patent: US10085999,2018,B1 .Location in patent: Page/Page column 125; 126
[2]Patent: US2019/100516,2019,A1 .Location in patent: Paragraph 1134; 1135
[3]Patent: US2020/102307,2020,A1 .Location in patent: Paragraph 1413-1415; 1748-1750

58
[ 71-23-8 ]
[ 4835-90-9 ]
propyl 3-hydroxy-2,2-dimethylpropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With sulfuric acid; at 20 - 80℃;Microwave irradiation;	A mixture of 3-hydroxy-2,2-dimethylpropanoic acid (1.15 g, 9.7 mmol) was charged and 1-propanol (15 mL) and conc. H2SO4 (70 muL, 1.3 mmol) in a 20 mL-microwave vial was stirred at room temperature and then heated in a microwave at 80 C. for 2 h, and stirred at room temperature overnight. When the desired product was identified by TLC (EtOAc/hexanes; 3:7) the mixture was concentrated under vacuum (40 C.) and diluted with EtOAc (80 mL) and H2O (30 mL). The organic layer was washed with H2O (twice), and brine, then dried (Na2SO4), filtered, and concentrated to give the product (57a) (1.18 g, 76%) as an oil. The material was used next step directly without purification. 1H NMR (300 MHz, CDCl3): delta 4.07 (t, J=6.6 Hz, 2H), 3.55 (s, 2H), 2.42 (br. s, 1H), 1.70-1.61 (m, 2H), 1.19 (s, 6H), 0.95 (t, J=7.5 Hz, 3H).
76%	With sulfuric acid; at 20 - 80℃;	A mixture of 99 3-hydroxy-2,2-dimethylpropanoic acid (1.15 g, 9.7 mmol) was charged and 553 1-propanol (15 mL) and 244 conc. H2SO4 (70 muL, 1.3 mmol) in a 20 mL-microwave vial was stirred at room temperature and then heated in a microwave at 80° C. for 2 h and stirred at room temperature overnight. When the desired product was identified by TLC (EtOAc/hexanes; 3:7) the mixture was concentrated under vacuum (40° C.) and diluted with EtOAc (80 mL) and H2O (30 mL). The organic layer was washed with H2O (twice), and brine, then dried (Na2SO4), filtered, and concentrated to give the 554 product (82a) (1.18 g, 76percent) as an oil. The material was used next step directly without purification. 1H-NMR (300 MHz, CDCl3): delta 4.07 (t, J=6.6 Hz, 2H), 3.55 (s, 2H), 2.42 (br. s, 1H), 1.70-1.61 (m, 2H), 1.19 (s, 6H), 0.95 (t, J=7.5 Hz, 3H).

Reference： [1]Patent: US10085999,2018,B1 .Location in patent: Page/Page column 189
[2]Patent: US2019/100516,2019,A1 .Location in patent: Paragraph 1341; 1342
[3]Patent: US2020/102307,2020,A1 .Location in patent: Paragraph 1620-1622

59
[ 4835-90-9 ]
[ 71-36-3 ]
[ 14002-76-7 ]

Yield	Reaction Conditions	Operation in experiment
81%	With sulfuric acid; at 80℃; for 2h;Microwave irradiation;	A mixture of 3-hydroxy-2,2-dimethylpropanoic acid (1.15 g, 9.7 mmol) was charged and 1-butanol (15 mL) and conc. H2SO4 (70 muL, 1.3 mmol) in a 20 mL-microwave vial was stirred at room temperature then heated in a microwave at 80 C. for 2 h, then stirred at room temperature overnight. When the desired product was identified by TLC (EtOAc/hexanes; 3:7) the mixture was concentrated under vacuum (40 C.; co-evaporated with toluene×3) and diluted with EtOAc (80 mL) and H2O (30 mL). The organic layer was washed with H2O (twice), and brine, then dried (Na2SO4), filtered and concentrated to give the product (58a) (1.24 g, 81%) as an oil. The material was used next step directly without purification. 1H NMR (300 MHz, CDCl3): delta 4.11 (t, J=6.5 Hz, 2H), 3.55 (s, 2H), 2.42 (br. s, 1H), 1.65-1.58 (m, 2H), 1.43-1.35 (m, 2H), 1.19 (s, 6H), 0.94 (t, J=7.5 Hz, 3H).
81%	With sulfuric acid; at 20 - 80℃;	A mixture of 99 3-hydroxy-2,2-dimethylpropanoic acid (1.15 g, 9.7 mmol) was charged and 561 1-butanol (15 mL) and 244 conc. H2SO4 (70 muL, 1.3 mmol) in a 20 mL-microwave vial was stirred at room temperature then heated in a microwave at 80° C. for 2 h, then stirred at room temperature overnight. When the desired product was identified by TLC (EtOAc/hexanes; 3:7) the mixture was concentrated under vacuum (40° C.; co-evaporated with toluene×3) and diluted with EtOAc (80 mL) and H2O (30 mL). The organic layer was washed with H2O (twice), and brine, then dried (Na2SO4), filtered and concentrated to give the 562 product (83a) (1.24 g, 81percent) as an oil. The material was used next step directly without purification. 1H-NMR (300 MHz, CDCl3): delta 4.11 (t, J=6.5 Hz, 2H), 3.55 (s, 2H), 2.42 (br. s, 1H), 1.65-1.58 (m, 2H), 1.43-1.35 (m, 2H), 1.19 (s, 6H), 0.94 (t, J=7.5 Hz, 3H).

Reference： [1]Patent: US10085999,2018,B1 .Location in patent: Page/Page column 190; 191
[2]Patent: US2019/100516,2019,A1 .Location in patent: Paragraph 1345; 1346
[3]Patent: US2020/102307,2020,A1 .Location in patent: Paragraph 1625-1626

60
[ 4835-90-9 ]
2-((4-(difluoromethoxy)phenyl)sulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole monohydrochloride [ No CAS ]
1-(5-[[4-(difluoromethoxy)benzene]sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2,2-dimethylpropan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
19%	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 2h;	Into a 50-mL round-bottom flask was placed 2-[[4- (difluoromethoxy)benzene]sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole hydrochloride (113 mg, 0.32 mmol, 1.00 equiv), dichloromethane (10 mL), 3-hydroxy-2,2-dimethylpropanoic acid (41 mg, 0.35 mmol, 1.10 equiv), DIEA (123 mg, 0.95 mmol, 3.00 equiv) and HATU (241 mg, 0.63 mmol, 2.00 equiv). The solution was stirred for 2 h at room temperature, then concentrated under vacuum. The crude product was purified by Prep-HPLC (Waters I: column: Xbridge Prep C18 5 mum 19x150mm; mobile phase gradient: CH3CN/water (0.05percent NH4OH) from 32percent to 47percent in 7 minute run; detector UV wavelength: 254nm.) to provide 25.3 mg (19percent) of 1-(5-[[4-(difluoromethoxy)benzene]sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2- yl)-3-hydroxy-2,2-dimethylpropan-1-one as a white solid. 1H NMR (300 MHz, DMSO-d6): delta ppm 7.89-7.92 (m, 2H), 7.39-7.42 (d, J = 7.8 Hz, 2H), 7.17-7.66 (t, J = 73.2 Hz, 1H), 4.68-4.72 (t, J = 5.4 Hz, 1H), 3.90-4.50 (m, 8H), 3.40-3.42 (d, J = 5.4 Hz, 2H), 1.09 (s, 6H). LC-MS (ESI) m/z: Calculated for C18H22F2N2O5S: 416.12; found: 417 [M+H]+.

Reference： [1]Patent: WO2018/175474,2018,A1 .Location in patent: Paragraph 00207-00209

61
[ 4835-90-9 ]
[ 91526-18-0 ]
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate [ No CAS ]

Reference： [1]Patent: US2019/100516,2019,A1

62
[ 4835-90-9 ]
[ 184778-33-4 ]
methyl 4-(5-(1-hydroxy-2-methylpropan-2-yl)-1,2,4-oxadiazol-3-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43.8%		To a solution of 3-hydroxy-2,2-dimethylpropanoic acid (125 mg, 1.06 mmol, CAS RN 4835-90-9) in DMF (5 mL) were added HOBT.H20 (162 mg, 1.06 mmol) and EDC (406 mg, 2.12 mmol) and the suspension was stirred at RT for 15 min. To this was added methyl (Z)-4-(N'-hydroxycarbamimidoyl)benzoate (205 mg, 1.06 mmol, CAS RN 184778- 33-4) and stirring was continued at RT for 15 min followed by stirring at 90°C for 3 days. The reaction mixture was poured on 0 and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed once with 0, dried over MgS04, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 12 g column using an MPLC system eluting with a gradient of n-heptane : EtOAc (100 : 0 to 50 : 50) to provide the desired compound as a colorless solid (0.128 g; 43.8percent). MS (ESI): m/z = 277.2 [M+H]+.

Reference： [1]Patent: WO2019/72785,2019,A1 .Location in patent: Page/Page column 240

63
[ 4835-90-9 ]
(R)-1-methylpyrrolidin-3-ylamine [ No CAS ]
(R)-3-hydroxy-2,2-dimethyl-N-(1-methylpyrrolidin-3-yl)propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;	A solution of 3-hydroxy-2,2-dimethylpropanoic acid (0.517 g, 4.37 mmol), (R)- \ - methylpyrrolidin-3-amine (0.438 g, 4.37 mmol), HATU (1.829 g, 4.81 mmol) and DIPEA (1.52 mL, 8.75 mmol) in DMF (5 mL) was stirred in a 100 mL round-bottomed flask at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by automated flash silica column chromatography (30 g NH column) eluting with a gradient of 0-5percent MeOH in DCM. The fractions containing the desired product were evaporated to give the title compound as a tan syrup (0.819 g, 94percent). ESI-MS [M+H]+ calc?d for C10H20N2O2, 201.16; found, 201.1.

Reference： [1]Patent: WO2019/169153,2019,A1 .Location in patent: Paragraph 0223

64
[ 4835-90-9 ]
trans-4-(4-chlorophenyl)-1-methylpyrrolidin-3-amine [ No CAS ]
trans-N-(4-(4-chlorophenyl)-1-methylpyrrolidin-3-yl)-3-hydroxy-2,2-dimethylpropanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;	In a 250 mL round-bottomed flask were combined 3-hydroxy-2,2- dimethylpropanoic acid (0.634 g, 5.36 mmol), /ra/i.v-4-(4-chlorophenyl)- 1 -methylpyrrolidin- 3-amine (1.13 g, 5.36 mmol), HATU (2.447 g, 6.44 mmol), and DIPEA (2.80 mL, 16.1 mmol) in DMF (12 mL) to give a yellow solution. The reaction mixture was stirred at room temperature overnight. The mixture was treated with water and extracted with EtOAc. The organic phase was dried over MgS04 and concentrated under reduced pressure. The residue was purified by automated flash silica column chromatography (80 g column) eluting with a gradient of 0-10percent MeOH in DCM. The fractions were evaporated to give the title compound as a syrup (1.36 g, 82percent). ESI-MS [M+H]+ calc?d for Ci6H23ClN202, 311.14; found, 311.4.

Reference： [1]Patent: WO2019/169153,2019,A1 .Location in patent: Paragraph 0259

Same Skeleton Products

Related Products

Historical Records

Related Functional Groups of
[ 4835-90-9 ]

Aliphatic Chain Hydrocarbons

[ 595-46-0 ]

2,2-Dimethylmalonic acid

Similarity: 0.95

[ 516-05-2 ]

2-Methylmalonic acid

Similarity: 0.89

[ 75-98-9 ]

Pivalic acid

Similarity: 0.89

[ 143174-36-1 ]

Sodium Trimethylacetate xHydrate

Similarity: 0.84

[ 19455-23-3 ]

Potassium pivalate

Similarity: 0.84

Alcohols

[ 14002-80-3 ]

Methyl 3-hydroxy-2,2-dimethylpropanoate

Similarity: 0.78

[ 72657-23-9 ]

(R)-Methyl 3-hydroxy-2-methylpropanoate

Similarity: 0.74

[ 80657-57-4 ]

(S)-Methyl 3-hydroxy-2-methylpropanoate

Similarity: 0.74

[ 14002-73-4 ]

Ethyl 3-hydroxy-2,2-dimethylpropanoate

Similarity: 0.72

[ 20605-01-0 ]

Diethyl 2,2-bis(hydroxymethyl)malonate

Similarity: 0.69

Carboxylic Acids

[ 595-46-0 ]

2,2-Dimethylmalonic acid

Similarity: 0.95

[ 516-05-2 ]

2-Methylmalonic acid

Similarity: 0.89

[ 75-98-9 ]

Pivalic acid

Similarity: 0.89

[ 28562-68-7 ]

3-Methyloxetane-3-carboxylic acid

Similarity: 0.82

[ 13051-21-3 ]

3-Methoxy-2,2-dimethyl-3-oxopropanoic acid

Similarity: 0.75

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
{[ item.p_purity ]}	{[ item.pr_size ]}	{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]}	{[ getRatePrice(item.pr_usd, 1,1) ]}	Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]}	{[ item.pr_usastock ]}	Inquiry -	{[ item.pr_chinastock ]}	Inquiry -

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 4835-90-9 ] {[proInfo.proName]}

Quality Control of [ 4835-90-9 ]

Related Doc. of [ 4835-90-9 ]

Product Details of [ 4835-90-9 ]

Calculated chemistry of [ 4835-90-9 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 4835-90-9 ]

Application In Synthesis of [ 4835-90-9 ]

[ 4835-90-9 ] Synthesis Path-Upstream 1~9

[ 4835-90-9 ] Synthesis Path-Downstream 1~64

Related Functional Groups of [ 4835-90-9 ]

Aliphatic Chain Hydrocarbons

Alcohols

Carboxylic Acids

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 4835-90-9 ]