Name: 625-08-1|3-Hydroxy-3-methylbutanoic acid|95%
Brand: Ambeed
SKU: A246884
Price: 7.0 USD
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1
[ 123-42-2 ]
[ 625-08-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; bromine; In water; at 0 - 5℃; for 6h;	The first step in the synthesis of HMB-L-Arginine consists of the preparation of sodium hypobromide. 100 portions of sodium hydroxide are dissolved in 400 portions of water under agitation.The solution is cooled to 0 Celsius. 192 portions of bromine are dropwise added to the solution, the temperature is maintained between 0 degree Celsius to 5 degree Celsius. The prepared sodium hypobromide solution is kept at 0 degree Celsius to 5 degree Celsius. The previously prepared sodium hypobromide is dropwise added to a solution of 46 portions of diacetone alcohol in 120 portions of water, agitated for 6 hours.Then 8 portions of sodium bisulfite are added to decolour the solution.The organic layer is separated from the mixture.The water layer is adjusted to a PH of 2 to 3 using dilute hydrochloric acid, and extracted by isobutanol. 120 portions of water are added to the above prepared isobutanol solution. 28 portions of L-Arginine are added to the solution and agitated for 1 hour under room temperature.The water layer was separated from the mixture, and the water was removed under vacuum. 46.4 portions of HMB-L-arginine were obtained as white crystalline powder with melting point 116 to 130 Celsius.
	With sodium hypochlorite; at 40 - 60℃;Industrial scale;	EXAMPLE 1 Production of HMB of High Purity?Production of Crude HMB in the Anterior Stage (0035) 1. Starting Materials and Auxiliary Materials (0036) Starting materials and auxiliary materials used in the production of crude HMB in the early stage are shown in Table 1. [table-us-00001-en] Name of the starting and auxiliary materials Quality Ratio hypochlorite Industrial grade 1000 kg 4-Methyl-4-Hydroxyl-2-Pentanone Industrial grade Depending on the (diacetone alcohol) reaction status Hydrochloric acid Food grade Depending on the pH Ethyl acetate Food grade 1000 kg (0037) 2. Operational Process and Processing Parameters (0038) 2.1 Oxidative Synthesis (It is a Strong Exothermic Reaction) (0039) Sodium hypochlorite was pumped into a reaction kettle and diacetone alcohol (DIA) was slowly added. The addition velocity was controlled to maintain the reaction temperature of the materials in the kettle in the range of from 10° C. to 20° C. during the course of the reaction. DIA was stopped adding until the temperature significantly decreased when adding DIA, which indicated that reaction was no more taken place and came to an end. (0040) 2.2 Acidification (0041) The reaction product obtained in 2.1 was pumped into a reaction kettle. The temperature was controlled to be about 20° C. Hydrochloric acid was added to adjust the pH to 2-3.5. After addition of the acid, the mixture was allowed to stand for 30 minutes. The by-product, chloroform, formed in the bottom was removed by observation by a sight glass. (0042) 2.3 Removal of Water by Evaporation (0043) The reaction product obtained in 2.2 was pumped into a reaction kettle and subjected to vacuum concentration until the volume of the product was reduced to about half of its initial volume. The product was cooled to 60° C. or below, discharged from the kettle and filtered. The resultant sodium chloride was removed by filtration. The filtrates were pooled and added to the reaction kettle. (0044) 2.4 Extraction (0045) The filtrate was extracted by ethyl acetate for three times. Before each extraction, the pH of the filtrate was adjusted to 23.5 by hydrochloric acid. And after each addition of ethyl acetate, the resultant mixture was thoroughly stirred and then subjected to standing and layering. The ethyl acetate layer was collected. (0046) 2.5 Removal of Ethyl Acetate (0047) The extracted ethyl acetate layers were pooled and pumped into a reaction kettle. Ethyl acetate was removed by vacuum distillation. The resultant product was cooled to 60° C. or below and discharged from the kettle to obtain a crude HMB.
		Step 1. Control the temperature at 5 ° C, add 200 Kg of diacetone alcohol to 2000 L of sodium hypochlorite aqueous solution (20percent), and stir at room temperature for 3 hours.The layer is allowed to stand, the lower layer liquid is separated, and the upper layer reaction liquid is washed;Step 2, adding 40Kg of sodium hydrogen sulfite to the upper reaction solution of step 1, and stirring at a temperature of 15 ° C.Add 600L of concentrated hydrochloric acid solution, adjust the pH value to 2, concentrate to remove water under reduced pressure, and filter to obtain crude beta-hydroxy-beta-methylbutyric acid solution; Step 3, adding the crude beta-hydroxy-beta-methylbutyric acid solution obtained in the step 2 to 1000 L of isobutanol for extraction, and extracting the organic phase and adding anhydrous sodium sulfate for drying for 18 hours.filter,The filtrate was concentrated at 80 ° C to give 162 Kg of beta-hydroxy-beta-methylbutyric acid compound.After testing, the obtained beta-hydroxy-beta-methylbutyric acid compound product,The content of beta-hydroxy-beta-methylbutyric acid is 99.1percent.The mono-content of acetic acid was 0.46percent.

Reference： [1]Monatshefte fur Chemie,1903,vol. 24,p. 770
[2]Journal of the American Chemical Society,1958,vol. 80,p. 2882,2886
[3]Journal of the American Chemical Society,1940,vol. 62,p. 2078
[4]Patent: US2004/176449,2004,A1 .Location in patent: Page/Page column 3
[5]Patent: US2016/52856,2016,A1 .Location in patent: Page/Page column 2-3
[6]Patent: CN108129294,2018,A .Location in patent: Paragraph 0081-0085; 0086-0090; 0091-0095; 0096-0101

2
[ 625-08-1 ]
C₈₉H₇₁F₁₀₂N₉O₈ [ No CAS ]
C₉₄H₇₉F₁₀₂N₉O₁₀ [ No CAS ]

Reference： [1]Chemical Communications,2003,p. 972 - 973

3
[ 870543-54-7 ]
[ 625-08-1 ]
[ 870543-30-9 ]

Yield	Reaction Conditions	Operation in experiment
75%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 25℃; for 2h;	Tetrasaccharide 19 (37 mg, 0.029 mmol) was dissolved under an Ar atmosphere in THF (6 ml_) and ammonia was condensed into the reaction vessel at - 789C until the mixture reached a volume of about 20 ml_. Small pieces of carefully washed sodium were added to the reaction vessel affording a solution with a deep blue color. After 30 min the reaction was quenched by adding some drops of methanol. Again, small pieces of sodium were added until the blue color persists for at least30 min. The reaction was quenched by adding several ml_ of methanol. The dry ice bath was removed, the reaction mixture was allowed to warm to room temperature in order to evaporate the ammonia. Dowex 50-X8 acidic resin (washed and dried) was added until pH 7 was reached. The mixture was filtered, rinsed and concentrated. The crude product <n="28"/>was purified by column chromatography using silica gel (dichloromethane/methanol 3:1). The product containing fractions were combined, concentrated and further purified by using a Sephadex column (ethanol/water 1 :1 ). The product containing fractions were combined and concentrated affording 12 mg (60percent) of a colorless film. This compound (7 mg, 0.010 mmol) was dissolved in DMF (2.5 ml_) and 3-hydroxy-3-methylbutyric acid (1.8 mg, 0.015 mmol) in 0.5 mL of DMF were added. HATU (5 mg, 0.015 mmol), followed by lambda/,lambda/-di/sopropylethylamine (2 mg, 2.5 mul_, 0.015 mmol) was added yielding a slightly yellow solution. The mixture is stirred at room temperature for 2 h. ESI-MS analysis showed complete conversion (m/z 806, [M + Na]+). All volatiles were removed in vacuo. The residue was purified by column chromatography using silica gel(dichloromethane/methanol 4:1 ) and further purified by using a Sephadex column (ethanol/water 1 :1) yielding 5 mg (75percent) of 2 as a colorless film: [alpha]D: -7.9 (c = 0.18, CHCI3), 1H NMR (CD3OD, 600 MHz) delta 1.21 (d, J = 6.2 Hz, 3H), 1.24 (d, J = 6.2 Hz, 3H), 1.25 (d, J= 6.2 Hz, 3H), 1.29 (m, 9H), 1.68 (m, 2H), 2.15 (m, 2H) 2.36 (pquart., 2H), 3.02 (dd, J = 9.1 Hz, J= 7.9 Hz, 1 H), 3.38 (m, 1 H), 3.40-3.44 (m, 3H), 3.51 (W = 9.6 Hz, 1 H), 3.55-3.60 (m, 2H), 3.66 (s, 3H), 3.67 (m, 1 H), 3.70-3.78 (m, 3H), 3.80 (m, 2H), 3.83 (m, 1 H), 3.90 (dd, J= 9.4 Hz, J= 3.3 Hz, 1 H), 4.05 (dd, J= 3.2 Hz, J= 1.9 Hz, 1 H), 4.18 (dd, J= 3.3 Hz, J= 1.7 Hz, 1 H), 4.62 (d, J= 7.8 Hz, 1 H), 4.77 (d, J = 1.6 Hz, 1 H), 4.91 (d, J= 1.8 Hz, 1 H), 4.96 (m, 1 H), 5.03 (m, 1 H), 5.05 (d, J = 1.6 Hz, 1 H), 5.83 (m, 1 H). 13C NMR (CD3OD, 150 MHz) delta 18.0, 18.1 , 18.2, 18.5, 29.6, 29.7, 30.0, 31.5, 49.8, 58.2, 61.2, 68.0, 70.0, 70.2, 70.6, 70.8, 71.8, 71.9, 72.2, 72.3, 73.2, 73.4, 74.4, 75.1 , 79.2, 80.2, 82.0, 85.7, 100.4, 103.6, 104.0, 105.5, 1 15.4, 139.4, 174.7. MALDI-HRMS: m/z [M + Na]+ calcd 806.3786, obsd 806.3797.

Reference： [1]Angewandte Chemie - International Edition,2005,vol. 44,p. 6315 - 6318
[2]Patent: WO2007/125089,2007,A2 .Location in patent: Page/Page column 26-27
[3]Journal of Organic Chemistry,2007,vol. 72,p. 6513 - 6520
[4]Journal of the American Chemical Society,2010,vol. 132,p. 10239 - 10241

4
5-(4-(4-(5-amino-4-(benzyloxy)tetrahydro-3-methoxy-6-methyl-2H-pyran-2-yloxy)tetrahydro-3,5-dihydroxy-6-methyl-2H-pyran-2-yloxy)-3,5-dihydroxytetrahydro-6-methyl-2H-pyran-2-yloxy)-6-(benzyloxy)tetrahydro-2-methyl-2H-pyran-3,4-diol [ No CAS ]
[ 625-08-1 ]
C₄₄H₆₅O₁₈N [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2007,vol. 46,p. 5206 - 5208
[2]Journal of Organic Chemistry,2008,vol. 73,p. 5211 - 5220

5
[ 629957-82-0 ]
[ 625-08-1 ]
[ 629948-76-1 ]

Yield	Reaction Conditions	Operation in experiment
	With 1,1'-carbonyldiimidazole; In dichloromethane; at 20℃;	Example 399 (1) In 12 ml of toluene was dissolved 1.17 g of (2R, [4S)-1- (N- (3,] 5-bistrifluoromethylbenzyl) -N- methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl)-4- (1- imidazolylcarbonyloxy) piperidine, and added thereto at room temperature was 1.14 g of [4-AMINO-1-BENZYLPIPERIDINE,] and the mixture was stirred for 3 days. To the reaction mixture was added ethyl acetate, and the mixture was washed with water and saturated brine and dried. The solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol=19: 1), to give 0.89 g of (2R, [4S)-1- {N-] (3, [5-BISTRIFLUOROMETHYLBENZYL)-N-METHYL}] aminocarbonyl-4- (l- benzylpiperidine-4-yl) [AMINOCARBONYLOXY-2- (4-FLUORO-2-] methylphenyl) piperidine. (2) In 10 ml of methanol was dissolved 890 mg of the compound of the above (1), and added thereto were 400 mg of palladium carbon and one drop of concentrated hydrochloric acid, and the mixture was stirred in hydrogen atmosphere for 4.5 hours. After the reaction mixture was filtered and the filtrate was evaporated in vacuo, the residue was crystallized (ethyl acetate-hexane), to give 802 mg of (2R, 4S)-l- {N- (3, 5-bistrifluoromethylbenzyl) -N- [METHYL} AMINOCARBONYL-2- (4-FLUORO-2-METHYLPHENYL)-4- (4-] piperidinyl) aminocarbonyloxypiperidine. (3) In 2 ml of dichloromethane was dissolved 14.2 mg of 3-hydroxy-3-methylbutanoic acid, and added thereto at room temperature was 21.1 mg of carbodiimidazole, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 61.9 mg of the compound of the above (2), and the mixture was further stirred overnight. To the reaction mixture was added water, and the mixture was extracted with chloroform. The organic layer was dried and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol=19: 1), to give 57.5 mg of (2R, [4S)-1- {N- (3,] 5-bistrifluoromethylbenzyl) -N- [METHYL} AMINOCARBONYL-2-(4-FLUORO-2-METHYLPHENYL)-4-{1-(3-] hydroxy-3-methylbutyryl) piperidine-4- yl} aminocarbonyloxypiperidine as shown in Table 104 below.

Reference： [1]Patent: WO2003/99787,2003,A1 .Location in patent: Page 123-124

6
[ 123-42-2 ]
[ 67-66-3 ]
[ 625-08-1 ]

Yield	Reaction Conditions	Operation in experiment
		To begin the procedure, the auxiliary chiller, chiller pump, and associated generator were turned on approximately 275 minutes prior to the charging of bleach into the reactor. The methanol/water solution exhibited a specific gravity of 0.935. After the cooling solution exhibited a temperature of 18° F. (-10° C.) or less at the chiller inlet temperature probe, 1,200 gallons of 12.5-15percent (pH 12.0-13.5) sodium hypochlorite was charged into the reactor to begin the reaction procedure. The agitator and the recycling cooling loop pump were turned on, and the temperature of the sodium hypochlorite was lowered to 0-5° C. After the target temperature for the sodium hypochlorite was reached, 957 pounds of diacetone alcohol was added at a rate of 1.3-2.9 pounds per minute. After DIA addition was completed, the DIA line was flushed with approximately 5 gallons of de-ionized water. The temperature of the reactor was then maintained at 3-10° C. for 30 minutes. After 30 minutes, approximately 2,120 pounds of 32percent hydrochloric acid was added to the reaction mixture. The acid was added at a rate of approximately 50-100 pounds per minute. At the completion of the acid addition, the reaction mixture was maintained for 30 minutes at 10-20° C. while the pH was adjusted to 3.0-3.2 by adding approximately 510 pounds of 32percent hydrochloric acid. Again, the acid was added at a rate of about 50-100 pounds per minute. The reaction mixture was then agitated for 10 minutes, after which the pH was determined to be 3.20. After approximately 20 minutes, the auxiliary chiller was shut down, while the cooling solution recirculating pump remained on for an additional 10 minutes. Subsequently, the cooling solution pump and the reaction mixture recycling pump were shut down. The reactor bottom valve was closed and the reaction mixture recycling cooling loop was flushed with water and then with a nitrogen blow. Next, the cooling solution flow to the reactor jacket was shut down and blown. The reactor agitator was shut off and the reaction mixture was allowed to settle for approximately 20 minutes. The chloroform layer which formed on the bottom of the reactor was drained through the reactor bottom valve, generating approximately 848 pounds of chloroform waste stored in 2 drums, to both of which 4 ounces of soda ash and 4 ounces of ethanol were added.

Reference： [1]Patent: US6392092,2002,B1 .Location in patent: Page column 10-11

7
[ 625-08-1 ]
[ 100-51-6 ]
[ 37526-90-2 ]

Yield	Reaction Conditions	Operation in experiment
7.2 g	With dmap; dicyclohexyl-carbodiimide; In dichloromethane;Cooling with ice;	4-Dimethylaminopyridine (0.78 g) was added to a solution of 3.76 g of 3-hydroxy-3-methylbutyric acid and 4.13 g of benzyl alcohol in anhydrous methylene chloride and the mixture was stirred under cooling with ice. After 9.9 g of N,N?-dicyclohexylcarbodiimide was added thereto, the ice bath was removed and the mixture was stirred overnight. After the insoluble deposit was filtered off, the mother liquor was concentrated to give 13 g of the residual oily product. This product was purified by a silica gel column chromatography to give 7.2 g of benzyl 3-hydroxy-3-methylbutyrate as a light yellow oily product.
	With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃;	4-Dimethylaminopyridine (0.78 g) was added to an anhydrous methylene chloride solution of 3-hydroxy-3-methylbutyric acid (3.76 6 g) and benzyl alcohol (4.13 g), and stirred with cooling on ice. N,N'-dicyclohexylcarbodiimide (9.9 g) was added thereto, then the ice bath was removed, and stirred overnight at room temperature. The precipitated insoluble matter was removed by filtration, and the mother liquid was concentrated to give a residual oil (13 g). This was purified through silica gel column chromatography to give benzyl 3-hydroxy-3-ethylbutyrate (7.2 g) as a pale yellow oil. 1H-NMR (CDCl3) delta: 1.28 (6H, s), 2.55 (2H, s), 5.16 (2H, s), 7.36 (5H, s)

Reference： [1]Patent: WO2006/59768,2006,A1 .Location in patent: Page/Page column 14-15
[2]Patent: KR2015/54011,2015,A .Location in patent: Paragraph 0146; 0147
[3]Patent: EP2025667,2009,A1 .Location in patent: Page/Page column 10

8
[ 174072-26-5 ]
[ 625-08-1 ]
4,7-dihydro-2-[4-(3-hydroxy-3-methylbutyrylamino)phenyl]-7-(2,6-difluorobenzyl)-3-(N-benzyl-N-methylaminomethyl)-5-isobutyryl-4-oxothieno[2,3-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane;	Example 13-1 Production of 4,7-dihydro-2-[4-(3-hydroxy-3-methylbutyrylamino)phenyl]-7-(2,6-difluorobenzyl)-3-(N-benzyl-N-methylaminomethyl)-5-isobutyryl-4-oxothieno[2,3-b]pyridine To a solution of the compound obtained in Reference Example 29 (1.14 g, 2.0 mmol) in dichloromethane (10 ml) were added diisopropylethylamine (1.04 g, 8 mmol) and 3-hydroxy-3-methylbutanoic acid (0.47 g, 4 mmol), followed by stirring under ice cooling conditions. To this solution was added benzotriazol-1-yloxytrisdimethylaminophosphonium hexafluorophosphate (BOP reagent) (1.76 g, 4 mmol). After stirring under ice cooling conditions for 1 hour, the solution was further stirred at room temperature for 4 days. The reaction mixture was concentrated to dryness under reduced pressure, and then the obtained residue was partitioned between water (50 ml) and chloroform (50 ml). The water layer was again extracted with chloroform (10 ml). The combined extracts were washed with saline, and dried (MgSO4), the solvent was distilled off under reduced pressure. The obtained residue was chromatographed on silica gel and recrystallized from ether to yield yellow powdery crystals (0.50 g, 37percent). 1H-NMR (300 MHz, CDCl3) delta: 1.17(6H,d), 1.39(6H,s), 2.11(3H,s), 2.58(2H,s), 3.12(1H, br s), 3.65(2H,s), 4.12-4.19(1H,m), 4.18(2H,s), 5.27(2H,s), 7.00(2H,t), 7.10-7.23(5H,m), 7.32-7.44(1H,m), 7.61(2H,d), 7.79(2H,d), 8.24(1H, s), 8.28(1H, s).

Reference： [1]Patent: US2001/1104,2001,A1

9
[ 853306-14-6 ]
[ 625-08-1 ]
(2R,4S)-1-[N-{1-(3,5-bistrifluoromethylphenyl-1-methyl)-ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(3-hydroxy-3-methylbutyroylamino)piperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;	Example 11 To 5 ml of an N,N-dimethylformamide solution containing 104 mg of (2R,4S)-4-amino-1-[N-{1-(3,5-bistrifluoromethylphenyl-1-methyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidine were added 25 mg of 3-hydroxy-3-methylbutanoic acid, 31 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 38 mg of 1-hydroxy-1H-benzotriazole, and the mixture was stirred at room temperature overnight. The reaction solution was extracted with ethyl acetate, the organic layer was washed twice with saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1-->2:3) to give 103 mg of (2R,4S)-1-[N-{1-(3,5-bistrifluoromethylphenyl-1-methyl)-ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(3-hydroxy-3-methylbutyroylamino)piperidine shown in the following Table 2.

Reference： [1]Patent: EP1693367,2006,A1 .Location in patent: Page/Page column 28

10
[ 879901-42-5 ]
[ 625-08-1 ]
(3S,4S)-3-(4-fluoro-2-methylphenyl)-1-(3-hydroxy-3-methylbutyryl)-4-{N-methyl-2-(3,5-bistrifluoromethyl-phenyl)isobutyrylamino}piperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 40℃; for 16h;	Example 19; 3.3 ml of an N,N-dimethylformamide solution containing 127 mg of (3S,4S)-3-(4-fluoro-2-methylphenyl)-4-{N-methyl-2-(3,5- bistrifluoromethylphenyl) isobutyrylamino}piperidine, 37 mg of beta- hydroxyisovaleric acid, 48 mg of 1-hydroxybenzotriazole monohydrate and 60 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydro.not. chloride was stirred at 4O0C for 16 hours. To the reaction mixture were added ethyl acetate and semi-saturated brine, and the mixture was separated, and then, the organic layer was washed successively with semi-saturated brine and a saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried by using CHEM ELUT (trade name, available from VARIAN INC.), and concentrated under reduced pressure. The obtained residue was purified by NH thin- layer silica gel column chromatography (chloroform:ethyl acetate= 20:1) to give 148 mg of (3S, 4S) -3- (4-fluoro-2-methylphenyl) -1- (3- hydroxy-3-methylbutyryl) -4-{N-methyl-2- (3, 5-bistrifluoromethyl- phenyl) isobutyrylamino}piperidine shown in the following Table 7.

Reference： [1]Patent: WO2006/30984,2006,A1 .Location in patent: Page/Page column 39-40; 72

11
[ 625-08-1 ]
[ 101752-05-0 ]
[ 6149-45-7 ]

Yield	Reaction Conditions	Operation in experiment
		Example 2 Synthesis of (2R)-2-(4'-octyloxybiphenyloxymethyl)-5,5-dimethyl-delta-valerolactone and (2S)-2-(4'octyloxybiphenyloxymethyl)-5,5-dimethyl-delta-valerolactone In 50 ml of 7 wt.% hydrochloric acid methanol solution was dissolved 1.18 g of beta-hydroxyisovaleric acid, and an reaction was allowed to proceed at room temperature overnight. The solvent was removed from the solution as reacted by distillation under a reduced pressure to obtain 1.30 g of crude methyl beta-hydroxyisovalerate.

Reference： [1]Patent: EP467721,1992,A1

12
5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride [ No CAS ]
[ 625-08-1 ]
TAK-285 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 120h;	Example 158 Production of N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxy-3-methylbutanamide A mixture of 5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg), 3-hydroxy-3-methylbutyric acid (68 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (166 mg), 1-hydroxybenzotriazole monohydrate (133 mg), triethylamine (0.40 mL) and N,N-dimethylformamide (5.0 mL) was stirred at room temperature for 5 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate --> ethyl acetate:methanol=9:1). Crystallization from ethyl acetate-diisopropyl ether gave the title compound (122 mg) as colorless crystals. 1H-NMR (CDCl3) delta: 1.33 (6H, s), 2.49 (2H, s), 2.65-2.77 (1H, m), 3.57-3.68 (2H, m), 4.44-4.53 (2H, m), 6.61 (1H, d, J= 3.0 Hz), 6.93-7.01 (1H, m), 7.07 (1H, d, J= 9.0 Hz), 7.09-7.15 (1H, m), 7.19 (1H, d, J= 3.0 Hz), 7.23-7.35 (2H, m), 7.40-7.45 (1H, m), 7.77 (1H, dd, J= 9.0, 2.7 Hz), 8.08 (1H, d, J= 2.7 Hz), 8.52 (1H, s), 8.66 (1H, s). melting point: 167-169°C

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 8030 - 8050
[2]Patent: EP1752457,2007,A1 .Location in patent: Page/Page column 193-194

13
N-(4-[5-(2-aminoethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yl]oxy}-2-chlorophenyl)-N'-[3-(trifluoromethyl)phenyl]urea dihydrochloride [ No CAS ]
[ 625-08-1 ]
N-[2-(4-{3-chloro-4-[([3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]-3-hydroxy-3-methylbutanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 4h;	To a solution of N- (4-{ [5- (2-aminoethyl) -5H-pyrrolo [3, 2- d]pyrimidin-4-yl]oxy}-2-chlorophenyl) -N' - [3- (trifluoromethyl) phenyl] urea dihydrochloride (500 mg, 0.89 miriol) and 3-hydroxy-3-methylbutanoic acid (157 mg, 1.33 mmol) in N,N-dimethylformamide (6.0 mL) were added triethylamine (618 muL, 4.43 mmol), l-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride (255 mg, 1.33 mmol) and 1-hydroxybenzotriazole (180 mg, 1.33 mmol), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, EPO <DP n="244"/>dried over anhydrous magnesium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, ethyl acetate/ethanol) and recrystallized from ethyl acetate- -hexane to give the title compound (286 mg, 55percent) as a white solid.1H-NMR (DMSOd6, 300 MHz) delta 1-06 (6H, s) , 2.13 (2H, s) , 3.54 - 3.64 (2H, m) , 4.45 - 4.56 (2H7-In), 4.70 (IH, s), -6.61 (IH, d, J = 3.0 Hz), 7.30 - 7.35 (2H, m) , 7.54 - 7.58 (3H, m) , 7.76 (IH, d, J = 3.0 Hz), 7.88 - 7.97 (IH, m) , 8.06 (IH, s) , 8.18(IH, d, J = 9.0 Hz), 8.32 (IH, s) , 8.46 (IH, br s) , 9.73 (IH, br s) .

Reference： [1]Patent: WO2007/4749,2007,A1 .Location in patent: Page/Page column 241-243

14
N-(4-[6-(aminomethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yl]oxy}-2-chlorophenyl)-N'-[3-(trifluoromethyl)phenyl]urea dihydrochloride [ No CAS ]
[ 625-08-1 ]
N-[(4-{3-chloro-4-[([3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methyl]-3-hydroxy-3-methylbutanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 4h;	To a solution of N- (4-{ [6- (aminomethyl) -5H-pyrrolo [3, 2- d]pyrimidin-4-yl]oxy}-2-chlorophenyl) -N' - [3- (trifluoromethyl) phenyl] urea dihydrochloride (500 mg, 0.91 mmol) and 3-hydroxy-3-methylbutanoic acid (161 mg, 1.36 mmol) in N,N-dimethylformamide (6.0 mL) were added triethylamine (634 muL, 4.55 mmol), l-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride (262 mg, 1.36 mmol) and 1-hydroxybenzotriazole (184 mg, 1.36 mmol), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with water, and extracted with ethyl EPO <DP n="248"/>acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, ethyl acetate/ethanol) and recrystallized from ethyl acetate- hexane to give the title compound (245 mg, 47percent) as a white solid.1H-NMR (DMSO-de, 300 MHz) delta 1.20 (6H, s) , 2.33 (2H, s) , 4.52 (2H, d, J = 6.0 Hz), 4.81 (IH, s) , 6.47 (IH, s) , 7.28 (IH, dd, J = 8.9, 2.9 Hz), 7.35 (IH, d, J = 7.2 Hz), 7.53 - 7.57 (3H, m) , 8.05 (IH, s), 8.15 (IH, d, J = 8.9 Hz), 8.29 (IH, s) , 8.40 - 8.47 (2H, m) , 9.74 (IH, s) , 12.23 (IH, s) .

Reference： [1]Patent: WO2007/4749,2007,A1 .Location in patent: Page/Page column 245-247

15
3-(4-[5-(2-aminoethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yl]amino}-2-chlorophenoxy)-N-(tert-butyl)-5-(trifluoromethyl)benzamide dihydrochloride [ No CAS ]
[ 625-08-1 ]
[ 940304-44-9 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃;	Production of N- ( tert-butyl ) -3- { 2-chloro-4- [ ( 5- { 2- [ (3-hydroxy-3-methylbutanoyl) amino] ethyl } -5H- jpyrrolo [3, 2-d] pyrimidin-4-yl ) amino] phenoxy } -5- ( trifluoromethyl ) benzamideA mixture o'f 3- ( 4- { [ 5- (2-aminoethyl ) -5H- pyrrolo [3, 2-d] pyrimidin-4-yl] amino }-2-chlorophenoxy) -N- (tert-butyl) -5- (trifluoromethyl ) benzamide dihydrochloride (186 mg) , 3-hydroxy-3-methylbutanoic acid (53 mg), l-ethyl-3- ( 3- dimethylaminopropyl ) carbodiimide hydrochloride .(86 mg), 1-hydroxybenzotriazole (69 mg) , triethylamine (0.100 mL) and N, N-dimethylformamide (3 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluent, methanol : ethyl acetate=0 : 100-10 : 90 ) . The objective fractions were concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to give the title compound (152 mg) as white crystals .1H-NMR (CDCl3) delta: 1.31 (6H, s), 1-48 (9H, s), 2.48 (2H, s), 3.54-3.66 (2H, m) , 4.41-4.53 (2H, m) , 6.01 (IH, br s), 6.57 (IH, d, J= 3.3 Hz), 7.07 (IH, d, J= 9.0 Hz), 7.18 (IH, d, J= 3.3 Hz), 7.25-7.35 (2H, m) , 7.48 (IH, m) , 7.62 (IH, m) , 7.78 (IH, dd, J= 2.4 Hz, 9.0 Hz), 8.10 (IH, d, J= 2.4 Hz), 8.49 (IH, s), 8.72 (IH, br s).

Reference： [1]Patent: WO2007/64045,2007,A1 .Location in patent: Page/Page column 348

16
5-(2-aminoethyl)-N-[3-chloro-4-(3-phenoxyphenoxy)phenyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride [ No CAS ]
[ 625-08-1 ]
[ 940349-70-2 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;	Production of N- [2- ( 4 - { [ 3-chloro-4- ( 3- phenoxyphenoxy) phenyl] amino }-5H-pyrrolo [3, 2-d] pyrimidin- 5-yl) ethyl] -3-hydroxy-3-methylbutanamide hydrochlorideA mixture of 5- ( 2-aminoethyl ) -N- [ 3-chloro-4- ( 3- phenoxyphenoxy) phenyl] -5H-pyrrolo [3, 2-d] pyrimidin-4- amine dihydrochloride (195 mg) , 3-hydroxy-3- methylbutanoic acid (0.058 mL) , l-ethyl-3- ( 3- dimethylaminopropyl ) carbodiimide hydrochloride (103 mg) , 1-hydroxybenzotriazole (72.5 mg) , triethylamine (0.15 mL) and N, N-dimethylformamide (6.9 mL) was stirred at room temperature for 16 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl <n="519"/>acetate->ethyl acetate :methanol=85 : 15 ). The fraction containing the title compound was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (4 mL) . 4N hydrochloric acid (0.169 raL) was added, and the mixture was crystallized from ethyl acetate to give the title compound (176 mg) . 1H-NMR (DMSO-d6) delta: 1.10 (6H, s), 2.19 (2H, s), 3.48 (2H, q, J= 6 Hz), 4.66 (2H, t, J= 6 Hz), 6.60 (IH, t, J= 3 Hz), 6.67 (IH, d, J=3 Hz), 6.72 (2H, dt , J= 3 Hz, 9 Hz), 7.06 (2H, d, J= 8 Hz), 7.17 (IH, t, J= 7 Hz), 7.29 (IH, d, J= 9 Hz), 7.40 (3H, m) , 7.67 (IH, dd, J= 3 Hz, 9 Hz), 7.92 (IH, d, J= 3 Hz), 7.98 (IH, d, J= 3 Hz), 8.40 (IH, m) , 8.71 (IH, s)

Reference： [1]Patent: WO2007/64045,2007,A1 .Location in patent: Page/Page column 517-518

17
5-(2-aminoethyl)-N-{3-chloro-4-[3-(1,1-difluoro-2,2-dimethylpropyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride [ No CAS ]
[ 625-08-1 ]
[ 940349-74-6 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃;	Production of N- { 2- [ 4- ( { 3-chloro-4- [ 3- ( 1 , 1- difluoro-2, 2-dimethylpropyl )phenoxy] phenyl} amino) -5H- pyrrolo [3, 2-d]pyrimidin-5-yl] ethyl }-3-hydroxy-3- methylbutanamide hydrochlorideA mixture of 5- (2-aminoethyl ) -N- { 3-chloro-4- [ 3- (1, l-difluoro-2, 2-dimethylpropyl ) phenoxy] phenyl } -5H- pyrrolo [ 3 , 2-d] pyrimidin-4-amine dihydrochloride (168 mg) , 3-hydroxy-3-methylbutanoic acid (53 mg), l-ethyl-3- ( 3-dimethylaminopropyl ) carbodiimide hydrochloride (86 mg), 1-hydroxybenzotriazole monohydrate (69 mg), triethylamine (0.100 mL) and N, N-dimethylformamide (3 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (eluent, methanol : ethyl acetate=0 : 100-20 : 80) . The objective fractions were concentrated under reduced pressure. The residue was dissolved in ethyl acetate-ethanol , and IN hydrogen chloride/ethyl acetate solution (0.3 mL) was added. The solvent was evaporated under reduced pressure and the <n="529"/>obtained residue was crystallized from ethyl acetate to give the title compound (134 mg) as a white powder. 1H-NMR (DMSO-de) delta: 0.99 (9H, s), 1.11 (6H, s), 2.20 (2H, s), 3.44-3.54 (2H, m) , 4.66 (2H, t, J = 7.0 Hz), 6.67 (IH, d, J = 3.2 Hz), 6.92 (IH, m) , 7.13 (IH, dd, J = 2.3 JHz, 8.1 Hz), 7.20 (IH, d, J = 7.7 Hz), 7.29 (IH, d, J = 8.9 Hz), 7.52 (IH, t, J = 8.0 Hz), 7.70 (IH, dd, J = 2.5 Hz, 8.9 Hz), 7.96 (IH, d, J = 2.5 Hz), 7.99 (IH, d, J = 3.2 Hz), 8.41 (IH, t, J = 5.1 Hz), 8.73 (IH, s), 10.28 (IH, br s)

Reference： [1]Patent: WO2007/64045,2007,A1 .Location in patent: Page/Page column 527-528

18
5-(2-aminoethyl)-N-[1-(3-fluorobenzyl)-1H-indazol-5-yl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine trihydrochloride [ No CAS ]
[ 625-08-1 ]
[ 940308-40-7 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 4h;	Production of N- [2- ( 4- { [ 1- ( 3-fluorobenzyl ) -lH-indazol-5- yl] amino} -5H-pyrrolo[3,2-d] pyrimidin-5-yl ) ethyl] -3- hydroxy-3-methylbutanamide A mixture of 5- ( 2-aminoethyl )'-N- [ 1- ( 3- fluorobenzyl) -lH-indazol-5-yl] -5H-pyrrolo [3, 2- d] pyrimidin-4-amine trihydrochloride (183' mg) , 3- hydroxy-3-methylbutanoic acid (0.058 mL) , l-ethyl-3- ( 3- dimethylaminopropyl ) carbodiimide hydrochloride (103 mg), 1-hydroxybenzotriazole (72.5 mg) , triethylamine (0.15 mL) and N, N-dimethylformamide (6.9 mL) was stirred at room temperature for 4 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate->ethyl acetate : methanol=85 : 15 ) and crystallized from isopropyl ether to give the title compound (100 mg) as crystals.1H-NMR (DMSO-de) delta: 1.12 (6H, s), 2.20 (2H, s), 3.44 (2H, q, J= 7 Hz), 4.52 (2H, t, J= 7 Hz), 4.69 (IH, s), 5.69 (2H, s), 6.44 (IH, d, J= 3 Hz), 7.00-7.20 (3H, m) , 7.30- 7.40 (IH, m) , 7.50-7.70 (3H, m) , 8.00 (IH, d, J= 2 Hz), 8.09 (IH, s), 8.20 (IH, s), 8.23 (IH, t, J= 7 Hz), 8.76 (IH, br s)

Reference： [1]Patent: WO2007/64045,2007,A1 .Location in patent: Page/Page column 569-570

19
5-(2-aminoethyl)-N-[1-(3-fluorobenzyl)-1H-indol-5-yl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride [ No CAS ]
[ 625-08-1 ]
[ 940308-42-9 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;	Production of N- [2- (4- [ 1- ( 3-fluorobenzyl) -IH- indol-5-yl ]amino}-5H-pyrrolo[3,2-d]pyrimidin-5- yl) ethyl] -3-hydroxy-3-methylbutanamideA mixture of 5- (2-aminoethyl) -N- [ 1- (3- fluorobenzyl) -lH-indol-5-yl] -5H-pyrrolo[3,2-d]pyrimidin- 4-amine dihydrochloride (183 mg) , 3-hydroxy-3- methylbutanoic acid (0.058 mL) , l-ethyl-3- ( 3- dimethylaminopropyl ) carbodiimide hydrochloride (103 mg), 1-hydroxybenzotriazole (72.5 mg) , triethylamine (0.15 mL) and N, N-dimethylformamide (6.9 mL) was stirred at room temperature for 16 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced <n="575"/>pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate->ethyl acetate :methanol=85 : 15 ) and crystallized from isopropyl ether to give the title compound (43 mg) as crystals.-1H-NMR (DMSO-d6) delta: 1.12 (6H, s), 2.20 (2H, s), 3.44 (2H, q, J= 7 Hz), 4.50 (2H, t, J= 7 Hz), 4.70 (IH, br s), 5.46 (2H, s), 6.41 (IH, d, J= 3 Hz), 6.47 (IH, d, J= 3 Hz), 6.9-7.2 (3H, m) , 7.20-7.50 (3H, m) , 7.52 (2H, t, J= 3 Hz), 7.76 (IH, s), 8.15 (IH, s), 8.19 (IH, t, J= 6 Hz) , 8.57 (IH, br s)

Reference： [1]Patent: WO2007/64045,2007,A1 .Location in patent: Page/Page column 573-574

20
5-(2-aminoethyl)-N-[1-(pyridin-2-ylmethyl)-1H-indol-5-yl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine tetrahydrochloride [ No CAS ]
[ 625-08-1 ]
[ 940308-45-2 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;	Production of 3-hydroxy-3-methyl-N- [2- ( 4- { [ 1- (pyridin-2-ylmethyl) -lH-indol-5-yl] amino} -5H- pyrrolo [3, 2-d] pyrimidin-5-yl ) ethyl] butanamideTo a solution of 5- ( 2-aminoethyl ) -N- [ 1- (pyridin-2- ylmethyl) -lH-indol-5-yl]-5H-pyrrolo[3,2-d] pyrimidin-4- amine tetrahydrochloride (200 mg) , 3-hydroxy-3- <n="578"/>methylbutanoic acid (67 mg) and 1-hydroxybenzotriazole (85 mg) in N, N-dimethylformamide (5.0 mL) were added triethylamine (0.52 mL) and l-ethyl-3- (3- dimethylaminopropyl ) carbodiimide hydrochloride (120 mg) under ice-cooling, and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate :methanol=100 : 0->70 : 30 ) and further recrystallized from ethyl acetate/diisopropyl ether to give the title compound (85.3 mg) as colorless crystals.1H-NMR (DMSO-de) delta: 1.26 (6H, s), 2.37 (2H, s), 3.55-3.7 (2H, m) , 4.35-4.45 (2H, m) , 5.45 (2H, s), 6.55 (2H, dd,J= 3.3 Hz, 7.8 Hz), 6.73 (IH, d, J= 7.8 Hz), 6.75-6.85 (IH, m) , 7.1-7.25 (3H, m) , 7.39 (IH, dd, J= 1.8 Hz, 8.7 Hz), 7.53 (IH, dt, J= 1.8 Hz, 7.8 Hz), 7.87 (IH, d, J=1.5 Hz), 8.22 (IH, s), 8.43 (IH, s), 8.58 (IH, d, J= 4.8Hz) .

Reference： [1]Patent: WO2007/64045,2007,A1 .Location in patent: Page/Page column 576-577

21
[ 625-08-1 ]
[ 74-88-4 ]
[ 6149-45-7 ]

Reference： [1]Patent: WO2007/108968,2007,A2 .Location in patent: Page/Page column 40

22
[ 625-08-1 ]
[ 1005784-98-4 ]
[ 200731-31-3 ]
N-[5-({2-[(3-hydroxy-3-methylbutanoyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;	Example 288 Production of N-[5-({2-[(3-hydroxy-3-methylbutanoyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide In the same manner as in Example 278 and using 3-hydroxy-3-methylbutanoic acid (74 mg, 0.63 mmol), N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide hydrochloride (200 mg, 0.48 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (240 mg, 0.63 mmol), N,N-diisopropylethylamine (190 mg, 1.5 mmol) and N,N-dimethylformamide (7 mL) as starting materials, the title compound (150 mg, 66percent) was obtained as a pale-yellow solid. 1H-NMR (DMSO-d6, 300 MHz) delta 1.19 (6H, s), 2.19 (3H, s), 2.25 (3H, s), 2.48 (2H, s), 3.98 (3H, s), 4.76 (1H, s), 6.81 (1H, s), 6.99-7.14 (2H, m), 7.28 (1H, d, J=2.3 Hz), 7.35 (1H, d, J=8.3 Hz), 7.94-8.06 (2H, m), 9.79 (1H, s), 10.58 (1H, s).

Reference： [1]Patent: US2009/137595,2009,A1

23
[ 625-08-1 ]
5-(2-aminoethyl)-N-[4-(1-benzothiophen-6-yloxy)-3-chlorophenyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride [ No CAS ]
[ 1033809-75-4 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃;	A mixture of 5-(2-aminoethyl)-N-[4-(1-benzothiophen-6-yloxy)-3-chlorophenyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (204 mg), 3-hydroxy-3-methylbutanoic acid (71 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg), 1-hydroxybenzotriazole (81 mg), triethylamine (0.167 mL) and N,N-dimethylformamide (5 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluent, methanol:ethyl acetate=0:100-->20:80). The object fraction was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (2 mL)/ethanol (2 mL), and 1N hydrochloric acid/ethyl acetate (0.5 mL) was added. The reaction mixture was concentrated under reduced pressure and the residue was crystallized from ethanol/ethyl acetate to give the title compound (220 mg) as a white powder. 1H-NMR (DMSO-d6) delta: 1.12 (6H, s), 2.20 (2H, s), 3.43-3.56 (2H, m), 4.65 (2H, t, J = 6.8 Hz), 6.67 (1H, d, J = 3.2 Hz), 7.13 (1H, dd, J = 2.3 Hz, 8.7 Hz), 7.19 (1H, d, J = 8.9 Hz), 7.46 (1H, dd, J = 0.8 Hz, 5.5 Hz), 7.62-7.68 (2H, m), 7.71 (1H, d, J = 5.5 Hz), 7.90-7.95 (2H, m), 7.98 (1H, d, J = 3.2 Hz), 8.38 (1H, t, J = 5.8 Hz), 8.72 (1H, s), 10.25 (1H, br s)

Reference： [1]Patent: EP2103620,2009,A1 .Location in patent: Page/Page column 78

24
[ 625-08-1 ]
5-(2-aminoethyl)-N-[4-(1-benzothiophen-4-yloxy)-3-chlorophenyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride [ No CAS ]
[ 1033807-36-1 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 5h;	A mixture of 5-(2-aminoethyl)-N-[4-(1-benzothiophen-4-yloxy)-3-chlorophenyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (120 mg) and 3-hydroxy-3-methylbutanoic acid (80 mg) were dissolved in N,N-dimethylformamide (3.0 mL), triethylamine (0.9 mL), 1-hydroxybenzotriazole (50 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (250 mg) were added, and the mixture was stirred at room temperature for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=20:80-->0:100-->ethyl acetate:methanol=85:15) to give the title compound (100 mg) as a white powder. 1H-NMR (DMSO-d6) delta: 1.13 (6H, s), 2.20 (2H, s), 3.37-3.49 (2H, m), 4.44-4.58 (2H, m), 4.67 (1H, s), 6.49 (1H, d, J = 3.2 Hz), 6.65 (1H, d, J = 7.3 Hz), 7.17 (1H, d, J = 8.8 Hz), 7.32 (1H, t, J = 7.3 Hz), 7.53 (1H, dd, J = 0.7 Hz, 5.4 Hz), 7.64 (1H, d, J = 2.4 Hz), 7.70-7.86 (3H, m), 8.05 (1H, d, J = 2.4 Hz), 8.19-8.36 (2H, m), 8.87 (1H, s)

Reference： [1]Patent: EP2103620,2009,A1 .Location in patent: Page/Page column 101-102

25
[ 625-08-1 ]
[ 1033810-44-4 ]
[ 1033808-59-1 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;	A mixture of tert-butyl [2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (148 mg), 3-chloro-4-(pyrazolo[1,5-a]pyridin-6-yloxy)aniline (130 mg), isopropyl alcohol (5 mL) and pyridine hydrochloride (5 mg) was stirred at 80°C overnight. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in methanol (4 mL), 4N hydrochloric acid/ethyl acetate solution (2 mL) was added, and the mixture was heated to 60°C and stirred for 1 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 3-Hydroxy-3-methylbutanoic acid (65 mg), 1-hydroxybenzotriazole (74 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (105 mg) and N,N-dimethylformamide (5 mL) were added to the residue, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate:methanol=100:0-->80:20) to give a coupling compound. The obtained coupling compound was dissolved in methanol (3 mL), 4N hydrochloric acid/ethyl acetate solution (1 mL) was added, and the mixture was concentrated under reduced pressure. The residue was crystallized from isopropyl alcohol/ethyl acetate to give the title compound (145 mg) as a white solid. 1H-NMR (DMSO-d6) delta: 1.11 (6H, s), 2.20 (2H, s), 3.47-3.51 (2H, m), 4.63-4.67 (2H, m), 6.67-6.70 (2H, m), 7.16-7.23 (2H, m), 7.61 (1H, dd, J= 2.1 Hz, 8.7 Hz), 7.81 (1H, d, J= 9.9 Hz), 7.92 (1H, d, J= 2.1 Hz), 7.97-8.02 (2H, m), 8.39 (1H, m), 8.60 (1H, m), 8.73 (1H, s), 10.32 (1H, br s)

Reference： [1]Patent: EP2103620,2009,A1 .Location in patent: Page/Page column 133

26
[ 625-08-1 ]
[ 1033809-17-4 ]
[ 1033806-78-8 ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of tert-butyl [2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (121 mg), 5-(4-amino-2-chlorophenoxy)-N-(tert-butyl)nicotinamide (119 mg), pyridine hydrochloride (5 mg) and isopropyl alcohol (5 mL) was stirred at 80°C overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluent, methanol:ethyl acetate=0:100-->20:80). The object fraction was concentrated under reduced pressure. Ethanol (2 mL) and 4N hydrochloric acid/ethyl acetate (2 mL) were added to the residue, and the mixture was stirred at 60°C for 3 hr. The reaction mixture was concentrated under reduced pressure. To a solution of the residue in N,N-dimethylformamide (5 mL) were added 3-hydroxy-3-methylbutanoic acid (71 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg), 1-hydroxybenzotriazole (81 mg) and triethylamine (0.223 mL), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (eluent, methanol:ethyl acetate=0:100-->2.0:80) The object fraction was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give the title compound (137 mg) as a white powder. 1H-NMR (DMSO-d6) delta: 1.13 (6H, s), 1.36 (9H, s), 2.20 (2H, s), 3.41 (2H, q, J = 6.5 Hz), 4.52 (2H, t, J = 7.0 Hz), 4.66 (1H, s), 6.49 (1H, d, J = 3.2 Hz), 7.28 (1H, d, J = 8.9 Hz), 7.56 (1H, dd, J = 1.7 Hz, 2.8 Hz), 7.64 (1H, d, J = 3.2 Hz), 7.83 (1H, dd, J = 2.5 Hz, 8.9 Hz), 8.03-8.09 (2H, m), 8.24 (1H, t, J = 5.7 Hz), 8.33 (1H, s), 8.47 (1H, d, J = 2.8 Hz), 8.73 (1H, d, J = 1.7 Hz), 8.90 (1H, brs)

Reference： [1]Patent: EP2103620,2009,A1 .Location in patent: Page/Page column 55

27
[ 625-08-1 ]
[ 1185855-70-2 ]
[ 1185280-08-3 ]

Yield	Reaction Conditions	Operation in experiment
		Example A56Synthesis of 3-(5-(5-(2-hydroxy-2-methylpropyl)-l,2,4-oxadiazol-3-ylamino)-2- methylphenyl)-l,7-dimethyl-l,6-naphthyridin-2(lH)-one <n="50"/> [00147] To a solution of 3-hydroxy-3-methylbutanoic acid (6 mg, 0.06 mmol) in DMF(1 mL) were added DIPEA (31 muL, 0.18 mmol) and HATU (23 mg, 0.06 mmol). After stirring at rt for 15 min, 17 (20 mg, 0.06 mmol) was added as a solution in DMF (0.5 mL). The reaction was stirred at rt until complete consumption of 17 was determined by LC/MS and then heated at 100 0C for 1 h. Subsequently the reaction was cooled to rt, filtered and purified by preparative LC/MS to give 3-(5-(5-(2-hydroxy-2-methylpropyl)-l,2,4-oxadiazol-3-ylamino)-2- methylphenyl)-l,7-dimethyl-l,6-naphthyridin-2(lH)-one (A56). MS m/z 420.4 (M+l).

Reference： [1]Patent: WO2009/105712,2009,A1 .Location in patent: Page/Page column 48-49; 77

28
[ 625-08-1 ]
[ 1201903-03-8 ]
[ 1201902-88-6 ]

Yield	Reaction Conditions	Operation in experiment
95%	In ethyl acetate; at 25 - 60℃;	Example 9- Synthesis of 2,5-dichloro-N-(2-{ [( IR)-I -(4,4-dimethyl-6-oxo-l,3,2-dioxabopinan-2- yl)-3-methylbutvnamino }-2-oxoethyl)benzamide (1-9)[0336] To a solution of beta-hydroxyisovalepic acid (0.0841 g, 0.712 mmol) in EtOAc (2 0 mL) with an internal temperature of about 60 0C was added a solution of N,N',N"-{boroxin-2,4,6-tpiyltpis[[(lR)-3- methylbutane-l,l-diyl]imino(2-oxoethane-2,l-diyl)] }tpis(2,5-dichlorobenzamide) (0 260 g, 0.253 mmol) in EtOAc (1.0 mL). The solution was cooled uncontrolled until the internal temperature was about 25 0C and the solvent was removed by evaporation to yield 2,5-dichloro-N-(2-{ [(lR)-l-(4,4- dimethyl-6-oxo-l,3,2-dioxabopinan-2-yl)-3-methylbutyl]amino}-2-oxoethyl)benzamide as a white solid (0296 g, 95percent). MS (m/z) in CH3CN: [M+ Et3N+H] calculated for C25H41BCl2N3O5, 544.3; found, 5440. MS {,n/z) in CH3CN: [M-H] calculated for C19H24BCl2N2O5, 441.1 ; found, 441 0..1.

Reference： [1]Patent: WO2009/154737,2009,A1 .Location in patent: Page/Page column 70

29
[ 625-08-1 ]
[ 1222105-31-8 ]
[ 1222104-65-5 ]

Yield	Reaction Conditions	Operation in experiment
67%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; for 16h;	5-(9-Isobutyl-6-morpholin-4-yl-8-piperazin-1-yl-9H-purin-2-yl)pyrimidin-2-amine (150 mg, 0.33 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (128 mg, 0.67 mmol), 1-hydroxybenzotriazole (45 mg, 0.33 mmol), and 3-hydroxy-3-methylbutanoic acid (79 mg, 0.67 mmol) were dissolved in dimethylformamide (5 ml) and the resulting mixture was stirred for 16 hours. The solvent was evaporated under reduced pressure and the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (120 mg, 67percent) as a white solid.1H-NMR (CDCl3) delta: 0.88 (3H, s), 0.90 (3H, s), 1.32 (6H, s), 2.46-2.50 (3H, m), 3.22-3.27 (4H, m), 3.66-3.67 (2H, m), 3.82-3.87 (6H, m), 3.92 (2H, d, J=7.6 Hz), 4.28 (4H, brs), 4.99 (1H, s), 5.23 (2H, s), 9.24 (2H, s).

Reference： [1]Patent: US2010/130492,2010,A1 .Location in patent: Page/Page column 135

30
[ 625-08-1 ]
[ 1246759-71-6 ]
[ 1246759-75-0 ]

Yield	Reaction Conditions	Operation in experiment
		To a mixture of methyl 5,6-diamino-4'-fluorobiphenyl-3-carbozylate (2.0 g, 7.68 mmol), 3-hydroxy-3-methylbutanoic acid (1.0 g, 8.45 rrunol), 1 -hydroxy- 7-azabenzotriazols (0.523 g, 3.84 mmol) and l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.58 g, 13.5 mmol) was added N,N- dimethylformamide (15.4 mL) followed by TEA (2.0 mL, 14.4 mmol). Reaction heated at 50 0C for 3 h. HCl (7.68 mL, 4M in dioxane, 30.7 mmol) was added, the reaction was transferred to a microwave vial and heated in the microwave at 125 0C for 15 min. Reaction cooled and filtered. Purification by reverse phase EtaPLC (C-18, 95percent water/acetonitrile - 5percent water/acetonitrile with 0.1percent TFA) gave the title compound (0.412 g): LC-MS [M+ 1] = 343.3.

Reference： [1]Patent: WO2010/111058,2010,A1 .Location in patent: Page/Page column 90

31
[ 940307-58-4 ]
[ 625-08-1 ]
[ 940307-59-5 ]

Yield	Reaction Conditions	Operation in experiment
		Production of N- [2- ( 4- { [4- ( 3-acetylphenoxy) -3- chlorophenyl] amino }-5H-pyrrolo [3, 2-d] pyrimidin-5- yl) ethyl] -3-hydroxy-3-methylbutanamideTo tert-butyl [2- ( 4- [ 4- ( 3-acetylphenoxy) -3- chlorophenyl] amino }-5H-pyrrolo [3, 2-d] pyrimidin-5- yl) ethyl ] carbamate (1.10 g) were added ethanol (2 piiL) and 4N hydrogen chloride/ethyl acetate solution (5 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. To a solution of the obtained residue in N, N-dimethylformamide (20 mL) were added 3-hydroxy-3- methylbutanoic acid (374 mg), l-ethyl-3- ( 3- dimethylaminopropyl ) carbodiimide hydrochloride (607 mg) , 1-hydroxybenzotriazole monohydrate (485 mg) and triethylamine (0.882 mL) and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluent, ethyl acetate:hexane=50:50-100: O-->methanol : ethyl <n="525"/>acetate=20 : 80 ) and basic silica gel column chromatography (eluent, methanol : ethyl acetate=0 : 100-->10 : 90) . The objective fractions were concentrated under reduced pressure to give the title compound (596 mg) as a white amorphous powder.-1H-NMR (CDCl3) delta: 1.32 (6H, s), 2.48 (2H, s), 2.59 (3H, s), 3.58-3.68 (2H, m) , 4.44-4.54 (2H, m) , 6.59 (IH, d, J = 3.3 Hz), 7.05 (IH, d, J = 8.8 Hz), 7.09-7.22 (3H, m) , 7.42 (IH, t, J = 7.8 Hz), 7.57 (IH, m) , 7.64-7.69 (IH, m) , 7.74 (IH, dd, J = 2.6 Hz, 8.8 Hz), 8.07 (IH, d, J = 2.6 Hz), 8.50 (IH, s), 8.66 (IH, br s).

Reference： [1]Patent: WO2007/64045,2007,A1 .Location in patent: Page/Page column 523-524

32
[ 625-08-1 ]
[ 1220635-19-7 ]
[ 1220635-21-1 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃;	This material was condensed independently with 3-hydroxy-3-methylbutyric acid and 2,2-dimethyl-3-hydroxy propionic acid to give PH1149 and PH1150

Reference： [1]Patent: US8013015,2011,B2 .Location in patent: Page/Page column 13-14

33
[ 625-08-1 ]
[ 1360553-46-3 ]
[ 1360551-13-8 ]

Yield	Reaction Conditions	Operation in experiment
		To a suspension of R-13 (118 mg, 1.0 mmol) in THF 10 ml) is added 1,1'- carbonyldiimidazole (162 mg, 1.0 mmol) at room temperature. The mixture is stirred at 50 °C for 30 minutes. After this time 1-21 (200 mg, 0.67 mmol) is added and the resulting mixture is heated under reflux for 3 hours. After this time the reaction is cooled to RT, treated with HOAc (1 ml) and warmed to 80°C. After stirring for 3 days the mixture is cooled to RT and concentrated. The remaining residue is purified via flash chromatography (silica gel, 0-8percent MeOH/DCM) to afford the title compound (80 mg).
80 mg		To a suspension of R-13 (118 mg, 1.0 mmol) in THF 10 ml) is added 1,1?-carbonyldiimidazole (162 mg, 1.0 mmol) at room temperature. The mixture is stirred at 50° C. for 30 minutes. After this time I-21 (200 mg, 0.67 mmol) is added and the resulting mixture is heated under reflux for 3 hours. After this time the reaction is cooled to RT, treated with HOAc (1 ml) and warmed to 80° C. After stifling for 3 days the mixture is cooled to RT and concentrated. The remaining residue is purified via flash chromatography (silica gel, 0-8percent MeOH/DCM) to afford the title compound (80 mg).

Reference： [1]Patent: WO2012/24150,2012,A1 .Location in patent: Page/Page column 177-178
[2]Patent: US2013/195879,2013,A1 .Location in patent: Paragraph 0495; 0496

34
[ 625-08-1 ]
[ 1361189-49-2 ]
[ 1361189-07-2 ]

Yield	Reaction Conditions	Operation in experiment
		Method 25Synthesis of l-(3-{ l-r4-(2-Amino-pyrimidin-5-yl)-phenyll-cyclobutyl\|-ri,2,41oxadiazol- 5-yl)-2-methyl-propan-2-ol (Example 279)To a suspension of R88 (125 mg, 1.06 mmol) in THF (10 ml) is added CDI (172 mg, 1.06 mmol) at room temperature. The mixture is stirred at 50° C for 30 minutes. After this time 1-2.5 (200 mg, 0.71 mmol) is added and the resulting mixture is heated at 80° C for 20 hours. After this time the reaction is cooled to ambient temperature and treated with AcOH (1 ml). The reaction is warmed to 80°C and stirred for 6h. The mixture is cooled to ambient temperature and stirred over night. The reaction is concentrated and the remaining residue is purified via column chromatography (25g silica gel, 0-5percentMeOH/DCM). Product-containing fractions are combined and concentrated to afford the title compound (100 mg). m/z 366.4 [M+l]

Reference： [1]Patent: WO2012/27322,2012,A1 .Location in patent: Page/Page column 150

35
[ 625-08-1 ]
2-[(N,N'-benzyl-benzyloxycarbonyl)amino]ethyl 4-amino-3-O-benzyl-4,6-dideoxy-2-O-methyl-β-D-glucopyranosyl-(1->3)-2,4-di-O-benzyl-α-L-rhamnopyranosyl-(1->3)-2,4-di-O-benzyl-α-L-rhamnopyranosyl-(1->2)-3,4-di-O-benzyl-α-L-rhamnopyranoside [ No CAS ]
[ 1384443-08-6 ]

Yield	Reaction Conditions	Operation in experiment
12 mg	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 18h;Inert atmosphere;	To a solution of 42 (29 mg, 18.2 mumol) in a mixture of CH2Cl2 (250 muL) and EtOH (1 mL) was added sodium borohydride (1.4 mg, 36.4 mumol) and a catalytic amount of NiCl2*6H2O. The reaction mixture was stirred at rt for 1 h and then was concentrated in vacuo. The residue was dissolved in CH2Cl2. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide 2-[(N,N'-benzyl-benzyloxycarbonyl)amino]ethyl 4-amino-3-O-benzyl-4,6-dideoxy-2-O-methyl-beta-glucopyranosyl-(1-->3)-2,4-di-O-benzyl-alpha-l-rhamnopyranosyl-(1-->3)-2,4-di-O-benzyl-alpha-l-rhamnopyranosyl-(1-->2)-3,4-di-O-benzyl-alpha-l-rhamnopyranoside which was used in the next step without purification. To a solution of crude amine in dry DMF (1 mL) was added dropwise 3-hydroxy-3-methylbutanoic acid (3 muL, 21.8 mumol), followed by HATU (8.8 mg, 21.8 mumol), and then DIPEA (4 muL, 21.8 mumol). The reaction mixture was stirred under argon at rt for 18 h and was then diluted with CH2Cl2, washed with saturated aqueous NaHCO3, and water. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using cyclohexane/EtOAc (6:4) as eluent to provide 43 (12 mg, 40percent over 2 steps) as a colorless oil (mixture of conformers). Rf 0.56 (cyclohexane/EtOAc 5:5); [alpha]D -32 (CHCl3, c 1.2); 1H NMR (600 MHz, CDCl3) delta 7.42-7.12 (m, 45H, NCOOCH2C6H5, 7 .x. OCH2C6H5, NCH2C6H5), 5.32 (br s, 1H, NH), 5.18 (br s, 2H, NCOOCH2C6H5), 5.10 (br s, 1H, H-1B), 5.05 (d, 1H, J1C,2C = 1.8 Hz, H-1C), 5.00 (d, 1H, JA,B = 10.6 Hz, A part of an AB system, OCHHC6H5), 4.86 (d, 1H, JA,B = 11.4 Hz, A part of an AB system, OCHHC6H5), 4.68 (d, 1H, JA,B = 11.4 Hz, A part of an AB system, OCHHC6H5), 4.65-4.46 (m, 14H, H-1A, H-1D, 4 .x. B part of an 4 .x. AB system, 4 .x. OCHHC6H5, 3 .x. OCH2C6H5, NCH2C6H5), 4.13-4.11 (m, 2H, H-3B, H-3C), 3.92-3.91 (m, 2H, H-2B, H-2D), 3.83-3.79 (m, 2H, H-5B, H-2C), 3.79-3.71 (m, 3H, H-5C, H-3D, A part of an AB system, OCHHCH2NH), 3.67-3.62 (m, 3H, H-4A, H-5A, H-4B), 3.64 (s, 3H, OCH3), 3.58-3.47 (m, 3H, H-4C, H-5D, B part of an AB system, OCHHCH2N), 3.47-3.34 (m, 3H, H-4D, OCH2CH2NH), 3.33 (br t, J = 9.2 Hz, H-3A), 3.18 (dd, 1H, J1A,2A = 7.8 Hz, J2A,3A = 8.7 Hz, H-2A), 2.22-2.18 (m, 1H, A part of an AB system, NHCOCHHC(CH3)2OH), 2.11-2.04 (m, 1H, B part of an AB system, NHCOCHHC(CH3)2OH), 1.26 (br s, 6H, NHCOCH2C(CH3)2OH), 1.35-1.19 (m, 9H, H-6B, H-6C, H-6D), 1.04 (d, 3H, J5A,6A = 6.0 Hz, H-6A); 13C NMR (75 MHz, CDCl3) delta 172.5 (NHCOCH2C(CH3)2OH), 156.9 and 156.4 (NCOOCH2C6H5), 139.1, 138.9, 138.6, 138.4, 137.9, 137.8, 128.7, 128.6, 128.4, 128.3, 128.2, 127.8, 127.5 (NCOOCH2C6H5, 7 .x. OCH2C6H5, NCH2C6H5), 103.9 (C-1A), 100.5 (C-1B), 99.3 (C-1C and C-1D), 85.1 (C-2A), 81.1 (C-4B), 80.7 (C-4C), 80.7 (C-4D), 80.3 (C-3A), 79.9 (C-3D), 79.4 (C-2B), 79.0 (C-3B), 78.1 (C-2C), 77.3 (C-3C), 75.6 (OCH2C6H5), 75.0 (C-2D), 74.8 (2 .x. OCH2C6H5), 74.7 (OCH2C6H5), 73.9 (OCH2C6H5), 72.4 (OCH2C6H5), 72.3 (OCH2C6H5), 71.1 (C-5A), 69.6 (NHCOCH2C(CH3)2OH), 68.9 (C-5C), 68.6 (C-5B), 68.3 (C-5D), 67.5 (NCOOCH2C6H5), 65.7 (OCH2CH2N), 60.7 (OCH3), 55.9 (C-4A), 51.9 and 51.8 (NCH2C6H5), 47.9 (NHCOCH2C(CH3)2OH), 47.0 and 46.0 (OCH2CH2N), 18.3, 18.2, 18.1 (C-6A, C-6B, C-6C and C-6D); HR-ESI-MS m/z calcd for C96H112N2O20 1635.7706 [M+Na]+, found 1635.7695.

Reference： [1]Carbohydrate Research,2012,vol. 356,p. 115 - 131

36
[ 64-17-5 ]
[ 625-08-1 ]
[ 18267-36-2 ]

Yield	Reaction Conditions	Operation in experiment
80%	With toluene-4-sulfonic acid In cyclohexane at 85℃; for 5h; Molecular sieve;

Reference： [1]Cheong, Ling-Zhi; Widzisz, Katarzyna; Wang, Yingyao; Jensen, Henrik Helligso; Theil, Peter Kappel; Guo, Zheng; Xu, Xuebing [Journal of the American Oil Chemists' Society, 2013, vol. 90, # 6, p. 919 - 922]

37
[ 625-08-1 ]
5-bromo-4-(cyclohexylmethyl)thiazol-2-amine [ No CAS ]
N-(5-bromo-4-(cyclohexylmethyl)thiazol-2-yl)-3-hydroxy-3-methylbutanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29%	With dicyclohexyl-carbodiimide; In N,N-dimethyl-formamide; at 20℃; for 12h;	Step 3: N-(5-Bromo-4-(cyclohexylmethyl)thiazol-2-yI)-3-hydroxy-3-methylbutanamide (200c)A mixture of compound 200b (548 mg, 2.0 mmol), DCC (412 mg, 2.0 mmol) and 3-hydroxy-3- methylbutanoic acid (236 mg, 2.0 mmol) in DMF (20 mL) was stirred at rt for 12 h, diluted with water (30 mL) and extracted with EA (3x 50 mL). The cobined organic layer was washed with brine, dried over Na2SC4 and evaporated to obtain compound 200c (220 mg, 29percent) as yellowish solid.

Reference： [1]Patent: WO2013/178362,2013,A1 .Location in patent: Page/Page column 184

38
[ 625-08-1 ]
[ 197573-96-9 ]
[ 1622442-13-0 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃;Inert atmosphere;	General procedure: To (R)/(S)-4-methyl-1-(1,4,5,8-tetramethxynaphthalen-2-yl)pent-3-en-1-ol (2, > 99percent e.e., 0.1 mmol) and carboxylic acid (0.11 mmol, 1.1 equiv) in dry CH2Cl2 were added DCC (0.2 mmol, 2equiv) and DMAP (0.01 mmol, 0.1 equiv) and the mixture was stirred for 2~4 h at room temperature under nitrogen atmosphere. After the completion of reaction, to the reaction mixture CAN (0.5 mmol, 5 equiv) in water was added and stirred for an additional 15 min at 0 C. Then the reaction mixture was extracted with CH2Cl2 and purified by silica gel column chromatography to give yellow oily compounds. Stirring of obtained yellow oily compounds and hydroxylamine hydrochloride (1.2 equiv, 0.12 mmol) respectively in dry ethanol with the presence of pyridine (0.2mmol, 2 equiv) produced a series of oxime derivatives.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 4304 - 4307
[2]ChemMedChem,2014,vol. 9,p. 2798 - 2808

39
[ 625-08-1 ]
[ 1239314-30-7 ]
[ 1385029-25-3 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃;Inert atmosphere;	General procedure: To (R)/(S)-4-methyl-1-(1,4,5,8-tetramethxynaphthalen-2-yl)pent-3-en-1-ol (2, > 99percent e.e., 0.1 mmol) and carboxylic acid (0.11 mmol, 1.1 equiv) in dry CH2Cl2 were added DCC (0.2 mmol, 2equiv) and DMAP (0.01 mmol, 0.1 equiv) and the mixture was stirred for 2~4 h at room temperature under nitrogen atmosphere. After the completion of reaction, to the reaction mixture CAN (0.5 mmol, 5 equiv) in water was added and stirred for an additional 15 min at 0 C. Then the reaction mixture was extracted with CH2Cl2 and purified by silica gel column chromatography to give yellow oily compounds. Stirring of obtained yellow oily compounds and hydroxylamine hydrochloride (1.2 equiv, 0.12 mmol) respectively in dry ethanol with the presence of pyridine (0.2mmol, 2 equiv) produced a series of oxime derivatives.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 4304 - 4307
[2]ChemMedChem,2014,vol. 9,p. 2798 - 2808

40
[ 625-08-1 ]
C₁₈H₁₇FN₄ [ No CAS ]
C₂₃H₂₅FN₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With triethylamine; HATU; In N,N-dimethyl-formamide; at 60℃; for 16h;	To a solution of compound A02-186 (50 mg, 0.162 mmol) in DMF (3 mL) were added 3-hydroxy-3-methylbutanoic acid (57 mg, 0.487 mmol), HATU (185 mg, 0.487 mmol) and triethylamine (82 mg, 0.810 mmol). The mixture was stirred at 60 °C for 16 h. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (2 x 15 mL). The organic layer was washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by Prep-HPLC to give A30- 012 as a white solid (20 mg, yield: 30percent). LC-MS 409 (M+H), purity 100percent (UV 214 nm); ?H NMR (400 MHz, MeOD-d4) oe 8.46 (s, 1 H), 8.05 (dd, J = 9.6 Hz, 2.8 Hz, 1 H), 7.78 (dd, J = 9.2 Hz, 5.2 Hz, 1 H), 7.63 (td, J = 8.0 Hz, 2.8 Hz, 1 H), 7.38 (s, 1 H), 7.30 (dd, J = 8.4 Hz, 2.4 Hz, 1 H), 7.08 (d, J = 8.4 Hz, 1 H), 4.68-4.60 (m, 1 H), 3.24 (dd, J = 15.6 Hz,4.8 Hz, 1 H), 3.08-2.86 (m, 3 H), 2.53 (s, 2 H), 2.32-2.27 (m, 1 H), 1.98-1.88 (m, 1 H)1.35 (s, 6 H).

Reference： [1]Patent: WO2014/145512,2014,A2 .Location in patent: Page/Page column 118; 119

41
[ 625-08-1 ]
C₁₇H₁₅FN₄ [ No CAS ]
C₂₂H₂₃FN₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%	With triethylamine; HATU; In N,N-dimethyl-formamide; at 40℃; for 16h;	To a solution of compound A02-171 (150 mg, 0.5 10 mol) in DMF (3 mL) were added 3-hydroxy-3-methylbutanoic acid (120 mg, 1.020 mmol), HATU (388 mg, 1.020 mmol) and triethylamine (515 mg, 5.10 mmol). The mixture was stirred at 40 °C for 16 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (2 x 20 mL). The organic layer was washed with water (15 mL) and brine (15 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by Prep-HPLC to give A29-061 as a white solid (40 mg, yield: 20percent). LC-MS 395 (M+H), purity 97percent (UV 214 nm); ?H NMR (400 MHz, DMSO-d6) oe 9.77 (s, 1 H), 8.52 (s, 1 H), 8.26 (d, J = 6.8 Hz, 1 H), 8.23 (dd, J = 10.0 Hz, 2.8 Hz, 1 H), 7.77 (dd, J = 9.2 Hz, 5.6 Hz, 1 H), 7.67 (td, J = 8.4 Hz, 2.8 Hz, 1 H), 7.58 (s, 1 H), 7.32 (dd, J = 8.4 Hz, 2.0 Hz, 1 H), 7.17 (d, J = 8.0 Hz, 1 H), 5.03-4.97 (m, 1 H), 4.76 (s, 1 H), 3.37-3.30 (m, 2 H), 3.05-2.95 (m, 2 H), 2.41 (s, 2 H), 1.22 (s, 6 H).

Reference： [1]Patent: WO2014/145512,2014,A2 .Location in patent: Page/Page column 83

42
[ 625-08-1 ]
C₁₇H₁₆N₄ [ No CAS ]
C₂₂H₂₄N₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15%	With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 8h;	To a solution of SP-0011507-051 (200 mg, 0.72 mmol) in DMF (2.0 mL) were added 3-hydroxy-3-methylbutanoic acid (170 mg, 1.44 mmoL), HATU (684 mg, 1.80 mmol) and triethylamine (0.52 mL, 3.60 mmol). The reaction mixture was stirred at room temprature for 8 h. The resulting mixture was evaporated and the residue was purified by Prep-HPLC to give A29-083 as a white solid (40 mg, yield: 15percent). LC-MS 377 (M+H) , purity 100percent (UV 214 nm); ?H NMR (400 MHz, DMSO-d6) oe 9.76 (s, 1 H), 8.51 (s, 1 H), 8.32 (t, J = 8.4 Hz, 2 H), 7.76 (d, J = 7.6 Hz, 1 H), 7.67 (d J = 7.6 Hz, 1 H), 7.57 (s, 1 H),7.49 (t, J = 7.2 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 7.16 (d, J = 8.0 Hz, 1 H), 5.05-4.99 (m, 1 H), 4.75 (s, 1 H), 3.37-3.30 (m, 2 H), 3.06-2.96 (m, 2 H), 2.40 (s, 2 H), 1.22 (s, 6 H).

Reference： [1]Patent: WO2014/145512,2014,A2 .Location in patent: Page/Page column 106

43
[ 625-08-1 ]
C₁₇H₁₅FN₄ [ No CAS ]
C₂₂H₂₃FN₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%	With triethylamine; HATU; In N,N-dimethyl-formamide; at 40℃; for 16h;	To a solution of compound SP-0011321-028 (120 mg, 0.408 mmol) in DMF (3 mL) was added 3 -hydroxy-3 -methylbutanoic acid (96 mg, 0.816 mmol), HATU (310 mg, 0.816 mmol) and triethylamine (410 mg, 0.408 mmol). The mixture was stirred at 40 °C for 16 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (2 x 20 mL). The organic layer was washed with water (15 mL) and brine (15 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by Prep-HPLC to give A29- 077 as a white solid (40 mg, yield: 20percent). LC-MS 395 (M+H), purity 97percent (UV 214 nm); ?H NMR (400 MHz, DMSO-d6) oe 9.77 (s, 1 H), 8.51 (s, 1 H), 8.47-8.41 (m, 2 H), 7.57 (s, 1 H), 7.44-7.39 (m, 2 H), 7.32 (d, J = 8.0 Hz, 1 H), 7.16 (d, J = 8.0 Hz, 1 H), 5.05-4.99 (m, 1 H), 4.76 (s, 1 H), 3.37-3.28 (m, 2 H), 3.00 (td, J = 17.2 Hz, 6.4 Hz, 2 H), 2.41 (s, 2 H), 1.22 (s, 6 H).

Reference： [1]Patent: WO2014/145512,2014,A2 .Location in patent: Page/Page column 102

44
[ 625-08-1 ]
C₁₈H₁₅N₅ [ No CAS ]
C₂₃H₂₃N₅O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
13%	With triethylamine; HATU; In N,N-dimethyl-formamide; at 80℃;	To a solution of A23-001 (150 mg, 0.50 mmol) in DMF (2.0 mL) was added 3- hydroxy-3-methylbutanoic acid (71 mg, 0.60 mmoL), HATU (285 mg, 0.75 mmol), triethylamine (0.10 mL, 0.72 mmol). The reaction mixture was stirred at 80 °C overnight. The resulting mixture was evaporated and the residue was purified by Prep-HPLC to give A29-002 as a white solid (25 mg, yield: 13percent). LC-MS 402 (M+H) , purity 100percent (UV 214 nm); ?H NMR (400 MHz, DMSO-d6) oe 8.78 (s, 1 H), 8.61 (s, 1 H), 8.01(d, J = 6.8 Hz, 1 H), 7.82 (d, J = 4.8 Hz, 1 H), 7.54 (s, 1 H), 7.31 (d, J = 8.4 Hz, 1 H), 7.22 (d, J = 4.8 Hz, 1 H), 5.19-5.15 (m, 1 H), 3.49-3.41 (s, 2 H), 3.14-3.05 (m, 2 H), 2.54 (s, 2 H), 1.35 (s, 6 H).

Reference： [1]Patent: WO2014/145512,2014,A2 .Location in patent: Page/Page column 41

45
[ 625-08-1 ]
C₁₇H₁₆FN₅ [ No CAS ]
C₂₂H₂₄FN₅O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22%	With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃;	To a solution of compound A32-OO1 (155 mg, 0.5 mmol), 2-hydroxy-2- methyipropanoic acid (118 mg, 1.0 mmol) in dry DMF (4.0 mL) were added HATU (286 mg, 0.75 mmol) and TEA (0.4 mL). The mixture was stirred at room temperature overnight. The resulting mixture was quenched by water (20 mL) and extracted with EtOAc (2 x 50 mL). The organic phase was washed with water (20 mL), brine (20 mL) and dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by Pre-HPLC to provide the title compound A32-008 (45 mg, yield: 22percent) as a white solid. LC-MS 410 (M+H), purity 97percent (UV 214 nm); ?H NMR (DMSO-d6, 400 MHz) oe 9.95 (s, 1 H), 8.49 (s, 1 H), 8.46 (s, 1 H), 8.26-8.23 (dd, J, = 2.8 Hz, J2 = 10.0 Hz, 1 H), 8.09 (d, J =7.2 Hz, 1 H), 7.86 (d, J = 2.4 Hz, 1 H), 7.79-7.66 (m, [1+ 1] H), 4.73 (s, 1 H), 4.64-4.62 (m, 1 H), 3.25-3.19 (m, 1 H), 2.97-2.88 (m, [1+2] H), 2.51-2.50 (m, 2 H), 2.16-2.14 (m, 1 H),1.90-1.84 (m, 1 H), 1.23 (s, [3+3] H).

Reference： [1]Patent: WO2014/145512,2014,A2 .Location in patent: Page/Page column 142

46
[ 625-08-1 ]
[ 5557-81-3 ]
(R)-benzyl 2-(3-hydroxy-3-methylbutanamido)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 0 - 20℃; for 1h;	DIPEA (8.9 mL, 77 mmol) was added to a mixture of 3-hydroxy-3- methylbutanoic acid (2.2 g, 18.6 mmol), (R)-benzyl 2-aminopropanoate hydrochloride (3.7 g, 17.1 mmol) and HATU (7.2 g, 18.9 mmol) in dichloromethane (50 mL) at 0°C. The reaction mixture was stirred for 1 h at room temperature. Water (100 mL) was added and the two layers were separated. The aqueous layer was extracted with dichloromethane (100 mL>ether/ethyl acetate = 10: 1 to 3: 1) to give (R)-benzyl 2-(3 -hydroxy-3 - methylbutanamido)propanoate (4.7 g, 98percent yield

Reference： [1]Patent: WO2014/152127,2014,A1 .Location in patent: Paragraph 00228

47
[ 7751-38-4 ]
[ 625-08-1 ]
C₁₁H₂₃ClO₃Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1H-imidazole; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 5h;	[0063] 3-hydoxy-3-methylbutyric acid (lg, 8.46mmol) and imidazole (0.69g, lO.lmmol) was dissolved in DMF (16mL). DIPEA (8.7mL) was added and the reaction mixture was cooled to 0°C. After cooling, diisopropyldichlorosilane (2.82g, 15.3mmol) was added and stirred for lh at 0°C, then 4h at room temperature.

Reference： [1]Patent: WO2014/171899,2014,A1 .Location in patent: Paragraph 0063

48
[ 948566-16-3 ]
[ 625-08-1 ]
S-[4-(3-hydroxy-3-methylbutyryloxy)-but-2-ynyl]-6α,9α-difluoro-17α-(furan-2-yl)carbonyloxy-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In dichloromethane; at 20℃; for 1h;	To a stirred mixture of S-(4-hydroxy-but-2-ynyl)6alpha,9alpha-difluoro-17alpha-(furan-2-yl)carbonyloxy-11beta-hydroxy-16alpha-methyl-3-oxoandrosta-1,4-diene-17beta-carbothioate (4.0g, 6.96mmol), 3-hydroxy-3-methylbutyric acid (1.23g, 10.4mmol) and triethylamine (2.9ml, 20.8mmol) in dry dichloromethane (50ml) was added (benztriazol-1-yloxy)-tris-(dimethyamino)phosphonium hexafluorophosphate (BOP) (4.6g, 10.4mmol) and the solution was stirred at room temperature for 1 hr. The reaction mixture was poured into DM water (100ml), the organic layer was separated and washed successively with DM water and saturated sodium chloride solution and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to yield the title compound as an off white solid. NMR (400 MHz in CDC13) delta: 1.05(d, J=7.09Hz, 3Eta), 1.17(s, 3H), 1.30(s, 3Eta), 1.32(s, 3H), 1.35-1.40(m, IH), 1.55(s, 3H), 1.65- 1.95(m, 3H), 2.28-2.5 l(m,4H), 2.53(s, 2H), 3.32(s, IH), 3.38(s, IH), 3.41-3.45(m, IH), 3.68(d, J=16.75Hz, IH), 3.76(d, J=16.75Hz, IH), 4.43(d, J=8.18Hz, IH), 4.69(s, IH), 5.32-5.49(m, IH), 6.39(dd, J;=10.79Hz, J2=1.23Hz, IH), 6.45(s, IH), 6.50(dd, J/=3.15Hz, J2=1.40Hz, IH), 7.12(d, J=3.36Hz, IH), 7.16(d, J=10.12Hz, IH), 7.59(s, IH). Mass: 674.93m/z [M+H] +.

Reference： [1]Patent: WO2014/192027,2014,A1 .Location in patent: Page/Page column 14; 15

49
[ 625-08-1 ]
[ 247225-81-6 ]
C₁₅H₁₇N₃O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃;

Reference： [1]Mikkelsen, Gitte Kobberøe; Langgård, Morten; Schrøder, Tenna Juul; Kreilgaard, Mads; Jørgensen, Erling B.; Brandt, Guillaume; Griffon, Yann; Boffey, Ray; Bang-Andersen, Benny [Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 6, p. 1212 - 1216]

50
[ 625-08-1 ]
4-[(4-{5-fluoro-6-[(3R)-piperidin-3-ylamino]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}piperazin-1-yl)methyl]phenol [ No CAS ]
4-[4-(5-fluoro-6-[(3R)-1-(3-hydroxy-3-methylbutanoyl)piperidin-3-yl]amino}-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)piperazin-1-yl]methyl}phenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
19%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 2h;	A mixture of 4-[(4-{5-fluoro-6-[(3R)-piperid in-3-ylamino]-2-pyrazolo[1 ,5-a]pyrid in-3- ylpyrimidin-4-yl}piperazin-1 -yl)methyl]phenol (Preparation 1 7c, 0.10 g, 0.20 mmol), 3- hydroxy-3-methylbutanoic acid (0.04 mL, 0.30 mmol), 1 -[bis(dimethylamino) methylene]-1 H-i ,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (0.11 g,0.30 mmol) and diisopropylethylamine (0.28 mL, 1 .62 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 2 hours. The reaction mixture was partitioned between water and dichloromethane, the organic layer was separated, dried over magnesium sulfate and the solvent was evaporated to dryness. The residue was purified by flash chromatography and reverse phase chromatography (usingwater/methanol as eluents) to yield the title compound (25 mg, 19percent) as a white solid.LRMS (m/z): 604 (M-f-2).1H-NMR (300 MHz, CDCI3): 1.13 (d, 6H), 1.75 -1.90 (m, 4H), 2.32 -2.47 (m,2H), 2.56 - 2.71 (m, 4H), 3.19 - 3.37 (m, 2H), 3.55 (s, 2H), 3.71 - 3.85 (m, 4H),3.90 -4.01 (m, 1H), 4.60 -4.75 (m, 1H), 5.40 (bs, 1H), 6.81 (m, 3H), 7.26 (m,3H), 8.33 - 8.56 (m, 3H).

Reference： [1]Patent: WO2015/86693,2015,A1 .Location in patent: Page/Page column 132

51
[ 625-08-1 ]
[ 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-3-methylbutan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	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

52
[ 625-08-1 ]
C₂₈H₄₇NO₅ [ No CAS ]
tetradecyl 3-O-benzoyl-4,6-dideoxy-4-(3-hydroxy-3-methylbutanamido)-2-O-methyl-β-D-glucopyranoside [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
395 mg	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 25℃; for 18h;Inert atmosphere;	NaBH4 (65mg; 1.7mmol) and a catalytic amount of NiCl2 ×6H2O were added to a solution of compound 13 (433mg; 0.86mmol) in amixture of dry CH2Cl2 (12.4mL)and EtOH (60 mL). The reaction mixture was stirred at rt for 1 h and concentrated under vacuum. The residue was dissolved in CH2Cl2 (50 mL). The organic layer was washed with water (20mL) and brine (20mL), dried over Na2SO4, filtered, and concentrated under vacuum. Compound 14 (398 mg; 97percent) was used in the nextstep without further purification. Rf = 0.45 (toluene:EtOAc 1:1)3-Hydroxy-3-methylbutanoic acid (157 muL, 1.24 mmol), HATU (475 mg,1.24 mmol), and DIPEA (207 muL, 1.24 mmol) were added to a solution of compound14 (398 mg, 0.83 mmol) in dry CH2Cl2 (19.5 mL). The reaction mixturewas stirred at rt under argon for 18 h. The reaction mixture was then diluted with CH2Cl2 (20 mL). The organic layer was washed with a saturated NaHCO3 aqueous solution of (2 ×10 mL) water (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography(silica gel, toluene:EtOAc 1:3) to give compound 15 (395 mg; 0.684 mmol; 79.5percentyield over two steps) as a colorless oil.Rf = 0.7 (toluene:EtOAc 1:3); 1H NMR (150 MHz, DMSO-d6): delta 7.98?7.54 (m,5H, Ph), 5.17 (dd, 1H, J3,4 = 10 Hz, H-3), 4.60 (s, 1H, -(CH3)2-OH), 4.46 (d, 1H,J = 7.8 Hz, H-1), 3.83 (1H, CH2b-O (TD)), 3.83 (1H, H-4), 3.59 (1H, H-5), 3.58(3H, CH3-O), 3.53 (1H, CH2a-O (TD)), 3.21 (dd, 1H, J = 7.7 Hz, J2,3 = 17 Hz, H-2),2.12 (NHCOCH2-), 1.58?1.36 (24H, CH2 (TD)), 1.14 (d, 3H, J = 6.3 Hz, H-6), 0.95(s, 6H, -(CH3)2-OH), 0.88 (3H, CH3 (TD)); 13C NMR (600.13 MHz, DMSO-d6):delta 171.0 (NH-CO-CH2), 165.7 (OCO-Ph), 133.3?128.6 (Ph), 102.1 (C-1), 81.5 (C-2), 74.5 (C-3), 69.8 (C-5), 68.7 (CH2-O (TD)), 68.3 (-CH2-C-(CH3)2-), 59.6 (CH3-O), 54.0 (C-4), 48.53 (NHCOCH2-), 31.2?22.0 (CH2 (TD)), 28.8 (-(CH3)2-OH),17.6 (C-6), 13.9 (CH3 (TD)); MS-ESI (m/z) Calcd. for C33H55NO7Na (M+Na+)600.4, Found 600.4; HRMS Calcd. for C33H55NO7Na (M+Na+) 600.3877, Found600.3881.

Reference： [1]Journal of Carbohydrate Chemistry,2016,vol. 35,p. 69 - 85

53
[ 625-08-1 ]
(3aS,6aR)-2-(1-(2-fluorophenyl)-1H-indazol-4-yl)hexahydropyrrolo[3,4-c]pyrrol-1(2H)-one [ No CAS ]
(3aS,6aR)-2-[1-(2-fluorophenyl)-1H-indazol-4-yl]-5-(3-hydroxy-3-methylbutanoyl)hexahydropyrrolo[3,4-c]pyrrol-1(2H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In tetrahydrofuran; at 20℃; for 3h;	To a solution of the product of Example 34C (1.36 g, 4.04 mmol), beta-hydroxyisovaleric acid (0.48 ml, 4.45 mmol) and N-ethyl-N-isopropylpropan-2-amine (2.8 ml, 16.2 mmol) in tetrahydrofuran (30 ml) was added dimethylamino-N,N'-dimethyl(3-oxido-1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)methaniminium hexafluorophosphate (HATU, 1.69 g, 4.45 mmol) portionwise over 15 minutes. This mixture was allowed to stir at ambient temperature for 3h and then was quenched with H2O (10 ml) and diluted with ethyl acetate (10 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 10 ml). The combined organic fractions were dried over anhydrous Na2SO4 filtered and concentrated. The residue was purified via column chromatography (SiO2, 20percent hexanes/ethyl acetate to 100percent ethyl acetate to 15percent methanol in ethyl acetate) to provide the title compound (1.2 g, 2.75 mmol, 68percent yield). H1 NMR (400 MHz, DMSO-d6) delta ppm 8.27(dd, J=2.9,0.7 Hz, 1H), 7.68(td, J=7.9,1.5 Hz, 1H), 7.64-7.52(m, 2H), 7.52-7.42(m, 2H), 7.31-7.22(m, 2H), 4.84(d, J=11.3 Hz, 1H), 4.33(ddd, J=9.9,6.2,3.8 Hz, 1H), 4.04-3.96(m, 1H), 3.93-3.85(m, 1H), 3.82-3.78(m, 2H), 3.61-3.37(m, 2H), 3.31-3.11(m, 1H), 2.48-2.36(m, 2H), 1.19(t, J=5.7 Hz, 6H); MS (ESI-) m/z 435 (M-H)-

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 3373 - 3391
[2]Patent: US2016/264582,2016,A1 .Location in patent: Paragraph 0360

54
[ 625-08-1 ]
(3aS,6aS)-5-[1-(2-fluorophenyl)-1H-indazol-4-yl]hexahydropyrrolo[3,4-b]pyrrol-6(1H)-one [ No CAS ]
(3aS,6aS)-5-[1-(2-fluorophenyl)-1H-indazol-4-yl]-1-(3-hydroxy-3-methylbutanoyl)hexahydropyrrolo[3,4-b]pyrrol-6-(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; for 0.5h;	To a 1L round bottom flask with the product of Example 2I (21.0 g, 62.6 mmol) in N,N'-dimethylformamide (100 ml), 3-hydroxy-3-methylbutanoic acid (9.46 ml, 75 mmol) and triethylamine (9.60 ml, 68.9 mmol) was added a N,N'-dimethylformamide (25 ml) solution of (dimethylamino)-N,N'-dimethyl(3-oxido-1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)methaniminium hexafluorophosphate (HATU, 26.2 g, 68.9 mmol). The reaction mixture was allowed to stir for 30 minutes and then was poured into ethyl acetate (500 ml) and transferred to a separatory funnel. The material was washed with water (100 ml) and brine (100 ml) and the organic layer was dried over anhydrous Na2SO4 filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, eluted with heptane/ethyl acetate 0-100percent over 30 minutes with 60 minute hold) to provide a 98:2 mixture of enantiomers as assessed by chiral supercritical fluid chromatography analysis using a Chiralcd® OD-H column eluting with 5-50percent methanol/CO2 at 3 ml/minute at 50 bar over 10 minutes. The material was further purified on a preparative Chiralcel® OD-H column eluting with 30percent methanol/CO2 at 80 ml/minute to give the title compound (17.01 g, 39mmol, 62percentyield). [alpha]D20°C -119. 20° (c 0.25, methanol); H1 NMR (500 MHz, DMSO-d6) delta ppm 8.35(d, J=1.0 Hz, 1H), 7.69(td, J=7.9,1.8 Hz, 1H), 7.65-7.41(m, 4H), 7.37-7.22(m, 2H), 5.12(d, J=8.0 Hz, 1H), 4.96(s, 1H), 4.30(ddd, J=9.9,6.4,3.6Hz, 1H), 3.78-3.45(m, 3H), 3.27-3.14(m, 1H), 2.82(d, J=15.1 Hz, 1H), 2.72(d, J=15.0 Hz, 1H), 2.40-2.19(m, 1H), 1.87(dq, J=13.0,9.0 Hz, 1H), 1.22(d, J=11.8 Hz, 6H); MS (DCI) m/z 437 [M+H]+

Reference： [1]Patent: US2016/264582,2016,A1 .Location in patent: Paragraph 0313
[2]Journal of Medicinal Chemistry,2016,vol. 59,p. 3373 - 3391

55
[ 625-08-1 ]
4-bromodeacetyl colchicine [ No CAS ]
4-bromo-N-(3-hydroxy-3-methylbutyryl)deacetyl colchicine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98.4%		Beta-hydroxy isovaleric acid (41 mg, 0.29x1.2 mmol) was dissolved in N.N-dimethylformamide (0.8 mL). 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (67 mg, 0.29x1.2 mmol) and 1-hydroxybenzotriazole monohydrate (47 mg, 0.29x1.2 mmol) were added, and stirred at room temperature for 30 minutes. 4-bromodeacetyl colchicine (127 mg, 0.29 mmol) was added, and stirred at 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 saturated sodium chloride solution, and dried with anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by Silica gel column chromatography (Biotage IsoleraOne, SANP 10 g, chloroform/methanol) to obtain title compound (a yellow solid, 153 mg, 98.4percent) .

Reference： [1]Patent: JP5829520,2015,B2 .Location in patent: Paragraph 0293

56
[ 625-08-1 ]
[ 1267986-38-8 ]
4-chloro-N-(3-hydroxy-3-methylbutyryl)deacetyl colchicine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%		Beta-hydroxy isovaleric acid (16 mul, 0.128 x 1.2 mmol) was dissolved in N.N-dimethylformamide (1 mL) under argon atmosphere, and cooled at 0 degree C. 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (29 mg, 0.128 x 1.2 mmol), 1-hydroxybenzotriazol monohydrate (21 mg, 0.128 x 1.2 mmol) was added, and stirred at 0 degree C for 30 minutes. 4-chloro deacetyl colchicine (50 mg, 0.128 mmol) was added, and stirred at room temperature for 3 hours. Water was added and reaction mixture was quenched, ethyl acetate was added, and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The ethyl acetate layer was dried with anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by Silica gel chromatography (Biotage Isolera One and SNAP 10 g, methanol/chloroform) to obtain title compound (white solid and 33 mg, 0.067 mmol, 52percent) .

Reference： [1]Patent: JP5829520,2015,B2 .Location in patent: Paragraph 0250

57
[ 625-08-1 ]
(3aS,6aR)-2-(1-(2-fluorophenyl)-1H-indazol-4-yl)hexahydropyrrolo[3,4-c]pyrrol-1(2H)-one [ No CAS ]
(3aS,6aR)-5-acetyl-2-[1-(2-fluorophenyl)-1H-indazol-4-yl]hexahydropyrrolo[3,4-c]pyrrol-1(2H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 4 - 9.4℃; for 1.15h;	To a solution of beta-hydroxyisovaleric acid (3.59 ml, 33.4 mmol, 45percent acetic acid impurity) and the product of Example 34C (10.2 g, 30.4 mmol) in N,N'-dimethylformamide (130 ml) at 4°C was added N,N'-diisopropylethylamine (21.5 ml, 124 mmol) followed by dimethylamino-N,N'-dimethyl(3-oxido-1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)methaniminium hexafluorophosphate (HATU, 12.7 g, 33.4 mmol) in N,N'-dimethylformamide (100 ml) dropwise. The HATU was added over 60 minutes and the temperature increased to 9.4°C after the addition was complete. The reaction mixture was allowed to stir for 15 minutes and then was poured into saturated aqueous NaHCO3 (100 ml) and was stirred for 5 minutes. The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 100 ml). The combined organic fractions were dried over anhydrous Na2SO4 filtered and concentrated under reduced pressure. The residue was purified via column chromatography (SiO2, eluted with a gradient 0-100percent ethyl acetate over 60 minutes with a 30 minute hold and then eluted with ethyl acetate/10percent methanol for 45 minutes with a 60 minute hold) to give the title compound (4.85 g, 12.82 mmol, 42percent yield) from the acetic acid impurity in the beta-hydroxyisovaleric acid. H1 NMR (400 MHz, DMSO-d6) delta ppm 8.27(ddd, J=17.0,3.7,0.8 Hz, 1H), 7.81-7.38(m, 5H), 7.36-7.19(m, 2H), 4.39-4.20(m, 1H), 4.10-3.99(m, 1H), 3.84(qdd, J=13.2,10.8,8.4 Hz, 2H), 3.69(dd, J=9.7,3.0 Hz, 1H), 3.61-3.40 (m, 1H), 3.28-3.08(m, 1H), 2.00(d, J=8.9 Hz, 3H), 1.28-1.00(m, 1H); MS (ESI+) m/z 379 [M+H]+

Reference： [1]Patent: US2016/264582,2016,A1 .Location in patent: Paragraph 0372

58
[ 625-08-1 ]
(3aR,6aR)-5-[1-(2-fluorophenyl)-1H-indazol-4-yl]hexahydropyrrolo[3,4-b]pyrrol-6(1H)-one [ No CAS ]
(3aR,6aR)-5-[1-(2-fluorophenyl)-1H-indazol-4-yl]-1-(3-hydroxy-3-methylbutanoyl)hexahydropyrrolo[3,4-b]pyrrol-6-(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In acetonitrile; for 2h;	To 3-hydroxy-3-methylbutanoic acid (0.287 ml,2.68 mmol) the product of Example 1Q (0.6 g, 1.784 mmol) and triethylamine (0.298 ml, 2.141 mmol) in acetonitrile (10 ml) was added (dimethylamino)-N,N'-dimethyl(3-oxido-1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)methaniminium hexafluorophosphate (HATU, 0.814 g, 2.141 mmol). The reaction was allowed to stir for 2 hours and then the mixture was diluted with ethyl acetate (25 ml). The material was washed with water (20 ml) and brine (20 ml) dried over anhydrous MgSO4 filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 5percent methanol in ethyl acetate) to afford the title compound (0.70 g, 1.60 mmol, 90percent yield). [alpha]D20, +120°(c 1.0, methanol); H1 NMR (400 MHz, methanol-d4) delta ppm 8.27(dd, J=11.2,1.0 Hz, 1H), 7.62(td, J=7.8,1.7 Hz, 1H), 7.60-7.53(m, 1H), 7.51(dd, J=8.5,7.4 Hz, 1H), 7.46-7.38(m, 2H), 7.31(dt, J=8.2,3.6 Hz, 1H), 7.25(dd, J=7.5,6.1 Hz, 1H), 5.20(dd, J=26.8,8.1 Hz, 1H), 4.36(dt, J=10.1,6.5 Hz, 1H), 3.85-3.60(m, 3H), 3.20(q, J=7.3 Hz, 1H), 2.92(q, J=15.2 Hz, 1H), 2.72-2.54(m, 1H), 2.51-2.35(m, 1H), 2.21-1.86(m, 1H), 1.39-1.28(m, 7H); MS (ESI) m/z 437 [M+H]+

Reference： [1]Patent: US2016/264582,2016,A1 .Location in patent: Paragraph 0302

59
[ 625-08-1 ]
5-[1-(2-fluorophenyl)-1H-indazol-4-yl]hexahydropyrrolo[3,4-b]pyrrol-6-(1H)-one [ No CAS ]
(3aS,6aS)-5-[1-(2-fluorophenyl)-1H-indazol-4-yl]-1-(3-hydroxy-3-methylbutanoyl)hexahydropyrrolo[3,4-b]pyrrol-6-(1H)-one [ No CAS ]
(3aR,6aR)-5-[1-(2-fluorophenyl)-1H-indazol-4-yl]-1-(3-hydroxy-3-methylbutanoyl)hexahydropyrrolo[3,4-b]pyrrol-6-(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29%; 27%	With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 0.333333h;	To the product of Example 1G (312 mg, 0.928 mmol) in N,N'-dimethylformamide (10 ml) was added 3-hydroxy-3-methylbutanoic acid (110mg, 0.928 mmol), triethylamine (0.129 ml, 0.928 mmol) and (dimethylamino)-N,N'-dimethyl-(3-oxido-1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)methaniminium hexafluorophosphate (HATU, 353 mg, 0.928 mmol). The mixture was stirred at ambient temperature for 20 minutes and then was poured into ethyl acetate (50 ml) in a separatory flannel. The mixture was washed with water (25 ml) and brine (25 ml) dried over anhydrous Na2SO4 filtered and concentrated under reduced pressure. The residue was purified via column chromatography (SiO2, eluted with heptaneethyl acetate-100percent over 30 minutes with 60 minute hold) to provide a racemic mixture of the title compound. The enantiomers were separated by supercritical fluid chromatography (SFC) using a Chiracel® OD-H column eluted at 80 ml/minute with methanol/CO2 to give the pure enantiomers with the first eluting compound being the title compound (26 mg, 0.06 mmol, 27percent yield). H1 NMR (500 MHz, DMSO-d6) delta ppm 8.35(d, J=0.8 Hz, 1H), 7.70(dt, J=5.9,2.9 Hz, 1H), 7.64-7.41(m, 5H), 7.37-7.27(m, 2H), 5.16(dd, J=37.6,8.1 Hz, 1H), 4.31(dt, J=13.4,4.9 Hz, 1H), 3.79-3.67(m, 1H), 3.58-3.47(m, 1H), 3.28-3.14(m, 1H), 3.10-3.00(m, 1H), 2.82(d, J=15.0 Hz, 1H), 2.71(d, J=15.0 Hz, 1H), 2.29(dddd, J=15.0,11.6,9.8,5.7Hz, 1H), 1.99-1.77(m, 1H), 1.22(t, J=9.7 Hz, 6H); MS (DCI) m/z 437 [M+H]+ The title compound was the second eluting isomer from Example 1H (3aS,6aS)-5-[1-(2-fluorophenyl)-1H-indazol-4-yl]-1-(3-hydroxy-3-methylbutanoyl)hexahydropyrrolo[3,4-b]pyrrol-6(1H)-one (28 mg, 0.064 mmol, 29percent yield). H1 NMR (500 MHz, DMSO-d6) delta ppm 8.35(d, J=0.8 Hz, 1H), 7.70(dt,J=5.9,2.9 Hz, 1H), 7.64-7.41(m, 5H), 7.37-7.27(m, 2H), 5.16(dd, J=37.6,8.1 Hz, 1H), 4.31(dt, J=13.4,4.9 Hz, 1H), 3.79-3.67(m, 1H), 3.58-3.47(m, 1H), 3.28-3.14(m, 1H), 3.10-3.00(m, 1H), 2.82(d, J=15.0 Hz, 1H), 2.71(d, J=15.0Hz, 1H), 2.29(dddd, J=15.0,11.6,9.8,5.7Hz, 1H), 1.99-1.77(m, 1H), 1.22(t, J=9.7 Hz, 6H); MS (DCI) m/z 437 [M+H]+

Reference： [1]Patent: US2016/264582,2016,A1 .Location in patent: Paragraph 0292; 0303

60
[ 625-08-1 ]
methyl 2,3-diamino-4,5-difluorobenzoate [ No CAS ]
4,5-difluoro-2-(2-hydroxy-2-methylpropyl)-1H-benzo[d]imidazole-7-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In water; at 120℃; for 16h;Sealed tube;	4,5-difluoro-2-(2-hydroxy-2-methylpropyl)-1H-benzo[d]imidazole-7-carboxylic acid. A mixture of 3-hydroxy-3-methylbutyric acid (1.6 mL, 15.1 mmol) and methyl 2,3-diamino-4,5-difluorobenzoate (1.529 g, 7.56 mmol) in HCl (7.5 mL of a 6 M aqueous soln) stirred at 120° C. in a sealed tube for 16 h. The mixture was cooled to rt and concentrated to remove HCl. The remaining solution was frozen and lyophilized to give the crude desired product. C12H12F2N2O3. 271.1 (M+1).

Reference： [1]Patent: US2016/333009,2016,A1 .Location in patent: Paragraph 1334; 1335

61
[ 625-08-1 ]
[ 1121057-75-7 ]
3-hydroxy-3-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl)butan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
17.8%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 25℃; for 4h;	To a solution of 3-hydroxy-3-methylbutanoic acid (7.94 g, 67.2 mmol), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (14.05 g, 73.3 mmol) and N,N-dimethylpyridin-4- amine (26.1 g, 214 mmol) in DCM (700 mL) was added 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1,2,3,6-tetrahydropyridine, HQ (15 g, 61.1 mmol). The reaction was stirred at 25 °C for 4 h. The reaction was diluted with DCM (500 mL), washed with IN HC1 (400 mL) and brine (400 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (0-100percent EtOAc/hexane) to give the title compound (4 g, 17.8 percent); 1H NMR (400 MHz, CDCl3-d): delta 1.16 - 1.35 (m, 18 H), 2.20 - 2.30 (m, 2 H), 2.42 (d, J=15.44 Hz, 2 H), 3.46 (t, J=5.73 Hz, 1 H), 3.63 (t, J=5.51 Hz, 1 H), 3.97 (q, J=2.65 Hz, 1 H), 4.12 (q, J=2.65 Hz, 1 H), 5.27 (d, J=12.35 Hz, 1 H), 6.35 - 6.54 (m, 1 H).

Reference： [1]Patent: WO2016/168641,2016,A1 .Location in patent: Page/Page column 206

62
[ 625-08-1 ]
[ 1121057-75-7 ]
3-methoxy-3-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl)butan-1-one [ No CAS ]

Reference： [1]Patent: WO2016/168641,2016,A1

63
[ 625-08-1 ]
C₃₁H₂₇N₅O [ No CAS ]
1-(4-(1-(3-hydroxy-3-methylbutanoyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-3-methyl-8-(quinolin-3-yl)-1H-imidazo[4,5-c]quinolin-2-(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 12h;	A solution of 0.5 g (l · 3 mmol) of Intermediate 27 was dissolved in 10 ml of dichloromethane solvent, and Et3N 0.3 ml(2.15 mmol), and 0.39 ml (3.1 mmol)bete-hydroxyisovaleric acid10 ml of dichloromethane, add EDCI(0.298, 1.51 mmol),HOBT (0.21 g, 1.5 mmol) was dissolved with stirring, and the above-mentioned standby solution was added, stirred at room temperature for 12 h,TLC detection, the end of the reaction, directly spin dry concentrated crude, crude silica gel G column chromatography [eluent (methanol: dichloromethane) =1: 30). Example 24 - (: 0.3 g of the title compound, yield 50.0percent).

Reference： [1]Patent: CN104411706,2016,B .Location in patent: Paragraph 0374-0376

64
[ 625-08-1 ]
(6RS)-6-amino-3-anilino-2-(pyridin-4-yl)-1,5,6,7,7-tetrahydro-4H-indol-4-one hydrochloride [ No CAS ]
3-hydroxy-3-methyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]butanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
9 mg	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 18 - 23℃; for 2h;	A mixture compdsngy]pyddnum chodde (5; 40 mg, 102 pmo), DMF (1.5 mL), DPEA (107 pL, 613 pmo), 3-hydroxy-3-methybutanocacd (33 pL, 307pmo) and T3P (184 iL, 50percent n DMF)was slirred at RTfor2 h.The mxture was ffltered and purified by prepararive HPLC (basic method) to give the titlecompound (9 mg, 20percent). 1H NMR (400 MHz, DMSO-d6) oe ppm 1.14 (6H), 2.21 (2H), 2.45 (1H), 2.53 (1H), 2.88 (1H), 3.17 (1H), 4.36 (1H), 4.73 (1H), 6.60 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.46 (2H), 8.21 (1H), 8.42 (2H), 11.97 (1H)

Reference： [1]Patent: WO2016/202755,2016,A1 .Location in patent: Page/Page column 122; 187; 188

65
[ 625-08-1 ]
6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile [ No CAS ]
4-(6-(4-(3-hydroxy-3-methylbutanoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;	To a solution of 6-(i-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-i-yl)pyridin-3-yl)pyrazolo[i,5-a]pyridine-3-carbonitrile (50 mg, 0.130 mmol) in DMF (4.34 mL) were added 3- hydroxy-3-methylbutanoic acid (210 jiL, 0. 195 mmol), DMAP (55.6 mg, 0.455 mmol), and EDCHC1 (3 i.2 mg, 0. i63 mmol). After stirring overnight at ambient temperature, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting crude residue was purified by silica chromatography (0-50percent, 20percent MeOHIDCM in EtOAc) to providethe title compound (51.1 mg, 80percent yield).MS (apci) m/z = 485.i (M+H).?HNMR (CDC13)?HNMR (CDC13)8.63 (d, iH), 8.37 (d, iH), 8.25 (s, iH), 7.77 (d, iH), 7.75 (d, iH), 7.67 (s, iH), 7.38 (s, iH), 6.78 (d, iH), 3.98 (s, 3H), 3.80 (m, 2H), 3.75 (m, 2H), 3.63 (m, 4H), 2.50 (s, 2H), 1.31 (s, 6H).

Reference： [1]Patent: WO2017/11776,2017,A1 .Location in patent: Paragraph 00832; 00833; 00834

66
[ 625-08-1 ]
4-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile dihydrochloride [ No CAS ]
4-(6-(4-(3-hydroxy-3-methylbutanoyl)-4,7-diazaspiro[2.5]octan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 48h;	DIEA (22 tL, 0.12 mmol), 3-hydroxy-3-methylbutanoic acid (4.9 mg, 0.041 mmol),and HATU (12 mg, 0.031 mmol) were added sequentially to a solution of 4-(6-(4,7- diazaspiro[2. 5]octan-7-yl)pyridin-3-yl)-6-(i -methyl- 1H-pyrazol-4-yl)pyrazolo[ 1 ,5-a]pyridine-3- carbonitrile dihydrochloride (10 mg, 0.021 mmol) in ACN (0.4 mL). The reaction mixture was stirred for 2 d at ambient temperature and then directly purified by reverse phase chromatography (5-75percent ACN/water) to afford the title compound (10.8 mg, 98percent yield). MS (apci) m/z = 511.1 (M+H).

Reference： [1]Patent: WO2017/11776,2017,A1 .Location in patent: Paragraph 00933; 00934; 00935

67
[ 625-08-1 ]
6-(1-methyl-1H-pyrazol-4-yl)-4-(5-methyl-6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile dihydrochloride [ No CAS ]
4-(6-(4-(3-hydroxy-3-methylbutanoyl)piperazin-1-yl)-5-methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%		3-hydroxy-3-methylbutanoic acid (4.51 mg, 0.0382 mmol) and HATU (14.5 mg,0.0382 mmol) were dissolved in DMA (159 tL) and the mixture was stirred at ambient temperature for 10 mi 6-( i-methyl- 1H-pyrazol-4-yl)-4-(5-methyl-6-(piperazin- 1 -yl)pyridin-3 - yl)pyrazolo[i,5-a]pyridine-3-carbonitrile dihydrochloride (Example 276, 15 mg, 0.03 18 mmol) was added in one portion followed by DIEA (27.7 tL, 0.159 mmol). After stirring for 45 mm, the reaction mixture was directly purified by reverse-phase chromatography (5-60percent ACN/water) to afford the title compound (10.2 mg, 62percent yield). MS (apci) m/z = 499.2 (M+H).

Reference： [1]Patent: WO2017/11776,2017,A1 .Location in patent: Paragraph 001197; 001198; 001199

68
[ 625-08-1 ]
2-((1R,2R)-2-aminocyclohexyl)-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)isoindolin-1-one hydrochloride [ No CAS ]
3-hydroxy-3-methyl-N-((1R,2R)-2-(1-oxo-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-1,3-dihydro-2H-isoindol-2-yl)cyclohexyl)butanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47.7 mg	With 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium; triethylamine; In ethanol; at 10 - 35℃;	A mixture of 2-((1R,2R)-2-aminocyclohexyl)-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)isoindolin-1-one hydrochloride (200 mg), 3-hydroxy-3-methylbutanoic acid (82 mg), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium (206 mg), TEA (201 mg) and ethanol (5 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (47.7 mg). (1284) 1H NMR (300 MHz, CDCl3) delta 0.82 (3H, s), 1.02 (3H, s), 1.32-1.53 (3H, m), 1.64-1.78 (1H, m), 1.81-2.02 (3H, m), 2.04-2.27 (3H, m), 3.92-4.30 (3H, m), 4.38-4.54 (1H, m), 4.60-4.78 (1H, m), 6.23 (1H, d, J=9.1 Hz), 7.63 (1H, d, J=8.7 Hz), 8.30 (1H, dd, J=7.9, 1.5 Hz), 8.55 (1H, d, J=0.8 Hz)

Reference： [1]Patent: US2017/15655,2017,A1 .Location in patent: Paragraph 1283-1284

69
[ 625-08-1 ]
N-(4-(piperidin-4-yl)phenyl)isoindoline-2-carboxamide hydrochloride [ No CAS ]
N-(4-(1-(3-hydroxy-3-methylbutanoyl)piperidin-4-yl)phenyl)isoindoline-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
144 mg	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;	A suspension of N-(4-(piperidin-4-yl)phenyl)isoindoline-2-carboxamide (400 mg, 1.244 mmol), 3-hydroxy-3-methylbutanoic acid (184 mg, 1.556 mmol), 1-hydroxybenzotriazole hydrate (262 mg, 1.711 mmol) and N-methylmorpholine (0.428 ml, 3.89 mmol) in dimethylformamide (10 ml) at room temperature was treated with N-(3-dimethylaminopropyl)-N?-ethylcarbodiimide hydrochloride (537 mg, 2.80 mmol). The suspension, which slowly dissolved over 1 h, was stirred overnight and then added to 100 ml water and 50 ml ethyl acetate; the separated aqueous layer was extracted with ethyl acetate (2 x 30 ml) and the combined organic layers were washed with brine (25 ml), dried with MgSO4, filtered and concentrated. The crude residue was flash chromatographed (50 mm silica column; 2percent MeOH/CH2Cl2) to give 144 mg (27percent yield) of the title compound as a white solid (note: this was a particularly poor coupling and not representative of other piperidinyl amides). 1H NMR (300 MHz, DMSO-d6) delta 8.26 (s, 1H), 7.52 ? 7.42 (m, 2H), 7.42 ? 7.26 (m, 4H), 7.18 ? 7.07 (m, 2H), 4.92 (s, 1H), 4.75 (s, 4H), 4.60 (d, J = 13.0 Hz, 1H), 4.10 (d, J = 13.5 Hz, 1H), 3.16 ? 3.00 (m, 1H), 2.78 ? 2.52 (m, 2H), 1.78 (d, J = 13.0 Hz, 2H), 1.47 (dqd, J = 37.3, 12.6, 4.0 Hz, 2H), 1.19 (s, 6H). MS (ESI(+)) m/e 422 (M+H)+.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 3317 - 3325

70
[ 625-08-1 ]
9-[2-(aminomethyl)-5-chloro-1H-indol-7-yl]methyl}-9H-purin-6-amine [ No CAS ]
N-({7-[(6-amino-9H-purin-9-yl)methyl]-5-chloro-1H-indol-2-yl}methyl)-3-hydroxy-3-methylbutanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70.9%		A mixture of 3-hydroxy-3-methylbutanoic acid (13.11 muL, 0.122 mmol), HATU (46.4 mg, 0.122 mmol) and N-ethyl-N-isopropylpropan-2-amine (63.9 muL, 0.366 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at ambient temperature for 5 minutes and then treated with Example 9b (40 mg, 0.122 mmol) and stirred at ambient temperature overnight. The mixture was diluted with ethyl acetate (30 mL), washed sequentially with water (2×) and brine, dried over MgSO4, and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (1-10percent methanol in dichloromethane) to give the title compound (37 mg, 0.086 mmol, 70.9percent yield). 1H NMR (400 MHz, DMSO-d6) delta 11.51 (s, 1H), 8.38 (t, J=5.6 Hz, 1H), 8.29 (s, 1H), 8.22 (s, 1H), 7.48 (d, J=1.8 Hz, 1H), 7.30 (s, 2H), 6.82 (d, J=1.9 Hz, 1H), 6.35 (d, J=1.5 Hz, 1H), 5.59 (s, 2H), 4.83 (s, 1H), 4.49 (d, J=5.6 Hz, 2H), 2.31 (s, 2H), 1.19 (s, 6H). MS (ESI+) m/z 428.0 (M+H)+

Reference： [1]Patent: US2017/174688,2017,A1 .Location in patent: Paragraph 0760

71
[ 625-08-1 ]
[ 2854-16-2 ]

Yield	Reaction Conditions	Operation in experiment
85%		5.91 g (50 mmol) of [beta] -hydroxyisovaleric acid was dissolved in 150 mL of THF,After adding 15 mL of N-methylmorpholine, 13.76 g (50 mmol) of diphenyl azide was added dropwise at room temperature,After 15 min dripping, the reaction was stirred for 4 h.Then add 60 mL of distilled water, stir and reflux for 2 h.After the reaction, the THF was evaporated under reduced pressure.Add 30 mL of ethyl acetate, stir,Adjust the pH to 2-3. The two phases were separated and the aqueous phase was extracted twice with ethyl acetate twice. The aqueous phase was further added 30 mL of ethyl acetate,Adjust the pH to 9 or so. Separate the two phases, extracted twice with water, 15 mL each time. Dried Na2SO4 and evaporated to dryness to obtain 3.79 gProduct (yield 85percent).

Reference： [1]Patent: CN106496085,2017,A .Location in patent: Paragraph 0018; 0019; 0023

72
[ 625-08-1 ]
3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[2,3-c]pyridin-4-one [ No CAS ]
6-(3-hydroxy-3-methylbutanoyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[2,3-c]pyridin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl acetamide; at 20℃; for 16h;	A solution of 3-hydroxy-3-methylbutanoic acid (39 mg, 0.33 mmol) and HATU (125 mg, 0,33 mmol) in DMA (1 mL) was added to a mixture of 3-(phenylamino)-2-(pyridin-4-yl)- 1 ,5,6,7-tetrahydro-4H-pyrrolo[2,3-c]pyridin-4-one (14: 50 mg, 0.16 mmol) and DIPEA (57 pL, 0.33 mmol) in DMA (1 mL) and stirred for 16 h at RT. The mixture was concentrated and purified by Biotage (SNAP NH 25g, MeOH:DCM) and digestion with DCM to give the title compound (48 mg, 68percent). 1H-NMR (400 MHz, DMSO-d6), delta [ppm]= 1.17+1 .21 (6H), 2.52+2.60 (2H), 4.17+4.25 (2H), 4.67+4.76 (1 H), 4.90+4.97 (2H), 6.55-6.65 (3H), 7.04 (2H), 7.48-7.54 (3H), 8.46 (2H), 12.24 (1 H)

Reference： [1]Patent: WO2017/102649,2017,A1 .Location in patent: Page/Page column 149

73
[ 625-08-1 ]
(1S,2S)-N-[4-(3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)pyridin-2-yl]-2-fluorocyclopropanecarboxamide [ No CAS ]
(1S,2S)-2-fluoro-N-{4-[6-(3-hydroxy-3-methylbutanoyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl]pyridin-2-yl}cyclopropanecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl acetamide; at 20℃; for 16h;	A solution of 3-hydroxy-3-methylbutanoic acid (29 mg, 0.25 mmol) and HATU (94 mg, 0,25 mmol) in DMA (1 ml.) was added to a mixture of (1 S,2S)-N-[4-(3-anilino-4-oxo- 4,5,6,7-tetrahydro-1 H-pyrrolo[2,3-c]pyridin-2-yl)pyridin-2-yl]-2- fluorocyclopropanecarboxamide (197; 50 mg, 0.12 mmol) 50 mg, 0.12 mmol) and DIPEA (43 muIota_, 0.25 mmol) in DMA (1 ml_) and stirred for 16 h at RT. The mixture was concentrated and purified by preparative HPLC (basic method) followed by preparative TLC (EtOH:DCM) to give the title compound (33 mg, 51 percent). 1H-NMR (400 MHz, DMSO-d6), delta [ppm]= 1.13-1 .26 (7H), 1 .65 (1 H), 2.21 (1 H), 2.53+2.58 (2H), 4.17+4.24 (2H), 4.67+4.74 (1 H), 4.89+4.95 (2H), 4.94 (1 H), 6.57 (2H), 6.60 (1 H), 7.02 (2H), 7.24 (1 H), 7.43+7.44 (1 H), 8.14 (1 H), 8.30 (1 H), 10.78 (1 H), 12.22+12.28 (1 H)

Reference： [1]Patent: WO2017/102649,2017,A1 .Location in patent: Page/Page column 219

74
[ 625-08-1 ]
N-{4-[4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl]pyridin-2-yl}acetamide [ No CAS ]
N-{4-[3-anilino-6-(3-hydroxy-3-methylbutanoyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl]pyridin-2-yl}acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl acetamide; at 20℃; for 3h;	A solution of 3-hydroxy-3-methylbutanoic acid (33 mg, 0.28 mmol) and HATU (105 mg, 0,28 mmol) in DMA (1 mL) was added to a mixture of N-{4-[4-oxo-3-(phenylamino)- 4,5,6,7-tetrahydro-1 H-pyrrolo[2,3-c]pyridin-2-yl]pyridin-2-yl}acetamide (24; 50 mg, 0.14 mmol) and DIPEA (48 pL, 0.28 mmol) in DMA (1 mL) and stirred for 3 h at RT. The mixture was concentrated and purified by preparative TLC (silica, MeOH:DCM) and digested with diethyl ether to give the title compound (30 mg, 46percent). 1H-NMR (400 MHz, DMSO-d6), delta [ppm]= 1.17+1 .21 (6H), 2.08 (3H), 2.53+2.59 (2H), 4.16+4.23 (2H), 4.68+4.75 (1 H), 4.89+4.95 (2H), 6.56 (2H), 6.59 (1 H), 7.02 (2H), 7.22 (1 H), 7.41 +7.42 (1 H), 8.13 (1 H), 8.28 (1 H), 10.40 (1 H), 12.21 +12.24 (1 H)

Reference： [1]Patent: WO2017/102649,2017,A1 .Location in patent: Page/Page column 207

75
[ 625-08-1 ]
2-((1r,4r)-4-(2-(aminomethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile hydrochloride [ No CAS ]
N-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)-3-hydroxy-3-methylbutanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 10℃; for 0.5h;	HATU (100 mg, 0.264 mmol) was added to a solution of 2-((lr,4r)-4-(2-(aminomethyl)imidazo[4, 5 -d]pyrrolo[2, 3 -b]pyridin- 1 (61])-yl)cyclohexyl)acetonitrilehydrochloride (Intermediate 5, 100 mg, 0.264 mmol, purity 91percent), beta-hydroxyisovaleric acid (31.2 mg, 0.264 mmol), DIEA (0.230 mL, 1.32 mmol), and CH2C12 (5 mL) and was stirred for 0.5 h at 10 °C. The reaction was diluted with CH2C12 (10 mL), washed with water (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was initiallypurified by preparative TLC (eluent: CH2C12: methanol = 10:1). The residue was then furtherpurified by preparative HPLC using an Agela DuraShell 150 mm x 25 mm, Sjim column (eluent:8percent to 38percent (v/v) CH3CN and H20 with 10mM NH4HCO3) to provide the title compound (30 mg,28percent yield). MS (ESI): mass calcd. for C22H28N602, 408.23; m/z found, 409.2 [M+H]t ?HNIVIR(400IVIHz, DMSO-d6): oe 11.89 (s, 1H), 8.53 (s, 1H), 8.52-8.47 (m, 1H), 7.48 (t, J 2.8Hz, 1H), 6.72 (s, 1H), 4.87 (s, 1H), 4.69 (d, J= 5.2 Hz, 2H), 4.61 -4.47 (m, 1H), 2.59 (d, J 6.0Hz, 2H), 2.42-2.32 (m, 2H), 2.30 (s, 2H), 2.10- 1.86 (m, 5H), 1.48 - 1.31 (m, 2H), 1.19 (s, 6H).

Reference： [1]Patent: WO2018/112382,2018,A1 .Location in patent: Page/Page column 239; 240

76
[ 625-08-1 ]
8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-(piperazin-1-yl)-9H-purine [ No CAS ]
4-{4-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]piperazin-1-yl}-2-methyl-4-oxobutan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%	With triethylamine; at 20℃;	General procedure: To a solution of 8 (0.2 mmol, 1 equiv) in CH2Cl2 (2 mL) were added NEt3 (0.6 mmol, 3 equiv), N,N,N?,N?-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU, 0.26 mmol, 1.3 equiv) and the appropriate carboxylic acid (1.25 equiv). The reaction was stirred overnight and then concentrated. The crude material was purified by silica gel column chromatography using a gradient of 0-100percent EtOAc/hexanes.

Reference： [1]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 4518 - 4531

77
[ 625-08-1 ]
[ 62-53-3 ]
[ 99985-75-8 ]

Reference： [1]Organic Letters,2018,vol. 20,p. 7371 - 7374

78
[ 625-08-1 ]
[ 90-04-0 ]
C₁₂H₁₇NO₃ [ No CAS ]

Reference： [1]Organic Letters,2018,vol. 20,p. 7371 - 7374

79
[ 625-08-1 ]
[ 536-90-3 ]
C₁₂H₁₇NO₃ [ No CAS ]

Reference： [1]Organic Letters,2018,vol. 20,p. 7371 - 7374

80
[ 625-08-1 ]
[ 108-69-0 ]
C₁₃H₁₉NO₂ [ No CAS ]

Reference： [1]Organic Letters,2018,vol. 20,p. 7371 - 7374

81
[ 625-08-1 ]
potassium β-hydroxy-β-methylbutyrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
14.8 g	With potassium hydroxide; In water; at 50℃;pH 8.85;	To 200 mL of the aqueous free HMB solution obtained in Reference Example 1, 114 mL of an aqueous 1 mol/L potassium hydroxide solution was added to adjust the pH to 8.85. 314 mL of the aqueous solution was concentrated under reduced pressure at 50° C. and 10 mbar to remove the solvent, and a crystal of potassium HMB was thereby caused to naturally develop. The crystal slurry was further vacuum-dried to obtain 14.8 g of a crystal.

Reference： [1]Patent: US2018/327344,2018,A1 .Location in patent: Paragraph 0104

82
[ 625-08-1 ]
[ 1019918-39-8 ]
N'-(4-bromopyridin-2-yl)-3-hydroxyl-3-methylbutanehydrazide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In tetrahydrofuran; at 20℃;	To a solution of 3 -hydroxy-3 -methylbutanoic acid (1.17 g, 9.9 mmol) and 4- bromo-2-hydrazinylpyridine (1.44 g, 7.7 mmol) in THF (20 mL) were added triethylamine (2.8 mL, 20.0 mmol) and HATU (4.62 g, 12.2 mmol). The reaction mixture was stirred at rt overnight and concentrated in vacuo. The residue was purified by a silica gel column chromatography (MeOH/DCM (v/v) = 1/30) to give the title compound as a white solid (1.66 g, 75percent).MS (ESI, pos. ion) m/z: 288.0 [M+H]+.
75%	With triethylamine; HATU; In tetrahydrofuran; at 20℃;	To 3-hydroxy-3-methylbutyric acid (1.17 g, 9.9 mmol)And 4-bromo-2-hydrazino pyridine (1.44g, 7.7mmol)Add in THF (20mL) solutionTriethylamine (2.8 mL, 20.0 mmol)And O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.62 g, 12.2 mmol).The reaction mixture was stirred at room temperature overnight.It was then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/30).The title compound was obtained as a white solid (1.66 g, 75percent).

Reference： [1]Patent: WO2019/99311,2019,A1 .Location in patent: Paragraph 000643
[2]Patent: CN109776522,2019,A .Location in patent: Paragraph 1815; 1819; 1820; 1821

83
[ 18267-36-2 ]
[ 625-08-1 ]

Yield	Reaction Conditions	Operation in experiment
93%	With water; sodium hydroxide; at 20℃;	To a solution of ethyl 3 -hydroxy-3 -methylbutanoate (1.56 g, 10.7 mmol) in water (20 mL) was added hydroxyl sodium (851.0 mg, 21.3 mmol). The reaction mixture was stirred at rt overnight and neutralized by concentrated hydrochloric acid to pH = 5, then extracted with EtOAc (50 mL c 3). The combined organic phases were dried over Na2S04 and concentrated in vacuo to give the title compound as yellow oil (1.17 g, 93percent).
93%	With sodium hydroxide; In water; at 20℃;	toEthyl 3-hydroxy-3-methylbutanoate (1.56 g, 10.7 mmol)In water (20mL) solutionSodium hydroxide (851.0 mg, 21.3 mmol).The reaction mixture was stirred at room temperature overnight.It was then adjusted to pH = 5 with hydrochloric acid and extracted with EtOAc (50 mL×3).The combined organic phases were dried over anhydrous sodium sulfate.Filter and concentrate under reduced pressure.The title compound is yellowOil (1.17 g, 93percent).

Reference： [1]Patent: WO2019/99311,2019,A1 .Location in patent: Paragraph 000642
[2]Patent: CN109776522,2019,A .Location in patent: Paragraph 1815; 1817; 1818

84
[ 67-56-1 ]
[ 625-08-1 ]
[ 6149-45-7 ]

Yield	Reaction Conditions	Operation in experiment
43.8%	With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; for 16h;	3-Hydroxy-3-methylbutyric acid (Compound 3) (20 g, 170 mmol, 1.0 eq) was dissolved in dichloromethane (400 mL), and triethylamine (51.5 g, 510 mmol, 3.0 eq) and methanol (16.3 g, 510 mmol, 3.0 eq) and HATU (95.6 g, 254 mmol, 1.5 eq), and the reaction was stirred at room temperature for 16 hours. After that, the reaction solution was washed with a saturated aqueous sodium hydrogen carbonate solution (200 mL × 3), and then dried over anhydrous Na 2 SO 4, and the solvent was removed by rotary evaporation under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain 9.80 g of a pale yellow oil (compound 4) with a yield of 43.8%.

Reference： [1]Patent: CN110372612,2019,A .Location in patent: Paragraph 0060; 0063-0064; 0075; 0078-0079; 0090; 0093-0094

85
[ 13635-04-6 ]
[ 625-08-1 ]

Yield	Reaction Conditions	Operation in experiment
26%	With water In aq. phosphate buffer at 37℃; for 24h; Enzymatic reaction;	Enzymatic hydrolysis of 3-hydroxy-3-methylbutyronitrile 3-hydroxy-3-methylbutyronitrile (54 mg, 0.54 mmol) was placed in a reaction vessel and dissolved in phosphate buffer (5 ml_, pH = 7, potassium dihydrogen phosphate / dipotassium hydrogen phosphate). A sample of 500 pL of the thus-obtained solution was mixed with nitrilase solution (10 mI_), NIT59 and NIT60 (c-LEcta, Leipzig), respectively. The reaction mixture was shaken for 24 h at 37°C. Product yields: Hydrolysis with enzyme NIT59: 20%; Hydrolysis with enzyme NIT60: 26%

Reference： [1]Current Patent Assignee: EVONIK INDUSTRIES AG - WO2020/200952, 2020, A1 Location in patent: Page/Page column 8-9

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	625-08-1	MDL No. :
Formula :	C₅H₁₀O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	AXFYFNCPONWUHW-UHFFFAOYSA-N
M.W :	118.13	Pubchem ID :	69362
Synonyms :	β-Hydroxy-β-methylbutyric Acid;β-Hydroxyisovaleric Acid;AUN-25081	Chemical Name :	3-Hydroxy-3-methylbutanoic acid

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 :	29.12
TPSA :	57.53 Å²

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) :	-7.26 cm/s

Log Po/w (iLOGP) :	0.95
Log Po/w (XLOGP3) :	-0.34
Log Po/w (WLOGP) :	0.23
Log Po/w (MLOGP) :	0.01
Log Po/w (SILICOS-IT) :	-0.29
Consensus Log Po/w :	0.11

[ CAS No. 625-08-1 ] {[proInfo.proName]}

Quality Control of [ 625-08-1 ]

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Calculated chemistry of [ 625-08-1 ]

Physicochemical Properties

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Medicinal Chemistry

Safety of [ 625-08-1 ]

Application In Synthesis of [ 625-08-1 ]

[ 625-08-1 ] Synthesis Path-Upstream 1~4

[ 625-08-1 ] Synthesis Path-Downstream 1~85

Precautionary Statements-General

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

Log S (ESOL) :	-0.23
Solubility :	70.2 mg/ml ; 0.594 mol/l
Class :	Very soluble
Log S (Ali) :	-0.41
Solubility :	46.3 mg/ml ; 0.392 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	0.14
Solubility :	165.0 mg/ml ; 1.4 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.18

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

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