[ CAS No. 832715-51-2 ]

Name: 832715-51-2|Isopropyl 4-hydroxypiperidine-1-carboxylate|98%
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Quality Control of [ 832715-51-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 832715-51-2 ]

Product Details of [ 832715-51-2 ]

CAS No. :	832715-51-2	MDL No. :	MFCD08460168
Formula :	C₉H₁₇NO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UKVIBHRSFKWRPA-UHFFFAOYSA-N
M.W :	187.24	Pubchem ID :	16745126
Synonyms :

Calculated chemistry of [ 832715-51-2 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.89
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	52.91
TPSA :	49.77 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.87 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.29
Log Po/w (XLOGP3) :	0.8
Log Po/w (WLOGP) :	0.61
Log Po/w (MLOGP) :	0.56
Log Po/w (SILICOS-IT) :	0.35
Consensus Log Po/w :	0.92

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.31
Solubility :	9.24 mg/ml ; 0.0493 mol/l
Class :	Very soluble
Log S (Ali) :	-1.43
Solubility :	7.01 mg/ml ; 0.0375 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.31
Solubility :	91.1 mg/ml ; 0.486 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.01

Safety of [ 832715-51-2 ]

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:

Application In Synthesis of [ 832715-51-2 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 832715-51-2 ]
Downstream synthetic route of [ 832715-51-2 ]

[ 832715-51-2 ] Synthesis Path-Upstream 1~1

1
[ 5382-16-1 ]
[ 108-23-6 ]
[ 832715-51-2 ]

Yield	Reaction Conditions	Operation in experiment
92%	With triethylamine In ethyl acetate at 10 - 20℃; for 18 h;	Example 3; Preparation of 4-Hydroxy-Piperidine-1-Carboxylic Acid Isopropyl Ester (5); To a stirred mixture of 4-hydroxypiperidine (53.8 g, 1.000 eq), triethylamine (71.8 g, 1.334 equivalents), and ethyl acetate (498.8 g) was added neat isopropyl chloroformate (78.0 g, 1.1966 equivalents) at a rate sufficiently slow to maintain the reaction mixture temperature at 10°-17° C. with reactor jacket cooling. After the addition had been completed, the reaction mixture was stirred at 20° C. for 18 hours. Then water (100 g) was added, and the resulting mixture was stirred for 15 minutes before the phases were separated. The organic phase was washed with two 100-gram-portions of 20 wt percent aqueous NaCl by stirring for 15 min at 150 rpm before separating the aqueous wash. After a final wash with water (100 g), the organic phase was concentrated by distillation on a rotary evaporator at reduced pressure to provide product (2) (91.1 g, 92.0 percent yield) as light amber oil of 96.8 percent purity by GC. Distillation of this crude product at 117-120° C., 0.3-1.0 torr gave a 95.7 percent recovery of product (2) as a colorless oil collected at 112°-119° C.
92%	With triethylamine In ethyl acetate at 10 - 20℃; for 18 h;	Example 2 Preparation of 4-Hydroxy-Piperidine-1-Carboxylic Acid Isopropyl Ester Intermediate (2) To a stirred mixture of 4-hydroxypiperidine (53.8 g, 1.000 eq), triethylamine (71.8 g, 1.334 equivalents), and ethyl acetate (498.8 g) was added neat isopropyl chloroformate (78.0 g, 1.1966 equivalents) at a rate sufficiently slow to maintain the reaction mixture temperature at 10°-17° C. with reactor jacket cooling. After the addition had been completed, the reaction mixture was stirred at 20° C. for 18 hours. Then water (100 g) was added, and the resulting mixture was stirred for 15 minutes before the phases were separated. The organic phase was washed with two 100-gram-portions of 20 wt percent aqueous NaCl by stirring for 15 min at 150 rpm before separating the aqueous wash. After a final wash with water (100 g), the organic phase was concentrated by distillation on a rotary evaporator at reduced pressure to provide product (2) (91.1 g, 92.0percent yield) as light amber oil of 96.8percent purity by GC.
86%	With N-ethyl-N,N-diisopropylamine In dichloromethane; toluene at 20℃; for 52 h;	Step 9: 1-Methylethyl 4-hydroxy-1 -piperidinecarboxylate (9)To a cold (5 ⁰C) solution of 4-hydroxypiperidine (40.46 g, 0.40 mol) and CH₂CI₂ (500 ml.) was added diisopropylethylamine (140 ml_, 0.80 mol) under N₂. A 1 M solution of isopropyl chloroformate (500 ml_, 0.50 mol) in toluene was added dropwise over a period of 4 h. The resulting reaction mixture was stirred at RT for 48 h. The reaction mixture was washed with water (2 x 100 ml.) and brine (1 x 100 ml_), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by flash <n="68"/>column chromatography to afford 64.60 g (86percent) of the title product 9 as colorless oil. ¹H NMR (400 MHz, DMSOd₆): δ 4.72 (m, 1 H), 3.68 - 3.62 (m, 2 H), 3.60 (septuplet, J = 4.4 Hz, 1 H), 2.96 (br m, 2 H), 1.68 - 1.62 (m, 2 H), 1.26 - 1.18 (m, 2 H), 1.14 (d, J = 6.4 Hz, 6 H).

86%	With triethylamine In ethyl acetate at 0 - 20℃; for 12 h;	Reference Example 2 isopropyl 4-hydroxypiperidine-1-carboxylate; To a mixture cooled to 0°C in an ice bath of 4-hydroxypiperidine (19.0 g, 188 mmol), triethylamine (25.4 g, 251 mmol), and ethyl acetate (250 mL) was added dropwise isopropyl chlorocarbonate (27.6 g, 225 mmol). The reaction mixture was stirred at room temperature for 12 hr. The reaction mixture was washed successively with 2N hydrochloric acid, aqueous potassium carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to give the title compound (30.3 g, yield 86percent) as a colorless oil. ¹H-NMR (300 MHz, CDCl₃)δ:1.24 (d, J = 6. 4 Hz, 6 H), 1. 40 - 1.55 (m, 2 H), 1.78 - 1.94 (m, 2 H), 3.00 - 3.15 (m, 2 H), 3.77-3.97 (m, 3 H), 4.83 - 4.99 (m, 1 H).
83%	With N-ethyl-N,N-diisopropylamine In dichloromethane; toluene at 10 - 15℃; for 4 h;	Example 3.1: Preparation of 4-Hydroxy-piperidine-l-carboxylic Acid Isopropyl Ester; A magnetically stirred solution of 4-hydroxypiperidine (70.3 g, 695 mmol) and NJN- diisopropylethylamine (105 mL, 600 mmol) in dichloromethane (1.0 L) was cooled to 10⁰C under N₂. A solution of isopropyl chloroformate (1.0 M in toluene, 580 mL, 580 mmol) was <n="29"/>added dropwise over 2 h, maintaining a temperature of 10-15 ⁰C. The reaction mixture was stirred for an additional 2 h and then extracted with 1 N HCl (1.2 L). The organic extract was dried over MgSO₄, and the solvent was removed under reduced pressure to give the title compound (90.3 g, 83percent) as a pale straw-colored oil. Exact Mass calculated for CsHi₇NO₃: 187.1, Found: LCMS m/z = 188.2 (M+H⁺), 210.3 (M+Nai); ¹H NMR (400 MHz, CDCl₃) δ 1.24 (d, J=6.3 Hz, 6 H)₅ 1.47 (m, 2 H), 1.86 (m, 2 H), 3.08 (m, 2 H)₅ 3.86 (m, 3 H), 4.90 (m, 1 H).
83%	With N-ethyl-N,N-diisopropylamine In dichloromethane; toluene at 10 - 15℃; for 4 h; Inert atmosphere	Example 3.3 Preparation of 4-Hydroxy-piperidine-1-carboxylic Acid Isopropyl Ester A magnetically stirred solution of 4-hydroxypiperidine (70.3 g, 695 mmol) and N,N-diisopropylethylamine (105 mL, 600 mmol) in dichloromethane (1.0 L) was cooled to 10° C. under N₂. A solution of isopropyl chloroformate (1.0 M in toluene, 580 mL, 580 mmol) was added dropwise over 2 h, maintaining a temperature of 10-15° C. The reaction mixture was stirred for an additional 2 h and then extracted with 1 N HCl (1.2 L). The organic extract was dried over MgSO₄, and the solvent was removed under reduced pressure to give the title compound (90.3 g, 83percent yield) as a pale straw-colored oil. Exact Mass calculated for C₉H₁₇NO₃: 187.1. Found: LCMS m/z=188.2 (M+H⁺), 210.3 (M+Na⁺); ¹H NMR (400 MHz, CDCl₃) δ 1.24 (d, J=6.3 Hz, 6H), 1.47 (m, 2H), 1.86 (m, 2H), 3.08 (m, 2H), 3.86 (m, 3H), 4.90 (m, 1H).

Reference： [1] Patent: US2006/154940, 2006, A1, . Location in patent: Page/Page column 17-18
[2] Patent: US2006/155129, 2006, A1, . Location in patent: Page/Page column 14-15
[3] Patent: WO2008/8895, 2008, A1, . Location in patent: Page/Page column 66; 67
[4] Patent: EP2399914, 2011, A1, . Location in patent: Page/Page column 91
[5] Patent: WO2008/5576, 2008, A1, . Location in patent: Page/Page column 27-28
[6] Patent: US2009/286816, 2009, A1, . Location in patent: Page/Page column 12
[7] Patent: WO2008/97428, 2008, A2, . Location in patent: Page/Page column 84
[8] Patent: US2009/23702, 2009, A1, . Location in patent: Page/Page column 105-106
[9] Patent: WO2010/149685, 2010, A1, . Location in patent: Page/Page column 33

[ 832715-51-2 ] Synthesis Path-Downstream 1~68

1
[ 1001398-30-6 ]
[ 832715-51-2 ]
[ 1001398-31-7 ]

Yield	Reaction Conditions	Operation in experiment
70 - 85%	With sodium hydride; In tetrahydrofuran; at 65℃; for 2h;Product distribution / selectivity;	Step 4: 1 -Methylethyl 4-[7-(4-bromophenyl)-6,7-dihydro-5H-pyrrolo[2,3- c/]pyrimidin-4-yl]oxy}-1 -piperidinecarboxylate (117)Following the procedure described for W (Example 1, Step 10), compound 116 (932 g, 3 mmol) was allowed to react, at 65 0C, with compound 9 (562 mg, 3 mmol) in presence of NaH (60% dispersion in oil, 360 mg, 9 mmol) in THF (40 ml.) for 2 h. Aqueous workup followed by SiO2 flash column chromatography afforded 966 mg (70%) of the title product HZ as a white solid. 1H NMR (400 MHz, DMSOd6): delta 8.32 (s, 1 H), 7.63 (d, J = 9.2 Hz, 2 H), 7.47 (d, J = 8.8 Hz, 2 H), 5.36 (m, 1 H), 4.92 (septuplet, J = 6.0 Hz, 1 H), 4.07 (t, J = 9.2 Hz, 2 H), 3.79 (br s, 2 H), 3.36 - 3.30 (m, 2 H), 3.07 (t, J = 8.8 Hz, 2 H), 2.02 - 1.97 (m, 2 H), 1.77 - 1.68 (m, 2 H), 1.25 (d, J = 6.4 Hz, 6 H); LCMS (ESI): m/z 463 (M + H)+.; Step 2: 1 -Methylethyl 4-[7-(4-bromophenyl)-6,7-dihydro-5H-pyrrolo[2,3- c/]pyrimidin-4-yl]oxy}-1 -piperidinecarboxylate (117) Following the procedure described for W (example 1 , step 10), the reagent 9 (1.51 g, 8.05 mmol), NaH (0.966 g, 24.2 mmol), and the compound U6 (2.50 g, 8.05 mmol) were refluxed for 2 h. The regular work-up and chromatography afforded 3.15 g (85%) of the title product 1I7 as a white solid 1H NMR (400 MHz, CDCI3): delta 8.30 (s, 1 H), 7.65 and 7.63 (app, dd, J1 = 8.8 Hz, J2 = 2.0 Hz, 2 H), 7.46 and 7.44 (app. dd, J1 = 9.2 Hz, J2 = 2.0 Hz, 2 H), 5.36-5.28 (m, 1 H), 4.92 (septuplet, J = 6.4 Hz, 1 H), 4.04 (t, J = 8.8 Hz, 2 H), 3.82 - 3.78 (br, m, 2 H), 3.36 - 3.30 (m, 2 H), 3.06 (t, J = 9.2 Hz, 2 H), 2.02 - 1.94 (m, 2 H), 1.76 - 1.68 (m, 2 H), 1.24 (d, J = 6.4 Hz, 6 H); LCMS (ESI): m/z 463 (M + H)+.

Reference： [1]Patent: WO2008/8895,2008,A1 .Location in patent: Page/Page column 121; 178
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 10972 - 10994

2
[ 1001399-29-6 ]
[ 832715-51-2 ]
[ 1001399-30-9 ]

Yield	Reaction Conditions	Operation in experiment
37%	With sodium hydride; In tetrahydrofuran; at 20℃; for 18h;Heating / reflux;	Step 3: 1 -Methylethyl 4-({7-[5-(methylthio)-2-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,3- c/]pyrimidin-4-yl}oxy)-1 -piperidinecarboxylate (201) To a stirred solution of 200 (652 mg, 2.35 mmol) and 1 -methylethyl 4-hydroxy-1- piperidinecarboxylate 9 (526 mg, 2.81 mmol) in THF (24 mL) was added NaH (60% dispersion in mineral oil, 282 mg, 7.05 mmol) in one portion at RT. The reaction mixture was heated to reflux for 18 h, cooled to RT, and quenched with water (20 mL). The mixture was extracted with EtOAc (3 x 50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude oil was purified using SiO2 flash chromatography (40% EtOAc in hexanes) to give 373 mg (37%) of the title product 201 as a colorless oil. 1H NMR (400 MHz, CDCI3): delta 8.73 - 8.66 (m, 1 H), 8.42 - 8.39 (m, 1 H), 8.30 (d, J = 2.4 Hz, 1 H), 8.77 - 8.70 (m, 1 H), 5.39 - 5.32 (m, 1 H), 4.92 (septuplet, J = 6.1 Hz, 1 H), 4.46 - 4.36 (m, 2 H), 3.85 - 3.76 (m, 2 H), 3.36 - 3.30 (m, 2 H), 3.12 - 3.05 (m, 2 H), 2.48 (s, 3 H), 2.03 - 1.95 (m, 2 H), 1.79 - 1.70 (m, 2 H), 1.25 (d, J = 6.4 Hz, 6 H); LCMS (ESI): m/z 430 (M + H)+.

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 10972 - 10994
[2]Patent: WO2008/8895,2008,A1 .Location in patent: Page/Page column 166

3
[ 1001399-33-2 ]
[ 832715-51-2 ]
[ 1001399-34-3 ]

Yield	Reaction Conditions	Operation in experiment
25%	With sodium hydride; In tetrahydrofuran; at 20℃; for 18h;Heating / reflux;	Step 3: 1 -Methylethyl 4-({7-[6-(methylthio)-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,3- c/]pyrimidin-4-yl}oxy)-1 -piperidinecarboxylate (206) To a stirred solution of 205 (1.31 g, 4.71 mmol) and 1 -methylethyl 4-hydroxy-1- piperidinecarboxylate 9 (1.06 g, 5.65 mmol) in THF (47 ml.) was added NaH (60% dispersion in mineral oil, 565 mg, 14.13 mmol) in one portion at RT. The reaction mixture was heated to reflux for 18 h, cooled to RT, and quenched with water (10 ml_). The mixture was extracted with EtOAc (3 x 75 ml_), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude oil was purified using SiO2 flash chromatography (40% EtOAc in hexanes) to give 500 mg (25%) of the title product 206 as a colorless oil. 1H NMR (400 MHz, CDCI3): delta 8.58 (d, J = 2.7 Hz, 1 H), 8.41 - 8.37 (m, 1 H), 8.27 (s, 1 H), 7.21 (d, J = 8.8 Hz, 1 H), 5.32 (septuplet, J = 3.9 Hz, 1 H), 4.91 (app. quintuplet, J = 6.1 Hz, 1 H), 4.05 (t, J = 8.8 Hz, 2 H), 3.82 - 3.75 (m, 2 H), 3.35 - 3.28 (m, 2 H), 3.08 (t, J = 8.8 Hz, 2 H), 2.59 (s, 3 H), 2.00 - 1.93 (m, 2 H), 1.75 - 1.67 (m, 2 H), 1.24 (d, J = 6.8 Hz, 6 H); LCMS (ESI): m/z 430 (M + H)+.

Reference： [1]Patent: WO2008/8895,2008,A1 .Location in patent: Page/Page column 169
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 10972 - 10994

4
[ 832715-51-2 ]
[ 53967-81-0 ]
[ 832753-77-2 ]

Yield	Reaction Conditions	Operation in experiment
39.8%	With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 0.5h;	To a solution of 4, 6-dichloro-5-ethyl-pyrimidine (1 g, 5.65 mmol) and 4-hydroxy-piperidine- 1-carboxylic acid isopropyl ester (1. 05 g, 5.65 mmol) in dry THF under nitrogen at 0C, potassium tert-butoxide (1M solution in THF, 6.78 mL) was added dropwise. The reaction was stirred at rt for 30 min. The mixture was quenched with water and extracted with EtOAc (3x). The organic layer was washed with water, sat. NH4C1 and brine, followed by drying over sodium sulfate and concentration under vacuo. The resulting oil was purified by HPLC to afford 4- (6-CHLORO-5-ETHYL-PYRIMIDIN-4- YLOXY)-PIPERIDINE-L-CARBOXYLIC acid isopropyl ester (0.74 g, 39.8%) as a colorless oil. Exact mass calculated for C15H22CIN303 327.13, found 328.2 (MU+).

Reference： [1]Patent: WO2005/7647,2005,A1 .Location in patent: Page/Page column 188; 189
[2]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 1750 - 1755

5
[ 832754-14-0 ]
[ 832715-51-2 ]
[ 832754-13-9 ]

Yield	Reaction Conditions	Operation in experiment
73.7%	With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 0.5h;	To a solution OF 4, 6-DICHLORO-5-CYCLOPROPYL-PYRIMIDINE (700 mg, 3.70 mmol) and 4-hydroxy- piperidine-1-carboxylic acid isopropyl ester (636.6 mg, 3.70 mmol) in dry THF under nitrogen at 0C, potassium tert-butoxide (1M solution in THF, 4.45 mL) was added dropwise. The reaction was stirred at rt for 30 min. The mixture was quenched with water and extracted with EtOAc (3x). The organic layer was washed with water, sat. NH4C1 and brine, followed by drying over sodium sulfate and concentration under vacuo. The resulting oil was purified by flash chromatography (0-20% EtOAc/Hexanes) to afford 4- (6-chloro-5-cyclopropyl-pyrimidin-4-yloxy)-piperidine-l-carboxylic acid isopropyl ester (0.927 g, 73.7%) as colorless oil. Exact mass calculated for C, 6H22CLN303 339.13, found 340.3 (MH+).

Reference： [1]Patent: WO2005/7647,2005,A1 .Location in patent: Page/Page column 195; 196
[2]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 1750 - 1755

6
[ 4316-97-6 ]
[ 832715-51-2 ]
[ 832752-64-4 ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium tert-butylate; In tetrahydrofuran; for 1h;	To a solution OF 4-HYDROXY-PIPERIDINE-1-CARBOXYLIC acid isopropyl ester (6.26 g, 33.4 mmol) and <strong>[4316-97-6]4,6-dichloro-5-methyl-pyrimidine</strong> (5.45 g, 33.4 mmol) in 100 mL THF, 1M potassium TERT- butoxide in THF (40 mL, 40 mmol) were added slowly by syringe pump. After 1 hour, everything had been added and mixture was concentrated. Residue was extracted with methylene chloride and water. Organic phases were dried over magnesium sulfate, filtered, and concentrated to give 4- (6- CHLORO-5-METHYL-PYRIMIDIN-4-YLOXY)-PIPERIDINE-1-CARBOXYLIC acid isopropyl'ester as a pale yellow solid (10.3 g, 98%). H NMR (CDC13, 400 MHz) 8 1.22-1. 24 (d, 6H), 1.74-1. 81 (M, 2H), 1.95-2. 04 (M, 2H), 2.24 (s, 3H), 3.40-3. 45 (M, 2H), 3.74-3. 81 (M, 2H), 4.90-4. 98 (M, 1H), 5.31-5. 37 (M, 1H), 8.40 (s, 1H).
96.3%	With potassium tert-butylate; In tetrahydrofuran; at -15 - 0℃; for 3h;	4,6-Dichloro-5-methylpyrimidine (1) (2.4235 Kg, 1.000 equivalents) and 4-hydroxypiperidine-1-carboxylic acid isopropyl ester (2) (2.8182 Kg, 1.012 equivalents) were dissolved in tetrahydrofuran (THF, 25.0028 Kg), and the resulting solution was cooled to -15 to -10 C. To the cold solution, potassium-tert-butoxide in tetrahydrofuran (1 M, 12.6051 Kg, 0.9399 equivalents) was added at a rate sufficiently slow to maintain the reaction mixture below 0 C. with reactor jacket cooling. The reaction mixture was then stirred at about -5 C. for about 2 hours before an additional portion of potassium-tert-butoxide in tetrahydrofuran (1 M, 0.5692 Kg, 0.0424 equivalents) was added to achieve >97% conversion of the pyrimidine after an additional hour of stirring at about -5 C. Most of the solvent was then removed by distillation at 30-65 C., 80 torr. Addition of water (19.9681 Kg) to the evaporation residue precipitated the product. Distillative removal of THF was then completed at 30-65 C., 80 torr, and the resulting stirred slurry was cooled to 0 C. for an hour. The solids were then collected by suction filtration, washed with water (8.011 Kg, 4 C.), and vacuum dried to constant weight at 50 C., 40 torr to provide product (3) (4.491 Kg, 96.3% yield).
80%		Preparation 6: Isopropyl 4-r(6-chloro-5-methylpyrimidin-4-yl)oxylpiperidine-1 - carboxylateTo a solution of isopropyl 4-hydroxypiperidine-1-carboxylate (482 mg, 2.68 mmol) in anhydrous tetrahydrofuran (15 mL) was added potassium te/t-butoxide (0.41 g, 3.6 mmol) at 0 degrees Celsius. The reaction mixture was stirred at 65 degrees Celsius for 10 minutes. To the above mixture was added <strong>[4316-97-6]4,6-dichloro-5-methylpyrimidine</strong> (0.40 g, 2.4 mmol). Then the resulting solution was stirred at 65 degrees Celsius for 1 hour. The mixture was cooled to ambient temperature, quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether : ethyl acetate = 20 : 1 ) to afford the product as a white solid (680 mg, 80 %).

80%		Isopropyl 4-r(6-chloro-5-methylpyrimidin-4-yl)oxylpiperidine-1 - carboxylateTo a solution of isopropyl 4-hydroxypiperidine-1-carboxylate (482 mg, 2.68 mmol) in anhydrous tetrahydrofuran (15 ml.) was added potassium te/t-butoxide (0.41 g, 3.6 mmol) at 0 degrees Celsius. The reaction mixture was stirred at 65 degrees Celsius for 10 minutes. To the above mixture was added <strong>[4316-97-6]4,6-dichloro-5-methylpyrimidine</strong> (0.40 g, 2.4 mmol). Then the resulting solution was stirred at 65 degrees Celsius for 1 hour. The mixture was cooled to ambient temperature, quenched with water (100 ml.) and extracted with ethyl acetate (100 ml. x 3). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 20 : 1 ) to afford the title compound as a white solid (680 mg, 80%).
76%	With potassium tert-butylate; In tetrahydrofuran; at 0 - 23℃; for 18h;Inert atmosphere;	To a solution of <strong>[4316-97-6]4,6-dichloro-5-methyl-pyrimidine</strong> (3.0 g, 18.4 mmol) and isopropyl 4-hydroxypiperidine-1-carboxylate (3.79 g, 20.2 mmol) in anhydrous tetrahydrofuran (100 ml.) at 0 degrees Celsius was added a 1 M solution of potassium fe/t-butoxide in tetrahydrofuran (3.1 g, 27.6 mmol). The reaction was allowed to warm to room temperature while stirring for 18 hours. The reaction was then quenched with water and extracted with ethyl acetate four times. The organic extracts were combined and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting material was purified by column chromatography (0-50 % ethyl acetate in heptane) to give isopropyl 4-[(6-chloro-5- methylpyrimidin-4-yl)oxy]piperidine-1-carboxylate as a white solid (4.4g, 76 %). 1H NMR (400 MHz, deuterochloroform) delta 1.23 (d, J=6.4 Hz, 6 H) 1.70 - 1.79 (m, 2 H) 1.91 - 2.01 (m, 2 H) 2.20 (s, 3 H) 3.34 - 3.42 (m, 2 H) 3.67 - 3.77 (m, 2 H) 4.86 - 4.95 (m, 1 H) 5.29 - 5.35 (m, 1 H) 8.36 (s, 1 H); LCMS (ES+): 314.2 (M+1 ).
32%	With potassium tert-butylate; In tetrahydrofuran; at 0℃; for 0.75h;	Example 3.4: Preparation of 4-(6-Chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-l- carboxylic Acid Isopropyl Ester; To a solution of isopropyl 4-hydroxypiperidine-l-carboxylate (29.0 g, 155 mmbl) and<strong>[4316-97-6]4,6-dichloro-5-methylpyrimidine</strong> (25.0 g, 153 mmol) in THF (250 mL), potassium tert-bvlambdaoxide in THF (1 M, 154 mL, 154 mmol) was added dropwise at 0 0C. After 45 min, the crude mixture was partitioned between ethyl acetate and H2O and the organic phase was washed with brine. The organic extract was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel with hexane/ethyl acetate (10% -> 15% v/v) to give the title compound (15.4 g, 32% yield) as a solid. Exact mass calculated for Ci4H20ClN3O3: 313.1, Found: LCMS /n/z = 314.4 (M+Hi); .H NMR (400 MHz, DMSO-rf6) delta 1.20 (d, /= 6.32 Hz, 6 H), 1.64-1.69 (m, 2 H), 1.92-1.97 (m, 2 H), 2.18 (s, 3 H), 3.33-3.39 (m, 2 H), 3.59-3.65 (m, 2 H), 4.79 (sept, J= 6.32 Hz, 1 H), 5.32-5.34 (m, IH)3 8.50 (s, 1 H).

Reference： [1]Patent: WO2005/7647,2005,A1 .Location in patent: Page/Page column 174
[2]Patent: US2006/155129,2006,A1 .Location in patent: Page/Page column 15
[3]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 1750 - 1755
[4]Patent: WO2011/36576,2011,A1 .Location in patent: Page/Page column 45
[5]Patent: WO2011/61679,2011,A1 .Location in patent: Page/Page column 51
[6]Patent: WO2010/128414,2010,A1 .Location in patent: Page/Page column 53-54
[7]Patent: WO2008/5576,2008,A1 .Location in patent: Page/Page column 29

7
[ 5382-16-1 ]
[ 108-23-6 ]
[ 832715-51-2 ]

Yield	Reaction Conditions	Operation in experiment
92.0%	With triethylamine; In ethyl acetate; at 10 - 20℃; for 18h;	Example 3; Preparation of 4-Hydroxy-Piperidine-1-Carboxylic Acid Isopropyl Ester (5); To a stirred mixture of 4-hydroxypiperidine (53.8 g, 1.000 eq), triethylamine (71.8 g, 1.334 equivalents), and ethyl acetate (498.8 g) was added neat isopropyl chloroformate (78.0 g, 1.1966 equivalents) at a rate sufficiently slow to maintain the reaction mixture temperature at 10-17 C. with reactor jacket cooling. After the addition had been completed, the reaction mixture was stirred at 20 C. for 18 hours. Then water (100 g) was added, and the resulting mixture was stirred for 15 minutes before the phases were separated. The organic phase was washed with two 100-gram-portions of 20 wt % aqueous NaCl by stirring for 15 min at 150 rpm before separating the aqueous wash. After a final wash with water (100 g), the organic phase was concentrated by distillation on a rotary evaporator at reduced pressure to provide product (2) (91.1 g, 92.0 % yield) as light amber oil of 96.8 % purity by GC. Distillation of this crude product at 117-120 C., 0.3-1.0 torr gave a 95.7 % recovery of product (2) as a colorless oil collected at 112-119 C.
92%	With triethylamine; In ethyl acetate; at 10 - 20℃; for 18h;	Example 2 Preparation of 4-Hydroxy-Piperidine-1-Carboxylic Acid Isopropyl Ester Intermediate (2) To a stirred mixture of 4-hydroxypiperidine (53.8 g, 1.000 eq), triethylamine (71.8 g, 1.334 equivalents), and ethyl acetate (498.8 g) was added neat isopropyl chloroformate (78.0 g, 1.1966 equivalents) at a rate sufficiently slow to maintain the reaction mixture temperature at 10-17 C. with reactor jacket cooling. After the addition had been completed, the reaction mixture was stirred at 20 C. for 18 hours. Then water (100 g) was added, and the resulting mixture was stirred for 15 minutes before the phases were separated. The organic phase was washed with two 100-gram-portions of 20 wt % aqueous NaCl by stirring for 15 min at 150 rpm before separating the aqueous wash. After a final wash with water (100 g), the organic phase was concentrated by distillation on a rotary evaporator at reduced pressure to provide product (2) (91.1 g, 92.0% yield) as light amber oil of 96.8% purity by GC.
86%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; toluene; at 20℃; for 52h;	Step 9: 1-Methylethyl 4-hydroxy-1 -piperidinecarboxylate (9)To a cold (5 0C) solution of 4-hydroxypiperidine (40.46 g, 0.40 mol) and CH2CI2 (500 ml.) was added diisopropylethylamine (140 ml_, 0.80 mol) under N2. A 1 M solution of isopropyl chloroformate (500 ml_, 0.50 mol) in toluene was added dropwise over a period of 4 h. The resulting reaction mixture was stirred at RT for 48 h. The reaction mixture was washed with water (2 x 100 ml.) and brine (1 x 100 ml_), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash <n="68"/>column chromatography to afford 64.60 g (86%) of the title product 9 as colorless oil. 1H NMR (400 MHz, DMSOd6): delta 4.72 (m, 1 H), 3.68 - 3.62 (m, 2 H), 3.60 (septuplet, J = 4.4 Hz, 1 H), 2.96 (br m, 2 H), 1.68 - 1.62 (m, 2 H), 1.26 - 1.18 (m, 2 H), 1.14 (d, J = 6.4 Hz, 6 H).

86%	With triethylamine; In ethyl acetate; at 0 - 20℃; for 12h;	Reference Example 2 isopropyl 4-hydroxypiperidine-1-carboxylate; To a mixture cooled to 0C in an ice bath of 4-hydroxypiperidine (19.0 g, 188 mmol), triethylamine (25.4 g, 251 mmol), and ethyl acetate (250 mL) was added dropwise isopropyl chlorocarbonate (27.6 g, 225 mmol). The reaction mixture was stirred at room temperature for 12 hr. The reaction mixture was washed successively with 2N hydrochloric acid, aqueous potassium carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to give the title compound (30.3 g, yield 86%) as a colorless oil. 1H-NMR (300 MHz, CDCl3)delta:1.24 (d, J = 6. 4 Hz, 6 H), 1. 40 - 1.55 (m, 2 H), 1.78 - 1.94 (m, 2 H), 3.00 - 3.15 (m, 2 H), 3.77-3.97 (m, 3 H), 4.83 - 4.99 (m, 1 H).
83%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; toluene; at 10 - 15℃; for 4h;	Example 3.1: Preparation of 4-Hydroxy-piperidine-l-carboxylic Acid Isopropyl Ester; A magnetically stirred solution of 4-hydroxypiperidine (70.3 g, 695 mmol) and NJN- diisopropylethylamine (105 mL, 600 mmol) in dichloromethane (1.0 L) was cooled to 100C under N2. A solution of isopropyl chloroformate (1.0 M in toluene, 580 mL, 580 mmol) was <n="29"/>added dropwise over 2 h, maintaining a temperature of 10-15 0C. The reaction mixture was stirred for an additional 2 h and then extracted with 1 N HCl (1.2 L). The organic extract was dried over MgSO4, and the solvent was removed under reduced pressure to give the title compound (90.3 g, 83%) as a pale straw-colored oil. Exact Mass calculated for CsHi7NO3: 187.1, Found: LCMS m/z = 188.2 (M+H+), 210.3 (M+Nai); 1H NMR (400 MHz, CDCl3) delta 1.24 (d, J=6.3 Hz, 6 H)5 1.47 (m, 2 H), 1.86 (m, 2 H), 3.08 (m, 2 H)5 3.86 (m, 3 H), 4.90 (m, 1 H).
83%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; toluene; at 10 - 15℃; for 4h;Inert atmosphere;	Example 3.3 Preparation of 4-Hydroxy-piperidine-1-carboxylic Acid Isopropyl Ester A magnetically stirred solution of 4-hydroxypiperidine (70.3 g, 695 mmol) and N,N-diisopropylethylamine (105 mL, 600 mmol) in dichloromethane (1.0 L) was cooled to 10 C. under N2. A solution of isopropyl chloroformate (1.0 M in toluene, 580 mL, 580 mmol) was added dropwise over 2 h, maintaining a temperature of 10-15 C. The reaction mixture was stirred for an additional 2 h and then extracted with 1 N HCl (1.2 L). The organic extract was dried over MgSO4, and the solvent was removed under reduced pressure to give the title compound (90.3 g, 83% yield) as a pale straw-colored oil. Exact Mass calculated for C9H17NO3: 187.1. Found: LCMS m/z=188.2 (M+H+), 210.3 (M+Na+); 1H NMR (400 MHz, CDCl3) delta 1.24 (d, J=6.3 Hz, 6H), 1.47 (m, 2H), 1.86 (m, 2H), 3.08 (m, 2H), 3.86 (m, 3H), 4.90 (m, 1H).
	With triethylamine; In ethyl acetate; toluene; at 0 - 20℃;	NEt3 (10.4 mL, 74.6 mmol) was added to a solution of 4- hydroxypiperidine (5.82 g, 57.5 mmol) in EtOAc (50 mL) at rt. The resulting suspension was cooled to 0 0C, treated with a solution of isopropyl chloroformate in toluene (1.0M, 69 mL) and stirred at rt overnight. The mixture was quenched with water and stirred for 15 minutes, until a clear solution formed. The organic phase was separated and the aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried (Na2SO4), concentrated, and the crude material was distilled under high vacuum to afford isopropyl 4-hydroxypiperidine-l-carboxylate (72b) as a clear oil. 1H- NMR (400 MHz, CDCl3) delta = 4.90 (septet, J = 6.0 Hz, IH), 3.95-3.82 (m, 2H), 3.10-3.03 (m, 2H), 1.90-1.83 (m, 2H), 1.70-1.61 (m, IH), 1.51-1.42 (m, 2H), 1.24 (d, J = 6.0 Hz, 6H); MS calcd. for [M+H]+ C9H18NO3: 188.1; found: 188.1.
	With triethylamine; In dichloromethane; toluene; at 0 - 20℃; for 1h;	To a stirring solution of piperidin-4-ol (5.22 g, 51.6 mmol, Aldrich), Et3N (13.2 mL, 95 mmol, Aldrich) in CH2Cl2 (50 mL) at 0 C. was added a solution of Isopropyl chloroformate (1 Molar in Toluene, 43.0 mL, 43.0 mmol, Aldrich) dropwise. The reaction mixture was stirred at room temperature for 1 h and washed with 1N HCl in H2O. The H2O layer was extracted with DCM (2×). The organic layers were combined and concentrated in vacuo to yield 5.71 g of the desired product as a light brown oil. MS (ESI) 188 (M+H).
	With triethylamine; In dichloromethane; toluene; at 20℃; for 3h;	To a solution of 4-hydroxyl-piperidine (8.1 g, 80 mmol) and triethylamine (11.2 mL, 1 eq) in 200 mL of DCM, was added isopropyl chloro formate (80 mL of a 1 M solution in toluene, 1 eq). The reaction mixture was stirred at room temperature for 3h, quenched with a saturated solution of bicarbonate and extracted with DCM twice. The combined extracts were washed with a saturated solution of bicarbonate, dried over magnesium sulfate and evaporated to give 2a.

Reference： [1]Patent: US2006/154940,2006,A1 .Location in patent: Page/Page column 17-18
[2]Patent: US2006/155129,2006,A1 .Location in patent: Page/Page column 14-15
[3]Patent: WO2008/8895,2008,A1 .Location in patent: Page/Page column 66; 67
[4]Patent: EP2399914,2011,A1 .Location in patent: Page/Page column 91
[5]Patent: WO2008/5576,2008,A1 .Location in patent: Page/Page column 27-28
[6]Patent: US2009/286816,2009,A1 .Location in patent: Page/Page column 12
[7]Patent: WO2008/97428,2008,A2 .Location in patent: Page/Page column 84
[8]Patent: US2009/23702,2009,A1 .Location in patent: Page/Page column 105-106
[9]Patent: WO2010/149685,2010,A1 .Location in patent: Page/Page column 33

8
[ 832715-51-2 ]
[ 5018-38-2 ]
[ 897732-25-1 ]

Yield	Reaction Conditions	Operation in experiment
98.6%	With potassium tert-butylate; In tetrahydrofuran; at 5 - 10℃; for 2h;Inert atmosphere;	Example 3.4 Preparation of 4-(6-Chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic Acid Isopropyl Ester A solution of 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (71.0 g, 380 mmol) and <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (71.6 g, 400 mmol) in anhydrous THF (1 L) was cooled to 5 C. under N2. A solution of potassium t-butoxide (1.0 M in THF, 380 mL, 380 mmol) was added dropwise over 1 h. The reaction temperature was kept under 10 C. during addition. The reaction mixture was stirred at 5-10 C. for 1 h, quenched with saturated NH4Cl (200 mL), and diluted with ether (1 L) and water (1 L). The aqueous phase was separated and discarded. The organic extract was washed with brine (800 mL), dried over MgSO4, and then concentrated. The residue was dissolved in hexane (400 mL) and filtered over Celite to remove a small amount of brown solid. The solvent was removed from the filtrate to afford a pale amber oil which gradually crystallized to give the title compound (130 g, 98.6% yield) as a pale amber solid. Exact Mass calculated for C14H20ClN3O4: 329.1. Found: LCMS m/z=330.2 (M+H+); 1H NMR (400 MHz, CDCl3) delta 1.25 (d, J=6.2 Hz, 6H), 1.82 (m, 2H), 2.02 (m, 2H), 3.40 (m, 2H), 3.80 (m, 2H), 3.91 (s, 3H), 4.95 (m, 1H), 5.39 (m, 1H), 8.27 (s, 1H).
85%	With potassium tert-butylate; In tetrahydrofuran; at 0℃; for 0.75h;	To a solution of 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (3.15 g, 17 mmol) and <strong>[5018-38-2]4,6-dichloro-5-methoxy-pyrimidine</strong> (3.00 mg, 17 mmol) in 15 ml of THF, 1M potassium-t-butoxide in THF (18.4 ml, 18.4 mmol) was added dropwise at 0 C. After 45 min, the crude mixture was extracted with CH2Cl2 and brine. Organic phase was dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel with hexane/ethyl acetate (3:1?1:1 v/v) to provide 4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester as a solid (4.7 g, 85%). 1HNMR (CDCl3, 400 MHz) delta 1.24-1.28 (d, 6H), 1.80-1.84 (m, 2H), 2.00-2.05 (m, 2H), 3.37-3.44 (m, 2H), 3.77-3.81 (m, 2H), 3.91 (s, 3H), 4.92-4.95 (m, 1H), 5.38-5.40 (m, 1H), 8.27 (s, 1H). Exact mass calculated for C14H20ClN3O4329.11, found 330.1 (MH+).
65%		To a solution of 2a (3.18 g, 17 mmol) in 18 mL of THF at room temperature, was added potassium tert-butoxide (2.06 g, 1.2 eq). The resulting mixture was stirred at room temperature for 30 minutes then 4,6-dichloro-5,methoxy-pyrimidine (3 g, 17 mmol) was added. The reaction mixture was stirred at room temperature for 8h then the solvent was evaporated. The residue was taken up with DCM and purified on silica gel (elution with 25% ethyl acetate in hexanes) to give 3.64 g of 8a (65% yield).

59%	With sodium hexamethyldisilazane; In tetrahydrofuran; 1,4-dioxane; at 100℃; for 10h;Inert atmosphere;	To a solution of <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (240 mg, 1.34 mmol) and isopropyl 4-hydroxypiperidine-1-carboxylate (326 mg, 1.74 mmol) in anhydrous 1 ,4- dioxane (3 ml.) at 100 0C, was added a 1 M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (1.34 ml_, 1.34 mmol, 1.0 M). The reaction mixture was heated for 10 hours and then allowed to cool to room temperature. The reaction was then quenched with water (3 ml.) and diluted with ethyl acetate (20 ml_). The solution was then washed with sequentially with saturated aqueous sodium bicarbonate solution (10 ml.) and brine (10 ml.) followed by drying over sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography (0 - 100% ethyl acetate in heptane) to give isopropyl 4-[(6- chloro-5-methoxypyrimidin-4-yl)oxy]piperidine-1-carboxylate as oil (260 mg, 59 %). 1H NMR (400 MHz, deuterochloroform) delta 8.25 (1 H, s) 5.29 - 5.44 (1 H, m) 4.84 - 5.01 (1 H, m) 3.90 (3 H, s) 3.72 - 3.82 (2 H, m) 3.31 - 3.47 (2 H, m) 1.93 - 2.10 (2 H, m) 1.72 - 1.89 (2 H, m) 1.25 (6 H, d, J=6.24 Hz); LCMS (ES+): 329.0 (M+1 ).
	With sodium hydride; In N,N-dimethyl-formamide; at -5 - 20℃; for 18h;Inert atmosphere;Product distribution / selectivity;	A 500 ml, 4-necked flask equipped with thermometer, mechanical stirrer and condenser with gas inlet was purged with N2 and charged with NaH (4.4 g; 0.1 1 mol) and N,N-dimethylformamide (50 ml). In a separate flask were dissolved 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (18.7 g; 0.1 mol) and <strong>[5018-38-2]4,6-dichloro-5-methoxy-pyrimidine</strong> (17.9 g; 0.1 mol) in DMF (50 ml; 0.5 L/mol). The prepared solution was then added dropwise to the above- mentioned NaH/DMF suspension while maintaining the temperature between - 10 and -5C. The resulting mixture is then stirred for one hour, then allowed to warm up to room temperature and stirred for 17 hours. Water (300 ml; 3 L/mol) was added dropwise while maintaining the temperature between 15-300C by cooling with tap water. Heptane (125 ml; 1.25 L/mol) was added and the resulting mixture was heated up to 55C. The aqueous layer was discarded; the organic layer was cooled down to 200C and stirred for another 3-2Oh. The resulting precipitate was filtered and dried in vacuum (at) 500C for 2Oh to yield the title compound as a residue.
	With sodium hydride; In N,N-dimethyl-formamide; at -10 - 20℃; for 18h;Inert atmosphere;Product distribution / selectivity;	Example 1 4-(6-Chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester A 500 ml, 4-necked flask equipped with thermometer, mechanical stirrer and condenser with gas inlet was purged with N2 and charged with NaH (4.4 g; 0.1 1 mol) and N,N-dimethylformamide (50 ml). In a separate flask were dissolved 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (18.7 g; 0.1 mol) and <strong>[5018-38-2]4,6-dichloro-5-methoxy-pyrimidine</strong> (17.9 g; 0.1 mol) in DMF (50 ml; 0.5 L/mol). The prepared solution was then added dropwise to the above- mentioned NaH/DMF suspension while maintaining the temperature between - 10 and -5C. The resulting mixture is then stirred for one hour, then allowed to warm up to room temperature and stirred for 17 hours. Water (300 ml; 3 L/mol) was added dropwise while maintaining the temperature between 15-300C by cooling with tap water. Heptane (125 ml; 1.25 L/mol) was added and the resulting mixture was heated up to 55C. The aqueous layer was discarded; the organic layer was cooled down to 200C and stirred for another 3-2Oh. The resulting precipitate was filtered and dried in vacuum at 500C for 2Oh to yield the title compound.

Reference： [1]Patent: US2009/286816,2009,A1 .Location in patent: Page/Page column 12-13
[2]Patent: US2006/155128,2006,A1 .Location in patent: Page/Page column 48
[3]Patent: WO2010/149685,2010,A1 .Location in patent: Page/Page column 41
[4]Patent: WO2010/128414,2010,A1 .Location in patent: Page/Page column 53
[5]Patent: WO2010/135505,2010,A2 .Location in patent: Page/Page column 33-34
[6]Patent: WO2010/135506,2010,A1 .Location in patent: Page/Page column 30; 31
[7]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 1750 - 1755

9
[ 832714-38-2 ]
[ 832715-51-2 ]
JNJ-28630368 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With sodium t-butanolate; In toluene; at 12 - 34℃; for 2.5h;Product distribution / selectivity;	Example 6; Alternate preparation of 4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (6); Toluene (1.6 L) was transferred to a 4 L jacketed reaction vessel fitted with a mechanical stirrer, nitrogen inlet and a temperature probe. 4-Chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (7) (97.0g, 0.297 mol) was added with stirring into the reaction vessel under nitrogen, and a slurry was obtained. The carbamate, 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (5) (66.57g, 0.356 mol), was added at room temperature. The reactor was cooled to 12 C. and sodium tert-butoxide (37.09g, 0.386 mol) was added with stirring. The internal temperature gradually increased to 34 C. due to an exotherm. Then the internal temperature was brought down to 23-25 C. The reaction mixture became a thick slurry and was stirred at room temperature for 2.5 h. The precipitate from the reaction mixture was filtered, washed with toluene (250 mL) followed by water (3×500 mL), and vacuum dried overnight at room temperature. The dried solid product was slurried in EtOH (500 mL) at room temperature, filtered, and washed with water (2.5 L) until the filtrate was neutral. The washed solid product was dissolved in refluxing EtOH (1.3 L), and the resulting clear solution was gradually cooled to room temperature. The product (6) crystallized out and was isolated by filtration and dried overnight in a vacuum oven at 40 C., 20 torr to provide 105.5 g of product (6) (74%). HPLC analysis, >99% (purity, by peak area). 1H NMR (Bruker 400 MHz, CDCl3) delta 8.62 (s, 1H, Ar-H), 8.32 (s, 1H, Ar-H), 7.93 (m, 3H, Ar-H), 5.62 (m, 1H, -O-CH-), 4.95 (m, 1H, CH3-CH-CH3), 3.91 (m, 2H, -CH2-), 3.37 (m, 2H, -CH2-), 3.12 (s, 3H, -SO2CH3), 2.09 (m, 2H, -CH2-), 1.87 (m, 2H, -CH2-), 1.27 (d, 6H, J=8 Hz, CH3-CH-CH3); mass spec. (electrospray) m/z 478 (M+H).

Reference： [1]Patent: US2006/154940,2006,A1 .Location in patent: Page/Page column 19

10
[ 832714-49-5 ]
[ 832715-51-2 ]
JNJ-28630368 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57.0%	With di-isopropyl azodicarboxylate; triphenylphosphine; In 4-methyl-morpholine; at 25 - 55℃; for 11.5h;Product distribution / selectivity;	Example 4; Preparation of 4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (6); Diisopropyl azodicarboxylate (2.9812 Kg, 1.1713 equivalents) was added to a stirred suspension of (4) (3.8806 Kg, 1.000 equivalent), triphenylphosphine (3.8532 Kg, 1.1671 equivalents), and 4-methylmorpholine (24.7942 Kg) at a rate sufficiently slow to maintain the reaction mixture at 20-30 C. with reactor jacket cooling. The resulting suspension was stirred for 30 minutes at about 25 C. and then heated to 50-55 C. for about two hours. A solution of <strong>[832715-51-2]4-hydroxypiperidine-1-carboxylic acid isopropyl ester</strong> (5) (2.7164 Kg, 1.15255 equivalents) in 4-methylmorpholine (3.0302 Kg) was then added to the reaction mixture at a rate sufficiently slow to maintain the reaction mixture at 45-55 C. About 1.5 hours after the addition of (5) had been completed and then again after another 1.5 hours, more triphenylphosphine (1.4856 Kg, 0.4500 equivalents and then 0.8897 Kg, 0.2695 equivalents) and more diisopropyl azodicarboxylate (1.1445 Kg, 0.4497 equivalents and then 0.6894 Kg, 0.2709 equivalents) were added to the stirred reaction mixture while it continued to be maintained at 50-55 C. After about six more hours of stirring at that temperature, the (6):(4) HPLC peak area ratio was greater than 9:1, and the product was crystallized by cooling the reaction mixture to 0-5 C. and stirring at that temperature for about four hours. The crystallized product was filtered, washed with 4-methylmorpholine (4.3802 Kg, 2 C.) and then with water (10.4754 Kg, ambient temperature), and then recrystallized from 4-methylmorpholine (20.7215 Kg, about 75 C.) by cooling to 2 C. and stirring at that temperature for about two hours. The recrystallized product was filtered, washed with 4-methylmorpholine (4.5893 Kg, 2 C.) and then with water (10.4955 Kg, ambient temperature), and then recrystallized from boiling absolute ethanol (35 Kg) by cooling to 25 C. and stirring at that temperature for about 18 hours. The recrystallized product was collected by filtration, washed with a 2 C. mixture of absolute ethanol (7.657 Kg) and water (3.8276 Kg), and dried to constant weight at 70 C., 40 torr to provide product (6) (3.4269 Kg, 57.0% yield).
	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 25 - 55℃; for 11.5h;Product distribution / selectivity;	A similar reaction was conducted using a similar manner as described in this example except for the use of THF as the solvent and portionwise addition of triphenylphosphine, DIAD, and <strong>[832715-51-2]4-hydroxypiperidine-1-carboxylic acid isopropyl ester</strong> (5), which enhanced stirreability and molar efficiency. The multiple crystallization operation from previous iteration of the technology was replaced by a single crystallization in alcohol and aqueous solvent mixture which resulted in higher overall yield and consistent purity for product (6).

Reference： [1]Patent: US2006/154940,2006,A1 .Location in patent: Page/Page column 18
[2]Patent: US2006/154940,2006,A1 .Location in patent: Page/Page column 18
[3]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3134 - 3141

11
[ 832715-51-2 ]
[ 109613-91-4 ]
[ 897732-34-2 ]

Yield	Reaction Conditions	Operation in experiment
24%	With sodium hydride; In 1,4-dioxane; at 100℃; for 1h;	To a solution of 2-chloro-3-methoxy-4-nitro-pyridine (102.3 mg, 0.543 mmol) and 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (110 mg, 0.587 mmol) in dioxane (3 mL), sodium hydride (60% dispersion, 32 mg, 0.8 mmol) were added. After stirring at 100 C. for 1 hour, mixture was purified by HPLC to give 4-(2-chloro-3-methoxy-pyridin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester as a white solid (42.0 mg, 24%). 1HNMR (CDCl3, 400 MHz) delta 8.16-8.15 (d, J=5.4 Hz, 1H), 6.92-6.90 (d, J=5.8 Hz), 4.97-4.91 (m, 1H), 4.72-4.68 (m, 1H), 3.91 (s, 3H), 3.75-3.68 (m, 2H), 3.75-3.68 (m, 2H), 3.55 (m, 2H), 2.02-1.85 (m, 4H), 1.27-1.26 (d, J=6.2 Hz, 6H). Exact mass calculated for C15H21ClN2O4 328.12, found 329.2 (MH+).

Reference： [1]Patent: US2006/155128,2006,A1 .Location in patent: Page/Page column 49

12
[ 832715-51-2 ]
[ 930093-72-4 ]
[ 930093-71-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium tert-butylate; In tetrahydrofuran; at 0 - 15℃; for 3h;Product distribution / selectivity;	Step B: Preparation of 4-[5-methyl-6-(2-methyl-pyridin-3-yloxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester. [Show Image] To a mixture of 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (1.3364g, 7.146mmol) and <strong>[930093-72-4]4-chloro-5-methyl-6-(2-methyl-pyridin-3-yloxy)-pyrimidine</strong> (1.683g, 7.146mmol) was added THF (8.8mL). The resulting solution was cooled to 0C, and potassium tert-butoxide (1M in THF, 7.2mL) was slowly introduced, the temperature was maintained below 5C. The crude mixture was allowed to warm to 15C (three hours), and the consumption of starting materials was monitored using LCMS. The mixture was diluted using heptane (16mL), and concentrated to 5mL. Heptane (11 mL) was added and the salts were filtered and washed by heptane (16mL). The volatiles were removed under reduced pressure to lead to crude colorless oil (2.75g, quantitative). LCMS: 387 (MH)+, 218.1, 170, 128.1. NMR (400MHz, delta ppm, DMSO d6): 8.36 (1H, dd, J), 8.23 (1H, s), 7.56 (1H, dd, J), 7.31 (1H, dd, J), 5.32 (1H, m), 4.78 (1H, sept., J), 3.65 (2H, m), 3.35 (2H, m), 2.28 (3H, s), 2.17 (3H, s), 1.95 (2H, m), 1.65 (2H, m), 1.19 (6H, d, J). The oil was dissolved back in mixture of heptane (16mL) and isopropanol (4.8mL), HCl (4N in dioxane, 3mL) was slowly added. The resulting mixture was heated to 80C for 15mm., and then cooled to 1C; the white solid was filtered, washed by heptane (2x16mL) and dried in vacuum oven at 50C for 24 hours. The desired compound was collected (2.3288g, yield: 77%). LCMS: 387.5 (MH)+, 218.1, 170.1, 128.1. NMR (400MHz, delta ppm, DMSO d6): 8.53 (1H, dd, J), 8.17 (1H, s), 8.12 (1H, dd, J), 7.75 (1H, dd, J), 5.35 (1H, m), 4.95 (1H, sept., J), 3.78 (2H, m), 3.42 (2H, m), 2.85 (3H, s), 2.23 (3H, s), 2.05 (2H, m), 1.8 (2H, m), 1.25 (6H, d, J).

Reference： [1]Patent: EP1931654,2009,B1 .Location in patent: Page/Page column 17

13
[ 832715-51-2 ]
[ 1224097-06-6 ]
JNJ-38431055 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In 1,4-dioxane;Product distribution / selectivity;	Example 24-[6-(6-Methanesulfonyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester A 100 mL Schlenk flask with a magnetic stir bar, septum, heating mantle, and thermocouple was charged with (6-chloro-5-methoxy-pyrimidin-4-yl)-(6-methanesulfonyl-2-methyl-pyridin-3-yl)-amine (658.1 mg, 2 mmol), blocked 4-hydroxypiperidine (3.753 g, 20 mmol), 1,4-dioxane (20 mL) followed by KO-t-Bu (455 mg, 4 mmol). On addition of KO-t-Bu a pronounced exotherm was observed. After the exotherm had subsided, the he resulting mixture was heated to 85 C. and followed by HPLC. When the reaction progress began to slow, an additional charge of KO-t-Bu (230 mg, 2.05 mmol) was added (Note 2). When the reaction progress began to slow again, a third charge of KO t-Bu (110 mg, 1 mmol) was added. The reaction mixture was quenched by pouring the reaction into well-stirred, saturated NH4Cl (250 mL), then extracted with EtOAc (2×50 mL), and concentration to yield an oil (3.63 g). The oil was taken up in MTBE and filtered through CELITE to remove insoluble components. The resulting solution (approximately 25 mL) was treated with heptane (100 mL), and the resulting mixture stirred rapidly until the formation of a solid was observed (30 min). The solid was filtered to yield the title compound. The solid product was recrystallized from EtOAc-heptane (1:2) to yield the title compound as a solid.1H NMR (300 MHz, CDCl3) delta: 9.02 (d, 1H, J=8.6 Hz), 8.20 (s, 1H), 7.97 (d, 1H, J=8.6 Hz), 7.31 (br s, 1H), 5.40 (m, 1H), 4.94 (sept, 1H, J=6.2 Hz), 4.00 (s, 3H), 3.80 (m, 2H), 3.41 (m, 2H), 3.19 (s, 3H), 2.66 (s, 3H), 2.04 (m, 2H), 1.83 (m, 2H), 1.26 (d, 6H, J=6.2 Hz).LCMS: [MH]+ m/z 480, [M+23]+ m/z 502.
	With potassium tert-butylate; In 1,4-dioxane;Product distribution / selectivity;	Example 24-[6-(6-Methanesulfonyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester A 100 mL Schlenk flask with a magnetic stir bar, septum, heating mantle, and thermocouple was charged with (6-chloro-5-methoxy-pyrimidin-4-yl)-(6-methanesulfonyl-2-methyl-pyridin-3-yl)-amine (658.1 mg, 2 mmol), blocked 4-hydroxypiperidine (3.753 g, 20 mmol), 1,4-dioxane (20 mL) followed by KO-t-Bu (455 mg, 4 mmol). On addition of KO-t-Bu a pronounced exotherm was observed. After the exotherm had subsided, the he resulting mixture was heated to 85 C. and followed by HPLC. When the reaction progress began to slow, an additional charge of KO-t-Bu (230 mg, 2.05 mmol) was added (Note 2). When the reaction progress began to slow again, a third charge of KO t-Bu (110 mg, 1 mmol) was added. The reaction mixture was quenched by pouring the reaction into well-stirred, saturated NH4Cl (250 mL), then extracted with EtOAc (2×50 mL), and concentration to yield an oil (3.63 g). The oil was taken up in MTBE and filtered through CELITE to remove insoluble components. The resulting solution (approximately 25 mL) was treated with heptane (100 mL), and the resulting mixture stirred rapidly until the formation of a solid was observed (30 min). The solid was filtered to yield the title compound. The solid product was recrystallized from EtOAc-heptane (1:2) to yield the title compound as a solid.1H NMR (300 MHz, CDCl3) delta: 9.02 (d, 1H, J=8.6 Hz), 8.20 (s, 1H), 7.97 (d, 1H, J=8.6 Hz), 7.31 (br s, 1H), 5.40 (m, 1H), 4.94 (sept, 1H, J=6.2 Hz), 4.00 (s, 3H), 3.80 (m, 2H), 3.41 (m, 2H), 3.19 (s, 3H), 2.66 (s, 3H), 2.04 (m, 2H), 1.83 (m, 2H), 1.26 (d, 6H, J=6.2 Hz).LCMS: [MH]+ m/z 480, [M+23]+ m/z 502.

Reference： [1]Patent: US2010/113479,2010,A1 .Location in patent: Page/Page column 33-34
[2]Patent: US2010/113480,2010,A1 .Location in patent: Page/Page column 34

14
[ 832715-51-2 ]
[ 32644-15-8 ]
[ 1245078-54-9 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of 4-hydroxypiperidine-l-carboxylic acid isopropyl ester (10.0g.53.4mmol) m THF (lOOinL), in an oven dried flask, under argon, was cooled to 00C. Sodium hydride (60% m mineral oil, 8.55g, 213.6mmol) was added, portion-wise, and the resulting mixture was stirred at 00C for 1 h before stirring at r.t for 30 mm. To the reaction was added a solution of (S)-2- bromopropionic acid (4.82g, 53 4mmol) in THF (4OmL), dropwise, over 30 min, followed by more THF (6OmL), and the mixture was stirred at r t for 16 h The reaction was quenched by the cautious addition of water, then the THF was removed in vacuo. The resulting aqueous mixture was washed with Et2O and acidified to pHl with 2M HCl. The mixture was exctacted with EtOAc (2 x 15OmL) then the organic fractions were combined, dried (MgSO4) and the solvent removed in vacuo to afford the title compound 1H NMR deltaH (400MHz , CDCl3)- 4 97 - 4.86 (m, IH), 4.19 - 4 09 (m, IH), 3 89 - 3 79 (m, 2H), 3 66 - 3 58 (m, IH), 3 18 - 3.08 (m, 2H), 1.91 - 1 80 (m, 2H), 1 65 - 1 50 (m, 2H), 1 47 (d, / = 7 0 Hz, 3H), 1 26 - 1 22 (m, 6H).

Reference： [1]Patent: WO2010/103335,2010,A1 .Location in patent: Page/Page column 19

16
[ 832715-51-2 ]
[ 106-41-2 ]
[ 1245140-41-3 ]

Yield	Reaction Conditions	Operation in experiment
	With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In dichloromethane; at 20℃;	4-Hydroxypiperidine-l-carboxylic acid isopropyl ester (Preparation 2, 4.68g, 25mmol), 4-bromophenol (5.19g, 30mmol) and triphenylphosphine (7.87g, 25mmol) were dissolved in DCM (125mL) and di terf-butylazodicarboxylate (6.9Og, 30mmol) was added, portionwise, over 20 min. The reaction was stirred at r.t. for 72h and then diluted with DCM (15OmL). The organic solution was washed with 2M NaOH solution (2 x 20OmL), brine (20OmL) then dried (MgSO4). Removal of the solvent in vacuo followed by purification by column chromatography (SiO2, IH:EtOAc, 90:10, 80:20, 70:30) afforded the title compound: RT = 4.09 min; mlz (ES+) = 342.1, 344.0 [M + H]+.

Reference： [1]Patent: WO2010/103333,2010,A1 .Location in patent: Page/Page column 24

17
[ 53939-30-3 ]
[ 832715-51-2 ]
[ 1245201-15-3 ]

Yield	Reaction Conditions	Operation in experiment
		A dry solution of 4-hydroxypiperidine- 1-carboxylic acid isopropyl ester (Preparation 2, 1Og, 53mmol) in DMF, under argon, was cooled to 00C. Sodium hydride (60% in mineral oil, 2.54g, 64mmol) was added in one portion. The reaction was allowed to reach r.t. before stirring for a further 45 min. 5-Bromo-2-chloropyridine (12.32g, 64mmol) was added and the reaction was heated to 600C for 4Oh. The reaction mixture was allowed to cool to r.t. then EtOAc was added. The organic solution was washed with brine, dried (MgSO4) and solvent was removed in vacuo. The crude material was triturated from o-hexane (2 x 6mL) then diethyl ether to afford the title compound: RT = 3.98 min; mlz (ES+) = 343.0, 345.0 [M + H]+.

Reference： [1]Patent: WO2010/103333,2010,A1 .Location in patent: Page/Page column 24

18
[ 1001397-19-8 ]
[ 832715-51-2 ]
[ 1001397-20-1 ]

Yield	Reaction Conditions	Operation in experiment
71%		Step 10: 1-Methylethyl 4-({7-[2-fluoro-4-(methylsulfonyl)phenyl]-6,7-dihydro-5H- pyrrolo[2,3-c/]pyrimidin-4-yl}oxy)-1 -piperidinecarboxylate (10)To a stirred solution of NaH (0.73 g, 60% dispersion in mineral oil, washed with anhydrous toluene) and anhydrous THF (15 ml.) was added 9 (1.09 g, 5.80 mmol) in THF (15 ml_). The mixture was refluxed for 0.5 h and then cooled to RT. Compound 8 (2.0 g, mmol) in THF (30 ml.) was added and the reaction refluxed for 1.5 h. The reaction mixture was cooled to RT, poured into H2O (150 ml.) and then extracted with CH2CI2 (4 x 60 ml_). The combined organic layer was dried over Na2SO4, filtered, and then concentrated under reduced pressure. The crude product was purified by flash SiO2 column chromatography using CHCI3: MeOH (100:0 to 98:02) as eluent to afford 1.96 g (71%) of the title product 10 as a white solid. 1H NMR (400 MHz, DMSO-d6): delta 8.22 (s, 1 H), 7.96 (app. t, J = 8.4 Hz, 1 H), 7.85 and 7.82 (dd, J1 = 1 1.2 Hz, J2 = 2.0 Hz, 1 H), 7.75 - 7.73 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1 H), 5.30 - 5.24 (m, 1 H), 4.76 (septuplet, J = 6.0 Hz, 1 H), 4.14 (t, J = 8.4 Hz, 2 H), 3.70 - 3.64 (m, 2 H), 3.25 (s, 3 H), 3.40 - 3.21 (m, 2 H), 3.05 (t, J = 8.8 Hz, 2 H), 1.95 - 1.90 (m, 2 H), 1.67 - 1.51 (m, 2 H), 1.17 (d, J = 6.0 Hz, 6 H); LCMS (ESI): m/z 479 (M + H)+.

Reference： [1]Patent: WO2008/8895,2008,A1 .Location in patent: Page/Page column 67
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 10972 - 10994

19
[ 1001399-11-6 ]
[ 832715-51-2 ]
[ 1001399-13-8 ]

Yield	Reaction Conditions	Operation in experiment
5%		Step 2: 1 -Methylethyl 4-[7-(5-cyano-2-pyridinyl)-6,7-dihydro-5H-pyrrolo[2,3- c/]pyrimidin-4-yl]oxy}-1 -piperidinecarboxylate (186) To a stirred solution of 9 (0.252 g, 1.35 mmol) and THF (2 mL) was added NaH (0.045 g, 95%, 1.89 mmol) and heated to 500C for 30 minutes. A solution of 185 (0.139 g, 0.54 mmol) in THF (3 mL) was added dropwise and the resulting mixture was refluxed for 16 h. The reaction mixture was cooled to RT, poured into H2O and then extracted with ethyl acetate. The combined organic layer was dried over MgSO4, filtered, and concentrated <n="160"/>under reduced pressure. The crude product was purified by recrystallization from methanol to give 0.012 g (5%) of the title product 186 as a white solid. 1H NMR (400 MHz, CDCI3): delta 8.85 - 8.90 (m, 1 H), 8.57 - 8.61 (m, 1 H), 8.42 (s, 1 H), 7.82 - 7.87 (m, 1 H), 5.33 - 5.42 (m, 1 H), 4.90 - 4.99 (m, 1 H), 4.35 (t, J = 8.61 Hz, 2 H), 3.74 - 3.89 (m, 2 H), 3.29 - 3.42 (m, 2 H), 3.07 (t, J = 8.06 Hz, 2 H), 1.94 - 2.08 (m, 2 H), 1.70 - 1.83 (m, 2 H), 1.27 (d, J = 6.23 Hz, 6 H); LCMS (ESI): m/z 409 (M + H)+.

Reference： [1]Patent: WO2008/8895,2008,A1 .Location in patent: Page/Page column 158; 159
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 10972 - 10994

20
[ 1001399-57-0 ]
[ 832715-51-2 ]
[ 1001399-58-1 ]

Yield	Reaction Conditions	Operation in experiment
7%		Step 5: 1 -Methylethyl 4-({2-amino-7-[2-fluoro-4-(methylsulfonyl)phenyl]-6,7- dihydro-5H-pyrrolo[2,3-c/]pyrimidin-4-yl}oxy)-1 -piperidinecarboxylate (224) To a suspension of 60% NaH/mineral oil (70 mg, 1.8 mmol) in THF (3 mL) was added 1- methylethyl 4-hydroxy-1-piperidinecarboxylate (0.16 g, 0.87 mmol) and the mixture was heated to 5O0C for 30 min under N2 then cooled to O0C. This mixture was added to a solution of crude 4-chloro-7-[2-fluoro-4-(methylsulfonyl)phenyl]-6,7-dihydro-5/-/- pyrrolo[2,3-c/]pyrimidin-2-amine (223) (51 mg, 0.15 mmol) in THF(I mL). The mixture was heated to 6O0C for 4 h then partitioned between saturated NH4CI/H2O and EtOAc. The organic phase was dried over Na2SO4, concentrated, and purified by Si2O flash column chromatography using EtOAc:hexanes (0:100 to 70:30) as eluent to afford 5 mg (7%) of the title product 224 as an off-white solid. 1H NMR (400 MHz, CDCI3): delta 8.10 - 8.00 (br s, 1 H), 7.7 - 7.65 (m, 2 H), 5.30 (br s, 1 H), 4.90 (heptuplet, J = 6.0 Hz, 1 H), 4.85 - 4.60 (m, 2 H), 4.15 (br t, J = 7.7 Hz, 2 H), 3.85 - 3.70 (m, 2 H), 3.40 - 3.30 (m, 2 <n="183"/>H), 3.05 (s, 3 H), 2.95 (t, J = 8.5 Hz, 2 H), 2.00 - 1.95 (m, 2 H), 1.85 - 1.80 (m, 2 H), 1.24 (d, J = 6.0 Hz, 6 H); LCMS (ESI): m/z 494 (M+H)+.

Reference： [1]Patent: WO2008/8895,2008,A1 .Location in patent: Page/Page column 181; 182
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 10972 - 10994

21
[ 1001399-60-5 ]
[ 832715-51-2 ]
[ 1001399-61-6 ]

Yield	Reaction Conditions	Operation in experiment
23%		Step 3: 1 -Methylethyl 4-[7-[2-fluoro-4-(methylsulfonyl)phenyl]-2-(methylamino)- 6,7-dihydro-5H-pyrrolo[2,3-c/]pyrimidin-4-yl]oxy}-1-piperidinecarboxylate (227) To a suspension of 60% NaH/mineral oil (8.4 mg, 0.21 mmol) in THF (1.5 ml.) was added 1 -methylethyl 4-hydroxy-1-piperidinecarboxylate (20 mg, 0.1 1 mmol) and the mixture was heated to 50 0C for 30 min under N2 then cooled to O0C. This mixture was added to a solution of 4-chloro-7-[2-fluoro-4-(methylsulfonyl)phenyl]-lambda/-methyl-6,7- dihydro-5H-pyrrolo[2,3-c/]pyrimidin-2-amine (226) (15 mg, 0.04 mmol) in THF(I ml_). The mixture was heated to 6O0C for 4 h then partitioned between saturated NH4CI/H2O and EtOAc. The organic phase was dried over Na2SO4, concentrated, and purified by preparative HPLC (C18 column, CH3CN:H2O gradient) followed by Si2O flash column chromatography using EtOAc:hexanes (0:100 to 70:30) as eluent to afford 5 mg (23%) of the title product 227 as an off-white solid foam. 1H NMR (400 MHz, CDCI3): 5 8.15 - 8.05 (br s, 1 H), 7.7 - 7.65 (m, 2 H), 5.30 (br s, 1 H), 4.90 (heptuplet, J = 6.0 Hz, 1 H), 4.85 - 4.60 (m, 1 H), 4.15 (br t, J = 7.3 Hz, 2 H), 3.85 - 3.70 (m, 2 H), 3.40 - 3.30 (m, 2 H), 3.05 (s, 3 H), 2.95 (t, J = 8.5 Hz, 2 H), 2.92 (d, J = 4.9 Hz, 3 H), 2.00 - 1.95 (m, 2 H), 1.85 - 1.80 (m, 2 H), 1.24 (d, J = 6.0 Hz, 6 H); LCMS (ESI): m/z 508 (M+H)+.

Reference： [1]Patent: WO2008/8895,2008,A1 .Location in patent: Page/Page column 183
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 10972 - 10994

22
[ 1193-21-1 ]
[ 832715-51-2 ]
[ 871681-64-0 ]

Yield	Reaction Conditions	Operation in experiment
69.6%	With potassium tert-butylate; In tetrahydrofuran; at 0 - 23℃;Inert atmosphere;	To a solution of <strong>[832715-51-2]isopropyl 4-hydroxypiperidine-1-carboxylate</strong> (660 mg, 3.52 mmol) and 4,6-dichloropyrimidine (500 mg, 3.36 mmol) in tetrahydrofuran (15 ml.) was added a 1 M solution of potassium te/t-butoxide in tetrahydrofuran (5.03 ml_, 5.03 mmol) at 0 degrees Celsius. The reaction mixture was allowed to slowly warmed to room temperature overnight. After 18 hours, the reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and then filtered, and the filtrate concentrated under reduced pressure. The crude residue was purified by column chromatography (0 - 50% ethyl acetate in heptane) to afford isopropyl 4-[(6-chloro-pyrimidin-4-yl)oxy]piperidine-1- carboxylate (700 mg, 69.6 %) as a colorless oil. 1H NMR (400 MHz, deuterochloroform) delta 1.25 (d, J=6.25 Hz, 6 H) 1.68 - 1.79 (m, 2 H) 1.94 - 2.03 (m, 2 H) 3.29 - 3.37 (m, 2 H) 3.75 - 3.83 (m, 2 H) 4.88 - 4.97 (m, 1 H) 5.28 - 5.36 (m, 1 H) 6.75 (d, J=0.78 Hz, 1 H) 8.55 (d, J=0.98 Hz, 1 H). LCMS (ES+): 300.3 (M+1 ).
67%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃;	Reference Example 14 1-methylethyl 4-[(6-chloropyrimidin-4-yl)oxy]piperidine-1-carboxylate; To a mixture of 4,6-dichloropyrimidine (1.58 g, 10.7 mmol) and <strong>[832715-51-2]isopropyl 4-hydroxypiperidine-1-carboxylate</strong> (2.01 g, 10.7 mmol) obtained in Reference Example 2 in N,N-dimethylformamide (50 mL) was added under ice-cooling sodium hydride (60%, oil, 450 mg, 11.3 mmol), 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 with saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated. The obtained residue was subjected to silica gel column chromatography (hexane-ethyl acetate 95:5 - 60:40, v/v) to give the title compound (2.15 g, yield 67%) as a white solid. Crystallization from hexane-ethyl acetate gave white crystals. 1H-NMR (300 MHz, CDCl3)delta:1.25 (d, J = 6.4 Hz, 6 H), 1.63 - 1.87 (m, 2 H), 1.86 - 2.22 (m, 2 H), 3.12 - 3.44 (m, 2 H), 3.67 - 4.02 (m, 2 H), 4.70 - 5.11 (m, 1 H), 5.33 (tt, J = 7.9, 3.8 Hz, 1 H), 6.76 (s, 1 H), 8.55 (s, 1 H).
44%		Preparation 5: Isopropyl 4-r(6-chloropyrimidin-4-yl)oxylpiperidine-1-carboxylateTo a solution of <strong>[832715-51-2]isopropyl 4-hydroxypiperidine-1-carboxylate</strong> (553 mg, 2.95 mmol) in anhydrous tetrahydrofuran (20 mL) was added potassium te/t-butoxide (0.450 g, 4.00 mmol) at 0 degrees Celsius. The reaction mixture was stirred at 65 degrees Celsius for 10 minutes. To the above mixture was added 4,6-dichloropyrimidine (0.400 g, 2.68 mmol). Then the resulting solution was stirred at 65 degrees Celsius for 1 hour. The mixture was cooled to ambient temperature, quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 20 : 1 ) to afford the product as a white solid (350 mg, 44 %).

44%		Isopropyl 4-r(6-chloropyrimidin-4-yl)oxylpiperidine-1-carboxylateTo a solution of <strong>[832715-51-2]isopropyl 4-hydroxypiperidine-1-carboxylate</strong> (553 mg, 2.95 mmol) in anhydrous tetrahydrofuran (20 ml.) was added potassium terf-butoxide (0.450 g, 4.00 mmol) at 0 degrees Celsius. The reaction mixture was stirred at 65 degrees Celsius for 10 minutes. To the above mixture was added 4,6-dichloropyrimidine (0.400 g, 2.68 mmol). Then the resulting solution was stirred at 65 degrees Celsius for 1 hour. The mixture was cooled to ambient temperature, quenched with water (100 ml.) and extracted with ethyl acetate (100 ml. x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 20 : 1 ) to afford the product as a white solid (350 mg, 44 %).
42%		To a solution of 2a (0.76 g, 4.06 mmol) in 10 mL of THF at room temperature, was added potassium tert-butoxide (0.65 g, 1.4 eq). The resulting mixture was stirred at room temperature for 30 minutes then 4,6-dichloropyrimidine (0.8 g, 1.3 eq) was added.The reaction mixture was stirred at room temperature for 16h then the solvent was removed under a stream of nitrogen. The residue was taken up with DCM and purified by flash chromatography (elution with 0-40% ethyl acetate and 0.1% TEA in hexanes) to give0.51 g of2b (42% yield).

Reference： [1]Patent: WO2010/128414,2010,A1 .Location in patent: Page/Page column 54
[2]Patent: EP2399914,2011,A1 .Location in patent: Page/Page column 93-94
[3]Patent: WO2011/36576,2011,A1 .Location in patent: Page/Page column 45
[4]Patent: WO2011/61679,2011,A1 .Location in patent: Page/Page column 51
[5]Patent: WO2010/149685,2010,A1 .Location in patent: Page/Page column 33
[6]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 1750 - 1755

23
[ 832715-51-2 ]
[ 1254360-62-7 ]
[ 1254361-04-0 ]

Yield	Reaction Conditions	Operation in experiment
31%		A mixture of ^(beta-chloro-pyrimidin^-yl^^-dihydro-I H-indole-delta-carboxylic acid (62.0 mg, 0.225 mmol) and <strong>[832715-51-2]4-hydroxypiperidine-1-carboxylic acid isopropyl ester</strong> (54.9 mg, 0.293 mmol) in anhydrous 1 ,4-dioxane (2.0 ml.) was heated to 105 degrees Celsius. After stirring for 5 minutes, a 1 M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (0.54 ml_, 0.54 mmol) was added. After 2 hours, the reaction mixture was diluted with water and concentrated under reduced pressure. The resulting residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate. The aqueous phase was extracted three times with dichloromethane, and the combined organic layers were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude residue was purified by column chromatography (20-70% ethyl acetate in heptane) to afford 1-[6-(1- isopropoxycarbonyl-piperidin^-yloxy^pyrimidin^-yO^^-dihydro-I H-indole-delta-carboxylic acid (30 mg, 31 %) as a white foam. 1H NMR (400 MHz, deuterochloroform) delta 1.24 (d, J=6.25 Hz, 6 H) 1.67 - 1.79 (m, 2 H) 1.93 - 2.05 (m, 2 H) 3.22 - 3.36 (m, 4 H) 3.75 - 3.87 (m, 2 H) 4.03 (t, J=8.69 Hz, 2 H) 4.87 - 4.97 (m, 1 H) 5.27 - 5.35 (m, 1 H) 5.97 (s, 1 H) 7.89 (s, 1 H) 7.98 (d, J=10.15 Hz, 1 H) 8.43 (d, J=8.00 Hz, 1 H) 8.49 (s, 1 H)

Reference： [1]Patent: WO2010/128414,2010,A1 .Location in patent: Page/Page column 90-91

24
[ 832715-51-2 ]
[ 1254360-68-3 ]
[ 1254361-09-5 ]

Yield	Reaction Conditions	Operation in experiment
55%		To a solution of isopropyl 4-hydroxypiperidine carboxylate (80.5 mg, 0.43 mmol) and anhydrous Lambda/,Lambda/-dimethylformamide (5 mL) was added sodium hydride (19 mg, 0.47 mmol), and the mixture was stirred for 20 minutes. 1-(6-Chloropyrimidin-4-yl)-2,3- dihydro-1 H-pyrrolo[3,2-b]pyridine (100 mg, 0.43 mmol) was added, and the reaction was heated at 60 degrees Celsius for 14 hours. The reaction was diluted with methyl fe/t-butyl ether and washed with water. The phases were separated, and the aqueous layer was extracted sequentially with methyl te/t-butyl ether and ethyl acetate. The combined organic extracts were washed with water followed by brine and then dried over sodium sulfate. The mixture was filtered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography (5% methanol/0.5% triethylamine in ethyl acetate) to give isopropyl 4-[6-(2,3-dihydro-1 H- pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-4-yl]oxy}piperidine-1 -carboxylate as a thick oil (90 mg, 55 %). 1H NMR (400 MHz, deuterochloroform): delta 8.63 (d, J=8.3 Hz, 0.5 H), 8.57 (d, J=8.3 Hz, 0.5 H), 8.60 (s, 0.5 H), 8.45 (s, 0.5 H), 8.16 (d, J=4.98 Hz, 0.5 H), 8.07 (d, J=4.98 Hz, 0.5 H), 7.10-7.15 (m, 1 H), 6.62 (s, 0.5 H), 5.92 (s, 0.5 H), 4.87-4.94 (m, 2 H), 4.00-4.13 (m, 2 H), 3.81-3.98 (m, 2 H), 3.30-3.4 (m, 2 H), 3.03-3.11 (m, 2 H), 1.83-2.03 (m, 2 H), 1.41-1.51 (m, 2 H), 1.17-1.26 (m, 6 H). LCMS (ES+): 384 (M+1 ).

Reference： [1]Patent: WO2010/128414,2010,A1 .Location in patent: Page/Page column 94-95

25
[ 524-38-9 ]
[ 832715-51-2 ]
[ 1259508-79-6 ]

Yield	Reaction Conditions	Operation in experiment
60%	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 18h;	Step 2A: Isopropyl 4-(l,3-Dioxo-l,3-dihydroisoindol-2-yloxy)piperidine-l-carboxylate (2a)4-Hydroxy-piperidine-l-carboxylic acid isopropyl ester (3.09 g, 17 mmol), N- hydroxyphthalimide (2.69 g, 17 mmol), and triphenylphosphine (4.32 g, 17 mmol) were combined in THF (30 mL). DEAD (2.6 mL, 17 mmol) was added and the mixture was stirred at room temperature for 18 h. The mixture was then concentrated under vacuum and the residue was purified by flash LC (elution with 10-50% ethyl acetate and 0.1% TEA in hexanes) to afford 3.31 g (60%) of 2a as a colorless oil: 1H NMR (300 MHz, CDCl3) delta 7.85-7.81 (m, 2 H), 7.83-7.29 (m, 2 H), 4.91 (quintet, J = 6.3 Hz, 1 H), 4.43 (septet, J = 3.9 Hz, 1 H), 3.94-3.86 (m, 2 H), 3.32-3.23 (m, 2 H), 1.99-1.78 (m, 4 H), 1.24 (d, J = 6.6 Hz, 6 H); LC-MS 333.1 (MH+).

Reference： [1]Patent: WO2010/149684,2010,A1 .Location in patent: Page/Page column 58

26
[ 3934-20-1 ]
[ 832715-51-2 ]
[ 1259510-83-2 ]
[ 1259510-82-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In tetrahydrofuran; at 0℃; for 1h;	2,4-Dichloro-pyrimidine (2.3 g) was added at 0 0C to a solution of 2a (3.1 g, 1 eq) and potassium tert-butoxide (1.74 g, 1 eq) in 20 mL of THF. The mixture was stirred for Ih then quenched with water. The product was extracted with ethyl acetate twice, washed with water and dried over sodium sulfate. The solvent was evaporated and the residue was taken up with methanol and dichloromethane and purified on silica gel (eluent: 20% ethyl acetate in hexane) to give a mixture of 12a and 12b. This was used directly on the next step.

Reference： [1]Patent: WO2010/149685,2010,A1 .Location in patent: Page/Page column 45

27
[ 1780-26-3 ]
[ 832715-51-2 ]
[ 1259510-75-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 8h;	4,6-Dichloro-2-methyl-pyrimidine (163 mg, 1 mmol) was dissolved in 4 mL of THF. A solution of tBuOK (112 mg, 1 mmol) and 2a (187 mg, 1 mmol) in 2 mL of THF was added slowly at room temperature. The mixture was stirred at room temperature for 8h and quenched with a saturated solution OfNH4Cl. The mixture was diluted with water and extracted with DCM. The organic layer was isolated, dried, filtered and evaporated to give 100 mg of 14a.

Reference： [1]Patent: WO2010/149685,2010,A1 .Location in patent: Page/Page column 46

28
[ 26452-80-2 ]
[ 832715-51-2 ]
[ 871681-78-6 ]
[ 871681-77-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In N,N-dimethyl-formamide; oil; at 90℃;	2,4-Dichloropyridine (0.52 g, 3.5 mmol) in 2 mL of DMF was added to a suspension of sodium hydride (60% in oil, 0.16 g, 3 eq) and 2a (0.55 g, 3 mmol) in 8 mL of DMF. The mixture was heated at 90 0C. The mixture was allowed to cool to room temperature, water was added to quench the excess sodium hydride and the solution was extracted with ethyl acetate twice, washed with a saturated solution of sodium bicarbonate, dried and evaporated. The crude material was purified on silica gel (eluent: 20% then 50% of ethyl acetate in hexane) to give 10a and 10b (0.55 g of the more polar product and 84 mg of the less polar product).

Reference： [1]Patent: WO2010/149685,2010,A1 .Location in patent: Page/Page column 43

29
[ 832715-51-2 ]
4-(2,3,5,6-tetrahydro-[1,3']bipyridinyl-4-ylideneaminooxy)piperidine-1-carboxylic acid isopropyl ester trifluoroacetate [ No CAS ]

Reference： [1]Patent: WO2010/149684,2010,A1

30
[ 832715-51-2 ]
[ 1259502-92-5 ]

Reference： [1]Patent: WO2010/149684,2010,A1

31
[ 832715-51-2 ]
[ 1259508-80-9 ]

Reference： [1]Patent: WO2010/149684,2010,A1

32
[ 832715-51-2 ]
[ 1259508-81-0 ]

Reference： [1]Patent: WO2010/149684,2010,A1

33
[ 832715-51-2 ]
[ 1259508-82-1 ]

Reference： [1]Patent: WO2010/149684,2010,A1

34
[ 832715-51-2 ]
4-[1(2-fluoro-4-methanesulfonylphenyl)piperidin-4-ylideneaminooxy]piperidine-1-carboxylic acid isopropyl ester trifluoroacetate [ No CAS ]

Reference： [1]Patent: WO2010/149684,2010,A1

35
[ 832715-51-2 ]
[ 1145657-67-5 ]

Reference： [1]Patent: WO2010/149685,2010,A1

36
[ 832715-51-2 ]
[ 1254361-09-5 ]

Reference： [1]Patent: WO2010/149685,2010,A1

37
[ 832715-51-2 ]
[ 1259510-46-7 ]

Reference： [1]Patent: WO2010/149685,2010,A1

38
[ 832715-51-2 ]
[ 1259510-52-5 ]

Reference： [1]Patent: WO2010/149685,2010,A1

39
[ 832715-51-2 ]
[ 1259510-71-8 ]

Reference： [1]Patent: WO2010/149685,2010,A1

40
[ 832715-51-2 ]
[ 1259510-78-5 ]
[ 1259510-79-6 ]

Reference： [1]Patent: WO2010/149685,2010,A1

41
[ 832715-51-2 ]
[ 1259510-47-8 ]

Reference： [1]Patent: WO2010/149685,2010,A1

42
[ 832715-51-2 ]
[ 1279698-90-6 ]

Reference： [1]Patent: WO2011/36576,2011,A1

43
[ 4316-97-6 ]
[ 832715-51-2 ]
[ 1279698-91-7 ]

Reference： [1]Patent: WO2011/36576,2011,A1

44
[ 832715-51-2 ]
[ 1279698-89-3 ]
[ 1279698-92-8 ]

Yield	Reaction Conditions	Operation in experiment
24%		Example 3: Isopropyl 4-{r5-cvano-6-(1 -methyl-4,6-dihvdropyrrolor3,4-clpyrazol-5(1 H)- yl)pyrimidin-4-ylloxy}piperidine-1-carboxylateTo a solution of <strong>[832715-51-2]isopropyl 4-hydroxypiperidine-1-carboxylate</strong> (77 mg, 0.63 mmol) in anhydrous tetrahydrofuran (4 mL) was added sodium bis(trimethylsilyl)amide (1.0M in anhydrous tetrahydrofuran, 0.63 mL, 0.63 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 2 hours. To the above mixture was added a solution of 4-chloro-6-(1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1 H)-yl)pyrimidine-5- carbonitrile from Preparation 7 (65 mg, 0.25 mmol) in anhydrous tetrahydrofuran (2 mL) at room temperature. The resulting mixture was stirred at 70 degrees Celsius for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (100 mL, three times). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC on a XBridge C18 column 150 x 30 mm eluting with a mobile phase of 66 % acetonitrile (0.05 % ammonium hydroxide as a modifier) in water (0.05 % ammonium hydroxide as a modifier) to afford the product as a white solid (25 mg, 24 %). 1 H NMR (400 MHz, deuterochloroform): delta 8.23 (s, 1 H), 7.24 (s, 1 H), 5.33-5.36 (m, 1 H), 4.83-4.89 (m, 5H), 3.80 (s, 3H), 3.64-3.70 (m, 2H), 3.38-3.41 (m, 2H), 1.80-1 .91 (m, 2H), 1 .75-1 .79 (m, 2H), 1.19-1.23 (d, J=6.4 Hz, 6H): LCMS (ES+): 434.4 (M+Na).

Reference： [1]Patent: WO2011/36576,2011,A1 .Location in patent: Page/Page column 49

45
[ 4316-97-6 ]
[ 832715-51-2 ]
[ 1308277-58-8 ]

Reference： [1]Patent: WO2011/61679,2011,A1

46
[ 832717-28-9 ]
[ 832715-51-2 ]
4-[3-(4-methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidin-7-yloxy]-piperidine-1-carboxylic acid isopropyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3134 - 3141

47
[ 832715-51-2 ]
[ 832714-07-5 ]
4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3134 - 3141

48
[ 832715-51-2 ]
[ 1145656-95-6 ]

Reference： [1]Patent: EP2399914,2011,A1

49
[ 832715-51-2 ]
[ 930093-71-3 ]