[ CAS No. 33024-60-1 ] {[proInfo.proName]}

Name: 33024-60-1|Tetrahydro-2H-pyran-4-amine hydrochloride|97%
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SKU: A155330
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Quality Control of [ 33024-60-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 33024-60-1 ]

Product Details of [ 33024-60-1 ]

CAS No. :	33024-60-1	MDL No. :	MFCD00100881
Formula :	C₅H₁₂ClNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KWZSCXIYGVEHOB-UHFFFAOYSA-N
M.W :	137.61	Pubchem ID :	44118693
Synonyms :

Calculated chemistry of [ 33024-60-1 ]

Physicochemical Properties

Num. heavy atoms :	8
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	34.79
TPSA :	35.25 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 :	Yes
Log Kp (skin permeation) :	-6.79 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	0.49
Log Po/w (WLOGP) :	0.93
Log Po/w (MLOGP) :	0.21
Log Po/w (SILICOS-IT) :	0.82
Consensus Log Po/w :	0.49

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.0
Solubility :	13.7 mg/ml ; 0.0996 mol/l
Class :	Very soluble
Log S (Ali) :	-0.8
Solubility :	21.8 mg/ml ; 0.159 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.34
Solubility :	62.6 mg/ml ; 0.455 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.41

Safety of [ 33024-60-1 ]

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 [ 33024-60-1 ]

* 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 [ 33024-60-1 ]
Downstream synthetic route of [ 33024-60-1 ]

[ 33024-60-1 ] Synthesis Path-Upstream 1~6

1
[ 675112-44-4 ]
[ 33024-60-1 ]

Reference： [1] Patent: WO2004/24728, 2004, A2, . Location in patent: Page 94
[2] Patent: US2009/131431, 2009, A1, . Location in patent: Page/Page column 76
[3] Patent: WO2007/36733, 2007, A1, . Location in patent: Page/Page column 154

2
[ 29943-42-8 ]
[ 33024-60-1 ]

Reference： [1] Patent: EP1535922, 2005, A1, . Location in patent: Page/Page column 40

3
[ 61128-73-2 ]
[ 33024-60-1 ]

Yield	Reaction Conditions	Operation in experiment
89%	With hydrogenchloride In 1,4-dioxane; methanol; ethanol	Step 2. Preparation of perhydro-2H-pyran-4-ylamine Hydrochloride. A mixture of 4-(hydroxyimino)-3,5,6-trihydro-2H-pyran (43.4 mmol) and Raney Nickel (200 mg) in ethanol was hydrogenated (90 psi) at room temperature for 3 days. The mixture was filtered through a pad of Celite, washed with MeOH, and concentrated. The residue was dissolved in MeOH, and treated with HCl (4 N in dioxane, 60 mmol), and concentrated to give perhydro-2H-pyran-4-ylamine hydrochloride (89percent).

Reference： [1] Patent: US2002/137939, 2002, A1,

4
[ 61128-73-2 ]
[ 33024-60-1 ]

Reference： [1] Patent: WO2007/36791, 2007, A1, . Location in patent: Page/Page column 42

5
[ 38041-19-9 ]
[ 33024-60-1 ]

Reference： [1] Patent: EP1661894, 2006, A1, . Location in patent: Page/Page column 9-10
[2] Patent: EP1661894, 2006, A1, . Location in patent: Page/Page column 11

6
[ 5337-03-1 ]
[ 33024-60-1 ]

Reference： [1] Angewandte Chemie - International Edition, 2018, vol. 57, # 30, p. 9501 - 9504[2] Angew. Chem., 2018, vol. 130, # 30, p. 9645 - 9648,4

[ 33024-60-1 ] Synthesis Path-Downstream 1~88

1
4-methyl-1H-indazole-5-carboxylic acid [ No CAS ]
[ 33024-60-1 ]
4-methyl-N-tetrahydro-2H-pyran-4-yl-1H-indazole-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52.7%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 4h;	Tetrahydro-2H-pyran-4-ylamine monohydrochloride (228 mg, 1.66 mmol), triethylamine (0.5 ml, 3.59 mmol), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide monohydrochloride (367 mg, 1.91 mmol) and hydroxybenzotriazole (190 mg, 1.41 mmol) were added to a solution of 4-methyl-1H-indazole-5-carboxylic acid (225 mg, 1.28 mmol) in N,N-dimethylformamide (5.5 ml), and the resulting mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogencarbonate solution. A small amount of the insoluble material was collected by filtration and then dried to obtain 4-methyl-N-tetrahydro-2H-pyran-4-yl-1H-indazole-5-carboxamide (41 mg). The filtrate was extracted with ethyl acetate and chloroform, and the combined organic layer was dehydrated over magnesium sulfate and then filtered. The filtrate was concentrated and the resulting residue was suspended in chloroform. The resulting suspension was filtered and the precipitate was dried to obtain 4-methyl-N-tetrahydro-2H-pyran-4-yl-1H-indazole-5-carboxamide (134 mg, 52.7percent).1H-NMR (DMSO-d6) delta; 1.45-1.58 (m, 2H), 1.76-1.80 (m, 2H), 2.58 (s, 3H), 3.33-3.42 (m, 2H), 3.84-4.03 (m, 3H), 7.29 (d, J=8.6Hz, 1H), 7.35 (d, J=8.6Hz, 1H), 8.13 (d, J=7.9Hz, 1H), 8.19 (d, J=0.9Hz, 1H), 13.11 (br, 1H).

Reference： [1]Patent: EP1403255,2004,A1 .Location in patent: Page 128

2
6-methyl-1H-indazole-5-carboxylic acid [ No CAS ]
[ 33024-60-1 ]
6-methyl-N-tetrahydro-2H-pyran-4-yl-1H-indazole-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In DMF (N,N-dimethyl-formamide);	Tetrahydro-2H-pyran-4-ylamine monohydrochloride (0.0402 g, 0.292 mmol), triethylamine (0.07 ml, 0.5 mmol), 1-hydroxybenztriazole (0.0460 g, 0.340 mmol) and 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide monohydrochloride (0.0606 g, 0.316 mmol) were added to a solution of 6-methyl-1H-indazole-5-carboxylic acid (0.0437 g, 0.248 mmol) in N,N-dimethylformamide (2 ml) and stirred overnight. A saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with chloroform (x 3), and the extract solution was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, followed by replacement with toluene (three times), whereby a solid was precipitated. The solid obtained was suspended in ethyl acetate and stirred to be washed, and then it was collected by filtration and dried under reduced pressure to obtain 6-methyl-N-tetrahydro-2H-pyran-4-yl-1H-indazole-5-carboxamide (0.0587 g, 91percent).1H-NMR (DMSO-d6) delta; 1.46-1.58 (2H, m), 1.75-1.82 (2H, m), 2.44 (3H, s), 3.39 (2H, td, J=1.9, 11.6Hz), 3.83-3.90 (2H, m), 3.91-4.02 (1H, m), 7.35 (1H, m), 7.73 (1H, s), 8.06 (1H, s), 8.23 (1H, d, J=7.7Hz), 13.01 (1H, br).

Reference： [1]Patent: EP1403255,2004,A1 .Location in patent: Page 130

3
(2R,3R,4R,5R)-4-(acetoxy)-2-(6-chloro-9H-purin-9-yl)-5-(prop-2-ynyl)tetrahydrofuran-3-yl acetate [ No CAS ]
[ 33024-60-1 ]
C₂₁H₂₅N₅O₆ [ No CAS ]
[ 674367-58-9 ]

Yield	Reaction Conditions	Operation in experiment
12%; 36%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; for 2.5h;	Intermediate [II] (43mg, 0. [114MMOL)] was reacted with 4-amino-tetrahydropyran hydrochloride salt (31 mg, 0. [23MMOL)] according to general procedure C (0. [45MMOL] DIPEA in isopropanol, heated for 2.5hours). Purification by preparative HPLC gave the desired product (purine N-9 linked to the 1-position of ribose) as a yellow gum, [(18MG,] 0.041 mmol, 36percent). m/z 444 [(MH +),] LCMS retention time 2.64min. The isomeric product (purine [N-7-LINKED)] was also obtained as a gum, (6mg, 0. [014MMOL,] 12percent). m/z 444 (MH +), LCMS retention time 2.52min.

Reference： [1]Patent: WO2004/26890,2004,A1 .Location in patent: Page 31; 32

4
[ 674367-27-2 ]
[ 33024-60-1 ]
[ 674367-41-0 ]

Yield	Reaction Conditions	Operation in experiment
79%	With N-ethyl-N,N-diisopropylamine; In propanal, 2-; at 90℃; for 6h;	Intermediate I (459mg, 1. [3MMOL),] [DIPEA] (1. [1 ML)] and 4-aminotetrahydropyran hydrochloride (219mg, 1. [6MMOL)] were heated in 2-propanal in a reacti-vial at [90°C] for 6 hours. The mixture was cooled to room temperature and evaporated. The residue was partitioned between ethyl acetate and saturated ammonium chloride. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organics were washed with saturated sodium bicarbonate, dried [(NA2SO4),] filtered and evaporated. The residue was purified by chromatography on silica using [BIOTAGENo., ]with cyclohexane containing ethyl acetate (60-80percent) as eluant, to give the desired intermediate (427mg, 79percent) as a white solid. LC/MS R5 2.70 min, mass spectrum [M/Z 430 [MH+].] An ice cold mixture of TFA-water (9: 1) (5mL) was added to the acetonide derivative (427mg, [1.] [OMMOL).] The mixture was left to stand at [0°C] overnight (17 hours) then added dropwise to a saturated solution of sodium bicarbonate, and extracted with ethyl acetate, dried [(NA2SO4),] filtered and evaporated. The residue was purified by chromatography on silica using [BIOTAGE,] with ethyl acetate containing ethanol (0-10percent) as eluant, to give the title compound (104mg, 27percent). 'H [NMR No. ] (DMSO) 1.56-1. 90 [(4H,] m), 3.36-3. 46 (2H, m), 3.49 [(1 H,] t), 3.63 [(1 H,] dd), 3.73 (1H, dd), 3.85-3. 94 (2H, m), 4.01-4. 07 (1H, m), 4.12-4. 17 (1H, m), 4.20 (2H, s), 4.26-4. 41 [(1 H,] m), 4.54-4. 62 (1H, m), 5.31 [(1 H,] d, OH), 5.52 (1H, d, OH), 5.91 (1H, d), 7.79 (1H, br. s, NH), 8.23 [(1 H,] s), 8.33 [(1 H,] s).

Reference： [1]Patent: WO2004/26890,2004,A1 .Location in patent: Page 22; 23

5
[ 675111-72-5 ]
[ 33024-60-1 ]
N-benzyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 85℃; for 16h;	Intermediate 17 (0. 031g, 0.1 mmol) was dissolved in acetonitrile (lml). [4-AMINOTETRAHYDROPYRAN HYDROCHLORIDE] (Intermediate 8A, [0.] [015G,] 0.11 mmol) and N, N- diisopropylethylamine (0. [08ML,] 0.5 mmol) were added and the mixture stirred under nitrogen at [85°C] for 16h, then concentrated in vacuo. The residue was partitioned between dichloromethane (DCM) and water. The layers were separated and the organic layer was concentrated in vacuo to afford Example 21 (0.027g). LCMS showed [MH+ =] [380] ; [TRET = 2. 92 MIN.]

Reference： [1]Patent: WO2004/24728,2004,A2 .Location in patent: Page 155

6
[ 33024-60-1 ]
[ 30720-25-3 ]
[ 675112-01-3 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 1 (2. [5G)] was dissolved in acetonitrile [(15ML).] 4-Aminotetrahydropyran hydrochloride [(1.] [LG)] and N, N-diisopropylethylamine (9. [4ML)] were added and the mixture stirred under nitrogen at [85°C] for 16h. A trace of starting material remained, so an additional portion of 4-aminotetrahydropyran hydrochloride [(O.] [L] lg) was added and stirring continued at [85°C] for a further [16H.] The mixture was then concentrated in vacuo. The residue was partitioned between DCM and water. The layers were separated and the organic layer was washed with further water [(2X20ML)] then dried [(NA2S04)] and concentrated in vacuo. The residue was further purified by chromatography using Biotage (silica, 90g), eluting with cyclohexane: ethyl acetate to afford Example 3 (2.45g). LCMS showed MH+ [= 319] ; TRET = 2. [90MIN.]

Reference： [1]Organic Process Research and Development,2010,vol. 14,p. 1153 - 1161
[2]Patent: WO2004/24728,2004,A2 .Location in patent: Page 150

7
[ 33024-60-1 ]
[ 41095-07-2 ]
[ 675114-55-3 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 85℃; for 24h;Product distribution / selectivity;	Alternative preparation of ethyl 1-ethyl-6-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H- pyrazolo[3,4-b]pyridine-5-carboxylate: 4-Aminotetrahydro-2/-/-pyran hydrochloride (e.g. see Intermediate 8A of WO 2004/024728 A2, 0.413g, 3.0mmol) is added to a mixture of ethyl 4-chloro-1-ethyl-6- methyl-1/-/-pyrazolo[3,4-]pyhdine-5-carboxylate (0.268g, LOmmol) and DIPEA (0.87ml, delta.Ommol) in MeCN (3ml). The resulting mixture is heated at 85 0C for 24 hours.Volatiles are removed in vacuo and the residue is dissolved in chloroform (1.5ml) and applied to a SPE cartridge (silica, 5g). The cartridge is eluted successively with Et2O, EtOAc and EtOAc-MeOH (9:1). Fractions containing the desired product (which might be contaminated with starting material) are combined and concentrated in vacuo. Further purification using a SPE cartridge (silica, 5g) eluting with EtOAc-cyclohexane (1 :3) affords ethyl 1-ethyl-6-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1/-/-pyrazolo[3,4- ]pyridine-5-carboxylate.
	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 85℃; for 24h;	4-Aminotetrahydropyran hydrochloride (Intermediate 8A, 0. [413G,] 3. 0mmol) was added to a mixture of Intermediate 51 (0.268g, [L.] Ommol) and N, N-diisopropylethylamine (0. [87ML,] [5.] [0MMOL)] in acetonitrile (3ml). The resulting mixture was heated at [85 °C FOR] 24 hours. Volatiles were removed in vacuo and the residue was dissolved in chloroform (1. [5ML)] and applied to a SPE cartridge (silica, 5g). The cartridge was eluted successively with [ET20,] EtOAc and EtOAc-MeOH (9/1). Fractions containing the desired product were combined and concentrated in vacuo to give the desired product contaminated with starting material (Intermediate [51).] Further purification using a SPE cartridge (silica, 5g) eluting with ethyl acetate-cyclohexane (1/3) afforded Example 189 (0.248g). LCMS showed [MH+ =] 333; [TRET] = 2.75min.

Reference： [1]Patent: WO2008/9735,2008,A1 .Location in patent: Page/Page column 122
[2]Patent: WO2004/24728,2004,A2 .Location in patent: Page 180

8
[ 675112-44-4 ]
[ 33024-60-1 ]

Yield	Reaction Conditions	Operation in experiment
		N, N-dibenzyltetrahydro-2H-pyran-4-amine (20. [5G)] was dissolved in ethanol [(210ML)] and hydrogenated over 10percent palladium on carbon catalyst (4g) at 100 psi for 72h at room temperature. The reaction mixture was filtered and the filtrate was adjusted to pH 1 with 2M-hydrogen chloride in diethyl ether. Evaporation of solvents gave a solid which was triturated with diethyl ether to give the product as a white solid (9. [23G). 1H] NMR [(400MHZ] in d6-DMSO, [27°C,] [SPPRN)] 8.24 (br. s, 3H), 3.86 (dd, 12,4Hz, 2H), 3.31 (dt, 2, [12HZ,] 2H), 3.20 (m, 1H), 1.84 (m, 2H), 1.55 (dq, 4, [12HZ,] 2H).
		N,N-dibenzyltetrahydro-2H-pyran-4-amine (20.5 g) is dissolved in ethanol (210 ml) and hydrogenated over 10percent palladium on carbon catalyst (4 g) at 100 psi for 72 h at room temperature. The reaction mixture is filtered and the filtrate is adjusted to pH 1 with 2M-hydrogen chloride in diethyl ether. Evaporation of solvents gives a residue (which may be a solid) which is triturated with diethyl ether to give the product (which may be a solid).
		Step 2: Tetrahydro-2H-pyran-4-amine hydrochloridelambda/,lambda/-dibenzyltetrahydro-2H-pyran-4-amine (20.5g) is dissolved in ethanol (210ml) and hydrogenated over 10percent palladium on carbon catalyst (4g) at 100 psi for 72h at room temperature. The reaction mixture is filtered and the filtrate is adjusted to pH 1 with 2M- hydrogen chloride in diethyl ether. Evaporation of solvents gives a residue (which may be a solid) which is triturated with diethyl ether to give the product (which may be a solid).

Reference： [1]Patent: WO2004/24728,2004,A2 .Location in patent: Page 94
[2]Patent: US2009/131431,2009,A1 .Location in patent: Page/Page column 76
[3]Patent: WO2007/36733,2007,A1 .Location in patent: Page/Page column 154

9
[ 299901-56-7 ]
[ 33024-60-1 ]
C₂₂H₃₀N₄O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A DMF (12 ml) solution of the compound of Reference Example 3 (340 mg) was mixed with tetrahydropyran-4-ylamine hydrochloride (367 mg) and potassium carbonate (672 mg), and the mixture was stirred in an oil bath of 50°C for 36 hours. After completion of the reaction, the reaction mixture was mixed with water and extracted with ethyl acetate. The insoluble matter was filtered, and the water layer was extracted with ethyl acetate. The organic layer was washed with water and then extracted with 1 M hydrochloric acid aqueous solution. The water layer was washed with chloroform, and then the water layer was adjusted to basic (pH 9 - 11) with saturated sodium bicarbonate aqueous solution and extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate and then concentrated under a reduced pressure. The resulting product was made into hydrochloride in the usual way and recrystallized from ethanol to obtain the title compound (77 mg).1H-NMR (DMSO-d6); 0.97 (s, 9 H), 1.71 (ddd, 2 H), 2.06 - 2.12 (m, 2 H), 3.27 - 3.38 (m, 3 H), 3.43 (br, 2 H), 3.47 (br, 3 H), 3.94 (dd, 2 H), 4.28 - 4.32 (m, 2 H), 7.66 (d, 1 H), 7.79 (d, 1 H), 8.24 (s, 1 H), 9.11 (s, 1 H), 9.32 - 9.54 (m, 2 H) MS (FAB +); 415 (M + 1).

Reference： [1]Patent: EP1486501,2004,A1 .Location in patent: Page 15

10
[ 33024-60-1 ]
(2E)-3-(1-benzhydryl-3-cyano-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-N-tetrahydro-2H-pyran-4-ylprop-2-enamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46.5%		Example 71 (2E)-3-(1-benzhydryl-3-cyano-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-N-tetrahydro-2H-pyran-4-ylprop-2-enamide To a solution of (2E)-3-(1-benzhydryl-3-cyano-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)propenoate (300 mg, 0.759 mmol) in THF (3 ml) were added DMF (0.03 ml) and oxalylchloride (0.0796 ml, 0.912 mmol), the mixture was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of <strong>[33024-60-1]tetrahydro-2H-pyran-4-ylamine hydrochloride</strong> (184 mg, 1.51 mmol), triethylamine (0.560 ml, 4.01 mmol) and THF (3 ml), the mixture was stirred under ice-cooling for 1 hour and at room temperature for 12 hours. The reaction solution was poured into water, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from hexane and ethyl acetate. Yield (amount) 173 mg, yield (rate) 46.5percent 1H-NMR (CDCl3) delta: 1.26-1.62 (2H, m), 1.84-1.90 (2H, m), 2.57 (3H, s), 2.75 (3H, s), 3.38-3.49 (2H, m), 3.92-4.10 (3H, m), 5.54 (1H, d, J = 8.2 Hz), 6.78 (1H, d, J = 15.8 Hz), 6.92 (1H, s), 7.20-7.45 (11H, m), 8.05 (1H, s). IR (KBr) cm-1; 3300, 2215, 1657, 1618, 1591, 1547, 1426, 1335, 912, 735, 698.

Reference： [1]Patent: EP1535922,2005,A1 .Location in patent: Page/Page column 41

11
[ 33024-60-1 ]
(2E)-3-{1-[bis(4-fluorophenyl)methyl]-3-cyano-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-(tetrahydro-2H-pyran-4-yl)prop-2-enamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66.7%		Example 79 (2E)-3-{1-[bis(4-fluorophenyl)methyl]-3-cyano-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-(tetrahydro-2H-pyran-4-yl)prop-2-enamide To a solution of (2E)-3-{1-[bis(4-fluorophenyl)methyl]-3-cyano-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (250 mg, 0.570 mmol) in THF (2.5 ml) were added DMF (0.025ml) and oxalylchloride (0.060 ml, 0.680 mmol), the mixture was stirred at room temperature for 1 hour and the solvent distilled off under reduced pressure. The residue was added under ice-cooling to a solution of <strong>[33024-60-1]tetrahydro-2H-pyran-4-ylamine hydrochloride</strong> (136 mg, 1.13 mmol), triethylamine (0.472 ml, 3.39 mmol) and THF (3 ml), and the mixture was stirred under ice-cooling for 2 hours and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the objective product as a solid material. The resultant material was recrystallized from hexane and ethyl acetate. Yield (amount) 200 mg, yield (rate) 66.7percent 1H-NMR (CDCl3) delta: 1.43-1.58 (2H, m), 1.87-1.92 (2H, m), 2.56 (3H, s), 2.75 (3H, s), 3.42-3.50 (2H, m), 3.94-4.05 (3H, m), 5.56 (1H, d, J = 7.8 Hz), 6.78 (1H, d, J = 15.3 Hz), 6.91-7.21 (9H, m), 7.43 (1H, d, J = 15.3 Hz), 7.92 (1H, s). IR (KBr) cm-1; 3277, 2924, 2216, 1661, 1607, 1549, 1510, 1231, 1161, 1013, 837, 801, 733.

Reference： [1]Patent: EP1535922,2005,A1 .Location in patent: Page/Page column 50

12
[ 29943-42-8 ]
[ 33024-60-1 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium formate;palladium 10% on activated carbon; In methanol; water; at 20℃;	Reference Example 17 Tetrahydro-2H-pyran-4-ylamine hydrochloride To a solution of tetrahydro-4H-pyran-4-one (4.30 g, 43.0 mmol) in methanol (112 ml) was added an aqueous solution (12.5 ml) of ammonium formate (25 g, 400 mmol). Insolubles were completely dissolved and then 10percent palladium carbon (5.1 g) was added thereto, which was stirred at room temperature overnight. After the insolubles were filtrated off to obtain a filtrate, which was concentrated, and to the residue was added ethanol (100 ml) and concentrated hydrochloric acid (7.5 ml). The solvent was distilled off under reduced pressure to give an objective product, which was collected by filtration and washed with ether. 1H-NMR (DMSO-d6) delta: 1.54-1.74 (2H, m), 1.82-1.98 (2H, m), 3.27-3.38 (3H, m), 3.87-3.94 (2H, m), 9.05 (3H, bs). IR (KBr) cm-1; 2966, 1377, 1163, 1088, 1015, 986, 862.

Reference： [1]Patent: EP1535922,2005,A1 .Location in patent: Page/Page column 40

13
[ 862997-24-8 ]
[ 33024-60-1 ]
C₂₂H₃₀F₃N₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 5; Intermediate 9 (192 mg, 0.538 mmol) was combined with 4-aminotetrahydropyran hydrochloride (81. 4 mg, 0.592 mmol) and diisopropylethylamine (113 VL, 0.946 mmol) in Ti (OiPr) 4 (3.5 mL). The resulting solution was stirred overnight at room temperature. Sodium borohydride (41 mg, 1.1 mmol) and methanol (2 mL) were added and the mixture was stirred at room temperature for 30 min. Water was added and the solid was filtered off and washed with methanol. The combined filtrates were evaporated to dryness and the crude product was extracted with EA (x3) and purified by preparative TLC (10percent MeOH/DCM) to give 12.5 mg of the title compound.

Reference： [1]Patent: WO2005/80371,2005,A1 .Location in patent: Page/Page column 60-61

14
[ 862997-48-6 ]
[ 33024-60-1 ]
C₂₇H₃₇F₆N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;Molecular sieve;	Step D; To a mixture of the compound described in Step C, Example 2 (240 mg, 0.455 mmol), 4- amino tetrahydrofuran HC1 salt (63 mg, 0.455 mmol), molecular sieve (9i, 200 mg), DIEA (7011L, 0.455 mmol) in DCM (15 mL), was added sodium triacetoxyborohydride (482 mg, 2.275 mmol) and the resulting mixture was stirred overnight at room temperature. The reaction was diluted with DCM, filtered through celite, and evaporated i7l vacuo. The residue was purified by preparative TLC (1000 micron, eluant: 6percent MeOH : 94percent DCM) to afford two separate single isomers (isomer 1, less polar, 75 mg, 28percent ; isomer 2, more polar, 58 mg, 22percent).

Reference： [1]Patent: WO2005/80371,2005,A1 .Location in patent: Page/Page column 58-59

15
[ 38041-19-9 ]
[ 33024-60-1 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In water; butan-1-ol;Product distribution / selectivity;	To a flask having an inner volume of 100 ml, made of glass and equipped with a stirring device, a thermometer and a reflux condenser were charged 30.0 g (158.7 mmol) of 4-hydrazinotetrahydropyran hydrochloride with a purity of 99percent and synthesized in the same manner as in Example 2(1), 3.0 g (0.70 mmol calculated as palladium atom) of 5percent by weight palladium/carbon (50percent wet product) and 150 ml of ethanol, and the mixture was reacted at 75°C for 24 hours under hydrogen atmosphere (0.1 MPa. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. When the concentrate was analyzed (internal standard method) by gas chromatography, 15.9 g (Reaction yield: 72percent) of 4-aminotetrahydropyran was found to be formed. Then, 200 ml of n-butyl alcohol and 17.4 g (166.8 mmol) of 12 mol/l hydrochloric acid were added to the concentrate, and the mixture was concentrated under reduced pressure to obtain 14.3 g (Isolation yield: 65percent) of 4-aminotetrahydropyran hydrochloride with a purity of 98percent (areal percentage by gas chromatography) as white crystals. Physical properties of the 4-aminotetrahydropyran hydrochloride were the same as those in Example 2(2).; To a flask having an inner volume of 100 ml, made of glass and equipped with a stirring device, a thermometer and a reflux condenser were charged 1.0 g (5.55 mmol) of 4-hydrazinotetrahydropyran hydrochloride with a purity of 99percent and synthesized in the same manner as in Example 2(1), 6.2 ml of ethanol, 1.2 ml (1.20 mmol) of 1 mol/l aqueous sodium hydroxide solution and 1.5 g (10 mmol) of copper (I) oxide, and the mixture was reacted at 65°C for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. When the concentrate was analyzed (internal standard method) by gas chromatography, 0.47 g (Reaction yield: 50percent) of 4-aminotetrahydropyran was found to be formed. Then, 5 ml of n-butyl alcohol and 10 ml (12.0 mmol) of 12 mol/l hydrochloric acid were added to the concentrate, and the resulting mixture was concentrated under reduced pressure to obtain 0.42 g (Isolation yield: 45percent) of 4-aminotetrahydropyran hydrochloride with a purity of 98percent (areal percentage by gas chromatography) as white crystals. Physical properties of the 4-aminotetrahydropyran hydrochloride were the same as those in Example 2(2).
	With hydrogenchloride; In water;Industry scale;Product distribution / selectivity;	To a flask having an inner volume of 20 L, made of glass and equipped with a stirring device, a thermometer, a dropping funnel and a reflux condenser were charged 5873 g (115 mol) of 98percent aqueous hydrazine solution and 2072 ml of ethanol, and the mixture was heated to 75°C with stirring. Then, a solution in which 2136 g (11.5 mol) of tetrahydropyranyl-4-methanesulfonate with a purity of 70percent had been dissolved in 2072 ml of ethanol was gradually added dropwise to the mixture, and the mixture was reacted at the same temperature for 4 hours with stirring. After completion of the reaction, the mixture was cooled to room temperature to obtain a reaction mixture comprising 4-hydrazinotetrahydropyran as a main product. Then, to a flask having an inner volume of 20 L, made of glass and equipped with a stirring device, a thermometer, a dropping funnel and a reflux condenser were charged 414.4 g (4.6 mol calculated as nickel atom) of 65percent by weight developed Raney nickel and 2072 ml of water, and the mixture was heated up to 60°C with stirring. Then, the reaction mixture was gradually added dropwise, and the resulting mixture was reacted at 80°C for 2 hours with stirring. After completion of the reaction, the reaction mixture was cooled up to 40°C, Raney nickel was filtered off, and the filtrate was concentrated under reduced pressure to obtain 818.0 g of the reaction solution containing 4-aminotetrahydropyran as a main product. To a flask having an inner volume of 20 L, made of glass and equipped with a stirring device, a thermometer, a dropping funnel, a reflux condenser and a distillation device under reduced pressure were charged the above reaction solution, 2072 ml (10.9 mol) of tetraethylenepentamine and 4100 ml of n-butyl alcohol, and the mixture was stirred at 80°C for 2 hours under reduced pressure. Then, 4-aminotetrahydropyran and n-butyl alcohol were removed by azeotropic distillation under reduced pressure. Thereafter, 4100 ml of n-butyl alcohol was added again, 4-aminotetrahydropyran and n-butyl alcohol were removed by azeotropic distillation under reduced pressure. This operation was repeated to three times to obtain 15000 ml of a distilled solution in total. To the distilled solution was added 575 ml (6.90 mol) of conc. hydrochloric acid, and then, the mixture was concentrated under reduced pressure. To the concentrate was again added 8200 ml of n-butyl alcohol, and water and n-butyl alcohol were removed by azeotropic distillation under reduced pressure. Then, 7460 ml of n-butyl alcohol and 3730 ml of ethanol were added to the residue, and the resulting mixture was once heated up to 115°C and stirred, then, it was gradually cooled to -5°C and stirred for 30 minutes. After the filtration, the filtrate was washed with cooled toluene and dried to obtain 788.9 g (Isolation yield based on tetrahydropyranyl-4-methanesulfonate: 50percent) of 4-aminotetrahydropyran hydrochloride with a purity of 99percent (internal standard method by gas chromatography) as white needle-like crystals. Physical properties of the 4-aminotetrahydropyran hydrochloride were the same as those in Example 2(2).

Reference： [1]Patent: EP1661894,2006,A1 .Location in patent: Page/Page column 9-10
[2]Patent: EP1661894,2006,A1 .Location in patent: Page/Page column 11

16
1-(tetrahydro-2H-pyran-4-yl)hydrazine hydrochloride [ No CAS ]
[ 33024-60-1 ]

Yield	Reaction Conditions	Operation in experiment
		To a flask having an inner volume of 500 ml, made of glass and equipped with a stirring device, a thermometer and a reflux condenser were charged 60.0 g (392 mmol) of 4-hydrazinotetrahydropyran hydrochloride with a purity of 99percent and synthesised in the same manner as in the above-mentioned (1), 12.0 g of a developed Raney nickel, 120 ml of ethanol and 120 ml of water, and the mixture was reacted at 75°C for 24 hours under hydrogen atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. Then, 200 ml of n-butyl alcohol and 50 ml (600 mmol) of 12 mol/l hydrochloric acid were added to the concentrate, and the mixture was concentrated under reduced pressure to obtain 38.5 g (Isolation yield: 70percent) of 4-aminotetrahydropyran hydrochloride with a purity of 98percent (areal percentage by gas chromatography) as white crystals. Physical properties of the 4-aminotetrahydropyran hydrochloride are as follows. CI-MS(m/e); 102 (M+1-HCl) 1H-NMR (DMSO-d6, delta (ppm)); 1.52 to 1.66 (2H, m), 1.84 to 1.90 (2H, m), 3.15 to 3.45 (3H, m), 3.84 to 3.89 (2H, m), 8.38 (3H, brs)

Reference： [1]Patent: EP1661894,2006,A1 .Location in patent: Page/Page column 8

17
benzoic acid 3R,4R-bis-benzoyloxy-5R-(2,6-dichloro-purin-9-yl)-tetrahydro-furan-2R-yl ester [ No CAS ]
[ 6192-52-5 ]
[ 33024-60-1 ]
[ 77-76-9 ]
{2,2-Dimethyl-6R-[6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-tetrahydro-(3AR,6AR)-furo[3,4-d][1,3]dioxol-4R-yl}-methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; N-ethyl-N,N-diisopropylamine; In methanol; isopropyl alcohol; acetone;	{2,2-Dimethyl-6R-[6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-tetrahydro-(3aR,6aR)-furo[3,4-d][1,3]dioxol-4R-yl}-methanol A mixture of benzoic acid 3R,4R-bis-benzoyloxy-5R-(2,6-dichloro-purin-9-yl)-tetrahydro-furan-2R-yl ester (8.25 g), tetrahydro-pyran-4-ylamine hydrochloride (1.92 g) and diisopropylethylamine (5.5 ml) in isopropanol (100 ml) was stirred under reflux, under nitrogen for 1.5 h. The solution was concentrated in vacuo and the residue was treated with potassium carbonate (4.5 g) in methanol (150 ml). After 24 h at 21° C. more potassium carbonate (4.5 g) was added and stirring was continued at 21° C. for 64 h. The solvent was evaporated in vacuo and the residue was absorbed on silica prior to purification by flash chromatography (250 g), with dichloromethane:methanol:ammonia (90:10:1) eluant to give an off-white foam (3.7 g). This material was dissolved in acetone (60 ml) and treated with para-toluenesulphonic acid monohydrate (2.0 g) and 2,2-dimethoxypropane (6 ml) and the resulting mixture was stirred at 22° C. overnight. The white suspension was concentrated in vacuo and the residue was partitioned between 8percent aqueous sodium bicarbonate and ethyl acetate. The aqueous layer was further extracted with ethyl acetate and combined organic extracts were washed with water, brine, dried (Na2SO4) and concentrated in vacuo to a foam which was purified by flash chromatography over silica (100 g) with ethyl acetate eluant to give the title compound as a colourless foam (3.49 g). TLC Silica (ethyl acetate) Rf=0.23.

Reference： [1]Patent: US6407076,2002,B1

18
methanolic ammonia [ No CAS ]
acetic acid 4R-acetoxy-2R-(6-chloro-purin-9-yl)-5R-trifluoromethoxymethyl-tetrahydro-furan-3R-yl ester [ No CAS ]
[ 33024-60-1 ]
[ 223761-50-0 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol;	EXAMPLE 1 N-(Tetrahydro-pyran-4-yl)-5'-O-trifluoromethyladenosine Acetic acid 4R-acetoxy-2R-(6-chloro-purin-9-yl)-5R-trifluoromethoxymethyl-tetrahydro-furan-3R-yl ester (170 mg), was heated under reflux with tetrahydro-pyran-4-ylamine hydrochloride (235 mg) and diisopropylethylamine (0.35 ml) in isopropanol (8 ml) for 20 h. After cooling, the solvent was removed in vacuo and saturated methanolic ammonia (15 ml) added and the solution allowed to stand at 22° C. for 3 h. The solvent was evaporated in vacuo and the crude product which was triturated with ether (6 ml) to afford the title compound as a colourless powder (96 mg). Mass spectrum m/z 420 (MH+); Microanalysis Found: C,45.7; H,4.9; N,16.3. C16H20F3N5O5 requires C,45.8; H,4.8; N,16.7percent.

Reference： [1]Patent: US6407076,2002,B1

19
{2,2-dimethyl-6R-[6-chloro-purin-9-yl]-tetrahydro-(3AR,6AR)-furo[3,4-d][1,3]dioxol-4R-yl}-methanol [ No CAS ]
[ 33024-60-1 ]
{2,2-Dimethyl-6R-[6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-tetrahydro-(3AR,6AR)-furo[3,4-d][1,3]dioxol-4R-yl}-methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In methanol; isopropyl alcohol;	{2,2-Dimethyl-6R-[6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-tetrahydro-(3aR,6aR)-furo[3,4-d][1,3]dioxol-4R-yl}-methanol A solution of {2,2-dimethyl-6R-[6-chloro-purin-9-yl]-tetrahydro-(3aR,6aR)-furo[3,4-d][1,3]dioxol-4R-yl}-methanol (2.00 g), tetrahydro-pyran-4-ylamine hydrochloride (926 mg) and diisopropylethylamine (2.67 ml) in propan-2-ol (15 ml) was heated under reflux under nitrogen for 24 h and left to cool to room temperature. The amber solution was concentrated under vacuum to give a brown oil which was purified by flash chromatography over silica (115 g) with ethyl acetate:methanol (195:5) eluant. This afforded the title compound as a white foam (2.2 g). TLC SiO2 (Methanol:ethyl acetate 5:195), Rf=0.30.

Reference： [1]Patent: US6407076,2002,B1

20
[ 61128-73-2 ]
aluminum nickel [ No CAS ]
[ 33024-60-1 ]

Yield	Reaction Conditions	Operation in experiment
89%	With hydrogenchloride; In 1,4-dioxane; methanol; ethanol;	Step 2. Preparation of perhydro-2H-pyran-4-ylamine Hydrochloride. A mixture of 4-(hydroxyimino)-3,5,6-trihydro-2H-pyran (43.4 mmol) and Raney Nickel (200 mg) in ethanol was hydrogenated (90 psi) at room temperature for 3 days. The mixture was filtered through a pad of Celite, washed with MeOH, and concentrated. The residue was dissolved in MeOH, and treated with HCl (4 N in dioxane, 60 mmol), and concentrated to give perhydro-2H-pyran-4-ylamine hydrochloride (89percent).

Reference： [1]Patent: US2002/137939,2002,A1

21
[ 253126-77-1 ]
[ 33024-60-1 ]
[ 7087-68-5 ]
(2R,3R,4S,5R)-2-(2H-Pyrazol-3-yl)-5-(6-tetrahydro-pyran-4-ylamino-purin-9yl)-tetrahydro-furan-3,4-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In methanol; dichloromethane; isopropyl alcohol;	EXAMPLE 29 (2R,3R,4S,5R)-2-(2H-Pyrazol-3-yl)-5-(6-tetrahydro-pyran-4-ylamino-purin-9yl)-tetrahydro-furan-3,4-diol (2R,3R,4S,5R)-2-(6-Chloro-purin-9-yl)-5-(2H-pyrazol-3-yl)-tetrahydro-furan-3,4-diol (35 mg) was dissolved in isopropanol (3 ml), N,N-di-isopropylethylamine (0.12 ml) and tetrahydro-pyran-4-ylamine hydrochloride (46 mg) were added, and the resulting solution was heated under reflux under nitrogen for 17 h. The solvent was removed in vacuo, the residue dissolved in methanol (10 ml), and 8percent sodium bicarbonate (3 ml) added, followed by silica gel (3 g). The solvents were removed in vacuo and the residue added to a flash column of silica gel packed in dichloromethane. Elution with dichloromethane-methanol (4:1) afforded the title compound as a clear viscous gum (5.2 mg). LCMS (system A) Rt=3.34 min. Mass spectrum m/z 388 (MH+)

Reference： [1]Patent: US6492348,2002,B1

22
[ 3056-18-6 ]
[ 96042-30-7 ]
[ 33024-60-1 ]
[ 253126-46-4 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In methanol; ethanol; isopropyl alcohol;	2-Chloro-N-(tetrahydro-pyran-4-yl)-adenosine A mixture of acetic acid 4R-acetoxy-5R-acetoxymethyl-2R-(2,6-dichloro-purin-9-yl)-tetrahydro-furan-3R-yl ester (10 g), diisopropylethylamine (5.7 ml), and 4-amino tetrahydropyran hydrochloride (2.02 g), in isopropanol (200 ml) was heated at 50° for 4 h. The cooled mixture was evaporated in vacuo, the residue re-dissolved in methanol (200 ml) and ammonia gas bubbled through the solution for 2 h. The mixture was stirred at 22° C. overnight, and evaporated in vacuo to give a brown oily solid. Purification by flash chromatography on silica gel (Merck 9385), eluding with 75:8:1 DCM:EtOH:880 NH3 to 50:8:1 DCM:EtOH:880NH3, gave the title compound as a pale brown oily solid (7.81 g). LC/MS (System B) Rt 2.24 min. Mass spectrum m/z 3.86 [MH+].

Reference： [1]Patent: US6492348,2002,B1

23
methanolic ammonia [ No CAS ]
Acetic acid 4S-acetoxy-2R-(2,6-dichloro-purin-9-yl)-5S-fluoromethyl-tetrahydro-furan-3R-yl ester [ No CAS ]
[ 33024-60-1 ]
[ 223774-69-4 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol;	EXAMPLE 3 2-Chloro-5'-deoxy-5'-fluoro-N-(tetrahydro-pyran-4-yl)-adenosine Acetic acid 4S-acetoxy-2R-(2,6-dichloro-purin-9-yl)-5S-fluoromethyl-tetrahydro-furan-3R-yl ester (50 mg) was heated at 55-58° C. with 4-aminotetrahydropyran hydrochloride (33 mg) and diisopropylethylamine (0.125 ml) in isopropanol (5 ml) for 21 h. On cooling to room temperature, methanolic ammonia (4 ml) was added, and the mixture was allowed to stand at room temperature (22° C.) overnight (16 h). The mixture was evaporated to dryness in vacuo to give the crude product which was purified by solid phase extraction (5 g, Varian Mega Bondelut cartridge, aminopropyl bonded phase, eluding with (i) CHCl3, (ii) acetone, to give the title compound (47 mg).

Reference： [1]Patent: US6455510,2002,B1

24
[ 253126-45-3 ]
[ 33024-60-1 ]
(2S,3S,4R,5R)-2-(5-tert-butyl-[1,3,4]oxadiazol-2-yl)-5-[6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol;	EXAMPLE 3 (2S,3S,4R,5R)-2-(5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-5-[6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol (2S,3S,4R,5R)-2-(5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-5-(6-chloro-purin-9-yl)-tetrahydro-furan-3,4-diol (41 mg) was heated under reflux with 4-aminotetrahydropyran hydrochloride (59 mg), diisopropylethylamine (0.11 ml), and isopropanol (5 ml) for 15 h. The solvent was evaporated in vacuo and the residue purified by chromatography on silica gel, eluding with ethyl acetate:methanol 100:0-90:10, to give the title compound (37 mg). LC/MS (System B) Rt 2.31 min. Mass Spectrum m/z 446 [MH+].

Reference： [1]Patent: US6492348,2002,B1

25
[ 253126-58-8 ]
[ 33024-60-1 ]
(2S,3S,4R,5R)-2-(5-ethyl-oxazol-2-yl)-5-[6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol;	EXAMPLE 16 (2S,3S,4R,5R)-2-(5-Ethyl-oxazol-2-yl)-5-[6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol To a solution of (2R,3R,4S,5S)-2-(6-chloro-purin-9-yl)-5-(5-ethyl-oxazol-2-yl)-tetrahydro-furan-3,4-diol (0.19 g), in isopropanol (15 ml) was added diisopropylethylamine (0.3 ml) and 4-aminotetrahydropyran hydrochloride (0.135 g). After stirring at reflux for 16 h, further diisopropylethylamine (0.2 ml) and 4-aminotetrahydropyran hydrochloride (60 mg) were added. Stirring was continued at reflux for a further 20 h before the mixture was cooled and concentrated in vacuo to give a yellow gum (0.8 g). Purification by chromatography on silica gel (Merck 7734) with dichloromethane:ethanol:ammonia (250:8:1)-(100:8:1), gave the title compound, as a white foam (0.182 g). Mass spectrum m/z 417 [MH+] NMR delta (CDCl3) 8.27 (1H,s,CH), 8.13 (1H,s,CH), 6.72 (1H,s,CH), 6.6-6.2 (1H,vbrs,-OH), 6.21 (1H,d,CH), 5.98 (1H,brd,NH), 5.31 (1H,d,CH), 4.79 (2H,m,2CH), 4.40 (1H,brs,CH), 4.02 (2H,brd,2CH equatorial), 3.57 (2H,t,2CH axial), 2.66 (2H,q,CH2), 2.07 (2H,brd,2CH equatorial), 1.63 (2H,brq,2*CH axial), 1.23 (3H,t,CH3).

Reference： [1]Patent: US6492348,2002,B1

26
[ 5909-24-0 ]
[ 33024-60-1 ]
[ 933794-99-1 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	Example 1: Synthesis of tert-butyl 4-['6-r2-methylphenyl)-7-oxo-8-(tetrahydro-2H'- pyran-4-yl)-7,8-dihvdropyridof2,3-cpipyrimidin-2-yl]ammo}piperidine-l-carboxylate (Compound No. 1) Step a: 2-MethylsuIfanyl-4-(tetrahydro-2H-pyran-4-ylamino)pyrimidine-5- carboxylic acid ethyl ester; To a suspension of ethyl-4-chloro-2-methylthio-5-pyrimidine carboxylate (commercially available) (3.0 g, 12 mmol) in dry tetrahydrofuran (50 mL) was added triethylamine (2.6 g, 25 mmol) and <strong>[33024-60-1]tetrahydro-2H-pyran-4-ylamine hydrochloride</strong> (1.94 g, EPO <DP n="44"/>14 mmol) at room temperature and the mixture was stirred for 4 hours. The organic solvent was evaporated under reduced pressure followed by addition of cold water. The residue thus obtained was filtered, washed with water and dried under vacuum to yield the title compound. Yield = 2.7 g.

Reference： [1]Patent: WO2007/36791,2007,A1 .Location in patent: Page/Page column 42-43

27
[ 865713-68-4 ]
[ 33024-60-1 ]
[ 865713-74-2 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 115 - 120℃;Product distribution / selectivity;	Intermediate 2 Ethyl 1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate Ethyl 4-chloro-1,6-diethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (0.50 g) (e.g. this can be as prepared in Intermediate 1) was dissolved in 1-methyl-2-pyrrolidinone (5 ml) and treated with <strong>[33024-60-1]tetrahydro-2H-pyran-4-amine hydrochloride</strong> (0.49 g) [e.g. this can be as prepared in Intermediate 52A, see below] and DIPEA (0.60 ml) at 120° C. overnight. The mixture was allowed to cool and was partitioned between ethyl acetate (3.x.50 ml) and water (50 ml). The organic layer was separated, dried and evaporated in vacuo. The residue was purified on an SPE cartridge (e.g. solid phase can be ca. 20 g or ca. 50 g; e.g. can be silica) eluting with from 5percent to 20percent ethyl acetate in cyclohexane to give the title compound as pale yellow solid (0.413 g). LCMS showed MH+=347; TRET=3.05 min.; Intermediate 2 (Alternative Synthesis B) Ethyl 1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate To a solution of ethyl 4-chloro-1,6-diethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (36 g, 127.8 mmol) (which can e.g. be as prepared in Intermediate 1) in 1-methyl-2-pyrrolidinone (300 ml) is added DIPEA (44.5 ml, 255.6 mmol). Tetrahydro-2H-pyran-4-amine (e.g. available from Peakdale and/or Combi-Blocks Inc., 15.5 g, 153.3 mmol) is added and the reaction mixture is heated at 115° C. with stirring overnight. The cooled mixture is poured into water (1200 ml), which may form an oily mixture. This is extracted with EtOAc (4.x.250 ml), and the organic extracts are combined, washed with water (50 ml), 5percent aqueous LiCl solution (50 ml), dried (MgSO4), filtered and evaporated. The residue is purified by silica gel (1 kg) chromatography eluting with 2:1 cyclohexane:EtOAc (6000 ml) followed by 1:1 cyclohexane:EtOAc (3000 ml). The fractions containing product are pooled and evaporated to give the title compound.
	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 120℃;Product distribution / selectivity;	Intermediate 2 Ethyl 1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H- pyrazolo[3,4-fo]pyridine-5-carboxylateEthyl 4-chloro-1 ,6-diethyl-1H-pyrazolo[3,4-ib]pyridine-5-carboxylate (0.5Og) (e.g. this can be as prepared in Intermediate 1) was dissolved in 1-methyl-2-pyrrolidinone (5ml) and treated with <strong>[33024-60-1]tetrahydro-2H-pyran-4-amine hydrochloride</strong> (0.49g) [e.g. this can be as prepared in Intermediate 52A, see below] and DIPEA (0.60ml) at 12O0C overnight. The mixture was allowed to cool and was partitioned between ethyl acetate (3 x 50ml) and water (50ml). The organic layer was separated, dried and evaporated in vacuo. The residue was purified on an SPE cartridge (e.g. solid phase can be ca. 2Og or ca. 5Og; e.g. can be silica) eluting with from 5percent to 20percent ethyl acetate in cyclohexane to give the title compound as pale yellow solid (0.413g). LCMS showed MH+ = 347; TRET = 3.05min.

Reference： [1]Patent: US2009/131431,2009,A1 .Location in patent: Page/Page column 63-64
[2]Patent: WO2007/36733,2007,A1 .Location in patent: Page/Page column 131

28
[ 61128-73-2 ]
[ 33024-60-1 ]

Yield	Reaction Conditions	Operation in experiment
		Example A: Synthesis of tetrahydro-4H-pyran-4-amine hydrochloride Step a: Tetrahydro-4H-pyran-4-one oxime; To a solution of tetrahydro-4H-pyran-4-one (commercially available) (20 g, 200 mmol) in ethanol (300 mL) was added hydroxylamine hydrochloride (41.7 g, 600 mmol). An aqueous solution of sodium acetate (57.4. g, 700 mmol) was added into the reaction mixture at 40- 50 0C and refluxed overnight. The reaction mixture was concentrated under reduced pressure and the residue thus obtained was then extracted with ethyl acetate. The combined organic layer was then washed with water, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to yield the title compound. Yield = 17 g.

Reference： [1]Patent: WO2007/36791,2007,A1 .Location in patent: Page/Page column 42

29
[ 911417-62-4 ]
[ 33024-60-1 ]
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(tetrahydro-2H-pyran-4-yl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%		A suspension of 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2- yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP.(R). (40 mg, 0.077 mmol), DIEA (24 muL, 0.14 mmol) in dry CH2Cl2 : DMF (2 : 0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added <strong>[33024-60-1]tetrahydro-2H-pyran-4-amine hydrochloride</strong> (13 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP.(R). were added. After stirring the solution for 15 minutes, 0.65 equivalents of tetrahydro-2H- pyran-4-amine hydrochloride were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (15-40_90 mins) to afford 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2- yl)phenoxy)-N-(tetrahydro-2H-pyran-4-yl)acetamide. (32 mg, 0.065 mmol, 46 percent)
46%		A suspension of 2-(3-(4-( 1H-indazol-5-ylamino)quinazolin-2- yl)phenoxy)acetiotac acid (70 mg, 0 14 mmol), PyBOP* (40 mg, 0 077 mmol), DItA (24 muL, 0 14 mmol) in dry CH2CI5 DMF (2 0 1 ml.) was stirred at RT for 15 minutes To this solution of activated acid was added <strong>[33024-60-1]tetrahydro-2H-pyran-4-amine hydrochloride</strong> ( 13 mg. 0.091 nimol). After 30 minutes, 1.0 equivalent of DlEA and 0.55 equivalents of PyBOP* were added. After stirring the solution for 15 minutes, 0.65 equivalents of tetrahydro-2H- pyran-4-amine hydrochloride were added and the mixture was stirred for an additional 30 minutes. The solvent was removed //; vacuo and the caide product was purified using prep HPLC (15-40_90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2- yl)phenochiy)-N-(tetrahydro-2H-pyran-4-yl)acetamide. (32 mg, 0.065 mmol, 46 percent).
46%		[0250] A suspension of 2-(3-(4-(lH-indazol~5-ylamino)quinazolin-2- yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP.(R). (40 mg, 0.077 mmol), DIEA (24 muL, 0.14 mmol) in dry CH2Cl2 : DMF (2 : 0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added <strong>[33024-60-1]tetrahydro-2H-pyran-4-amine hydrochloride</strong> (13 mg, EPO <DP n="129"/>0.091 mmol). After 30 minutes, 1.0 equivalent of DlEA and 0.55 equivalents of PyBOP.(R). were added. After stirring the solution for 15 minutes, 0.65 equivalents of tetrahydro~2H- pyran-4-amine hydrochloride were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (15-40_90 mins) to afford 2-(3-(4-(lH-mdazol-5-ylamino)qumazolin-2- yl)phenoxy)-N-(tetrahydro-2H-pyran-4-yl)acetamide. (32 mg, 0.065 mmol, 46 percent)

Reference： [1]Patent: WO2008/54599,2008,A2 .Location in patent: Page/Page column 142-143
[2]Patent: WO2010/104851,2010,A1 .Location in patent: Page/Page column 138; 139
[3]Patent: WO2006/105081,2006,A2 .Location in patent: Page/Page column 127; 128

30
[ 1027351-81-0 ]
[ 33024-60-1 ]
[ 1027348-95-3 ]

Yield	Reaction Conditions	Operation in experiment
	With 1,8-diazabicyclo[5.4.0]undec-7-ene; triethylamine; In dichloromethane; at 20℃; for 16h;	Example 159: 3-Fluoro-8-isopropyl-11-oxo-/V-(tetrahydro-2W-pyran-4-yl)-10,11- dihydrodibenzo[6,/][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide <n="192"/>[0489] Triethylamine (0.173 g, 1.71 mmol), 7,11-diazabicyclo[5.4.0]undec-11 -ene (0.142 g, 0.930 mmol), and 4-aminotetrahydropyran hydrochloride (0.128 g, 0.930 mmol) were dissolved in dichloromethane (5 ml_), and 3-fluoro-8-isopropyl-5,5- dioxido-11 -oxo-10,11-dihydrodibenzo[6,f\|[1 ,4]thiazepine-7-sulfonyl chloride (6.25 mL of 0.124 M solution, 0.775 mmol) was added as a solution in dichloromethane. The mixture was stirred 16 hours at room temperature, then poured into dilute hydrochloric acid. The aqueous layer was extracted twice with dichloromethane, and the combined organic layers were dried over magnesium sulfate and concentrated to afford a brown oil, which was purified by silica gel column chromatography (hexane/ethyl acetate, 70/30 to 0/100) to afford 3-fluoro-8-isopropyl-11-oxo-lambda/- (tetrahydro-2H-pyran-4-yl)-10, 11 -dihydrodibenzo[6, /][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide (0.129 g) as a white solid. MS (ES) m/z 482.8;HPLC purity 100.0percent at 210-370 nm, 8.8 minutes.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 minutes, hold 4 minutes.

Reference： [1]Patent: WO2008/61029,2008,A1 .Location in patent: Page/Page column 190-191

31
[ 1027351-97-8 ]
[ 33024-60-1 ]
[ 1027349-10-5 ]

Yield	Reaction Conditions	Operation in experiment
	With 1,8-diazabicyclo[5.4.0]undec-7-ene; triethylamine; In dichloromethane; at 20℃; for 16h;	Example 168: 8-lsopropy 1-11 -oxo-/V-(tetrahydro-2W-py ran -4-yl )-10,11 - dihydrodibenzo[/),/][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide206 <n="208"/>[0506] Triethylamine (0.222 g, 2.19 mmol), 7,11-diazabicyclo[5.4.0]undec-11 -ene (0.182 g, 1.19 mnnol), and 4-aminotetrahydropyran hydrochloride (0.164 g, 1.19 mmol) were dissolved in dichloromethane (5 ml_), and 8-isopropyl-5,5-dioxido-11- oxo-10,11-dihydrodibenzo[6,f\|[1 ,4]thiazepine-7-sulfonyl chloride (6.25 mL of 0.159 M solution, 0.994 mmol) was added as a solution in dichloromethane. The mixture was stirred 16 hours at room temperature, then poured into dilute hydrochloric acid. The aqueous layer was extracted twice with dichloromethane, and the combined organic layers were dried over magnesium sulfate and concentrated to afford a brown oil, which was purified by silica gel column chromatography (hexane/ethyl acetate, 70/30 to 0/100) to afford 8-isopropyl-11 -oxo-/V-(tetrahydro-2H-pyran-4-yl)-10,11- dihydrodibenzo[ft,/][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide (0.87 g) as a white solid.MS (ES) m/z 464.9;HPLC purity 100.0percent at 210-370 nm, 8.4 minutes.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 minutes, hold 4 minutes.HRMS: calculated for C2I H24N2O6S2 + H+, 465.11485; found (ESI, [M+H]+), 465.1219;

Reference： [1]Patent: WO2008/61029,2008,A1 .Location in patent: Page/Page column 206-207

32
[ 4926-28-7 ]
[ 33024-60-1 ]
2-(N-(tetrahydro-2H-pyran-4-yl)amino)-4-methylpyridine [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2008,vol. 6,p. 437 - 439
[2]Journal of Medicinal Chemistry,2008,vol. 51,p. 5630 - 5640

33
[ 4926-28-7 ]
[ 33024-60-1 ]
[ 865-48-5 ]
2-(N-(tetrahydro-2H-pyran-4-yl)amino)-4-methylpyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.11 g (49%)	tris-(dibenzylideneacetone)dipalladium(0); In hexane; ethyl acetate; toluene;	4-Methyl-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine Example 3d Compound 3d was prepared according to general procedure B from 2-bromo-4-methylpyridine (0.20 g, 1.2 mmol), <strong>[33024-60-1]tetrahydro-2H-pyran-4-amine hydrochloride</strong> (0.19 g, 1.4 mmol), NaOt-Bu (0.27 g, 2.8 mmol), Pd2(dba)3 (21 mg, 0.023 mmol), BINAP (29 mg, 0.046 mmol), and toluene (30 mL) within 2 h at 70° C. flash chromatography: SiO2, from n-hexane/EtOAc 1:1 to 100percent EtOAc yield: 0.11 g (49percent)

Reference： [1]Patent: US2009/270462,2009,A1

34
1-(1,3-dimethoxypropan-2-yl)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid [ No CAS ]
[ 33024-60-1 ]
1-(1,3-dimethoxypropan-2-yl)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-N-(tetrahydro-2H-pyran-4-yl)-1,4-dihydroquinoline-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		-(l,3-Dimethoxypropan-2-yl)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2- yl)pypidin-3-yl)-4-oxo-l,4-dihydroquinoline-3-carboxylic acid (Example 4, 0.112 g, 0.18 mmol) was suspended in DMF (1 niL). O-(7-Azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HATU) (0.105 g, 0.28 mmol) was added, followed by diisopropylethylamine (0.193 mL, 1.11 mmol). The reaction mixture was stirred for 15 min at RT. The 4-aminotetrahydropyran hydrochloride (0.038 g, 0.28 mmol) was added in one portion and the mixture was stirred at RT for 2 days. Water was added and the resultant solid was purified by column chromatography (silica, 95:5 methylene chloride/methanol) to provide the product as a solid. The solid was further purified by trituration with CH2Cl2 and hexanes.LC/MS (ES+)[(M+H)+]: 689 for C32H35F3N6O6S1H NMR (DMSO^6): 59.99 (m, IH); 9.46 (s, IH); 8.93 (s, IH); 8.50 (s, IH); 8.32 (d, 2H); 8.24 (s, IH); 8.15 (d, IH); 7.73 (m, IH); 7.61 (m, IH); 5.45 (br s, IH); 3.92 (m, 7H); 3.45 (m, 2H); 3.25 (m, 8H); 1.87 (m, 2H); 1.50 (m, 2H); 1.11 (t, 3H).

Reference： [1]Patent: WO2009/147433,2009,A1 .Location in patent: Page/Page column 130-131

35
[ 897030-99-8 ]
[ 33024-60-1 ]
[ 1220812-03-2 ]

Yield	Reaction Conditions	Operation in experiment
51.7%	With triethylamine; In ethanol; water; for 72h;Reflux;	Scheme B; [00196] To a suspension of 4-chloro-5-iodo-6-methylpyrimidin-2-amine (16.0 g, 59.3 mmol) in EtOH (200 mL) and H2O (250 mL) was added triethylamine ( 30.0 mL, 207.5 mmol) and 4-aminotetrahydropyran HCl salt (9.75g, 71.2 mmol) successively. The reaction was heated to reflux, stirred for 72 h, and then cooled to RT. About 80percent of the solvent was evaporated under reduced pressure. The mixture was partitioned between ethyl acetate and H2O. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to afford the crude product. The product was purified by a flash chromatography (50percent ethyl acetate/hexanes to 100percent ethyl acetate) to afford 5-iodo-6-methyl-//-(tetrahydro-2H-pyran- 4-yl)pyrimidine-2,4-diamine as a light yellow crystal (yield: 10.23g, 51.7percent). LC/MS: calculated for Ci0Hi5IN4O (334.03); found: 335.08 (MH+). HPLC analytical purity: > 99.0 percent.

Reference： [1]Patent: WO2010/39740,2010,A1 .Location in patent: Page/Page column 40

36
[ 39906-04-2 ]
[ 33024-60-1 ]
[ 1231220-81-7 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 60 - 100℃;	In a 300 mL glass pressure reactor, combine 5-amino-4,6-dichloro-2-methylpyrimidine (20.0 g, 97percent, 109.0 mmol), 4-aminotetrahydropyran hydrochloride (21.0 g, 152.6 mmol), di-isopropylethylamine (57.0 mL, 326.9 mmol) and isopropyl alcohol (100 mL). Seal the pressure vessel tightly, start stirring, and adjust the set-point for heat control to 100° C. Stir the mixture at 100° C. for 24 hours. Cool the reactor contents to 60° C., vent the vessel of pressure, and add 4-aminotetrahydropyran hydrochloride (2.25 g, 16.3 mmol). Re-seal the vessel, heat the contents to an internal temperature of 100° C., and stir for an additional 24 hours. Cool the reaction mixture to ambient temperature, vent the reactor of pressure, and transfer the contents to a recovery flask. Concentrate the mixture under reduced pressure to approximately 1/3 of its original volume. Add water (200 mL) and ethyl acetate (200 mL) and transfer the resulting mixture to a separatory funnel Separate the layers, re-extract the aqueous layer with ethyl acetate (100 mL) and combine all organics. Wash with water (2100 mL) and brine (100 mL), then dry the organic layer over anhydrous sodium sulfate. Concentrate under reduced pressure to afford 6-chloro-2-methyl-N4*-(tetrahydro-2H-pyran-4-yl)-pyrimidine-4,5-diamine as an off-white solid (25.0 g). MS (m/z): 243/245 (M+1).

Reference： [1]Patent: US2010/160288,2010,A1 .Location in patent: Page/Page column 47

37
[ 83217-23-6 ]
[ 33024-60-1 ]
[ 1250868-19-9 ]
[ 1250868-18-8 ]

Yield	Reaction Conditions	Operation in experiment
25%		500 mg, 1.85 mmol) in dichloromethane (25 ml_) to give a white suspension. Tetrahydro-2H- pyan-4-amine, HCI (280 mg, 2.04 mmol) was added followed by addition of triethylamine (0.11 ml_, 5.55 mmol). The mixture was stirred at room temperature for 19 hours and was then heated under reflux for 21 hour. Excess potassium carbonate was added and heating under reflux was continued for 6 hours. The mixture was cooled to room temperature and stirred at room temperature for 2 weeks. LCMS showed formation of the expected product 6-chloro-2-(4- nitrophenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine along with the N,N-diethylamine product 6-chloro-N,N-diethyl-2-(4-nitrophenyl)pyrimidin-4-amine. The mixture was diluted with dichloromethane and washed with saturated NaHCO3. The organic phase was dried (MgSO4), filtered and concentrated. The crude product was purified by silica gel chromatography (20-60percent ethyl acetate in hexanes) to give two products: 6-chloro-2-(4-nitrophenyl)-N-(tetrahydro-2H- pyran-4-yl)pyrimidin-4-amine: 152 mg (25percent) of a yellow solid. HRMS: 335.0909 [M+H]+. For [M+H]+ mass error = 0.4 mDa or 1.15 ppm. 6-chloro-N,N-diethyl-2-(4-nitrophenyl)pyrimidin-4- amine: 72 mg. HRMS: 307.0962 [M+H]+. For [M+H]+ mass error = 0.5 mDa or 1.73 ppm.

Reference： [1]Patent: WO2010/120998,2010,A1 .Location in patent: Page/Page column 54; 83-84

38
[ 1250867-26-5 ]
[ 33024-60-1 ]
[ 1250868-21-3 ]
[ 1250868-20-2 ]

Yield	Reaction Conditions	Operation in experiment
		In a 2-5 mL microwave vial was placed 8-(6-chloro-2-(4-nitrophenyl)pyrimidin-4-yl)-3- oxa-8-azabicyclo[3.2.1]octane (36, 143 mg, 0.412 mmol) and tetrahydro-2H-pyran-4-amine.HCI (1 13 mg, 0.825 mmol) in dioxane to give a yellow suspension. Triethylamine (0.23 mL, 1.65 mmol) was added and the mixture was heated under microwave irradiation at 18O0C for 30 min, followed by heating at 22O0C for 30 min. Additional tetrahydro-2H-pyran-4-amine.HCI (1 13 mg) was added along with Hunig's base (0.25 mL) and the mixture was heated for 2.5 hours at 25O0C resulting in complete conversion of starting material into a mixture of products. The mixture contained among others 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-(4-nitrophenyl)-N- (tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine as well as 2-(4-aminophenyl)-6-(3-oxa-8- azabicyclobeta^.iloctan-delta-yO-N-^etrahydro^H-pyran-4-yOpyrimidin-4-amine. The mixture was concentrated and used in step 2 without further purification.

Reference： [1]Patent: WO2010/120998,2010,A1 .Location in patent: Page/Page column 55; 84-85

39
[ 33024-60-1 ]
1H-1-[3-(tetrahydropyran-4-yl)amino-2-carbamoylpyridin-5-yl]carbazole-4-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Patent: US2011/166169,2011,A1

40
[ 33024-60-1 ]
[ 1190424-24-8 ]

Reference： [1]Patent: US2011/166169,2011,A1

41
[ 33024-60-1 ]
[ 1190424-20-4 ]

Reference： [1]Patent: US2011/166169,2011,A1

42
[ 33024-60-1 ]
C₃₀H₂₆FN₅O₄ [ No CAS ]
C₃₀H₂₆FN₅O₄ [ No CAS ]

Reference： [1]Patent: US2011/166169,2011,A1

43
[ 33024-60-1 ]
[ 1190424-72-6 ]

Reference： [1]Patent: US2011/166169,2011,A1

44
(1-benzyl-3-methylimidazol-2-ylidene)(1,3-divinyltetramethyldisiloxane)platinum⁽⁰⁾ [ No CAS ]
[ 7553-56-2 ]
[ 33024-60-1 ]
trans-diiodo(N-4-aminotetrahydropyran)(1-methyl-3-benzylimidazol-2-ylidene)platinum(II) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; for 18h;	EXAMPLE 29trans-diiodo(N-4-aminotetrahydropyran)(1-methyl-3-benzylimidazol-2-ylidene)platinum(II)To a solution of the complex [1-methyl-3-benzylimidazol-2-ylidene](1,3-divinyl-1,1,3,3-tetramethyldisiloxane)]platinum(0), obtained in Step 1 of Example 5, (0.2 g, 0.361 mmol) in 5 ml of tetrahydrofuran at 0° C., there is added a solution of diiodine (96.2 mg, 0.379 mmol) in 5 ml of tetrahydrofuran. Next, a solution of 54.7 mg (0.397 mmol) of 4-aminotetrahydrohydropyran hydrochloride in 2 ml of tetrahydrofuran and 0.1 ml of diisopropylethylamine is added to the mixture. The reaction mixture is stirred for 18 h at room temperature and then evaporated to dryness. The residue obtained is purified by flash chromatography on silica gel, eluting with dichloromethane. 0.320 g (82percent) of trans-diiodo(N-4-aminotetrahydropyran)(1-methyl-3-benzylimidazol-2-ylidene)platinum(II) is thus obtained in the form of a yellow powder whose characteristics are the following:1H NMR spectrum (400 MHz, CDCl3) delta ppm: 1.54-1.72 (m, 2H) 2.20-2.35 (m, 2H) 2.94-3.20 (m, 2H) 3.37-3.64 (m, 3H) 3.94 (s, 3H) 3.97-4.09 (m, 2H) 5.63 (s, 2H) 6.62 (d, J=2.2 Hz, 1H) 6.84 (d, J=2.2 Hz, 1H) 7.35-7.46 (m, 3H) 7.45-7.52 (m, 2H).

Reference： [1]Patent: US2011/172199,2011,A1 .Location in patent: Page/Page column 24

45
[1-methyl-3-(4-trifluoromethylbenzyl)imidazol-2-ylidene](1,3-divinyl-1,1,3,3-tetramethyldisiloxane)platinum⁽⁰⁾ [ No CAS ]
[ 7553-56-2 ]
[ 33024-60-1 ]
trans-diiodo(N-tetrahydropyran-4-ylamine)(1-methyl-3-(4-trifluoromethylbenzyl)imidazol-2-ylidene)platinum(II) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃;	EXAMPLE 37trans-diiodo(N-tetrahydropyran-4-ylamine)(1-methyl-3-(4-trifluoro-methylbenzyl)imidazol-2-ylidene)platinum(II)To a solution of [1-methyl-3-(4-trifluoromethylbenzyl)imidazol-2-ylidene](1,3-divinyl-1,1,3,3-tetramethyldisiloxane)]platinum(0), obtained in Step 2 of Example 11, (0.4 g, 0.643 mmol) in 5 ml of tetrahydrofuran at 0° C., there is added a solution of diiodine (171.5 mg, 0.676 mmol) in 5 ml of tetrahydrofuran. Next, a solution of 71.6 mg (0.708 mmol) of 4-aminotetrahydropyran chloride in 2 ml of tetrahydrofuran and 0.1 ml of diisopropylethylamine is added to the mixture. The reaction mixture is stirred overnight at room temperature and then evaporated to dryness. The residue obtained is purified by flash chromatography on silica gel, eluting with a mixture of heptane and ethyl acetate (80/20 by volume), 180 mg (35percent) of trans-diiodo(N-tetra hydropyran-4-ylamine)(1-methyl-3-(4-trifluoromethyl benzyl)imidazol-2-ylidene)platinum(II) are thus obtained in the form of a yellow powder whose characteristics are the following:1H NMR spectrum (400 MHz, CDCl3) delta ppm: 1.61-1.68 (m, 2H) 2.26 (d, J=14.0 Hz, 2H) 2.96-3.18 (m, 2H) 3.35-3.62 (m, 3H) 3.96 (s, 3H) 3.99-4.08 (m, 2H) 5.73 (s, 2H) 6.65 (s, 1H) 6.90 (s, 1H) 7.54-7.65 (m, 2H) 7.66-7.73 (m, 2H)LC/MS: Column ACQUITY BEH C18 1.7 mum of 2.1.x.50 mm, at 50° C. Solvents: A=water containing 0.1percent of formic acid; B=acetonitrile containing 0.1percent of formic acid. Gradient: from 5 to 50percent of B in 0.8 min, and then from 50 to 100percent of B in 0.4 min, and then 0.65 min at 100percent of B, and then from 100 to 5percent of B in 0.15 min Flow rate: 1 ml/min Retention time=1.12 min

Reference： [1]Patent: US2011/172199,2011,A1 .Location in patent: Page/Page column 27

46
[ 1313733-33-3 ]
[ 33024-60-1 ]
[ 1313732-28-3 ]

Yield	Reaction Conditions	Operation in experiment
	In butan-1-ol; at 180 - 185℃;Microwave irradiation;	A solution of the appropriate chloride (1 eq) (ex: 5-chloro-6-methyl-3-(3- trifluoromethoxy-phenyl)-7,8-dihydro-6H-9-oxa-1 ,2,3a,4,6-pentaaza-cyclopenta- (ajnaphthalene) and the appropriate amine (3 to 5 eq) (ex: 1-methyl-piperidin-4- ylamine) in nBuOH (15 mL/mmol) was heated up to 180- 185°C under microwave irradiation for 5 h - 10 h (or 24 h at 160-180°C in a silicon bath). The solvent was evaporated under vacuum and the residue was purified by flash chromatography (Isolute/Flash, Sill, 2.5percent MeOH with 7N ammonia in DCM) or by semi-preparative HPLC (Gemini C18 (150 10 mm; 5 m), Solvent A: water with 0.1 percent formic acid; Solvent B: acetonitrile with 0.1 percent formic acid. Gradient: 40percent of A to 0percent of A).The NH-BOC-protected amines got deprotected in the reaction conditions and reacted giving a mixture of regioisomers. Amine: 4-aminotetrahydropyran hydrochlorideHPLC-MS (method 1): Rt=5.42 min, [M+Hfm/z 451.2.1H NMR (300 MHz, CDCI3) delta 8.58 (s, 1H), 8.47 - 8.41 (m, 1H), 7.53 (t, J = 8.1, 1H), 7.34 - 7.28 (m, 1H), 4.96 (d, J = 6.9, 1H), 4.53 - 4.43 (m, 2H), 4.05 (dt, J = 7.1, 3.8, 3H), 3.60 (td, J = 11.7, 2.1, 2H), 3.27-3.18 (m, 2H), 2.76 (s, 3H), 2.18 (dd, J = 12.3, 2.2, 2H), 1.73-1.55 (m, 2H).

Reference： [1]Patent: WO2011/80510,2011,A1 .Location in patent: Page/Page column 86-87; 98

47
C₁₆H₁₃ClF₃N₅O₂ [ No CAS ]
[ 33024-60-1 ]
[ 1313732-19-2 ]

Yield	Reaction Conditions	Operation in experiment
	In butan-1-ol; at 180 - 185℃;Microwave irradiation;	A solution of the appropriate chloride (1 eq) (ex: 5-chloro-6-methyl-3-(3- trifluoromethoxy-phenyl)-7,8-dihydro-6H-9-oxa-1 ,2,3a,4,6-pentaaza-cyclopenta- (ajnaphthalene) and the appropriate amine (3 to 5 eq) (ex: 1-methyl-piperidin-4- ylamine) in nBuOH (15 mL/mmol) was heated up to 180- 185°C under microwave irradiation for 5 h - 10 h (or 24 h at 160-180°C in a silicon bath). The solvent was evaporated under vacuum and the residue was purified by flash chromatography (Isolute/Flash, Sill, 2.5percent MeOH with 7N ammonia in DCM) or by semi-preparative HPLC (Gemini C18 (150 10 mm; 5 m), Solvent A: water with 0.1 percent formic acid; Solvent B: acetonitrile with 0.1 percent formic acid. Gradient: 40percent of A to 0percent of A).The NH-BOC-protected amines got deprotected in the reaction conditions and reacted giving a mixture of regioisomers. Amine: 4-aminotetrahydropyran hydrochlorideHPLC-MS (method 1 ): Rt = 6.06 min, [M+H]+ m/z 465.3.1H NMR (300 MHz, CDCI3) delta 8.61 (s, 1 H), 8.43 (d, J = 8.0 Hz, 1 H), 7.50 (m, 1 H), 7.26 (m, 1 H), 4.75 (d, J = 7.3 Hz, 1 H), 4.28 (m, 4H), 4.03 (m, 3H), 3.55 (m, 4H), 2.13 (m, 2H), 1.59 (m, 2H), 1.25 (t, J = 7.0 Hz, 3H).

Reference： [1]Patent: WO2011/80510,2011,A1 .Location in patent: Page/Page column 86-87; 93

48
[ 1331742-80-3 ]
[ 33024-60-1 ]
[ 1331741-81-1 ]

Yield	Reaction Conditions	Operation in experiment
54%	With triethylamine; In acetonitrile; at 150℃; for 4h;Microwave irradiation;	Route 2a Preparation of final product 2-10 The intermediate I-08, 5-chloro-3-(3-trifluoromethoxy-phenyl)-3H- [1 ,2,3]triazolo[4,5-b]pyridine (0.075 g; 0.238 mmol), was added to a microwave reaction vessel. Dry acetonitrile (2 mL) was added, followed by 4- aminotetrahydropyran hydrochloride (0.953 mmol, 4 eq) and triethylamine (0.953 mmol). The reaction was heated in the microwave reactor (Biotage) at 150 °C for 4h. Then, the solvent was evaporated and the reaction was worked up (DCM/Bicarb). The obtained crude product was purified on silica (Biotage 12M, EtOAc/CYhexane. EtOAc 5percent 5CV, Gradient to 50percent over 12 CV, Gradient to 100percent EtOAc over 3 CV, 100percent EtOAc 3 CV). Evaporation of the relevant fractions gave the desired final compound 2-10, tetrahydro-pyran-4-yl)-[3-(3- trifluoromethoxy-phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl]-amine; in total, 57 mgs of compound 2-10 were isolated (Y: 54percent), as beige-white solid.

Reference： [1]Patent: WO2011/101644,2011,A1 .Location in patent: Page/Page column 87

49
[ 1331742-81-4 ]
[ 33024-60-1 ]
[ 1331742-64-3 ]

Yield	Reaction Conditions	Operation in experiment
	With tris(dibenzylideneacetone)dipalladium(0) chloroform complex; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In 1,4-dioxane; at 100℃;	Route 2e Preparation of final product 2-93 Intermediate 1-10 (36 mg; 0.1 19 mmol), 4-aminotetrahydropyran chloridrate salt (33 mg; 0.237 mmol), rac-BINAP (7 mg; 0.012 mmol), NaOtBu (34 mg; 0.357 mmol) and Pd2DBA3 (5 mg; 0.006 mmol) was dissolved in dry, de-oxygenated dioxane (2 mL) and heated at 100 °C overnight. The solvent was evaporated and the residue was taken up in DCM, bicarbonate was added and it was extracted with DCM. The organic layers were separated, dried over Na2S0 , evaporated. The residue was purified in the biotage using a 25M cartridge and cyclohexane/ethyl acetate as solvents. The compound was in the column, so the purification was repeated using the same column, but dichloromethane/methanol as solvents.

Reference： [1]Patent: WO2011/101644,2011,A1 .Location in patent: Page/Page column 89; 90

50
[ 1334041-91-6 ]
[ 33024-60-1 ]
[ 7693-46-1 ]
[ 1334041-63-2 ]

Yield	Reaction Conditions	Operation in experiment
49%		Procedure: 4-Nitrophenyl chloroformate (43 mg, 0.216 mmol) was added to DIEA (18 mg, 0.135 mmol), DMAP (26 mg, 0.216 mmol) and carbamate 433 (15 mg, 0.027 mmol) in dry CH2C12 (1 mL) under N2 and allowed to stir for 12 hours. Tetrahydro-pyran-4-ylamine hydrochloride salt (11 mg, 0.081 mmol) was added. Then the mixture was stirred at room temperature for another 2 hours. TLC showed the reaction was completed. Water (15 mL) was added and the mixture was extracted with DCM (3 x 15 mL). The combined organic layers were dried over Na2S04, filtered and concentrated to give SW-127 which was purified by preparative HPLC (9.07 mg, 49percent). LCMS (m/z): [M+H]+ 685

Reference： [1]Patent: WO2011/109657,2011,A1 .Location in patent: Page/Page column 437

51
[ 1236404-96-8 ]
[ 33024-60-1 ]
[ 1236403-82-9 ]

Yield	Reaction Conditions	Operation in experiment
10%		Example 14 N-{8-methyl-3-[(tetrahydro-2H-pyran-4-ylamino)methyl]quinolin-7-yl}-4-(tetrahydrofuran-2-ylmethoxy)benzamide [Show Image] N-(3-Formyl-8-methylquinolin-7-yl)-4-(tetrahydrofuran-2-ylmethoxy)benzamide (2.5 g) obtained in Reference Example 2 and <strong>[33024-60-1]tetrahydro-2H-pyran-4-amine hydrochloride</strong> (1.37 g) were suspended in 1-methyl-2-pyrrolidone (20 mL) and acetic acid (7.0 mL) and the mixture was stirred at room temperature for 3 hr. Sodium triacetoxyborohydride (3.5 g) was added, and the mixture was stirred at room temperature for 3 hr. 1N Aqueous sodium hydroxide solution was added to quench the reaction and basify the mixture. The mixture was partitioned and extracted with ethyl acetate, the organic layer was added to a solution of citric acid (4.0 g) in water (40 mL)-dimethyl sulfoxide (20 mL), and the mixture was washed with ethyl acetate. 1N Aqueous sodium hydroxide solution was added to the aqueous layer, and the mixture was partitioned and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was recrystallized from ethyl acetate-diisopropyl ether to give the title compound (300 mg, yield 10percent) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) delta: 1.26 - 1.37 (2 H, m), 1.66 - 1.75 (1 H, m), 1.80-1.94 (4 H, m), 1.97 -2.06 (1 H, m), 2.42 (1 H, br), 2.59 - 2.69 (1 H, m), 2.64 (3 H, s), 3.23 - 3.39 (2 H, m), 3.69 (1 H, q, J=8.1 Hz), 3.76 - 3.85 (3 H, m), 3.94 (2 H, s), 3.98 - 4.10 (2 H, m), 4.17 - 4.21 (1 H, m), 7.08 (2 H, d, J=8.7 Hz), 7.57 (1 H, d, J=8.7 Hz), 7.77 (1 H, d, J=8.7 Hz), 8.01 (2 H, d, J=8.7 Hz), 8.21 (1 H, s), 8.90 (1 H, s), 10.04 (1 H, s). elemental analysis value (C28H33N3O4*1.0H2O) Calculated: C, 68.13; H, 7.15; N, 8.51. Found: C, 68.00; H, 6.97; N, 8.39.

Reference： [1]Patent: EP2392573,2011,A1 .Location in patent: Page/Page column 49

52
[ 1236405-08-5 ]
[ 33024-60-1 ]
[ 1236404-12-8 ]

Yield	Reaction Conditions	Operation in experiment
16%		Example 31 N-{8-methyl-3-[(tetrahydro-2H-pyran-4-ylamino)methyl]quinolin-7-yl}-4-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide [Show Image] N-(3-Formyl-8-methylquinolin-7-yl)-4-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide (3.0 g) obtained in Reference Example 9 and <strong>[33024-60-1]tetrahydro-2H-pyran-4-amine hydrochloride</strong> (3.0 g) were suspended in 1-methyl-2-pyrrolidone (20 mL) and acetic acid (7.0 mL) and the mixture was stirred at room temperature for 3 hr. Sodium triacetoxyborohydride (4.0 g) was added, and the mixture was stirred at room temperature for 3 hr. 1N Aqueous sodium hydroxide solution was added to quench the reaction and basify the mixture. The mixture was partitioned and extracted with ethyl acetate, the organic layer was added to a solution of citric acid (4.0 g) in water (40 mL)-dimethyl sulfoxide (20 mL), and the mixture was washed with ethyl acetate. 1N Aqueous sodium hydroxide solution was added to the aqueous layer, and the mixture was partitioned and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was recrystallized from ethyl acetate-diisopropyl ether to give the title compound (576 mg, yield 16percent) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) delta: 1.25 - 1.38 (2 H, m), 1.66 - 1.75 (1 H, m), 1.80 - 1.94 (4 H, m), 1.97 - 2.05 (1 H, m), 2.35 (1 H, br), 2.63 (3 H, s), 3.23 - 3.27 (2 H, m), 3.66 - 3.73 (1 H, m), 3.76 - 3.85 (4 H, m), 3.94 (2 H, s), 3.98 - 4.10 (2 H, m), 4.17 - 4.21 (1 H, m), 7.08 (2 H, d, J=9.0 Hz), 7.57 (1 H, d, J=9.0 Hz), 7.77 (1 H, d, J=9.0 Hz), 8.01 (2 H, d, J=9.0 Hz), 8.21 (1 H, s), 8.89 (1 H, s), 10.03 (1 H, s). melting point: 158-159°C elemental analysis value (C28H33N3O4) Calculated: C, 70.71; H, 6.99; N, 8.84. Found: C, 70.44; H, 6.84; N, 8.86.

Reference： [1]Patent: EP2392573,2011,A1 .Location in patent: Page/Page column 59-60

53
[ 1236405-00-7 ]
[ 33024-60-1 ]
[ 1236403-72-7 ]

Yield	Reaction Conditions	Operation in experiment
10%		Example 8 N-{8-methyl-3-[(tetrahydro-2H-pyran-4-ylamino)methyl]quinolin-7-yl}-4-(tetrahydrofuran-3-ylmethoxy)benzamide [Show Image] N-(3-Formyl-8-methylquinolin-7-yl)-4-(tetrahydrofuran-3-ylmethoxy)benzamide (1.5 g) obtained in Reference Example 4 and tetrahydra-2H-pyran-4-amine hydrochloride (743 mg) were suspended in 1-methyl-2-pyrrolidone (20 mL) and acetic acid (7.0 mL) and the mixture was stirred at room temperature for 3 hr. Sodium triacetoxyborohydride (2.35 g) was added and the mixture was stirred at room temperature for 3 hr. 1N Aqueous sodium hydroxide solution was added to quench the reaction and basify the mixture, and the mixture was partitioned and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [developing solvent; methanol:ethyl acetate=0:100 (volume ratio)-->methanol:ethyl acetate=20:80 (volume ratio)] to give the title compound (187 mg, yield 10percent) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) delta: 1.24 - 1.37 (2 H, m), 1.65 - 1.74 (1 H, m), 1.80 - 1.84 (2 H, m), 1.99 - 2.10 (1 H, m), 2.58 (2 H, s), 2.61 - 2.73 (1 H, m),2.63 (3 H, s), 3.22 - 3.39 (4 H, m), 3.54 - 3.63 (1 H, m), 3.66 - 3.75 (1 H, m), 3.77 - 3.85 (3 H, m), 3.94 (1 H, s), 3.98 - 4.08 (2 H, m), 7.08 (2 H, d, J=8.7 Hz), 7.57 (1 H, d, J=8.7 Hz), 7.77 (1 H, d, J=8.7 Hz), 8.02 (2 H, d, J=8.7 Hz), 8.20 (1 H, s), 8. 90 (1 H, s), 10.05 (1 H, s). elemental analysis value (C28H33N3O4*1.6H2O) Calculated: C, 66.67; H, 7.23; N, 8.33. Found: C, 66.50; H, 7.06; N, 8.03.

Reference： [1]Patent: EP2392573,2011,A1 .Location in patent: Page/Page column 45-46

54
[ 1236405-06-3 ]
[ 33024-60-1 ]
[ 1236403-93-2 ]

Yield	Reaction Conditions	Operation in experiment
14%		Example 20 N-{8-methyl-3-[(tetrahydro-2H-pyran-4-ylamino)methyl]quinolin-7-yl}-4-[(2R)-tetrahydrofuran-2-ylmethoxy]benzamide [Show Image] N-(3-Formyl-8-methylquinolin-7-yl)-4-[(2R)-tetrahydrofuran-2-ylmethoxy]benzamide (3.5 g) obtained in Reference Example 6 and <strong>[33024-60-1]tetrahydro-2H-pyran-4-amine hydrochloride</strong> (3.57 g) were suspended in 1-methyl-2-pyrrolidone (20 mL) and acetic acid (7.0 mL) and the mixture was stirred at room temperature for 3 hr. Sodium triacetoxyborohydride (4.0 g) was added, and the mixture was stirred at room temperature for 3 hr. 1N Aqueous sodium hydroxide solution was added to quench the reaction and basify the mixture. The mixture was partitioned and extracted with ethyl acetate, the organic layer was added to a solution of citric acid (4.0 g) in water (40 mL)-dimethyl sulfoxide (20 mL), and the mixture was washed with ethyl acetate. 1N Aqueous sodium hydroxide solution was added to the aqueous layer, and the mixture was partitioned and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was recrystallized from ethyl acetate-diisopropyl ether to give the title compound (583 mg, yield 14percent) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) delta: 1.28 - 1.33 (2 H, m), 1.69 - 1.73 (1 H, m), 1.78 - 1.86 (4 H, m), 1.98 - 2.03 (1 H, m), 2.53 - 2.58 (2 H, m), 2.64 (3 H, s), 3.23 - 3.30 (2 H, m), 3.66 - 3.83 (4 H, m), 3.94 (2 H, s), 4.01 - 4.06 (2 H, m), 4.16 - 4.20 (1 H, m), 7.08 (2 H, d, J=8.4 Hz), 7.57 (1 H, d, J=8.4 Hz), 7.77 (1 H, d, J=8.4 Hz), 8.01 (2 H, d, J=8.4 Hz), 8.20 (1 H, s), 8.90 (1 H, s), 10.04 (1 H, s). elemental analysis value (C28H33N3O4*0.75H2O) Calculated: C, 68.76; H, 7.11; N, 8.59. Found: C, 68.77; H, 7.09; N, 8.68.

Reference： [1]Patent: EP2392573,2011,A1 .Location in patent: Page/Page column 52-53

55
[ 33024-60-1 ]
[ 24241-18-7 ]
5-bromo-N₃-(tetrahydro-2H-pyran-4-yl)pyrazine-2,3-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 150℃; for 13h;Microwave irradiation;	PREPARATION 81 5-Bromo-3-(tetrahydro-2H-pyran-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one [Show Image]a) 5-Bromo-N3-(tetrahydro-2H-pyran-4-yl)pyrazine-2,3-diamine A mixture of 3,5-dibromopyrazin-2-amine (0.400 g, 1.6 mmol), <strong>[33024-60-1]tetrahydro-2H-pyran-4-amine hydrochloride</strong> (0.441 g, 3.20 mmol) and N,N-diisopropylethylamine (0.83 mL, 4.8 mmol) in n-butanol (3 mL) was stirred and heated under microwave irradiation ("Initiator sixty" from Biotage.(R).) at 150 °C. After 13 hours, the mixture was cooled and the mixture was partitioned between ethyl acetate and water. The organic layer was dried (MgSO4) and concentrated and the residue was purified by flash chromatography (2:1 hexanes/ethyl acetate) to give the title compound (0.34 g, 78percent) as a white solid. LRMS (m/z): 273, 275 (M+1)+.1H NMR (300 MHz, CDCl3) delta ppm 1.54 (dd, 2H), 1.97 - 2.18 (m, 2H), 3.57 (t, 2H), 3.93 - 4.21 (m, 5H), 7.26 - 7.28 (m, 1H), 7.47 (s, 1H).
78%	With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 150℃; for 13h;Microwave irradiation;	PREPARATION 81 5-Bromo-3-(tetrahydro-2H-pyran-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one a) 5-Bromo-N3-(tetrahydro-2H-pyran-4-yl)pyrazine-2,3-diamine A mixture of 3,5-dibromopyrazin-2-amine (0.400 g, 1.6 mmol), <strong>[33024-60-1]tetrahydro-2H-pyran-4-amine hydrochloride</strong> (0.441 g, 3.20 mmol) and N,N-diisopropylethylamine (0.83 mL, 4.8 mmol) in n-butanol (3 mL) was stirred and heated under microwave irradiation ("Initiator sixty" from Biotage.(R).) at 150 °C. After 13 hours, the mixture was cooled and the mixture was partitioned between ethyl acetate and water. The organic layer was dried (MgSO4) and concentrated and the residue was purified by flash chromatography (2:1 hexanes/ethyl acetate) to give the title compound (0.34 g, 78percent) as a white solid. LRMS (m/z): 273, 275 (M+1)+.1H NMR (300 MHz, CDCl3) delta ppm 1.54 (dd, 2H), 1.97 - 2.18 (m, 2H), 3.57 (t, 2H), 3.93 - 4.21 (m, 5H), 7.26 - 7.28 (m, 1H), 7.47 (s, 1H).

Reference： [1]Patent: EP2397482,2011,A1 .Location in patent: Page/Page column 90-91
[2]Patent: WO2011/157397,2011,A1 .Location in patent: Page/Page column 152-153

56
[ 33024-60-1 ]
[ 49845-33-2 ]
[ 899806-21-4 ]

Yield	Reaction Conditions	Operation in experiment
93%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -78℃; for 2.25h;Inert atmosphere;	PREPARATION 2 2-Chloro-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one [Show Image]a) 2-Chloro-5-nitro-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine Diisopropylethylamine (19.80 mL, 110 mmol) was added dropwise over 15 minutes to a stirred suspension of 2,4-dichloro-5-nitropyrimidine (11.56 g, 60 mmol) and <strong>[33024-60-1]tetrahydro-2H-pyran-4-amine hydrochloride</strong> (WO200424728 A2) (7.81 g, 60 mmol) in dichloromethane (400 mL) at -78 °C under a nitrogen atmosphere. The reaction mixture was stirred at -78 °C for 2 hours and then was allowed to warm to ambient temperature. The solvent was evaporated, water was added and the resultant solid was filtered, washed with water and dried to yield the title compound (13.62 g, 93percent) as a yellow solid. LRMS (m/z): 259 (M+1)+.1H NMR (300 MHz, CDCl3) delta ppm 1.62 - 1.80 (m, 2H), 2.06 (d, 2H), 3.59 (t, 2H), 4.04 (d, 2H), 4.45 (td, 1H), 8.33 (br s, 1H), 9.07 (s, 1H).
93%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -78℃; for 2.25h;Inert atmosphere;	PREPARATION 2 2-Chloro-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one a) 2-Chloro-5-nitro-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine Diisopropylethylamine (19.80 mL, 110 mmol) was added dropwise over 15 minutes to a stirred suspension of 2,4-dichloro-5-nitropyrimidine (11.56 g, 60 mmol) and <strong>[33024-60-1]tetrahydro-2H-pyran-4-amine hydrochloride</strong> (WO200424728 A2) (7.81 g, 60 mmol) in dichloromethane (400 mL) at -78 °C under a nitrogen atmosphere. The reaction mixture was stirred at -78 °C for 2 hours and then was allowed to warm to ambient temperature. The solvent was evaporated, water was added and the resultant solid was filtered, washed with water and dried to yield the title compound (13.62 g, 93percent) as a yellow solid. LRMS (m/z): 259 (M+1)+.1H NMR (300 MHz, CDCl3) delta ppm 1.62 - 1.80 (m, 2H), 2.06 (d, 2H), 3.59 (t, 2H), 4.04 (d, 2H), 4.45 (td, 1H), 8.33 (br s, 1H), 9.07 (s, 1H).
93%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -78 - 20℃;Inert atmosphere;	a)2-Chloro-5-nitro-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amineDiisopropylethylamine (19.80 mL, 110 mmol) was added dropwise over 15 minutes to a stirred suspension of 2,4-dichloro-5-nitropyrimidine (11.56 g, 60 mmol) and <strong>[33024-60-1]tetrahydro-2H-pyran-4-amine hydrochloride</strong> (prepared as described in ), 7.81 g, 60 mmol) in dichloromethane (400 mL) at -78 ºC under a nitrogen atmosphere.The reaction mixture was stirred at -78 ºC for 2 hours and then was allowed to warm to ambient temperature.The solvent was evaporated, water was added and the resultant solid was filtered, washed with water and dried to yield the title compound (13.62 g, 93percent) as a yellow solid.LRMS (m/z): 259 (M+1)+.1H NMR delta (300 MHz, CDCl3): 1.62-1.80 (m, 2H), 2.06 (d, 2H), 3.59 (t, 2H), 4.04 (d, 2H), 4.45 (td, 1 H), 8.33 (br s, 1 H), 9.07 (s, 1 H).

93%

With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -78℃; for 2.25h;Inert atmosphere;

PREPARATION 12-Chloro-9-(tetrahydro-2H^yran-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl}-7,9- dihydro-8H-purin-8-one a) 2-Chloro-5-nitro-yV-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amineLambda/,Lambda/'-Diisopropylethylamine (19.80 ml_, 1 10 mmol) was added dropwise over 15 minutes to a stirred suspension of 2,4-dichloro-5-nitropyrimidine (1 1.56 g, 60 mmol) and tetrahydro-2/-/-pyran-4-amine hydrochloride (prepared as described in WO200424728(A2), 7.81 g, 60 mmol) in dichloromethane (400 mL) at -78 °C under a nitrogen atmosphere. The reaction mixture was stirred at -78 °C for 2 hours and then was allowed to warm to ambient temperature. The solvent was evaporated, water was added and the resultant solid was filtered, washed with water and dried to yield the title compound (13.62 g, 93percent) as a yellow solid.LRMS (m/z): 259 (M+1 )+.1H NMR delta (300 MHz, CDCI3): 1 .62-1 .80 (m, 2H), 2.06 (d, 2H), 3.59 (t, 2H), 4.04 (d, 2H), 4.45 (td, 1 H), 8.33 (br s, 1 H), 9.07 (s, 1 H). b)

Reference： [1]Patent: EP2397482,2011,A1 .Location in patent: Page/Page column 33
[2]Patent: WO2011/157397,2011,A1 .Location in patent: Page/Page column 80-81
[3]Patent: EP2527344,2012,A1 .Location in patent: Page/Page column 20
[4]Patent: WO2012/160030,2012,A1 .Location in patent: Page/Page column 62-63

57
[ 33024-60-1 ]
[ 1299420-86-2 ]

Reference： [1]Patent: WO2011/157397,2011,A1
[2]Patent: EP2527344,2012,A1
[3]Patent: WO2012/160030,2012,A1

58
[ 33024-60-1 ]
[ 1299420-88-4 ]

Reference： [1]Patent: WO2011/157397,2011,A1
[2]Patent: EP2527344,2012,A1
[3]Patent: WO2012/160030,2012,A1
[4]Patent: WO2018/114999,2018,A1

59
[ 33024-60-1 ]
[ 1299420-90-8 ]

Reference： [1]Patent: WO2011/157397,2011,A1
[2]Patent: WO2018/114999,2018,A1

60
[ 33024-60-1 ]
[ 1352622-53-7 ]

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61
[ 33024-60-1 ]
[ 1352622-65-1 ]

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62
[ 33024-60-1 ]
[ 1352622-67-3 ]

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63
[ 33024-60-1 ]
[ 1352623-67-6 ]

Reference： [1]Patent: WO2011/157397,2011,A1
[2]Patent: EP2527344,2012,A1
[3]Patent: WO2012/160030,2012,A1

64
[ 33024-60-1 ]
[ 1352623-68-7 ]

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65
[ 33024-60-1 ]
[ 1352623-83-6 ]

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66
[ 33024-60-1 ]
[ 1352625-32-1 ]

Reference： [1]Patent: EP2397482,2011,A1
[2]Patent: WO2011/157397,2011,A1

67
[ 33024-60-1 ]
[ 1352625-66-1 ]

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[ 33024-60-1 ]
[ 1352625-67-2 ]

Reference： [1]Patent: WO2011/157397,2011,A1

69
[ 33024-60-1 ]
[ 82671-06-5 ]
[ 1352624-89-5 ]

Yield	Reaction Conditions	Operation in experiment
39%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 130℃; for 21h;Microwave irradiation;	PREPARATION 79 5-Chloro-6-fluoro-3-(tetrahydro-2H-pyran-4-yl)-1-[2-(trimethylsilyl)ethoxy] methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one [Show Image]a) 6-Chloro-5-fluoro-2-(tetrahydro-2H-pyran-4-ylamino)nicotinic acid A mixture of 2,6-dichloro-5-fluoronicotinic acid (1.01 g, 4.8 mmol), diisopropylethylamine (11 mL, 62.5 mmol) and <strong>[33024-60-1]tetrahydro-2H-pyran-4-amine hydrochloride</strong> (3.30 g, 24 mmol) in acetonitrile (5 mL) was stirred and heated under microwave irradiation ("Initiator sixty" from Biotage.(R).) at 130 °C for 21 hours. The mixture was then cooled and dichloromethane was added and the organic layer was washed with 5percent aqueous citric acid, water, brine, dried (MgSO4) and the solvent was evaporated. The residue was purified by reverse phase chromatography (C-18 silica from Waters.(C)., water/acetonitrile/methanol as eluents [0.1percent v/v formic acid buffered] 0percent to 100percent) to give the title compound (0.51 g, 39percent) of as a white solid. LRMS (m/z): 273 (M-1)+.1H NMR (300 MHz, CDCl3) delta ppm 1.48 - 1.69 (m, 2H), 1.97 - 2.14 (m, 2H), 3.58 (t, 2H), 4.03 (dd, 2H), 4.29 (ddd, 1H), 5.04 (d, 1H), 7.84 (d, 1H).
39%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 130℃; for 21h;Microwave irradiation;	PREPARATION 79 5-Chloro-6-fluoro-3-(tetrahydro-2H-pyran-4-yl)-1-[2-(trimethylsilyl)ethoxy] methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one a) 6-Chloro-5-fluoro-2-(tetrahydro-2H-pyran-4-ylamino)nicotinic acid A mixture of 2,6-dichloro-5-fluoronicotinic acid (1.01 g, 4.8 mmol), diisopropylethylamine (11 mL, 62.5 mmol) and <strong>[33024-60-1]tetrahydro-2H-pyran-4-amine hydrochloride</strong> (3.30 g, 24 mmol) in acetonitrile (5 mL) was stirred and heated under microwave irradiation ("Initiator sixty" from Biotage.(R).) at 130 °C for 21 hours. The mixture was then cooled and dichloromethane was added and the organic layer was washed with 5percent aqueous citric acid, water, brine, dried (MgSO4) and the solvent was evaporated. The residue was purified by reverse phase chromatography (C-18 silica from Waters.(C)., water/acetonitrile/methanol as eluents [0.1percent v/v formic acid buffered] 0percent to 100percent) to give the title compound (0.51 g, 39percent) of as a white solid. LRMS (m/z): 273 (M-1)+.1H NMR (300 MHz, CDCl3) delta ppm 1.48 - 1.69 (m, 2H), 1.97 - 2.14 (m, 2H), 3.58 (t, 2H), 4.03 (dd, 2H), 4.29 (ddd, 1H), 5.04 (d, 1H), 7.84 (d, 1H).
39%		a)6-Chloro-5-fluoro-2-(tetrahydro-2H-pyran-4-ylamino)nicotinic acidA mixture of 2,6-dichloro-5-fluoronicotinic acid (1.01 g, 4.8 mmol), diisopropylethylamine (11 mL, 62.5 mmol) and <strong>[33024-60-1]tetrahydro-2H-pyran-4-amine hydrochloride</strong> (prepared as described in ), 3.30 g, 24 mmol) in acetonitrile (5 mL) was stirred and heated under microwave irradiation at 130 °C for 21 hours.The mixture was then cooled, dichloromethane was added and the organic layer was washed with 5percent aqueous citric acid solution, water and brine, dried (MgSO4) and the solvent was evaporated.The residue was purified by reverse phase chromatography (C-18 silica from Waters©, water/acetonitrile/methanol as eluents [0.1percent v/v formic acid buffered] 0percent to 100percent) to give the title compound (0.51 g, 39percent) as a white solid.LRMS (m/z): 273 (M-1)+.1H NMR delta (300 MHz, CDCl3): 1.48-1.69 (m, 2H), 1.97-2.14 (m, 2H), 3.58 (t, 2H), 4.03 (dd, 2H), 4.29 (ddd, 1H), 5.04 (d, 1H), 7.84 (d, 1H).

39%

With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 130℃; for 21h;microwave irradiation;

a) 6-Chloro-5-fluoro-2-(tetrahydro-2H-pyran-4-ylamino)nicotinic acidA mixture of 2,6-dichloro-5-fluoronicotinic acid (1 .01 g, 4.8 mmol), diisopropylethylamine (1 1 ml_, 62.5 mmol) and tetrahydro-2/-/-pyran-4-amine hydrochloride (prepared as described in WO200424728(A2), 3.30 g, 24 mmol) in acetonitrile (5 mL) was stirred and heated under microwave irradiation at 130 °C for 21 hours. The mixture was then cooled, dichloromethane was added and the organic layer was washed with 5percent aqueous citric acid solution, water and brine, dried (MgS04) and the solvent was evaporated. The residue was purified by reverse phase chromatography (C-18 silica from Waters.(C)., water/acetonitrile/methanol as eluents [0.1 percent v/v formic acid buffered] 0percent to 100percent) to give the title compound (0.51 g, 39percent) as a white solid.LRMS (m/z): 273 (M-1 )+.1H NMR delta (300 MHz, CDCI3): 1 .48-1 .69 (m, 2H), 1 .97-2.14 (m, 2H), 3.58 (t, 2H), 4.03 (dd, 2H), 4.29 (ddd, 1 H), 5.04 (d, 1 H), 7.84 (d, 1 H).

Reference： [1]Patent: EP2397482,2011,A1 .Location in patent: Page/Page column 89
[2]Patent: WO2011/157397,2011,A1 .Location in patent: Page/Page column 150-151
[3]Patent: EP2527344,2012,A1 .Location in patent: Page/Page column 31-32
[4]Patent: WO2012/160030,2012,A1 .Location in patent: Page/Page column 134

70
[ 33024-60-1 ]
[ 1352622-69-5 ]

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71
[ 33024-60-1 ]
[ 1352623-87-0 ]

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72
[ 33024-60-1 ]
[ 1352623-92-7 ]

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73
[ 33024-60-1 ]
[ 1352623-91-6 ]

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74
[ 33024-60-1 ]
[ 1005492-05-6 ]

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75
[ 33024-60-1 ]
[ 1352625-02-5 ]

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76
[ 33024-60-1 ]
[ 1352625-00-3 ]

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77
[ 33024-60-1 ]
[ 1352625-01-4 ]

Reference： [1]Patent: WO2011/157397,2011,A1

78
[ 33024-60-1 ]
C₂₁H₁₉N₇O₄ [ No CAS ]

Reference： [1]Patent: WO2011/157397,2011,A1

79
[ 33024-60-1 ]
[ 82671-06-5 ]
[ 1352624-90-8 ]

Reference： [1]Patent: WO2011/157397,2011,A1
[2]Patent: WO2012/160030,2012,A1

80
[ 33024-60-1 ]
[ 1352625-53-6 ]

Reference： [1]Patent: WO2011/157397,2011,A1

81
[ 13923-34-7 ]
[ 33024-60-1 ]
[ 1352625-47-8 ]

Yield	Reaction Conditions	Operation in experiment
89%	With triethylamine; In dichloromethane; at 0 - 20℃;	b) 2-Chloro-6-mprpholin-4-yl-5-nitro-A/-(tetrahydro-2 -pyran-4-yl)pyrimidin-4- amine Triethylamine (0.567 mL, 4.07 mmol) was added to a cooled (0 °C) suspension of <strong>[33024-60-1]tetrahydro-2H-pyran-4-amine hydrochloride</strong> (prepared as described in WO200424728- A2, 280 mg, 2.03 mmol) in methylene chloride (8 mL). A solution of 4-(2,6-dichloro-5- nitropyrimidin-4-yl)morpholine (Preparation 112a, 379 mg, 1.36 mmol) in methylene chloride (8 mL) was then added and the resulting mixture was stirred at 0 °C for 1 hour and at ambient temperature overnight. An aqueous, saturated sodium hydrogen carbonate solution was added and the aqueous layer was separated and washed with methylene chloride (x3). The combined organic layers were dried (MgS04), the solvent was evaporated and the resulting crude was purified by flash chromatography (1 :9 hexanes/ethyl acetate to 100percent ethyl acetate) to give the title compound (414 mg, 89percent) as a yellow solid. LRMS (m/z): 344 (M+1)+ 1H NMR (300 MHz, CDCI3) delta ppm 8.42 (br. s., 1 H), 4.24 - 4.50 (m, 1 H), 3.92 - 4.06 (m, 2H), 3.71 - 3.84 (m, 4H), 3.46 - 3.64 (m, 6H), 1.95 - 2.09 (m, 2H), 1.53 - 1.74 (m, 2H).
89%	With triethylamine; In dichloromethane; at 20℃;Cooling with ice;	c)2-Chloro-6-morpholino-5-nitro-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amineA solution of <strong>[33024-60-1]tetrahydro-2H-pyran-4-amine hydrochloride</strong> (prepared as described in ), 0.280 g, 2.0 mmol) and triethylamine (0.57 mL, 4.1 mmol) in dichloromethane (4 mL) was added dropwise to a cooled (ice-bath), stirred solution of 4-(2,6-dichloro-5-nitropyrimidin-4-yl)morpholine (Preparation 23b, 0.379 g, 1.4 mmol) in dichloromethane (4 mL).The mixture was warmed to ambient temperature and stirred for 30 minutes.After this period the mixture was diluted with saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane.The organic extract was dried (MgSO4) and concentrated and the residue was purified by flash chromatography (4:1 hexanes/ethyl acetate) to give the title compound (0.414 g, 89percent) as a yellow solid.LRMS (m/z): 344(M+1)+.1H NMR delta (300 MHz, CDCl3): 1.57-1.63 (m, 2H), 2.00 (m, 2H), 3.56 (m, 6H), 3.77 (m, 4H), 3.99 (m, 2H), 4.34 (m, 1H), 8.40 (br s, 1H).
89%	With triethylamine; In dichloromethane; at 20℃; for 0.5h;Cooling with ice;	c) 2-Chloro-6-morpholino-5-nitro-W-(tetrahydro-2H^yran-4-yl)pyrimidin-4-amineA solution of tetrahydro-2/-/-pyran-4-amine hydrochloride (prepared as described in WO200424728(A2), 0.280 g, 2.0 mmol) and triethylamine (0.57 mL, 4.1 mmol) in dichloromethane (4 mL) was added dropwise to a cooled (ice-bath), stirred solution of 4-(2,6-dichloro-5-nitropyrimidin-4-yl)morpholine (Preparation 74b, 0.379 g, 1 .4 mmol) in dichloromethane (4 mL). The mixture was warmed to ambient temperature and stirred for 30 minutes. After this period the mixture was diluted with saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic extract was dried (MgS04) and concentrated and the residue was purified by flash chromatography (4:1 hexanes/ethyl acetate) to give the title compound (0.414 g, 89percent) as a yellow solid.LRMS (m/z): 344 (M+1 )+.1H NMR delta (300 MHz, CDCI3): 1 .57-1 .63 (m, 2H), 2.00 (m, 2H), 3.56 (m, 6H), 3.77 (m, 4H), 3.99 (m, 2H), 4.34 (m, 1 H), 8.40 (br s, 1 H).

Reference： [1]Patent: WO2011/157397,2011,A1 .Location in patent: Page/Page column 183
[2]Patent: EP2527344,2012,A1 .Location in patent: Page/Page column 33
[3]Patent: WO2012/160030,2012,A1 .Location in patent: Page/Page column 137

82
[ 33024-60-1 ]
[ 7693-46-1 ]
[ 932114-22-2 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -15 - 0℃; for 2h;	Step 5.1. 4-Nitrophenyl tetrahydro-2ff-pyran-4-ylcarbamateTo a solution of 5.00 g (36.3 mmol) of tetrahydro-2H-pyran- 4-yl-amine hydrochloride (CAS 38041-19-9) in 300 ml of dichloromethane, cooled to -15°C are added portionwise 13.2 g (65.4 mmol) of 4-nitrophenyl chloroformate (CAS 7693- 46-1) and then 12.7 ml (72.7 mmol) of diisopropylethylamine. Stirring is continued at -0°C for 2 hours, and 20 ml of saturated aqueous sodium hydrogen carbonate solution are then added. The organic phase is separated out by settling and dried over sodium sulfate and the solvent is evaporated off under reduced pressure. The residue is purified by chromatography on a column 80 g of silica gel, eluting with a mixture of 20percent acetone in dichloromethane, to give 8.26 g of 4-nitrophenyl tetrahydro-2H-pyran-4-ylcarbamate in the form of a white powder,m.p.: 174-176°CXH NMR (CDC13) delta : 8.25 (d, 2H) ; 7.35 (d, 2H) ; 5.10 (broad d, 1H) ; 4.05 (m d, 2H) ; 3.85 (m, 1H) ; 3.50 (t d, 2H) ; 2.0 (m, 2H) ; 1.60 (m, 2H) ppm.
8.26 g	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 2h;	To a solution of 5.00 g (36.3 mmol) of tetrahydro-2H-pyran-4-yl-amine hydrochloride (CAS 38041-19-9) in 300 ml of dichloromethane, cooled to -15° C. are added portionwise 13.2 g (65.4 mmol) of 4-nitrophenyl chloroformate (CAS 7693-46-1) and then 12.7 ml (72.7 mmol) of diisopropylethylamine. Stirring is continued at -0° C. for 2 hours, and 20 ml of saturated aqueous sodium hydrogen carbonate solution are then added. The organic phase is separated out by settling and dried over sodium sulfate and the solvent is evaporated off under reduced pressure. The residue is purified by chromatography on a column 80 g of silica gel, eluting with a mixture of 20percent acetone in dichloromethane, to give 8.26 g of 4-nitrophenyl tetrahydro-2H-pyran-4-ylcarbamate in the form of a white powder. m.p.: 174-176° C. 1H NMR (CDCl3) delta: 8.25 (d, 2H); 7.35 (d, 2H); 5.10 (broad d, 1H); 4.05 (m d, 2H); 3.85 (m, 1H); 3.50 (t d, 2H); 2.0 (m, 2H); 1.60 (m, 2H) ppm.

Reference： [1]Patent: WO2011/161537,2011,A2 .Location in patent: Page/Page column 67
[2]Patent: US2013/90340,2013,A1 .Location in patent: Paragraph 0524-0527

83
[ 33024-60-1 ]
[ 1352087-00-3 ]

Reference： [1]Patent: WO2011/161537,2011,A2

84
[ 33024-60-1 ]
[ 1246306-82-0 ]

Reference： [1]Patent: US2012/10241,2012,A1

85
[ 33024-60-1 ]
[ 1246306-83-1 ]

Reference： [1]Patent: US2012/10241,2012,A1

86
[ 33024-60-1 ]
[ 1414804-98-0 ]

Reference： [1]Patent: EP2527344,2012,A1
[2]Patent: WO2012/160030,2012,A1

87
[ 33024-60-1 ]
[ 1414805-56-3 ]

Reference： [1]Patent: EP2527344,2012,A1
[2]Patent: WO2012/160030,2012,A1

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[ 33024-60-1 ]
[ 1414804-99-1 ]

Reference： [1]Patent: EP2527344,2012,A1
[2]Patent: WO2012/160030,2012,A1

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H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 33024-60-1 ] {[proInfo.proName]}

Quality Control of [ 33024-60-1 ]

Related Doc. of [ 33024-60-1 ]

Product Details of [ 33024-60-1 ]

Calculated chemistry of [ 33024-60-1 ]

Physicochemical Properties

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Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

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Application In Synthesis of [ 33024-60-1 ]

[ 33024-60-1 ] Synthesis Path-Upstream 1~6

[ 33024-60-1 ] Synthesis Path-Downstream 1~88

Related Functional Groups of [ 33024-60-1 ]

Amines

Related Parent Nucleus of [ 33024-60-1 ]

Aliphatic Heterocycles

Tetrahydropyrans

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[ 33024-60-1 ]

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[ 33024-60-1 ]