1228947-14-5|trans-4-Morpholinocyclohexanol| Ambeed

Structure of 1228947-14-5

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Quality Control of [ 1228947-14-5 ] Purity: 95% SDS Specification

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Product Details of [ 1228947-14-5 ]

CAS No. :	1228947-14-5
Formula :	C₁₀H₁₉NO₂
M.W :	185.26
SMILES Code :	O[C@H]1CC[C@H](N2CCOCC2)CC1
MDL No. :	MFCD20259655
InChI Key :	AIFIVCWONKRRJQ-UHFFFAOYSA-N
Pubchem ID :	58205557

Safety of [ 1228947-14-5 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 1228947-14-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	0
Fraction Csp3	1.0
Num. rotatable bonds	1
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	55.01
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	32.7 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.25
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	0.2
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.24
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.64
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	1.17
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.9

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.05
Solubility	16.6 mg/ml ; 0.0894 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-0.45
Solubility	66.4 mg/ml ; 0.359 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-0.7
Solubility	37.1 mg/ml ; 0.2 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-7.29 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.55

Application In Synthesis of [ 1228947-14-5 ]

* 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.

Downstream synthetic route of [ 1228947-14-5 ]

[ 1228947-14-5 ] Synthesis Path-Downstream 1~35

1
[ 5414-19-7 ]
[ 27489-62-9 ]
[ 1228947-14-5 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In acetonitrile; at 60℃;	(0392) Trans-4-Aminocyclohexanol (0.5 g), 1-bromo-2-(2-bromoethoxyl)ethane (1.07 g) and triethylamine (2.42 ml) were dissolved in anhydrous acetonitrile (20 ml). The reaction mixture was heated at 60 C. overnight. The organic solvent was removed under vacuum. The residue was purified with flash column chromatography on silica gel eluting with 7%-10% methanol in dichloromethane to give the title compound.

References: [1]Patent: US10213433,2019,B2 .Location in patent: Page/Page column 90.

2
[ 64-18-6 ]
[ 62226-17-9 ]
[ 1228947-14-5 ]
4-[4-(thieno[2,3-b]pyridin-4-yloxy)cyclohexyl]morpholine formate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%		131. 4-(4-[thieno[2,3-b]pyridin-4-yloxy]cyclohexyl)morpholine.Page 221 of 4072009184-0008 Molecular Weight: 169.63 Molecular Weight: 379.191Into a 50-mL round-bottom flask, was placed a solution of 4-(morpholin-4-yl)cyclohexan-l-ol (164 mg, 0.89 mmol, 1.50 equiv) in N,N-dimethylformamide (15 mL), sodium hydride (47 mg, 1.96 mmol, 2.00 equiv). The resulting mixture was stirred at 80 C for 30 minutes. Then 4- chlorothieno[2,3-b]pyridine (100 mg, 0.59 mmol, 1.00 equiv) was added to the mixture. The resulting solution was stirred for 4 h at 120C in an oil bath. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 3x30 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x 15 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10: 1). The crude product (120 mg) was purified by Prep-HPLC with the following conditions: Column, SunFire Prep C18, 19* 150mm 5um; mobile phase, CH3CN and water with 0.05% HCOOH (10.0% water with 0.05% HCOOH up to 50.0% in 10 min, up to 100.0% in 2 min, down to 10.0% in 2 min); Detector, uv 254/220nm. This resulted in 72.2 mg (32%) of 4-(4-[thieno[2,3- b]pyridin-4-yloxy]cyclohexyl)morpholine as a white semi-solid. MS:(ES,/n/z): 319.10 [M+H]+ NMR (400 MHz, O20, ppm): 51.53-1.71 (m, 4H), 2.19-2.33 (dd, Jl= 29.7 Hz , J2= 9.3Hz, 4H), 3.24-3.30(m, 3H),3. 1(m, 2H), 4.07(s, 2H), 4.60(m, 1H), 6.98(d, J= 4.5 Hz , 1H), 7.37(d, J= 4.5Hz , 1H), 7.52(d, J= 4.5Hz , 1H), 8.33(d, J= 4.5Hz , 1H).

References: [1]Patent: WO2012/97013,2012,A1 .Location in patent: Page/Page column 221-222.

3
[ 1228947-14-5 ]
[ 1388894-15-2 ]

References: [1]Patent: WO2012/97013,2012,A1 .

4
[ 1228947-14-5 ]
[ 1388894-16-3 ]

References: [1]Patent: WO2012/97013,2012,A1 .

5
[ 1228947-14-5 ]
[ 1388894-17-4 ]

References: [1]Patent: WO2012/97013,2012,A1 .

6
[ 1228947-14-5 ]
[ 1388894-05-0 ]
[ 1388894-14-1 ]

Yield	Reaction Conditions	Operation in experiment
63%		Example 29: Synthesis of 2-((R)-4-(((lr,4R)-4-morpholinocyclohexyl)oxy)-6,7- dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-5-yl)acetamide.Page 280 of 4072009184-0008 33b[00638] Synthesis of compound 31b. 4-(Morpholin-4-yl)cyclohexan-l-ol (commercially available; 218 mg, 1.2 mmol, 1.50 equiv) was treated with NaH NMR (60% dispersion in mineral oil, 128 mg, 3.2 mmol, 4 equiv) in freshly distilled tetrahydrofuran (15 mL) for 30 min at 0 C in a water/ice bath under nitrogen. Then a solution of intermediate Hb (289 mg, 0.8 mmol, 1.00 equiv) in 5 mL of THF was added via syringe and the resulting solution was allowed to stir for an additional 3 h at 60 C in an oil bath. The reaction was then quenched with saturated aqueous NH4CI and extracted with 3 x 50 mL of ethyl acetate. The combined organic layers were washed with brine, dried (Na2S04) and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :5-1 :2) and purified to afford compound 31b (260 mg, 63%) as a colorless oil.[00639] Synthesis of compound 32b. To a solution of 31b (260 mg, 0.5 mmol, 1.0 equiv) in 10 mL of DCM was added 0.5 mL of concentrated hydrochloric acid in an ice/water bath. The resulting solution was stirred for 2 h and concentrated in vacuo. The residue was neutralized with saturated aqueous Na2C( j and extracted with 3 x 50 mL of ethyl acetate. The organic layers were combined, washed with brine, dried (Na2S04) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with DCM/MeOH NMR ( 15: 1 ) to afford the desired alcohol 32b ( 185 mg, 91 %) as a colorless oil.[00640] Synthesis of compound 33b. Alcohol 32b (185 mg, 0.46 mmol, 1.00 equiv) was oxidized with dipyridinium dichromate (752 mg, 2.00 mmol, 4.36 equiv) in 50 mL of DMF forPage 281 of 4072009184-0008 24 h at room temperature. The resulting solution was diluted with water and extracted with 3 x 50 mL of mixed solutions of CHCU/iso-PrOH. The organic layers were combined, dried (Na2S04) and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (5: 1 to 1 : 1 ) and purified to afford 105 mg (55%) of acid 33b as a yellow oil.[00641] Synthesis of Compound. A 50 mL round-bottom flask containing a solution of acid 33b (105 mg, 0.25 mmol, 1.00 equiv), NH4C1 (80 mg, 1.50 mmol, 6.00 equiv), EDCI (57 mg, 0.3 mmol, 1.2 equiv), 4-dimethylaminopyridine (37 mg, 0.3 mmol, 1.2 equiv) and HOBt (40 mg, 0.3 mmol, 1.2 equiv) in 5 mL of anhydrous DMF was stirred for 24 h at room temperature. The resulting solution was diluted with water and extracted with 4 x 50 mL of mixed solution of CHCI3: iso-PrOH. The combined organic layers were concentrated under vacuum. The crude product was purified by preparative HPLC (SHIMADZU) under the following conditions: column: SunFire Prep C I 8, 19* 150mm 5um; mobile phase: water (0.05% Nu¾?3) and CH3CN (6.0% CH3CN up to 50.0% in 25 min); UV detection at 254/220 nm. The product containing fractions were collected and concentrated to give the product (22.5 mg) as a white solid. MR (300 MHz, CD3OD) delta 8.43 (s, 1H), 5.27-5.20 (m, 1H), 3.80-3.70 (m, 5H), 3.29-3.27 (m, 1 H), 3.12-2.90 (m, 2H), 2.73-2.67 (m, 5H), 2.49-2.42 (m, 1H), 2.32-2.19 (m, 4H), 2.10-2.06 (d, 2H), 1.67- 1.46 (m, 4H). MS: m/z 417 (M+H)+.

References: [1]Patent: WO2012/97013,2012,A1 .Location in patent: Page/Page column 280-282.

7
[ 1228947-14-5 ]
[ 1447956-33-3 ]
C₂₆H₃₆N₈O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
200mg		Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4- (morpholin-4-yl)cyclohexan-l-ol (111 mg, 0.60 mmol, 1.20 equiv) in 5 mL of distilled THF at 0 C. This was followed by the addition of NaHMDS (0.75 mL, 2 M in THF) dropwise via a syringe and stirring for 30 min. To a solution of 202.9 (135 mg, 0.50 mmol, 1.00 equiv) in 2 mL of THF was added and the resulting solution was stirred for 2 h at 0 C. The reaction was then quenched by the addition of 5 mL of water and the pH value of the solution was adjusted to 5 with 1 M hydrochloric acid and extracted with 5 x 10 mL of chloroform/i-PrOH (3: 1). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give the resultant 1-234 (200 mg, crude) as a white solid. MS (ES): m/z 418 (M+H)+. 'H-NMR (400 MHz ,CDC13): delta 8.48 (1H, s), 5.25-5.12 (1H, m), 3.87 (4H, brs), 3.30 (1H, dd), 3.08-2.74 (9H, m), 2.45-2.25 (3H, m), 2.19-1.88 (3H, m), 1.80-1.50 (4H, m).

References: [1]Patent: WO2013/106535,2013,A1 .Location in patent: Paragraph 001035.

8
[ 1228947-14-5 ]
5,6-dihydro-6,6-dimethyl-4-chloro-8H-pyrano[4',3':4,5]thieno[2,3-d]pyrimidine [ No CAS ]
[ 1447952-51-3 ]

Yield	Reaction Conditions	Operation in experiment
66%		207.4 1-193 [001073] Sodium hydride (118.1 mg, 2.95 mmol, 5.01 equiv, 60%) was treated with trans- 4-(morpholin-4-yl)cyclohexan-l-ol (218.7 mg, 1.18 mmol, 2.00 equiv) in 10 mL of distilled THF for 30 min under nitrogen. 207.4 (150.2 mg, 0.59 mmol, 1.00 equiv) was added and the resulting solution was stirred for 3 h at 55 C. After cooled down to rt, the reaction was then quenched by the addition of NH4CI (aq.) and extracted with 3 x 60 mL of DCM. The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20: 1) to provide the desired 158.1 mg (66%) of 1-193 as an off-white solid. MS (ES): m/z 404 (M+H)+. 'H-NMR (300 MHz, CD3OD): delta 8.49 (1H, s), 5.35-5.15 (1H, m), 3.72 (4H, t), 2.93 (2H, s), 2.63 (4H, t), 2.45-2.25 (3H, m), 2.15-2.02 (2H, m), 1.69-1.40 (4H, m), 1.34 (6H, s).

References: [1]Patent: WO2013/106535,2013,A1 .Location in patent: Paragraph 001072.

9
[ 1228947-14-5 ]
[ 1447957-40-5 ]
[ 1447957-43-8 ]

References: [1]Patent: WO2013/106535,2013,A1 .

10
[ 1228947-14-5 ]
[ 1447957-40-5 ]
[ 1447957-41-6 ]
[ 1447957-42-7 ]

Yield	Reaction Conditions	Operation in experiment
30%; 76mg		?ras-4-(Morpholin-4-yl)cyclohexan-l-ol (76 mg, 0.41 mmol, 1.20 equiv) was treated with NaHMDS (0.25 mL, 1.50 equiv) in 6 mL of distilled THF for 20 min at 0 C under nitrogen. Then a solution of 254.7 (100 mg, 0.32 mmol, 1.00 equiv) in dry THF (3 mL) was added via syringe. After stirring for lh at this temperature, the reaction was then quenched with water and extracted with 3 x 20 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10) to give 45 mg (30%) of 254.8 as a white solid. 76 mg of by-product 254.9 were also obtained as a white solid.

References: [1]Patent: WO2013/106535,2013,A1 .Location in patent: Paragraph 001237.

11
[ 1228947-14-5 ]
[ 1521711-12-5 ]
[ 1533422-03-5 ]

Yield	Reaction Conditions	Operation in experiment
62.7 mg		To a solution of trans-4-(morpholin-4-yl)cyclohexan-l-ol (213 mg, 1.15 mmol, 2.00 equiv) in distilled N,N-dimethylformamide (10 mL) was added sodium hydride (69 mg, 2.88 mmol, 3.00 equiv, 60% dispersion in mineral oil) at room temperature and the resulting solution was stirred for 0.5 h at 80 C in an oil bath under nitrogen. Then a solution of 12-chloro-7- thiatricyclo[6.4.0.0A[2,6]]dodeca-l(12),2(6),8,10-tetraene (120 mg, 0.57 mmol, 1.00 equiv) in 3 mL of DMF was added via syringe and the resulting mixture was stirred at 80 C for 3 hours. After cooling, the reaction was quenched with water and extracted with 5 x 50 mL of dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The crude product (100 mg) was purified by preparative HPLC under the following conditions (Waters): Column: Xbridge Prep C18, 5 muiotaeta, 19*50m; water (with 0.05%> NH4HC03) and CH3CN (10% CH3CN up to 40% CH3CN in 10 min); flow rate: 20 mL/min; UV detection at 254 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired 4-(4-[7-thiatricyclo[6.4.0.0A[2,6]]dodeca-l(12),2(6),8,10-tetraen-12- yloxy]cyclohexyl)morpholine (62.7 mg) as a white solid. MS (ES): m/z 359 (M+H)+. 1H NMR (300 MHz, CDC13): delta 1.51-1.72 (4H, m), 1.82-2.06 (2H, m), 2.22-2.30 (3H, m), 2.42-2.50 (2H, m), 2.68 (4H, m), 2.78-3.06 (4H, m), 3.51-3.96 (4H, m) , 4.30-4.48 (1H, m), 6.63 (1H, d, J = 5.4Hz), 8.25 (1H, d, J= 5.4Hz).

References: [1]Patent: WO2014/11906,2014,A2 .Location in patent: Paragraph 00272.

12
[ 1228947-14-5 ]
[ 40142-92-5 ]
[ 1537184-66-9 ]

Yield	Reaction Conditions	Operation in experiment
29 mg		Sodium hydride (70 mg, 1.75 mmol, 3.00 equiv, 60% dispersion in mineral oil) was treated with trans-4-(morpholin-4-yl)cyclohexan-l-ol (214 mg, 1.16 mmol, 2.00 equiv) in 20 mL of distilled THF at room temperature for 30 minutes. Then 4-chlorobenzo[4,5]thieno[2,3- d]pyrimidine (128 mg, 0.58 mmol, 1.00 equiv) was added to the mixture and the resulting solution was stirred for 5 h at room temperature. The reaction was then quenched by the addition of 5 mL of H20, extracted with 3 x 30 mL of dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Waters): Column, Xbridge Prep CI 8, 5um, 19* 50mm; mobile phase, water with 0.05%> NH4HCO3 and CH3CN (10% CH3CN up to 35% in 10 min, up to 95% in 1.5 min, down to 10% in 1.5 min); Flow rate: 20 mL/min; UV detection at 254/220 nm. This resulted in 29 mg of 4-((lr,4r)-4- (benzo[4,5]thieno[2,3-d]pyrimidin-4-yloxy)cyclohexyl)morpholine as a white solid. LC-MS: (ES, m/z) 370 (M+H+). 1H-NMR (300 MHz, CD3OD) delta 1.45-1.60 (2H, m), 1.66-1.80 (2H, m), 2.10 (2H, m), 2.41 (2H, m), 2.68 (4H, m), 3.78 (4H, m), 5.40 (1H, m), 7.52-7.56 (2H, m), 7.96 (1H, m), 8.40 (1H, m), 8.65 (1H, s).

References: [1]Patent: WO2014/11902,2014,A1 .Location in patent: Paragraph 00270-00271.

13
[ 1228947-14-5 ]
[ 1537184-75-0 ]
[ 1537184-76-1 ]

Yield	Reaction Conditions	Operation in experiment
68%		Into a 50-mL 3-necked round-bottom flask containing a solution of trans-4- (morpholin-4-yl)cyclohexan-l-ol (85 mg, 0.46 mmol, 1.93 equiv) in anhydrous tetrahydrofuran (4 mL) was added sodium hydride (60%> dispersion in mineral oil, 80 mg, 2.00 mmol, 8.42 equiv) at 0C under nitrogen. After stirred for 1 h at room temperature, a solution of 6-(2-((tert- butyldimethylsilyl)oxy)ethyl)-4-chlorobenzo[4,5]thieno[2,3-d]pyrimidine (90 mg, 0.24 mmol, 1.00 equiv) in THF (3 mL) was added and the resulting solution was stirred overnight at ambient temperature. The reaction was then quenched with water, extracted with 3 x 50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/1) to provide 85 mg (68%) of the corresponding 4-((lr,4r)-4-((6- (2-((tert-butyldimethylsilyl)oxy)ethyl)benzo [4,5 Jthieno [2,3 -d]pyrimidin-4- yl)oxy)cyclohexyl)morpholine as a white solid. LCMS (ES, m/z): 528 (M+H+).

References: [1]Patent: WO2014/11902,2014,A1 .Location in patent: Paragraph 00303-00304.

14
[ 64-18-6 ]
[ 1228947-14-5 ]
[ 24391-41-1 ]
4-(trans-(4-morpholinocyclohexyl)oxy)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile*0.7(formic acid) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34%		To a solution of trans-4-(morpholin-4-yl)cyclohexan-l-ol (520 mg, 2.81 mmol, 5.01 equiv) in tetrahydrofuran (10 mL) was added sodium hydride (360 mg, 9.00 mmol, 16.07 equiv, 60%)). The resulting solution was stirred for 0.5 h at 0C. Then 4-chloro-7H-pyrrolo[2,3- d]pyrimidine-5-carbonitrile (100 mg, 0.56 mmol, 1.00 equiv) was added. The resulting solution was stirred for 16 h at 70C. The reaction was then quenched by the addition of 2 mL of water. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions: Column, Xbridge Prep CI 8 5um, 19* 150mm; mobile phase, water with 0.1% HCOOH and CH3CN (5.0% CH3CN up to 40.0% in 12 min, up to 92.0% in 2 min, down to 5.0% in 2 min); Detector, 220/254nm. This resulted in 70.2 mg (34%) of 4-(tra/75-(4-morpholinocyclohexyl)oxy)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile as a white solid. LC-MS: (ES,m z): 328[M-0.7HCOOH+H] + 1H NMR (300 MHz, DMSO, ppm): 51.54-1.88 (m, 4H), 2.13-2.14 (m, 2H), 2.16-2.23 (m, 2H), 2.27-2.29 (m, 1H), 2.45-2.55 (m, 4H), 3.46-3.55 (m, 4H), 5.14-5.21 (m, 1H) , 8.09 (s, 0.7H), 8.27 (s, 1H), 8.50 (s, 1H), 12.97 (brs, 0.9H).

References: [1]Patent: WO2014/11911,2014,A2 .Location in patent: Paragraph 00279; 00280.

15
[ 64-18-6 ]
[ 1228947-14-5 ]
[ 582313-57-3 ]
4-((trans)-4-((5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)cyclohexyl)morpholine*0.58(formic acid) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of trans-4-(morpholin-4-yl)cyclohexan-l-ol (550 mg, 2.97 mmol, 5.09 equiv) in tetrahydrofuran (10 mL) was added sodium hydride (600 mg, 15.00 mmol, 25.73 equiv, 60%)). After stirring for 30 min at 0C, 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.58 mmol, 1.00 equiv) was added. The resulting solution was heated to reflux overnight and then quenched by the addition of 2 mL of water. The resulting mixture was concentrated under vacuum. The crude product (80 mg) was purified by Prep-HPLC with the following conditions: Column, SunFire Prep CI 8, 19* 150mm 5um; mobile phase, water with 50mL HCOOH and CH3CN (5.0% CH3CN up to 43.0% in 10 min, up to 90.0% in 3 min, down to 5.0% in 3 min); Detector, 220/254nm. This resulted in 29.8 mg (14%) of 4-((trarcs)-4-((5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)cyclohexyl)morpholine as an off-white solid. LC-MS: (ES,m/z): 321 [M+H]+ . 1H NMR (300 MHz, CD3OD, ppm): delta 1.60-1.40 (m, 4H), 2.11-2.15 (m, 2H), 2.32-2.35 (m, 2H), 2.64-2.67 (m, 1H), 2.84-2.87 (m, 4H), 3.77-3.82 (m, 4H), 5.20-5.27 (m, 1H), 6.98 (d, 1H), 8.28 (s, 1H), 8.40-8.45 (brs, 0.58H).

References: [1]Patent: WO2014/11911,2014,A2 .Location in patent: Paragraph 00285; 00286.

16
[ 918340-51-9 ]
[ 1228947-14-5 ]
[ 1534374-67-8 ]

Yield	Reaction Conditions	Operation in experiment
52%		To a stirred solution of <strong>[1228947-14-5]trans-4-morpholinocyclohexanol</strong> (220 mg, 1.19 mmol, 3.06 equiv) in freshly distilled THF (10 ml), cooled to 0C, was slowly added sodium hydride (65 mg, 1.62 mmol, 4.19 equiv, 60% dispersion in mineral oil) under nitrogen. The mixture was stirred at 0C for 30 min and then 4-chlorofuro[2,3-d]pyrimidine (60 mg, 0.39 mmol, 1.00 equiv) was added and the reaction was stirred overnight at 40C. The reaction was then quenched with water, extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (SHIMADZU): Column, SunFire Prep C I 8, 19* 150mm 5um; mobile phase, water with 1% HCOOH and CH3CN (3.0% CH3CN up to 10.0% in 15 min); Flow rate: 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove solvents under reduced pressure. The residue was lyophilized overnight to give 69.9 mg (52%) of the desired 4-(((trans)-4- morpholinocyclohexyl)oxy)furo[2,3-d]pyrimidine as a white solid. LCMS (ES, m/z): 304 [M+H]+. 1H-NMR: (400 MHz, CD3OD) delta 8.49 (1H, s), 7.82 (1H, d), 6.92 (1H, d), 5.33-5.25 (1H, m), 3.75-3.73 (4H, m), 2.69-2.66 (4H, m), 2.45-2.39 (1H, m), 2.38-2.30 (2H, m), 2.13 (2H, d), 1.67-1.47 (4H, m).

References: [1]Patent: WO2014/11911,2014,A2 .Location in patent: Paragraph 00300; 00301.

17
[ 1228947-14-5 ]
2-methyl-N-(1-methyl-1H-pyrazol-4-yl)-7-(((1r,4r)-4-morpholinocyclohexyl)oxy)thiazolo[5,4-d]pyrimidin-5-amine [ No CAS ]

References: [1]Patent: WO2015/48281,2015,A1 .

18
[ 1228947-14-5 ]
N-(1-ethyl-1H-pyrazol-4-yl)-2-methyl-7-(((1r,4r)-4-morpholinocyclohexyl)oxy)thiazolo[5,4-d]pyrimidin-5-amine [ No CAS ]

References: [1]Patent: WO2015/48281,2015,A1 .

19
[ 1228947-14-5 ]
N-(1-isopropyl-1H-pyrazol-4-yl)-2-methyl-7-(((1r,4r)-4-morpholinocyclohexyl)oxy)thiazolo[5,4-d]pyrimidin-5-amine [ No CAS ]

References: [1]Patent: WO2015/48281,2015,A1 .

20
[ 1228947-14-5 ]
5,7-dichloro-2-ethyl-[1,3]thiazolo[5,4-d]pyrimidine [ No CAS ]
C₁₇H₂₃ClN₄O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hexamethyldisilazane; In tetrahydrofuran; for 0.166667h;Inert atmosphere;	Into a 25 mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (lr,4r)-4- (morpholin-4-yl)cyclohexan-1-ol (380 mg, 2.05 mmol, 1.20 equiv) in THF (2 mL). This was followed by the addition of NaHMDS (1.28 mL, 1.50 equiv) dropwise with stirring at 0C. To the reaction was added a solution of intermediate 7.6 (400 mg, 1.71 mmol, 1.00 equiv) in THF (8 mL) dropwise with stirring at 0 C. The reaction was stirred for 10 mm at 0 C then quenched by the addition of NH4C1(aq.) and extracted with 3 x 10 mL of ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated under vacuum. The crude product was purified using flash column chromatography to furnish 220 mg (34%) of intermediate 25.1 as a light yellow solid.

References: [1]Patent: WO2015/48281,2015,A1 .Location in patent: Paragraph 00401; 00402.

21
[ 1228947-14-5 ]
C₁₁H₉ClN₂ [ No CAS ]
4-((1r,4r)-4-((8,9-dihydro-7H-cyclopenta[f]quinazolin1-yl)oxy)cyclohexyl)morpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%		Compound 4.1 (102 mg, 0.55 mmol, 1.50 equiv) was treated with NaHMDS (2 M in THF, 0.5 mL, 1.50 equiv) in 5 mL of distilled THF at 0C under nitrogen. After stirring for 30 min, compound 29.8 (134 mg, 0.65 mmol, 1.00 equiv), was added and the resulting solution was stirred for 20 min at 0C. The reaction was then quenched by the addition of NH4C1 (aq.), extracted with 3 x 80 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. Crude was purified using flash column chromatography to give 75.5 mg (33%) of 4-((lr,4r)-4-((8,9-dihydro-7H- cyclopenta[f]quinazolin-l-yl)oxy)cyclohexyl)morpholine, 1-31 as a white solid. LCMS (ES, m/z): 354 [M+H]+. 1H NMR (300MHz, CD3OD) delta 8.59 (s, 1H), 7.83-7.80 (d, 1H), 7.77-7.75 (d, 1H), 5.37-5.14 (m, 1H), 3.79-3.72 (m, 4H), 3.49-3.47 (m, 2H), 3.14-3.09 (m, 2H), 2.84-2.63 (m, 4H), 2.51-2.48 (m, 3H), 2.31-2.17 (m, 2H), 2.13-2.01 (m, 2H), 1.75-1.29 (m, 4H).

References: [1]Patent: WO2015/164374,2015,A1 .Location in patent: Paragraph 00368; 00369.

22
[ 38267-96-8 ]
[ 1228947-14-5 ]
4-((1r,4r)-4-((6-bromoquinazolin-4-yl)oxy)cyclohexyl)morpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%		To a solution of trans-4-(morpholin-4-yl)cyclohexan-l-ol, compound 4.1 (364 mg, 1.96 mmol, 1.20 equiv) in distilled THF (10 mL) was added NaHDMS (2.45 mL, 3.00 equiv, 2 M in THF) dropwise via syringe at 0 C under nitrogen. Subsequently a solution of 6-bromo-4- chloroquinazoline (400 mg, 1.64 mmol, 1.00 equiv) in THF (5 mL) was added slowly at 0C and the reaction was stirred for 1 hour at this temperature. The reaction was then quenched with saturated aqueous NH4C1, extracted with 3 x 60 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. Crude was purified via flash column chromatography to furnish 357 mg (55%) of 4- ((lr,4r)-4-((6-bromoquinazolin-4-yl)oxy)cyclohexyl)morpholine, 1-4, as a white solid. LCMS (ES, m/z): 393 [M+H]+; 1H NMR (300 MHz, CD3OD) delta 8.75 (s, 1H), 8.30 (d, 1H), 8.02 (dd, 1H), 7.80 (d, 1H), 5.40-5.30 (m, 1H), 3.73 (t, 4H), 2.64 (t, 4H), 2.42-2.35 (m, 3H), 2.12 (d, 2H), 1.78- 1.60 (m, 2H), 1.58-1.49 (m, 2H).
	With sodium hydride; In tetrahydrofuran; N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; for 18h;	Trans-4-morpholinocyclohexanol (0.134 g, 0.723 mmol) was dissolved in THF (10.95 ml) and added to a slurry of 6-bromo-4-chloroquinazoline (0.16 g, 0.657 mmol) in N,N- dimethylformamide (0.349 mL). The reaction was cooled to 0 C and sodium hydride (0.053 g, 1.31 mmol) was added to the reaction mixture at 0 C and the reaction was allowed to stir at rt for 18 h. The reaction was quenched with saturated aqeuous sodium bicarbonate and the aqueous layer was extracted with 25% IPA/CHCI3 (2x), dried over anhydrous sodium sulfate, filtered and purified by mass triggered reverse phase HPLC (ACN/water with 0.1% NH4OH modifier) to afford the title compound. MS: 392/394 (M + 1). 1H NMR (600 MHz, dmso) delta 8.78 (s, 1H), 8.21 (d, J= 2.2, 1H), 8.04 (dd, J= 2.3, 8.9, 1H), 7.82 (d, J= 8.9, 1H), 5.26 - 5.17 (m, 1H), 3.57 - 3.51 (m, 4H), 2.46 - 2.42 (m, 4H), 2.30 - 2.22 (m, 1H), 2.21 - 2.13 (m, 2H), 1.92 - 1.83 (m, 2H), 1.62 - 1.50 (m, 2H), 1.46 - 1.33 (m, 2H).

References: [1]Patent: WO2015/164374,2015,A1 .Location in patent: Paragraph 00280; 00281.
[2]Patent: WO2016/53772,2016,A1 .Location in patent: Page/Page column 39.

23
[ 1228947-14-5 ]
C₇H₆Cl₂N₄ [ No CAS ]
C₁₇H₂₄ClN₅O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With lithium hexamethyldisilazane; In tetrahydrofuran; at 25℃; for 12h;	<strong>[1228947-14-5](1r,4r)-<strong>[1228947-14-5]4-(morpholin-4-yl)cyclohexan-1-ol</strong></strong> (93 mg, 0.50 mmol, 1.00 eq.) was placed into a 25-mL round-bottom flask and dissolved in THF (2.0 mL). Then LiHMDS (1M in THF) (0.5 mL, 1.00 eq.) was added followed by compound 3.6 (108 mg, 0.50 mmol, 1.00 eq.). Then the reaction was stirred for 12 hours at 25 C. The resulting mixture was concentrated in vacuo and purified by column chromatography to furnish 115 mg (63%) of compound 5.1 as a yellow solid.

References: [1]Patent: WO2017/4133,2017,A1 .Location in patent: Paragraph 00332.

24
[ 1228947-14-5 ]
C₅H₃Cl₂N₅ [ No CAS ]
C₁₅H₂₁ClN₆O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With lithium hexamethyldisilazane; In tetrahydrofuran; at 25℃; for 1h;	<strong>[1228947-14-5](1r,4r)-<strong>[1228947-14-5]4-(morpholin-4-yl)cyclohexan-1-ol</strong></strong> (205 mg, 1.11 mmol, 1.10 eq.) was dissolved in THF (5 mL). Then LiHMDS (1M in THF) (1.1 mL, 1.10 eq.) was added followed by compound 11.3 (204 mg, 1.00 mmol, 1.00 eq.). The reaction was stirred for 1 h at 25 C. The resulting mixture was concentrated in vacuo and purified by column chromatography to furnish in 200 mg (57%) of compound 12.1 as a yellow solid.

References: [1]Patent: WO2017/4133,2017,A1 .Location in patent: Paragraph 00359.

25
[ 939979-32-5 ]
[ 1228947-14-5 ]
C₁₆H₂₂ClN₅O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%		<strong>[1228947-14-5](1r,4r)-<strong>[1228947-14-5]4-(morpholin-4-yl)cyclohexan-1-ol</strong></strong> (201 mg, 1.08 mmol, 1.10 eq.) was placed into a 25-mL 3-necked round-bottom flask and dissolved in THF (1 mL). The reaction was cooled to at 0 C and LiHMDS-THF (1 mL, 1.10 eq.) was added dropwise. The resulting solution was stirred for 15 min at room temperature and then compound 1.1 (200 mg, 0.99 mmol, 1.00 eq.) was added. The reaction was stirred for 1 h at room temperature. Upon completion, the mixture was concentrated in vacuo and diluted with water and CH2CI2. The resulting solution was extracted with 3 x 10 mL of CH2CI2, and the organic layers were combined, dried over anhydrous Na2S04 and concentrated in vacuo. Crude material was purified by column chromatography to furnish 260 mg (75%) of compound 4.1 as yellow oil.

References: [1]Patent: WO2017/4133,2017,A1 .Location in patent: Paragraph 00330.

26
[ 939979-32-5 ]
[ 1228947-14-5 ]
1-methyl-N-(1-methyl-1H-pyrazol-4-yl)-7-(((1r,4r)-4-morpholinocyclohexyl)oxy)-1H-pyrazolo[4,3-d]pyrimidin-5-amine [ No CAS ]

References: [1]Patent: WO2017/4133,2017,A1 .

27
[ 39551-54-7 ]
[ 1228947-14-5 ]
3-methyl-N-(4-(((1r,4r)-4-morpholinocyclohexyl)oxy)pyrido[3,2-d]pyrimidin-2-yl)isothiazol-5-amine [ No CAS ]

References: [1]Patent: WO2017/205766,2017,A1 .

28
[ 39551-54-7 ]
[ 1228947-14-5 ]
4-((1r,4r)-4-((2-chloropyrido[3,2-d]pyrimidin-4-yl)oxy)cyclohexyl)morpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%		A mixture of (lr,4r)-4-morpholinocyclohexan-1-ol (0.31 g, 1.7 mmol, 1.1 eq) in 5.0 mL of THF was prepared and 60% NaH (0.35 g, 8.7 mmol, 5.6 eq) was added. The reaction mixture was stirred at room temperature for 30 mm and 2,4-dichloropyrido[3,2-djpyrimidine (0.31 g, 1.6 mmol, 1.0 eq) was added and the resulting mixture was heated at 60 C for 3.5 hr. The reaction was cooled to room temperature and quenched with saturated aqueous ammonium chloride. The quenched mixture was rotary evaporated and purified on normal phase Combi-Flash using a 40 g column and eluting with a gradient of 0-20% MeOH/CH2C12 in 10 mm. The product containing fractions were combined and rotary evaporated to give 4- ((1 r,4r)-4-((2-chloropyrido [3 ,2-djpyrimidin-4-yl)oxy)cyclohexyl)morpholine (0.15 g, 0.42 mmol, 25% yield) as an orange solid. LC-MS: M+H=349.1

References: [1]Patent: WO2017/205766,2017,A1 .Location in patent: Paragraph 00445.

29
[ 956034-07-4 ]
[ 1228947-14-5 ]
N-(3-methylisothiazol-5 yl)-4-(((1r,4r)-4-morpholinocyclohexyl)oxy)furo[3,2-d]pyrimidin-2-amine [ No CAS ]

References: [1]Patent: WO2017/205766,2017,A1 .

30
[ 956034-07-4 ]
[ 1228947-14-5 ]
2-chloro-4-(((1r,4r)-4-morpholinocyclohexyl)oxy)furo[3,2-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%		A mixture of(lr,4r)-4-morpholinocyclohexan-1-ol (0.53 g, 2.9 mmol, 1.1 eq) in 5.0 mL of THF was prepared and 60% NaH (0.56 g, 14 mmol, 5.3 eq) was added. The reaction mixture was stirred at room temperature for 30 mm and 2,4-dichlorofuro[3,2-djpyrimidine (0.50 g, 2.6 mmol, 1.0 eq) was added and the resulting mixture was heated at 60 C for 3 hr. The reaction was cooled to room temperature and quenched with saturated aqueous ammonium chloride. The quenched mixture was rotary evaporated and purified on normal phase Combi-Flash using a 40 g column and eluting with a gradient of 0-20% MeOH/CH2C12 in 10 mm. The product containing fractions were combined and rotary evaporated to give 2-chloro-4-(((lr,4r)-4- morpholinocyclohexyl)oxy)furo[3,2-djpyrimidine (0.59 g, 1.7 mmol, 60% yield) as a white solid. LC-MS:M+H=338.0

References: [1]Patent: WO2017/205766,2017,A1 .Location in patent: Paragraph 00447.

31
[ 1228947-14-5 ]
4-((1r,4r)-4-((5-(3,6-dihydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)cyclohexyl)-morpholine [ No CAS ]