[ CAS No. 1142953-55-6 ] {[proInfo.proName]}

Name: 1142953-55-6|(R)-2-(Bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxine|95+%
Brand: Ambeed
SKU: A562118
Rating: 95 (27 reviews)

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

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Quality Control of [ 1142953-55-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 1142953-55-6 ]

CAS No. :	1142953-55-6	MDL No. :	MFCD12756174
Formula :	C₉H₉BrO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QYLFKNVZIFTCIY-ZETCQYMHSA-N
M.W :	229.07	Pubchem ID :	6932008
Synonyms :

Calculated chemistry of [ 1142953-55-6 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.33
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	49.99
TPSA :	18.46 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.95 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.4
Log Po/w (XLOGP3) :	2.46
Log Po/w (WLOGP) :	2.22
Log Po/w (MLOGP) :	1.85
Log Po/w (SILICOS-IT) :	2.73
Consensus Log Po/w :	2.33

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.11
Solubility :	0.176 mg/ml ; 0.000769 mol/l
Class :	Soluble
Log S (Ali) :	-2.49
Solubility :	0.739 mg/ml ; 0.00322 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.46
Solubility :	0.0789 mg/ml ; 0.000344 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.0

Safety of [ 1142953-55-6 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P261-P264-P271-P280-P302+P352-P304+P340-P305+P351+P338-P310-P332+P313-P362-P403+P233-P405-P501	UN#:	1759
Hazard Statements:	H315-H318-H335	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 1142953-55-6 ]

* 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 [ 1142953-55-6 ]

[ 1142953-55-6 ] Synthesis Path-Downstream 1~31

1
[ 1142953-55-6 ]
C₁₂H₁₈N₄*2ClH [ No CAS ]
[ 1142953-46-5 ]

Yield	Reaction Conditions	Operation in experiment
	In water; acetonitrile at 150℃; for 0.75h; Microwave irradiation;

Reference： [1]Location in patent: scheme or table Dounay, Amy B.; Barta, Nancy S.; Bikker, Jack A.; Borosky, Susan A.; Campbell, Brian M.; Crawford, Terry; Denny, Lynne; Evans, Lori M.; Gray, David L.; Lee, Pil; Lenoir, Edward A.; Xu, Wenjian [Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 4, p. 1159 - 1163]

2
[ 98572-00-0 ]
[ 1142953-55-6 ]

Yield	Reaction Conditions	Operation in experiment
58%	With carbon tetrabromide; triphenylphosphine In dichloromethane at 0 - 20℃; for 2.5h;	(R)-2-(bromomethyl)-2,3 -dihydrobenzo [bj [1 ,4]dioxine: A solution of (S)-(2,3-dihydrobenzo[bj[1,4jdioxin-2-yl)methanol (0.40 g, 2.41 mmol) and CBr4 (0.87 g, 2.62 mmol) in CH2C12 (1.0 mL) was cooled to 0 °C. PPh3 (0.69 g, 2.65 mmol) was added in portions over 30 mm with vigorous stirring. Upon the addition of the phosphine, the colorless solution turned a pale brown color and was stirred for an additional 2 h at room temperature. The mixture was concentrated and n-hexane was added, the whiteprecipitate filtered and purified by flash chromatography (n-hexane 100 %) to obtain pureproduct as colorless oil (0.32 g, 58 % yield). [a]5 = -20.8° (EtOH; c = 0.94). ‘H-NMR (400MHz, CDC13): 6.92-6.83 (m, 4H), 4.44-4.38 (m, 1H), 4.35 (dd, J= 11.5, 2.3 Hz, 1H), 4.19(dd, J= 11.4, 5.9 Hz, 1H), 3.59-3.47 (m, 2H).
	With carbon tetrabromide; triphenylphosphine In dichloromethane at 20℃; for 16h;

Reference： [1]Current Patent Assignee: MASSACHUSETTS INSTITUTE OF TECHNOLOGY; BROAD INSTITUTE - WO2016/100940, 2016, A1 Location in patent: Page/Page column 149
[2]Location in patent: scheme or table Dounay, Amy B.; Barta, Nancy S.; Bikker, Jack A.; Borosky, Susan A.; Campbell, Brian M.; Crawford, Terry; Denny, Lynne; Evans, Lori M.; Gray, David L.; Lee, Pil; Lenoir, Edward A.; Xu, Wenjian [Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 4, p. 1159 - 1163]

3
[ 1142953-55-6 ]
3-(2-(piperidin-4-yl)ethyl)oxazolidin-2-one [ No CAS ]
(S)-3-(2-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperidin-4-yl)ethyl)oxazolidin-2-one hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate; potassium iodide / acetonitrile / 8 h / 80 °C 2: hydrogenchloride / methanol; isopropyl alcohol

Reference： [1]Current Patent Assignee: PIERRE FABRE PARCIPATIONS - US2015/336943, 2015, A1

4
[ 1142953-55-6 ]
3-(2-(piperidin-4-yl)ethyl)oxazolidin-2-one [ No CAS ]
(S)-3-(2-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperidin-4-yl)ethyl)oxazolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24%	With potassium carbonate; potassium iodide In acetonitrile at 80℃; for 8h;	1 (S)-3-(2-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperidin-4-yl)ethyl)oxazolidin-2-one In a 100-mL single-necked flask, 0.8 g (3.58 mmol) of (R)-2-(bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxin 2.1 are added to a solution of 0.71 g (3.58 mmol) of 3-(2-(piperidin-4-yl)ethyl)oxazolidin-2-one 3.1 in 15 ml of acetonitrile. Then 0.65 g (4.7 mmol) of K2CO3 and a spatula tip of KI are introduced. This is heated at 80° C. for 8 hours. After return to room temperature, the medium is concentrated, then washed with water and extracted with dichloromethane. The organic phase is dried on MgSO4, filtered, evaporated and purified by flash chromatography on silica gel (eluent: dichloromethane/ethyl acetate=85/15%). 0.3 g (0.87 mmol) of compound 1 are recovered in the form of a colorless oil. Yield: 24% 1H NMR (CDCl3) δ: 1.29 (ls, 3H); 1.48 (m, 2H); 1.71 (is, 2H); 2.09 (m, 2H); 2.55 (m, 1H); 2.65 (m, 1H); 2.89 (m, 1H); 2.99 (m, 1H); 3.31 (t, 2H, J=7.2 Hz); 3.54 (t, 2H, J=8.4 Hz); 3.97 (dd, 1H, J=7.8 and 8 Hz); 4.31 (m, 4H); 6.85 (m, 4H).

Reference： [1]Current Patent Assignee: PIERRE FABRE PARCIPATIONS - US2015/336943, 2015, A1 Location in patent: Paragraph 0080-0083

5
[ 1142953-55-6 ]
6-methoxy-3-(2-(piperidin-4-yl)ethyl)benzo[d]oxazol-2(3H)-one [ No CAS ]
(S)-3-(2-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperidin-4-yl)ethyl)-6-methoxybenzo[d]oxazol-2(3H)-one oxalate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: caesium carbonate / N,N-dimethyl-formamide / 8 h / 80 °C 2: methanol; acetone

Reference： [1]Current Patent Assignee: PIERRE FABRE PARCIPATIONS - US2015/336943, 2015, A1

6
[ 1142953-55-6 ]
6-methoxy-3-(2-(piperidin-4-yl)ethyl)benzo[d]oxazol-2(3H)-one [ No CAS ]
(S)-3-(2-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperidin-4-yl)ethyl)-6-methoxybenzo[d]oxazol-2(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 8h;	20 (S)-3-(2-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperidin-4-yl)ethyl)oxazolidin-2-one General procedure: In a 100-mL single-necked flask, 0.8 g (3.58 mmol) of (R)-2-(bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxin 2.1 are added to a solution of 0.71 g (3.58 mmol) of 3-(2-(piperidin-4-yl)ethyl)oxazolidin-2-one 3.1 in 15 ml of acetonitrile. Then 0.65 g (4.7 mmol) of K2CO3 and a spatula tip of KI are introduced. This is heated at 80° C. for 8 hours. After return to room temperature, the medium is concentrated, then washed with water and extracted with dichloromethane. The organic phase is dried on MgSO4, filtered, evaporated and purified by flash chromatography on silica gel (eluent: dichloromethane/ethyl acetate=85/15%). 0.3 g (0.87 mmol) of compound 1 are recovered in the form of a colorless oil. Yield: 24% By proceeding as in Example 1 but replacing 3-(2-(piperidin-4-yl)ethyl)oxazolidin-2-one 3.1 by 6-methoxy-3-(2-(piperidin-4-yl)ethyl)benzo[d]oxazol-2(3H)-one 3.3, K2CO3 by Cs2CO3 and acetonitrile by DMF, 0.4 g (0.94 mmol) of compound 20 are obtained in the form of a cream solid, after purification by flash chromatography on silica gel (eluent n-heptane=100%, then dichloromethane/ethyl acetate=70/30% then dichloromethane/methanol=95/5%). Yield: 47%. 1H NMR (CDCl3) δ: 1.32 (ls, 3H); 1.73 (m, 4H); 2.09 (m, 2H); 2.54 (m, 1H); 2.65 (m, 1H); 2.90 (m, 1H); 2.99 (m, 1H); 3.83 (m, 5H); 3.97 (dd, 1H J=11.6 and 7.6 Hz); 4.30 (m, 2H); 6.73 (dd, 1H, J=8.4 and 2.4 Hz); 6.85 (m, 6H).

Reference： [1]Current Patent Assignee: PIERRE FABRE PARCIPATIONS - US2015/336943, 2015, A1 Location in patent: Paragraph 0081; 0243-0246

7
[ 1142953-55-6 ]
(R)-4-(hydroxymethyl)-3-(2-(piperidin-4-yl)ethyl)oxazolidin-2-one [ No CAS ]
(R)-3-(2-(1-(((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperidin-4-yl)ethyl)-4-(hydroxymethyl)oxazolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	With caesium carbonate In acetonitrile at 80℃; for 8h;	49 (S)-3-(2-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperidin-4-yl)ethyl)oxazolidin-2-one General procedure: In a 100-mL single-necked flask, 0.8 g (3.58 mmol) of (R)-2-(bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxin 2.1 are added to a solution of 0.71 g (3.58 mmol) of 3-(2-(piperidin-4-yl)ethyl)oxazolidin-2-one 3.1 in 15 ml of acetonitrile. Then 0.65 g (4.7 mmol) of K2CO3 and a spatula tip of KI are introduced. This is heated at 80° C. for 8 hours. After return to room temperature, the medium is concentrated, then washed with water and extracted with dichloromethane. The organic phase is dried on MgSO4, filtered, evaporated and purified by flash chromatography on silica gel (eluent: dichloromethane/ethyl acetate=85/15%). 0.3 g (0.87 mmol) of compound 1 are recovered in the form of a colorless oil. Yield: 24% By proceeding as in Example 1 but replacing 3-(2-(piperidin-4-yl)ethyl)oxazolidin-2-one 3.1 by ((R)-4-(hydroxymethyl)-3-(2-(piperidin-4-yl)ethyl)oxazolidin-2-one 3.21 and K2CO3 by Cs2CO3, 0.4 g (1.06 mmol) of compound 49 are obtained in the form of a colorless oil, after purification on silica gel (gradient: dichloromethane=100% to dichloromethane/methanol=90/10% over 30 min). Yield: 36% 1H NMR (CDCl3) δ: 1.29 (m, 3H); 1.51 (m, 2H); 1.72 (m, 2H); 2.09 (m, 2H); 2.54 (dd, 1H, J=13.4 and 6.4 Hz); 2.65 (dd, 1H, J=13.2 and 5.6 Hz); 2.88 (m, 1H); 2.99 (m, 1H); 3.15 (m, 1H); 3.52 (m, 1H); 3.70 (dd, 1H, J=11.4 and 4 Hz); 3.79 (dd, 1H, J=11.4 and 4 Hz); 3.96 (dd, 1H, J=11.6 and 7.6 Hz); 4.29 (m, 2H); 4.36 (m, 1H); 6.85 (m, 4H).

Reference： [1]Current Patent Assignee: PIERRE FABRE PARCIPATIONS - US2015/336943, 2015, A1 Location in patent: Paragraph 0081; 0516-0519

8
[ 1142953-55-6 ]
(S)-4-isopropyl-3-(2-(piperidin-4-yl)ethyl)oxazolidin-2-one [ No CAS ]
(S)-3-(2-(1-(((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperidin-4-yl)ethyl)-4-isopropyloxazolidin-2-one hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate; potassium iodide / dimethyl sulfoxide / 8 h / 80 °C 2: hydrogenchloride / isopropyl alcohol; ethanol

Reference： [1]Current Patent Assignee: PIERRE FABRE PARCIPATIONS - US2015/336943, 2015, A1

9
[ 1142953-55-6 ]
(S)-4-isopropyl-3-(2-(piperidin-4-yl)ethyl)oxazolidin-2-one [ No CAS ]
(S)-3-(2-(1-(((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperidin-4-yl)ethyl)-4-isopropyloxazolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With potassium carbonate; potassium iodide In dimethyl sulfoxide at 80℃; for 8h;	18 (S)-3-(2-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperidin-4-yl)ethyl)oxazolidin-2-one General procedure: In a 100-mL single-necked flask, 0.8 g (3.58 mmol) of (R)-2-(bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxin 2.1 are added to a solution of 0.71 g (3.58 mmol) of 3-(2-(piperidin-4-yl)ethyl)oxazolidin-2-one 3.1 in 15 ml of acetonitrile. Then 0.65 g (4.7 mmol) of K2CO3 and a spatula tip of KI are introduced. This is heated at 80° C. for 8 hours. After return to room temperature, the medium is concentrated, then washed with water and extracted with dichloromethane. The organic phase is dried on MgSO4, filtered, evaporated and purified by flash chromatography on silica gel (eluent: dichloromethane/ethyl acetate=85/15%). 0.3 g (0.87 mmol) of compound 1 are recovered in the form of a colorless oil. Yield: 24% By proceeding as in Example 1 but replacing 3-(2-(piperidin-4-yl)ethyl)oxazolidin-2-one 3.1 by (S)-4-isopropyl-3-(2-(piperidin-4-yl)ethyl)oxazolidin-2-one 3.2, and acetonitrile by DMSO, 0.68 g (1.75 mmol) of compound 18 are obtained in the form of a pale yellow oil, after purification by flash chromatography on silica gel (gradient over 40 min 100% dichloromethane to dichloromethane/methanol=95/5%). Yield: 70%. 0.68 g (1.75 mmol) of compound 18 are dissolved in a minimal amount of ethanol and 0.5 ml (2.5 mmol) of a 5 N solution of HCl in isopropanol are added. The medium is concentrated and triturated with ethyl ether. The precipitate is filtered and left to dry in the vacuum chamber. 0.53 g (1.25 mmol) of compound 18 hydrochloride are obtained in the form of a white solid.

Reference： [1]Current Patent Assignee: PIERRE FABRE PARCIPATIONS - US2015/336943, 2015, A1 Location in patent: Paragraph 0081; 0226-0228

10
[ 120-80-9 ]
[ 1142953-55-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 16 h / 60 °C 2: triphenylphosphine; carbon tetrabromide / dichloromethane / 2.5 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: MASSACHUSETTS INSTITUTE OF TECHNOLOGY; BROAD INSTITUTE - WO2016/100940, 2016, A1

11
[ 1142953-55-6 ]
N-(4-(piperazin-1-yl)-1,2,5-thiadiazol-3-yl)acetamide trifluoroacetate [ No CAS ]
(S)-N-(4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,2,5-thiadiazol-3-yl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.037 g	With sodium carbonate In N,N-dimethyl-formamide at 100 - 120℃; Inert atmosphere;	16.5 (S)-N-(4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,2,5-thiadiazol-3-yl)acetamide General procedure: Piperazin-1-yl derivative (1 eq.) was dissolved in DMF under nitrogen. (2R)- 2- (bromomethyl)-2,3-dihydro-1,4-benzodioxin or (1-1.4 eq.) and Na2CO3 or K2C03 (1.5-2.5 eq.) were added and the reaction mixture was heated at 100-120 °C for 3-4 h. The reaction mixture was allowed to cool down to RT and 1 M HC1-solution was added. The mixture wasextracted with MTBE. The pH of the water phase was adjusted to 10 with Na2CO3 and then extracted with EtOAc. The EtOAc phase was washed with brine and concentrated under reduced pressure. (S)-N-(4-(4-((2,3 -dihydrobenzo[b] [1,4] dioxin-2-yl)methyl)piperazin- 1 -yl)- 1,2,5 -thiadiazol-3 - yl)acetamide was prepared according to the general procedure A2 using trifluoroacetic acid salt of N-(4-(piperazin-1-yl)-1,2,5-thiadiazol-3-yl)acetamide (0.10 g, 0.29 mmol), Na2CO3 (0.078 g, 0.73 mmol), (2R)- 2-(bromomethyl)-2,3-dihydro-1,4-benzodioxin (0.074 g, 0.32 mmol) and DMF (1.5 ml). The evaporation residue was purified by reverse phase columnchromatography (0.1% NH4OH-acetonitrile) to afford 0.037 g of (S)-N-(4-(4-((2,3-dihydrobenzo[b] [1,4] dioxin-2-yl)methyl)piperazin- l-yl)-l ,2,5 -thiadiazol-3 -yl)acetamide as white solid.‘H NMR (400 MHz, CDC13) ö ppm 2.43 (3 H, br s), 2.64 - 2.83 (6 H, m), 3.20 - 3.30 (4 H, m), 4.00 - 4.07 (1 H, m), 4.28 - 4.38 (2 H, m), 6.80 - 6.93 (4 H, m), 7.51 (1 H, br s)

Reference： [1]Current Patent Assignee: ORION OYJ - WO2016/193551, 2016, A1 Location in patent: Page/Page column 44; 45

12
[ 1142953-55-6 ]
3,3-dimethyl-1-(4-(piperazin-1-yl)-1,2,5-thiadiazol-3-yl)pyrrolidin-2-one [ No CAS ]
(S)-1-(4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,2,5-thiadiazol-3-yl)-3,3-dimethylpyrrolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.039 g	With sodium carbonate In N,N-dimethyl-formamide at 100 - 120℃; Inert atmosphere;	17.6 (S)-1-(4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,2,5-thiadiazol-3-yl)-3,3-dimethylpyrrolidin-2-one General procedure: Piperazin-1-yl derivative (1 eq.) was dissolved in DMF under nitrogen. (2R)- 2- (bromomethyl)-2,3-dihydro-1,4-benzodioxin or (1-1.4 eq.) and Na2CO3 or K2C03 (1.5-2.5 eq.) were added and the reaction mixture was heated at 100-120 °C for 3-4 h. The reaction mixture was allowed to cool down to RT and 1 M HC1-solution was added. The mixture wasextracted with MTBE. The pH of the water phase was adjusted to 10 with Na2CO3 and then extracted with EtOAc. The EtOAc phase was washed with brine and concentrated under reduced pressure. (S)-1 -(4-(4-((2,3 -Dihydrobenzo[b] [1 ,4]dioxin-2-yl)methyl)piperazin- 1 -yl)- 1,2,5 -thiadiazol-3 - yl)-3,3-dimethylpyrrolidin-2-one was prepared according to the general procedure A2 using3 ,3-dimethyl- 1 -(4-(piperazin- 1 -yl)- 1 ,2,5-thiadiazol-3-yl)pyrrolidin-2-one (0.074 g, 0.26 mmol), Na2CO3 (0.042 g, 0.39 mmol), (2R)- 2-(bromomethyl)-2,3-dihydro-1,4-benzodioxin (0.066 g, 0.29 mmol) and DMF (1 ml). The evaporation residue was purified by reverse phase column chromatography (0.1% NH4OH-acetonitrile) to afford 0.039 g of (5)-i -(4-(4- ((2,3 -dihydrobenzo [b] [1 ,4]dioxin-2-yl)methyl)piperazin- 1 -yl)- 1,2,5 -thiadiazol-3 -yl)-3 ,3 -dimethylpyrrolidin-2-one as white solid.‘H NMR (400 MHz, CDC13) ö ppm 1.26 (6 H, s), 2.07 (2 H, t), 2.59 - 2.69 (3 H, m), 2.69 -2.77 (3 H, m), 3.31 -3.41 (4 H, m), 3.78 (2 H, t), 4.02 (1 H, dd), 4.29 -4.36 (2 H, m), 6.81- 6.91 (4 H, m)

Reference： [1]Current Patent Assignee: ORION OYJ - WO2016/193551, 2016, A1 Location in patent: Page/Page column 20; 46; 47

13
[ 1142953-55-6 ]
1-(1,5-dimethyl-3-(piperazin-1-yl)-1H-pyrazol-4-yl)-3,3-dimethylpyrrolidine-2,5-dione hydrochloride [ No CAS ]
(S)-1-(3-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,5-dimethyl-1H-pyrazol-4-yl)-3,3-dimethylpyrrolidine-2,5-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51 mg	With potassium carbonate; N-ethyl-N,N-diisopropylamine In acetonitrile at 120℃; for 4h; Inert atmosphere; Microwave irradiation;	1.6 (S)-1-(3-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,5-dimethyl-1H-pyrazol-4-yl)-3,3-dimethylpyrrolidine-2,5-dione General procedure: (S)-1-(3 -(4-((2,3-Dihydrobenzo[b] [1 ,4]dioxin-2-yl)methyl)piperazin- i-yl)-i ,5 -dimethyl- 1 Hpyrazol-4-yl)-3 ,3 -dimethylpyrrolidine-2,5 -dione was prepared according to the generalprocedure Al using 1 -(1,5 -dimethyl-3 -(piperazin- i-yl)- 1 H-pyrazol-4-yl)-3 ,3 - dimethylpyrrolidine-2,5-dione, HC1 (100mg, 0.293 mmol), DIPEA (0.051 ml, 0.293 mmol), K2C03 (60.6 mg, 0.439 mmol), (2R)- 2-(bromomethyl)-2,3-dihydro-1,4-benzodioxin (67.0 mg, 0.293 mmol) and ACN (1.4 ml). The product was purified by flash chromatography using 2% MeOH in DCM as eluent to afford 51 mg of oil. LC-MS (ES+) [M+1]: 454.2,‘H NMR (400 MHz, CDC13) ö ppm 1.36 - 1.49 (m, 6H) 1.92 - 2.04 (m, 3H) 2.51 - 2.68 (m,6H) 2.69 - 2.73 (m, 2H) 2.97 - 3.16 (m, 4H) 3.62 - 3.73 (m, 3H) 3.90 - 4.06 (m, 1H) 4.21 -4.37 (m, 2H) 6.75 - 6.96 (m, 4H). Piperazin-1-yl derivative (1 eq.) was dissolved in ACN. DIPEA (1 eqv) was added, followed by addition of K2C03 (1.5 eqv) and (2R)-2-(bromomethyl)-2,3 -dihydro- 1 ,4-benzodioxin (1-1.4 eqv). The vial was flushed with nitrogen and sealed. The reaction mixture was heated in the microwave at 120°C for 4 hours. The solvents were removed under reduced pressure. The procedure could be performed with only DIPEA or K2CO3 as a base.

Reference： [1]Current Patent Assignee: ORION OYJ - WO2016/193551, 2016, A1 Location in patent: Page/Page column 20; 22

14
[ 1142953-55-6 ]
N-methyl-4-(piperazin-1-yl)-1,2,5-thiadiazole-3-carboxamide hydrochloride [ No CAS ]
(S)-4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-N-methyl-1,2,5-thiadiazole-3-carboxamide hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31 mg	Stage #1: (R)-2-(bromomethyl)-2,3-dihydrobenzo [b][1,4] dioxine; N-methyl-4-(piperazin-1-yl)-1,2,5-thiadiazole-3-carboxamide hydrochloride With potassium carbonate; N-ethyl-N,N-diisopropylamine In acetonitrile at 120℃; for 4h; Inert atmosphere; Microwave irradiation; Stage #2: With hydrogenchloride In diethyl ether; acetonitrile	29.3 (S)-4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-N-methyl-1,2,5-thiadiazole-3-carboxamide hydrochloride General procedure: Piperazin-1-yl derivative (1 eq.) was dissolved in ACN. DIPEA (1 eqv) was added, followed by addition of K2C03 (1.5 eqv) and (2R)-2-(bromomethyl)-2,3 -dihydro- 1 ,4-benzodioxin (1-1.4 eqv). The vial was flushed with nitrogen and sealed. The reaction mixture was heated in the microwave at 120°C for 4 hours. The solvents were removed under reduced pressure. The procedure could be performed with only DIPEA or K2CO3 as a base. Prepared using general procedure Al from N-methyl-4-(piperazin- 1 -yl)- 1 ,2,5-thiadiazole-3-carboxamide hydrochloride (0.15 g, 0.57 mmol), (R)-2-(bromomethyl)-2,3-dihydrobenzo[b][l,4]dioxine (0.16 g, 0.68 mmol), and K2C03 (0.20 g, 1.42 mmol) in ACN (2 ml). The free base was converted to HC1 salt with 1 M HC1 in Et20 yielding 31 mg Nmethyl-4-(piperazin- 1 -yl)- 1,2,5 -thiadiazole-3 -carboxamide hydrochloride.‘H NMR (400 MHz, DMSO-d6): 2.79 (3H, d), 3.22-3.66 (7H, m), 3.72-3.87 (1H, m), 3.99-4.13 (3H, m), 4.30-4.40 (1H, m), 4.91-5.02 (1H, m), 6.82-7.02 (4H, m), 8.70-8.83 (1H, m),11.50 (1H, br s).

Reference： [1]Current Patent Assignee: ORION OYJ - WO2016/193551, 2016, A1 Location in patent: Page/Page column 20; 59

15
[ 1142953-55-6 ]
N-(2-(benzyloxy)pyridin-3-yl)-4-(piperazin-1-yl)-1,2,5-thiadiazol-3-amine trifluoroacetate [ No CAS ]
(S)-N-(2-(benzyloxy)pyridin-3-yl)-4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,2,5-thiadiazol-3-amine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; N-ethyl-N,N-diisopropylamine In acetonitrile at 120℃; for 4h; Inert atmosphere; Sealed tube; Microwave irradiation;	37.3 (S)-N-(2-(benzyloxy)pyridin-3-yl)-4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,2,5-thiadiazol-3-amine hydrochloride General procedure: Piperazin-1-yl derivative (1 eq.) was dissolved in ACN. DIPEA (1 eqv) was added, followed by addition of K2C03 (1.5 eqv) and (2R)-2-(bromomethyl)-2,3 -dihydro- 1 ,4-benzodioxin (1-1.4 eqv). The vial was flushed with nitrogen and sealed. The reaction mixture was heated in the microwave at 120°C for 4 hours. The solvents were removed under reduced pressure. The procedure could be performed with only DIPEA or K2C03 as a base. Prepared using general procedure Al from N-(2-(benzyloxy)pyridin-3 -yl)-4-(piperazin- 1 -yl)1,2,5 -thiadiazol-3 -amine trifluoroacetate (0.10 g, 0.21 mmol), (R)-2-(bromomethyl)-2,3 - dihydrobenzo[b][l,4]dioxine (75 mg, 0.33 mmol), and K2C03 (83 mg, 0.60 mmol) in ACN(2 ml) yielding 61 mg (S)-N-(2-(benzyloxy)pyridin-3-yl)-4-(4-((2,3- dihydrobenzo[b] [1,4] dioxin-2-yl)methyl)piperazin- 1 -yl)- 1,2,5 -thiadiazol-3 -amine hydrochloride after conversion of free base to HCl salt.‘H NMR (400 MHz, CDC13): 3.05-4.09 (1OH, m), 4.10-4.23 (1H, m), 4.25-4.36 (1H, m), 5.22 (2H, s), 5.25-5.44 (1H, br s), 6.32 (1H, t), 6.86-6.94 (4H, m), 6.95-7.00 (1H, m), 7.27-7.40 (5H, m), 8.17 (1H, s), 8.26-8.33 (1H, m), 13.75 (1H, br s).

Reference： [1]Current Patent Assignee: ORION OYJ - WO2016/193551, 2016, A1 Location in patent: Page/Page column 68

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[ 503147-26-0 ]
[ 1142953-55-6 ]
(S)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-(3-methyl-1-(pyridin2-yl)-1H-pyrazol-5-yl)piperazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.194 g	With sodium carbonate In N,N-dimethyl-formamide at 110 - 120℃; for 2h;	38.4 (S)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-(3-methyl-1-(pyridin2-yl)-1H-pyrazol-5-yl)piperazine A flask was charged with 1 -(3-methyl-i -(pyridin-2-yl)- 1 H-pyrazol-5 -yl)piperazine (0.250 g,1.03 mmol), (R)-2-(bromomethyl)-2,3-dihydrobenzo[b][i,4]dioxine (0.259 g, 1.13 mmol),Na2CO3 (0.163 g, 1.54 mmol) and DMF (5 mL). Mixture was heated to 110-120 °C for 2 h.Reaction was cooled to RT, then EtOAc (20 mL) and water (20 mL) were added. Aqueousphase was extracted with EtOAc (20 mL). Combined organic phases were washed with brine(20 mL), dried with anhydrous Na2SO4 and evaporated to dry. Crude product was purifiedwith reverse phase chromatography (Ci8) using 10-100% MeCN / 0.5% HCO2H solutionfollowed by another purification (Ci8) with 10-100% MeCN / 0.1% NH4OH solution to give 0.194 g of (5)-i -((2,3 -dihydrobenzo[b] [1,4] dioxin-2-yl)methyl)-4-(3 -methyl-i -(pyridin2-yl)- 1 H-pyrazol-5 -yl)piperazine as white powder.‘H NMR (400 MHz, CDC13) ö ppm 2.29 (3H, s), 2.56-2.66 (3H, m), 2.66-2.79 (3H, m),2.91-3.05 (4H, m), 4.00 (iH, dd), 4.23-4.36 (2H, m), 5.70 (iH, s), 6.77-6.93 (4H, m), 7.17(iH, ddd), 7.76 (iH, ddd), 7.85 (iH, dt), 8.54 (iH, ddd).

Reference： [1]Current Patent Assignee: ORION OYJ - WO2016/193551, 2016, A1 Location in patent: Page/Page column 70

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[ 1142953-55-6 ]
1-(1-(6-methoxypyridin-2-yl)-3-methyl-1H-pyrazol-5-yl)piperazine [ No CAS ]
(S)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-(1-(6-methoxypyridin-2-yl)-3-methyl-1H-pyrazol-5-yl)piperazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.234 g	With sodium carbonate In N,N-dimethyl-formamide at 110 - 120℃; for 3h;	39.4 (S)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-(1-(6-methoxypyridin-2-yl)-3-methyl-1H-pyrazol-5-yl)piperazine A flask was charged with 1 -(1 -(6-methoxypyridin-2-yl)-3 -methyl-i H-pyrazol-5 -yl)piperazine(0.244 g, 0.89 mmol), (R)-2-(bromomethyl)-2,3-dihydrobenzo[b] [1 ,4]dioxine (0.259 g, 1.13mmol), Na2CO3 (0.142 g, 1.34 mmol) andDMF (5 mL). Reaction was heated to 110-120°Cfor 3 h. Mixture was cooled to RT and 1 M HC1 (15 mL) was added. This mixture was washed with MTBE (2 x 10 mL). MTBE phase was backextrated with 1 M HC1 (5 mL) and org. phase was discarded. Aq. phases were basified with Na2CO3 and the extracted with EtOAc (2 x 20 mL). Combined organic phases were washed with brine (20 mL), dried withanhydrous Na2SO4 and evaporated to dry. Crude product was purified with reverse phase chromatography (C18) using 10-100% MeCN / 0.1% NH4OH solution to give 0.234 g of (5)-i -((2,3 -dihydrobenzo[b] [1,4] dioxin-2-yl)methyl)-4-( 1 -(6-methoxypyridin-2-yl)-3 -methyl1 H-pyrazol-5 -yl)piperazine as white solids.‘H NMR (400 MHz, CDC13) ö ppm 2.28 (3H, s), 2.5 1-2.77 (6H, m), 2.93-3.07 (4H, m), 3.94-4.06 (4H, m), 4.23-4.36 (2H, m), 5.67 (1H, s), 6.65 (1H, d), 6.77-6.93 (4H, m), 7.28(1H, d), 7.64 (1H, t).

Reference： [1]Current Patent Assignee: ORION OYJ - WO2016/193551, 2016, A1 Location in patent: Page/Page column 71; 72

18
[ 1142953-55-6 ]
1-(3-methyl-1-(6-methylpyridin-2-yl)-1H-pyrazol-5-yl)piperazine [ No CAS ]
(S)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-(3-methyl-1-(6-methylpyridin-2-yl)-1H-pyrazol-5-yl)piperazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.234 g	With sodium carbonate In N,N-dimethyl-formamide at 110 - 120℃; for 4h;	40.5 (S)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-(3-methyl-1-(6-methylpyridin-2-yl)-1H-pyrazol-5-yl)piperazine A flask was charged 1 -(3-methyl-i -(6-methylpyridin-2-yl)- 1 H-pyrazol-5 -yl)piperazine (0.5 14g, 1.997 mmol), (R)-2-(bromomethyl)-2,3-dihydrobenzo[b][i,4]dioxine (0.503 g, 2.00mmol), Na2CO3 (0.3 18 g, 3.00 mmol) and DMF (10 mL). Reaction was heated to 110-120°C for 4 h. Mixture was cooled to RT and 1 M HC1 (30 mL) was added. Mixture waswashed with MTBE (2 x 15 mL). MTBE phase was back extracted with1 M HC1 (10 mL) and org. phase was discarded. Aq. phases were basified with Na2CO3 andthe extracted with EtOAc (2 x 30 mL). Combined organic phases were washed with brine (20 mL), dried with anhydrous Na2SO4 and evaporated to dry. Crude product was purified with reverse phase chromatography (C 18) using 10-100% MeCN / 0.1% NH4OH solution to give 0.234 g of (5)-i -((2,3-dihydrobenzo[b] [1 ,4]dioxin-2-yl)methyl)-4-(3-methyl- 1 -(6- methylpyridin-2-yl)- 1 H-pyrazol-5 -yl)piperazine as semisolid.‘H NMR (400 MHz, CDC13) ö ppm 2.28 (3H, s), 2.60 (3H, s), 2.57-2.77 (6H, m), 2.93-3.03(4H, m), 4.00 (1H, dd), 4.25-4.34 (2H, m), 5.29 (1H, s), 5.68 (1H, s), 6.78-6.91 (4H, m), 7.00-7.06 (1H, m), 7.58-7.69 (2H, m).

Reference： [1]Current Patent Assignee: ORION OYJ - WO2016/193551, 2016, A1 Location in patent: Page/Page column 73

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[ 1142953-55-6 ]
1-(1,5-dimethyl-3-(piperazin-1-yl)-1H-pyrazol-4-yl)azetidin-2-one trifluoroacetate [ No CAS ]
(S)-1-(3-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,5-dimethyl-1H-pyrazol-4-yl)azetidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71 mg	With potassium carbonate; N-ethyl-N,N-diisopropylamine In acetonitrile at 120℃; for 4h; Inert atmosphere; Microwave irradiation;	4.5 (S)-1-(3-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,5-dimethyl-1H-pyrazol-4-yl)azetidin-2-one General procedure: Piperazin-1-yl derivative (1 eq.) was dissolved in ACN. DIPEA (1 eqv) was added, followed by addition of K2C03 (1.5 eqv) and (2R)-2-(bromomethyl)-2,3 -dihydro- 1 ,4-benzodioxin (1-1.4 eqv). The vial was flushed with nitrogen and sealed. The reaction mixture was heated in the microwave at 120°C for 4 hours. The solvents were removed under reduced pressure. The procedure could be performed with only DIPEA or K2C03 as a base. (S)- 1 -(3 -(4-((2,3 -Dihydrobenzo[b] [1 ,4]dioxin-2-yl)methyl)piperazin- 1 -yl)- 1,5 -dimethyl- 1 Hpyrazol-4-yl)azetidin-2-one was prepared according to the general procedure Al using 1-(1,5 -dimethyl-3 -(piperazin- 1 -yl)- 1 H-pyrazol-4-yl)azetidin-2-one, TFA (200 mg, 0.700mmol), (2R)- 2-(bromomethyl)-2,3-dihydro-l,4-benzodioxin (160 mg, 0.700 mmol), DIPEA (0.122 ml, 0.700 mmol), K2C03 (145 mg, 1.050 mmol) and ACN (4 ml). The product was purified by flash chromatography using 2-4 % gradient of MeOH in DCM as eluent to afford 71 mg of oil. LC-MS (ES+) [M+1]: 396.2, ‘H NMR (400 MHz, CDCl3) δ ppm 2.15 (s, 3H) 2.54 - 2.77 (m, 6H) 3.01 - 3.24 (m, 6H)3.44 - 3.54 (m, 2H) 3.59 (s, 3H) 3.95 - 4.13 (m, 1H) 4.23 - 4.42 (m, 2H) 6.76 - 6.97 (m,4H).

Reference： [1]Current Patent Assignee: ORION OYJ - WO2016/193551, 2016, A1 Location in patent: Page/Page column 20; 25; 26

20
[ 1142953-55-6 ]
3-(1,5-dimethyl-3-(piperazin-1-yl)-1H-pyrazol-4-yl)oxazolidin-2-one hydrochloride [ No CAS ]
(S)-3-(3-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,5-dimethyl-1H-pyrazol-4-yl)oxazolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53.4 mg	With sodium carbonate In N,N-dimethyl-formamide at 100 - 120℃; Inert atmosphere;	5.7 (S)-3-(3-(4-((2,3-Dihydrobenzo [bj [1 ,4j dioxin-2-yl)methyl)piperazin- l-yl)-l ,5- dimethyl- 1H-pyrazol-4-yl)oxazolidin-2-one General procedure: (S)-3 -(3 -(4-((2,3 -Dihydrobenzo[b] [1 ,4]dioxin-2-yl)methyl)piperazin- 1 -yl)- 1,5 -dimethyl- 1 Hpyrazol-4-yl)oxazolidin-2-one was prepared according to the general procedure A2 using 3- (1,5 -dimethyl-3 -(piperazin- 1 -yl)- 1H-pyrazol-4-yl)oxazolidin-2-one, HC1 (132 mg, 0.437 mmol), (2R)- 2-(bromomethyl)-2,3-dihydro-1,4-benzodioxin (100 mg, 0.437 mmol), Na2CO3 (69.4 mg, 0.65 5 mmol) and DMF (2 ml). The product was purified by reversed phase flashchromatography using 0.1% HCOOH/ ACN as eluent to afford 53.4 mg of white solid. LCMS (ES+) [M+1]: 414.2,‘H NMR (400 MHz, CDC13) ö ppm 2.13 (s, 3H) 2.50 - 2.85 (m, 6H) 3.06 - 3.30 (m, 4H)3.63 (s, 3H) 3.78 - 3.91 (m, 2H) 4.02 (dd, 1H) 4.25 - 4.42 (m, 2H) 4.43 - 4.54 (m, 2H) 6.78- 6.94 (m, 4H). Piperazin-1-yl derivative (1 eq.) was dissolved in DMF under nitrogen. (2R)- 2- (bromomethyl)-2,3-dihydro-1,4-benzodioxin or (1-1.4 eq.) and Na2CO3 or K2C03 (1.5-2.5 eq.) were added and the reaction mixture was heated at 100-120 °C for 3-4 h. The reaction mixture was allowed to cool down to RT and 1 M HC1-solution was added. The mixture wasextracted with MTBE. The pH of the water phase was adjusted to 10 with Na2CO3 and then extracted with EtOAc. The EtOAc phase was washed with brine and concentrated under reduced pressure.

Reference： [1]Current Patent Assignee: ORION OYJ - WO2016/193551, 2016, A1 Location in patent: Page/Page column 20; 28

21
[ 1142953-55-6 ]
5-(methoxymethyl)-4-(piperazin-1-yl)thiazole [ No CAS ]
(S)-4-(4-((2,3-dihydrobenzo[b][1,4]-dioxin-2-yl)methyl)piperazin-1-yl)-5-(methoxymethyl)thiazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.08 g	With potassium carbonate; N-ethyl-N,N-diisopropylamine In acetonitrile at 120℃; for 4h; Inert atmosphere; Microwave irradiation;	8.6 (S)-4-(4-((2,3-dihydrobenzo[b][1,4]-dioxin-2-yl)methyl)piperazin-1-yl)-5-(methoxymethyl)thiazole General procedure: Piperazin-1-yl derivative (1 eq.) was dissolved in ACN. DIPEA (1 eqv) was added, followed by addition of K2C03 (1.5 eqv) and (2R)-2-(bromomethyl)-2,3 -dihydro- 1 ,4-benzodioxin (1-1.4 eqv). The vial was flushed with nitrogen and sealed. The reaction mixture was heated in the microwave at 120°C for 4 hours. The solvents were removed under reduced pressure. The procedure could be performed with only DIPEA or K2CO3 as a base. (S)-4-(4-((2,3 -dihydrobenzo[b] [1,4] dioxin-2-yl)methyl)piperazin- 1 -yl)-5 -(methoxymethyl)thiazole was prepared according to the general procedure Al using 5-(methoxymethyl)-4-(piperazin-l-yl)thiazole (0.10 g, 0.47 mmol), K2C03 (0.097 g, 0.70mmol), (2R)- 2-(bromomethyl)-2,3 -dihydro- 1 ,4-benzodioxin (0.107 g, 0.47 mmol) andacetonitrile (1.25 ml). After the general procedure work-up, the evaporation residue wastaken in mixture of EtOAc and water. Organic layer was separated and the water layer was extracted with EtOAc. Combined organic phases were washed with water and brine, dried and concentrated. The evaporation residue was purified by flash chromatography using 20- 80% EtOAc in heptane as eluent to afford 0.080 g of(S)-4-(4-((2,3-dihydrobenzo[b][l,4]-dioxin-2-yl)methyl)piperazin- 1 -yl)-5 -(methoxymethyl)thiazole as semi-solid.‘H NMR (400 MHz, CDC13) ö ppm 2.62 - 2.70 (3 H, m), 2.71 - 2.79 (3 H, m), 3.22 - 3.29 (4 H, m), 3.39 (3 H, s), 4.03 (1 H, dd), 4.31 - 4.38 (2 H, m), 4.55 (2 H, s), 6.81 - 6.91 (4 H, m), 8.55 (1 H, s).

Reference： [1]Current Patent Assignee: ORION OYJ - WO2016/193551, 2016, A1 Location in patent: Page/Page column 20; 33

22
[ 1142953-55-6 ]
1-(1,5-dimethyl-3-(piperazin-1-yl)-1H-pyrazol-4-yl)imidazolidin-2-one bis(trifluoroacetate) [ No CAS ]
(S)-1-(3-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,5-dimethyl-1H-pyrazol-4-yl)imidazolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.06 g	With potassium carbonate; N-ethyl-N,N-diisopropylamine In acetonitrile at 120℃; for 4h; Inert atmosphere; Microwave irradiation;	9.5 (S)-1-(3-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,5-dimethyl-1H-pyrazol-4-yl)imidazolidin-2-one General procedure: Piperazin-1-yl derivative (1 eq.) was dissolved in ACN. DIPEA (1 eqv) was added, followed by addition of K2C03 (1.5 eqv) and (2R)-2-(bromomethyl)-2,3 -dihydro- 1 ,4-benzodioxin (1-1.4 eqv). The vial was flushed with nitrogen and sealed. The reaction mixture was heated in the microwave at 120°C for 4 hours. The solvents were removed under reduced pressure. The procedure could be performed with only DIPEA or K2C03 as a base. (S)-i -(3 -(4-((2,3 -dihydrobenzo[b] [1,4] dioxin-2-yl)methyl)piperazin- 1 -yl)- 1,5 -dimethyl- 1 H30 pyrazol-4-yl)imidazolidin-2-one was prepared according to the general procedure Al using bis-trifluoroacetic acid salt of 1 -(1,5 -dimethyl-3 -(piperazin- l-yl)-l H-pyrazol-4- yl)imidazolidin-2-one 0.10 g, 0.20 mmol), di-isopropylethylamine (0.035 ml, 0.20 mmol), K2C03 (0.056 g, 0.41 mmol), (2R)- 2-(bromomethyl)-2,3-dihydro-1,4-benzodioxin (0.047 g,0.20 mmol) and acetonitrile (1 ml). The product was purified by flash chromatography (0-10% MeOH in dichloromethane) to afford 0.060 g of(S)-1-(3-(4-((2,3- dihydrobenzo[b] [1,4] dioxin-2-yl)methyl)piperazin- 1 -yl)- 1,5 -dimethyl- 1 H-pyrazol-4- yl)imidazolidin-2-one as a yellowish solid.‘H NMR (400 MHz, DMSO-d6) ö ppm 1.99 (3 H, s), 2.53 - 2.64 (5 H, m), 3.96 - 3.06 (4 H, m), 3.34 - 3.39 (2 H, m), 3.48 - 3.56 (2 H, m), 3.54 (3H, obs.s), 3.96 (1H, dd), 4.27 - 4.32(1 H, m), 4.36 (1 H, br s), 6.44 (1 H, s), 6.78 - 6.89 (4 H, m).

Reference： [1]Current Patent Assignee: ORION OYJ - WO2016/193551, 2016, A1 Location in patent: Page/Page column 20; 25; 26; 34; 35

23
[ 1142953-55-6 ]
(S)-3,4,4-trimethyl-1-(piperidin-3-yl)imidazolidin-2-one [ No CAS ]
1-((S)-1-(((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperidin-3-yl)-3,4,4-trimethylimidazolidin-2-one hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67 mg	Stage #1: (R)-2-(bromomethyl)-2,3-dihydrobenzo [b][1,4] dioxine; (S)-3,4,4-trimethyl-1-(piperidin-3-yl)imidazolidin-2-one With potassium carbonate; N-ethyl-N,N-diisopropylamine In acetonitrile at 120℃; for 3h; Sealed tube; Inert atmosphere; Stage #2: With hydrogenchloride In 1,4-dioxane; dichloromethane	51.3 General procedure A General procedure: 1 -(Piperidin-3 -yl)derivative (1 eq) was dissolved in acetonitrile or DMF ( 1 M) in microvial.DIPEA (0-1.2 eq), K2C03 (1.5-2.5 eq) and benzodioxin derivative (1-1.2 eqv) were addedunder nitrogen and the vial was sealed. The reaction mixture was heated at 120°C for 3hours. The solvents were removed under reduced pressure.

Reference： [1]Current Patent Assignee: ORION S R L - WO2018/2437, 2018, A1 Location in patent: Page/Page column 23; 69; 70

24
[ 1142953-55-6 ]
1-(1-phenylethyl)-3-((S)-piperidin-3-yl)imidazolidin-2-one hydrochloride [ No CAS ]
1-((S)-1-(((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperidin-3-yl)-3-(1-phenylethyl)imidazolidin-2-one hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86 mg	Stage #1: (R)-2-(bromomethyl)-2,3-dihydrobenzo [b][1,4] dioxine; 1-(1-phenylethyl)-3-((S)-piperidin-3-yl)imidazolidin-2-one hydrochloride With potassium carbonate; N-ethyl-N,N-diisopropylamine In acetonitrile at 120℃; for 3h; Sealed tube; Inert atmosphere; Stage #2: With hydrogenchloride In diethyl ether	52.7 General procedure A General procedure: 1 -(Piperidin-3 -yl)derivative (1 eq) was dissolved in acetonitrile or DMF ( 1 M) in microvial.DIPEA (0-1.2 eq), K2C03 (1.5-2.5 eq) and benzodioxin derivative (1-1.2 eqv) were addedunder nitrogen and the vial was sealed. The reaction mixture was heated at 120°C for 3hours. The solvents were removed under reduced pressure.

Reference： [1]Current Patent Assignee: ORION S R L - WO2018/2437, 2018, A1 Location in patent: Page/Page column 23; 71; 72

25
[ 1142953-55-6 ]
(S)-2-(piperidin-3-yl)-2,3-dihydrobenzo[d]isothiazole-1,1-dioxide hydrochloride [ No CAS ]
2-((S)-1-(((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperidin-3-yl)-2,3-dihydrobenzo[d]isothiazole-1,1-dioxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.128 g	With potassium carbonate In acetonitrile at 120℃; for 4h; Sealed tube; Microwave irradiation;	81.5 Step 5: 2-((S)- 1-(((S)-2,3-Dihydrobenzo [bj [1 ,4j dioxin-2-yl)methyl)piperidin-3-yl)-2,3- dihydrobenzo [dj isothiazole 1,1-dioxide A sealed tube was charged with (S)-2-(piperidin-3-yl)-2,3-dihydrobenzo[d]isothiazole 1,1- dioxide, hydrochloride (0.127 g, 0.441 mmol), (2R)-2-(bromomethyl)-2,3 -dihydro- 1,4- benzodioxin (0.138 g, 0.604 mmol), potassium carbonate (0.139 g, 1.007 mmol) andacetonitrile (3 mL). Tube was sealed and reaction was heated with microvawe irridation to120°C for 4 hours. Mixture was cooled, filtered and washed with acetonitrile. Solvents were evaporated to dryness. Residue was purified with silica gel chromatography using EtOAc / heptanes to give 0.128 g of 2-((S)- 1 -(((S)-2,3-dihydrobenzo[b] [1 ,4]dioxin-2- yl)methyl)piperidin-3 -yl)-2,3 -dihydrobenzo [d]isothiazole- 1,1-dioxide.‘H NMR (400 MHz, DMSO-d6) ö ppm 1.52-1.71 (m, 2H), 1.71-1.8 1 (m, 1H), 1.90-1.97 (m,1H), 2.13-2.25 (m, 1H), 2.42 (dd, 1H), 2.64 (d, 2H), 2.74-2.83 (m, 1H), 3.07-3.15 (m, 1H),3.57-3.69 (m, 1H), 3.96 (dd, 1H), 4.24-4.41 (m, 2H), 4.49-4.64 (m, 2H), 6.75-6.91 (m, 4H),7.53-7.64 (m, 2H), 7.71 (ddd, 1H), 7.84 (d, 1H).

Reference： [1]Current Patent Assignee: ORION S R L - WO2018/2437, 2018, A1 Location in patent: Page/Page column 100; 101

26
[ 1142953-55-6 ]
3-methyl-1-((S)-piperidin-3-yl)pyrrolidin-2-one hydrochloride [ No CAS ]
1-((S)-1-(((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperidin-3-yl)-3-methylpyrrolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.08 g	With potassium carbonate In acetonitrile at 120℃; for 4h; Microwave irradiation;	97.3 Step 3: 1-((S)- 1-(((S)-2,3-Dihydrobenzo [bj [1 ,4j dioxin-2-yl)methyl)piperidin-3-yl)-3-methylpyrrolidin-2-one A mixture of 3-methyl-i -((S)-piperidin-3-yl)pyrrolidin-2-one hydrochloride (0.10 g, 0.46mmol), (R)-2-(bromomethyl)-2,3 -dihydrobenzo [b] [1 ,4]dioxine (0.126 g, 0.55 mmol) andK2C03 (0.114 g, 0.82 mmol) in MeCN (1.6 nil) was heated to 120°C in microwave reactor.After 4 hours, the reaction mixture was cooled to rt and solvents were evaporated.Evaporation residue was taken into a mixture of water (10 ml) and EtOAc (10 ml) and layers were separated. Aqueous phase was extracted with EtOAc. Combined organic layers were washed with water and brine, dried (Na2SO4) and concentrated. Purification of the evaporation residue by reverse phase column chromatography (C 18, 0.1% aq. HCOOH / MeCN) afforded 0.080 g of 1 -((5)-i -(((S)-2,3-dihydrobenzo[b] [1 ,4]dioxin-2-yl)methyl)piperidin-3 -yl)-3 -methylpyrrolidin-2-one as colorless oil.‘H NMR (400 MHz, CDC13) ö ppm 1.17 - 1.21 (3 H, m, CH3 from both diastereomers), 1.34- 1.49 (1 H, m), 1.52 - 1.63 (1 H, m), 1.64 - 1.78 (3 H, m), 2.08 -2.26 (3 H, m), 2.38 -2.50(1 H, m), 2.60 - 2.66 (2 H, m), 2.77-2.85 (1 H, m), 2.85 - 2.94 (1 H, m), 3.19 - 3.40 (2 H,m), 3.97 - 4.05 (1 H, m), 4.06 - 4.16 (1 H, m), 4.23 - 4.32 (2 H, m), 6.79 - 6.89 (4 H, m).

Reference： [1]Current Patent Assignee: ORION S R L - WO2018/2437, 2018, A1 Location in patent: Page/Page column 112

27
[ 1142953-55-6 ]
(S)-3,3-dimethyl-1-(piperidin-3-yl)pyrrolidin-2-one hydrochloride [ No CAS ]
1-((S)-1-(((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperidin-3-yl)-3,3-dimethylpyrrolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.1 g	With potassium carbonate In acetonitrile at 120℃; for 4h; Microwave irradiation;	100.3 Step 3: 1-((S)- 1-(((S)-2,3-Dihydrobenzo [bj [1 ,4j dioxin-2-yl)methyl)piperidin-3-yl)-3,3-dimethylpyrrolidin-2-one A mixture of (S)-3 ,3 -dimethyl- 1 -(piperidin-3 -yl)pyrrolidin-2-one hydrochloride (0.10 g, 0.43mol), (R)-2-(bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxine (0.116 g, 0.51 mmol) andK2C03 (0.105 g, 0.76 mmol) in MeCN (1.5 ml) was heated to 120°C in microwave reactor.After 4 hours, the reaction mixture was cooled to rt and solvents were evaporated.Evaporation residue was taken into a mixture of water (10 ml) and EtOAc (10 ml) and layerswere separated. Aqueous phase was extracted with EtOAc. Combined organic layers werewashed with water and brine, dried (Na2SO4) and concentrated. Purification of the evaporation residue by colunm chromatography (silica gel, EtOAc - heptane) afforded 0.10 g of 1 -((5)-i -(((S)-2,3 -dihydrobenzo[b] [1,4] dioxin-2-yl)methyl)piperidin-3 -yl)-3 ,3 - dimethylpyrrolidin-2-one as colorless oil.‘H NMR (400 MHz, CDC13) öppm 1.13(6 H, d), 1.36- 1.48(1 H, m), 1.63- 1.78(3 H,m), 1.82 (2 H, t), 2.08 - 2.19 (2 H, m), 2.61 - 2.67 (2 H, m), 2.78 - 2.85 (1 H, m), 2.86 -2.92 (1 H, m), 3.19 - 3.34 (2 H, m), 3.97 - 4.04 (1 H, m), 4.04 - 4.13 (1 H, m), 4.24 - 4.34(2 H, m), 6.79 - 6.89 (4 H, m)

Reference： [1]Current Patent Assignee: ORION S R L - WO2018/2437, 2018, A1 Location in patent: Page/Page column 114

28
[ 1142953-55-6 ]
2C₂HF₃O₂*C₁₈H₃₁N₃O₄ [ No CAS ]
3-((S)-1-(((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperidin-3-yl)-1-isopropyl-5,5-dimethylimidazolidine-2,4-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.046 g	With potassium carbonate; N-ethyl-N,N-diisopropylamine In acetonitrile at 120℃; for 4h; Microwave irradiation;	116.5 Step 5: 3-((S)- 1-(((S)-2,3-Dihydrobenzo [bj [1 ,4j dioxin-2-yl)methyl)piperidin-3-yl)- 1- isopropyl-5,5-dimethylimidazolidine-2,4-dione A mixture of of (5)-i -isopropyl-5 ,5-dimethyl-3-(piperidin-3-yl)imidazolidine-2,4-dione (bis)trifluoroacetate (0.11 g, 0.30 mol), (R)-2-(bromomethyl)-2,3- dihydrobenzo[b][1,4]dioxine (0.075 g, 0.33 mmol) and K2C03 (0.083 g, 0.60 mmol) and diisopropylethylamine (52 iii, 0.30 mmol) in MeCN (1 ml) was heated to 120°C in microwave reactor. After 4 hours, the reaction mixture was cooled to rt and solvents wereevaporated. Evaporation residue was taken into CH2C12 (20 nil) and the mixture was washed with sat. NaHCO3, dried (Na2SO4) and concentrated to dryness. Purification of the evaporation residue by reverse phase column chromatography (C 18, 0.1% aq. HCOOH / MeCN) afforded 0.046 g of 3 -((5)-i -(((5)-2,3 -dihydrobenzo[b] [1,4] dioxin-2- yl)methyl)piperidin-3-yl)- 1 -isopropyl-5 ,5-dimethyl-imidazolidine-2,4-dione, as colorless oil.‘H NMR (400 MHz, CDC13) ö ppm 1.34 (6 H, s), 1.43 (6 H, d), 1.56 - 1.77 (3 H, m), 2.07 -2.23 (2 H, m), 2.60 - 2.67 (1 H, m), 2.67 - 2.74 (1 H, m), 2.77 - 2.88 (3 H, m), 3.43 (1 H, spt), 4.00 (1 H, dd), 4.06 - 4.16 (1 H, m), 4.23 - 4.34 (2 H, m), 6.79 - 6.88 (4 H, m).

Reference： [1]Current Patent Assignee: ORION S R L - WO2018/2437, 2018, A1 Location in patent: Page/Page column 127

29
[ 1142953-55-6 ]
(S)-5,5-dimethyl-2-(piperidin-3-yl)isothiazolidine-1,1-dioxide hydrochloride [ No CAS ]
2-((S)-1-(((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperidin-3-yl)-5,5-dimethylisothiazolidine-1,1-dioxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.057 g	With potassium carbonate In acetonitrile at 120℃; for 3h; Microwave irradiation;	162.5 Step 5: 2-((S)- 1-(((S)-2,3-Dihydrobenzo [bj [1 ,4j dioxin-2-yl)methyl)piperidin-3-yl)-5,5- dimethylisothiazolidine 1,1-dioxide A mixture of of (5)-S ,5 -dimethyl-2-(piperidin-3 -yl)isothiazolidine 1,1-dioxide hydrochloride (0.10 g, 0.37 mmol), (R)-2-(bromomethyl)-2,3-dihydrobenzo[b] [1 ,4]dioxine (0.128 g, 0.56 mmol) and K2C03 (0.129 g, 0.93 mmol) in MeCN (2 ml) was heated to 120°C in mictowavereactor. After 3 hours, the reaction mixture was cooled to rt, filtered and solvents were evaporated from the filtrate. Purification of the evaporation residue by column chromatography (silica gel, EtOAc-heptane) afforded 0.057 g of 2-((S)-i-(((S)-2,3- dihydrobenzo[b] [1 ,4]dioxin-2-yl)methyl)piperidin-3 -yl)-S ,5 -dimethylisothiazolidine 1,1 - dioxide as solid.‘H NMR (400 MHz, CDC13) öppm 1.41 (6 H, d), 1.43- 1.55(1 H, m), 1.59- 1.78(2 H,m), 1.88 - 1.96 (1 H, m), 2.06 -2.17 (3 H, m), 2.24 (1 H, t), 2.58 -2.71 (2 H, m), 2.77 -2.84(1 H, m), 3.04-3.11 (1 H, m), 3.15 -3.29(2 H, m), 3.60-3.69(1 H, m), 4.00(1 H, dd), 4.25 - 4.33 (2 H, m), 6.79 - 6.89 (4 H, m)

Reference： [1]Current Patent Assignee: ORION S R L - WO2018/2437, 2018, A1 Location in patent: Page/Page column 164; 165

30
[ 1142953-55-6 ]
(S)-4,4-dimethyl-1-(piperidin-3-yl)pyrrolidin-2-one [ No CAS ]
1-((S)-1-(((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperidin-3-yl)-4,4-dimethylpyrrolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98 mg	With potassium carbonate; N-ethyl-N,N-diisopropylamine In acetonitrile at 120℃; for 3h; Sealed tube; Inert atmosphere;	1.3 General procedure A General procedure: 1 -(Piperidin-3 -yl)derivative (1 eq) was dissolved in acetonitrile or DMF ( 1 M) in microvial.DIPEA (0-1.2 eq), K2C03 (1.5-2.5 eq) and benzodioxin derivative (1-1.2 eqv) were addedunder nitrogen and the vial was sealed. The reaction mixture was heated at 120°C for 3hours. The solvents were removed under reduced pressure.; The 1 -((5)-i -(((S)-2,3 -dihydrobenzo[b] [1,4] dioxin-2-yl)methyl)piperidin-3 -yl)-4,4- dimethylpyrrolidin-2-one was prepared according to the general procedure A using (S)-4,4- dimethyl-1-(piperidin-3-yl)pyrrolidin-2-one (100 mg, 0.509 mmol), acetonitrile (0.5 ml), DIPEA(0.106 ml, 0.611 mmol), K2C03 (106 mg, 0.764 mmol) and (2R)-2-(bromomethyl)-2,3-dihydro-1,4-benzodioxin (117 mg, 0.509 mmol). The crude product was purified by reversed phase flash chromatography to obtain 98 mg of the product. ‘HNMR(400 MHz, CDC13)öppm 1.13- 1.15(m,6H), 1.25- 1.45(m, 1H), 1.63-1.78 (m, 3H), 2.06 - 2.17 (m, 2H), 2.21 (s, 2H), 2.64 (d, 2H), 2.81 (d, 1H), 2.87 - 2.94 (m, 1H), 3.05-3.14 (m, 2H), 3.95-4.05 (m, 1H), 4.11 -4.21 (m, 1H), 4.25-4.33 (m, 2H), 6.81 -6.89(m,4H).

Reference： [1]Current Patent Assignee: ORION S R L - WO2018/2437, 2018, A1 Location in patent: Page/Page column 23; 25

31
[ 1142953-55-6 ]
[ 17356-08-0 ]
(R)-2-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methylisothiourea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol at 60℃; for 3h;	7 2-Bromomethyl-1,4-benzodioxane was purchased from TCI (Shanghai) Chemical Industry Development Co., Ltd. Thiourea (150 g, 1.97 mmol) and 2-bromomethyl-1,4-benzodioxane (524.41 g, 2.29 mol) were dissolved in 200 mL of absolute ethanol and reacted at 60 ° C for 3 h.After the reaction is completed, the ethanol is removed by rotary evaporation, and the obtained oily product is transferred to 500 mL.The crystals were allowed to stand in a beaker, filtered and dried in vacuo to give the product 17.

Reference： [1]Current Patent Assignee: THE PLA GENERAL HOSPITAL - CN108997172, 2018, A Location in patent: Paragraph 0069; 0070; 0071; 0072; 0073; 0074-0076

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

[ CAS No. 1142953-55-6 ] {[proInfo.proName]}

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[ 1142953-55-6 ] Synthesis Path-Downstream 1~31

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Bromides

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Benzodioxans

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[ 1142953-55-6 ]

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