[ CAS No. 89830-98-8 ] {[proInfo.proName]}

Name: 89830-98-8|5-Cyclopropyl-1H-imidazole|97%
Brand: Ambeed
SKU: A120140
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Quality Control of [ 89830-98-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 89830-98-8 ]

Product Details of [ 89830-98-8 ]

CAS No. :	89830-98-8	MDL No. :	MFCD18711516
Formula :	C₆H₈N₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BNFGUBCFRVUHJH-UHFFFAOYSA-N
M.W :	108.14	Pubchem ID :	19031522
Synonyms :

Calculated chemistry of [ 89830-98-8 ]

Physicochemical Properties

Num. heavy atoms :	8
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.5
Num. rotatable bonds :	1
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	31.05
TPSA :	28.68 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.51 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.03
Log Po/w (XLOGP3) :	0.64
Log Po/w (WLOGP) :	1.22
Log Po/w (MLOGP) :	0.32
Log Po/w (SILICOS-IT) :	2.12
Consensus Log Po/w :	1.07

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.31
Solubility :	5.29 mg/ml ; 0.049 mol/l
Class :	Very soluble
Log S (Ali) :	-0.82
Solubility :	16.5 mg/ml ; 0.152 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.77
Solubility :	1.84 mg/ml ; 0.0171 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.76

Safety of [ 89830-98-8 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 89830-98-8 ]

* 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 [ 89830-98-8 ]
Downstream synthetic route of [ 89830-98-8 ]

[ 89830-98-8 ] Synthesis Path-Upstream 1~5

1
[ 773837-37-9 ]
[ 38622-91-2 ]
[ 1489-69-6 ]
[ 89830-98-8 ]

Yield	Reaction Conditions	Operation in experiment
65%	Stage #1: at 20℃; for 1 h; Stage #2: With ammonia In methanol at 110℃; for 16 h;	NaCN (360 mg; 7.35 mmol) was added to a suspension of cyclopropane- carboxaldehyde (5 g; 71 .3 mmol) and tosylmethyl-isocyanide (13.7 g; 69.9 mmol) in EtOH (200 mL). The resulting mixture was stirred for 1 h at RT. The solvent was removed under reduced pressure and the residue was washed with a mixture of heptane/ether (1 :1 ). The beige dried powder was stirred in NH₃/MeOH 7N (480 mL; 3.36 mol) and the mixture was stirred at 100°C in steel bomb for 16 h. The mixture was cooled to RT and the solvant was evaporated under reduced pressure. iPr₂0 was added to the residue and the solid was filtered. The filtrate was evaporated to dryness and the crude was purified by preparative LC on (Irregular SiOH 20-45??? 1000g DAVISIL). Mobile phase (0.5percent NH₄OH, 94percent DCM, 6percent MeOH). The pure fraction was collected and evaporated to give 4.9 g of intermediate J-1 a as a brown oil (65percent yield). 1 H NMR (DMSO-de, 400MHz) : ? (ppm) 8.60 (br. s., 1 H), 7.58 (s, 1 H), 6.76 (s, 1 H), 1 .85 (m, 1 H), 0.86 (m, 2H), 0.71 (m, 2H).

Reference： [1] Patent: WO2013/68438, 2013, A1, . Location in patent: Page/Page column 16

2
[ 69267-75-0 ]
[ 3473-63-0 ]
[ 89830-98-8 ]

Reference： [1] Patent: WO2010/96395, 2010, A1, . Location in patent: Page/Page column 34; 35
[2] Patent: US2011/9410, 2011, A1, . Location in patent: Page/Page column 30

3
[ 69267-75-0 ]
[ 89830-98-8 ]

Reference： [1] Patent: WO2018/151830, 2018, A1, . Location in patent: Paragraph 0303

4
[ 765-43-5 ]
[ 89830-98-8 ]

Reference： [1] Patent: WO2018/151830, 2018, A1,

5
[ 89830-98-8 ]
[ 1448428-04-3 ]

Reference： [1] Patent: WO2016/106384, 2016, A1,
[2] Patent: WO2016/106384, 2016, A1,

[ 89830-98-8 ] Synthesis Path-Downstream 1~88

1
[ 69267-75-0 ]
[ 3473-63-0 ]
[ 89830-98-8 ]

Yield	Reaction Conditions	Operation in experiment
93.7%	In 1,2-dimethoxyethane; at 110℃; for 15h;	The compound 2-bromo-1-cyclopropylethanone (12.0 g, 74.1 mmol) and formamidine acetate (23.1 g, 222.3 mmol) were dissolved in 100 mL of ethylene glycol and reacted at 110 C for 15 hours. After the reaction was completed, 500 mL of water was added, and the mixture was washed three times with dichloromethane (500 mL×3), then the aqueous phase was adjusted to pH 8 with a 1 M aqueous NaOH solution, and the aqueous phase was extracted twice with dichloromethane (500 mL×2), organic phase was dried and concentrated to give the desired product 7.5g, yield 93.7%.
	In ethylene glycol; at 135℃;	A mixture of 2-bromo-l-cyclopropylethanone (1.63 g, 10.0 mmol) and formimidamide acetate (5.24 g, 50.0 mmol) in ethylene glycol (50 mL) was heated at 135deg;C overnight. After cooling, the mixture was diluted with water (50 mL), and extracted several times with ether. The combined organic layers were dried over MgSO4, filtered, and concentrated to afford the crude product which was directly used in next step reaction without further purification. LCMS: (M+H)+= 109.3.
	With ammonia; at -78 - 20℃;Sealed tube;	A. Preparation of 4-cyclopropyl-1H-imidazole Ammonia (~75 mL) was condensed into a pressure vessel containing formamidine acetate (60 g, 0.58 mol) and a stir bar at -78 C. 2-bromo-1-cyclopropyl-ethanone (10.2 g, 0.063 mol) was added dropwise and the pressure vessel was sealed and warmed to room temperature and stirred for 12 hours. The reaction mixture was then cooled to -78 C. before being carefully opened. The cooling bath was removed and the ammonia was allowed to evaporate. The residue was dissolved in 100 mL of water and 20 mL saturated sodium bicarbonate solution, and then solid sodium chloride was added until the solution was saturated. This mixture was extracted with ethyl acetate (4*100 mL) and the organic phase was dried with sodium sulfate before being evaporated to yield 4-cyclopropyl-1H-imidazole as a yellow oil (70-80% purity, 5.3 g, 78% yield, M+1=109.1) which was used without further purification. Reverse-phase HPLC (0.1% HCl H2O, MeCN) of the crude compound gave an analytically pure sample (1.0 g).

Reference： [1]Patent: CN110294746,2019,A .Location in patent: Paragraph 0121-0124; 0176-0179; 0217-0220
[2]Patent: WO2010/96395,2010,A1 .Location in patent: Page/Page column 34; 35
[3]Patent: US2011/9410,2011,A1 .Location in patent: Page/Page column 30

2
[ 89830-98-8 ]
[ 54962-75-3 ]
[ 1240347-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;copper(l) iodide; 8-quinolinol; In dimethyl sulfoxide; at 120℃;Inert atmosphere; Microwaves;	A mixture of 3-bromo-5-(trifluoromethyl)aniline (0.48 g, 2.0 mmol), 4-cyclopropyl-lH- imidazole (0.26g, 2.4 mmol), K2CO3 (0.35g, 2.5 mmol), CuI (57 mg, 0.30 mmol), and 8- hydroxyquinoline (44 mg, 0.30 mmol) in dry DMSO (2 mL) in a microwave tube was cooled to -78deg;C, and degassed by vacuum and refilled with N2 for three times. The mixture was heated at1200C overnight. The mixture was cooled to 40-500C and 14percent aq. NH4OH was added. The mixture was stirred at 40-500C for 1 h. After cooling, the mixture was diluted with water, and extracted with ethyl acetate (3x15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column (5percent MeOH in CH2Cl2) to afford the crude product (0.41 g). LCMS: (M+H)+= 268.3.

Reference： [1]Patent: WO2010/96395,2010,A1 .Location in patent: Page/Page column 35

3
[ 89830-98-8 ]
4-cyclopropyl-1H-imidazole hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In water; acetonitrile;	Example 12Preparation of 4-Alkyl Substituted ImidazolesA. Preparation of <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> Ammonia (75 mL) was condensed into a pressure vessel containing formamidine acetate (60 g, 0.58 mol) and a stir bar at -78° C. 2-bromo-1-cyclopropyl-ethanone (10.2 g, 0.063 mol) was added dropwise and the pressure vessel was sealed and warmed to room temperature and stirred for 12 hours. The reaction mixture was then cooled to -78° C. before being carefully opened. The cooling bath was removed and the ammonia was allowed to evaporate. The residue was dissolved in 100 mL of water and 20 mL saturated sodium bicarbonate solution, and then solid sodium chloride was added until the solution was saturated. This mixture was extracted with ethyl acetate (4.x.100 mL) and the organic phase was dried with sodium sulfate before being evaporated to yield <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> as a yellow oil (70-80percent purity, 5.3 g, 78percent yield, M+1=109.1) which was used without further purification. Reverse-phase HPLC (0.1percent HCl H2O, MeCN) of the crude compound gave an analytically pure sample (1.0 g). 1H NMR of HCl salt (DMSO) d 8.96 (s, 1H), 7.38 (s, 1H), 1.96 (m, 1H), 0.97 (m, 2H), 0.79 (m, 2H).

Reference： [1]Patent: US2011/9410,2011,A1 .Location in patent: Page/Page column 30

4
[ 1354412-73-9 ]
[ 89830-98-8 ]
[ 1354413-11-8 ]

Yield	Reaction Conditions	Operation in experiment
13%	With 8-quinolinol; caesium carbonate; In propyl cyanide; at 100℃; for 16h;	A suspension 4-bromo-N-(5-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiophen-3-yl)picolinamide (63 mg, 0.16 mmol), <strong>[89830-98-8]4-cyclopropyl imidazole</strong> (35 mg, 0.24 mmol), Cu2O (1.2 mg, 0.0081 mmol), 4,7-dimethoxy-1,10-phenanthroline (5.9 mg, 0.024 mmol, (or 8-hydroxy-quinoline may be used as the ligand with comparable results), cesium carbonate (116 mg, 0.36 mmol), and PEG-3350 (32 mg) in butyronitrile (1 mL) was heated at 100° C. for 16 hours. The solvent was removed and the residue was purified by reverse-phase HPLC to 4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(5-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiophen-3-yl)picolinamide as a white powder (9.2 mg, 0.377 mmol, 13percent yield). C21H19N7OS. 418.2 (M+1). 1H NMR (DMSO) delta 11.42 (s, 1H), 8.77 (s, 1H), 8.60 (s, 1H), 8.54 (s, 1H), 8.37 (d, J=2 Hz, 1H), 8.33 (d, J=2 Hz, 1H), 8.04 (d, J=1 Hz, 1H), 7.97 (dd, J=2, 5 Hz, 1H), 7.85 (s, 1H), 3.55-3.59 (m, 1H), 1.85-1.88 (m, 1H), 1.22-1.26 (m, 2H), 1.11-1.13 (m, 2H), 0.82-0.86 (m, 2H), 0.72-0.75 (m, 2H).

Reference： [1]Patent: US2012/4267,2012,A1 .Location in patent: Page/Page column 23-24

5
[ 886371-78-4 ]
[ 89830-98-8 ]
4-(4-cyclopropyl-1H-imidazol-1-yl)picolinic acid hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%		A mixture of 4-fluoropicolinic acid (400 mg, 2.84 mmol) and <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (322 mg, 2.98 mmol) were dissolved in N,N-dimethylformamide, and N-methylmorpholine (0.36 ml, 3.28 mmol) was added. The reaction was warmed to 35° C., and stirred for 20 hours. The solvent was then removed under reduced pressure to afford a viscous oily residue. This residue was dissolved in 1N hydrochloric acid (5 mL), and the aqueous layer was extracted with ethyl acetate (2*5 mL). The aqueous layer was concentrated under reduced pressure to afford a yellow solid. To this residue was added 5 mL of acetonitrile/methanol (20:1) and the mixture was sonicated to afford a fine suspension of solids.The solids were collected by filtration, washed several times with acetonitrile, and dried on the filter funnel.The yellow solids were collected to afford 520 mg (69percent yield) of 4-(4-cyclopropyl-1H-imidazol-1-yl)picolinic acid as the hydrochloride salt. M+1=230.1

Reference： [1]Patent: US2012/4267,2012,A1 .Location in patent: Page/Page column 22

6
[ 1354412-82-0 ]
[ 89830-98-8 ]
[ 1354412-83-1 ]

Yield	Reaction Conditions	Operation in experiment
73%	With caesium carbonate; In propyl cyanide; at 105℃; for 2h;	Step 2-Preparation of a Compound of Formula (19A) in which R is Hydrogen, X2 is CH, X3 is S, X4 is CH, X5 is N, and Y is 4-(4-cyclopropyl-1H-imidazol-1-yl)To a solution of methyl 4-(4-fluoropicolinamido)thiophene-2-carboxylate (400 mg, 1.4 mmol) in butyronitrile (5 mL), was added <strong>[89830-98-8]4-cyclopropyl imidazole</strong> (310 mg, 2.9 mmol), and caesium carbonate (840 mg, 2.6 mmol) and the reaction was heated to 105° C. for 2 hours.The reaction was filtered and the solids were washed with acetonitrile, methylene chloride, and the filtrate was evaporated under reduced pressure.The residue was suspended in acetonitrile, and the solids were collected by filtration to provide 384 mg (73percent) of methyl 4-(4-(4-cyclopropyl-1H-imidazol-1-yl)picolinamido)thiophene-2-carboxylate. M+1=369.1

Reference： [1]Patent: US2012/4267,2012,A1 .Location in patent: Page/Page column 19

7
[ 1354412-90-0 ]
[ 89830-98-8 ]
[ 1354412-91-1 ]

Yield	Reaction Conditions	Operation in experiment
51%	With 8-quinolinol; caesium carbonate;copper(I) oxide; In butyronitile; at 120℃; for 16h;Inert atmosphere;	A suspension of isopropyl 5-iodo-2-methoxybenzoate (1.52 g, 4.75 mmol), <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (0.777 g, 7.13 mmol), copper(I) oxide (0.067 g, 0.047 mmol), 8-hydroxyquinoline (0.103 g, 0.71 mmol), cesium carbonate (2.41 g, 7.41 mmol), PEG-3350 (1.18 g) and butyronitile (60 ml) was placed in a sealed tube, which was flushed with nitrogen and heated at 120° C. for 16 hours.The solvent was removed under reduced pressure, and the residue was purified by reversed phase HPLC to provide isopropyl 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-methoxybenzoate. (0.720 g, 2.4 mmol).51percent yield. 301 (M+1).Step 3-Preparation of 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-methoxybenzoic acid

Reference： [1]Patent: US2012/4267,2012,A1 .Location in patent: Page/Page column 21

8
[ 773837-37-9 ]
[ 38622-91-2 ]
[ 1489-69-6 ]
[ 89830-98-8 ]

Yield	Reaction Conditions	Operation in experiment
65%		NaCN (360 mg; 7.35 mmol) was added to a suspension of cyclopropane- carboxaldehyde (5 g; 71 .3 mmol) and tosylmethyl-isocyanide (13.7 g; 69.9 mmol) in EtOH (200 mL). The resulting mixture was stirred for 1 h at RT. The solvent was removed under reduced pressure and the residue was washed with a mixture of heptane/ether (1 :1 ). The beige dried powder was stirred in NH3/MeOH 7N (480 mL; 3.36 mol) and the mixture was stirred at 100°C in steel bomb for 16 h. The mixture was cooled to RT and the solvant was evaporated under reduced pressure. iPr20 was added to the residue and the solid was filtered. The filtrate was evaporated to dryness and the crude was purified by preparative LC on (Irregular SiOH 20-45??? 1000g DAVISIL). Mobile phase (0.5percent NH4OH, 94percent DCM, 6percent MeOH). The pure fraction was collected and evaporated to give 4.9 g of intermediate J-1 a as a brown oil (65percent yield). 1 H NMR (DMSO-de, 400MHz) : ? (ppm) 8.60 (br. s., 1 H), 7.58 (s, 1 H), 6.76 (s, 1 H), 1 .85 (m, 1 H), 0.86 (m, 2H), 0.71 (m, 2H).

Reference： [1]Patent: WO2013/68438,2013,A1 .Location in patent: Page/Page column 16

9
[ 76513-69-4 ]
[ 89830-98-8 ]
[ 1434588-82-5 ]
[ 1434588-77-8 ]

Yield	Reaction Conditions	Operation in experiment
		J-1 a (4.84 g; 44.8 mmol) in TH F (60 mL) was added dropwise to a suspension of NaH (1 .97 g; 49.2 mmol) in TH F (200 mL) at 0°C under N2. The mixture was stirred at RT for 30 min and SEM-CI (9.9 mL; 55.9 mmol) in THF(20 mL) was added dropwise at 0°C. The mixture was stirred at RT under N2 for 16 h. Water was added and the product was extracted with DCM. The organic layer was dried over MgS04, filtered and concentrated under reduced pressure. The crude was purified by preparative LC (Irregular SiOH 20-45 [Jim , 150g Merck, Mobile phase Gradient from 50percent DCM, 50percent heptane to 100percent DCM). The fractions containing pure compound were combined and the solvent was removed under reduced pressure to give 6.6 g of J-1 b as a yellow oil (62percent).Mixture of 2 regioisomers : 70/30Minoritory regioisomer : 1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.64 (s, 1 H), 6.56 (s, 1 H), 5.34 (s, 1 H), 3.45 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.52-0.57 (m, 2H), -0.04 (s, 9H).Majoritory regioisomer :1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.56 (s, 1 H), 6.94 (s, 1 H), 5.20 (s, 1 H), 3.43 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.56-0.62 (m, 2H), -0.04 (s, 9H). BuLi (1.6M in hexane)(1 1 mL; 17.6 mmol) was added to a solution of J-1 b (3.5 g; 14.7 mmol) in THF (60 mL) at -50°C. The mixture was stirred at the sametemperature for 30 min and DMF (1 .7 mL; 22 mmol) was added. The mixture was warmed slowly to RT in 1 h and NH2OH,HCI (970 mg; 29.4 mmol) was added and the mixture was stirred at RT for 16h. Water was added and the product was extracted with DCM (3 times), washed with brine, dried over MgS04 and the solvent was removed under reduced pressure to give 4.1 g (quantitative yield) of the mixture of isomers K-1 as yellow oil.HPLC Rt (min) = 5.30, 5.41 and 5.90 ; MS M+ (H+): 282 (method V2002V2002) K-1 ( 3.1 g; 1 1 mmol) was dissolved in DCM (18 mL) and pyridine (19 mL) at RT. The mixture was cooled to 0°C and TFAA (4.6 mL; 33 mmol) was added. The mixture was stirred at RT for 24h. The solvent was removed under reduced pressure and the residue was dissolved in AcOEt. The organic layer was washed with water and brine, dried over MgS04, filtered and the solvent was removed under reduced pressure. The crude was purified by preparative LC (irregular SiOH 15-40??? 90g merck, mobile phase Heptane/DCM 30/70 to DCM 100percent) to give 2.14 g of intermediate J-1 (73percent) as a mixture of two isomers.HPLC Rt (min) = 6.51 ; MS M+ (H+): 264 (method V2002V2002)

Reference： [1]Patent: WO2013/68438,2013,A1 .Location in patent: Page/Page column 18

10
[ 76513-69-4 ]
[ 89830-98-8 ]
[ 1434588-68-7 ]
[ 1434588-73-4 ]

Yield	Reaction Conditions	Operation in experiment
		J-1 a (4.84 g; 44.8 mmol) in TH F (60 mL) was added dropwise to a suspension of NaH (1 .97 g; 49.2 mmol) in TH F (200 mL) at 0°C under N2. The mixture was stirred at RT for 30 min and SEM-CI (9.9 mL; 55.9 mmol) in THF(20 mL) was added dropwise at 0°C. The mixture was stirred at RT under N2 for 16 h. Water was added and the product was extracted with DCM. The organic layer was dried over MgS04, filtered and concentrated under reduced pressure. The crude was purified by preparative LC (Irregular SiOH 20-45 [Jim , 150g Merck, Mobile phase Gradient from 50percent DCM, 50percent heptane to 100percent DCM). The fractions containing pure compound were combined and the solvent was removed under reduced pressure to give 6.6 g of J-1 b as a yellow oil (62percent).Mixture of 2 regioisomers : 70/30Minoritory regioisomer : 1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.64 (s, 1 H), 6.56 (s, 1 H), 5.34 (s, 1 H), 3.45 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.52-0.57 (m, 2H), -0.04 (s, 9H).Majoritory regioisomer :1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.56 (s, 1 H), 6.94 (s, 1 H), 5.20 (s, 1 H), 3.43 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.56-0.62 (m, 2H), -0.04 (s, 9H).

Reference： [1]Patent: WO2013/68438,2013,A1 .Location in patent: Page/Page column 16

11
[ 76513-69-4 ]
[ 89830-98-8 ]
[ 1434588-92-7 ]
[ 1434588-87-0 ]

Yield	Reaction Conditions	Operation in experiment
		J-1 a (4.84 g; 44.8 mmol) in TH F (60 mL) was added dropwise to a suspension of NaH (1 .97 g; 49.2 mmol) in TH F (200 mL) at 0°C under N2. The mixture was stirred at RT for 30 min and SEM-CI (9.9 mL; 55.9 mmol) in THF(20 mL) was added dropwise at 0°C. The mixture was stirred at RT under N2 for 16 h. Water was added and the product was extracted with DCM. The organic layer was dried over MgS04, filtered and concentrated under reduced pressure. The crude was purified by preparative LC (Irregular SiOH 20-45 [Jim , 150g Merck, Mobile phase Gradient from 50percent DCM, 50percent heptane to 100percent DCM). The fractions containing pure compound were combined and the solvent was removed under reduced pressure to give 6.6 g of J-1 b as a yellow oil (62percent).Mixture of 2 regioisomers : 70/30Minoritory regioisomer : 1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.64 (s, 1 H), 6.56 (s, 1 H), 5.34 (s, 1 H), 3.45 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.52-0.57 (m, 2H), -0.04 (s, 9H).Majoritory regioisomer :1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.56 (s, 1 H), 6.94 (s, 1 H), 5.20 (s, 1 H), 3.43 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.56-0.62 (m, 2H), -0.04 (s, 9H). BuLi (1.6M in hexane)(1 1 mL; 17.6 mmol) was added to a solution of J-1 b (3.5 g; 14.7 mmol) in THF (60 mL) at -50°C. The mixture was stirred at the sametemperature for 30 min and DMF (1 .7 mL; 22 mmol) was added. The mixture was warmed slowly to RT in 1 h and NH2OH,HCI (970 mg; 29.4 mmol) was added and the mixture was stirred at RT for 16h. Water was added and the product was extracted with DCM (3 times), washed with brine, dried over MgS04 and the solvent was removed under reduced pressure to give 4.1 g (quantitative yield) of the mixture of isomers K-1 as yellow oil.HPLC Rt (min) = 5.30, 5.41 and 5.90 ; MS M+ (H+): 282 (method V2002V2002)

Reference： [1]Patent: WO2013/68438,2013,A1 .Location in patent: Page/Page column 16

12
[ 506-68-3 ]
[ 76513-69-4 ]
[ 89830-98-8 ]
[ 1434588-82-5 ]
[ 1434588-77-8 ]

Yield	Reaction Conditions	Operation in experiment
		J-1 a (4.84 g; 44.8 mmol) in TH F (60 mL) was added dropwise to a suspension of NaH (1 .97 g; 49.2 mmol) in TH F (200 mL) at 0°C under N2. The mixture was stirred at RT for 30 min and SEM-CI (9.9 mL; 55.9 mmol) in THF(20 mL) was added dropwise at 0°C. The mixture was stirred at RT under N2 for 16 h. Water was added and the product was extracted with DCM. The organic layer was dried over MgS04, filtered and concentrated under reduced pressure. The crude was purified by preparative LC (Irregular SiOH 20-45 [Jim , 150g Merck, Mobile phase Gradient from 50percent DCM, 50percent heptane to 100percent DCM). The fractions containing pure compound were combined and the solvent was removed under reduced pressure to give 6.6 g of J-1 b as a yellow oil (62percent).Mixture of 2 regioisomers : 70/30Minoritory regioisomer : 1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.64 (s, 1 H), 6.56 (s, 1 H), 5.34 (s, 1 H), 3.45 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.52-0.57 (m, 2H), -0.04 (s, 9H).Majoritory regioisomer :1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.56 (s, 1 H), 6.94 (s, 1 H), 5.20 (s, 1 H), 3.43 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.56-0.62 (m, 2H), -0.04 (s, 9H). BrCN (6.1 1 g; 57.7 mmol) was added to a solution of DMAP (7.05 g; 57.7 mmol) in DMF (60 mL) at 10°C. The reaction was exothermic to 35°C and a pale yellow precipitate was formed. The mixture was cooled to 10°C and J-1 b (5.5 g; 23.1 mmol) was added. The mixture was stirred at 40°C for 6 h. Water was added and product was extracted with Et20 (2 times). The combined organic layers were washed with brine, dried over MgS04, filtered and the solvent was removed under reduced pressure.The crude was purified by preparative LC (Irregular SiOH 15-40 ??? 220 g grace, mobile phase Heptane/DCM 50/50 to 10/90) to give 2.2 g impure J-1 , which was further purified by preparative LC (irregular SiOH 15-40 ??? 90 g Merck, mobile phase heptane/DCM 30/70) to give 0.94 g of J-1 as a mixture of two region-isomers(15percent yield).HPLC Rt (min) = 6.1 1 ; MS M+ (H+): 264 (method V1004V1012)

Reference： [1]Patent: WO2013/68438,2013,A1 .Location in patent: Page/Page column 17

13
[ 506-68-3 ]
[ 76513-69-4 ]
[ 89830-98-8 ]
[ 565473-06-5 ]
[ 1434584-96-9 ]

Yield	Reaction Conditions	Operation in experiment
120 mg		J-1 a (4.84 g; 44.8 mmol) in TH F (60 mL) was added dropwise to a suspension of NaH (1 .97 g; 49.2 mmol) in TH F (200 mL) at 0°C under N2. The mixture was stirred at RT for 30 min and SEM-CI (9.9 mL; 55.9 mmol) in THF(20 mL) was added dropwise at 0°C. The mixture was stirred at RT under N2 for 16 h. Water was added and the product was extracted with DCM. The organic layer was dried over MgS04, filtered and concentrated under reduced pressure. The crude was purified by preparative LC (Irregular SiOH 20-45 [Jim , 150g Merck, Mobile phase Gradient from 50percent DCM, 50percent heptane to 100percent DCM). The fractions containing pure compound were combined and the solvent was removed under reduced pressure to give 6.6 g of J-1 b as a yellow oil (62percent).Mixture of 2 regioisomers : 70/30Minoritory regioisomer : 1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.64 (s, 1 H), 6.56 (s, 1 H), 5.34 (s, 1 H), 3.45 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.52-0.57 (m, 2H), -0.04 (s, 9H).Majoritory regioisomer :1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.56 (s, 1 H), 6.94 (s, 1 H), 5.20 (s, 1 H), 3.43 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.56-0.62 (m, 2H), -0.04 (s, 9H). BrCN (6.1 1 g; 57.7 mmol) was added to a solution of DMAP (7.05 g; 57.7 mmol) in DMF (60 mL) at 10°C. The reaction was exothermic to 35°C and a pale yellow precipitate was formed. The mixture was cooled to 10°C and J-1 b (5.5 g; 23.1 mmol) was added. The mixture was stirred at 40°C for 6 h. Water was added and product was extracted with Et20 (2 times). The combined organic layers were washed with brine, dried over MgS04, filtered and the solvent was removed under reduced pressure.The crude was purified by preparative LC (Irregular SiOH 15-40 ??? 220 g grace, mobile phase Heptane/DCM 50/50 to 10/90) to give 2.2 g impure J-1 , which was further purified by preparative LC (irregular SiOH 15-40 ??? 90 g Merck, mobile phase heptane/DCM 30/70) to give 0.94 g of J-1 as a mixture of two region-isomers(15percent yield).HPLC Rt (min) = 6.1 1 ; MS M+ (H+): 264 (method V1004V1012) EtONa (904 mg; 13.3 mmol) was added to a solution of 2-cyano-imidazole 1-1 (0.7 g; 2.66 mmol) and intermediate C-1 (736 mg; 2.66 mmol) in EtOH (30 ml_). The mixture was stirred at 90°C for 16 h. The solvent was removed under reduced pressure. The crude was purified by preparative LC (irregular SiOH 45g Merck, mobile phase 97/3/0.1 to 95/5/0.5) to give 0.51 g of the SEM-protected ethoxy intermediate as a lightly yellow solid (38percent yield).HPLC Rt (min) = 7.45 ; MS M+ (H+): 506 method (v2003v2002) NaF (170 mg; 4.05 mmol) was added to a solution of SEM-protected ethoxy intermediate (0.41 g; 0.81 1 mmol) in THF (28 ml_), HCI (37percent in H20) (28 mL) and MeOH (10 mL). The mixture was stirred at 40°C for 16h. The mixture was cooled to RT and a 10percent solution of K2C03 was added until the pH of the solution was basic. The aqueous layer was saturated with K2C03 powder and the product was extracted with DCM/MeOH (5percent) (3 times). The combined organic layers were dried over MgS04, filtered and the solvent was removed under reduced pressure. The crude was purified by preparative LC (irregular SiOH 15-40??"?, mobile phase DCM/MeOH/NH3aq 95/5/0.5 to 90/10/0.5) to give 120 mg of compound 1 as a white powder (43percent yield)

Reference： [1]Patent: WO2013/68438,2013,A1 .Location in patent: Page/Page column 15; 17

14
[ 506-68-3 ]
[ 76513-69-4 ]
[ 89830-98-8 ]
[ 565473-06-5 ]
C₂₄H₃₁N₇O₂Si [ No CAS ]
C₂₄H₃₁N₇O₂Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		J-1 a (4.84 g; 44.8 mmol) in TH F (60 mL) was added dropwise to a suspension of NaH (1 .97 g; 49.2 mmol) in TH F (200 mL) at 0°C under N2. The mixture was stirred at RT for 30 min and SEM-CI (9.9 mL; 55.9 mmol) in THF(20 mL) was added dropwise at 0°C. The mixture was stirred at RT under N2 for 16 h. Water was added and the product was extracted with DCM. The organic layer was dried over MgS04, filtered and concentrated under reduced pressure. The crude was purified by preparative LC (Irregular SiOH 20-45 [Jim , 150g Merck, Mobile phase Gradient from 50percent DCM, 50percent heptane to 100percent DCM). The fractions containing pure compound were combined and the solvent was removed under reduced pressure to give 6.6 g of J-1 b as a yellow oil (62percent).Mixture of 2 regioisomers : 70/30Minoritory regioisomer : 1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.64 (s, 1 H), 6.56 (s, 1 H), 5.34 (s, 1 H), 3.45 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.52-0.57 (m, 2H), -0.04 (s, 9H).Majoritory regioisomer :1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.56 (s, 1 H), 6.94 (s, 1 H), 5.20 (s, 1 H), 3.43 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.56-0.62 (m, 2H), -0.04 (s, 9H). BrCN (6.1 1 g; 57.7 mmol) was added to a solution of DMAP (7.05 g; 57.7 mmol) in DMF (60 mL) at 10°C. The reaction was exothermic to 35°C and a pale yellow precipitate was formed. The mixture was cooled to 10°C and J-1 b (5.5 g; 23.1 mmol) was added. The mixture was stirred at 40°C for 6 h. Water was added and product was extracted with Et20 (2 times). The combined organic layers were washed with brine, dried over MgS04, filtered and the solvent was removed under reduced pressure.The crude was purified by preparative LC (Irregular SiOH 15-40 ??? 220 g grace, mobile phase Heptane/DCM 50/50 to 10/90) to give 2.2 g impure J-1 , which was further purified by preparative LC (irregular SiOH 15-40 ??? 90 g Merck, mobile phase heptane/DCM 30/70) to give 0.94 g of J-1 as a mixture of two region-isomers(15percent yield).HPLC Rt (min) = 6.1 1 ; MS M+ (H+): 264 (method V1004V1012) EtONa (904 mg; 13.3 mmol) was added to a solution of 2-cyano-imidazole 1-1 (0.7 g; 2.66 mmol) and intermediate C-1 (736 mg; 2.66 mmol) in EtOH (30 ml_). The mixture was stirred at 90°C for 16 h. The solvent was removed under reduced pressure. The crude was purified by preparative LC (irregular SiOH 45g Merck, mobile phase 97/3/0.1 to 95/5/0.5) to give 0.51 g of the SEM-protected ethoxy intermediate as a lightly yellow solid (38percent yield).HPLC Rt (min) = 7.45 ; MS M+ (H+): 506 method (v2003v2002)

Reference： [1]Patent: WO2013/68438,2013,A1 .Location in patent: Page/Page column 15; 17

15
[ 1571143-30-0 ]
[ 89830-98-8 ]
[ 1571145-89-5 ]

Yield	Reaction Conditions	Operation in experiment
1.48 g		Step 1: 9-bromo-2-(4-cyclopropyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one. 95-1-1 To a stirred solution of 9-bromo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (2.0 g, 6.51 mmol) in 1,2-dichloroethane (65 mL) was added POCl3 (1.21 mL, 13.02 mmol) at RT and the resulting suspension was stirred at 100° C. for 1 h. The reaction mixture was cooled to rt and concentrated under reduced pressure to dryness. For complete removal of POCl3 the residue was taken up in toluene and the solvent was evaporated under reduced pressure. The residue was dried under high vacuo at RT. The resulting crude chloro intermediate was dissolved in 1,2-dichloroethane (50 mL), a solution of <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (2.11 g, 19.53 mmol) in 1,2-dichloroethane (15 mL) was added and the mixture was stirred at 100° C. for 2 h. The reaction mixture was allowed to warm to rt and diluted with DCM. Saturated aqueous NaHCO3 solution was added and the mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera Four, eluent: 1percent MeOH in DCM for 5 min, then from 1percent MeOH in DCM to 4percent MeOH in DCM in 25 min, 4percent MeOH in DCM for 5 min) to yield 1.72 g of a redbrown foam. A second flash-column chromatography over silicagel was done (Biotage Isolera Four, eluent: 20percent AcOEt in DCM for 3 min, then from 20percent AcOEt in DCM to 80percent AcOEt in DCM in 25 min, followed by 80percent AcOEt in DCM for 10 min) to yield the title compound as a yellow solid (1.48 g). UPLC-MS: MS 397.1/399.1 (M+H+); UPLC rt 1.00 min.

Reference： [1]Patent: US2014/57902,2014,A1 .Location in patent: Paragraph 0947-0949

16
[ 1571145-49-7 ]
[ 89830-98-8 ]
[ 1571144-53-0 ]

Reference： [1]Patent: US2014/57902,2014,A1

17
[ 1571145-49-7 ]
[ 89830-98-8 ]
[ 1571145-97-5 ]

Yield	Reaction Conditions	Operation in experiment
11 mg		Step 1: 2-(4-cyclopropyl-1H-imidazol-1-yl)-9-iodo-1-methyl-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one. 107-1 A mixture of 9-iodo-1-methyl-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (30 mg, 81 mumol) in DCE (2 mL) is treated with POCl3 (15 muL, 0.16 mmol) and heated to 100° C. for 3 h. The mixture was then allowed to cool to RT, poured onto H2O and extracted with DCM. The org. phases were dried over Na2SO4, filtered and concentrated in vacuo. The brown residue obtained was taken up in DCE (2 mL) and <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (31 mg, 0.28 mmol) and pyridine (20 muL, 0.24 mmol) were then added. The mixture was heated to 100° C. for 4.5 h, and then allowed to cool to RT, poured onto H2O and extracted with DCM. The org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. Filtration through a pad of SiO2 (AcOEt) afforded a brown solid that was purified by SFC (column: Diol 5 mum, 250*30 mm, 60A, Princeton; eluent: 13percent MeOH/CO2 for 1 min, then from 13percent MeOH/CO2 to 18percent MeOH/CO2 in 6 min; then from 18percent MeOH/CO2 to 50percent MeOH/CO2 in 1 min; flow 100 mL/min; UV detection at 220 nm) to give the title compound (11 mg) as a white powder. UPLC-MS: MS 459.0 (M+H+); UPLC rt 0.98 min.

Reference： [1]Patent: US2014/57902,2014,A1 .Location in patent: Paragraph 1003-1004

18
[ 1571145-95-3 ]
[ 89830-98-8 ]
[ 1571144-43-8 ]

Yield	Reaction Conditions	Operation in experiment
42 mg		Step 4: 2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(isoxazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one A solution of 9-(isoxazol-5-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (90 mg, 0.31 mmol) in DCE (4 mL) was treated with POCl3 (57 muL, 0.61 mmol) and the mixture was heated to 100° C. for 1 h. The mixture was then allowed to cool to RT, poured onto H2O and extracted with DCM. The org. phases were then dried over Na2SO4, filtered and concentrated in vacuo. The brown residue obtained was taken up in DCE (4 mL) and <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (50 mg, 0.46 mmol) and pyridine (74 muL, 0.91 mmol) were then added. The mixture was heated to 110° C. for 1 h, and then allowed to cool to RT, poured onto H2O and extracted with DCM. The org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, cHex/AcOEt 100:0 to 0:100 and DCm/MeOH 99:1 to 90:10) afforded the title compound (42 mg) as a pale red solid. UPLC-MS: MS 386.2 (M+H+); UPLC rt 0.85 min. 1H NMR (400 MHz, CHLOROFORM-d): delta ppm 0.67-0.79 (m, 2H); 0.80-0.91 (m, 2H); 1.80-1.91 (m, 1H); 3.17 (t, J=6.06 Hz, 2H); 3.90 (t, J=6.19 Hz, 2H); 4.37 (s, 2H); 6.47 (s, 1H); 6.63 (s, 1H); 7.18 (s, 1H); 7.50 (t, J=7.83 Hz, 1H); 7.70-7.83 (m, 2H); 7.88 (s, 1H); 8.38 (s, 1H).

Reference： [1]Patent: US2014/57902,2014,A1 .Location in patent: Paragraph 0986; 0990

19
[ 1571146-00-3 ]
[ 89830-98-8 ]
[ 1571144-54-1 ]

Yield	Reaction Conditions	Operation in experiment
42 mg		Step 4: 2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(2-methyloxazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one A mixture of 9-(2-methyloxazol-4-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (140 mg, 0.45 mmol) in DCE (10 mL) was treated with POCl3 (84 muL, 0.91 mmol) and heated to 100° C. for 1 h. The mixture was then allowed to cool to RT, poured onto cold H2O and extracted with DCM. The org. phases were dried over Na2SO4, filtered and concentrated in vacuo. The brown residue obtained was taken up in DCE (5 mL) and <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (59 mg, 0.54 mmol) and pyridine (110 muL, 1.36 mmol) were then added. The mixture was heated to 100° C. for 1 h, and then allowed to cool to RT, poured onto H2O and extracted with DCM. The org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. Purification by SFC (column: 2-Ethylpyridine 5 mum, 250*30 mm, 60A, Princeton; eluent: 10percent MeOH/CO2 for 1 min, then from 10percent MeOH/CO2 to 15percent MeOH/CO2 in 6 min; then from 15percent MeOH/CO2 to 50percent MeOH/CO2 in 1 min; flow 100 mL/min; UV detection at 220 nm) afforded the title compound (42 mg) as beige powder. UPLC-MS: MS 400.2 (M+H+); UPLC rt 0.86 min. 1H NMR (400 MHz, CHLOROFORM-d): delta ppm 0.61-0.82 (m, 2H); 0.82-0.91 (m, 2H); 1.78-1.96 (m, 1H); 2.56 (s, 3H); 3.16 (t, J=6.02 Hz, 2H); 3.89 (t, J=6.15 Hz, 2H); 4.37 (br. s., 2H); 6.62 (s, 1H); 7.19 (d, J=1.25 Hz, 1H); 7.38-7.48 (m, 1H); 7.63-7.70 (m, 2H); 7.78 (dd, J=7.65, 1.13 Hz, 1H); 7.89 (d, J=1.26 Hz, 1H).

Reference： [1]Patent: US2014/57902,2014,A1 .Location in patent: Paragraph 1006; 1010

20
[ 1571146-01-4 ]
[ 89830-98-8 ]
[ 1571144-58-5 ]

Yield	Reaction Conditions	Operation in experiment
7 mg		Step 2: 2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(oxazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one A mixture of 9-(oxazol-5-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (180 mg, 0.61 mmol) in DCE (10 mL) was treated with POCl3 (114 muL, 1.22 mmol) and heated to 100° C. for 1 h. The mixture was then allowed to cool to RT, poured onto cold H2O and extracted with DCM. The org. phases were dried over Na2SO4, filtered and concentrated in vacuo. The brown residue obtained was taken up in DCE (5 mL) and <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (79 mg, 0.73 mmol) and pyridine (148 muL, 1.83 mmol) were then added. The mixture was heated to 100° C. for 1 h, and then allowed to cool to RT, poured onto H2O and extracted with DCM. The org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. Purification by SFC (column: 2-Ethylpyridine 5 mum, 250*30 mm, 60A, Princeton; eluent: 9percent MeOH/CO2 for 1 min, then from 9percent MeOH/CO2 to 14percent MeOH/CO2 in 6 min; then from 14percent MeOH/CO2 to 50percent MeOH/CO2 in 1 min; flow 100 mL/min; UV detection at 220 nm) afforded the title compound (7 mg) as pale brown solid. UPLC-MS: MS 386.1 (M+H+); UPLC rt 0.79 min. 1H NMR (400 MHz, CHLOROFORM-d): delta ppm 0.78 (m, 2H); 0.81-0.87 (m, 2H); 1.79-1.93 (m, 1H); 3.14 (t, J=6.02 Hz, 2H); 3.94 (t, J=6.15 Hz, 2H); 4.38 (br. s., 2H); 6.66 (s, 1H); 7.20 (s, 1H); 7.30 (s, 1H); 7.42-7.60 (m, 1H); 7.77 (d, J=7.78 Hz, 1H); 7.74 (d, J=8.03 Hz, 1H); 7.90 (s, 1H); 8.03 (s, 1H).

Reference： [1]Patent: US2014/57902,2014,A1 .Location in patent: Paragraph 1015; 1017

21
[ 1571146-19-4 ]
[ 89830-98-8 ]
[ 1571144-91-6 ]

Yield	Reaction Conditions	Operation in experiment
116 mg		Step 2: methyl 2-(4-cyclopropyl-1H-imidazol-1-yl)-5-oxo-4,5,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-9-carboxylate A solution of methyl 2,5-dioxo-2,3,4,5,7,8-hexahydro-[1,4]diazepino[7,1-a]isoquinoline-9-carboxylate (225 mg, 0.79 mmol) in DCE (20 mL) was treated with POCl3 (0.37 mL, 3.93 mmol) and the mixture was heated to 100° C. for 1 h. The mixture was then allowed to cool to RT, and then concentrated in vacuo, and dried azeotropically with toluene. The residue obtained was taken up in DCE (40 mL) and <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (261 mg, 2.41 mmol) were added. The mixture was heated to to 100° C. for 1 h and then allowed to cool to RT, diluted with DCM and washed with a saturated aq, solution of NaHCO3. The org. layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, AcOEt/MeOH 100:0 to 90:10) and crystallization in Et2O/petroleum ether gave the title compound (116 mg). UPLC-MS: MS 377.2 (M+H+); UPLC rt 0.88 min. 1H NMR (600 MHz, DMSO-d6): delta ppm 0.54-0.73 (m, 2H); 0.73-0.88 (m, 2H); 1.74-1.89 (m, 1H); 3.25 (br s, 2H); 3.67-3.82 (m, 2H); 3.88 (s, 3H); 4.25 (br s, 2H); 7.13 (s, 1H); 7.44 (s, 1H); 7.48-7.57 (m, 1H); 7.96 (d, J=7.65 Hz, 1H); 8.09 (s, 1H); 8.19 (d, J=7.91, 1H).

Reference： [1]Patent: US2014/57902,2014,A1 .Location in patent: Paragraph 1077; 1079

22
[ 1571146-21-8 ]
[ 89830-98-8 ]
[ 1571144-97-2 ]

Yield	Reaction Conditions	Operation in experiment
21 mg		Step 2: 2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(2H-1,2,3-triazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one To a stirred solution of 9-(2H-1,2,3-triazol-2-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (97 mg, 0.328 mmol) in 1,2-dichloroethane (3 mL) was added POCl3 (0.061 mL, 0.657 mmol) at rt and the resulting suspension was stirred at 100° C. for 35 min. The reaction mixture was cooled to rt and concentrated under reduced pressure to dryness. For complete removal of POCl3 the residue was taken up in toluene and the solvent was evaporated under reduced pressure. The residue was dried under high vacuo at rt. The resulting crude chloro intermediate was dissolved in 1,2-dichloroethane (3 mL), <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (107 mg, 0.985 mmol) was added and the mixture was stirred at 100° C. for 2 h. The reaction mixture was allowed to warm to rt and diluted with DCM. Saturated aqueous NaHCO3 solution was added and the mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera Four, eluent: pure DCM for 3 min, then from 0percent MeOH in DCM to 5percent MeOH in DCM in 14 min, 5percent MeOH in DCM for 3 min) to yield a yellow foam.

Reference： [1]Patent: US2014/57902,2014,A1 .Location in patent: Paragraph 1088; 1090-1091

23
[ 1571146-31-0 ]
[ 89830-98-8 ]
[ 1571145-89-5 ]

Yield	Reaction Conditions	Operation in experiment
1.48 g	In 1,2-dichloro-ethane; at 100℃; for 2h;	To a stirred solution of 9-bromo-3,4,7,8-tetrahydro- [1 ,4]diazepino[7,1-a]isoquinoline-2,5-dione (2.0 g, 6.51 mmol) in 1 ,2-dichioroethane (65 mL) was added POCI3 (1 .21 mL, 13.02 mmol) at RT and the resulting suspension was stirred at 100°C for 1h. The reaction mixture was cooled to rt and concentrated under reduced pressure to dryness. For complete removal of POCI3 the residue was taken up in toluene and the solvent was evaporated under reduced pressure. The residue was dried under high vacuo at RT. The resulting crude chloro intermediate was dissolved in 1 ,2-dichloroethane (50 mL), a solution of 4-cyclopropyl-lH-imidazole (2.11 g, 19.53 mmol) in 1 ,2-dichloroethane (15 mL) was added and the mixture was stirred at 100°C for 2h. The reaction mixture was allowed to warm to rt and diluted with DCM. Saturated aqueous NaHC03 solution was added and the mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera Four, euent 1 percent MeOH in DCM for 5 min, then from 1percent MeOH in DCM to 4percent MeOH in DCM in 25 min, 4percent MeOH in DCM for 5 min) to yield 1.72 g of a redbrown foam. A second flash-column chromatography over silicagel was done (Biotage Isolera Four, euent: 20percent AcOEt in DCM for 3 min, then from 20percent AcOEt in DCM to 80percent AcOEt in DCM in 25 min, followed by 80percent AcOEt in DCM for 10 min) to yield the title compound as a yellow solid (1.48 g). UPLC-MS: MS 397.1 /399.1 (M+H*); UPLC rt 1.00 min.

Reference： [1]Patent: WO2014/30128,2014,A1 .Location in patent: Page/Page column 143

24
C₁₆H₁₂ClN₃O₂ [ No CAS ]
[ 89830-98-8 ]
[ 1571144-43-8 ]

Yield	Reaction Conditions	Operation in experiment
42 mg	With pyridine; In 1,2-dichloro-ethane; at 110℃; for 1h;	A solution of 9-(isoxazol-5-yl)- 3,4,7,8-tetrahydro-[1 ,4]diazepino[7,1-a]isoquinoline-2,5-dione (90 mg, 0.31 mmol) in DCE (4 mL) was treated with POCI3 (57 mu, 0,61 mmol) and the mixture was heated to 100 °C for 1 h. The mixture was then allowed to cool to RT, poured onto H20 and extracted with DCM. The org. phases were then dried over Na2S04, filtered and concentrated in vacuo. The brown residue obtained was taken up in DCE (4 mL) and 4-cyclopropyl-1 H-imidazole (50 mg, 0.46 mmol) and pyridine (74 , 0.91 mmol) were then added. The mixture was heated to 110 °C for 1 h, and then allowed to cool to RT, poured onto H20 and extracted with DCM. The org. layers were then dried over Na2SO,, filtered and concentrated in vacuo. Purification by flash chromatography (Si02, cHex AcOEt 100:0 to 0:100 and DCm/MeOH 99: 1 to 90:10) afforded the title compound (42 mg) as a pale red solid. UPLC-MS: MS 386.2 (M+H*); UPLC rt 0.85 min. 1H NMR (400 MHz, CHL OROFORM-d) : delta ppm 0.67 - 0.79 (m, 2 H); 0.80 - 0.91 (m, 2 H); 1.80 - 1.91 (m, 1 H); 3.17 (t, J=6.06 Hz, 2 H); 3.90 (t, J=6.19 Hz, 2H); 4.37 (s, 2 H); 6.47 (s, 1 H); 6.63 (s, 1 H); 7.18 (s, 1 H); 7.50 (t, J=7.83 Hz, 1 H); 7.70 - 7.83 (m, 2 H); 7.88 (s, 1 H); 8.38 (s, 1 H).

Reference： [1]Patent: WO2014/30128,2014,A1 .Location in patent: Page/Page column 159

25
C₁₄H₁₂ClIN₂O [ No CAS ]
[ 89830-98-8 ]
[ 1571145-97-5 ]

Yield	Reaction Conditions	Operation in experiment
11 mg	With pyridine; In 1,2-dichloro-ethane; at 100℃; for 4.5h;	A mixture of 9-iodo-1-methyl-3,4,7,8- tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (30 mg, 81 muGammaetaomicronIota) in DCE (2 mL) is treated with POCI3 (15 mu, 0.16 mmol) and heated to 100 °C for 3 h. The mixture was then allowed to cool to RT, poured onto H20 and extracted with DCM, The org. phases were dried over Na2S0 , filtered and concentrated in vacuo. The brown residue obtained was taken up in DCE (2 mL) and <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (31 mg, 0.28 mmol) and pyridine (20 mu, 0.24 mmol) were then added. The mixture was heated to 100 °C for 4.5 h, and then allowed to cool to RT, poured onto H20 and extracted with DCM. The org. layers were then dried over Na2S04, filtered and concentrated in vacuo. Filtration through a pad of Si02 (AcOEt) afforded a brown solid that was purified by SFC (column: Diol 5 muiotaeta, 250 x 30 mm, 60A, Princeton; euent: 13percent MeOH/C02 for 1 min, then from 13percent MeOH/C02 to 18percent MeOH/C02 in 6 min; then from 18percent MeOH/C02 to 50percent MeOH/C02 in 1 min; flow 100 mL/min; UV detection at 220 nm) to give the title compound (11 mg) as a white powder. UPLC-MS: MS 459.0 (M+hf ); UPLC rt 0.98 min.

Reference： [1]Patent: WO2014/30128,2014,A1 .Location in patent: Page/Page column 165

26
C₁₇H₁₄ClN₃O₂ [ No CAS ]
[ 89830-98-8 ]
[ 1571144-54-1 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In 1,2-dichloro-ethane; at 100℃; for 1h;	General procedure: A mixture of 9-(2-methyloxazol- 4-yl)-3,4,7,8-tetrahydro-[1 ,4]diazepino[7,1-a]isoquinoline-2,5-dione (140 mg, 0.45 mmol) in DCE (10 mL) was treated with POCI3 (84 mu, 0.91 mmol) and heated to 100 °C for 1 h. The mixture was then allowed to cool to RT, poured onto cold H20 and extracted with DCM. The org. phases were dried over Na2SO,, filtered and concentrated in vacuo. The brown residue obtained was taken up in DCE (5 mL) and <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (59 mg, 0.54 mmol) and pyridine (110 mu, 1.36 mmol) were then added. The mixture was heated to 100 DC for 1 h, and then allowed to cool to RT, poured onto H20 and extracted with DCM. The org. layers were then dried over Na2S04. filtered and concentrated in vacuo. Purification by SFC (column: 2-Ethylpyridine 5 muetaiota, 250 x 30 mm, 60A, Princeton; eluent: 10percent MeOH/C02 for 1 min, then from 10percent MeOH/C02 to 15percent MeOH/C02 in 6 min; then from 15percent MeOH/C02 to 50percent MeOH/C02 in 1 min; flow 100 mL/min; UV detection at 220 nm) afforded the title compound (42 mg) as beige powder. UPLC-MS: MS 400.2 (M+H+); UPLC rt 0.86 min. 1H NMR (400 MHz, CHLOROFORM- : delta ppm 0.61 - 0.82 (m, 2 H); 0.82 - 0.91 (mr 2 H); 1.78 - 1.96 (m, 1 H); 2.56 (s, 3 H); 3.16 (t, J=6.02 Hz, 2 H); 3.89 (t, J=6.15 Hz, 2 H); 4.37 (br. s., 2 H); 6.62 (s, 1 H); 7.19 (d, J=1.25 Hz, 1 H); 7.38 - 7.48 (m, 1 H); 7.63 - 7.70 (m, 2 H); 7.78 (dd, J=7.65, .13 Hz, 1 H); 7.89 (d, J=1.26 Hz, 1 H).

Reference： [1]Patent: WO2014/30128,2014,A1 .Location in patent: Page/Page column 167; 168

27
C₁₆H₁₂ClN₃O₂ [ No CAS ]
[ 89830-98-8 ]
[ 1571144-58-5 ]

Yield	Reaction Conditions	Operation in experiment
7 mg	With pyridine; In 1,2-dichloro-ethane; at 100℃; for 1h;	A mixture of 9-(oxazol-5-yl)-3,4,7,8-tetrahydro-[1 ,4]diazepino[7,1-a]isoquinoline-2,5-dione (180 mg, 0.61 mmol) in DCE (10 mL) was treated with POCI3 (114 muIota_, 1 .22 mmol) and heated to 100 °C for 1 h. The mixture was then allowed to cool to RT, poured onto cold H20 and extracted with DCM. The org. phases were dried over Na2S04, filtered and concentrated in vacuo. The brown residue obtained was taken up in DCE (5 mL) and 4-cyclopropyH H-imidazole (79 mg, 0.73 mmol) and pyridine (148 muIota_, 1.83 mmol) were then added. The mixture was heated to 100 °C for 1 h, and then allowed to cool to RT, poured onto H20 and extracted with DCM. The org. layers were then dried over filtered and concentrated in vacuo. Purification by SFC (column: 2-Ethylpyridine 5 mueta, 250 x 30 mm, 60A, Princeton; eluent: 9percent MeOH/C02 for 1 min, then from 9percent MeOH/C02 to 14percent MeOH/C02 in 6 min; then from 14percent MeOH/C02 to 50percent MeOH/C02 in 1 min; flow 100 mL min; UV detection at 220 nm) afforded the title compound (7 mg) as pale brown solid. UPLC-MS: MS 386.1 (M+Hf); UPLC rt 0.79 min. H NMR (400 MHz, CHLOROFORM-d): 8 ppm 0.78 (m, 2 H); 0.81 - 0.87 (m, 2 H); 1.79 - 1.93 (m, 1 H); 3.14 (t, J=6.02 Hz, 2 H); 3.94 (t, J=6.15 Hz, 2 H); 4.38 (br. s., 2 H); 6.66 (s, 1 H); 7.20 (s, 1 H); 7.30 (s, 1 H); 7.42 - 7.60 (m, 1 H); 7.77 (d, J=7.78 Hz, 1 H); 7.74 (d, J=8.03 Hz, 1 H); 7.90 (s, 1 H); 8.03 (s, 1 H).

Reference： [1]Patent: WO2014/30128,2014,A1 .Location in patent: Page/Page column 169; 170

28
C₁₅H₁₃ClN₂O₃ [ No CAS ]
[ 89830-98-8 ]
[ 1571144-91-6 ]

Yield	Reaction Conditions	Operation in experiment
116 mg	In 1,2-dichloro-ethane; at 100℃; for 1h;	A solution of methyl 2,5- dioxo-2,3,4,5,7,8-hexahydro-[1,4]diazepino[7,1-a]isoquinoline-9-carboxylate (225 mg, 0.79 mmol) in DCE (20 mL) was treated with POCI3 (0.37 mL, 3.93 mmol) and the mixture was heated to 100 °C for 1 h. The mixture was then allowed to cool to RT, and then concentrated in vacuo, and dried azeotropically with toluene. The residue obtained was taken up in DCE (40 mL) and <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (261 mg, 2.41 mmol) were added. The mixture was heated to to 100 °C for 1h and then allowed to cool to RT, diluted with DCM and washed with a saturated aq, solution of NaHC03. The org. layer was dried over Na2S04, filtered and concentrated in vacuo. Purification by flash chromatography (Si02, AcOEt MeOH 100. to 90: 10) and crystallization in Et20/petroleum ether gave the title compound (116 mg). UPLC- MS: MS 377.2 (M+H+); UPLC rt 0.88 min. 1H NMR (600 MHz, DMSO-c/6): delta ppm 0.54-0.73 (m, 2H); 0.73-0.88 (m, 2H); 1.74-1.89 (m, 1 H); 3.25 (br s, 2H); 3.67-3.82 (m, 2H); 3.88 (s, 3H); 4.25 (br s, 2H); 7.13 (s, 1H); 7.44 (s, 1H); 7.48-7.57 (m, 1H); 7.96 (d, J=7.65 Hz, 1H); 8.09 (s, 1H); 8.19 (d, J=7.91 , 1H).

Reference： [1]Patent: WO2014/30128,2014,A1 .Location in patent: Page/Page column 191

29
[ 1571146-40-1 ]
[ 89830-98-8 ]
[ 1571144-97-2 ]

Yield	Reaction Conditions	Operation in experiment
21 mg	In 1,2-dichloro-ethane; at 100℃; for 2h;	To a stirred solution of 9-(2H- 1 ,2,3-triazol-2-y)-3,4,7,8-tetrahydro-[1 ,4]diazepino[7,1-a]isoquinoine-2,5-dione (97 mg, 0.328 mmol) in 1 ,2-dichloroethane (3 mL) was added POCI3 (0.061 mL, 0.657 mmol) at rt and the resulting suspension was stirred at 100°C for 35 min. The reaction mixture was cooled to rt and concentrated under reduced pressure to dryness. For complete removal of POCI3 the residue was taken up in toluene and the solvent was evaporated under reduced pressure. The residue was dried under high vacuo at rt. The resulting crude choro intermediate was dissolved in 1 ,2-dichloroethane (3 ml_), 4- cyclopropyl-1 H-imidazole (107 mg, 0.985 mmol) was added and the mixture was stirred at 100°C for 2h. The reaction mixture was allowed to warm to rt and diluted with DCM. Saturated aqueous NaHC03 solution was added and the mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera Four, eluent: pure DCM for 3 min, then from 0percent MeOH in DCM to 5percent MeOH in DCM in 14 min, 5percent MeOH in DCM for 3 min) to yield a yellow foam. Further purification by SFC (column: 2-Ethylpyridine 5 mutauiota, 250 x 30 mm, 60A, Princeton; eluent: 8percent MeOH/C02 for 1 min, then from 8percent MeOH/C02 to 13percent MeOH/C02 in 6 min ; flow 100 ml_ min ; U V detection at 220 n m) gave the title compound as slightly yellow foam (21 mg). UPLC-MS: MS 386.2 (M+hT); UPLC rt 0.86 min. 1H NMR (400 MHz, DMSO-d6) delta ppm 0.58 - 0.70 (m, 2 H), 0.74 - 0.82 (m, 2 H), 1.74 - 1.86 (m, 1 H), 2.91 (t, J=5.75 Hz, 2 H), 3.75 (t, J=5.&7 Hz, 2 H), 4.25 (s, 2 H), 7.22 (s, 1 H), 7.43 (s, 1 H), 7.54 - 7.63 (m, 1 H), 7.76 (d, J=8.80 Hz, 1 H), 8.10 (s, 1 H), 8.14 - 8.21 (m, 3 H).

Reference： [1]Patent: WO2014/30128,2014,A1 .Location in patent: Page/Page column 195; 196

30
[ 884494-49-9 ]
[ 89830-98-8 ]
[ 1616383-33-5 ]

Yield	Reaction Conditions	Operation in experiment
57%	With copper(I) oxide; 8-quinolinol; caesium carbonate; at 65℃; for 16h;	A mixture of <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (1.95 g, 18.1 mmol), 2-chloro-5-fluoro-4- iodopyridine (3.1 g, 12.0 mmol), Cu20 (105 mg, 0.6 mmol), 8-hydroxyquinoline (353 mg,2.4 mmol), and C52CO3 (11.7 g, 36 mmol) in butyronitrile (100 mL) was stirred at 65C for16 h. After cooling down to room temperature, 100 mL of water was added and the resulting mixture was extracted with EtOAc (100 mL x2). The organic layer was dried over Na2504, filtered, and evaporated. The residue was purified by silica gel column chromatography with PE/EtOAc (3:1) to afford 1.7 g (57%) of 2-chloro-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropyridine as white solid.
42%	With copper(I) oxide; 8-quinolinol; propyl cyanide; caesium carbonate; at 65℃; for 16h;Inert atmosphere;	A suspension 2-chloro-5-fluoro-4-iodopyridine (1.8 g, 1.00 mmol), <strong>[89830-98-8]4-cyclopropyl imidazole</strong> (982 mg, 9.10 mmol), Cu2O (100 mg, 0.700 mmol), 8-hydroxyquinoline (152 mg, 1.05 mmol), cesium carbonate (4.60 g, 14.0 mmol), and PEG-3350 (1.4 g) in butyronitrile (50 mL) was heated at 65 C. for 16 hours. The reaction mixture was filtered through Celite, concentrated and the residue was partitioned between dichlormethane and water. The layers were separated and the aqueous layer washed twice with dichloromethane. The combined organic layers were dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (15?60% EtOAc in hexanes) to afford 2-chloro-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropyridine (702 mg, 42% yield).
21%	With copper(l) iodide; 2-methyl-8-quinolinol; potassium carbonate; In dimethyl sulfoxide; at 90℃;Inert atmosphere;	To a flask were added 2-chloro-5-fluoro-4-iodopyridine (23.0 g, 89.3 mmol), <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (29.0 g, 268 mmol), potassium carbonate (30.8 g, 223 mmol), cuprous iodide (340 mg, 1.79 mmol), 8-hydroxyquinaldine (569 mg, 3.57 mmol) and dimethylsulfoxide (80 mL) under nitrogen. The mixture was heated to 90 C and stirred overnight. The resulting mixture was cooled to rt naturally and quenched with water (100 mL) and then extracted with EtOAc (200 mL x 2). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica-gel column chromatography (DCMIEtOAc (V/V) = 10/1-5/1) to give the title compound as a yellow solid (4.50 g, 2 1%).?HNIVIR(400MH4 CDCl3)8.40(d,J=2.7H4 1H), 7.92 (s, 1H), 7.38 (d,J= 5.4 H4 1H), 7.11 (s, 1H), 1.96-1.82 (m, 1H), 0.96 - 0.87 (m, 2H), 0.86- 0.80 (m, 2H?).

	With copper(I) oxide; 8-quinolinol; caesium carbonate; at 65℃; for 16h;Inert atmosphere;	Step 1: Preparation of 2-chloro-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropyridine A suspension 2-chloro-5-fluoro-4-iodopyridine (1.8 g, 1.00 mmol), <strong>[89830-98-8]4-cyclopropyl imidazole</strong> (982 mg, 9.10 mmol), Cu2O (100 mg, 0.700 mmol), 8-hydroxyquinoline (152 mg, 1.05 mmol), cesium carbonate (4.60 g, 14.0 mmol), and PEG-3350 (1.4 g) in butyronitrile (50 mL) was heated at 65 C. for 16 hours. The reaction mixture was filtered through Celite, concentrated and the residue was partitioned between dichlormethane and water. The layers were separated and the aqueous layer washed twice with dichloromethane. The combined organic layers were dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (15?60% EtOAc in hexanes) to afford 2-chloro-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropyridine.
	With copper(I) oxide; 8-quinolinol; caesium carbonate; at 70℃; for 16h;Inert atmosphere;	2-chloro-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropyridine (19a) To a mixture of <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (1.4 g, 12.95 mmol) and 2-chloro-5-fluoro-4-iodopyridine (3.50 g, 13.59 mmol) in butyronitrile (210 mL) was added Cu2O (185.25 mg, 1.29 mmol), 8-hydroxyquinoline (281.88 mg, 1.94 mmol), Cs2CO3 (8.44 g, 25.89 mmol) and PEG-3350 (1.09 g, 12.95 mmol) at 20 C. under N2. The mixture was stirred at 20 C. for 10 min, then heated to 70 C. and stirred for 16 hours. LCMS showed one new peak with desired MS. The mixture was cooled to 25 C. and filtered and concentrated in vacuo. The residue was dissolved in DCM (50 mL) and H2O (40 mL) was added, the mixture was extracted with DCM (30 mL3). The combined organic layers were washed with brine (20 mL2), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Petroleum ether:Ethyl acetate=100:1 to 30:1) to give 2-chloro-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropyridine (19a). 1H NMR (400 MHz, CHLOROFORM-d) delta 8.41 (d, J=2.7 Hz, 1H), 7.90 (s, 1H), 7.37 (d, J=5.4 Hz, 1H), 7.10 (s, 1H), 1.95-1.86 (m, 1H), 0.95-0.89 (m, 2H), 0.87-0.81 (m, 2H).

Reference： [1]Patent: WO2018/209354,2018,A1 .Location in patent: Page/Page column 70
[2]Patent: US2014/179663,2014,A1 .Location in patent: Paragraph 0183
[3]Patent: WO2019/34096,2019,A1 .Location in patent: Paragraph 00241
[4]Patent: US2015/175597,2015,A1 .Location in patent: Paragraph 0186; 0187
[5]Patent: US2019/315767,2019,A1 .Location in patent: Paragraph 0456; 0457

31
[ 89830-98-8 ]
[ 1616383-36-8 ]

Reference： [1]Patent: US2014/179663,2014,A1

32
[ 89830-98-8 ]
4-(4-cyclopropylimidazol-1-yl)-N-[2-(4-cyclopropyl-1,2,4-triazol-3-yl)-1,3-thiazol-4-yl]-5-(3-hydroxypyrrolidin-1-yl)pyridine-2-carboxamide hydrochloride [ No CAS ]

Reference： [1]Patent: US2014/179663,2014,A1

33
[ 89830-98-8 ]
[ 1616383-34-6 ]

Reference： [1]Patent: US2014/179663,2014,A1
[2]Patent: US2015/175597,2015,A1
[3]Patent: WO2018/209354,2018,A1
[4]Patent: US2019/315767,2019,A1

34
[ 89830-98-8 ]
4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropicolinic acid hydrochloride [ No CAS ]

Reference： [1]Patent: US2014/179663,2014,A1

35
[ 89830-98-8 ]
4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(2-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiazol-4-yl)-5-morpholinopicolinamide hydrochloride [ No CAS ]

Reference： [1]Patent: US2014/179663,2014,A1

36
[ 89830-98-8 ]
4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropyridine-2-carboxylic acid [ No CAS ]

Reference： [1]Patent: US2015/175597,2015,A1
[2]Patent: WO2018/209354,2018,A1

37
[ 89830-98-8 ]
[ 1448428-03-2 ]

Reference： [1]Patent: WO2016/106384,2016,A1
[2]Patent: WO2016/106384,2016,A1

38
[ 89830-98-8 ]
5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzoyl chloride [ No CAS ]

Reference： [1]Patent: WO2016/106384,2016,A1
[2]Patent: WO2016/106384,2016,A1
[3]Patent: US2019/315767,2019,A1

39
[ 89830-98-8 ]
[ 1448428-04-3 ]

Reference： [1]Patent: WO2016/106384,2016,A1
[2]Patent: WO2016/106384,2016,A1

40
2-fluoro-5-iodo-4-methylbenzoic acid [ No CAS ]
[ 89830-98-8 ]
5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With copper(I) oxide; potassium phosphate; 8-quinolinol; In dimethyl sulfoxide; for 22h;	Coupling of Compound (K) and Compound (L-a) to provide Compound (D) Compound (L-a) (1.0 eq), Compound (K) (1.5 eq), potassium phosphate (5.0 eq), copper(I) oxide (0.05 eq), and 8-hydroxyquinoline, Compound 2-2 (0.2 eq) were combined with degassed DMSO (about 6 vols). The reaction mixture was heated to about 95 C to about 105 C and stirred for about 22 h. Upon reaction completion, the mixture was cooled to ambient temperature and diluted with water (about 6 vols) and isopropyl acetate (about 5 vols). The aqueous layer was washed with isopropyl acetate (about 5 vols), and the pH was adjusted to about 6 by the addition of 8 M HC1. The solution was seeded with about about 0.003 equiv of Compound (D) seed, which was synthesized as described in U.S. Patent No. 8,742, 126, and the pH was further adjusted to pH about 4.8. The resultant slurry was cooled to about 0 C for about 2 h, filtered, and washed with cold dilute HC1 (pH about 4.8, about 2 vols) and cold isopropyl alcohol (about 2 vols) to provide Compound (D). 1H NMR (400 MHz, DMSO-d6): delta 7.69 (d, 1H, J= 2.0 Hz), 7.67 (d, 1H, J= 8.0 Hz), 7.40 (d, 1H, J= 8.0 Hz), 7.15 (d, 1H, J= 2.0 Hz), 2.20 (s, 3H), 1.87-1.80 (m, 1H), 0.81-0.77 (m, 2H), 0.71-0.67 (m, 2H).13C MR (100 MHz, DMSO- d6): 164.52, 164.48, 161.68, 159.12, 143.95, 141.63, 141.53, 137.34, 133.21, 133.18, 129.70, 119.85, 119.61, 118.08, 117.97, 116.25, 18.02, 9.21, 7.48.
	With copper(I) oxide; 8-quinolinol; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 6h;Inert atmosphere;	General Procedure Synthesis of (1a) To a mixture of <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (4 g, 37 mmol) and 2-fluoro-5-iodo-4-methyl-benzoic acid (1 eq) in DMSO (200 mL) was added Cu2O (0.05 eq), Cs2CO3 (5 eq) and 8-hydroxyquinioline (0.2 eq) in one portion at 20 C. under N2. The mixture was stirred at 20 C. for 5 min, then heated to 100 C. and stirred for 6 hours. LC-MS showed one main peak with the desired MS. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO2, EtOAc:MeOH:AcOH=1:0:0 to 5:1:0.005) to give 5-(4-cyclopropylimidazol-1-yl)-2-fluoro-4-methyl-benzoic acid (1a). MS mass calculated for [M+1]+ (C14H13FN2O2) requires m/z 261.1, LCMS found m/z 261.1; 1H NMR (400 MHz, DMSO-d6) delta 13.47 (br s, 1H), 8.03-6.96 (m, 4H), 2.20 (s, 3H), 1.94-1.77 (m, 1H), 0.80 (br s, 2H), 0.70 (br s, 2H).

Reference： [1]Patent: WO2016/106384,2016,A1 .Location in patent: Page/Page column 79
[2]Patent: US2019/315767,2019,A1 .Location in patent: Paragraph 0380; 0381

41
C₈H₈BFO₄ [ No CAS ]
[ 89830-98-8 ]
5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With copper diacetate; In methanol; at 23 - 45℃; for 20h;	Coupling of Compound (L-b) with Compound (K) to provide Compound (D) Compound (L-b) (1 equiv), Compound (K) (1.2 equiv), and Cu(OAc)2(1 equiv) was added methanol (about 20 vols) followed by pyridine (2.2 equiv). The mixture was then stirred at about 23 °C for about 16 h, then at about 45 °C for about 4 h.The reaction mixture was diluted with methanol (about 60 vols), filtered though a pad of celite and concentrated in vacuo to afford Compound (D) . 1H MR (400 MHz, DMSO-d6): delta 7.69 (d, 1H, J= 2.0 Hz), 7.67 (d, 1H, J= 8.0 Hz), 7.40 (d, 1H, J= 8.0 Hz), 7.15 (d, 1H, J= 2.0 Hz), 2.20 (s, 3H), 1.87-1.80 (m, 1H), 0.81-0.77 (m, 2H), 0.71-0.67 (m, 2H).13C MR (100 MHz, DMSO-d6): 164.52, 164.48, 161.68, 159.12, 143.95, 141.63, 141.53, 137.34, 133.21, 133.18, 129.70, 119.85, 119.61, 118.08, 117.97, 116.25, 18.02, 9.21, 7.48.

Reference： [1]Patent: WO2016/106384,2016,A1 .Location in patent: Page/Page column 80; 81

42
2-chloro-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide [ No CAS ]
[ 89830-98-8 ]
2-(4-cyclopropyl-1H-imidazol-1-yl)-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetonitrile; at 120 - 140℃; for 3h;Microwave irradiation;	To a solution of 2-chloro-N-(2 ,4-d imethoxybenzyl)-5-n itrobenzenesulfonamide (700 mg,1.81 mmol) in acetonitrile (14 mL) were added 5-cyclopropyl-1H-imidazole (294 mg,2.71 mmol, CAS-RN 89830-98-8) and powdered potassium carbonate (750 mg,5.43 mmol) and the mixture was irradiated for lh at 12000 in the microwave. 4- Cyclopropyl-1H-imidazole (196 mg, 1.81 mmol) was added, and microwave irradiation was continued for 2h at 140°C. The reaction mixture was filtered and concentrated in vacuo, and the residue was extracted with dichloromethane and water. The aqueous phase was washed three times with dichloromethane. Then the combined organic phaseswere washed with brine and dried using a Whatman filter. Concentration under reduced pressure led to the title compound that was purified by flash chromatography (309 mg, 22percent yield, 60percent purity).LC-MS (Method A): Rt = 1.06 mm; MS (ESIpos): mlz = 459 [M+H]1HNMR (400MHz, DMSO-d6) oe [ppm]: 0.71 (m, 2H), 0.82 (m, 2H), 1.87 (m, 1H), 3.61 (s,3H), 3.68 (s, 3H), 4.01 (d, 2H), 6.33 (d, 1H), 6.36 (dd, 1H), 7.02 (d, 1H), 7.17 (s, 1H), 7.67 (d, 1H), 7.74 (s, 1H), 8.41 (dd, 1H), 8.43 (d, 1H), 8.49 (t, 1H).

Reference： [1]Patent: WO2017/191000,2017,A1 .Location in patent: Page/Page column 125; 126

43
C₉H₈INO₃ [ No CAS ]
[ 89830-98-8 ]
C₁₅H₁₅N₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
19.0%	With copper(I) oxide; potassium phosphate; 8-quinolinol; In dimethyl sulfoxide; at 100℃; for 4h;Inert atmosphere;	[0527] A slurry of Example 109a (450 mg, 1.48 mmol) and Example 109b (239 mg, 2.21 mmol) in DMSO (20 mL) was added 8-quinilinol (42.92 mg, 0.30 mmol), Cu20 (47.36 mg, 0.30 mmol) and K3P04 (1.57 g, 7.40 mmol). Then the mixture was degassed by bubbling N2 through the solution for 2 min using a syringe needle. After that, the mixture was heated at 100°Cfor 4h. The mixture was directly purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 m, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min)to give product (Example 109c, 80 mg, yield: 19.0percent) as white solid. LCMS [M+l] + = 286.0

Reference： [1]Patent: WO2018/151830,2018,A1 .Location in patent: Paragraph 0527; 0516

44
formimidamide acetate [ No CAS ]
[ 69267-75-0 ]
[ 89830-98-8 ]

Yield	Reaction Conditions	Operation in experiment
	In ethylene glycol; at 135℃;	[0303] A mixture of 2-bromo-l-cyclopropylethanone (3.2 g, 20.0 mmol) and formimidamide acetate (10.4 g, 50.0 mmol) in ethylene glycol (100 mL) was heated at 135°C overnight. After cooling, the mixture was diluted with water (100 mL), and extracted several times with ether. The combined organic layers were dried over MgS04, filtered, and concentrated to afford the crude product (lg yellow oil) which was directly used in next step reaction without further purification. LCMS: [M+l] += 109.3.

Reference： [1]Patent: WO2018/151830,2018,A1 .Location in patent: Paragraph 0303

45
C₇H₆INO₃ [ No CAS ]
[ 89830-98-8 ]
C₁₃H₁₃N₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With copper(l) iodide; caesium carbonate; (1R,2S)-N1,N2- dimethylcyclohexane-1,2-diamine; In N,N-dimethyl-formamide; at 130℃; for 10h;Inert atmosphere;	[0316] To a suspension of Example 6b (1.00 g, 3.58 mmol), Example lc (483 mg, 4.48 mmol) and Cs2C03 (3.50 g, 10.75 mmol) in DMF (12.5 mL) was added Cul (68 mg, 0.36 mmol) and (1R,2S)-N',N2- dimethylcyclohexane-l,2-diamine (112 mg, 0.79mmol) under N2 at room temperature. The reaction mixture was heated to 130°C and stirred for 10 h. The reaction mixture was cooled to room temperature and diluted with MeOH (20 mL) and filtered. The filter cake was washed with MeOH (30 mL*3) and the filtrate was concentrated to afford the crude product Example 6c (1.48 g, containing DMF, crude yield >100percent), which was used for the next step without further purification. LC-MS [M+l]+ = 260

Reference： [1]Patent: WO2018/151830,2018,A1 .Location in patent: Paragraph 0316

46
C₆H₄INO₃ [ No CAS ]
[ 89830-98-8 ]
C₁₂H₁₁N₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With copper(l) iodide; caesium carbonate; (1R,2S)-N1,N2- dimethylcyclohexane-1,2-diamine; In N,N-dimethyl-formamide; at 130℃; for 16h;Inert atmosphere;	[0287] To a suspension of Example lb (1.00 g, 3.77 mmol), Example lc (0.51 g, 4.72 mmol) and Cs2C03 (3.69 g, 11.32 mmol) in DMF (12.5 mL) was added Cul (72 mg, 0.37 mmol) and (1R,2S)-N',N2- dimethylcyclohexane-l,2-diamine (107 mg, 0.75 mmol) under N2 at room temperature. The reaction mixture was heated to 130°C and stirred for 16 h. The reaction mixture was cooled to room temperature and diluted with MeOH and filtered. The cake was washed with MeOH and the filtrate was concentrated to afford crude product Example Id (1.00 g, containing DMF, crude yield >100percent), which was used for the next step without further purification. LC-MS [M+H]+= 246.0

Reference： [1]Patent: WO2018/151830,2018,A1 .Location in patent: Paragraph 0287

47
[ 765-43-5 ]
[ 89830-98-8 ]

Reference： [1]Patent: WO2018/151830,2018,A1

48
[ 89830-98-8 ]
8-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-oxo-1,2,3,5-tetrahydroindolizine-6-carboxamide [ No CAS ]

Reference： [1]Patent: WO2018/151830,2018,A1

49
[ 89830-98-8 ]
8-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-oxo-1,2,3,5-tetrahydroindolizine-6-carboxamide [ No CAS ]

Reference： [1]Patent: WO2018/151830,2018,A1

50
[ 89830-98-8 ]
2-(5-(4-cyclopropyl-1H-imidazol-1-yl)-2,3-dihydrobenzofuran-7-carboxamido)-6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine 1-oxide [ No CAS ]

Reference： [1]Patent: WO2018/151830,2018,A1

51
[ 89830-98-8 ]
5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,3-dihydrobenzofuran-7-carboxamide [ No CAS ]

Reference： [1]Patent: WO2018/151830,2018,A1

52
[ 89830-98-8 ]
5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(3-(4-isopropyl-4H-1,2,4-triazol-3-yl)phenyl)-1,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxamide [ No CAS ]

Reference： [1]Patent: WO2018/151830,2018,A1
[2]Patent: WO2018/151830,2018,A1

53
[ 89830-98-8 ]
C₁₅H₁₇N₃O₃ [ No CAS ]

Reference： [1]Patent: WO2018/151830,2018,A1

54
[ 89830-98-8 ]
C₁₄H₁₅N₃O₃ [ No CAS ]

Reference： [1]Patent: WO2018/151830,2018,A1

55
[ 89830-98-8 ]
5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxamide [ No CAS ]

Reference： [1]Patent: WO2018/151830,2018,A1
[2]Patent: WO2018/151830,2018,A1

56
[ 89830-98-8 ]
C₁₄H₁₅N₃O₃ [ No CAS ]

Reference： [1]Patent: WO2018/151830,2018,A1

57
[ 89830-98-8 ]
C₁₃H₁₃N₃O₃ [ No CAS ]

Reference： [1]Patent: WO2018/151830,2018,A1

58
[ 89830-98-8 ]
5-(5-cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,3-dihydrobenzofuran-7-carboxamide [ No CAS ]

Reference： [1]Patent: WO2018/151830,2018,A1

59
[ 89830-98-8 ]
5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide [ No CAS ]

Reference： [1]Patent: WO2018/151830,2018,A1

60
[ 89830-98-8 ]
6-(4-cyclopropyl-1H-imidazol-1-yl)-3-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)quinazolin-4(3H)-one [ No CAS ]

Reference： [1]Patent: WO2018/151830,2018,A1

61
[ 89830-98-8 ]
7-(4-cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)isoquinolin-1(2H)-one [ No CAS ]

Reference： [1]Patent: WO2018/151830,2018,A1

62
[ 41177-72-4 ]
[ 89830-98-8 ]
C₁₅H₁₄N₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
200 mg	With potassium phosphate; copper(l) iodide; tetrabutylammomium bromide; 1,10-phenanthroline-4,7-diol; In water; at 100℃;Inert atmosphere;	[0304] A mixture of Example 3j (600 mg, 2.4 mmol) and Example 3i (400 mg, 3.6 mmol), Cul (45 mg, 0.24 mmol), K3P04 (1 g, 4.8 mmol), 4,7-Dihydroxy-l, 10-phenanthroline(9 mg, 0.48 mmol), TBAB (386 mg, 1.2 mmol) in H20 (10 mL) under N2 was heated at 100°C overnight. After cooling, the reaction mixture was filtered and concentrated under reduced pressure to give the crude and further purified by silica chromatography to give the product 200 mg as yellow solid.

Reference： [1]Patent: WO2018/151830,2018,A1 .Location in patent: Paragraph 0304

63
[ 41177-72-4 ]
[ 89830-98-8 ]
C₁₅H₁₄N₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
200 mg	With potassium phosphate; copper(l) iodide; tetrabutylammomium bromide; 1,10-phenanthroline-4,7-diol; In water; at 100℃;Inert atmosphere;	[0345] A mixture of Example 13a (600 mg, 5.55mmol) and Example 13b (400 mg, 1.65 mmol) Cul (45 mg, 0.24 mmol), K3P04 (1 g, 4.7 mmol), 4,7-Dihydroxy-l,10-phenanthroline (cas: 3922-40-5, 90 mg, 0.42 mmol), TBAB (386 mg, 1.2 mmol) in H20 (10 mL) under N2 was heated at 100 oC overnight. After cooling, filtered and concentrated under reduced pressure to give the crude and further purified by silica gelchromatography to give the product 200 mg as yellow solid. LCMS [M+1] + =271.0

Reference： [1]Patent: WO2018/151830,2018,A1 .Location in patent: Paragraph 0345

64
7-iodo-6-methyl-3,4-dihydro-2H-isoquinolin-1-one [ No CAS ]
[ 89830-98-8 ]
7-(4-cyclopropyl-1H-imidazol-1-yl)-6-methyl-3,4-dihydroisoquinoline-1(2H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47.68%	With copper(l) iodide; potassium carbonate; L-proline; In dimethyl sulfoxide; at 130℃; for 5h;Inert atmosphere; Microwave irradiation;	To a suspension of 7-iodo-6-methyl-3,4-dihydro-2H-isoquinolin-1-one (446.0 mg, 1.476 mmol), <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (218.4 mg, 1.919 mmol) in DMSO (2.5 mL) is added K2C03 (0.408 g, 2.952 mmol). The mixture is degassed with a stream of N2 for 5minutes. L-Proline (0.034 g, 0.295 mmol) and CuT (0.0562 g, 0.295 mmol) are added sequentially and the resulting mixture is stirred at 130 C for 5 hours under microwave conditions. The reaction mixture is slowly quenched with water (30 mL). The aqueous phase is extracted with EtOAc (2x80 mL) and washed with saturated brine (25 mL). The organic extracts are dried over Na2 SO4, filtered, and evaporated to dryness. The crude product is purified by silica gel flash chromatography, eluting with a gradient of 0% to 4% MeOH in DCM to give the title compound (0.198 g, 47.68%) as a white solid. ES/MS (m/z):268.0 (M+H).
	With copper(l) iodide; caesium carbonate; cis-N,N'-dimethyl-1,2-diaminocyclohexane; In N,N-dimethyl-formamide; at 130℃; for 16h;	[0335] A mixture of Example lOe (928 mg, 3.23 mmol), Example lOf (437 mg, 4.04 mmol), Cul (62 mg, 0.32 mmol), Cs2C03 (3.16 g, 9.69 mmol) and N,N'-Dimethyl-l,2-cyclo-hexanediamine (92 mg, 0.65 mmol) in DMF (11.5 mL) was heated at 130C for 16 h.The reaction mixture was diluted with EtOAc (50 mL) and filtered. The filtrate was concentrated under reduced pressure to afford crude product (2.64 g) as brown oil (containing DMF). Part of the crude product (0.70 g) was purified by prep-TLC (DCM/MeOH = 100/4) to give the desired product Example lOg (150 mg, yield 17% (64% if the whole crude product was purified)) as a brown solid. [0336] LCMS [M+l] + =268.1

Reference： [1]Patent: WO2018/160406,2018,A1 .Location in patent: Page/Page column 12; 13
[2]Patent: WO2018/151830,2018,A1 .Location in patent: Paragraph 0335-0336

65
7-iodo-6-methyl-3,4-dihydro-2H-isoquinolin-1-one [ No CAS ]
[ 89830-98-8 ]
7-(4-cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-methyl-3,4-dihydroisoquinoline-1(2H)-one [ No CAS ]

Reference： [1]Patent: WO2018/151830,2018,A1

66
[ 16064-08-7 ]
[ 89830-98-8 ]
C₁₄H₁₂N₄O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12%	With copper(l) iodide; caesium carbonate; cis-N,N'-dimethyl-1,2-diaminocyclohexane; In N,N-dimethyl-formamide; at 130℃; for 2h;Microwave irradiation; Inert atmosphere;	[0357] To a solution of Example 18a (1.00 g, 3.67 mmol) in DMF (10 mL) were added Cul (351 mg, 1.83 mmol), Cs2C03 (2.38 g, 7.30mmol), Example 18b(476 mg, 4.41 mmol), andN1,N2-dimethyl- cyclohexane-l,2-diamine (105 mg, 0.74 mmol). The resulting mixture was degassed with N2 and stirred at 130°C under microwave for 2 h. The mixture was diluted with MeOH and filtered. The filtrate was concentrated under vacuum and the residue was purified byPrep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 mum, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min)to give the desired product Example 18c (110 mg, yield 12percent) as a yellow solid. LC-MS: [M+H]+ = 253.0

Reference： [1]Patent: WO2018/151830,2018,A1 .Location in patent: Paragraph 0357

67
C₈H₈INO₃ [ No CAS ]
[ 89830-98-8 ]
C₁₄H₁₅N₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40 mg	With copper(I) oxide; potassium phosphate; 8-quinolinol; In dimethyl sulfoxide; at 100℃; for 2h;Inert atmosphere;	[0584] A mixture of Example 137d (200 mg, 0.68 mmol), Example 137e (1 11 mg, 1.02 mmol), 8- quinilinol (19 mg, 0.136 mmol), Cu20 (22 mg, 0.136 mmol) and K3P04 (720 mg, 3.40 mmol) in DMSO (10 mL) was degassed by bubbling N2 through the solution for 2 min using a syringe needle. After that, the mixture was heated at 100°C for 2h. The mixture was directly purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 mupiiota, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) givethe desired product Example 137f (40 mg, yield 22percent) as a white solid. LCMS [M+l]+ = 274.0

Reference： [1]Patent: WO2018/151830,2018,A1 .Location in patent: Paragraph 0584

68
3-bromo-7,8-dihydro-1,6-naphthyridin-5(6H)-one [ No CAS ]
[ 89830-98-8 ]
3-(4-cyclopropylimidazol-1-yl)-7,8-dihydro-6H-1,6-naphthyridin-5-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48.6%	With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In N,N-dimethyl-formamide; at 110℃; for 16h;Inert atmosphere;	To a solution of 3-bromo-7,8-dihydro-6H-1,6-naphthyridin-5-one (0.100 g, 0.437mmol) and <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (0.0709 g, 0.65 5 mmol) in DMF (5.00 mL) is addedK2C03 (0.18 1 g, 1.31 mmol). The mixture is degassed with a stream of N2 for 5 minutes. DMEDA (0.0193 g, 0.218 mmol) and CuT (0.0832 g, 0.437 mmol) are added sequentially and the resulting mixture is stirred at 110 C for 16 hours under N2. The mixture is extracted with EtOAc (2x75mL) and washed with saturated brine (3 x25 mL). The organic extracts aredried over Na2SO4, filtered, and evaporated to dryness. The crude product is purified by silica gel flash chromatography, eluting with a gradient of 0% to 5% MeOH in DCM to give the title compound (0.060 g, 48.6%) as a light green solid. ES/MS (m/z): 255.0 (M+H), ?H NMR (400 IVIHz, CDC13) 8.74 (d, J=3.2 Hz, 1H), 8.33 (d, J=2.4 Hz, 1H), 7.81 (s, 1H), 7.10 (s, 1H), 6.31 (br s, 1H), 3.73 (dt, J=3.2, 6.8 Hz, 2H), 3.39 -3.15 (m, 2H), 1.99- 1.90 (m, 1H),0.96-0.88(m,4H)

Reference： [1]Patent: WO2018/160406,2018,A1 .Location in patent: Page/Page column 15

69
((5 -bromo-4-(difluoromethyl)-2-fluorobenzyl)oxy)(tert-butyl)dimethylsilane [ No CAS ]
[ 89830-98-8 ]
1-(5-(((tert-butyldimethylsilyl)oxy)methyl)-2-(difluoromethyl)-4-fluorophenyl)-4-cyclopropyl-1H-imidazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%	With 2-di-tertbutylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; toluene; at 120℃; for 0.05h;Inert atmosphere;	To a reaction vial was charged with tris(dibenzylideneacetone)dipalladium(0) (32.4 mg,0.035 mmol) and Me4tButylXphos (42.6 mg, 0.089 mmol) in toluene/1,4-dioxane (1.0 mL,4/1) and heated at 120 °C for 3 mm for pre-complexation. The resulting dark solution was cooled to rt and transferred to a separate vial charged with ((5-bromo-4-(difluoromethyl)-2- fluorobenzyl)oxy)(tert-butyl)dimethylsilane (327 mg, 0.885 mmol), 4-cyclopropyl- 1H- imidazole (192 mg, 1.771 mmol) and K3P04 (376 mg, 1.771 mmol) in toluene/1,4-dioxane (3.4 mL, 4/1). The reaction mixture was degassed vigorously under N2 and allowed to stir at120 °C for overnight. The reaction was cooled to rt, filtered and concentrated. The residue was purified by chromatography on silica gel (0->30percent EtOAc in hexanes) to afford 1-(5- (((tert-butyldimethylsilyl)oxy)methyl)-2-(difluoromethyl)-4-fluorophenyl)-4-cyclopropyl- 1 Himidazole as pale brown oil (130 mg, 37percent yield).

Reference： [1]Patent: WO2018/209354,2018,A1 .Location in patent: Page/Page column 60; 62

70
[ 89830-98-8 ]
5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-(((2-methoxyethoxy)methoxy)methyl)benzaldehyde [ No CAS ]

Reference： [1]Patent: WO2018/209354,2018,A1

71
[ 89830-98-8 ]
5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-(((2-methoxyethoxy)methoxy)methyl)benzoic acid [ No CAS ]

Reference： [1]Patent: WO2018/209354,2018,A1

72
[ 89830-98-8 ]
butyl 4-(4-cyclopropyl-1H-imidazol-1-yl)-5-(trifluoromethyl)picolinate [ No CAS ]

Reference： [1]Patent: WO2018/209354,2018,A1

73
[ 89830-98-8 ]
4-(4-cyclopropyl-1H-imidazol-1-yl)-5-(trifluoromethyl)picolinic acid [ No CAS ]

Reference： [1]Patent: WO2018/209354,2018,A1

74
[ 89830-98-8 ]
(R)-2-(5-(6-(4-(4-cyclopropyl-1H-imidazol-1-yl)-5-(trifluoromethyl)picolinamido)pyridin-2-yl)-1H-tetrazol-1-yl)propyl acetate [ No CAS ]

Reference： [1]Patent: WO2018/209354,2018,A1

75
[ 89830-98-8 ]
C₁₉H₁₈FN₉OS [ No CAS ]

Reference： [1]Patent: WO2018/209354,2018,A1

76
[ 89830-98-8 ]
C₂₁H₂₀FN₉O [ No CAS ]

Reference： [1]Patent: WO2018/209354,2018,A1

77
[ 89830-98-8 ]
C₂₆H₃₀N₁₀O [ No CAS ]

Reference： [1]Patent: WO2018/209354,2018,A1

78
[ 89830-98-8 ]
C₂₄H₂₈N₁₀OS [ No CAS ]

Reference： [1]Patent: WO2018/209354,2018,A1

79
[ 89830-98-8 ]
C₂₂H₂₀F₃N₉O [ No CAS ]

Reference： [1]Patent: WO2018/209354,2018,A1

80
[ 89830-98-8 ]
C₂₂H₂₀F₃N₉O₂ [ No CAS ]

Reference： [1]Patent: WO2018/209354,2018,A1

81
(5-bromo-2-fluoro-4-(((2-methoxyethoxy)methoxy)methyl)phenyl)methanol [ No CAS ]
[ 89830-98-8 ]
(5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-(((2-methoxyethoxy)methoxy)methyl)phenyl)methanol [ No CAS ]

Reference： [1]Patent: WO2018/209354,2018,A1 .Location in patent: Page/Page column 64; 65

82
C₁₄H₁₉BrF₄OSi [ No CAS ]
[ 89830-98-8 ]
C₂₀H₂₆F₄N₂OSi [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22%	With 2-di-tertbutylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; 5,5-dimethyl-1,3-cyclohexadiene; at 120℃;Inert atmosphere;	A mixture of Pd2(dba)3 (9.5 mg, 10.3 imol) and Me4t-ButylXphos (12.4 mg, 0.03 mmol) in0.5 ml. of 4:1 PhMe:1,4-dioxane was sparged withN2 for 5 minutes. The reaction was heatedat 120 °C for 5 minutes to pre-form the active Pd species. The reaction was cooled to rt. In aseparate vial, a mixture of ((5-bromo-2-fluoro-4-(trifluoromethyl)benzyl)oxy)(tert-butyl)dimethylsilane (100 mg, 0.26 mmol), <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (55.8 mg, 0.52 mmol), and K3P04 (110mg, 0.52 mmol) in 0.7 mL of 4:1 PhMe:1,4-dioxane was sparged with N2 for 5 minutes. The catalyst solution was added to the remaining reaction mixture and the reaction was heated at 120 °C overnight. The reaction was filtered through celite, rinsed with DCM, and concentrated under reduced pressure. The resultant brown oil was purified bycolumn chromatography eluting with hexanes/EtOAc (0percent EtOAc ?* 20percent EtOAc) to give 1-(5 -(((tert-butyldimethylsilyl)oxy)methyl)-4-fluoro-2-(trifluoromethyl)phenyl)-<strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (23.3 mg, 0.06 mmol, 22 percentyield) as a pale yellow oil: LCMS (m/z)415.17[M+lj; ?H NMR (400 MI-Tz, Chloroform-d) oe 7.70 (s, 1H), 7.55 (d, J= 6.2 Hz, 1H), 7.47 (d, J= 9.4 Hz, 1H), 6.84 (s, 1H), 4.85 (s, 2H), 1.98 (ddd, J= 13.3, 8.4, 5.1 Hz, 1H), 0.98 (dt, J=8.0, 2.7 Hz, 2H), 0.94-0.91 (comp, 11H), 0.14 (s, 6H).

Reference： [1]Patent: WO2018/209354,2018,A1 .Location in patent: Page/Page column 66; 67

83
methyl 4-chloro-5-(difluoromethyl)pyridine-2-carboxylate [ No CAS ]
[ 89830-98-8 ]
4-(4-cyclopropyl-1H-imidazol-1-yl)-5-(difluoromethyl)pyridine-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62.4%	With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h;	A mixture of methyl 4-chloro-5-(difluoromethyl)pyridine-2-carboxylate (700 mg,3.16 mmol), <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (409.9 mg, 3.79 mmol) and C52CO3 (2058.5 mg,6.32 mmol) in DMF (10 mL) was stirred at 100 °C for 2 h. The mixture was cooled down toroom temperature and acidified to pH 34 with HC1 (aq). Solvent was removed undervacuum and the crude product was purified by revere phase chromatography with 0-20percentMeCN/H20 to afford 4-(4-cyclopropyl- 1 H-imidazol- 1 -yl)-5 -(difluoromethyl)pyridine-2-carboxylic acid (550 mg, 62.4percent) as a yellow solid.

Reference： [1]Patent: WO2018/209354,2018,A1 .Location in patent: Page/Page column 73; 74

84
[ 888327-38-6 ]
[ 89830-98-8 ]
2-chloro-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-(trifluoromethyl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%	With potassium carbonate; In N,N-dimethyl-formamide; at 70℃;	Into a 50-mL round-bottom flask purged with nitrogen, was placed a solution of 2,4- dichloro-5-(trifluoromethyl)pyridine (800 mg, 3.7 mmol) in DMF (2 mL), 4-cyclopropyl-1H- imidazole (482 mg, 4.4 mmol) and K2C03 (1.53 g, 11.1 mmol). The resulting mixture was stirred at 70°C overnight. Solvent was removed in vacuo. Purification of the crude product on a silica gel column with 30percent EtOAc/PE afforded 360 mg (38percent) of 2-chloro-4-(4-cyclopropyl- 1 H-imidazol- 1 -yl)-5 -(trifluoromethyl)pyridine as a yellow solid.

Reference： [1]Patent: WO2018/209354,2018,A1 .Location in patent: Page/Page column 75

85
6-bromo-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)isoquinoline-3-carboxamide [ No CAS ]
[ 89830-98-8 ]
C₂₆H₂₄N₈O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12%	With copper(I) thiophene-2-carboxylate; potassium carbonate; In dimethyl sulfoxide; at 140℃; for 2h;Microwave irradiation;	A mixture of 6-bromo-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2- yl)isoquinoline-3-carboxamide (30 mg, 0.07 mmol), <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (9.0 mg, 0.08 mmol), K2CO3 (19 mg, 0.14 mmol), and copper(I)-thiophene-2-carboxylate (6.5 mg, 0.034 mmol) in DMSO (0.34 mL) were combined in a microwave vial. The vial was purged with nitrogen and the reaction heated at 140 °C in the microwave for 2 h. The reaction was diluted with EtOAc and H2O, and the mixture was filtered to remove a brown solid. The layers were separated and the organic layer was washed with H2O (2x) and brine. The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. The resultant brown gum was purified by column chromatography eluting with CH2Cl2/MeOH (0percent MeOH? 8percent MeOH) to give Example 22 (3.8 mg, 8.2 mumol, 12 percent yield) as a yellow gum.

Reference： [1]Patent: WO2018/218042,2018,A1 .Location in patent: Page/Page column 74-75; 84

86
6-bromo-2-(4-methoxybenzyl)isoindolin-1-one [ No CAS ]
[ 89830-98-8 ]
6-(4-cyclopropyl-1H-imidazol-1-yl)-2-(4-methoxybenzyl)isoindolin-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With 2-di-tertbutylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; toluene; at 120℃; for 18h;	To a solution of 6-bromo-2-(4-methoxybenzyl)isoindolin-l-one (1 g, 3.01 mmol) in toluene (12 mL) and dioxane (3 mL) was added <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (0.651 g, 6.02 mmol), K3PO4 (1.278 g, 6.02 mmol), Pd2(dba)3 (110 mg, 0.12 mmol) and Me4-di-tBuXPhos (145 mg, 0.301 mmol). The reaction was degassed and allowed to stir at 120° C. for overnight. The crude was filtered and concentrated. The residue was purified by chromatography on silica gel using 0->10percent MeOH in DCM to afford 490 mg white solid as compound 4 (45percent yield). 1H NMR (500 MHz, DMSO-d6) delta8.22 (d, J=1.5 Hz, 1H), 7.92 (d, J=2.1 Hz, 1H), 7.83 (dd, J=8.2, 2.2 Hz, 1H), 7.66 (d, J=8.2 Hz, 1H), 7.62 (d, J=1.5 Hz, 1H), 7.24 (d, J=8.7 Hz, 2H), 6.92 (d, J=8.7 Hz, 2H), 4.69 (s, 2H), 4.36 (s, 2H), 3.74 (s, 3H), 1.84 (td, J=8.4, 4.2 Hz, 1H), 0.81 (dt, J=8.3, 2.9 Hz, 2H), 0.73-0.69 (m, 2H).

Reference： [1]Patent: US2019/62310,2019,A1 .Location in patent: Paragraph 0175; 0177

87
[3-[3-[6-(4-isopropyl-1,2,4-triazol-3-yl)-2-pyridyl]-2-oxo-imidazolidin-1-yl]cyclobutyl] methanesulfonate [ No CAS ]
[ 89830-98-8 ]
1-[3-(4-cyclopropylimidazol-1-yl)cyclobutyl]-3-[6-(4-isopropyl-1,2,4-triazol-3-yl)-2-pyridyl]imidazolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Sodium hydride (60 mass percent) in 54 mineral oil (1.5 g, 39.0 mmol) is added to a solution of 55 <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (2.8 g, 26.0 mmol) in 56 DMF (50 mL) at room temperature. The mixture is stirred at room temperature for 30 minutes. 40 [3-[3-[6-(4-Isopropyl-1,2,4-triazol-3-yl)-2-pyridyl]-2-oxo-imidazolidin-1-yl]cyclobutyl]methanesulfonate (5.7 g, 13 mmol) is added to the solution and the mixture is heated to 80° C. and stirred for 17 hours. The reaction is quenched with water (80 mL) and the product is extracted with DCM (3×150 mL). The organic extracts are washed with brine (30 mL), dried over Na2SO4, and concentrated in vacuo. The residue is purified by silica gel flash chromatography, eluting with a gradient of 0percent to 4percent 4 MeOH in 3 DCM followed by Preparative HPLC eluting with an isocratic system of 23percent 57 ACN (0.5percent FA) in 34 H2O (0.1percent FA) for 41 min; column temperature: room temperature; flow rate: 30 mL/min, t(R)=27.1 minutes (UV). The material is concentrated, dissolved in 21 water, and lyophilized to give the 58 title compound. ES/MS (m/z): 433.3 (M+1).

Reference： [1]Patent: US2019/71413,2019,A1 .Location in patent: Paragraph 0063-0064

88
tert-butyl (1-bromopropan-2-yl)carbamate [ No CAS ]
[ 89830-98-8 ]
1-(4-cyclopropylimidazol-1-yl)propan-2-amine [ No CAS ]
1-(5-cyclopropylimidazol-1-yl)propan-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Potassium hydroxide (73.9 mg, 1.3 177 mmol%) and tert-butyl N-[(2R)-2-bromopropyl]carbamate (230.1mg, 0.96634 mmol) are added to a solution of <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (100 mg, 0.087849 mmol) in DMSO (2 mL) at 0 C. The mixture is stirred at room temperature for 65 hours. The reaction is quenched with water and extracted with EtOAc (3x). The organic extracts are washed with saturated NaC1 (3x), dried over Na2SO4, filtered, and concentrated to dryness. The residue is purified bysilica gel flash chromatography with 4% MeOH in DCM to give the title compounds as a mixture of 2 regioisomers (112 mg, 22.82%) and as a yellow oil. ES/MS (m/z): 266 (M+ 1). TFA (2 mL, 26.45 mmol) is added to racemic tert-butyl N-[2-(4-cyclopropylimidazol- i-yl)-i -methyl-ethyl] carbamate and to racemic tert-butyl N- [2-(5 -cyclopropylimidazol-1-yl)-1-methyl-ethyl]carbamate (112 mg, 0.2005 mmol) in DCM(10 mL) at room temperature. The mixture is stirred at room temperature for 1 hour andis concentrated to give the crude title compounds as a mixture of regioisomers (69.8 mg,100%) as a yellow oil. ES/MS (m/z): 166 (M+1).

Reference： [1]Patent: WO2019/50794,2019,A1 .Location in patent: Page/Page column 10; 11

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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. 89830-98-8 ] {[proInfo.proName]}

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