[ CAS No. 13374-30-6 ] {[proInfo.proName]}

Name: 13374-30-6|(1S,2S)-2-Aminocyclohexanol hydrochloride|97%
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SKU: A165056
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2D 3D

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Quality Control of [ 13374-30-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 13374-30-6 ]

Product Details of [ 13374-30-6 ]

CAS No. :	13374-30-6	MDL No. :	MFCD09259963
Formula :	C₆H₁₄ClNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LKKCSUHCVGCGFA-GEMLJDPKSA-N
M.W :	151.63	Pubchem ID :	11715205
Synonyms :

Calculated chemistry of [ 13374-30-6 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	2.0
Molar Refractivity :	39.68
TPSA :	46.25 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.7 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	0.74
Log Po/w (WLOGP) :	1.05
Log Po/w (MLOGP) :	0.57
Log Po/w (SILICOS-IT) :	0.39
Consensus Log Po/w :	0.55

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.25
Solubility :	8.6 mg/ml ; 0.0567 mol/l
Class :	Very soluble
Log S (Ali) :	-1.29
Solubility :	7.77 mg/ml ; 0.0512 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.1
Solubility :	122.0 mg/ml ; 0.802 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.97

Safety of [ 13374-30-6 ]

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

Application In Synthesis of [ 13374-30-6 ]

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

Upstream synthesis route of [ 13374-30-6 ]
Downstream synthetic route of [ 13374-30-6 ]

[ 13374-30-6 ] Synthesis Path-Upstream 1~6

1
[ 13374-30-6 ]
[ 214679-17-1 ]

Reference： [1] Patent: WO2011/29027, 2011, A1,

2
[ 221110-45-8 ]
[ 13374-30-6 ]

Reference： [1] Journal of Organic Chemistry, 1997, vol. 62, # 12, p. 4197 - 4199

3
[ 202461-26-5 ]
[ 13374-30-6 ]

Reference： [1] Tetrahedron, 2000, vol. 56, # 50, p. 9773 - 9779

4
[ 931-15-7 ]
[ 13374-30-6 ]

Reference： [1] Journal of Organic Chemistry, 1997, vol. 62, # 12, p. 4197 - 4199

5
[ 24424-99-5 ]
[ 13374-30-6 ]
[ 121282-70-0 ]

Yield	Reaction Conditions	Operation in experiment
88%	With triethylamine In dichloromethane at 20℃; for 2 h;	To a stirred suspension of (lS,2S)-(+)-2-aminocyclohexanol hydrochloride (1.04 g, 6.86 mmol) in DCM (20 mL) was added triethylamine (2.39 mL, 17.1 mmol). A solution of di-tert-butyl dicarbonate (1.80 g, 8.23 mmol) in DCM (15 mL) was added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours. The reaction was diluted with DCM and washed successively with IN HC1, saturated aqueous NaHCC"3 and brine, dried and concentrated. The residue was purified by column chromatography (hexane/EtOAc, 1 : 1) to give tert-butyl (l S,2S)-2- hydroxycyclohexylcarbamate (1.30 g, 88percent).

Reference： [1] Patent: WO2011/29027, 2011, A1, . Location in patent: Page/Page column 130; 131

6
[ 34619-03-9 ]
[ 13374-30-6 ]
[ 121282-70-0 ]

Yield	Reaction Conditions	Operation in experiment
96%	With sodium hydrogencarbonate In dichloromethane	Step A (+-)-trans-2-(tert-Butoxycarbonylamino)-cyclohexanol To a vigoursly stirring solution of trans-2-aminocyclohexanol hydrochloride (5.5 g, 36 mmol) in 100 mL methylene chloride and saturated sodium bicarbonate solution (1:1) at 0° C. was added di-tert-butylcarbonate (13.09 g, 60 mmol). The resulting heterogeneous mixture was warmed to the room temperature and stirred overnight. The methylene chloride layer was washed with brine, dried and evaporated. The solid obtained was triturated with hexane and filtered to give 5.86 g (96percent) of (+-)-trans-2-N-(tert-butoxycarbonyl)-cyclohexanol. ¹ H NMR (500 MHz, CDCl₃): δ4.61(brs, 1H), 3.27 (m, 1H), 2.73 (brs, 1H), 2.02-1.69 (m, 4H), 1,45 (s, 9H), 1.42-1.09(m, 4H). ¹³ C NMR (125 MHz, CDCl₃): δ75.42, 56.62, 34.22, 31.84, 28.43, 27.48, 24.78, 24.11.

Reference： [1] Patent: US6043358, 2000, A,

[ 13374-30-6 ] Synthesis Path-Downstream 1~75

1
[ 108-24-7 ]
[ 13374-30-6 ]
[ 74080-31-2 ]

Reference： [1]Canadian Journal of Chemistry,1980,vol. 58,p. 387 - 392

2
[ 931-15-7 ]
[ 13374-30-6 ]

Reference： [1]Journal of Organic Chemistry,1997,vol. 62,p. 4197 - 4199

3
[ 108-24-7 ]
[ 13374-30-6 ]
[ 190848-36-3 ]

Reference： [1]Journal of the American Chemical Society,2019,vol. 141,p. 11151 - 11160
[2]Journal of Organic Chemistry,1997,vol. 62,p. 4197 - 4199

4
[ 13374-30-6 ]
Zincke salt [ No CAS ]
[ 74023-84-0 ]

Reference： [1]Canadian Journal of Chemistry,1980,vol. 58,p. 387 - 392

5
[ 202461-26-5 ]
[ 13374-30-6 ]

Reference： [1]Tetrahedron,2000,vol. 56,p. 9773 - 9779

6
[ 13374-30-6 ]
[ 821801-03-0 ]
[ 821801-07-4 ]

Reference： [1]Organic and Biomolecular Chemistry,2004,vol. 2,p. 3329 - 3336

7
[ 13374-30-6 ]
[ 141-75-3 ]
[ 823177-21-5 ]

Reference： [1]Organic and Biomolecular Chemistry,2004,vol. 2,p. 3329 - 3336

8
[ 953770-87-1 ]
[ 13374-30-6 ]
4-((2-(((1S,2S)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N-methylpicolinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 110℃; for 24h;	Example 16 Preparation of 4-(2-((1S,2S)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (Table 2, Compound 137) To the solution of 4-(2-methanesulfinyl-benzothiazol-6-yloxy)-pyridine-2-carboxylic acid methylamide (70 mg, 0.202 mmol, 1.0 eq) in DMA (600 muL), was added <strong>[13374-30-6](1S,2S)-2-aminocyclohexanol hydrochloride</strong> (92 mg, 0.606 mmol, 3.0 eq) followed by diisopropylethylamine (0.21 mL, 1.21 mmol). The reaction was heated at 110 C. for 24-hours. The neat reaction mixture was purified on reverse phase preparatory HPLC. Pure fractions were lyophilized as TFA salts. M+H=398

Reference： [1]Patent: US2008/45528,2008,A1 .Location in patent: Page/Page column 48

9
[ 13374-30-6 ]
(1S)-N-(2-oxocyclohexyl)butyramide [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2004,vol. 2,p. 3329 - 3336

10
[ 13374-30-6 ]
(1R,2S)-2-aminocyclohexanol hydrochloride [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1997,vol. 62,p. 4197 - 4199

11
[ 221110-45-8 ]
[ 13374-30-6 ]

Reference： [1]Journal of Organic Chemistry,1997,vol. 62,p. 4197 - 4199

12
[ 13374-30-6 ]
[ 74023-78-2 ]

Reference： [1]Canadian Journal of Chemistry,1980,vol. 58,p. 387 - 392

13
[ 13374-30-6 ]
[ 74023-79-3 ]

Reference： [1]Canadian Journal of Chemistry,1980,vol. 58,p. 387 - 392

14
[ 13374-30-6 ]
[ 74023-85-1 ]

Reference： [1]Canadian Journal of Chemistry,1980,vol. 58,p. 387 - 392

15
[ 13374-30-6 ]
5-(4-chlorophenyl)-3-methyl-2-(methylthio)-1,3,4-thiadiazolium perchlorate [ No CAS ]
(1S,2S)-2-[5-(4-chloro-phenyl)-3-methyl-3H-[1,3,4]thiadiazol-2-ylideneamino]-cyclohexanol [ No CAS ]

Reference： [1]Patent: EP1193261,2002,A1 .Location in patent: Page 23

16
[ 13374-30-6 ]
[ 1489-69-6 ]
(1,2-trans)-2-[(cyclopropylmethyl)amino]cyclohexanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26%		To a stirred, cooled [(5-10C)] slurry of <strong>[13374-30-6]trans-2-aminocyclohexanol hydrochloride</strong> (9.86 g, 65 mmol) in toluene (30 [ML)] was added consecutively magnesium sulfate (0.79g, 6.5 mmol), triethylamine (13.6 mL, 97.5 mmol) and [CYCLOPROPANECARBOXALDEHYDE] (4.9 g, 70 mmol) and the mixture stirred in the ice bath overnight, rising to RT overnight as the ice melted. The mixture was filtered, the salt cake washed with a little toluene and the filtrate stripped in vacuo. The resulting residue, dissolved in methanol (30 mL), was cooled in an ice bath as sodium borohydride (2.70 g, 71.3 mmol) was added portionwise with stirring. The mixture was stirred in the bath as the ice melted for 2.5 h, re-cooled in an ice bath and treated cautiously with acetone (6.5 mL). After stirring for 15 min the solvent was stripped, the residue treated with ether, the solids filtered off, washed with ether and the filtrate stripped in vacuo. The resulting material was [KUGELROHRED] and the title compound was collected at 170- [210/2] torr (bulb temperature), soft white solid (2.90 g, 26%). The material was used in the next step without further purification. lH NMR (300 MHz, CDCl3) [60.] 06-0.17 (m, 2H), 0.42- 0.53 (m, 2H), 0.87-1. 00 (m, 2H), 1.14-1. 35 (m, 4H), 1.71-1. 73 (m, 2H), 2.02-2. 07 (m, 3H), 2. [18-2.] 27 (m, 1H), 2.44-2. 56 (m, 2H), 3.13-3. 21 (m, 1H).

Reference： [1]Patent: WO2004/31154,2004,A1 .Location in patent: Page 163

17
C₁₇H₁₁Cl₂FN₂O₂ [ No CAS ]
[ 13374-30-6 ]
2-(2,4-dichlorophenyl)-N-(trans-2-hydroxycyclohexyl)-1-(4-methoxyphenyl)-1H-imidazole-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
23%	In 1,2-dichloro-ethane;	In a 20-mL screw-cap vial, 182 mg (0.5 mmol) 2-(2,4-dichlorophenyl)-1-(4- methoxyphenyl)-lH-imidazole-4-carboxylic acid, 145 mg (0.55 mmol) TFFH, and 5.0 equiv. PS- DIEA (loading level: 3.50 mmol/g, 716 mg, 2.5 mmol) were heated in 10 mL 1,2-dichloroethane at 35C overnight. The formation of acyl fluoride was monitored by LC-MS. To the mixture, 1.1 equiv. (84 mg, 0.55 mmol) <strong>[13374-30-6]trans-2-aminocyclohexanol hydrochloride</strong> was added and the reaction continued overnight. The mixture was filtered through a filter tube (polypropylene frit), and the filtrate was evaporated under reduced pressure. The crude product was redissolved in 1 mL MeOH and purified by preparative HPLC to give 53 mg of 2-(2,4-dichlorophenyl)-N-(trans-2- hydroxycyclohexyl)-l-(4-methoxyphenyl)-lH-imidazole-4-carboxamide (amber oil, 23% yield). ¹H NMR (400 MHz, CD2Cl2) 8 7.90 (s, 1 H), 7.30-7.50 (m, 4 H), 7.10 (d, 2 H), 6.90 (d, 2 H), 3.85 (s, 3 H), 3.80 (m, 1 H), 3.50 (m, 1 H), 3.25 (bs, 1 H), 2.0 (m, 2 H), 1.75 (m, 2 H), 1.30-1.50 (m, 4 H) ; LC-MS m/z 460.2 (MH+), retention time 3.31 min (method 2).

Reference： [1]Patent: WO2005/99705,2005,A2 .Location in patent: Page/Page column 24

18
morpholine resin [ No CAS ]
3-methyl-2-methylthio[1,3,4]thiadiazolium perchlorate [ No CAS ]
[ 13374-30-6 ]
(1R*,2S*)-2-[5-(4-Chloro-phenyl)-3-methyl-3H-[1,3,4]thiadiazol-2-ylideneamino]-cyclohexanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; ethanol;	(1R,2R)-2-[5-(4-Chloro-phenyl)-3-methyl-3H-[1,3,4]thiadiazol-2-ylideneamino]-cyclohexanol The compound I8 was prepared by the procedure described in Example I3 using appropriate intermediates and reagents (Protocol A). Triethylamine was replaced by morpholine resin (2.1 mmol, 0.61 g, loading 3.47 mmol/g); the mixture of morpholine resin and <strong>[13374-30-6]trans-2-aminocyclohexanol hydrochloride</strong> (2.1 mmol, 0.318 g) was stirred in ethanol (3.5 mL) at RT for 5 minutes before the addition of 3-methyl-2-methylthio[1,3,4]thiadiazolium perchlorate (3a) (0.7 mmol, 0.25 g). The residue was subjected to silica gel chromatography (Alltech column, 2 g silica) eluding with dichloromethane containing from 0% to 1% methanol. Yield: 0.050 g, 22%. 1H-NMR (400 MHz, DMSO) delta ppm: 1.10-1.25 (m, 4H), 1.50-1.66 (m, 3H), 1.71-1.79 (b, 1H), 2.28-2.33 (m, 1H), 3.21-3.27 (m, 1H), 3.40 (s, 3H), 4.38 (s, 1H), 7.42 (dd, 2H), 7.54 (dd, 2H). MS (m/z)/M+1=324/326.

Reference： [1]Patent: US2003/45557,2003,A1

19
[ 13374-30-6 ]
[ 208124-34-9 ]
trans-2-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)-amino-1-cyclohexanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 2-4 Synthesis of trans-2-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)-amino-1-cyclohexanol Following General Procedure C above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and <strong>[13374-30-6]trans-2-aminocyclohexanol hydrochloride</strong> (Aldrich), the title compound was prepared as a solid having a melting point of 189-191 C. The reaction was monitored by tlc on silica gel (Rf=0.85 in 9% methanol/dichloromethane) and purification was by flash chromatography using 9% methanol/dichloromethane as the eluant. NMR data was as follows: 1H-nmr (CD3OD): delta=6.8-6.6 (m, 3H), 4.1 (m, J=7.2 Hz, 1H), 3.4 (m, 4H), 3.1 (m, 1H), 1.8-1.4 (m, 4H), 1.1 (m, 7H). 13C-nmr (CD3OD) delta=175.4, 173.0, 113.9, 113.6, 103.9, 103.6, 74.3, 56.9, 51.4, 51.4, 50.4, 43.4, 43.3, 43.31, 36.0, 35.5, 32.9, 32.8, 26.2, 26.2, 25.9, 25.8, 18.8, 18.7.

Reference： [1]Patent: US2002/45747,2002,A1

20
[ 34619-03-9 ]
[ 13374-30-6 ]
(+-)-trans-2-N-(tert-butoxycarbonyl)-cyclohexanol [ No CAS ]
[ 121282-70-0 ]

Yield	Reaction Conditions	Operation in experiment
5.86 g (96%)	With sodium hydrogencarbonate; In dichloromethane;	Step A (+-)-trans-2-(tert-Butoxycarbonylamino)-cyclohexanol To a vigoursly stirring solution of trans-2-aminocyclohexanol hydrochloride (5.5 g, 36 mmol) in 100 mL methylene chloride and saturated sodium bicarbonate solution (1:1) at 0 C. was added di-tert-butylcarbonate (13.09 g, 60 mmol). The resulting heterogeneous mixture was warmed to the room temperature and stirred overnight. The methylene chloride layer was washed with brine, dried and evaporated. The solid obtained was triturated with hexane and filtered to give 5.86 g (96%) of (+-)-trans-2-N-(tert-butoxycarbonyl)-cyclohexanol. 1 H NMR (500 MHz, CDCl3): delta4.61(brs, 1H), 3.27 (m, 1H), 2.73 (brs, 1H), 2.02-1.69 (m, 4H), 1,45 (s, 9H), 1.42-1.09(m, 4H). 13 C NMR (125 MHz, CDCl3): delta75.42, 56.62, 34.22, 31.84, 28.43, 27.48, 24.78, 24.11.

Reference： [1]Patent: US6043358,2000,A

21
[ 13374-30-6 ]
[ 1269650-09-0 ]

Reference： [1]Patent: WO2011/29027,2011,A1

22
[ 13374-30-6 ]
[ 214679-17-1 ]

Reference： [1]Patent: WO2011/29027,2011,A1

23
[ 13374-30-6 ]
[ 21651-79-6 ]

Reference： [1]Patent: WO2011/29027,2011,A1

24
[ 24424-99-5 ]
[ 13374-30-6 ]
[ 121282-70-0 ]

Yield	Reaction Conditions	Operation in experiment
88%	With triethylamine; In dichloromethane; at 20℃; for 2h;	To a stirred suspension of (lS,2S)-(+)-2-aminocyclohexanol hydrochloride (1.04 g, 6.86 mmol) in DCM (20 mL) was added triethylamine (2.39 mL, 17.1 mmol). A solution of di-tert-butyl dicarbonate (1.80 g, 8.23 mmol) in DCM (15 mL) was added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours. The reaction was diluted with DCM and washed successively with IN HC1, saturated aqueous NaHCC"3 and brine, dried and concentrated. The residue was purified by column chromatography (hexane/EtOAc, 1 : 1) to give tert-butyl (l S,2S)-2- hydroxycyclohexylcarbamate (1.30 g, 88%).

Reference： [1]Patent: WO2011/29027,2011,A1 .Location in patent: Page/Page column 130; 131

25
[ 1203712-03-1 ]
[ 13374-30-6 ]
[ 1443361-84-9 ]

Yield	Reaction Conditions	Operation in experiment
0.23 g	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃;	To a solution of 5,8-difluoro-1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.30 g) obtained in Reference Example 1 in DMF (10 mL) were added <strong>[13374-30-6](1S,2S)-2-hydroxycyclohexylamine hydrochloride</strong> (0.20 g), N-[(ethylimino)methylene]-N',N'-dimethylpropane-1,3-diamine hydrochloride (0.25 g), 1-hydroxybenzotriazole (0.20 g) and triethylamine (0.36 mL), and the mixture was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction solution, and the mixture was stirred. The organic layer was separated, washed with 1 N hydrochloric acid, saturated sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate and concentrated. The residue was solidified with diisopropyl ether to give the title compound (0.23 g) as a pale-yellow solid. MS (ESI+): [M+H]+ 443.1 1H NMR (400 MHz, DMSO-d6) delta 1.14-1.37 (4H, m), 1.54-1.69 (2H, m), 1.80-1.91 (1H, m), 1.96-2.07 (1H, m), 3.36-3.43 (1H, m), 3.58-3.74 (4H, m), 4.82 (1H, d, J = 5.1 Hz), 5.70 (2H, d, J = 2.4 Hz), 6.90 (2H, d, J = 8.8 Hz), 7.07 (2H, d, J = 8.6 Hz), 7.19-7.30 (1H, m), 7.65 (1H, ddd, J = 13.9, 9.2, 4.3 Hz), 8.88 (1H, s), 9.79 (1H, d, J = 7.3 Hz).

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5151 - 5172
[2]Patent: EP2821401,2015,A1 .Location in patent: Paragraph 0291

26
[ 1364677-29-1 ]
[ 13374-30-6 ]
[ 1493777-26-6 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 9874 - 9896

27
[ 1018782-76-7 ]
[ 13374-30-6 ]
[ 1493777-55-1 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 9874 - 9896

28
[ 1414772-61-4 ]
[ 13374-30-6 ]
[ 1610454-12-0 ]

Yield	Reaction Conditions	Operation in experiment
8%	With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 150℃; for 72h;	150 mg (0.56 mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine and 168.7 mg (1.11 mmol) <strong>[13374-30-6](1S,2S)-2-aminocyclohexanol hydrochloride</strong> (1:1) and 0.48 mL (2.78 mmol) N-ethyl-N-isopropylpropan-2-amine in 5.0 mL butan-1-ol were stirred 72 h at 150C. The solvent was removed. The residue was purified by HPLC to yield 15 mg (8%) product. LC-MS (Method 2): Rt = 1.04 min; MS (ESIpos) m/z = 349 [M+H]+. 1H-NMR (600 MHz ,DMSO-d6), delta [ppm]= 1.19-1.27 (1H), 1.31-1.39 (1H), 1.40-1.51 (2H), 1.71-1.80 (2H), 1.96-2.02 (1H), 2.33-2.39 (1H), 3.51-3.57 (1H), 3.63-3.69 (1H), 4.73-4.75 (1H), 6.86-6.90 (1H), 7.13-7.17 (1H), 7.28-7.31 (1H), 7.32-7.36 (1H), 7.58-7.60 (1H), 7.63-7.66 (1H), 7.68-7.71 (1H), 7.81-7.84 (1H), 7.92-7.96 (1H).

Reference： [1]Patent: WO2014/76162,2014,A1 .Location in patent: Page/Page column 58; 59

29
1-(4-carbamoylbenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid [ No CAS ]
[ 13374-30-6 ]
1-(4-carbamoylbenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
162 mg	With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 15h;	To a solution of 1-(4-carbamoylbenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (200 mg) obtained in Reference Example 3 in DMF (5 mL) were added <strong>[13374-30-6](1S,2S)-2-hydroxycyclohexylamine hydrochloride</strong> (93 mg), 0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (353 mg) and triethylamine (0.26 mL), and the mixture was stirred at room temperature for 15 hr. Water (10 mL) was added to the reaction solution, the mixture was stirred, and the precipitated solid was collected by filtration. The crude crystals were recrystallized from ethanol to give the title compound (162 mg). MS (ESI+): [M+H]+ 420.3 1H NMR (300 MHz, DMSO-d6) delta 1.30 (4H, d, J = 8.3 Hz), 1.55-1.71 (2H, m), 1.87 (1H, d, J = 8.3 Hz), 2.03 (1H, d, J = 10.6 Hz), 3.34-3.46 (1H, m), 3.71 (1H, d, J = 8.7 Hz), 4.81 (1H, d, J = 4.9 Hz), 5.85 (2H, s), 7.28 (2H, d, J = 8.3 Hz), 7.34 (1H, brs), 7.50 (1H, t, J = 7.2 Hz), 7.65-7.77 (2H, m), 7.82 (2H, d, J = 8.3 Hz), 7.92 (1H, brs), 8.36 (1H, d, J = 7.6 Hz), 9.09 (1H, s), 10.08 (1H, d, J = 7.6 Hz).

Reference： [1]Patent: EP2821401,2015,A1 .Location in patent: Paragraph 0285

30
1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid [ No CAS ]
[ 13374-30-6 ]
N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In dichloromethane; at 20℃;	In a 100 rriL pear-shaped flask, lH-pyrrolo[3,2-b]pyridine-3-carboxylic acid (863 mg, 5.32 mmol), (lS,2S)-(+)-2-aminocyclohexanol hydrochloride (888 mg, 5.85 mmol) and BOP (3.06 g, 6.92 mmol) were combined with dichloromethane (31.9 ml) and triethylamine (2.15 g, 2.97 ml, 21.3 mmol). The reaction mixture was stirred at room temperature overnight, extracted three times with dichloromethane. The organic phases were washed with water and concentrated in vacuo. The crude material was purified on silica eluting with a gradient formed from dichloromethane and methanol (0 to 10 ) to provide 0.86 g (62 ) of the title compound as a white solid. MS (m/e): 260.5 (M+H)+.

Reference： [1]Patent: WO2015/28483,2015,A1 .Location in patent: Page/Page column 24; 25

31
[ 13374-30-6 ]
N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-methylbenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide [ No CAS ]

Reference： [1]Patent: WO2015/28483,2015,A1

32
[ 13374-30-6 ]
1-(3-fluoro-4-methylbenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide [ No CAS ]

Reference： [1]Patent: WO2015/28483,2015,A1

33
1-((6-chloropyridin-3-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid hydrochloride [ No CAS ]
[ 13374-30-6 ]
1-((6-chloropyridin-3-yl)methyl)-N-((1S,2S)-2-hydroxycyclohexyl )-1H-pyrrolo[3,2-b]pyridine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In dichloromethane; at 20℃; for 4h;	General procedure: To a suspension of l-(5-bromo-2-fluorobenzyl)-lH-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example A.l) (21 mg, 60.1 muiotaetaomicron) in dichloromethane (400 mu) was added (lS,2S)-2- aminocyclohexanol hydrochloride (10.9 mg, 72.2 muiotaetaomicron), (benzotriazol-l-yloxy)tris- (dimethylamino)phosphonium hexafluorophosphate (BOP) (34.6 mg, 78.2 muiotaetaomicron) and triethylamine (24.3 mg, 33.5 mu, 241 muiotaetaomicron). The yellow solution was stirred at room temperature for 4 hours. The solution was diluted with dichloromethane and washed once with water. The aqueous layer was separated and extracted twice with dichloromethane. The combined organic fractions were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified on silica eluting with a gradient formed from n-heptane and ethyl acetate (0 to 100 %) to provide 17 mg (63 %) of the title compound as a white solid. MS (m/e): 448.4 (M+H)+. In analogy to example 1, examples 2 to 36 of the following table were prepared by coupling an acid derivative with an amine

Reference： [1]Patent: WO2015/28483,2015,A1 .Location in patent: Page/Page column 26; 27

34
1-(5-bromo-2-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid [ No CAS ]
[ 13374-30-6 ]
1-(5-bromo-2-fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In dichloromethane; at 20℃; for 4h;	To a suspension of l-(5-bromo-2-fluorobenzyl)-lH-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example A.l) (21 mg, 60.1 muiotaetaomicron) in dichloromethane (400 mu) was added (lS,2S)-2- aminocyclohexanol hydrochloride (10.9 mg, 72.2 muiotaetaomicron), (benzotriazol-l-yloxy)tris- (dimethylamino)phosphonium hexafluorophosphate (BOP) (34.6 mg, 78.2 muiotaetaomicron) and triethylamine (24.3 mg, 33.5 mu, 241 muiotaetaomicron). The yellow solution was stirred at room temperature for 4 hours. The solution was diluted with dichloromethane and washed once with water. The aqueous layer was separated and extracted twice with dichloromethane. The combined organic fractions were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified on silica eluting with a gradient formed from n-heptane and ethyl acetate (0 to 100 %) to provide 17 mg (63 %) of the title compound as a white solid. MS (m/e): 448.4 (M+H)+.

Reference： [1]Patent: WO2015/28483,2015,A1 .Location in patent: Page/Page column 26

35
[ 201230-82-2 ]
tert-butyl 7-cyano-3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate [ No CAS ]
[ 13374-30-6 ]
tert-butyl 7-cyano-3-(((1S,2S)-2-hydroxycyclohexyl)carbamoyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With palladium diacetate; triethylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 80℃; for 5h;	(tert-Butyl 7-cyano-3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (Intermediate 25), (4.92 g), palladium (II) acetate (90 mg), <strong>[13374-30-6](1S,2S)-2-aminocyclohexanol hydrochloride</strong> (3.03 g), XantPhos (0.46 g) toluene (121 mL) and TEA (5.57 mL) were added to a one necked round bottom flask. This was purged with CO and stirred at 80 C. for 5 hr under CO. The reaction mixture was diluted with EtOAc and transferred to a separatory funnel Remaining solid in the microwave tube was dissolved in THF by sonication and added to the separatory funnel. The combined organic layers were washed with water (2) then brine. The combined aqueous layers were extracted with EtOAc (2) and the combined organic extracts dried over MgSO4, filtered and evaporated in vacuo to the crude desired compound which was taken on as such without further purification. LCMS: m/z 385.65 [M+H]+, m/z 285.56 [M+H-Boc]+.
	With palladium diacetate; triethylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 80℃; for 5h;	(tert-Butyl 7-cyano-3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (Intermediate 25), (4.92 g), palladium (II) acetate (90 mg), <strong>[13374-30-6](1S,2S)-2-aminocyclohexanol hydrochloride</strong> (3.03 g), XantPhos (0.46 g) toluene (121 mL) and TEA (5.57 mL) were added to a one necked round bottom flask. This was purged with CO and stirred at 80 C. for 5 hr under CO. The reaction mixture was diluted with EtOAc and transferred to a separatory funnel Remaining solid in the microwave tube was dissolved in THF by sonication and added to the separatory funnel. The combined organic layers were washed with water (2) then brine. The combined aqueous layers were extracted with EtOAc (2) and the combined organic extracts dried over MgSO4, filtered and evaporated in vacuo to the crude desired compound which was taken on as such without further purification. LCMS: m/z 385.65 [M+H]+, m/z 285.56 [M+H-Boc]+.

Reference： [1]Patent: US2015/94328,2015,A1 .Location in patent: Paragraph 0409; 0422-0423
[2]Patent: WO2015/49574,2015,A1 .Location in patent: Page/Page column 47; 48

36
[ 201230-82-2 ]
tert-butyl 3-iodo-7-methoxy-1H-pyrrolo[3,2-b]pyridine-1-carboxylate [ No CAS ]
[ 13374-30-6 ]
tert-butyl 3-(((1S,2S)-2-hydroxycyclohexyl)carbamoyl)-7-methoxy-1H-pyrrolo[3,2-b]pyridine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.22 g	With palladium diacetate; triethylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 80℃;	tert-Butyl 3-iodo-7-methoxy-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (Intermediate 43), (924 mg), Pd(OAc)2 (33 mg), <strong>[13374-30-6](1S,2S)-2-aminocyclohexanol hydrochloride</strong> (562 mg), XantPhos (169 mg), toluene (22 mL) and TEA (1.03 mL) were added to a round bottomed flask. This was purged with CO and stirred at 80 C. overnight under CO. The reaction mixture was diluted with EtOAc (250 mL) and washed with water (2*70 mL) and brine (70 mL). The combined aqueous layers were extracted with EtOAc (70 mL) and the combined organic layers dried over MgSO4, filtered and evaporated under vacuum to give a solid (1.22 g) which was taken on as such without further purification. LCMS: m/z 390.65 [M+H]+.
1.22 g	With palladium diacetate; triethylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 80℃;	tert-Butyl 3-iodo-7-methoxy-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (Intermediate 43), (924 mg), Pd(OAc)2 (33 mg), <strong>[13374-30-6](1S,2S)-2-aminocyclohexanol hydrochloride</strong> (562 mg), XantPhos (169 mg), toluene (22 mL) and TEA (1.03 mL) were added to a round bottomed flask. This was purged with CO and stirred at 80 C. overnight under CO. The reaction mixture was diluted with EtOAc (250 mL) and washed with water (2*70 mL) and brine (70 mL). The combined aqueous layers were extracted with EtOAc (70 mL) and the combined organic layers dried over MgSO4, filtered and evaporated under vacuum to give a solid (1.22 g) which was taken on as such without further purification. LCMS: m/z 390.65 [M+H]+.

Reference： [1]Patent: US2015/94328,2015,A1 .Location in patent: Paragraph 0450; 0469-0470
[2]Patent: WO2015/49574,2015,A1 .Location in patent: Page/Page column 53; 55

37
[ 201230-82-2 ]
tert-butyl 3-iodo-5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-carboxylate [ No CAS ]
[ 13374-30-6 ]
tert-butyl 3-(((1S,2S)-2-hydroxycyclohexyl)carbamoyl)-5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With palladium diacetate; triethylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 80℃; for 2.25h;	tert-Butyl 3-iodo-5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (Intermediate 47), (950 mg), <strong>[13374-30-6](1S,2S)-2-aminocyclohexanol hydrochloride</strong> (577 mg), palladium (II) acetate (17.10 mg), XantPhos (88 mg), toluene (23 mL) and TEA (1.2 mL) were placed in a 25 mL microwave tube with a balloon of CO. The reaction mixture was purged with CO then heated to 80 C. for 2 h 15 min (CO was bubbled through reaction mixture when it first reached 80 C.). The reaction mixture was cooled, poured onto EtOAc and the remaining solid in the reaction flask was added to the EtOAc organic phases by dissolving in water and the organic phases washed with water (2*) then brine. The combined organic extracts were dried (MgSO4), filter and evaporate under vacuum to give the crude desired compound (989 mg), which was used crude. LCMS: m/z 390.64 [M+H]+
	With palladium diacetate; triethylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 80℃; for 2.25h;	tert-Butyl 3-iodo-5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (Intermediate 47), (950 mg), <strong>[13374-30-6](1S,2S)-2-aminocyclohexanol hydrochloride</strong> (577 mg), palladium (II) acetate (17.10 mg), XantPhos (88 mg), toluene (23 mL) and TEA (1.2 mL) were placed in a 25 mL microwave tube with a balloon of CO. The reaction mixture was purged with CO then heated to 80 C. for 2 h 15 min (CO was bubbled through reaction mixture when it first reached 80 C.). The reaction mixture was cooled, poured onto EtOAc and the remaining solid in the reaction flask was added to the EtOAc organic phases by dissolving in water and the organic phases washed with water (2*) then brine. The combined organic extracts were dried (MgSO4), filter and evaporate under vacuum to give the crude desired compound (989 mg), which was used crude. LCMS: m/z 390.64 [M+H]+

Reference： [1]Patent: US2015/94328,2015,A1 .Location in patent: Paragraph 0474; 0480; 0481
[2]Patent: WO2015/49574,2015,A1 .Location in patent: Page/Page column 56; 57

38
[ 201230-82-2 ]
tert-butyl 5-chloro-3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate [ No CAS ]
[ 13374-30-6 ]
tert-butyl 5-chloro-3-(((1S,2S)-2-hydroxycyclohexyl)carbamoyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With palladium diacetate; triethylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 80℃; for 2h;	tert-Butyl 5-chloro-3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (Intermediate 51), (600 mg), <strong>[13374-30-6](1S,2S)-2-aminocyclohexanol hydrochloride</strong> (360 mg), palladium (II) acetate (10.7 mg), XantPhos (55 mg), toluene (14.4 mL) and TEA (0.72 mL) were placed in a 25 mL microwave tube with a balloon of CO. The reaction mixture was purged with CO then heated to 80 C. for 2 h (CO was bubbled through reaction mixture when it first reached 80 C.). The reaction mixture was cooled and poured onto EtOAc and the remaining solid in the reaction flask was added to the EtOAc organic phases by dissolving in water and the organic phases washed with water (2*) then brine and the combined organic extracts dried (MgSO4), filtered and evaporated under vacuum. The crude desired compound was taken on as such. LCMS: m/z 394.58 [M+H]+.
	With palladium diacetate; triethylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 80℃; for 2h;	tert-Butyl 5-chloro-3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (Intermediate 51), (600 mg), <strong>[13374-30-6](1S,2S)-2-aminocyclohexanol hydrochloride</strong> (360 mg), palladium (II) acetate (10.7 mg), XantPhos (55 mg), toluene (14.4 mL) and TEA (0.72 mL) were placed in a 25 mL microwave tube with a balloon of CO. The reaction mixture was purged with CO then heated to 80 C. for 2 h (CO was bubbled through reaction mixture when it first reached 80 C.). The reaction mixture was cooled and poured onto EtOAc and the remaining solid in the reaction flask was added to the EtOAc organic phases by dissolving in water and the organic phases washed with water (2*) then brine and the combined organic extracts dried (MgSO4), filtered and evaporated under vacuum. The crude desired compound was taken on as such. LCMS: m/z 394.58 [M+H]+.

Reference： [1]Patent: US2015/94328,2015,A1 .Location in patent: Paragraph 0485; 0491-0492
[2]Patent: WO2015/49574,2015,A1 .Location in patent: Page/Page column 58; 59

39
[ 201230-82-2 ]
1-(4-(1H-pyrazol-1-yl)benzyl)-3-bromo-5-methyl-1H-pyrrolo[3,2-b]pyridine [ No CAS ]
[ 13374-30-6 ]
1-(4-(1H-pyrazol-1-yl)benzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-5-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90 mg	With palladium diacetate; triethylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 80℃;	1-(4-(1H-pyrazol-1-yl)benzyl)-3-bromo-5-methyl-1H-pyrrolo[3,2-b]pyridine (Intermediate 58) (150 mg), palladium (II) acetate (2.8 mg), XantPhos (14.2 mg), trans-<strong>[13374-30-6](1S,2S)-2-aminocyclohexanol hydrochloride</strong> (93 mg), toluene (2.6 mL) and TEA (0.17 mL) were placed in a microwave tube with a CO balloon. The microwave tube was purged with CO then heated to 80 C. overnight to give a dark reaction mixture with a solid precipitate. Palladium (II) acetate (2.8 mg) and XantPhos (14.2 mg) were added and the reaction was stirred overnight at 80 C. under CO. The solvent was transferred to a round bottom flask then the solid remaining in the microwave tube was dissolved in THF (?1 mL) with sonication and transferred to the round bottom flask and the solvents evaporated. To the resulting solid was added DMF (3 mL) and the suspension sonicated and filtered to remove the small amount of insoluble solid remaining Preparative LCMS followed by column chromatography (normal phase, 10 g silica, Biotage SNAP cartridge KP-Sil, gradient 0% to 10% EtOAc in n-hexane) gave the desired compound (90 mg). LCMS: m/z 430.65 [M+H]+. 1H NMR (400 MHz, CDCl3) ppm 1.21-1.62 (m, 4H) 1.79 (d, J=9.5 Hz, 2H) 2.07-2.24 (m, 2H) 2.72 (br. s., 3H) 3.65 (br. s., 1H) 3.79-3.94 (m, 1H) 5.33-5.45 (m, 2H) 6.48 (t, J=2.1 Hz, 1H) 7.07 (d, J=7.8 Hz, 1H) 7.18-7.33 (m, 2H) 7.65-7.77 (m, 2H) 7.90 (d, J=2.1 Hz, 1H) 9.32 (br. s., 1H)
90 mg	With palladium diacetate; triethylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 80℃;	1-(4-(1H-pyrazol-1-yl)benzyl)-3-bromo-5-methyl-1H-pyrrolo[3,2-b]pyridine (Intermediate 58) (150 mg), palladium (II) acetate (2.8 mg), XantPhos (14.2 mg), trans-<strong>[13374-30-6](1S,2S)-2-aminocyclohexanol hydrochloride</strong> (93 mg), toluene (2.6 mL) and TEA (0.17 mL) were placed in a microwave tube with a CO balloon. The microwave tube was purged with CO then heated to 80 C. overnight to give a dark reaction mixture with a solid precipitate. Palladium (II) acetate (2.8 mg) and XantPhos (14.2 mg) were added and the reaction was stirred overnight at 80 C. under CO. The solvent was transferred to a round bottom flask then the solid remaining in the microwave tube was dissolved in THF (?1 mL) with sonication and transferred to the round bottom flask and the solvents evaporated. To the resulting solid was added DMF (3 mL) and the suspension sonicated and filtered to remove the small amount of insoluble solid remaining Preparative LCMS followed by column chromatography (normal phase, 10 g silica, Biotage SNAP cartridge KP-Sil, gradient 0% to 10% EtOAc in n-hexane) gave the desired compound (90 mg). LCMS: m/z 430.65 [M+H]+. 1H NMR (400 MHz, CDCl3) ppm 1.21-1.62 (m, 4H) 1.79 (d, J=9.5 Hz, 2H) 2.07-2.24 (m, 2H) 2.72 (br. s., 3H) 3.65 (br. s., 1H) 3.79-3.94 (m, 1H) 5.33-5.45 (m, 2H) 6.48 (t, J=2.1 Hz, 1H) 7.07 (d, J=7.8 Hz, 1H) 7.18-7.33 (m, 2H) 7.65-7.77 (m, 2H) 7.90 (d, J=2.1 Hz, 1H) 9.32 (br. s., 1H)

Reference： [1]Patent: US2015/94328,2015,A1 .Location in patent: Paragraph 0696-0698
[2]Patent: WO2015/49574,2015,A1 .Location in patent: Page/Page column 87

40
[ 201230-82-2 ]
tert-butyl 5-cyano-3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate [ No CAS ]
[ 13374-30-6 ]
tert-butyl 5-cyano-3-(((1S,2S)-2-hydroxycyclohexyl)carbamoyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With palladium diacetate; triethylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 80℃;	tert-Butyl 5-cyano-3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (Intermediate 61), (490 mg), palladium (II) acetate (8.9 mg), XantPhos (46.1 mg), <strong>[13374-30-6](1S,2S)-2-aminocyclohexanol hydrochloride</strong> (302 mg), toluene (12.0 mL) and TEA (0.56 mL) were placed in a microwave tube with a CO balloon. The microwave tube was purged with CO then heated to 80 C. overnight. The reaction mixture was diluted with EtOAc and the remaining solid in the reaction flask was dissolved/suspended in a small amount of THF (?2 mL) by sonication then added to the EtOAc organic phases then the combined organic phases washed with water (2*) then brine, dried (MgSO4), filtered and evaporated under vacuum to give the crude product, which was used as such for Boc removal. LCMS: m/z 385.58 [M+H]+ and m/z 285.52 [M+H-Boc]+.
	With palladium diacetate; triethylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 80℃;	tert-Butyl 5-cyano-3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (Intermediate 61), (490 mg), palladium (II) acetate (8.9 mg), XantPhos (46.1 mg), <strong>[13374-30-6](1S,2S)-2-aminocyclohexanol hydrochloride</strong> (302 mg), toluene (12.0 mL) and TEA (0.56 mL) were placed in a microwave tube with a CO balloon. The microwave tube was purged with CO then heated to 80 C. overnight. The reaction mixture was diluted with EtOAc and the remaining solid in the reaction flask was dissolved/suspended in a small amount of THF (?2 mL) by sonication then added to the EtOAc organic phases then the combined organic phases washed with water (2*) then brine, dried (MgSO4), filtered and evaporated under vacuum to give the crude product, which was used as such for Boc removal. LCMS: m/z 385.58 [M+H]+ and m/z 285.52 [M+H-Boc]+.

Reference： [1]Patent: US2015/94328,2015,A1 .Location in patent: Paragraph 0511; 0519; 0520
[2]Patent: WO2015/49574,2015,A1 .Location in patent: Page/Page column 61; 62; 63

41
[ 201230-82-2 ]
[ 1316228-21-3 ]
[ 13374-30-6 ]
tert-butyl 3-(((1S,2S)-2-hydroxycyclohexyl)carbamoyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With palladium diacetate; triethylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 80℃;	tert-Butyl 3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (Intermediate 2), (8 g), <strong>[13374-30-6](1S,2S)-2-aminocyclohexanol hydrochloride</strong> (Purchased from Greenchempharm Inc.), (5.29 g), palladium (II) acetate (0.157 g), XantPhos (0.807 g), toluene (210 mL) and TEA (9.72 mL) were placed in a 500 mL three necked flask with a CO balloon and condenser attached. The reaction mixture was purged with CO then heated to 80 C. over a weekend. The reaction was cooled to rt and poured onto EtOAc, the remaining solid in the reaction flask was sonicated with a small amount of THF and the slurry added to the EtOAc organic phases. The combined organic phases were washed with water (2) then brine and the combined aqueous phases extracted with EtOAc (1). The combined organic extracts were dried (MgSO4), filtered and evaporated under vacuum to give the desired compound (8.72 g), which was taken on crude. LCMS: m/z 360.60 [M+H]+.
	With palladium diacetate; triethylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 80℃;	tert-Butyl 3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (Intermediate 2), (8 g), <strong>[13374-30-6](1S,2S)-2-aminocyclohexanol hydrochloride</strong> (Purchased from Greenchempharm Inc.), (5.29 g), palladium (II) acetate (0.157 g), XantPhos (0.807 g), toluene (210 mL) and TEA (9.72 mL) were placed in a 500 mL three necked flask with a CO balloon and condenser attached. The reaction mixture was purged with CO then heated to 80 C. over a weekend. The reaction was cooled to rt and poured onto EtOAc, the remaining solid in the reaction flask was sonicated with a small amount of THF and the slurry added to the EtOAc organic phases. The combined organic phases were washed with water (2) then brine and the combined aqueous phases extracted with EtOAc (1). The combined organic extracts were dried (MgSO4), filtered and evaporated under vacuum to give the desired compound (8.72 g), which was taken on crude. LCMS: m/z 360.60 [M+H]+.

Reference： [1]Patent: US2015/94328,2015,A1 .Location in patent: Paragraph 0349; 0356; 0357
[2]Patent: WO2015/49574,2015,A1 .Location in patent: Page/Page column 38; 39

42
[ 201230-82-2 ]
3-iodo-1-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-1H-pyrrolo[3,2-b]pyridine [ No CAS ]
[ 13374-30-6 ]
N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55 mg	With palladium diacetate; sodium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 80℃;	A mixture of 3-iodo-1-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-1H-pyrrolo[3,2-b]pyridine (made by alkylation of Intermediate 1, using a method analogous to that described in Intermediate 18), (200 mg), palladium (II) acetate (3 mg), XantPhos (7 mg), <strong>[13374-30-6](1S,2S)-2-aminocyclohexanol hydrochloride</strong> (226 mg), sodium carbonate (200 mg) and toluene (5 mL) were purged with CO then heated to 80 C. overnight. The reaction mixture was filtered and the filtrate was reduced in vacuo. The residue was purified by column chromatography to give the desired compound (55 mg). LCMS: m/z 430.30 [M+H]+. 1H NMR (400 MHz, DMSO-d6): ppm 1.10-1.39 (m, 4H) 1.55-1.70 (m, 2H) 1.81-2.05 (m, 2H) 3.35-3.45 (m, 1H) 3.68-3.78 (m, 1H) 3.84 (s, 3H) 4.81 (d, J=5.2H, 1H) 5.50 (s, 2H) 7.24-7.34 (m, 3H) 7.51 (d, J=8.0 Hz, 2H) 7.81 (s, 1H) 8.06-8.14 (m, 2H) 8.41 (s, 1H) 8.49 (dd, J=4.8, 1.2 Hz, 1H) 8.75 (d, J=7.6 Hz, 1H)
55 mg	With palladium diacetate; sodium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 80℃;	A mixture of 3-iodo-1-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-1H-pyrrolo[3,2-b]pyridine (made by alkylation of Intermediate 1, using a method analogous to that described in Intermediate 18), (200 mg), palladium (II) acetate (3 mg), XantPhos (7 mg), <strong>[13374-30-6](1S,2S)-2-aminocyclohexanol hydrochloride</strong> (226 mg), sodium carbonate (200 mg) and toluene (5 mL) were purged with CO then heated to 80 C. overnight. The reaction mixture was filtered and the filtrate was reduced in vacuo. The residue was purified by column chromatography to give the desired compound (55 mg). LCMS: m/z 430.30 [M+H]+. 1H NMR (400 MHz, DMSO-d6): ppm 1.10-1.39 (m, 4H) 1.55-1.70 (m, 2H) 1.81-2.05 (m, 2H) 3.35-3.45 (m, 1H) 3.68-3.78 (m, 1H) 3.84 (s, 3H) 4.81 (d, J=5.2H, 1H) 5.50 (s, 2H) 7.24-7.34 (m, 3H) 7.51 (d, J=8.0 Hz, 2H) 7.81 (s, 1H) 8.06-8.14 (m, 2H) 8.41 (s, 1H) 8.49 (dd, J=4.8, 1.2 Hz, 1H) 8.75 (d, J=7.6 Hz, 1H)

Reference： [1]Patent: US2015/94328,2015,A1 .Location in patent: Paragraph 0749-0751
[2]Patent: WO2015/49574,2015,A1 .Location in patent: Page/Page column 94; 95

43
[ 201230-82-2 ]
tert-butyl 3-iodo-7-methyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate [ No CAS ]
[ 13374-30-6 ]
tert-butyl 3-(((1S,2S)-2-hydroxycyclohexyl)carbamoyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.147 g	With palladium diacetate; triethylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 80℃;Microwave irradiation;	1S,2S)-2-Aminocyclohexanol hydrochloride (1.096 g), XantPhos (251 mg), tert-butyl 3-iodo-7-methyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (Intermediate 11), (2.588 g), palladium (II) acetate (49 mg) toluene (46.2 mL) and TEA (3.02 mL) were placed in a sealed microwave vial with a CO balloon attached. The microwave tube was purged with CO then heated to 80 C. overnight at which point LC-MS indicated completion. The reaction was then cooled to rt and filtered through celite, washing with EtOAc. The residue at the bottom of the flask was then sonicated in EtOAc and filtered through the same celite pad. The filtrate was reduced in vacuo. The residue was dissolved in MeOH (5 mL) and loaded onto an SCX-2 cartridge, washing with 5 CV MeOH, then eluting with 5 CV 2M NH3/MeOH. The NH3-containing fractions were combined and reduced in vacuo. The residue was purified by column chromatography (normal phase, 25 g, Biotage SNAP cartridge KP-Sil, 25 mL per min, gradient 0% to 100% EtOAc in hexane followed by 0% to 100% EtOAc in hexane). To yield the desired product (2.147 g). LCMS: m/z 374.62 [M+H]+. 1H NMR (400 MHz, CDCl3) ppm 1.24-1.57 (m, 4H) 1.67 (s, 9H) 1.79 (d, J=10.2 Hz, 2H) 2.14 (d, J=11.4 Hz, 2H) 2.76 (s, 3H) 3.60 (d, J=4.3 Hz, 1H) 3.89 (br. S., 1H) 7.13 (d, J=4.8 Hz, 1H) 8.40 (d, J=5.0 Hz, 1H) 8.57 (br. s., 1H) 9.43 (d, J=6.2 Hz, 1H)
2.147 g	With palladium diacetate; triethylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 80℃;Microwave irradiation;	1S,2S)-2-Aminocyclohexanol hydrochloride (1.096 g), XantPhos (251 mg), tert-butyl 3-iodo-7-methyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (Intermediate 11), (2.588 g), palladium (II) acetate (49 mg) toluene (46.2 mL) and TEA (3.02 mL) were placed in a sealed microwave vial with a CO balloon attached. The microwave tube was purged with CO then heated to 80 C. overnight at which point LC-MS indicated completion. The reaction was then cooled to rt and filtered through celite, washing with EtOAc. The residue at the bottom of the flask was then sonicated in EtOAc and filtered through the same celite pad. The filtrate was reduced in vacuo. The residue was dissolved in MeOH (5 mL) and loaded onto an SCX-2 cartridge, washing with 5 CV MeOH, then eluting with 5 CV 2M NH3/MeOH. The NH3-containing fractions were combined and reduced in vacuo. The residue was purified by column chromatography (normal phase, 25 g, Biotage SNAP cartridge KP-Sil, 25 mL per min, gradient 0% to 100% EtOAc in hexane followed by 0% to 100% EtOAc in hexane). To yield the desired product (2.147 g). LCMS: m/z 374.62 [M+H]+. 1H NMR (400 MHz, CDCl3) ppm 1.24-1.57 (m, 4H) 1.67 (s, 9H) 1.79 (d, J=10.2 Hz, 2H) 2.14 (d, J=11.4 Hz, 2H) 2.76 (s, 3H) 3.60 (d, J=4.3 Hz, 1H) 3.89 (br. S., 1H) 7.13 (d, J=4.8 Hz, 1H) 8.40 (d, J=5.0 Hz, 1H) 8.57 (br. s., 1H) 9.43 (d, J=6.2 Hz, 1H)

Reference： [1]Patent: US2015/94328,2015,A1 .Location in patent: Paragraph 0363; 0380-0382
[2]Patent: WO2015/49574,2015,A1 .Location in patent: Page/Page column 40; 42; 43

44
[ 201230-82-2 ]
tert-butyl 7-chloro-3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate [ No CAS ]
[ 13374-30-6 ]
tert-butyl 7-chloro-3-(((1S,2S)-2-hydroxycyclohexyl)carbamoyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With palladium diacetate; triethylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 80℃;	tert-Butyl 7-chloro-3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (Intermediate 15), (6.04 g), Pd(OAc)2 (107 mg), <strong>[13374-30-6](1S,2S)-2-aminocyclohexanol hydrochloride</strong> (3.63 g), XantPhos (554 mg), toluene (144 mL) and TEA (6.67 mL) was added to a two-neck round-bottomed flask fitted with a reflux condenser. This was purged with CO and stirred at 80 C. overnight under a CO balloon. The reaction mixture was allowed to cool to rt and then diluted with EtOAc and transferred to a separatory funnel. The remaining solid in the microwave tube was dissolved in THF by sonication and added to the EtOAc layer. The organic layer was washed with water (2*) and brine. The combined aqueous layers were extracted with EtOAc and the combined organic layers dried over MgSO4, filtered and evaporated under vacuum to give a solid (8.48 g) which was taken on crude without further purification. LCMS: m/z 394.57 [M+H]+-.
	With palladium diacetate; triethylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 80℃;	tert-Butyl 7-chloro-3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (Intermediate 15), (6.04 g), Pd(OAc)2 (107 mg), <strong>[13374-30-6](1S,2S)-2-aminocyclohexanol hydrochloride</strong> (3.63 g), XantPhos (554 mg), toluene (144 mL) and TEA (6.67 mL) was added to a two-neck round-bottomed flask fitted with a reflux condenser. This was purged with CO and stirred at 80 C. overnight under a CO balloon. The reaction mixture was allowed to cool to rt and then diluted with EtOAc and transferred to a separatory funnel. The remaining solid in the microwave tube was dissolved in THF by sonication and added to the EtOAc layer. The organic layer was washed with water (2*) and brine. The combined aqueous layers were extracted with EtOAc and the combined organic layers dried over MgSO4, filtered and evaporated under vacuum to give a solid (8.48 g) which was taken on crude without further purification. LCMS: m/z 394.57 [M+H]+-.

Reference： [1]Patent: US2015/94328,2015,A1 .Location in patent: Paragraph 0386; 0393-0394
[2]Patent: WO2015/49574,2015,A1 .Location in patent: Page/Page column 43; 44

45
4-(4-(1H-pyrazol-1-yl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic acid [ No CAS ]
[ 13374-30-6 ]
4-(4-(1H-pyrazol-1-yl)benzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A vial was charged with 4-(4-( lH-pyrazol- 1 -yl)benzyl)-3 ,4-dihydro-2H- benzo[£][l,4]oxazine-2-carboxylic acid (intermediate A3, 50 mg, 0.15 mmol), HATU (1 14 mg, 0.3 mmol), DIPEA (78 mu^, 0.5 mmol), and DMF (1 mL). The reaction mixture was stirred for 5 min at room temperature then (lS,25)-£raws-2-aminocyclohexanol hydrochloride (23 mg, 0.2 mmol) was added. After 15 min, the reaction mixture was purified by reverse- phase HPLC (basic) to provide the title compound, example B 1 , as a mixture of diastereomers. LC-MS, >98% (215, 254 nm), rt = 1.082, m/z = 432.9 [M+H].

Reference： [1]Patent: WO2015/80904,2015,A1 .Location in patent: Paragraph 00532

46
4-(4-(1H-pyrazol-1-yl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic acid [ No CAS ]
[ 13374-30-6 ]
(2R)-4-(4-(1H-pyrazol-1-yl)benzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide [ No CAS ]
(2S)-4-(4-(1H-pyrazol-1-yl)benzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		The reaction described above for Example A was repeated on tenfold scale (1.5 mmol). Briefly, a vial was charged with 4-(4-(lH-pyrazol-l-yl)benzyl)-3,4-dihydro-2H- benzo[£][l,4]oxazine-2-carboxylic acid (intermediate A3, 500 mg, 01.5 mmol), HATU (1140 mg, 3.0 mmol), DIPEA (780 /L, 5.0 mmol), and DMF (10 mL). The reaction mixture was stirred for 5 min at room temperature then (lS,25)-£raws-2-aminocyclohexanol hydrochloride (230 mg, 2.0 mmol) was added. After 15 min, the reaction mixture was purified directly by reverse-phase HPLC (basic) using a custom gradient to afford separated individual diastereomers (first and second eluting, peak A and B) in >98% purity by analytical HPLC, SFC, and XH NMR. NMR data for two diastereomers, diastereomer A (first eluting RP-HPLC, compound B29) and diastereomer B (second eluting RP-HPLC, compound B41), is given below. [00538] Diastereomer A: NMR (400 MHz, DMSO-i/6) delta 7.78 (s, 1H), 7.76 (s, 1H), 7.71 (d, J= 1.5, 1H), 7.59 (d, J = 8.0, 1H), 7.40 (d, J = 8.5 Hz, 2H), 6.85 (dd, J = 1.3, 7.9 Hz, 1H), 6.71 (m, 2H), 6.58 (m, 2H), 6.51 (t, J = 2.1, 1H), 4.64 (dd, J= 2.7, 7.3 Hz, 1H), 4.62 (d, J= 5.2 Hz, 1H), 4.51, 4.47 (ABq, 2H, JAB = 16.2 Hz), 3.54 (dd, J = 2.8, 12 Hz, 1H), 3.45 (m, 1H), 3.33 (m, 2H), 1.84-1.71 (m, 2H), 1.60 (m, 1H), 1.53 (m, 1H), 1.16 (m, 4H); LC-MS, >98% (215, 254 nm), rt = 1.057, m/z = 432.9 [M+H]. [00539] Diastereomer B: XH NMR (400 MHz, DMSO-i) delta 8.44 (d, J= 2.4 Hz, 1H), 7.78 (s, 1H), 7.76 (s, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.41 (d, J= 8.5 Hz, 2H), 6.85 (br d, J= 8.4 Hz, 1H), 6.72 (m, 2H), 6.59 (dt, J= 2.3, 6.4 Hz, 1H), 6.51 (d, J= 2.1 Hz, 1H), 4.62 (dd, J= 2.6, 7.8 Hz, 1H), 4.54 (d, J = 5.2 Hz, 1H), 4.54, 4.45 (ABq, 2H, JAB = 16.2 Hz), 3.54 (dd, J= 2.8, 12 Hz, 1H), 3.45 (m, 1H), 3.33 (m, 2H), 1.79 (m, 2H), 1.60 (m, 1H), 1.55 (m, 1H), 1.17 (m, 4H); LC-MS, >98% (215, 254 nm), rt = 1.061, m/z = 432.9 [M+H].

Reference： [1]Patent: WO2015/80904,2015,A1 .Location in patent: Paragraph 00537-00539

47
4-(4-bromo-2,6-difluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic acid [ No CAS ]
[ 13374-30-6 ]
4-(4-bromo-2,6-difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%		A vial was charged with 4-(4-bromo-2,6-difluorobenzyl)-3,4-dihydro-2H- benzo[£][l,4]oxazine-2-carboxylic acid (intermediate A4, 50 mg, 0.13 mmol), HATU (49 mg, 0.13 mmol), DIPEA (30 //L, 0.2 mmol), and DMF (1 mL). The reaction mixture was stirred for 5 min at room temperature then (lS,25)-£raws-2-aminocyclohexanol hydrochloride (14 mg, 0.15 mmol) was added. After 15 min, the reaction mixture was purified by reverse- phase HPLC (basic) to provide the title compound, example B4, (45 mg 73%). LC-MS, >98% (215, 254 nm), rt = 1.216, m/z = 481.1 [M+H].

Reference： [1]Patent: WO2015/80904,2015,A1 .Location in patent: Paragraph 00534

48
[ 18791-02-1 ]
[ 13374-30-6 ]
2-bromo-N-((1S,2S)-2-hydroxycyclohexyl)acrylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In water; acetone; for 0.5h;	A round-bottom flask was charged with 2,3-dibromopropanoyl chloride (1.15 mL, 10 mmol), (l S,2S)-2-aminocyclohexanol hydrochloride (1.5 g, 10 mmol), and acetone (20 mL). To this mixture was added sodium bicarbonate (2.5 g, 30 mmol) and water (1 mL). After 30 min, the volatiles were removed. The crude product was partitioned between dichloromethane (10 mL) and water (10 mL). The product was extracted with dichloromethane (2 x 5 mL) and the combined organics were concentrated to afford the product which was used directly in the next step: NMR (500 MHz, CDC13) delta 7.04 (d, J= 1.5 Hz, 1H), 6.10 (d, J= 1.5 Hz, 1H), 3.75-3.67 (m, 1H), 3.47 (ddd, J= 4.3, 9.9, 10.0 Hz, 1H), 3.13-2.03 (m, 2H), 1.81-1.74 (m, 1H), 1.45-1.27 (m, 4H); 13C NMR (125 MHz, CDC13) delta 174.3, 128.3, 99.9, 74.7, 56.6, 34.3, 31.2, 24.4, 23.9; LC-MS >98% (215, 254 nm), rt = 0.614, m/z = 247.9 [M+H].

Reference： [1]Patent: WO2015/80904,2015,A1 .Location in patent: Paragraph 00530

49
4-bromo-1-fluoro-2-naphthoic acid [ No CAS ]
[ 13374-30-6 ]
4-bromo-1-fluoro-N-((1S,2S)-2-hydroxycyclohexyl)-2-naphthamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In dichloromethane; at 20℃; for 21h;	Step 1: 4-Bromo- 1 -fluoro-N- ((iS ,25)-2-hydroxycyclohexyl)-2-naphthamideTo a suspension of 4-bromo-1-fluoro-2-naphthoic acid (example A.1, step 1; 500 mg, 1.86 mmol) in dichloromethane (10 ml) were added (1S,25)-2-aminocyclohexanol hydrochloride (282 mg, 1.86 mmol), BOP (1.09 g, 2.47 mmol) and triethylamine (564 mg, 776 jil, 5.57 mmol). The solution was stirred at room remperature for 21 hours. The solvent was removed in vacuo. The crude product was purified by silica gel chromatography using a heptane/EtOAc gradient as eluent to provide the title compound (328 mg, 48%) as white solid. MS (mle):366.4 (M), 368.4(M+2)
48%	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In dichloromethane; at 20℃; for 21h;	Step 1: 4-Bromo-1-fluoro-N-((1S,2S)-2-hydroxycyclohexyl)-2-naphthamide To a suspension of 4-bromo-1-fluoro-2-naphthoic acid (example A.1, step 1; 500 mg, 1.86 mmol) in dichloromethane (10 ml) were added <strong>[13374-30-6](1S,2S)-2-aminocyclohexanol hydrochloride</strong> (282 mg, 1.86 mmol), BOP (1.09 g, 2.47 mmol) and triethylamine (564 mg, 776 mul, 5.57 mmol). The solution was stirred at room temperature for 21 hours. The solvent was removed in vacuo. The crude product was purified by silica gel chromatography using a heptane/EtOAc gradient as eluent to provide the title compound (328 mg, 48%) as white solid. MS (m/e): 366.4 (M)+, 368.4 (M+2)+

Reference： [1]Patent: WO2015/110370,2015,A1 .Location in patent: Page/Page column 28
[2]Patent: US2016/326144,2016,A1 .Location in patent: Paragraph 0122

50
4-[(6-chloro-3-pyridyl)methyl]-1-fluoro-naphthalene-2-carboxylic acid [ No CAS ]
[ 13374-30-6 ]
4-((6-chloropyridin-3-yl)methyl)-1-fluoro-N-((1S,2S)-2-hydroxycyclohexyl)-2-naphthamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In dichloromethane; at 20℃; for 22h;	General procedure: Example 14-((6-Chloropyridin-3-yl)methyl)-1-fluoro-N-((1 SR,2SR)-2-hydroxycyclohexyl)-2-naphthamide To a suspension of 4- ((6-chloropyridin-3-yl)methyl)- 1 -fluoro-2-naphthoic acid (example A. 1; 147.2 mg, 466 imol) in dichloromethane (3 ml) were added <strong>[13374-30-6]trans-2-aminocyclohexanol hydrochloride</strong> (89.0 mg, 581 j.imol), BOP (282.1 mg, 625 imol) and triethylamine (189 mg, 260 jil, 1.86 mmol). The solution was stuffed at room temperature for 22 h, then diluted with dichloromethane and washed twice with water. The aqueous layer was back-extracted once with dichloromethane. The combined organic layers were dried over Na2504, filtered and concentrated. The crude product was purified by silica gel column chromatography using a heptane/EtOAc gradient as eluent to provide the title compound (165 mg, 86%) as white solid.

Reference： [1]Patent: WO2015/110370,2015,A1 .Location in patent: Page/Page column 20; 21

51
5-chloro-6-methyl-4-[4-(1H-pyrazol-1-yl)benzyl]pyridine-2-carboxylic acid [ No CAS ]
[ 13374-30-6 ]
5-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methyl-4-[4-(1H-pyrazol-1-yl)benzyl]pyridine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
7.0 mg	With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 20h;	A mixture of C36 (25 mg, 73 pmol) and sodium hydroxide (12 mg, 0.30 mmol) in methanol (3 mL) and water (1 mL) was stirred at 70 C for 3 hours, whereupon the pH was adjusted to approximately 7 via addition of 1 M hydrochloric acid. The resulting mixture was concentrated to dryness to provide the crude carboxylic acid as an off15 white solid (25 mg). This material was combined with (1S,2S)-2-aminocyclohexanol,hydrochloride salt (23 mg, 0.15 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N?,N- tetramethyluronium hexafluorophosphate (43.3 mg, 0.114 mmol) and triethylamine (15 mg, 0.15 mmol) in N,N-dimethylformamide (12 mL), and the reaction mixture was stirred at room temperature for 20 hours. It was then concentrated to dryness, dilutedwith water (20 mL), and extracted with ethyl acetate (4 x 30 mL). The combined organic layers were dried, filtered, and concentrated under reduced pressure. Preparative thin layer chromatography (Eluent: 1:2 petroleum ether I ethyl acetate) afforded the product as an off-white solid. Yield: 7.0 mg, 16 pmol, 22%. LCMS m/z447.0 [M+Na]. 1H NMR (400 MHz, CDCI3) oe 7.99 (br d, J=6 Hz, 1H), 7.92 (5, 1H), 7.87-7.92 (m, 1H), 7.71 (5,1 H), 7.63 (d, J=8.3 Hz, 2H), 7.25-7.32 (m, 2H, assumed; partially obscured by solvent peak), 6.44-6.48 (m, 1H), 4.17 (5, 2H), 3.74-3.86 (m, 1H), 3.45-3.55 (m, 1H), 3.31-3.39 (m, 1H), 2.67 (5, 3H), 2.00-2.17 (m, 2H), 1.72-1.84 (m, 2H), 1.22-1.48 (m, 4H).

Reference： [1]Patent: WO2016/9297,2016,A1 .Location in patent: Page/Page column 115

52
4-(4-(4-(((3R,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methoxy)-3-methylphenyl)piperazin-1-yl)benzoic acid [ No CAS ]
[ 13374-30-6 ]
4-(4-(4-(((3R,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methoxy)-3-methylphenyl)piperazin-1-yl)-N-((1S,2S)-2-hydroxycyclohexyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In pyridine; at 20℃; for 16h;	To a mixture of intermediate 6 (100 mg, 0.17 mmol), EDCI (65 mg, 0.34 mmol) and DMAP (2.07 mg, 0.017 mmol) in pyridine (1.0 mL) was added (1 S,2S)-2-aminocyclohexanol hydrochloride (51.4 mg, 0.34 mmol). The reaction mixture was stirred at RT for 16 h and was then diluted with DCM (8.0 mL) and washed with 1 M hydrochloric acid (2.0 mL). The mixture was passed through a phase separator and the organics were evaporated in vacuo. The crude product so obtained was purified by flash column chromatography (S1O2, 12 g, 0-5% MeOH in EtOAc, gradient elution) to afford the title compound, (la) as a white solid (75 mg, 64%).

Reference： [1]Patent: WO2016/185225,2016,A1 .Location in patent: Page/Page column 16; 17

53
4-(4-(1H-pyrazol-1-yl)benzyl)-5-cyanopicolinic acid [ No CAS ]
[ 13374-30-6 ]
5-cyano-N-((1S,2S)-2-hydroxycyclohexyl)-4-(4-(1H-pyrazol-1-yl)benzyl)pyridine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30.4 mg	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃;	To a mixture of 4-(4-(1H-pyrazol-1-yl)benzyl)-5-cyanopicolinic acid obtained in the previous step, <strong>[13374-30-6](1S,2S)-2-aminocyclohexanol hydrochloride</strong> (23.9 mg), WSC (33.1 mg), HOBt monohydrate (26.7 mg) in DMF (2.1 mL) was added triethylamine (53.2 mg), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water, and extracted twice with ethyl acetate. The combined organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (30.4 mg). 1H NMR (300 MHz, CDCl3) delta1.29-1.49 (4H, m), 1.72-1.84 (2H, m), 2.06-2.15 (2H, m), 3.02 (1H, brs), 3.48 (1H, brs), 3.74-3.89 (1H, m), 4.27 (2H, s), 6.42-6.51 (1H, m), 7.30-7.39 (2H, m), 7.61-7.76 (3H, m), 7.90 (1H, d, J = 2.4 Hz), 7.97 (1H, d, J = 7.5 Hz), 8.17 (1H, s), 8.75 (1H, s).

Reference： [1]Patent: EP3156397,2017,A1 .Location in patent: Paragraph 329

54
5,6-dimethyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid [ No CAS ]
[ 13374-30-6 ]
4-bromo-N-((1S,2S)-2-hydroxycyclohexyl)-5,6-dimethylpicolinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.8 g		To a solution of 5,6-dimethyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid (2.01 g) in DMF (20 mL) was added hosphorus tribromide (6.50 g) at 0C, and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added DIPEA (6.50 g) at 0C to adjust the reaction solution to pH=7-8. To the reaction mixture were added <strong>[13374-30-6](1S,2S)-2-aminocyclohexanol hydrochloride</strong> (2.92 g), HOBt (1.62 g), WSC (4.61 g) and DIPEA (4.64 g) and the mixture was stirred under a nitrogen atmosphere at room temperature for 16 hr. Three batches of the above reaction were performed and mixed at this time point. The reaction mixture was poured into water, and the mixture was extracted 8 times with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified twice by silica gel column chromatography (ethyl acetate/dichloromethane) to give the title compound (1.80 g). 1H NMR (400 MHz, CDCl3) delta1.25-1.45 (4H, m), 1.75-1.86 (2H, m), 2.05-2.19 (2H, m), 2.43 (3H, s), 2.58 (3H, s), 3.41-3.51 (1H, m), 3.51-3.63 (1H, m), 3.78-3.89 (1H, m), 7.98 (1H, d, J = 7.6 Hz), 8.19 (1H, s).

Reference： [1]Patent: EP3156397,2017,A1 .Location in patent: Paragraph 0340

55
5-chloro-4-[4-(1H-pyrazol-1-yl)benzyl]pyridine-2-carboxylic acid [ No CAS ]
[ 13374-30-6 ]
5-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-4-(4-(1H-pyrazol-1-yl)benzyl)pyridine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
420 mg	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃;	To a mixture of 4-(4-(1H-pyrazol-1-yl)benzyl)-5-chloropicolinic acid obtained in the previous step, <strong>[13374-30-6](1S,2S)-2-aminocyclohexanol hydrochloride</strong> (278 mg), WSC (381 mg), and HOBt monohydrate (234 mg) in DMF (15 mL) was added triethylamine (464 mg), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water, and extracted with ethyl acetate. The obtained organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (420 mg). 1H NMR (300 MHz, CDCl3) delta1.18-1.49 (4H, m), 1.68-1.87 (2H, m), 1.96-2.21 (2H, m), 3.24 (1H, d, J = 4.3 Hz), 3.38-3.58 (1H, m), 3.66-3.89 (1H, m), 4.13 (2H, s), 6.45 (1H, dd, J = 2.1, 1.8 Hz), 7.26-7.30 (2H, m), 7.54-7.66 (2H, m), 7.71 (1H, d, J = 1.4 Hz), 7.89 (1H, dd, J = 2.5, 0.5 Hz), 7.92 (1H, brs), 8.05 (1H, s), 8.48 (1H, s).

Reference： [1]Patent: EP3156397,2017,A1 .Location in patent: Paragraph 0283

56
[ 934-60-1 ]
[ 13374-30-6 ]
N-((1S,2S)-2-hydroxycyclohexyl)-6-methylpicolinamide [ No CAS ]

Reference： [1]Organic Letters,2017,vol. 19,p. 74 - 77

57
6-(4-chlorophenyl)-2-(3-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid [ No CAS ]
[ 13374-30-6 ]
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46.9 mg	With dmap; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 14h;	A solution of 75 mg intermediate 17, 66 mg (1 S,2S)-(+)-2-amino-cyclohexanol hydrochlorid (1 :1 ), 165.5 mg HATU, 0.1 1 mL ethyldiisopropylamine and 1 .3 mg 4-dimethylaminopyridine in 2 mL of DMF was stirred at room temperature for 14 hours. Then the reaction mixture was filtered and subjected to RP-HPLC (Instrument: Waters Autopurification MS SingleQuad; Column: Waters XBrigde C18 5mu 100x30mm; eluent A: water + 0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-5.5 min 5-100% B; flow 70 mL/min; temperature: 25 C; DAD scan: 210-400 nm) to yield 46.9 mg 6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(1 S,2S)-2- methylcyclohexyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide. 1H NMR (400 MHz, DMSO-de) delta ppm = 1.15 - 1 .36 (m, 4 H), 1.48 - 1.71 (m, 2 H), 1.85 (m, 1 H), 1 .97 - 2.10 (m, 1 H), 3.55 - 3.72 (m, 1 H), 4.83 (d, 1 H), 7.31 - 7.42 (m, 1 H), 7.50 - 7.74 (m, 5 H), 7.99 (d, 2 H), 8.64 (s, 1 H), 9.42 (d, 1 H).

Reference： [1]Patent: WO2017/202816,2017,A1 .Location in patent: Page/Page column 161; 162

58
1-methyl-4-(2-fluoropyridin-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid [ No CAS ]
[ 13374-30-6 ]
N-[(1S,2S)-2-hydroxycyclohexyl]-4-(2-fluoropyridin-4-ylmethyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.25 g		To a solution of l-methyl-4-(2-fluoropyridin-4-ylmethyl)-lH-pyrrolo[2,3- b]pyridine-6-carboxylic acid (0.23 g, 0.00081 mole) in DMF (10 mL) at 25 C under N2, was added HATU (0.372 g, 0.00009 mole) stirred for 10 minutes, followed by addition of (lS,2S)-2-amino cyclohexanol hydrochloride (0.136 g, 0.00089 mole) and DIPEA (0.6 mL, 0.0032 mole) in 10 minutes of time interval and stirred for 15 hours. Reaction mixture was quenched in to ice water (50 mL) and extracted with ethyl acetate (30 mL x 3). Organic layer was washed with brine solution (50 mL) and dried over Na2S04. Organic layer was concentrated under vacuum to obtain the crude compound which was further purified by flash chromatography using ethyl acetate: n-hexane (65:35) to afford the title compound. Yield: 0.25 g; - NMR (DMSO- 6, 400 MHz ) delta ppm: 1.25 - 1.27 (m, 4H), 1.64- 1.67 (m, 2H), 1.89-1.95 (m, 2H), 3.47 - 3.48 (m, 1H), 3.60 - 3.62 (m, 1H), 3.91 (s, 3H), 4.39 (s, 2H), 4.71- 4.72 (d, J = 5.3 Hz, 1H), 6.67- 6.68 (d, J = 3.1 Hz, 1H), 7.14 (s, 1H), 7.23 - 7.24 (d, J = 4.4 Hz, 1H), 7.68 - 7.69 (d, J = 3.2 Hz, 1H), 7.72 (s, 1H), 8.11 - 8.12 (d, J = 5.0 Hz, 1H), 8.28 - 8.30 (d, J = 7.9 Hz, 1H); Mass (m/z): 383.4 (M+H)+.

Reference： [1]Patent: WO2018/42362,2018,A1 .Location in patent: Page/Page column 60-61

59
8-(2,3-difluorobenzyl)-2,3-dihydro[1,4]dioxino[2,3-b]pyridine-6-carboxylic acid [ No CAS ]
[ 13374-30-6 ]
N-[(1S,2S)-2-hydroxycyclohexyl]-8-(2,3-difluorobenzyl)-2,3-dihydro[1,4]dioxino[2,3-b]pyridine-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.007 g		To a solution of 8-(2,3-difluorobenzyl)-2,3-dihydro-[l,4]dioxino[2,3-b]pyridine- 6-carboxylic acid (0.01 g, 0.00003 mole) in DMF (5 mL) at 25 C under N2, was added HATU (0.016 g, 0.00004 mole) stirred for 10 minutes, followed by addition of (IS, 2S)- 2-amino cyclohexanol hydrochloride (0.0041 g, 0.00003 mole) and DIPEA (0.023 mL, 0.0001 mole) in 10 minutes of time interval and stirred for 15 hours. Reaction mixture was quenched in to ice water (20 mL) and extracted with ethyl acetate (20 mL x 3). Organic layer was washed with brine solution (15 mL) and dried over Na2S04. Organic layer was concentrated under vacuum to obtain the title compound. Yield: 0.007 g; lH - NMR (CDC13, 400 MHz) delta ppm: 1.25 - 1.30 (m, 4H), 1.64 - 1.67 (m, 2H), 2.00 - 2.04 (m, 2H), 2.77 - 2.80 (m, 1H), 3.42 - 3.44 (m, 1H), 4.02 (s, 2H), 4.42 - 4.43 (d, J = 2.52 Hz, 2H), 4.47 - 4.48 (d, J = 2.22 Hz, 2H), 4.40 - 4.51 (d, J = 4.38 Hz, 1H), 6.87 - 6.90 (m, 1H ), 6.91 - 7.08 (m, 2H ), 7.30 (s, 1H), 8.41 - 8.43 (d, J =8.43 Hz, 1H); Mass (m/z): 405.1 (M+H)+

Reference： [1]Patent: WO2018/42362,2018,A1 .Location in patent: Page/Page column 119-120

60
[ 13374-30-6 ]
[ 5794-88-7 ]
2-amino-5-bromo-N-((1S,2S)-2-hydroxycyclohexyl)benzamide [ No CAS ]