[ CAS No. 30766-22-4 ] {[proInfo.proName]}

Name: 30766-22-4|Methyl 5-hydroxynicotinate|98%
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Quality Control of [ 30766-22-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 30766-22-4 ]

Product Details of [ 30766-22-4 ]

CAS No. :	30766-22-4	MDL No. :	MFCD00191521
Formula :	C₇H₇NO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KJJSHOHQQHACLE-UHFFFAOYSA-N
M.W :	153.14	Pubchem ID :	354317
Synonyms :

Calculated chemistry of [ 30766-22-4 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	37.54
TPSA :	59.42 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.99 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.24
Log Po/w (XLOGP3) :	0.35
Log Po/w (WLOGP) :	0.57
Log Po/w (MLOGP) :	-0.26
Log Po/w (SILICOS-IT) :	0.71
Consensus Log Po/w :	0.52

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.28
Solubility :	8.01 mg/ml ; 0.0523 mol/l
Class :	Very soluble
Log S (Ali) :	-1.16
Solubility :	10.5 mg/ml ; 0.0688 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.51
Solubility :	4.73 mg/ml ; 0.0309 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.5

Safety of [ 30766-22-4 ]

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 [ 30766-22-4 ]

* 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 [ 30766-22-4 ]
Downstream synthetic route of [ 30766-22-4 ]

[ 30766-22-4 ] Synthesis Path-Upstream 1~9

1
[ 30766-22-4 ]
[ 455-70-9 ]

Reference： [1] Organic Letters, 2015, vol. 17, # 3, p. 544 - 547
[2] Organic Letters, 2013, vol. 15, # 21, p. 5602 - 5605

2
[ 30766-22-4 ]
[ 74-95-3 ]
[ 4591-55-3 ]

Reference： [1] CrystEngComm, 2013, vol. 15, # 36, p. 7257 - 7266

3
[ 30766-22-4 ]
[ 20826-03-3 ]

Reference： [1] Journal of Medicinal Chemistry, 2000, vol. 43, # 16, p. 3168 - 3185
[2] Patent: WO2016/34673, 2016, A1,

4
[ 67-56-1 ]
[ 27828-71-3 ]
[ 30766-22-4 ]

Yield	Reaction Conditions	Operation in experiment
85%	With sulfuric acid In methanol at 30℃; for 168 h; Inert atmosphere; Reflux	Method A. Step A. Methyl 5 -hydroxynicotinate. To a solution of 5-hydroxynicotinic acid (833 g, 5.99 mol) in methanol (6.7 L) was added H₂SO₄ (292 mL) dropwise at a rate to keep the temperature of the mixture under 30 C. After addition, the reaction mixture was stirred at reflux for 7 days. The reaction mixture was cooled to rt and concentrated under reduce pressure. Water (4 L) was added and the mixture adjusted to pH 8 with NaHC0₃ which induced precipitation of a white solid. After stirring the reaction mixture for 1 h at rt, the solid was filtered and dried under vacuum at 60 C for 3 days to afford the title compound (783 g, 85percent) as a white solid. 1H NMR (DMSO-< ₆, 400 MHz) δ 10.46 (s, 1H), 8.54 (s, 1H), 8.34-8.35 (d, J = 2.8 Hz, 1H), 7.59 (s, 1H), 3.85 (s, 3H).
82%	at 70℃; for 18 h; Sealed tube; Heating / reflux	EXAMPLE 36A. <n="93"/>[00198] To a solution of 5-hydroxynicotinic acid (200 mg, 1.438 mmol) in MeOH (2 mL) was added concentrated H₂SO₄ (0.077 mL, 1.438 mmol). The sealed reaction vessel was placed on a shaker and was heated to reflux at 70⁰C for 18 h, then was cooled to RT. The volatiles were removed in vacuo, and the residue was purified by preparative HPLC (Phenomenex Luna AXIA 5u C18 30 x l00 mm column; detection at 220 nm; flow rate = 40 mL/min; continuous gradient from 0percent B to 100percent B over 10 min + 2 min hold time at 100percent B, where A = 90: 10:0.1 H₂O:MeOH:TFA and B = 90: 10:0.1 MeOH:H₂O:TFA) to give Part A methyl ester (180 mg, 82percent yield) as a white solid.
79%	for 20 h; Reflux	General procedure: 4-Hydroxypicolinic acid 3 (348 mg, 2.5 mmol) was added to methanol (25 mL), and then concentrated sulfuric acid (0.2 mL). The mixture was refluxed for 20 h, then the solvent was evaporated under vacuum. The residue was neutralized with saturated aqueous sodium bicarbonate solution, extracted with DCM/MeOH (10/1, 5×30 mL), dried over anhydrous Na₂SO₄, concentrated under vacuum to give compound 4 (196 mg, 51percent) as a white solid. ¹H NMR (400 MHz, Methanol-d₄) δ 7.92 (d, J = 7.0 Hz, 1H), 7.14 (s, 1H), 6.63 (d, J = 7.0 Hz, 1H), 3.99 (s, 3H). MS (ESI) m/z = 154.1 ([M+H]⁺). To a solution of compound 4 (77 mg, 0.5mmol) in DMF (2 mL) was added potassium carbonate (104 mg, 0.75 mmol), then 1,4-dibromobutane (325 mg, 1.5 mmol) at 0°C. The mixture was stirred at room temperature for 3 h, and then partitioned between water (30 mL) and ethyl acetate (EA, 30 mL). The organic phase was washed with water (3×30 mL), saturated brine (30 mL), dried over anhydrous Na₂SO₄, concentrated under vacuum, purified by column chromatography using DCM : MeOH (100:1) as eluent to give 5 (95 mg, 66percent) as a light yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.51 (d, J = 5.6 Hz, 1H), 7.55 (d, J = 2.6 Hz, 1H), 7.22 (dd, J = 5.7, 2.6 Hz, 1H), 4.19 (t, J = 6.2 Hz, 2H), 3.62 (t, J = 6.5 Hz, 2H), 1.98 (p, J = 6.7 Hz, 2H), 1.92 – 1.83 (m, 2H). MS (ESI) m/z = 288.2 ([M+H]⁺). Corresponding arylpiperazine (arylpiperidine) (0.24 mmol), 5 (90 mg, 0.31 mmol), potassium carbonate (83 mg, 0.6mmol) and potassium iodide (40 mg, 0.24 mmol) were added to acetonitrile (5 mL). The reaction mixture was refluxed overnight, cooled to room temperature, partitioned between EA and water. The organic layer was dried over anhydrous Na₂SO₄, concentrated under vacuum to give 6a–6e which was used directly in the next step without further purification.

75%	at 20℃;	Synthesis of methyl 5-hydroxynicotinateO OHSOCI2 MeOHHO HO UNTo a stirred solution of 5-hydroxynicotinic acid (10 g, 71 .9 mmol) in MeOH (100 mL)was added sulfurous dichloride (1 mL) drop wise over 5mm The resulting mixturewas stirred at room temperature overnight. The resulted solution was added 100 mLof NaHCO3.The precipitate was filtrated and washed with MeOH for several cycles togive 8.5 g of A031 -2 (75percent yields), which was used for the nest step without furtherpurification.
75%	at 20℃; for 0.0833333 h;	To a stirred solution of 5-hydroxynicotinic acid (10 g, 71.9 mmol) in MeOH (100 mL) was added sulfurous dichloride (1 mL) drop wise over 5 min. The resulting mixture was stirred at room temperature overnight. The resulted solution was added 100 mL of NaHCO₃. The precipitate was filtrated and washed with MeOH for several cycles to give 8.5 g of A031-2 (75percent yields), which was used for the nest step without further purification.
75%	at 20℃;	To a stirred solution of 5-hydroxynicotinic acid (10 g, 71 .9 mmol) in MeOH (100 mL) was added sulfurous dichloride (1 mL) drop wise over 5 min. The resulting mixture was stirred at room temperature overnight. The resulted solution was added 100 mL of NaHCOs.The precipitate was filtrated and washed with MeOH for several cycles to give 8.5 g (75percent yields), which was used for the next step without further purification.
75%	at 20℃;	To a stirred solution of 5-hydroxynicotinic acid (10 g, 71.9 mmol) in MeOH (100 mL) was added sulfurous dichloride (1 mL) drop wise over 5 min. The resulting mixture was stirred at room temperature overnight. The resulted solution was added 100 mL of NaHCO₃. The precipitate was filtrated and washed with MeOH for several cycles to give 8.5 g of A031-2 (75percent yields), which was used for the nest step without further purification.
71%	at 70℃;	A mixture of 5-hydroxynicotinic acid (3 g, 21.6 mmol), cone H2SO4 (2.2 g, 21.6 mmol) in MeOH (50 mL) was heat at 70 °C overnight. The mixture was concentrated, poured into water (100 mL) and extracted with EA (100 mL X 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford methyl 5-hydro
68%	Stage #1: Reflux Stage #2: With sodium hydrogencarbonate In water	Preparation of Compound A29A mixture of compound A28 (25.0 g, 180 mmol) and concentrated H₂SO₄(10 mL) in CH₃OH (100 mL) was heated to reflux for overnight. The mixture was concentrated, the residue was washed with aqueous NaHCO₃(50 mL) and extracted with ethyl acetate (2.x.100 mL). The organic layer was dried over Na₂SO₄, filtered and concentrated to afford compound A29 (18.7 g, yield: 68percent).¹H NMR (300 MHz, DMSO-d₆): δ: 10.42 (s, 1H), 8.60 (d, J=1.6 Hz, 1H), 8.36 (d, J=2.8 Hz, 1H), 7.60-7.61 (m, 1H), 3.87 (s, 3H).
68%	Reflux	[0444] Preparation of compound A29: A mixture of compound A28 (25.0 g, 180 mmol) and concentrated H₂SO₄ (10 mL) in CH₃OH (100 mL) was heated to reflux for overnight. The mixture was concentrated, the residue was washed with aqueous NaHC0₃ (50 mL) and extracted with ethyl acetate (2 x 100 mL). The organic layer was dried over a₂S04, filtered and concentrated to afford compound A29 (18.7 g, yield: 68percent). [0445] 1H NMR (300 MHz, DMSO-i ₆): δ: 10.42 (s, 1H), 8.60 (d, J = 1.6 Hz, 1H), 8.36 (d, J = 2.8 Hz, 1H), 7.60-7.61 (m, 1H), 3.87 (s, 3H). [0446] Preparation of compound A30: BnOH (3.90 g, 36.1 mmol, 1.1 eq) and PPh₃ (17.1 g, 65.4 mmol, 2.0eq) was added to a solution of compound A29 (5.00 g, 32.7 mmol) in THF (100 mL), then DEAD (6.80 g, 39.2 mmol, 1.2eq) was added at 0°C. The mixture was stirred at room temperature for overnight. The solvent was evaporated, the residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate = 10: 1) to afford the compound A30 (5.70 g, yield: 71percent) as white solid. [0447] 1H NMR (300 MHz, CDC1₃): δ: 8.83 (d, J = 1.6 Hz, 1H), 8.54(d, J = 2.8 Hz, 1H), 7.85-7.86 (m, 1H), 7.27-7.46 (m, 5H), 5.15 (s, 2H), 3.95 (s, 3H). [0448] Preparation of compound A31: A solution of compound A30 (12.8 g, 52.9mmol) in methylamine alcohol solution in sealed tube was stirred at 70 °C for overnight. Then the mixture was cooled to room temperature and the solvent was evaporated to afford the compound A31 (12.0 g, yield: 100percent). [0449] 1H NMR (300 MHz, CDC1₃): δ: 8.50 (d, J = 1.6 Hz, 1H), 8.48(d, J = 2.8 Hz, 1H), 7.73-7.74 (m, 1H), 7.73-7.74 (m, 5H), 6.16(s, 1H), 3.15 (s, 2H), 3.04 (d, J = 4.4 Hz, 3H). A32 A33 [0450] Preparation of compound A32: The solution of compound A31 (11.0 g, 45.5 mmol) in SOCl₂ (100 mL) was heated to reflux for 4h. Then, SOCl₂ was removed under vacuum and the residue was dissolved in MeCN (200 mL). TMSN₃ (12.5 g, 90.0 mmol, 2.0eq) was added slowly and the mixture was stirred at 90°C for 3h. Then the solvent was evaporated and the residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate = 2: 3) to afford the compound A32 (9.50 g, yield: 78percent). [0451] 1H NMR (300 MHz, CDC1₃): δ: 8.59 (d, J = 2.8 Hz, 1H), 8.56(d, J = 1.6 Hz, 1H), 7.68-7.69 (m, 1H), 7.3-7.46 (m, 5H), 5.21 (s, 2H), 4.17 (s, 3H). [0452] Preparation of compound A33: To a solution of compound A32 (5.00 g, 18.7 mmol) in CH₃OH (100 mL) was added Pd(OH)₂ ( 0.50 g), The mixture was stirred at room temperature under H₂ atmosphere for 3h. The solid was filtered off and the filtrate was concentrated to get compound A33 (1.60 g, yield: 48percent). [0453] 1H NMR (300 MHz, DMSO-i ₆): δ: 10.56 (s, 1H), 8.49 (d, J = 1.6 Hz, 1H), 8.36(d, J = 2.8 Hz, 1H), 7.61-7.62 (m, 1H), 4.19(s, 3H).
65%	With thionyl chloride In methanol at 20 - 60℃;	Thionyl chloride (780 jil, 10.7 mmol) was added drop-wise to a suspension of 5- hydroxynicotinic acid (497 mg, 3.57 mmol) in MeOH (5 ml) at ambient temperature. The mixture was heated at 60 °C overnight. 0.1 M Potassium phosphate buffer (pH 7) (50 ml) was added and the mixture extracted with EtOAc. The combined organic layers were dried(Mg504). Yield: 354 mg (65percent); white solid.

Reference： [1] Patent: WO2015/164508, 2015, A1, . Location in patent: Page/Page column 52
[2] Patent: WO2008/154563, 2008, A1, . Location in patent: Page/Page column 91-92
[3] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 4, p. 606 - 611
[4] Patent: WO2014/154727, 2014, A1, . Location in patent: Page/Page column 43
[5] Patent: US2014/296239, 2014, A1, . Location in patent: Paragraph 0114; 0115
[6] Patent: WO2014/154726, 2014, A1, . Location in patent: Page/Page column 43
[7] Patent: US2014/296296, 2014, A1, . Location in patent: Paragraph 0123; 0124
[8] Patent: WO2015/103317, 2015, A1, . Location in patent: Page/Page column 78
[9] Patent: US2012/238751, 2012, A1, . Location in patent: Page/Page column 33
[10] Patent: WO2014/43272, 2014, A1, . Location in patent: Paragraph 0443; 0444; 0445
[11] Patent: WO2017/108282, 2017, A1, . Location in patent: Page/Page column 113
[12] Patent: WO2007/67511, 2007, A2, . Location in patent: Page/Page column 33
[13] Patent: EP3348269, 2018, A1, . Location in patent: Paragraph 0347; 0348

5
[ 958266-11-0 ]
[ 30766-22-4 ]

Reference： [1] European Journal of Organic Chemistry, 2007, # 26, p. 4408 - 4430

6
[ 30766-22-4 ]
[ 915107-30-1 ]

Yield	Reaction Conditions	Operation in experiment
42%	With sodium hypochlorite In water at 0℃; for 0.5 h;	Example V Preparation of [(5-methoxy-6-chloropyridin-3-yl)methyl](methyl)-oxido-λ⁴-sulfanylidenecyanamide (5) To a flask containing methyl-5-hydroxynicotinate (4.5 g, 29 mmol) was added sodium hypochlorite aqueous solution (6.15percent, 26.7 mL, 22 mmol) dropwise under ice bath cooling. After 30 min of stirring, 2 M HCl (20 mL) was added and the resulting white crystals collected by filtration to give 2.31 g of 6-chloro-5-hydroxynicotinic acid methyl ester in 42percent yield. ¹H NMR (400 MHz, CDCl₃) δ 10.32 (bs, 1H), 8.48 (d, 1H), 7.84 (d, 1H), 7.40 (s, 1H), 3.93 (s. 3H); LC-MS (ELSD): mass calcd for C₇H₆ClNO₃[M]⁺ 187. Found 187.
33%	With hypochloric acid In water at 0℃; for 1.16 h; Inert atmosphere	Methyl 6-chloro-5-hydroxynicotinate At 0° C., to a solution of methyl 5-hydroxypyridine-3-carboxylate (1.8 g, 11.75 mmol) in water (15 mL) was added HClO (651 mg, 12.4 mmol) in portions over 10 min period. The resulting solution was stirred for 1 h at 0° C., warmed to room temperature and treated with hydrochloric acid solution (2 M, 20 mL). The precipitate that formed were collected by filtration and dried in oven under vacuum to yield methyl 6-chloro-5-hydroxynicotinate as off-white solid (800 mg, 33percent).
31%	With N-chloro-succinimide In N,N-dimethyl-formamide at 80℃; for 18 h;	Step 1 . Preparation of methyl 6-chloro-5-hydroxynicotinate (C5). N-Chlorosuccinimide (95percent, 881 mg, 6.27 mmol) was added to a solution of methyl 5- hydroxynicotinate (800 mg, 5.22 mmol) in W.W-dimethylformamide (5.2 mL). The mixture was stirred at 80 °C for 18 hours, then concentrated in vacuo. Two purifications by chromatography on silica (Gradient: 20percent to 100percent ethyl acetate in heptane) provided the title product as a white solid. Yield : 306 mg, 1 .63 mmol, 31 percent. LCMS m/z 188.3, 190.3 (M+1 ). ¹ H NMR (400 MHz, CD₃OD) δ 3.92 (s, 3H), 7.77 (d, J=1 .9 Hz, 1 H), 8.41 (d, J=1 .9 Hz, 1 H).

Reference： [1] Patent: US2008/108667, 2008, A1, . Location in patent: Page/Page column 9-10
[2] Patent: US2016/376283, 2016, A1, . Location in patent: Paragraph 0493; 0494
[3] Patent: WO2011/48525, 2011, A1, . Location in patent: Page/Page column 43
[4] Patent: US2009/131468, 2009, A1, . Location in patent: Page/Page column 65
[5] Patent: WO2009/64251, 2009, A1, . Location in patent: Page/Page column 137
[6] Patent: EP2816032, 2014, A1, . Location in patent: Paragraph 0484; 0485

7
[ 100-39-0 ]
[ 30766-22-4 ]
[ 915107-30-1 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 23, p. 7100 - 7105

8
[ 30766-22-4 ]
[ 915107-31-2 ]

Reference： [1] Patent: WO2011/48525, 2011, A1,
[2] Patent: US2016/376283, 2016, A1,

9
[ 30766-22-4 ]
[ 1095010-47-1 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 10, p. 3095 - 3098
[2] Patent: WO2015/103137, 2015, A1,
[3] Patent: WO2015/164508, 2015, A1,

[ 30766-22-4 ] Synthesis Path-Downstream 1~64

1
[ 30766-22-4 ]
[ 74-88-4 ]
[ 29681-46-7 ]

Yield	Reaction Conditions	Operation in experiment
23%		To a suspension of NaH (60% in mineral oil, 1 .46 g, 0.03 mol, washed three times with hexane) in DMF (50 mL) was added methyl-5-hydroxynicotinate (4.0 g, 0.04 mol) portion- wise, keeping the temperature below 10 C. After 30 minutes, methyl iodide (3.87 g, 0.03 mol) was added dropwise over 20 minutes. The mixture was stirred at room temperature for 3 hours, then quenched with MeOH and concentrated in vacuo. The residue was dissolved in chloroform and partitioned against saturated NaHCOa and brine. The organic layer was separated and the aqueous layer was extracted with chloroform, the combined organic fractions were dried (Nai>S04) and concentrated in vacuo. The residue obtained was purified by flash silica gel chromatography (petroleum ether/EtOAc = 5/1 then 3/1 ) to give the title compound (1.0 g, 23%) as a white solid. LCMS-C: RT 1 .16 min; m/z 168.1 [M+H]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 3168 - 3185
[2]Patent: WO2016/34673,2016,A1 .Location in patent: Page/Page column 125

2
[ 30766-22-4 ]
[ 350-46-9 ]
[ 284462-57-3 ]

Yield	Reaction Conditions	Operation in experiment
	With NaH; In methanol; water; N,N-dimethyl-formamide;	Step 1. Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene To a slurry of NaH (0.63 g, 26.1 mmol) in DMF (20 mL) was added a solution of methyl 5-hydroxynicotinate (2.0 g, 13.1 mmol) in DMF (10 mL). The resulting mixture was added to a solution of 4-fluoronitrobenzene (1.4 mL, 13.1 mmol) in DMF (10 mL) and the resulting mixture was heated at 70 C. overnight, cooled to room temp., and treated with MeOH (5 mL) followed by water (50 mL). The resulting mixture was extracted with EtOAc (100 mL). The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc/70% hexane) to afford 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.60 g).
	With NaH; In methanol; water; N,N-dimethyl-formamide;	To a slurry of NaH (0.63 g, 26.1 mmol) in DMF (20 mL) was added a solution of methyl 5-hydroxynicotinate (2.0 g, 13.1 mmol) in DMF (10 mL). The resulting mixture was added to a solution of 4-fluoronitrobenzene (1.4 mL, 13.1 mmol) in DMF (10 mL) and the resulting mixture was heated at 70 C. overnight, cooled to room temp., and treated with MeOH (5 mL) followed by water (50 mL). The resulting mixture was extracted with EtOAc (100 mL). The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc/70% hexane) to afford 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.60 g).
	With NaH; In methanol; water; N,N-dimethyl-formamide;	Step 1. Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene To a slurry of NaH (0.63 g, 26.1 mmol) in DMF (20 mL) was added a solution of methyl 5-hydroxynicotinate (2.0 g, 13.1 mmol) in DMF (10 mL). The resulting mixture was added to a solution of 4-fluoronitrobenzene (1.4 mL, 13.1 mmol) in DMF (10 mL) and the resulting mixture was heated at 70 C. overnight, cooled to room temp., and treated with MeOH (5 mL) followed by water (50 mL). The resulting mixture was extracted with EtOAc (100 mL). The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc/70% hexane) to afford 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.60 g).

	With sodium hydride; In N,N-dimethyl-formamide; at 70℃;	Step 1. Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene To a slurry of NaH (0.63 g, 26.1 mmol) in DMF (20 mL) was added a solution of methyl 5-hydroxynicotinate (2.0 g, 13.1 mmol) in DMF (10 mL). The resulting mixture was added to a solution of 4-fluoronitrobenzene (1.4 mL, 13.1 mmol) in DMF (10 mL) and the resulting mixture was heated at 70 C. overnight, cooled to room temp., and treated with MeOH (5 mL) followed by water (50 mL). The resulting mixture was extracted with EtOAc (100 mL). The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc/70% hexane) to afford 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.60 g).
	With sodium hydride;	EXAMPLE 89; Ethyl 6-(4-aminophenoxy)-l,4-dihydroxy-2-oxo-l52-dihydro-l,8-naphthyridine-3-carboxylate; Step 1 : Methyl 5-(4-nitrophenoxy)nicotinate; The title compound was prepared from <strong>[30766-22-4]5-hydroxynicotinic acid methyl ester</strong> (available from TCI-US) and l-fluoro-4-nitrobenzene essentially according to the method described in Khire, U. R. et al Bioorg. Med. Chem. Lett. 2004, 14, 783-786, substituting cesium carbonate for sodium hydride as the base.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 783 - 786
[2]Patent: US2003/181442,2003,A1
[3]Patent: US2001/11135,2001,A1
[4]Patent: US2002/165394,2002,A1
[5]Patent: US2003/207872,2003,A1 .Location in patent: Page/Page column 14
[6]Patent: WO2008/10964,2008,A1 .Location in patent: Page/Page column 95

3
[ 61296-22-8 ]
[ 30766-22-4 ]
[ 1001327-27-0 ]

Yield	Reaction Conditions	Operation in experiment
67%	With caesium carbonate; In acetone; at 55℃; for 18h;Heating / reflux;	B.[00199] To a solution of Part A compound (180 mg, 1.175 mmol) in acetone (5 mL) was added <strong>[61296-22-8]2-amino-5-bromothiazole monohydrobromide</strong> (611 mg, 2.351 mmol) and Cs2CO3 (957 mg, 2.94 mmol). The mixture was stirred at reflux (55 0C) for 18 h, then was cooled to RT and was filtered. The filtrate was concentrated in vacuo. The residue was taken up in EtOAc and was washed with H2O and brine, then was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex Luna AXIA 5u C18 30 x l00 mm column; detection at 220 nm; flow rate = 40 mL/min; continuous gradient from 30% B to 100% B over 10 min + 5 min hold time at 100% B, where A = 90: 10:0.1 H2O:MeOH:TFA and B = 90: 10:0.1 MeOH:H2O:TFA) to give Part B compound (200 mg, 67% yield) as a yellow solid.
33%	With caesium carbonate; In acetone; for 12h;Heating / reflux;	To a solution of 5-hydroxynicotinic acid methyl ester (610 mg, 4.0 mmol) in acetone (10 mL), was added <strong>[61296-22-8]5-bromothiazol-2-amine hydrobromide</strong> (2.1 g, 8.0 mmol) and cesium carbonate (3.3 g, 10.0 mmol). The reaction mixture was stirred at reflux for 12 h, then was cooled to RT. The mixture was filtered and washed with acetone. The combined filtrates were concentrated in vacuo, then was partitioned between EtOAc and H2O. The organic phase was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex Luna 5u C18 21.2×100 mm column; detection at 220 nm; flow rate=20 mL/min; continuous gradient from 0% B to 100% B over 8 min+7 min hold time at 100% B, where A=90: 10:0.1 H2O:MeOH:TFA and B=90: 10:0.1 MeOH:H2O:TFA) to provide Part A compound (327 mg, 33% yield) as a white solid.

Reference： [1]Patent: WO2008/154563,2008,A1 .Location in patent: Page/Page column 92
[2]Patent: US2008/21052,2008,A1 .Location in patent: Page/Page column 26-27

4
[ 1013908-99-0 ]
[ 30766-22-4 ]
5-[3'-([4-(1-ethyl-propyl)-phenyl]-isopropyl-amino}-methyl)-biphenyl-4-ylmethoxy]-nicotinic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With 1H-imidazole; 1,1'-azodicarbonyl-dipiperidine; trimethylphosphane; In tetrahydrofuran; toluene; at 20℃; for 1h;	Example 4a5- [3' - ( { [4- (1 -ethyl-propyl) -phenyl] -isopropyl-amino } -methyl) - biphenyl-4-ylmethoxy] -nicotinic acid methyl esterTrimethylphosphine (IM in toluene; 0.49 mL, 0.49 mmol) is added dropwise to a stirring solution of [3' -({ [4- (1-ethyl- propyl) -phenyl] -isopropyl-amino} -methyl) -biphenyl-4-yl] - methanol (0.10 g, 0.24 mmol), 5-Hydroxy-nicotinic acid methyl ester (0.04 g, 0.29 mmol), 1, 1' - (azodicarbonyl) dipiperidine (0.12 g, 0.49 mmol), and imidazole (0.03 g, 0.49 mmol) in THF (5 mL, 0.05 M) at room temperature. After stirring for 1 hour, an equal amount of heptane is added and the resulting precipitate is removed by filtration. The filtrate is concentrated and purified by flash chromatography (20% ethyl acetate in heptane) to give 5- [3' -({ [4- (1-ethyl-propyl) - phenyl] -isopropyl-amino} -methyl) -biphenyl-4-ylmethoxy] - nicotinic acid methyl ester (0.09 g, 68%) as a white solid. 1H NMR (CDCl3, 300 MHz) delta 8.83 (s, 1 H), 8.54 (s, 1 H), 7.85 (s, 1 H), 7.58 (d, J = 8.2 Hz, 2 H), 7.47 (s, 1 H), 7.46 (d, J = 8.2 Hz, 2 H), 7.42-7.29 (m, 3 H), 6.91 (d, J = 8.7 Hz, 2 H), 6.64 (d, J = 8.7 Hz, 2 H), 5.16 (s, 2 H), 4.44 (s, 2 H), 4.28-4.20 (m, 1 H), 3.95 (s, 3 H), 2.21-2.13 (m, 1 H), 1.66-1.57 (m, 2 H), 1.51-1.42 (m, 2 H), 1.21 (d, J = 6.4 Hz, 6 H), 0.77 (t, J = 7.3 Hz, 6 H) .

Reference： [1]Patent: WO2008/33455,2008,A2 .Location in patent: Page/Page column 109

5
[ 30766-22-4 ]
[ 20826-03-3 ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 3168 - 3185
[2]Patent: WO2016/34673,2016,A1

6
[ 30766-22-4 ]
[ 298204-74-7 ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 3168 - 3185

7
[ 30766-22-4 ]
[ 119646-50-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: NaOMe / dimethylformamide / 0.5 h / 20 °C 1.2: 33 percent / NaOMe / dimethylformamide / 20 °C 2.1: 100 percent / NaOH; EtOH / 3 h / Heating 3.1: thionyl chloride / Heating 4.1: NH₃(g) / 1,2-dichloro-ethane / -30 - 20 °C

Reference： [1]Khanna; Yu; Huff; Weier; Xu; Koszyk; Collins; Cogburn; Isakson; Koboldt; Masferrer; Perkins; Seibert; Veenhuizen; Yuan; Yang; Zhang [Journal of Medicinal Chemistry, 2000, vol. 43, # 16, p. 3168 - 3185]

8
[ 37595-74-7 ]
[ 30766-22-4 ]
[ 342024-50-4 ]

Yield	Reaction Conditions	Operation in experiment
97%	With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 1h;	Sodium hydride (60%, oily, 2.88 g) was added to a solution of <strong>[30766-22-4]methyl 5-hydroxy-3-pyridinecarboxylate</strong> (10.00 g) and N-phenyltrifluoromethanesulfonimide (24.00 g) in tetrahydrofuran (200 ml) at 0C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium bicarbonate solution, then with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl 5-trifluoromethanesulfonyloxy-3-pyridinecarboxylate (18.06 g, yield 97%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio). NMR(CDCl3)delta : 4.01(3H, s), 8.23(1H, dd, J=1.4, 2.6 Hz), 8.77(1H, d, J=2.6 Hz), 9.26(1H, d, J=1.4 Hz).

Reference： [1]Patent: EP1228067,2004,B1 .Location in patent: Page 58

9
[ 30766-22-4 ]
[ 103788-61-0 ]
methyl 5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridinecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃;	A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (13.4 g), <strong>[30766-22-4]methyl 5-hydroxypyridine-3-carboxylate</strong> (9.84 g), anhydrous potassium carbonate (8.90 g) and N,N-dimethylformamide (100 mL) was stirred overnight at 80 DEG C. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (12.42 g, 59%) of methyl 5-(5-methyl-2-phenyl-4-oxazolyl)methoxy-3-pyridinecarboxylate from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 119-120 DEG C.
59%	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 80℃;	A mixture of <strong>[30766-22-4]methyl 5-hydroxy-3-pyridinecarboxylate</strong> (9.84 g), 4-chloromethyl-5-methyl-2-phenyloxazole (13.40 g), potassium carbonate (8.90 g) and N,N-dimethylformamide (100 ml) was stirred at 80C overnight. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl 5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridinecarboxylate (12.42 g, yield 59%) as pale yellow crystals from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 119-120C

Reference： [1]Patent: EP1357115,2003,A1 .Location in patent: Page/Page column 50
[2]Patent: EP1228067,2004,B1 .Location in patent: Page 54

10
[ 776312-20-0 ]
[ 30766-22-4 ]
5-(4-{4-[4-(1-propylbutyl)benzyloxy]phenyl}thiazol-2-ylmethoxy)nicotinic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With potassium carbonate; potassium iodide; In N,N-dimethyl acetamide; at 75℃; for 2h;	(5) 5-(4-{4-[4-(1-Propylbutyl)benzyloxy]phenyl}thiazol-2-ylmethoxy)nicotinic acid methyl ester;[] N,N-Dimethylacetamide (104 ml), methyl 5-hydroxynicotinate (5.25 g, 40.8 mmol), potassium carbonate (13.0 g, 94.2 mmol) and potassium iodide (520 mg, 3.1 mmol) were added to (4-(4-(4-(1-propylbutyl)benzyloxy)phenyl)thiazol-2-yl)methyl chloride (13.0 g, 31.4 mmol) obtained in Example 3-1(4) and the mixture was stirred at 75C for 2 hr. After allowing to cool, ethyl acetate was added and the mixture was washed successively with water, a saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate. After filtration, the solvent was removed and the residue was purified by silica gel column chromatography (eluent; toluene-ethyl acetate, 5:1). The obtained crude crystals were slurried for washing with ether to give the title compound (9.91 g, yield 59%).

Reference： [1]Patent: EP1553091,2005,A1 .Location in patent: Page/Page column 154-155

11
[ 776312-28-8 ]
[ 30766-22-4 ]
5-(4-{4-[4-(1-propylbutyl)phenoxymethyl]phenyl}thiophen-2-ylmethoxy)nicotinic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With tetrabutylammomium bromide; caesium carbonate; potassium iodide; In N,N-dimethyl acetamide; at 60℃; for 1.5h;	(5) 5-(4-{4-[4-(1-Propylbutyl)phenoxymethyl]phenyl}thiophen-2-ylmethoxy)nicotinic acid methyl ester; [] To (4-(4-(4-(1-propylbutyl)phenoxymethyl)phenyl)thiophen-2-yl)methyl chloride (5.00 g, 12.1 mmol) were added N,N-dimethylacetamide (25 ml), <strong>[30766-22-4]5-hydroxynicotinic acid methyl ester</strong> (2.04 g, 13.3 mmol), cesium carbonate (11.8 g, 36.3 mmol), potassium iodide (201 mg, 1.21 mmol) and tetra-n-butylammonium bromide (390 mg, 1.21 mmol) and the mixture was stirred at 60C for 1.5 hr. After allowing to cool, ethyl acetate was added and the mixture was washed successively with water and saturated brine. After concentration, the concentrate was purified by silica gel column chromatography (ethyl acetate:hexane=2:5?1:2) to give the title compound (5.19 g, 81%).;

Reference： [1]Patent: EP1553091,2005,A1 .Location in patent: Page/Page column 193-194

12
[ 30766-22-4 ]
[ 108-93-0 ]
[ 862507-05-9 ]

Yield	Reaction Conditions	Operation in experiment
29%	With triphenylphosphine; diethylazodicarboxylate; In dichloromethane; at 20℃; for 16h;	To a stirred solution of methyl 5-hydroxynicotinate (2.40 g, 15.7 mmol) in methylene chloride (40 mL) was added cyclohexanol (1.73 g, 1.80 mL, 17.2 mmol) and triphenylphosphine (5.75 g, 21.9 mmol). The solution was treated with diethyl azodicarboxylate (3.20 mL, 20.4 mmol), resulting in a mild exotherm and development of an orange colored solution. The reaction mixture was allowed to stir at room temperature. After 16 hours, the cloudy yellow suspension was filtered, and the filtrate was washed with saturated sodium bicarbonate solution and brine, dried (magnesium sulfate), filtered, and concentrated to provide a yellow oil. Flash chromatography over silica (hexanes/ethyl acetate) afforded 1.08 g (29%) of the desired product as a colorless oil: 1H NMR (CDCl3) delta 8.77 (d, J=1.7 Hz, 1H), 8.43 (d, J=2.9 Hz, 1H), 7.74 (dd, J=1.7, 2.9 Hz, 1H), 4.37-4.31 (m, 1H), 3.94 (s, 3H), 2.01-1.93 (m, 2H), 1.85-1.75 (m, 2H), 1.62-1.49 (m, 3H), 1.46-1.31 (m, 3H) ppm. 13C NMR (CDCl3) delta 166.2, 154.0, 144.2, 142.9, 126.6, 122.3, 76.3, 52.7, 31.6, 25.6, 23.7 ppm.

Reference： [1]Patent: US2005/176761,2005,A1 .Location in patent: Page/Page column 14-15

13
4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butan-1-ol [ No CAS ]
[ 30766-22-4 ]
methyl-5-{4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butoxy}nicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 16h;	Diisopropyl azodicarboxylate (0.040 g, 0.20 mmol) was added to a mixture of <strong>[30766-22-4]5-hydroxynicotinic acid methyl ester</strong> (0.038 g, 0.25 mmol), 4-[5-(4- fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butan-l-ol (0.060 g, 0.20 mmol), triphenylphosphine (0.052 g, 0.20 mol) and tetrahydrofuran (3.0 mL) at room temperature with stirring. After 16 h, the solvent was removed in vacuo. The residue was diluted with ethyl acetate (50 mL) and washed with sodium bicarbonate (1 x 40 mL). The organic solution was concentrated and purified by column chromatography (1.5-5% methanol/dichloromethane) to give 7 mg (8 %) methyl 5-4-[5-(4- fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butoxynicotinate as white solid. MS [M+H] = 438.1, LC/MS (EI) tR 4.63 min (Method D), 1H NMR (CDCl3) delta (ppm) 9.02 (s, IH), 8.82 (s, IH), 8.38 (s, IH), 7.68 (s, IH), 7.42-7.35 (m, 2H), 7.34 (s, IH), 7.20-7.10 (m, 2H), 3.97 (s, 3H), 3.88 (t, J = 6.3 Hz, 2H), 2.72 (t, J = 7.2 Hz, 2H), 1.81-1.66 (m, 2H), 1.66- 1.53 (m, 2H)

Reference： [1]Patent: WO2006/71988,2006,A1 .Location in patent: Page/Page column 129

14
[ 30766-22-4 ]
[ 74-88-4 ]
[ 26218-80-4 ]

Yield	Reaction Conditions	Operation in experiment
	In N-methyl-acetamide; chloroform; isopropyl alcohol;	PREPARATION 235 5-Methoxy-nicotinic acid To sodium hydride (0.42 g, 10.5 mmol, washed with hexanes 3) in dimethylformamide (15 mL) was added 5-hydroxy-nicotinic acid methyl ester (1.53 g, 10.0 mmol) in dimethylformamide (10 mL). After three minutes, iodomethane (0.65 mL, 10.5 mmol) was added dropwise while stirring at room temperature. After 1 h, the reaction was quenched with methanol and concentrated to a brown oil. The solution was dissolved in 20% isopropanol/chloroform, washed with saturated aqueous sodium bicarbonate solution, brine (3), dried over magnesium sulfate and concentrated to give 1.46 g of 6-methoxynicotinic acid methyl ester.

Reference： [1]Patent: US2003/100576,2003,A1

15
[ 30766-22-4 ]
[ 874285-24-2 ]

Yield	Reaction Conditions	Operation in experiment
47%		Example 2.28: methyl 5-isopropoxynicotinate; [0266] A solution of 677 mg (3.28 mmol) of dicyclohexylcarbodiimide (DCC), 0.3 mL (3.92 mmol) of isopropanol, and 7.7 mg (0.078 mmol) of CuCl was heated at 60 0C. After 13 h, 460 mg (3.0 mmol) of <strong>[30766-22-4]5-hydroxynicotinic acid methyl ester</strong> and 10 mL of benzene were added and heated at 105 0C for 24.5 h. The mixture was diluted with chloroform and filtered. The organic layer was washed with 15 mL of sat. NaHCO3, water, and brine and dried over Na2SO4. Purification by flash silica gel chromatography (100% CHCl3) provided 274 mg of methyl 5-isopropoxynicotinate as a yellow oil in 47% yield.

Reference： [1]Patent: WO2006/110668,2006,A1 .Location in patent: Page/Page column 62

16
[ 30766-22-4 ]
[ 174258-31-2 ]
methyl 5-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]nicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine; In tetrahydrofuran; at 1 - 30℃; for 15h;	To a mixture of [3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenyl]methanol (1.92 g), methyl 5-hydroxynicotinate (1.0 g), tributylphosphine (1.98 g) and tetrahydrofuran (100 mL) was added 1,1'-(azodicarbonyl)dipiperidine (2.47 g) at room temperature and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration. The filtrate was concentrated and the residue was subjected to silica gel column chromatography to give crystals (2.21 g, 79%) of methyl 5-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]nicotinate from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 96-97 DEG C.

Reference： [1]Patent: EP1357115,2003,A1 .Location in patent: Page/Page column 57

17
[ 30766-22-4 ]
[ 250602-53-0 ]
methyl 5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridinecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With sodium hydride; In N,N-dimethyl-formamide; at 0 - 30℃; for 3h;	To a mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (4.52 g), <strong>[30766-22-4]methyl 5-hydroxy-3-pyridinecarboxylate</strong> (2.0 g), and N,N-dimethylformamide (30 mL) was added sodium hydride (60%, oil, 0.58 g) under ice-cooling, and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration. The crystals were subjected to silica gel column chromatography to give crystals (2.41 g, 43%) of methyl 5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridinecarboxylate from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 138-139 DEG C.

Reference： [1]Patent: EP1357115,2003,A1 .Location in patent: Page/Page column 49

18
[ 138-24-9 ]
[ 30766-22-4 ]
[ 29681-46-7 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In acetonitrile at 80℃; for 6h;	10.2 A mixture of 0.5 g of methyl 5-hydroxynicotinate, 1.2 g (2 equiv) of phenyltrimethylammonium chloride, 4.8 g (3 equiv) of cesium carbonate, and 5 mL of anhydrous acetonitrile was heated to 800C for 6 h, cooled, filtered and concentrated under reduced pressure. The residue was taken up in 25 mL of ethyl acetate, filtered and conentrated. Purification by flash chromatography (0-50% ethyl acetate in hexane) gave the product as white crystalline solid: MS (m+1) = 168.1; 1H NMR (400 MHz, CDC13) 8.72 (s, IH), 8.4 (s, IH)5 7.67 (s, IH), 3.83 (s, 3H), 3.82 (s, 3H).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2007/67511, 2007, A2 Location in patent: Page/Page column 34

19
[ 67-56-1 ]
[ 27828-71-3 ]
[ 30766-22-4 ]

Yield	Reaction Conditions	Operation in experiment
85%	With sulfuric acid; In methanol; at 30℃; for 168h;Inert atmosphere; Reflux;	Method A. Step A. Methyl 5 -hydroxynicotinate. To a solution of <strong>[27828-71-3]5-hydroxynicotinic acid</strong> (833 g, 5.99 mol) in methanol (6.7 L) was added H2SO4 (292 mL) dropwise at a rate to keep the temperature of the mixture under 30 C. After addition, the reaction mixture was stirred at reflux for 7 days. The reaction mixture was cooled to rt and concentrated under reduce pressure. Water (4 L) was added and the mixture adjusted to pH 8 with NaHC03 which induced precipitation of a white solid. After stirring the reaction mixture for 1 h at rt, the solid was filtered and dried under vacuum at 60 C for 3 days to afford the title compound (783 g, 85%) as a white solid. 1H NMR (DMSO-< 6, 400 MHz) delta 10.46 (s, 1H), 8.54 (s, 1H), 8.34-8.35 (d, J = 2.8 Hz, 1H), 7.59 (s, 1H), 3.85 (s, 3H).
82%	sulfuric acid; at 70℃; for 18h;Sealed tube; Heating / reflux;	EXAMPLE 36A. <n="93"/>[00198] To a solution of <strong>[27828-71-3]5-hydroxynicotinic acid</strong> (200 mg, 1.438 mmol) in MeOH (2 mL) was added concentrated H2SO4 (0.077 mL, 1.438 mmol). The sealed reaction vessel was placed on a shaker and was heated to reflux at 700C for 18 h, then was cooled to RT. The volatiles were removed in vacuo, and the residue was purified by preparative HPLC (Phenomenex Luna AXIA 5u C18 30 x l00 mm column; detection at 220 nm; flow rate = 40 mL/min; continuous gradient from 0% B to 100% B over 10 min + 2 min hold time at 100% B, where A = 90: 10:0.1 H2O:MeOH:TFA and B = 90: 10:0.1 MeOH:H2O:TFA) to give Part A methyl ester (180 mg, 82% yield) as a white solid.
79%	With sulfuric acid; for 20h;Reflux;	General procedure: 4-Hydroxypicolinic acid 3 (348 mg, 2.5 mmol) was added to methanol (25 mL), and then concentrated sulfuric acid (0.2 mL). The mixture was refluxed for 20 h, then the solvent was evaporated under vacuum. The residue was neutralized with saturated aqueous sodium bicarbonate solution, extracted with DCM/MeOH (10/1, 5×30 mL), dried over anhydrous Na2SO4, concentrated under vacuum to give compound 4 (196 mg, 51%) as a white solid. 1H NMR (400 MHz, Methanol-d4) delta 7.92 (d, J = 7.0 Hz, 1H), 7.14 (s, 1H), 6.63 (d, J = 7.0 Hz, 1H), 3.99 (s, 3H). MS (ESI) m/z = 154.1 ([M+H]+). To a solution of compound 4 (77 mg, 0.5mmol) in DMF (2 mL) was added potassium carbonate (104 mg, 0.75 mmol), then 1,4-dibromobutane (325 mg, 1.5 mmol) at 0C. The mixture was stirred at room temperature for 3 h, and then partitioned between water (30 mL) and ethyl acetate (EA, 30 mL). The organic phase was washed with water (3×30 mL), saturated brine (30 mL), dried over anhydrous Na2SO4, concentrated under vacuum, purified by column chromatography using DCM : MeOH (100:1) as eluent to give 5 (95 mg, 66%) as a light yellow oil. 1H NMR (400 MHz, DMSO-d6) delta 8.51 (d, J = 5.6 Hz, 1H), 7.55 (d, J = 2.6 Hz, 1H), 7.22 (dd, J = 5.7, 2.6 Hz, 1H), 4.19 (t, J = 6.2 Hz, 2H), 3.62 (t, J = 6.5 Hz, 2H), 1.98 (p, J = 6.7 Hz, 2H), 1.92 - 1.83 (m, 2H). MS (ESI) m/z = 288.2 ([M+H]+). Corresponding arylpiperazine (arylpiperidine) (0.24 mmol), 5 (90 mg, 0.31 mmol), potassium carbonate (83 mg, 0.6mmol) and potassium iodide (40 mg, 0.24 mmol) were added to acetonitrile (5 mL). The reaction mixture was refluxed overnight, cooled to room temperature, partitioned between EA and water. The organic layer was dried over anhydrous Na2SO4, concentrated under vacuum to give 6a-6e which was used directly in the next step without further purification.

75%	With thionyl chloride; at 20℃;	Synthesis of methyl 5-hydroxynicotinateO OHSOCI2 MeOHHO HO UNTo a stirred solution of <strong>[27828-71-3]5-hydroxynicotinic acid</strong> (10 g, 71 .9 mmol) in MeOH (100 mL)was added sulfurous dichloride (1 mL) drop wise over 5mm The resulting mixturewas stirred at room temperature overnight. The resulted solution was added 100 mLof NaHCO3.The precipitate was filtrated and washed with MeOH for several cycles togive 8.5 g of A031 -2 (75% yields), which was used for the nest step without furtherpurification.
75%	With thionyl chloride; at 20℃; for 0.0833333h;	To a stirred solution of <strong>[27828-71-3]5-hydroxynicotinic acid</strong> (10 g, 71.9 mmol) in MeOH (100 mL) was added sulfurous dichloride (1 mL) drop wise over 5 min. The resulting mixture was stirred at room temperature overnight. The resulted solution was added 100 mL of NaHCO3. The precipitate was filtrated and washed with MeOH for several cycles to give 8.5 g of A031-2 (75% yields), which was used for the nest step without further purification.
75%	With thionyl chloride; at 20℃;	To a stirred solution of <strong>[27828-71-3]5-hydroxynicotinic acid</strong> (10 g, 71 .9 mmol) in MeOH (100 mL) was added sulfurous dichloride (1 mL) drop wise over 5 min. The resulting mixture was stirred at room temperature overnight. The resulted solution was added 100 mL of NaHCOs.The precipitate was filtrated and washed with MeOH for several cycles to give 8.5 g (75% yields), which was used for the next step without further purification.
75%	With thionyl chloride; at 20℃;	To a stirred solution of <strong>[27828-71-3]5-hydroxynicotinic acid</strong> (10 g, 71.9 mmol) in MeOH (100 mL) was added sulfurous dichloride (1 mL) drop wise over 5 min. The resulting mixture was stirred at room temperature overnight. The resulted solution was added 100 mL of NaHCO3. The precipitate was filtrated and washed with MeOH for several cycles to give 8.5 g of A031-2 (75% yields), which was used for the nest step without further purification.
71%	With sulfuric acid; at 70℃;	A mixture of <strong>[27828-71-3]5-hydroxynicotinic acid</strong> (3 g, 21.6 mmol), cone H2SO4 (2.2 g, 21.6 mmol) in MeOH (50 mL) was heat at 70 C overnight. The mixture was concentrated, poured into water (100 mL) and extracted with EA (100 mL X 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford methyl 5-hydro
68%		Preparation of Compound A29A mixture of compound A28 (25.0 g, 180 mmol) and concentrated H2SO4 (10 mL) in CH3OH (100 mL) was heated to reflux for overnight. The mixture was concentrated, the residue was washed with aqueous NaHCO3 (50 mL) and extracted with ethyl acetate (2×100 mL). The organic layer was dried over Na2SO4, filtered and concentrated to afford compound A29 (18.7 g, yield: 68%).1H NMR (300 MHz, DMSO-d6): delta: 10.42 (s, 1H), 8.60 (d, J=1.6 Hz, 1H), 8.36 (d, J=2.8 Hz, 1H), 7.60-7.61 (m, 1H), 3.87 (s, 3H).
68%	With sulfuric acid;Reflux;	[0444] Preparation of compound A29: A mixture of compound A28 (25.0 g, 180 mmol) and concentrated H2SO4 (10 mL) in CH3OH (100 mL) was heated to reflux for overnight. The mixture was concentrated, the residue was washed with aqueous NaHC03 (50 mL) and extracted with ethyl acetate (2 x 100 mL). The organic layer was dried over a2S04, filtered and concentrated to afford compound A29 (18.7 g, yield: 68%). [0445] 1H NMR (300 MHz, DMSO-i 6): delta: 10.42 (s, 1H), 8.60 (d, J = 1.6 Hz, 1H), 8.36 (d, J = 2.8 Hz, 1H), 7.60-7.61 (m, 1H), 3.87 (s, 3H). [0446] Preparation of compound A30: BnOH (3.90 g, 36.1 mmol, 1.1 eq) and PPh3 (17.1 g, 65.4 mmol, 2.0eq) was added to a solution of compound A29 (5.00 g, 32.7 mmol) in THF (100 mL), then DEAD (6.80 g, 39.2 mmol, 1.2eq) was added at 0C. The mixture was stirred at room temperature for overnight. The solvent was evaporated, the residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate = 10: 1) to afford the compound A30 (5.70 g, yield: 71%) as white solid. [0447] 1H NMR (300 MHz, CDC13): delta: 8.83 (d, J = 1.6 Hz, 1H), 8.54(d, J = 2.8 Hz, 1H), 7.85-7.86 (m, 1H), 7.27-7.46 (m, 5H), 5.15 (s, 2H), 3.95 (s, 3H). [0448] Preparation of compound A31: A solution of compound A30 (12.8 g, 52.9mmol) in methylamine alcohol solution in sealed tube was stirred at 70 C for overnight. Then the mixture was cooled to room temperature and the solvent was evaporated to afford the compound A31 (12.0 g, yield: 100%). [0449] 1H NMR (300 MHz, CDC13): delta: 8.50 (d, J = 1.6 Hz, 1H), 8.48(d, J = 2.8 Hz, 1H), 7.73-7.74 (m, 1H), 7.73-7.74 (m, 5H), 6.16(s, 1H), 3.15 (s, 2H), 3.04 (d, J = 4.4 Hz, 3H). A32 A33 [0450] Preparation of compound A32: The solution of compound A31 (11.0 g, 45.5 mmol) in SOCl2 (100 mL) was heated to reflux for 4h. Then, SOCl2 was removed under vacuum and the residue was dissolved in MeCN (200 mL). TMSN3 (12.5 g, 90.0 mmol, 2.0eq) was added slowly and the mixture was stirred at 90C for 3h. Then the solvent was evaporated and the residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate = 2: 3) to afford the compound A32 (9.50 g, yield: 78%). [0451] 1H NMR (300 MHz, CDC13): delta: 8.59 (d, J = 2.8 Hz, 1H), 8.56(d, J = 1.6 Hz, 1H), 7.68-7.69 (m, 1H), 7.3-7.46 (m, 5H), 5.21 (s, 2H), 4.17 (s, 3H). [0452] Preparation of compound A33: To a solution of compound A32 (5.00 g, 18.7 mmol) in CH3OH (100 mL) was added Pd(OH)2 ( 0.50 g), The mixture was stirred at room temperature under H2 atmosphere for 3h. The solid was filtered off and the filtrate was concentrated to get compound A33 (1.60 g, yield: 48%). [0453] 1H NMR (300 MHz, DMSO-i 6): delta: 10.56 (s, 1H), 8.49 (d, J = 1.6 Hz, 1H), 8.36(d, J = 2.8 Hz, 1H), 7.61-7.62 (m, 1H), 4.19(s, 3H).
65%	With thionyl chloride; In methanol; at 20 - 60℃;	Thionyl chloride (780 jil, 10.7 mmol) was added drop-wise to a suspension of 5- hydroxynicotinic acid (497 mg, 3.57 mmol) in MeOH (5 ml) at ambient temperature. The mixture was heated at 60 C overnight. 0.1 M Potassium phosphate buffer (pH 7) (50 ml) was added and the mixture extracted with EtOAc. The combined organic layers were dried(Mg504). Yield: 354 mg (65%); white solid.
		A mixture of 1 g of <strong>[27828-71-3]5-hydroxynicotinic acid</strong>, 2 g Amberlyst 15 ion-exchange resin and 150 mL of methanol was heated to reflux with stirring for 24 hrs, cooled, basified with 10% ammonia in methanol, <n="35"/>filtered and concentrated under reduced pressure. The residue was taken up in 50 mL of chloroform and dried over MgSO4- Concentration under reduced pressure gave a tan crystalline solid: MS (m+1) = 154.1; 1H NMR (400 MHz, CDC13) 8.68 (s, IH), 8.32 (s, IH)3 7.72 (s, IH), 3.94 (s, 3H).
	With thionyl chloride; at 60℃; for 4h;	10 mmol of <strong>[27828-71-3]5-hydroxy-3-carboxypyridine</strong> was dissolved in 100 mL of methanol. 5 mL of thionyl chloride was slowly added and reacted at 60 C for 4 hours. The solvent was distilled off under reduced pressure. The resulting product was used in the next reaction without purification.
	With sulfuric acid; at 70℃; for 12h;Inert atmosphere;	Step 1 Methyl 5-hydroxynicotinate <strong>[27828-71-3]5-Hydroxynicotinic acid</strong> (2.50 g, 17.97 mmol) was dissolved in methanol (20.00 mL), added with sulfuric acid (18M, 47.90 uL), and then stirred at 70 C. under nitrogen atmosphere for 12 hours. After the reaction mixture was concentrated, the residue was dissolved in dichloromethane (50.00 mL) and the system was adjusted to pH=8 with saturated sodium bicarbonate solution. A white solid was slowly precipitated and filtered to give methyl 5-hydroxynicotinate (a white solid, 1.5 g, crude product). 1H NMR (400 MHz, CDCl3) 8.25 (s, 1H), 8.13 (d, J=1.8 Hz, 1H), 7.38 (br. s., 1H), 3.17 (s, 3H).

Reference： [1]Patent: WO2015/164508,2015,A1 .Location in patent: Page/Page column 52
[2]Patent: WO2008/154563,2008,A1 .Location in patent: Page/Page column 91-92
[3]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 606 - 611
[4]Patent: WO2014/154727,2014,A1 .Location in patent: Page/Page column 43
[5]Patent: US2014/296239,2014,A1 .Location in patent: Paragraph 0114; 0115
[6]Patent: WO2014/154726,2014,A1 .Location in patent: Page/Page column 43
[7]Patent: US2014/296296,2014,A1 .Location in patent: Paragraph 0123; 0124
[8]Patent: WO2015/103317,2015,A1 .Location in patent: Page/Page column 78
[9]Patent: US2012/238751,2012,A1 .Location in patent: Page/Page column 33
[10]Patent: WO2014/43272,2014,A1 .Location in patent: Paragraph 0443; 0444; 0445
[11]Patent: WO2017/108282,2017,A1 .Location in patent: Page/Page column 113
[12]Patent: WO2007/67511,2007,A2 .Location in patent: Page/Page column 33
[13]Patent: EP3348269,2018,A1 .Location in patent: Paragraph 0347; 0348
[14]Patent: US2018/346438,2018,A1 .Location in patent: Paragraph 0236-0238

20
[ 958266-11-0 ]
[ 30766-22-4 ]

Reference： [1]European Journal of Organic Chemistry,2007,p. 4408 - 4430

21
[ 30766-22-4 ]
[ 915107-30-1 ]

Yield	Reaction Conditions	Operation in experiment
49%	With N-chloro-succinimide; In N,N-dimethyl-formamide; at 80℃; for 16h;	To a solution of methyl 5-hydroxynicotinate (100 g, 0.65 mol) in DMF(1000 ml_), NCS (130.5 g, 0.97 mol) was added and the reaction mixture was heated to 80C for 16 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was taken in EtOAc (2L) and washed with saturated sodium chloride solution (500 ml_). The organic layer was dried over Na2S04 and concentrated. The crude product was purified by column chromatography on 230-400 silica gel using 0-30% ethyl acetate in petroleum ether as an eluent. Fractions were collected and concentrated to afford the title compound as yellow oil (60 g, 49% yield), LCMS (ESI) m/z 187.9 (M+1 ).
42%	With sodium hypochlorite; In water; at 0℃; for 0.5h;	Example V Preparation of [(5-methoxy-6-chloropyridin-3-yl)methyl](methyl)-oxido-lambda4-sulfanylidenecyanamide (5) To a flask containing methyl-5-hydroxynicotinate (4.5 g, 29 mmol) was added sodium hypochlorite aqueous solution (6.15%, 26.7 mL, 22 mmol) dropwise under ice bath cooling. After 30 min of stirring, 2 M HCl (20 mL) was added and the resulting white crystals collected by filtration to give 2.31 g of 6-chloro-<strong>[30766-22-4]5-hydroxynicotinic acid methyl ester</strong> in 42% yield. 1H NMR (400 MHz, CDCl3) delta 10.32 (bs, 1H), 8.48 (d, 1H), 7.84 (d, 1H), 7.40 (s, 1H), 3.93 (s. 3H); LC-MS (ELSD): mass calcd for C7H6ClNO3 [M]+ 187. Found 187.
33%	With hypochloric acid; In water; at 0℃; for 1.16h;Inert atmosphere;	Methyl 6-chloro-5-hydroxynicotinate At 0 C., to a solution of <strong>[30766-22-4]methyl 5-hydroxypyridine-3-carboxylate</strong> (1.8 g, 11.75 mmol) in water (15 mL) was added HClO (651 mg, 12.4 mmol) in portions over 10 min period. The resulting solution was stirred for 1 h at 0 C., warmed to room temperature and treated with hydrochloric acid solution (2 M, 20 mL). The precipitate that formed were collected by filtration and dried in oven under vacuum to yield methyl 6-chloro-5-hydroxynicotinate as off-white solid (800 mg, 33%).

31%	With N-chloro-succinimide; In N,N-dimethyl-formamide; at 80℃; for 18h;	Step 1 . Preparation of methyl 6-chloro-5-hydroxynicotinate (C5). N-Chlorosuccinimide (95%, 881 mg, 6.27 mmol) was added to a solution of methyl 5- hydroxynicotinate (800 mg, 5.22 mmol) in W.W-dimethylformamide (5.2 mL). The mixture was stirred at 80 C for 18 hours, then concentrated in vacuo. Two purifications by chromatography on silica (Gradient: 20% to 100% ethyl acetate in heptane) provided the title product as a white solid. Yield : 306 mg, 1 .63 mmol, 31 %. LCMS m/z 188.3, 190.3 (M+1 ). 1 H NMR (400 MHz, CD3OD) delta 3.92 (s, 3H), 7.77 (d, J=1 .9 Hz, 1 H), 8.41 (d, J=1 .9 Hz, 1 H).
27%		To a cold (0 C.) vessel containing R-i (5.00 g, 33 mmol) is added an aqueous (6% by wt) solution of sodium hypochlorite (30 mE). The mixture is stirred for 30 mm then treated with 1M aqueous RC1 (50 mE) and stirred overnight. Additional aqueous sodium hypochiorite is added followed by stirring for 8 h then solid is filtered, collected, and dried to afford 1-2 (1.8 g, 27%), m/z=188.0 [M+R], R1=0.6 (5i02, EtOAc/petrol ether 1/1)
	With N-chloro-succinimide; In N,N-dimethyl-formamide; at 80℃;	N-Chlorosuccinimide (2.093 g, 15.67 mmol) was added to a solution of methyl 5-hydroxynicotinate (2.0 g, 13.06 mmol) in N,N-dimetylformamide (20 mL). The reaction mixture was heated at 80 C. over night and the solvent was evaporated. Purification by column chromatography, using heptane/ethyl acetate (3:1-1:1) as the eluent, gave 0.957 g of the title compound.MS (ESI) m/z 186, 188, 190 [M-1]-.
	With N-chloro-succinimide; In N,N-dimethyl-formamide; at 80℃;	N-Chlorosuccinimide (2.093 g, 15.67 mmol) was added to a solution of methyl 5- hydroxynicotinate (2.0 g, 13.06 mmol) in N,N-dimetylformamide (20 mL). The reaction mixture was heated at 80 0C over night and the solvent was evaporated. Purification by column chromatography, using heptane/ethyl acetate (3:1 -1:1) as the eluent, gave 0.957 g of the title compound. MS (ESI) m/z 186, 188, 190 [M-I]".
	With sodium hypochlorite; In water; at 0℃; for 2h;	A) methyl 6-chloro-5-hydroxynicotinate To a mixture of methyl 5-hydroxynicotinate (10.0 g) and water (2.0 mL) was added dropwise 5% aqueous sodium hypochlorite solution (69.2 mL) at 0C, and the mixture was stirred for 2 hr. 2N Hydrochloric acid (50 mL) was added to the reaction mixture at 0C, and the resulting white precipitate was collected by filtration. The crude crystals were washed with water, and the obtained solid was dissolved in acetonitrile. The solvent was evaporated under reduced pressure to give a crude product of the title compound (3.71 g) as a pale-yellow solid.

Reference： [1]Patent: WO2019/69293,2019,A1 .Location in patent: Paragraph 00622; 00623; 00625; 00627; 00628
[2]Patent: US2008/108667,2008,A1 .Location in patent: Page/Page column 9-10
[3]Patent: US2016/376283,2016,A1 .Location in patent: Paragraph 0493; 0494
[4]Patent: WO2011/48525,2011,A1 .Location in patent: Page/Page column 43
[5]Patent: US2018/354968,2018,A1 .Location in patent: Paragraph 0327; 0328
[6]Patent: US2009/131468,2009,A1 .Location in patent: Page/Page column 65
[7]Patent: WO2009/64251,2009,A1 .Location in patent: Page/Page column 137
[8]Patent: EP2816032,2014,A1 .Location in patent: Paragraph 0484; 0485

22
[ 30766-22-4 ]
[ 109384-19-2 ]
[ 874285-29-7 ]

Yield	Reaction Conditions	Operation in experiment
58%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;	To a solution of methyl 5-hydroxynicotinate (500 mg, 3.3 mmol) in dry THF (10 mL) at 0 C were added ieri-butyl 4-hydroxypiperidine-1 -carboxylate (660 mg, 3.3 mmol), DIAD (870 mg, 4.3 mmol) and PP (950 mg, 3.6 mmol). The mixture was stirred at 0 C for 1 hour then allowed to warm slowly to room temperature and stirred overnight. The mixture was diluted with EtOAc (100 mL) and washed with water (100 mL) and brine (100 mL), dried (Na2S04) and concentrated. The residue obtained was purified by column chromatography (20% EtOAc/petroleum ether) to give the title compound as yellow oil (580 mg, 58%). LCMS-C: RT 2.77 min, m/z 337.2 [M+H]+
	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 55℃; for 40.3333h;Inert atmosphere;	Intermediate 80: methyl 5 -( 1 -(tert-butoxycarbonyl)piperidin-4-yloxy)nicotinateMethyl 5-hydroxynicotinate (3 g, 19.59 mmol), tert-butyl 4-hydroxypiperidine-l- carboxylate (4.93 g, 24.49 mmol), and triphenylphosphine (6.42 g, 24.49 mmol) in THF (106 ml) at 0 C was added diisopropyl azodicarboxylate (4.85 ml, 24.49 mmol) drop wise over 10 min . The reaction was removed from the ice bath and stirred at RT for 10 min, then heated to 55 C and stirred under nitrogen for 40 hours. The reaction mixture was concentrated, and residue was treated with EtOAc (45 ml) followed by Hexanes (45 ml). The mixture was stirred at RT overnight. The white precipitate was filtered off with a glass funnel, rinsed with EtOAc/Hexanes (1 : 1) and discarded. The filtrate was concentrated and purified by MPLC (330 g column, 0-100% EtOAc in Hexanes to yield Methyl 5-(l-(tert-butoxycarbonyl)piperidin-4-yloxy)nicotinate (5.98 g) LC-MS (ES, m/z) Ci7H24N205: 336; Found: 337 [M+H]+.
	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 12h;	To a stirred solution of tert-butyl 4-hydroxypiperidine-l-carboxylate (2 g, 9.937 mmol), 5-hydroxynicotinic methyl ester (1.52 g, 9.937 mmol), and triphenyl phosphine (3.9 g, 14.9 mmol) in THF (40 ml) at room temperature, diethyl azodicarboxylate (2.34 ml, 14.9 mmol) is added dropwise. The solution is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in THF (20 ml), treated with NaOH (17.9 ml, 89.43 mmol, 5N), and stirred for 4 hours. The reaction is extracted with CH2CI2 (20 ml) three times, and the aqueous layer acidified to pH 5 by addition of <n="221"/>concentrated HCl. The aqueous phase is then extracted with CH2CI2 (20 ml) three times, the organic layer is dried over Na2SO4, filtered, and concentrated in vacuo. Solids are then triturated in Et2O for 12 hours to provide 5-(l-( tert-butoxycarbonyl)piperidin-4- yloxy)nicotinic acid (2.08 g, 65%).

Reference： [1]Patent: WO2016/34673,2016,A1 .Location in patent: Page/Page column 124
[2]Patent: WO2012/164071,2012,A1 .Location in patent: Page/Page column 71
[3]Patent: WO2008/109613,2008,A1 .Location in patent: Page/Page column 219-220

23
[ 126301-16-4 ]
[ 30766-22-4 ]
[ 1055969-29-3 ]

Yield	Reaction Conditions	Operation in experiment
33.6%	With caesium carbonate; In N,N-dimethyl-formamide; at 25℃;	A suspension of (25*)-2-[(tert-butoxycarbonyl)amino]propyl methanesulfonate (6.53 g, 25.8 mmol ), <strong>[30766-22-4]5-hydroxynicotinic acid methyl ester</strong> (3.96 g, 25.8 mmol) and cesium carbonate (16.81 g, 51.6 mmol) in N,N-dimethylformamide (79 ml) is stirred at 25C overnight. N,N-dimethylformamide is removed by rotary evaporator. Ethyl acetate (500 ml) is added and the cesium solid is filtered away. The ethyl acetate layer is washed with 5N sodium hydroxide solution, dried over Na2SO4, filtered and evaporated. The resulting residue is dissolved in hot 5: 1 hexane/diethyl ether, then filtered through a 7.0 cm column of hydrous magnesium silicate. Fractions are eluted from the column with hexane and diethyl ether = 1 : 1 (300 ml). Fractions 2 and 3 are collected and evaporated to provide 2.69 g (33.6 %) of a white solid which is characterized as (5,S)-(2-tert-butoxycarbonylamino- propoxy)-nicotinic acid methyl ester. MS (ESI) m/z 311.3.

Reference： [1]Patent: WO2008/109613,2008,A1 .Location in patent: Page/Page column 225
[2]European Journal of Medicinal Chemistry,2010,vol. 45,p. 1379 - 1386

24
[ 1678-49-5 ]
[ 30766-22-4 ]
[ 1055971-82-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;Aliquat 336; In acetone; for 6h;Heating / reflux;	A mixture of 3 g (13.7 mmol) of 3-bromo-4-nitropyridine 1-oxide, 2.1 g (13.7 mmol) of methyl 5-hydroxynicotinate, and 5.7 g (41.1 mmol) of potassium carbonate in 60 ml of acetone containing 1 drop of Aliquat-336 is stirred at reflux for 6 hours. The mixture is diluted with acetone and filtered through magnesium silicate. The solvent is removed and the 2.6 g of 3-(5-(methoxycarbonyl)pyridin-3-yloxy)-4-nitropyridine 1-oxide is obtained after chromatography.

Reference： [1]Patent: WO2008/109613,2008,A1 .Location in patent: Page/Page column 250

25
[ 944470-58-0 ]
[ 30766-22-4 ]
[ 1055968-94-9 ]

Yield	Reaction Conditions	Operation in experiment
56%	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 3.16667h;	Tert-butyl r(lS)-l-(2-chlorobenzvl)-2- hydroxyethyl]carbamate (4013 mg, 14.04 mmol), PPh3 (4419 mg, 14.04 mmol), and 5- hydroxynicotinic acid methyl ester (2121 mg, 14.04 mmol) are dissolved in 60 ml of dry THF and added DEAD (2.65 ml, 16.85 mmol) in 12 ml of dry THF over 10 minutes. The solution is stirred at room temperature for 3 hours then concentrated in vacuo. The residue is dissolved in Et2theta, and stirred for 1 hour and then filtered. The filtrate is washed with 3x200 ml of 0.5N NaOH and the organic layer is dried over MgSO4 and concentrated in vacuo. The residue is <n="196"/>purified by silica gel chromatography using hexanes and ether with a gradient elution of 10- 50 % to provide methyl 5-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(2- chlorophenyl)propyl]oxy}nicotinate (1.780 g, 56%). MS: 421.2 (M+H)+1.

Reference： [1]European Journal of Medicinal Chemistry,2010,vol. 45,p. 1379 - 1386
[2]Patent: WO2008/109613,2008,A1 .Location in patent: Page/Page column 194-195

26
[ 940890-90-4 ]
[ 30766-22-4 ]
[ 1055963-74-0 ]

Yield	Reaction Conditions	Operation in experiment
27%	With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 40℃; for 71h;	[0400] A suspension of (S)-3-Methanesulfonyloxy-piperidine-l-carboxylic acid tert-bupsilonXyl ester (2 g, 7.15 mmol), 5-hydroxynicotinic acid methyl ester (2.19 g, 14.32 mmol), and CS2CO3 (4.89 g, 15.03 mmol) in DMF (14 ml) is stirred at room temperature for 1 hour. The reaction is then heated to 40° C for 70 hours. After cooling to room temperature and concentration in vacuo, the reaction is dissolved in water (100 ml), extracted with EtOAc (50 ml), dried over MgSO4, filtered, and concentrated in vacuo. The residue is then purified by silica gel chromatography (10-50percent EtOAc/Hexanes) to provide (R)-methyl 5-(l-( tert- butoxycarbonyl)piperidin-3-yloxy)nicotinate (643 mg, 27percent).

Reference： [1]Patent: WO2008/109613,2008,A1 .Location in patent: Page/Page column 218

27
[ 1018909-03-9 ]
[ 30766-22-4 ]
[ 1055969-28-2 ]

Yield	Reaction Conditions	Operation in experiment
22%	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 12h;	To a stirred solution of tert-butyl 4-fluorobenzyl(2- hydroxyethyl)carbamate (2.2 g, 8.169 mmol), 5-hydroxynicotinic methyl ester (1.25 g, 8.169 <n="225"/>mmol), and triphenyl phosphine (6.63 g, 25.32 mmol) in THF (40 ml) at room temperature, diethyl azodicarboxylate (3.85 ml, 24.5 mmol) is added dropwise. The solution is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc (50 ml) and extracted with HCl (20 ml, 0.5N) three times. The aqueous phase is neutralized with NaHCtheta3, extracted with EtOAc (30 ml) three times, dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified by silica gel chromatography to provide methyl 5-(2-(tert-butoxycarbonyl(4-fluorobenzyl)amino)ethoxy)nicotinate (736.2 mg, 22%).

Reference： [1]Patent: WO2008/109613,2008,A1 .Location in patent: Page/Page column 223-224

28
[ 1007-15-4 ]
[ 30766-22-4 ]
[ 1100767-32-5 ]

Yield	Reaction Conditions	Operation in experiment
28%	With 18-crown-6 ether; 40% potassium fluoride/alumina; In acetonitrile; for 72h;Heating / reflux;	Methyl-5-hydroxynicotinate (1.0 g, 6.53 mmol), <strong>[1007-15-4]3'-bromo-4'-fluoroacetophenone</strong> (1.42 g, 6.53 mmol), 18-crown-6 (155.3 mg, 0.59 mmol) and potassium fluoride (40 wt. % on alumina, 996 mg, 6.86 mmol) were dissolved in ACN (10 ml_). The reaction was refluxed for three days. After cooling the mixture was quenched with 2N aqueous potassium carbonate solution, extracted with ether, dried with sodium sulphate, filtered, evaporated and purified by silica gel chromatography (ethyl acetate: n-heptane 1 :4). 635 mg (yield: 28%) of the pure compound was obtained. LC/MS (method D) (M+H)+: 351

Reference： [1]Patent: WO2009/7015,2009,A1 .Location in patent: Page/Page column 39-40

29
[ 100-39-0 ]
[ 30766-22-4 ]
[ 219817-42-2 ]

Yield	Reaction Conditions	Operation in experiment
50%		To a solution of 13.5 g (88.2 mmol) <strong>[30766-22-4]5-hydroxynicotinic acid methyl ester</strong> in 220 ml DMF were added in small portions 4.6 g (97 mmol) sodium hydride (55% dispersion in oil) at 0 C. After stirring at this temperature for 1 h a solution of 11 ml (93 mmol) benzyl bromide in 40 ml DMF was added dropwise over a period of 15 min. After completed addition the reaction mixture was allowed to warm to room temperature over night. The mixture was diluted with water and extracted with five portions of tert-butyl methyl ether. The combined organic extracts were washed with two portions of water, dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 10.7 g (50%) of the title compound as a light yellow solid.
50%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 6.5h;	(1) Methyl 5-(benzyloxy)nicotinate Methyl 5-hydroxynicotinate (3.8 g, 25 mmol), benzyl bromide (5.1 g, 30 mmol) and potassium carbonate (6.9 g, 50 mmol) were dissolved in N,N-dimethylformamide (150 mL), followed by stirring at 60 C. for 6.5 hours. After the reaction solution was concentrated under reduced pressure, the resulting residue was dissolved in ethyl acetate, and the organic layer was washed with water. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (Moritex Corporation, elution solvent:hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.50 (hexane/ethyl acetate=2/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (3.0 g, 12 mmol) as a yellow oil (yield 50%). 1H-NMR (500 MHz, CDCl3) delta: 8.84 (1H, s), 8.55 (1H, s), 7.85 (1H, s), 7.50-7.34 (5H, m), 5.15 (2H, s), 3.95 (3H, s).
30.7%	With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h;	Synthesis of methyl 5-(benzyloxy)nicotinate To a stirred solution of methyl 5-hydroxynicotinate (8.5 g, 55.6 mmol) and K2003 (11.5 g, 83.3 mmol) in DMF (20 mL) at 0 C was added (bromomethyl)benzene (8 mL,66.7 mmol) drop wise over 5 mm. The resulting mixture was stirred at room temperature for 2 hours. The mixture was quenched with water (100 mL) and extracted with EA (lOOmL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4. After filtration and evaporation of the solvent, the residue was purified by silica gel column chromatography eluting with petroleumether/ethyl acetate (4:1) to give methyl 5-(benzyloxy)nicotinate (4 g, 30.7%) as a yellow oil.

30.7%	With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 2.08h;	To a stirred solution of methyl 5-hydroxynicotinate (8.5 g, 55.6 mmol) and K2CO3 (11.5 g, 83.3 mmol) in DMF (20 mL) at 0 C. was added (bromomethyl)benzene (8 mL, 66.7 mmol) drop wise over 5 min. The resulting mixture was stirred at room temperature for 2 hours. The mixture was quenched with water (100 mL) and extracted with EA (100 mL*3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4. After filtration and evaporation of the solvent, the residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (4:1) to give methyl 5-(benzyloxy)nicotinate (4 g, 30.7%) as a yellow oil.
30.7%	With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 2.08333h;	To a stirred solution of methyl 5-hydroxynicotinate (8.5 g, 55.6 mmol) and K2CO3 (1 1 .5 g, 83.3 mmol) in DMF (20 mL) at 0 C was added (bromomethyl)benzene (8 mL, 66.7 mmol) drop wise over 5 min. The resulting mixture was stirred at room temperature for 2 hours. The mixture was quenched with water (100 mL) and extracted with EA (100ml_ x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4. After filtration and evaporation of the solvent, the residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (4:1 ) to give methyl 5-(benzyloxy)nicotinate (4 g, 30.7%) as a yellow oil.
30.7%	With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 2.08h;	To a stirred solution of methyl 5-hydroxynicotinate (8.5 g, 55.6 mmol) and K2CO3 (11.5 g, 83.3 mmol) in DMF (20 mL) at 0 C. was added (bromomethyl)benzene (8 mL, 66.7 mmol) drop wise over 5 min. The resulting mixture was stirred at room temperature for 2 hours. The mixture was quenched with water (100 mL) and extracted with EA (100 mL*3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4. After filtration and evaporation of the solvent, the residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (4:1) to give methyl 5-(benzyloxy)nicotinate (4 g, 30.7%) as a yellow oil.
28%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 16h;	Example 1.1.40: (5-(benzyloxy)pyridin-3-yl)methanamine; A mixture of 818 mg (5.34 mmol) of 5-hydroxynicotinic acid, 1.70 g (12.3 mmol) of K2CO3, and 1.0 mL (8.41 mmol) of benzyl bromide in 25 mL of DMF was heated at 60 0C under Ar for 16 h. The mixture was filtered through cotton, and the residue was dissolved in CHCl3. The organic layer was washed with water (2x30 mL), brine (30 mL), dried over <n="90"/>Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography provided 363 mg of methyl 5-(benzyloxy)nicotinate in 28% yield as an orange oil.
	With potassium carbonate; In acetone; for 5h;Heating / reflux;	Example 22 To a solution of methyl 5-hydroxynicotinate (5.0 g) in acetone (150 ml) were added potassium carbonate (13.5 g) and benzyl bromide (9.71 ml), followed by heating under reflux for 5 hours. The reaction mixture was cooled to room temperature, the insoluble material was then removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; EtOAc: methanol=10:1 (V/V)) to obtain methyl 5-benzyloxynicotinate (1.70 g) as a pale yellow crystal. To a mixed solution of methyl 5-benzyloxynicotinate (1.70 g) in methanol (40 ml)/THF (10 ml) was added a 1 M aqueous sodium hydroxide solution (7.34 ml) under ice-cooling, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the precipitated crystal was then collected by filtration, and washed with EtOAc to obtain sodium 5-benzyloxynicotinate (1.66 g). To a solution of sodium 5-benzyloxynicotinate (1.66 g) in DMF (26 ml) was added TEA (1.10 ml) at room temperature, and further diphenylphosphorylazide (1.56 ml) was added thereto under ice-cooling, followed by stirring at room temperature for 5 hours. To the reaction mixture was added water, followed by extraction with EtOAc, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain 5-(benzyloxy)nicotinoylazide. A solution of 5-(benzyloxy)nicotinoylazide (1.68 g) in Tol (20 ml) was stirred at 120C for 2 hours. This solution was added to a solution of 1-[3-(2-cyclohexylethoxy)benzoyl]piperazine hydrochloride (1.55 g) and TEA (1.23 ml) in THF (20 ml) under ice-cooling, followed by stirring for 2 hours, and further stirring at room temperature for 10 hours. To the reaction mixture was added water, followed by extraction with EtOAc, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, and saturated brine in this order, and then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (eluent; hexane:EtOAc=2:1 (V/V)) to obtain N-[5-(benzyloxy)pyridin-3-yl]-4-[3-(2-cyclohexylethoxy)benzoyl]piperazine-1-carboxamide (1.78 g) as a pale yellow amorphous substance. To a solution of N-[5-(benzyloxy)pyridin-3-yl]-4-[3-(2-cyclohexylethoxy)benzoyl]piperazine-1-carboxamide (1.78 g) in methanol (20 ml) was added 5% palladium carbon (698 mg), followed by stirring at room temperature overnight under a hydrogen atmosphere. The catalyst was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol=10:1 (V/V)) to obtain 4-[3-(2-cyclohexylethoxy)benzoyl]-N-(5-hydroxypyridin-3-yl)piperazine-1-carboxamide (1.15 g) as a pale yellow amorphous substance.

Reference： [1]Patent: US2006/30600,2006,A1 .Location in patent: Page/Page column 15-16
[2]Patent: US2011/112103,2011,A1 .Location in patent: Page/Page column 70
[3]Patent: WO2014/154727,2014,A1 .Location in patent: Page/Page column 43; 44
[4]Patent: US2014/296239,2014,A1 .Location in patent: Paragraph 0116; 0117
[5]Patent: WO2014/154726,2014,A1 .Location in patent: Page/Page column 43-44
[6]Patent: US2014/296296,2014,A1 .Location in patent: Paragraph 0125; 0126
[7]Patent: WO2009/42694,2009,A1 .Location in patent: Page/Page column 88-89
[8]Patent: EP2065369,2009,A1 .Location in patent: Page/Page column 40

30
[ 30766-22-4 ]
[ 1189816-87-2 ]

Yield	Reaction Conditions	Operation in experiment
93%	With iodine; sodium carbonate; In tetrahydrofuran; water; at 20℃; for 2.33h;Inert atmosphere;	Methyl 5-hydroxy-6-iodonicotinate To a solution of <strong>[30766-22-4]methyl 5-hydroxypyridine-3-carboxylate</strong> (9.50 g, 62.04 mmol) in water (200 mL) was added sodium carbonate (19.72 g, 186.08 mmol) at room temperature. The resulting solution was then added by a solution of I2 (39.35 g, 155.07 mmol) in THF (200 mL) dropwise over 2 h period at room temperature. The reaction mixture was stirred for 20 min at room temperature. When the reaction was done, it was quenched by the addition of NaHSO3 and the pH value of the mixture was adjusted to 4 with hydrogen chloride solution (12 N). The resulting mixture was extracted with ethyl acetate (100 mL*3) and the organic layers were combined, washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to yield methyl 5-hydroxy-6-iodopyridine-3-carboxylate as a off-white solid (16.28 g, 93%). MS: m/z=279.3 [M+H]+.
90%	With iodine; sodium carbonate; In tetrahydrofuran; water; at 20℃; for 4h;	To a solution of methyl 5-hydroxynicotinate (2.5?g, 16.3?mmol) in THF/H2O (50 mL/50?mL), was added Na2CO3 (5.2?g, 49?mmol) and I2 (11?g, 41?mmol).After stirred at room temperature for 4?h, the mixture was quenched with H2O (50?mL), and extracted with ethyl acetate (100?mL x 3).The combined organic mixture was washed with sat. Na2S2O3 (20?mL x 2), dried over Na2SO4 and concentrated to give 7b (4.1?g, 90%) as a grey solid. 1H NMR (400?MHz, DMSO-d6) delta 11.41 (s, 1H, OH), 8.33 (d, J?=?1.6?Hz, 1H, 2-pyridine H), 7.53 (d, J?=?2.0?Hz, 1H, 4-pyridine H), 3.86 (s, 3H, COOCH3).
86%	With iodine; sodium carbonate; In water; at 20℃;	To a solution of R-i (103 g, 67i mmol) in water (1.3 E) is added Na2CO3 (149 g, 1410 mmol) followed by iodine (170 g, 671 mmol). The reaction is stirred overnight at ambient temperature then neutralized with concentrated RC1. The solid is filtered, collected, and dried to afford I-i (161 g, 86%) m/z=280.7 [M+R], R1=0.4 (5i02, EtOAc/ petrol ether 3/7)

81.2%		Example 219; N-(2-chloro-4-(dimethylcarbamoyl)phenyl)-N-methyl-(3-hydroxymethyl-6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepine)-9-carboxamide 309; To solution of 5-hydroxy-nicotinic acid methyl ester (2.50 g, 16.3 mmol) in tetrahydrofuran (50.0 mL, 616 mmol)/water (50.0 mL, 2780 mmol) was added sodium carbonate (5.19 g, 49.0 mmol) and iodine (10.4 g, 40.8 mmol). The reaction mixture was stirred at room temperature 4 h. The aqueous layer containing product was separated and wash with hexane. The organic layer was neutralized to pH 7 with HCl, extracted EtOAc 4×. The combined organic layers was dried Na2SO4, concentrated. The crude product was purified by flash chromatography (EtOAc/DCM) (eluted at 40 EtOAc) to give methyl 5-hydroxy-6-iodonicotinate (81.2%). MS: (ESI+) 280.0
67%	With iodine; sodium carbonate; In tetrahydrofuran; water; at 20℃; for 4h;	To a stirred solution of methyl 5-hydroxynicotinate (10 g, 65.29 mmol) in a mixture of THF (200 mL) and water (200 mL) were added I2 (41.4 g, 163.2 mmol) and Na2C03 (20.7 g, 195.8 mmol) and the stirring was continued at RT for 4 h. Completion of the reaction was monitored by TLC. The reaction mixture was quenched with sat. aq. Na2S203 and then neutralized with aq. HCI (6 N). The resulting mixture was extracted with EtOAc (2 x 200 mL) and the combined organic layer was dried over Na2S04 and concentrated to afford the title compound. Yield: 67% (1.5 g, brown gum). 1H NMR (400 MHz, DMSO-cfe): d 1 1.42 (s, 1 H), 8.33 (d, J = 2.0 Hz, 1 H), 7.54 (d, J = 1.6 Hz, 1 H), 3.86 (s, 3H). LCMS: (Method A) 280.0 (M+H), Rt. 2.7 min, 92.5% (Max).
35%	With iodine; sodium carbonate; In water; at 20℃; for 1.5h;	The material from above (354 mg, 2.31 mmol) was suspended in water (35 ml). Sodium carbonate (490 mg, 4.62 mmol) and iodine (586 mg, 2.31 mmol) were added. The mixture was stirred at ambient temperature for 1.5 h. The mixture was neutralized using 1 M HC1. Theaqueous mixture was extracted with EtOAc and the combined organic layers were dried (Mg504) and evaporated. The residue was purified by flash chromatography using 2% MeOH in DCM as eluent. Yield: 226.3 mg; (35%) white solid.

Reference： [1]Patent: US2016/376283,2016,A1 .Location in patent: Paragraph 1041; 1042
[2]European Journal of Medicinal Chemistry,2018,vol. 149,p. 110 - 121
[3]Patent: US2018/354968,2018,A1 .Location in patent: Paragraph 0325; 0326
[4]Patent: US2009/247567,2009,A1 .Location in patent: Page/Page column 190
[5]Patent: WO2020/39028,2020,A1 .Location in patent: Page/Page column 139
[6]Patent: WO2017/108282,2017,A1 .Location in patent: Page/Page column 113

31
[ 1072002-52-8 ]
[ 30766-22-4 ]
methyl 5-([6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-yl]methoxy)nicotinate 5/2 hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%		(Example 17) Methyl 5-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-yl]methoxy}nicotinate 5/2 hydrochloride (5/2 hydrochloride of Compound No. 1-136) Tri-n-butylphosphine (0.61 g, 3.0 mmol) and 1,1'-(azodicarbonyl)dipiperidine (0.76 g, 3.0 mmol) were added to a solution of {6-[4-(tert-butyloxycarbonylamino)-3,5-dimethylphenoxy]-1-methyl-1H-benzimidazol-2-yl}methanol (0.60 g, 1.5 mmol) and methyl 5-hydroxynicotinate (0.34 g, 2.3 mmol) in toluene, followed by stirring for 10 hours. The reaction solution was concentrated and then purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate = 1/2). Then, a 4 N hydrogen chloride/1,4-dioxane solution (10 mL) was added, followed by stirring for two hours. The precipitated solid was collected by filtration and washed with ethyl acetate and ether. The desired title compound (0.48 g, yield: 61%) was obtained by drying under reduced pressure. 1H-NMR (DMSO-d6, 400 MHz) delta: 2.34 (6H, s), 3.91 (3H, s), 3.93 (3H, s), 5.80 (2H, s), 6.79 (2H, s), 7.15 (1H, dd, J = 2.0, 8.0 Hz), 7.58 (1H, d, J = 2.0 Hz), 7.78 (1H, d, J = 8.6 Hz), 8.09 (1H, dd, J = 1.6, 2.7 Hz), 8.75 (1H, d, J = 2.7 Hz), 8.78 (1H, d, J = 1.6 Hz). MS (ESI+) m/z: 433 (M+H)+, 455 (M+Na)+. HRMS (ESI+) m/Z: 433.18576 (M+H)+, calcd 433.18758 (-1.82 mmu).

Reference： [1]Patent: EP2138484,2009,A1 .Location in patent: Page/Page column 29-30

32
[ 106930-51-2 ]
[ 30766-22-4 ]
[ 1220512-31-1 ]

Reference： [1]European Journal of Medicinal Chemistry,2010,vol. 45,p. 1379 - 1386

33
[ 30766-22-4 ]
[ 150736-72-4 ]
C₁₆H₂₄N₂O₅ [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2010,vol. 45,p. 1379 - 1386

34
[ 30766-22-4 ]
[ 158932-00-4 ]
[ 1055968-89-2 ]

Reference： [1]European Journal of Medicinal Chemistry,2010,vol. 45,p. 1379 - 1386

35
[ 30766-22-4 ]
methyl cis-5-hydroxypiperidine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen;Rh/Al2O3; In methanol; at 70℃; under 3040.2 Torr; for 72h;	Step 1: Preparation of l-tert-butyl 3-methyl Lambdaralpha«s-5-hydroxypiperidine-l,3~dicarboxylateA solution of methyl 5-hydroxynicotinate (1.50 g) in MeOH (30 ml) was hydrogenated (ca. 4 atm) for 3 days in a Parr low-pressure hydrogenation apparatus with a 5 wt, % Rh on Al2O3 catalyst (300 mg) at 70 0C, Rh on Al2O3 catalyst was filtered off and the filtrate was concentrated in vacuo to give the crude methyl m-5~hydroxypiperidine-3-carboxylate as a pale yellow oil.The crude 3}5-cw~cordinated piperidine was dissolved into dioxane (30 ml). To the solution was added di-tert-butyl dicarbonate (3 ml) and TEA (3 ml) at room temperature. After 2 hours stirring at room temperature, the mixture was concentrated in vacuo. And the residue was purified with silica gel column chromatography (eluent : CHCl3 / MeOH = 100 / 0 ~ 90 / 10) to give -tert-buty 3-methyl £rar°-5-hydroxypiperidine-l,3-dicarboxylate as a pale yellow oil.

Reference： [1]Patent: WO2010/111056,2010,A1 .Location in patent: Page/Page column 32

36
[ 30766-22-4 ]
[ 915107-31-2 ]

Reference： [1]Patent: WO2011/48525,2011,A1
[2]Patent: US2016/376283,2016,A1

37
[ 30766-22-4 ]
[ 1095010-44-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	With Rh/Al2O3; hydrogen; In methanol; at 70℃; under 3102.97 Torr; for 72h;Sealed tube;	[00370] Step 1 : A solution of methyl 5-hydroxynicotinate (4.50 g, 29.4 mmol) in methanol (90 mL) in a 500 mL Parr bomb equipped with inlet valve and pressure gauge was treated with Rh/Al (5%) (1.21 g, 0.588 mmol) (Degussa type G214 RA/D, Aldrich catalog 663468). The bomb was sealed and purged with hydrogen gas for 5 minutes. The pressure was then adjusted to 60 psi with hydrogen gas and stirred at 70 C in an oil bath. After 24 hours, LC/MS shows a very early eluting peak with the correct mass for product plus a later eluting peak with starting material mass. The reaction was allowed to proceed for another 48 hours. LC/MS at that point showed complete loss of starting material, and the early eluting product peak as major. The reaction was filtered through GF/F filter paper with methanol, and the filtrate concentrated to provide methyl 5-hydroxypiperidine-3-carboxylate (4.6 grams, quantitative yield) as an oil. It is assumed that the cis product is favored.
	With palladium on activated charcoal; hydrogen; In acetic acid; at 60℃; under 2585.81 Torr;	Step B. Methyl 5-hydroxypiperidine-3-carboxylate. To a solution of methyl 5- hydroxynicotinate (100 g, 0.65 mol) in AcOH (1000 mL) was added Pd/C (20 g) at rt. The mixture was stirred under a hydrogen atmosphere (50 psi) at 60 C overnight. The reaction mixture was cooled to rt and filtered. The filtrate was concentrated under reduce pressure to afford the title compound as a brown oil, which was used in the next step without further purification. 1H NMR (DMSO-< 6, 400 MHz) delta 3.62 (s, 3H), 2.68-2.99 (m, 4H), 2.33-2.45 (m, 1H), 2.03-2.14 (m, 2H), 1.37-1.82 (m, 3H).

Reference： [1]Patent: WO2015/103137,2015,A1 .Location in patent: Paragraph 00370
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3095 - 3098
[3]Patent: WO2015/164508,2015,A1 .Location in patent: Page/Page column 52

38
[ 30766-22-4 ]
[ 1095010-47-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3095 - 3098
[2]Patent: WO2015/103137,2015,A1
[3]Patent: WO2015/164508,2015,A1

39
[ 30766-22-4 ]
[ 100-51-6 ]
[ 219817-42-2 ]

Yield	Reaction Conditions	Operation in experiment
71%	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 20℃;	Preparation of Compound A30:BnOH (3.90 g, 36.1 mmol, 1.1 eq) and PPh3 (17.1 g, 65.4 mmol, 2.0 eq) was added to a solution of compound A29 (5.00 g, 32.7 mmol) in THF (100 mL), then DEAD (6.80 g, 39.2 mmol, 1.2 eq) was added at 0 C. The mixture was stirred at room temperature for overnight. The solvent was evaporated, the residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate=10:1) to afford the compound A30 (5.70 g, yield: 71%) as white solid.1H NMR (300 MHz, CDCl3): delta: 8.83 (d, J=1.6 Hz, 1H), 8.54 (d, J=2.8 Hz, 1H), 7.85-7.86 (m, 1H), 7.27-7.46 (m, 5H), 5.15 (s, 2H), 3.95 (s, 3H).
71%	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 20℃;	[0444] Preparation of compound A29: A mixture of compound A28 (25.0 g, 180 mmol) and concentrated H2SO4 (10 mL) in CH3OH (100 mL) was heated to reflux for overnight. The mixture was concentrated, the residue was washed with aqueous NaHC03 (50 mL) and extracted with ethyl acetate (2 x 100 mL). The organic layer was dried over a2S04, filtered and concentrated to afford compound A29 (18.7 g, yield: 68%). [0445] 1H NMR (300 MHz, DMSO-i 6): delta: 10.42 (s, 1H), 8.60 (d, J = 1.6 Hz, 1H), 8.36 (d, J = 2.8 Hz, 1H), 7.60-7.61 (m, 1H), 3.87 (s, 3H). [0446] Preparation of compound A30: BnOH (3.90 g, 36.1 mmol, 1.1 eq) and PPh3 (17.1 g, 65.4 mmol, 2.0eq) was added to a solution of compound A29 (5.00 g, 32.7 mmol) in THF (100 mL), then DEAD (6.80 g, 39.2 mmol, 1.2eq) was added at 0C. The mixture was stirred at room temperature for overnight. The solvent was evaporated, the residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate = 10: 1) to afford the compound A30 (5.70 g, yield: 71%) as white solid. [0447] 1H NMR (300 MHz, CDC13): delta: 8.83 (d, J = 1.6 Hz, 1H), 8.54(d, J = 2.8 Hz, 1H), 7.85-7.86 (m, 1H), 7.27-7.46 (m, 5H), 5.15 (s, 2H), 3.95 (s, 3H). [0448] Preparation of compound A31: A solution of compound A30 (12.8 g, 52.9mmol) in methylamine alcohol solution in sealed tube was stirred at 70 C for overnight. Then the mixture was cooled to room temperature and the solvent was evaporated to afford the compound A31 (12.0 g, yield: 100%). [0449] 1H NMR (300 MHz, CDC13): delta: 8.50 (d, J = 1.6 Hz, 1H), 8.48(d, J = 2.8 Hz, 1H), 7.73-7.74 (m, 1H), 7.73-7.74 (m, 5H), 6.16(s, 1H), 3.15 (s, 2H), 3.04 (d, J = 4.4 Hz, 3H). A32 A33 [0450] Preparation of compound A32: The solution of compound A31 (11.0 g, 45.5 mmol) in SOCl2 (100 mL) was heated to reflux for 4h. Then, SOCl2 was removed under vacuum and the residue was dissolved in MeCN (200 mL). TMSN3 (12.5 g, 90.0 mmol, 2.0eq) was added slowly and the mixture was stirred at 90C for 3h. Then the solvent was evaporated and the residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate = 2: 3) to afford the compound A32 (9.50 g, yield: 78%). [0451] 1H NMR (300 MHz, CDC13): delta: 8.59 (d, J = 2.8 Hz, 1H), 8.56(d, J = 1.6 Hz, 1H), 7.68-7.69 (m, 1H), 7.3-7.46 (m, 5H), 5.21 (s, 2H), 4.17 (s, 3H). [0452] Preparation of compound A33: To a solution of compound A32 (5.00 g, 18.7 mmol) in CH3OH (100 mL) was added Pd(OH)2 ( 0.50 g), The mixture was stirred at room temperature under H2 atmosphere for 3h. The solid was filtered off and the filtrate was concentrated to get compound A33 (1.60 g, yield: 48%). [0453] 1H NMR (300 MHz, DMSO-i 6): delta: 10.56 (s, 1H), 8.49 (d, J = 1.6 Hz, 1H), 8.36(d, J = 2.8 Hz, 1H), 7.61-7.62 (m, 1H), 4.19(s, 3H).

Reference： [1]Patent: US2012/238751,2012,A1 .Location in patent: Page/Page column 33
[2]Patent: WO2014/43272,2014,A1 .Location in patent: Paragraph 0443; 0446; 0447

40
[ 100-39-0 ]
[ 30766-22-4 ]
[ 915107-30-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 7100 - 7105

41
[ 30766-22-4 ]
[ 71-36-3 ]
[ 1417411-58-5 ]

Yield	Reaction Conditions	Operation in experiment
50.3%		Intermediate 10 (I- 10)To a stirred solution of <strong>[30766-22-4]5-hydroxynicotinic acid methyl ester</strong> (0.8 g, 5.22 mmol) and di- tert-butylazadicarboxylate (1.8 g, 7.83 mmol) in THF (6 mL), triphenylphosphine (2.05 g, 7.83 mmol) was added portionwise at r.t.. The mixture was stirred at this temperature for 5 min and then BuOH (2 mL) was added and the stirring was continued at r.t. for 30 min. Then the solvent was evaporated and the crude compound purified by chromatography (silica, EtOAc in heptane 0/100 to 20/80) the desired fractions were collected and evaporated in vacuo to give intermediate 1-10 as colorless oil (0.55 g, 50.3%). CiiHisNOs, LCMS: Rt 2.71, m/z 210 [M + H]+ (method 8).
50.3%		Intermediate 3 (1-3) To a stirred solution of <strong>[30766-22-4]5-hydroxynicotinic acid methyl ester</strong> (0.8 g, 5.22 mmol) and di-tert-butylazadicarboxylate (1.8 g, 7.83 mmol) in THF (6 mL), triphenylphosphine (2.05 g, 7.83 mmol) was added portionwise at r.t.. The mixture was stirred at this temperature for 5 min and then BuOH (2 mL) was added and the stirring was continued at r.t. for 30 min. Then the solvent was evaporated and the crude compound purified by chromatography (silica, EtOAc in heptane 0/100 to 20/80) the desired fractions were collected and evaporated in vacuo to give intermediate 1-3 as colorless oil (0.55 g, 50.3%). CiiHisNOs, LCMS: Rt 2.71, m/z 210 [M + H]+ (method 5).

Reference： [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 282 - 286
[2]Patent: WO2013/924,2013,A1 .Location in patent: Page/Page column 61-62
[3]Patent: WO2014/1314,2014,A1 .Location in patent: Page/Page column 51
[4]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 1049 - 1053

42
[ 20098-48-0 ]
[ 30766-22-4 ]
[ 1428957-61-2 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 50℃; for 18h;	General procedure: A 4-halonitrobenzene (1.0 equiv), a hydroxyarene, and Cs2CO3 (1.1 equiv) were combined in DMF and the resulting heterogeneous mixture was stirred vigorously at 25-70 C until all 4-halonitrobenzene was consumed (2-24 h). The reaction mixture was diluted with H2O and was adjusted to pH 5 with 2 N HCl (aq). The solution was extracted three times with EtOAc, and the organic layers were combined, washed once with brine solution, dried over MgSO4, filtered and concentrated in vacuo to furnish the desired diaryl ether that was used directly without further purification.

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 979 - 992

43
[ 627-42-9 ]
[ 30766-22-4 ]
[ 874285-28-6 ]

Reference： [1]Organic Letters,2013,vol. 15,p. 168 - 171

44
[ 1196672-22-6 ]
[ 30766-22-4 ]
[ 1450659-62-7 ]

Yield	Reaction Conditions	Operation in experiment
70%		General procedure: To a solution of 1,3-benzenediol 218 mg (1.98 mmol) in 10 mL DMF at 0 C was added NaH (60% in mineral oil, 87 mg, 2.18 mmol). After 30 min, a solution of 4-bromopyridine 500 mg (1.98 mmol) in 4 mL DMF was introduced. The resulting reaction mixture was allowed to react at 0 C for additional 2 hours before quenched with 50 muL H2O. Most of the solvent was removed under reduced pressure and 15 mL H2O was added followed by an extraction with EtOAc, and the organic phase was dried over anhydrous Na2SO4. The crude product was further purified via silica-gel chromatography (EtOAc/Hexanes = 1/1), and a white solid 183 mg was obtained, 46%. M. p. 85-87 C. 1H NMR (500 MHz, DMSO) delta 5.11 (s, 2H), 6.36-6.38 (m, 2H), 6.42 (d, J = 8.0 Hz, 1H), 7.05 (t, J = 8.0 Hz, 1H), 7.40 (d, J =5.5 Hz, 2H), 8.56 (d, J = 5.5 Hz, 2H); 13C NMR (125 MHz, DMSO) delta 67.2, 102.0, 105.3, 108.3,121.7, 129.9, 146.4, 149.7, 158.6, 159.0 ppm; MS (ESI): 202.3 (M+H)+.
70%		With reference to scheme 5, ether synthesis was first used to connect the aminopyridine component to the pyridinyl linker, then the methyl ester was reduced with Dibal-H to the aldehyde. Reductive amination produced compound 34. (Compounds incorporating a chlorophenyl moiety are available through use of a corresponding chloro-substituted amine.) Compound 5 was obtained successfully after removing the protecting group.

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 5323 - 5331
[2]Patent: US2014/256016,2014,A1 .Location in patent: Paragraph 0023; 0024

45
[ 30766-22-4 ]
[ 74-95-3 ]
[ 4591-55-3 ]

Reference： [1]CrystEngComm,2013,vol. 15,p. 7257 - 7266

46
[ 30766-22-4 ]
[ 455-70-9 ]

Reference： [1]Organic Letters,2015,vol. 17,p. 544 - 547
[2]Organic Letters,2013,vol. 15,p. 5602 - 5605

47
[ 1400808-33-4 ]
[ 30766-22-4 ]
[ 1581683-73-9 ]

Yield	Reaction Conditions	Operation in experiment
44%	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 110℃; for 0.5h;	Example 3a Process to make of dimethyl 5,5'-((8-((tert- butoxycarbonyl)(methyl)amino)-6-fluoro-9H-pyrimido[4,5-Z>]indole-2,4- diyl)bis(oxy))dinicotinate: [0349] tert-butyl (2,4-bis(benzylsulfonyl)-6-fluoro-9H-pyrimido[4,5-]indol-8- yl)(methyl)carbamate (91mg, 0.146mmol), methyl 5-hydroxynicotinate (157mg, 1.022mmol) and potassium carbonate (121mg, 0.876mmol) were mixed in NMP (1.5ml) and heated at 110C for 30min. The crude reaction mixture was purified by RPLC to yield the title compound (40mg, 0.065mmol, 44%). LCMS m/z: 619.1 (M+l). of dimethyl 5-((4-((6-aminohexyl)amino)-8-((tert- butoxycarbonyl)(methyl)amino)-6-fluoro-9H-pyrimido[4,5-Z>]indol-2-yl)oxy)nicotinic acid: [0350] 5,5'-((8-((ieri-butoxycarbonyl)(methyl)amino)-6-fluoro-9H-pyrimido[4,5- ]indole-2,4-diyl)bis(oxy))dinicotinate (40mg, 0.065mmol) and hexane-l,6-diamine (75mg, 0.647mmol) were mixed in NMP (1ml) and heated at 110C for 2hours. 2M NaOH (excess) was added and the mixture was heated at 100C for 5min. The crude reaction mixture was purified by RPLC to yield the title compound (21mg, 0.052mmol, 72%). LCMS m/z: 568.2 (M+l). Macrocyclization: [0351] 5-((4-((6-aminohexyl)amino)-8-((iert-butoxycarbonyl)(methyl)amino)-6- fluoro-9H-pyrimido[4,5- ?]indol-2-yl)oxy)nicotinic acid (21mg, 0.037mmol), triethylamine (11.2mg, O.l l lmmol) and BOP (49.1mg, O.l l lmmol) were mixed in DCM/NMP (1 : 1, 2ml) at 0C. The mixture was warmed to 40C over a period of lh. LCMS indicated only traces of product formation. EDC (42.6mg, 0.222mmol) was added and the mixture was heated at 40 for a period of 2h. NMP (1ml) was added and the DCM removed under reduced pressure. The crude reaction mixture was purified by RPLC to yield the macrocyclic compound (15mg, 0.027mmol, 74%). LCMS m/z: 550.2 (M+l). Boc-deprotection of the Macrocyclic compound: [0352] The Boc-protected macrocycle (15mg, 0.027mmol) was mixed with DCM/TFA (4: 1, 1ml) and heated at 40C for 15min. To the stirring mixture was added diethyl ether (8ml) and hexane (2ml). The precipitated deprotected macrocycle was isolated in form of its TFA salt by filtration (13mg, 0.023mmol, 85%). LCMS m/z: 449.1 (M+l).

Reference： [1]Patent: WO2014/43272,2014,A1 .Location in patent: Paragraph 0348; 0349

48
[ 78-77-3 ]
[ 30766-22-4 ]
methyl 5-isobutoxypyridine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 5h;	To a solution of methyl 5-hydroxynicotinate (1.5 g, 9.80mmol) in dimethylformamide (20 ml) was added potassium carbonate (2.7 g, 19.6 mmol) and 1 -bromo-2-methylpropane (1 .2 ml_, 1 1 .0 mmol). The reaction mixture was stirred at 80C for 5 hours and then allowed to cool to room temperature. The mixture was concentrated at reduced pressure and the residue partitioned between ethyl acetate and water. After separation of the layers, the aqueous phase was re-extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate, filtered and the solvent evaporated at reduced pressure. The residue was purified by silica gel chromatography eluting with 0 - 100% ethyl acetate in iso-hexane to yield the title compound (1.29g, 63%). m/z 210 (MH+), C11 H 15NO3 exact mass 209.105.
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h;Inert atmosphere;	A) methyl 5-isobutoxynicotinate Under a nitrogen atmosphere, to a solution of methyl 5-hydroxynicotinate (5.00 g) in DMF (50 mL) were added isobutyl bromide (5.33 mL) and potassium carbonate (9.04 g), and the mixture was stirred at 80C for 2 hr. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give a crude product of the title compound (5.13 g) as a pale-brown oil.

Reference： [1]Patent: WO2015/135976,2015,A1 .Location in patent: Page/Page column 85
[2]Patent: EP2816032,2014,A1 .Location in patent: Paragraph 0466; 0467

49
[ 459-57-4 ]
[ 30766-22-4 ]
methyl 5-(4-formylphenoxy)nicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With potassium carbonate; In N,N-dimethyl-formamide; at 70℃;	A mixture of methyl 5-hydroxynicotinate (2 g, 0.01 mol), 4-fluorobenzaldehyde (2.1 g, 0.13 mol) and K2CO3 (3.6 g, 0.02 mol) in DMF (50 mL) was heated at 70 C for overnight. The mixture was diluted with water (100 mL) and extracted with EA (100 mL X 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by flash chromatography (PE/EA = 6/1, v/v) afforded methyl 5-(4- formylphenoxy)nicotinate as a yellow solid (2.2 g, 65%).

Reference： [1]Patent: WO2015/103317,2015,A1 .Location in patent: Page/Page column 78

50
[ 30766-22-4 ]
[ 1303974-96-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: palladium on activated charcoal; hydrogen / acetic acid / 60 °C / 2585.81 Torr 2.1: triethylamine / methanol / 0 - 20 °C / Inert atmosphere 3.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 1 h / -60 °C / Inert atmosphere 3.2: 1 h / -60 °C
	Multi-step reaction with 2 steps 1.1: Rh/Al<SUB>2</SUB>O<SUB>3</SUB>; sulfuric acid; hydrogen / methanol / 26 h / 80 °C / 7500.75 Torr / Inert atmosphere 1.2: 3 h / 20 °C 2.1: Dess-Martin periodane / dichloromethane / 3.25 h / 20 °C

Reference： [1]Current Patent Assignee: DART NEUROSCIENCE LLC - WO2015/164508, 2015, A1
[2]Hauke, Tobias J.; Wein, Thomas; Höfner, Georg; Wanner, Klaus T. [Journal of Medicinal Chemistry, 2018, vol. 61, # 22, p. 10310 - 10332]

51
[ 30766-22-4 ]
[ 1255667-06-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: palladium on activated charcoal; hydrogen / glacial acetic acid / 60 °C / 2585.81 Torr 2.1: triethylamine / methanol / 0 - 20 °C / Inert atmosphere 3.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 1 h / -60 °C / Inert atmosphere 3.2: 1 h / -60 °C 4.1: diethylamino-sulfur trifluoride / dichloromethane / -20 °C / Inert atmosphere
	Multi-step reaction with 6 steps 1.1: hydrogen; glacial acetic acid; palladium 10% on activated carbon / 72 h / 70 °C / 2585.81 Torr 2.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C 3.1: oxalyl dichloride / dimethyl sulfoxide; dichloromethane / 2 h / -78 °C 3.2: 0.5 h / -78 °C 4.1: diethylamino-sulfur trifluoride / dichloromethane / 0 - 20 °C 5.1: hydrogen; Pearlman’s catalyst; palladium 10% on activated carbon / methanol / 20 °C 6.1: triethylamine / dichloromethane / 20 °C

Reference： [1]Current Patent Assignee: DART NEUROSCIENCE LLC - WO2015/164508, 2015, A1
[2]Current Patent Assignee: INVENTISBIO CO LTD - WO2022/2102, 2022, A1

52
[ 30766-22-4 ]
[ 67-63-0 ]
[ 874285-24-2 ]

Yield	Reaction Conditions	Operation in experiment
24%		A mixture of DCC (1 .62 g, 7.84 mmol) and CuCI (129 mg, 1.31 mmol) in isopropanol (20 mL) was heated at 60 C. After 13 hours, <strong>[30766-22-4]5-hydroxynicotinic acid methyl ester</strong> (1 .0 g, 6.53 mmol) and benzene (20 mL) were added and the reaction heated at 105 C for 24 hours. The mixture was diluted with chloroform and filtered. The organic filtrate was washed with saturated NaHC03 (15 mL), water and brine, dried ( a2S04) and concentrated. Purification by flash silica gel chromatography (EtOAc/petroleum ether = 1/6) gave the title compound (300 mg, 24%) as a white solid. LCMS-C: RT 2.32 min; m/z 196.1 [M+H]

Reference： [1]Patent: WO2016/34673,2016,A1 .Location in patent: Page/Page column 126

53
[ 30766-22-4 ]
[ 3958-57-4 ]
methyl 5-((3-nitrobenzyl)oxy)nicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;	Methyl 5-((3-Nitrobenzyl)oxy)nicotinate (IA2) To a solution of 3-nitrobenzyl bromide (IA1, 9.50 g, 44 mmol) in DMF (80 mL) were added methyl 5-hydroxynicotinate (6.12 g, 40 mmol) and Cs2CO3 (26.1 g, 80 mmol) and the mixture was allowed to stir at rt for 12 h. After water (200 ml) was added, the precipitate was filtered, washed with hexanes, and dried in vacuo to yield compound IA2 as a light yellow solid (8.64 g, 75%). 1H NMR (CDCl3, 600 MHz) delta 8.89 (d, J=1.2 Hz, 1H), 8.58 (d, J=3.0 Hz, 1H), 8.35 (s, 1H), 8.24 (d, J=8.4 Hz, 1H), 7.87 (dd, J=3.0, 1.8, Hz, 1H), 7.79 (d, J=7.2 Hz, 1H), 6.61 (dd, J=7.8, 7.8 Hz, 1H), 5.25 (s, 2H), 3.97 (s, 3H). HRMS (ESI+) calcd for C14H13N2O5 (M+H)+ 289.0824, found 289.0820.

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 2928 - 2941
[2]Patent: US2016/376238,2016,A1 .Location in patent: Paragraph 0102; 0103
[3]ChemMedChem,2020

54
[ 30766-22-4 ]
sodium 5-hydroxypiperidine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen; sodium hydroxide; In water; at 20℃; under 3000.3 Torr; for 24h;	Methyl 3-hydroxynicotinate (1.51 g) was dissolved in a mixture of water (40 mL) and 6 mol/L sodium hydroxide aqueous solution (5 mL) by sonication. After adding of rhodium (0.75 g; supported by 5% weight alumina), the reaction mixture was stirred for 24 hours at room temperature under a medium pressure-hydrogen atmosphere (0.4 MPa). The reaction solution was filtered with Celite, and the filtrate was concentrated under reduced pressure to give sodium 5-hydroxypiperidine-3-carboxylate as a white solid. In a 200 mL recovery flask, the sodium 5-hydroxypiperidine-3-carboxylate described above was suspended into methanol (10 mL). To the mixture, a methanol solution (5 mL) of Boc2O (2.18 g) was added while stirring. After stirred for 1.5 hours at room temperature, the reaction solution was neutralized with 0.2 mol/L hydrochloric acid (20 mL). After extraction with ethyl acetate (150 mL), the organic layer was dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, the obtained residue was purified with silica gel column chromatography (chloroform/methanol=96/4 to 88/12) to give 1-(tert-butoxycarbonyl)-5-hydroxypiperidine-3-calboxylic acid (794 mg) as a solid. 1H NMR (300 MHz, CDCl3) delta 1.46 (s, 9H), 1.70-1.90 (m, 1H), 2.15-2.30 (m, 1H), 2.55-2.70 (m, 1H), 3.00-3.15 (m, 1H), 3.35 (br, 1H), 3.60-3.95 (m, 4H) MS m/z 244 [M-H]

Reference： [1]Patent: US2016/221948,2016,A1 .Location in patent: Paragraph 0396-0399

55
[ 56124-60-8 ]
[ 30766-22-4 ]
methyl 5-((4-nitro-2,3-dihydro-1H-inden-1-yl)oxy)nicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 12h;	Methyl 5-((4-Nitro-2,3-dihydro-1H-inden-1-yl)oxy)nicotinate (IC3a) To a solution of IC2a (1.28 g, 7.16 mmol), methyl 5-hydroxynicotinate (1.32 g, 8.59 mmol), and Ph3P (2.82 g, 10.7 mmol) in anhydrous THF (45 mL) at rt was added DIAD (2.17 g, 10.7 mmol) dropwise. After the mixture was stirred for 12 h and the solvent removed, the residue was purified by flash column chromatography (EtOAc/hexanes) to afford IC3a as a yellow solid (1.70 g, 76%). 1H NMR (600 MHz, DMSO) delta 8.74 (s, 1H), 8.61 (d, J=3.0 Hz, 1H), 8.20 (d, J=7.8 Hz, 1H), 7.93 (s, 1H), 7.88 (d, J=6.6 Hz, 1H), 7.59 (dd, J=7.8, 7.8 Hz, 1H), 6.17 (dd, J=4.2, 6.6 Hz, 1H), 3.91 (s, 3H), 3.52-3.45 (m, 1H), 3.40-3.34 (m, 1H), 2.71-2.64 (m, 1H), 2.17-2.10 (m, 1H). HRMS (ESI+) calcd for C16H15N2O5 (M+H)+ 315.0975, found 315.0983.

Reference： [1]Patent: US2016/376238,2016,A1 .Location in patent: Paragraph 0264; 0268

56
C₇H₄⁽²⁾H₂BrNO₂ [ No CAS ]
[ 30766-22-4 ]
C₁₄H₁₀⁽²⁾H₂N₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;	ID37 (0370) A mixture of methyl 5-hydroxynicotinate (1.03 g, 6.10 mmol), CsCO3 (3.97 g, 12.2 mmol) and ID36 (1.33 g, 6.10 mmol) in DMF (80 mL) was allowed to stir at rt for 12 h. After water (200 mL) was added, the precipitate was filtered, washed with hexanes, and dried in vacuo to afford ID37 as a white solid (1.40 g, 79%). 1H NMR (CDCl3, 600 MHz) delta 8.89 (d, J=1.8 Hz, 1H), 8.57 (d, J=3.0 Hz, 1H), 8.35 (dd, J=1.8, 1.8 Hz, 1H), 8.24 (dd, J=7.8, 1.8 Hz, 1H), 7.87 (dd, J=3.0, 1.8 Hz, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.62 (dd, J=8.1, 8.1 Hz, 1H), 3.97 (s, 3H). HRMS (ESI+) calcd for C14H11D2N2O5 (M+H)+ 291.0945, found 291.0955.

Reference： [1]Patent: US2016/376238,2016,A1 .Location in patent: Paragraph 0370

57
[ 30766-22-4 ]
[ 98799-27-0 ]
C₁₅H₁₄N₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;	IF4a (0411) A mixture of methyl 5-hydroxynicotinate (0.893 g, 5.83 mmol), CsCO3 (3.45 g, 10.6 mmol) and IF3a (1.22 g, 5.30 mmol) in DMF (80 mL) was allowed to stir at rt for 12 h. After water (200 mL) was added, the solid precipitate was filtered, washed with hexanes, and dried under vacuum to afford IF4a as a light yellow solid (1.14 g, 71%). 1H NMR (CDCl3, 600 MHz) delta 8.90 (d, J=1.8 Hz, 1H), 8.59 (d, J=3.0 Hz, 1H), 8.35 (d, J=2.4 Hz, 1H), 8.15 (dd, J=7.8, 2.4 Hz, 1H), 7.90 (dd, J=3.0, 1.8 Hz, 1H), 7.41 (d, J=7.8 Hz, 1H), 5.18 (s, 2H), 3.98 (s, 3H), 2.49 (s, 3H). HRMS (ESI+) calcd for C15H15N2O5 (M+H)+ 303.0976, found 303.0985.

Reference： [1]Patent: US2016/376238,2016,A1 .Location in patent: Paragraph 0395; 0411

58
[ 23876-13-3 ]
[ 30766-22-4 ]
C₁₅H₁₄N₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
320 mg	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 12h;	IF4f (0416) To a solution of IF2f (700 mg, 4.19 mmol) and methyl 5-hydroxynicotinate (706 mg, 4.61 mmol) and Ph3P (1.65 g, 6.29 mmol) in anhydrous THF (40 mL) at rt was added DIAD (1.27 g, 6.29 mmol) dropwise. After the mixture was allowed to stir at rt for 12 h and the solvent removed, the resulting residue was purified by flash column chromatography (EtOAc/hexanes) to afford IF4f as a yellow solid (320 mg, 255). 1H NMR (CDCl3, 600 MHz) delta 7.88 (d, J=7.8 Hz, 1H), 7.82 (s, 1H), 7.61 (s, 1H), 7.45 (dd, J=7.8, 7.8 Hz, 1H), 7.40 (s, 1H), 7.35 (d, J=7.8 Hz, 1H), 5.40 (s, 2H), 3.93 (s, 3H), 2.42 (s, 3H). HRMS (ESI+) calcd for C15H15N2O5 (M+H)+ 303.0976, found 303.0980.

Reference： [1]Patent: US2016/376238,2016,A1 .Location in patent: Paragraph 0395; 0416

59
[ 30766-22-4 ]
[ 1256810-93-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: hypochloric acid / water / 1.16 h / 0 °C / Inert atmosphere 2: N,N-dimethyl-formamide / 8 h / 20 °C / Inert atmosphere 3: phosphorus(V) oxybromide / toluene / 16 h / 90 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: MERCK KGAA - US2016/376283, 2016, A1

60
[ 30766-22-4 ]
[ 586-78-7 ]
[ 284462-57-3 ]

Yield	Reaction Conditions	Operation in experiment
85%	With caesium carbonate; In N,N-dimethyl-formamide; at 140℃; for 4h;	In a round-bottom flask, mix 4.2 g (0.02 mol) of methyl 5- hydroxypyridine-3-carboxylate, 50 ml of DMF, 13 g (0.04 mol) of Cs2CO3 and 4.44 g (0.022 mol) of 1-bromo-4-nitrobenzene. Heat the reaction mass to 140 and stir at this temperature for 4 h; use the TLC method to ensure the completeness of the reaction. Distill off the solvent under the reduced pressure, add 50 ml of water. Filter the resulting precipitate, wash with 15 ml of water and 15 ml of hexane. Yield: 4.66 g (85%).

Reference： [1]Patent: WO2018/92047,2018,A1 .Location in patent: Page/Page column 118-119

61
[ 239074-29-4 ]
[ 30766-22-4 ]
methyl 5-((trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)methoxy)nicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.12 g	With azodicarboxylic acid bis(2-methoxyethyl) ester; triphenylphosphine; In tetrahydrofuran; at 20℃;Cooling with ice;	To a solution of <strong>[239074-29-4]tert-butyl (trans-4-(hydroxymethyl)cyclohexyl)carbamate</strong> (0.10 g, 0.44 mmol), methyl 5-hydroxynicotinate (0.10 g, 0.65 mmol) and triphenylphosphine (0.17 g, 0.65 mmol) in THF (5 mL), bis (2-methoxyethyl) azodicarboxylate (0.15 g, 0.65 mmol) was added under cooling on ice. After stirring the obtained solution overnight at room temperature, water was added to the reaction solution, and the obtained solution was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under vacuum. The obtained crude product was purified by silica gel column chromatography (eluent; hexane:ethyl acetate = 80:20 ? 55:45) to obtain the title compound (0.12 g). 1H-NMR (400 MHz, CDCl3) delta (ppm): 1.13 - 1.24 (4H, m), 1.45 (9H, s), 1.76 - 1.80 (1H, m), 1.94 - 1.96 (2H, m), 2.06 - 2.09 (2H, m), 3.42 (1H, brs), 3.84 (2H, d, J = 6.3 Hz), 3.95 (3H, s), 4.41 (1H, brs), 7.73 - 7.73 (1H, m), 8.45 (1H, d, J = 2.9 Hz), 8.81 (1H, d, J = 1.5 Hz).

Reference： [1]Patent: EP3345893,2018,A1 .Location in patent: Paragraph 0343

62
[ 30766-22-4 ]
[ 18162-48-6 ]
methyl 5-[(tert-butyldimethylsilyl)oxy]-nicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With 1H-imidazole; In dichloromethane; at 20℃; for 10h;Inert atmosphere;	Under an argon stream,Imidazole (1.8 g, 26 mmol) was added dropwise to a solution of methyl 5-hydroxynicotinate (Compound 11) (2.0 g, 13 mmol), tert-butyldimethylchlorosilane (2.4 g, 16 mmol) in dichloromethane And the mixture was stirred at the same temperature for 10 hours. After completion of the reaction, distilled water was added and the mixture was extracted three times with chloroform. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4 (volume ratio)) , Compound 12 (known compound) was obtained as a pale yellow liquid (3.4 g, yield 95%).

Reference： [1]Patent: JP2015/193545,2015,A .Location in patent: Paragraph 0023; 0073; 0074

63
[ 30766-22-4 ]
[ 161511-85-9 ]
(S)-methyl 5-((1-(tert-butoxycarbonyl)azetidine-2-yl)methoxy)nicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; toluene; at 0 - 20℃; for 24h;Inert atmosphere;	Triphenylphoshine (1052 mg, 4.01 mmol), 40% diethyl azodicarboxylatetoluene solution (698 mg, 4.01 mmol), and methyl 5-hydroxynicotinate(613 mg, 4.01 mmol) were added to a solution of 6(500 mg, 2.67 mmol) in tetrahydrofuran (18.0 mL) at 0 C under nitrogenatmospheric conditions. The resulting mixture was stirred for10 min and for an additional 24 h at room temperature and concentratedunder reduced pressure. The residue was purified by silica gelcolumn chromatography (petrolem ether/ethyl acetate=1/1) to yield7 (766 mg, 89%) in the form of a colorless oil: 1H NMR (300 MHz,CDCl3) delta: 8.83 (d, J=1.3 Hz, 1H), 8.51 (d, J=2.8 Hz, 1H), 7.81 (dd,J=2.8, 1.3 Hz 1H), 4.58-4.51 (m, 1H), 4.41-4.36 (m, 1H), 4.17 (dd,J=6.9, 2.9 Hz, 1H), 3.95 (s, 3H), 3.90 (t, J=7.5 Hz, 2H), 2.41-2.34(m, 1H), 2.31-2.26 (m, 1H), 1.42 (s, 9H); 13C NMR (75 MHz, CDCl3) delta:165.5, 155.9, 155.8, 142.9, 142.4, 126.3, 120.8, 79.5, 68.7, 59.8, 52.2, 46.9, 28.2 (3), 18.8; IR (CHCl3) cm-1: 3007, 2978, 2934, 1724, 1686,1589, 1394, 1367, 1302, 1151; FAB-MS m/z: 323.1611 (Calcd forC16H23N2O5: 323.1607); MS (FAB) m/z:323 (M++H, 62);[alpha]D20=-60.28 (c=1.01, CHCl3).
88%	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; toluene; at 0 - 20℃;Inert atmosphere;	Under N2 stream, to a solution of 1 (0.50 g, 2.7 mmol) in THF(18 mL), triphenylphosphine (0.61 g, 4.0 mmol), diethyl azodicarboxylate (40% solution in toluene, 1.87 mL), and methyl 5-hydroxynicotinate(0.61 g, 4.0 mmol) at 0 C were added. The mixture was stirred at 0 C for 10 min and then warmed up to room temperature and stirred overnight. After the reaction, solvent was removed under reduced pressure, followed by silica gel chromatography (petroleume ther/ethyl acetate=1/1) to yield 2 (0.77 g, 2.4 mmol, 88%) as a colorless oil. 1H NMR (300 MHz, CDCl3) delta; 8.83 (d, J=1.3 Hz, 1H),8.51 (d, J=2.8 Hz, 1H), 7.81 (dd, J=2.8, 1.3 Hz, 1H), 4.58-4.51 (m,1H), 4.41-4.36 (m, 1H), 4.17 (dd, J=6.9, 2.9 Hz, 1H), 3.95 (s, 3H),3.90 (t, J=7.5 Hz, 2H), 2.41-2.34 (m, 1H), 2.31-2.26 (m, 1H), 1.42 (s,9H). 13C NMR (75 MHz, CDCl3) delta; 165.5,155.9, 155.8, 142.9, 142.4,126.3, 120.8, 79.5, 68.7, 59.8, 52.2, 46.9, 28.2, 18.8. MS (FAB+) m/z;323 ([M+H]+). HRMS (FAB+) m/z; 323.1611 (Calcd: 323.1607 for C16H23N2O5+). [alpha]D20= -60.28 (c=1.01, CHCl3).

Reference： [1]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 2245 - 2252
[2]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 4200 - 4210

64
[ 30766-22-4 ]
[ 1095010-45-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: hydrogen; glacial acetic acid; palladium 10% on activated carbon / 72 h / 70 °C / 2585.81 Torr 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C

Reference： [1]Current Patent Assignee: INVENTISBIO CO LTD - WO2022/2102, 2022, A1

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[ 30766-22-4 ] Synthesis Path-Upstream 1~9

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