[ CAS No. 158669-26-2 ] {[proInfo.proName]}

Name: 158669-26-2|4-Iodo-2-methoxynicotinaldehyde|98%
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Quality Control of [ 158669-26-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 158669-26-2 ]

Product Details of [ 158669-26-2 ]

CAS No. :	158669-26-2	MDL No. :	MFCD05662396
Formula :	C₇H₆INO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	GNBKAOHTTIVAMT-UHFFFAOYSA-N
M.W :	263.03	Pubchem ID :	10038381
Synonyms :

Calculated chemistry of [ 158669-26-2 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	48.83
TPSA :	39.19 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.0 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.65
Log Po/w (XLOGP3) :	1.27
Log Po/w (WLOGP) :	1.51
Log Po/w (MLOGP) :	0.84
Log Po/w (SILICOS-IT) :	2.44
Consensus Log Po/w :	1.54

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.54
Solubility :	0.754 mg/ml ; 0.00287 mol/l
Class :	Soluble
Log S (Ali) :	-1.69
Solubility :	5.34 mg/ml ; 0.0203 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-3.05
Solubility :	0.232 mg/ml ; 0.000883 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	1.84

Safety of [ 158669-26-2 ]

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

Application In Synthesis of [ 158669-26-2 ]

* 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 [ 158669-26-2 ]
Downstream synthetic route of [ 158669-26-2 ]

[ 158669-26-2 ] Synthesis Path-Upstream 1~8

1
[ 124-41-4 ]
[ 113975-22-7 ]
[ 109-94-4 ]
[ 158669-26-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; n-heptane at -75 - -20℃; for 2 h; Stage #2: at -75℃; for 0.166667 h; Stage #3: at -75 - 20℃;	A mixture of DIPA (3.5 mL, 25 mmol) in THF (100 mL) was cooled to -20 °C and nBuLi (2.7 M in heptane, 9.2 mL, 25 mmol) was added dropwise. After stirring 10 mm, the r.m. was cooled to -75 °C and 2-fluoro-3-iodopyridine (5.55 g, 25 mmol) in THF (50 mL) was added dropwise. Stirring was continued for 2 h at -65 °C. The r.m. was cooled to -75 °C and ethyl formate (2.3 mL, 28 mmol) in THF (25 mL) was added dropwise. After 10 mill sodium methoxide (5.8 mL, 0.95 g/mL, 25 mmol, 25percent purity) was added dropwise. The cooling bath was removed and the r.m. was allowed to come to r.t. and treated with brine (50 mL), Et20 (100 mL) and the layers were separated. The aq. layer was extracted with Et20 (100 mL) and the combined organic layers weretreated with brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo to afford intermediate 1 (6.15 g, 94percent), which was used as such in the next reaction step.
64%	Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran at -78 - -8℃; for 2.5 h; Stage #2: at -78 - 20℃; Stage #3: With water In tetrahydrofuran; methanol at 0℃;	To a solution of diisopropylamine (345 mL, 249 g, 2.46 mol) in anhydrous THF (5 L) at -8 to -10° C. under a blanket of N₂was added n-BuLi (880 mL, 158 g, 2.46 mol) dropwise via cannula. The mixture was stirred at -10° C. for 30 min, cooled to -78° C. and treated with a solution of 2-fluoro-3-iodopyridine (500 g, 2.24 mol) in dry THF (2 L) dropwise. After the addition, the reaction mixture was warmed to -60° C. and this temperature was maintained for 2 h. The mixture was then cooled to -78° C., treated with ethyl formate (183 g, 2.47 mol) dropwise, followed by sodium methoxide (149 g, 2.75 mol) in MeOH (1.5 L) and warmed to ambient temperature. The reaction mixture was quenched with ice water and extracted with EtOAc. The layers were separated and the organic phase was washed with water and brine, dried (Na₂SO₄) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to afford 4-iodo-2-methoxynicotinaldehyde (380 g, 64percent) as a solid.
44 g	Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -66 - -10℃; for 2 h; Inert atmosphere Stage #2: at -66℃; Inert atmosphere	Under the stream of nitrogen, a THF (500 mL) solution of diisopropylamine (25 g) was added into a 2L-fourneckedflask. The solution was cooled to -25°C, and n-butyl lithium - hexane solution (1.57 mol/L) (157 mL) was droppedto the solution for 20 minutes (-25°C → -15°C), and the solution was stirred at -10°C for 30 minutes. The resulting solutionwas cooled to -66°C, and a THF (200 mL) solution of 2-fluoro-3-iodopyridine (CAS registration No.: 113975-22-7) (50g) was dropped thereto for 25 minutes, and stirred at -60°C for two hours. The resulting solution was cooled to -66°C,and ethyl formate (18.3 g) was dropped thereto for 10 minutes. Then, 28percent solution of sodium methoxide methanolsolution (53.2 g) in methanol (100 mL) was dropped, and lifted up from dry ice bath. The resulting product was naturallycooled to room temperature, and ice water (100 mL) was dropped thereto. A saturated saline solution (1 L) was addedthereto. The resulting solution was extracted with ethyl acetate (1 L), and washed with water (700 mL) and a saturatedsaline solution (700 mL). The water layer was combined and extracted with ethyl acetate (500 mL 3 2), and washedwith water (500 mL) and a saturated saline solution (500 mL). The organic layer was combined and dried over anhydroussodium sulfate, and the solvent was removed by evaporation under reduced pressure. The obtained residue was purifiedby column chromatography on silica gel (hexane : ethyl acetate = 9:1 → 6:1 → 5:1 → 4:1 → 3:1) to obtain the titlecompound (44 g) having the following physical property values

Reference： [1] Patent: WO2018/162444, 2018, A1, . Location in patent: Page/Page column 25; 26
[2] Patent: US2008/114033, 2008, A1, . Location in patent: Page/Page column 7
[3] Patent: EP3067356, 2016, A1, . Location in patent: Paragraph 0375

2
[ 1628-89-3 ]
[ 105669-53-2 ]
[ 158669-26-2 ]

Yield	Reaction Conditions	Operation in experiment
29%	Stage #1: With 2,4,6-trimethylphenyl bromide; tert.-butyl lithium In tetrahydrofuran at -78 - 0℃; for 3 h; Stage #2: at -78℃; for 0.5 h;	Synthesis of Difluoro Compound General Scheme; [00632] 4-Iodo-2-methoxynicotinic aldehyde: To a solution of t-BuLi (1.7 M, 7.36 niL, 12.51 mmol) in 20 niL THF at -78 °C was added dropwise 2-bromomesitylene (0.91 niL, 5.95 mmol). After stirred for 1 h, 2-methoxypyridine (0.48 mL, 4.58 mmol) was added dropwise, and the mixture was warmed to 0 °C and stirred for 2 h. The solution was cooled to -78 °C and JV-formyl-iV, iV,7V-trimethylethylenediamine (0.7 mL, 5.06 mmol) was added. The mixture was stirred at -78 °C for 30 min and then warmed to -23 °C. A hexane solution of W-BuLi (2.5 M, 2.75 mL, 6.87 mmol) was added dropwise, and the resulting yellow mixture was stirred for 3 h. The mixture was cooled to -78 °C and transferred via a double- tipped needle to a solution of iodine (2.17 g, 8.23 mmol) in 30 mL of THF at -78 °C. After stirred at -78 °C for 30 min, the cooling bath was removed and the reaction mixture was allowed to warm to the room temperature. After the reaction mixture was cooled to -5 °C, aqueous solution OfNH₄Cl (20 mL) was added dropwise and stirred for 15 min. The reaction mixture was poured into brine (300 mL) and extracted with EtOAc (5 xlOO mL). The combined extracts were washed with brine (2 x 50 mL), dried over Na₂SO₄ and concentrated. The residue was purified by chromatography (25:1 hexanes/EtOAc) to afford the title <n="345"/>compound (350 mg, 29percent). ¹H NMR (CDCl₃) δ 4.05 (s, 3H, CH₃), 7.53 (d, J= 6 Hz, IH, ArH), 7.85 (d, J= 6 Hz, IH, ArH), 10.20 (s, IH, CHO).

Reference： [1] Tetrahedron, 2002, vol. 58, # 32, p. 6329 - 6341
[2] Patent: WO2007/56155, 2007, A1, . Location in patent: Page/Page column 341-343
[3] Journal of Organic Chemistry, 1994, vol. 59, # 21, p. 6142 - 1643
[4] Patent: US2004/44203, 2004, A1, . Location in patent: Page 26

3
[ 124-41-4 ]
[ 22282-70-8 ]
[ 109-94-4 ]
[ 158669-26-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; n-heptane at -75 - -65℃; for 2 h; Stage #2: at -75 - 20℃;	A mixture of DIP A (3.5 mL, 25 mmol) in THF (100 mL) was cooled to -20 °C and n- BuLi (2.7 M in heptane, 9.2 mL, 25 mmol) was added dropwise. After stirring 10 min, the r.m. was cooled to -75 °C and 2-fluoro-3-iodopyridine (5.55 g, 25 mmol) in THF (50 mL) was added dropwise. Stirring was continued for 2 h at -65 °C. The r.m. was cooled to -75 °C and ethyl formate (2.3 mL, 28 mmol) in THF (25 mL) was added dropwise. After 10 min sodium methoxide (5.8 mL, 0.95 g/mL, 25 mmol, 25percent purity) was added dropwise. The cooling bath was removed and the r.m. was allowed to come to r.t. and treated with brine (50 mL), Et₂0 (100 mL) and the layers were separated. The aq. layer was extracted with Et₂0 (100 mL) and the combined organic layers were treated with brine (50 mL), dried over MgSC^, filtered and concentrated in vacuo to afford intermediate 1 (6.15 g, 94percent), which was used as such in the next reaction step.

Reference： [1] Patent: WO2018/162445, 2018, A1, . Location in patent: Page/Page column 28; 29

4
[ 916851-24-6 ]
[ 158669-26-2 ]

Yield	Reaction Conditions	Operation in experiment
54%	Stage #1: With tert.-butyl lithium In tetrahydrofuran; pentane at -75 - -60℃; for 1 h; Stage #2: at -75 - -60℃; for 0.5 h;	Synthesis of 4-iodo-2-methoxypyridine-3-carbaldehyde (DeTMS-PM) t-Butyllithium (1.5 M in n-pentane, 6.9 mL, 9.16 * 1.1 mmol) was added dropwise to a dry THF (7.5 mL) solution of 2-methoxypyridine (1.00 g, 9.16 mmol) between -75°C and -60°C and stirred at the same temperature for 1 hour. A dry THF (10 mL) solution of FEO (1.44 g, 9.16 * 1.2 mmol) was added dropwise at the same temperature and stirred for 30 minutes. The temperature was raised to around -23°C, ethylene glycol dimethyl ether (DME, organic synthesis grade, 7.5 mL) was added, and subsequently n-butyllithium (1.6 M in n-hexane, 9.9 mL, 9.16 * 1.7 mmol) was added dropwise at between -15°C and -25°C and stirred at around -23°C for 2 hours. The mixture was cooled to around -70°C, a DME (10 mL) solution of iodine (4.42 g, 9.16 * 1.9 mmol) was added at one-portion, and stirred at around -70°C for 30 minutes. The temperature was raised to room temperature, 10percent Na₂SO₃ (appropriate amount, until the iodine color disappeared) was added and it was stirred for 10 minutes, followed by adding water, brine, and ethyl acetate (50 mL). The organic layer was separated, dried over Na₂SO₄, filtered, and then concentrated to dryness. The residue (brown solid) was dissolved in chloroform and purified by medium pressure silica gel column chromatography (n-hexane:ethyl acetate = 1000:1 --> 100:1). Desired fractions were concentrated to dryness, and DeTMS-PM (1.31 g, 4.98 mmol, 54percent) was obtained as a yellow solid. ¹H-NMR (400 MHz, CDCl₃) δ: 4.05 (3H, s, MeO), 7.54 (1H, d, J = 5.4 Hz, aromatic-H), 7.85 (1H, d, J = 5.4 Hz, aromatic-H), 10.21 (1H, s, CHO). IR (KBr) (cm^-1): 2943, 1697 (CHO), 1543, 1458, 1362, 1015. EI-MS (m/z): 263 [M]⁺ (100percent)

Reference： [1] Patent: EP1900740, 2008, A1, . Location in patent: Page/Page column 14-15

5
[ 105669-53-2 ]
[ 158669-26-2 ]

Reference： [1] Patent: WO2004/63151, 2004, A2, . Location in patent: Page 37-38
[2] Patent: US2005/187218, 2005, A1, . Location in patent: Page/Page column 11

6
[ 1628-89-3 ]
[ 158669-26-2 ]

Yield	Reaction Conditions	Operation in experiment
19%	Stage #1: With tert.-butyl lithium In tetrahydrofuran at -78 - -60℃; for 1 h; Stage #2: at -78 - -20℃; for 1.25 h;	A solution of 2-methoxypyridine (2.18 g, 20 mmol) in 100 ml THF is cooled to -78 ⁰C and t-BuLi (13 ml of 1.7 M solution) is added which results in a color shift of the solution from clear to yellow/orange. Stirring at same temperature is continued for 30 min and at -60 ⁰C for another 30 min. After cooling down to -78 ⁰C, N- (2-Dimethylaminoethyl)-N-methylformimidine (3.08 ml, 22 mmol) is added within a few minutes. Stirring is continued for another 30 min at -78 ⁰C and 45 min at -20 ⁰C. The reaction mixture is now cooled to -40 ⁰C, n-BuLi (15.6 ml of a 1.6 M solution) is added and stirring at that temperature is continued for 90-120 min. After cooling the reaction mixture to -78 ⁰C, a pre-cooled solution of iodine (10.1 g, 40 mmol) in 100 ml THF is added via syringe until de-colorization stops to occur. Stirring at -78 ⁰C is continued for another 30 min, and the reaction mixture is allowed to warm up to 0⁰C before the mixture is quenched with 150 ml of saturatedNa2S2O3-solution and 100 ml of water. The formed precipitate is dissolving and the solution is loosing its color slowly during stirring overnight at RT. Purification is accomplished by phase separation and extraction of the aqueous phase with diethylether. The combined organic phases are washed with IN aqueous HCl, saturated aqueous sodium bicarbonate and brine. After drying and evaporation of solvent, 3.5 g of raw product is furnished. The product is purified by flash chromatography using a heptan/ethyl acetate (9:1) eluent yielding 1.0 g (19percent) of the desired product. Thoroughly dried glass ware is needed as well as inert gas atmosphere has to be applied for all reactions.

Reference： [1] Patent: WO2009/24332, 2009, A1, . Location in patent: Page/Page column 27

7
[ 1628-89-3 ]
[ 158669-26-2 ]

Yield	Reaction Conditions	Operation in experiment
23%	Stage #1: With tert.-butyl lithium In tetrahydrofuran at -78℃; for 0.5 h; Stage #2: With n-butyllithium In tetrahydrofuran at -78 - -20℃; for 2.75 h; Stage #3: With iodine In tetrahydrofuran at -78 - 0℃; for 0.5 h;	Example A5: A -78°C solution of 2-methoxypyridine (40 g, 0.37 mol) in THF (1 L) was treated with t-BuLi (163 mL, 0.41 mol), stirred at -78°C for 0.5 h, treated with N-(2-dimethylaminoethyl)-N-methylformamidine (52.9 g, 0.41 mol) over 10 mm, stirred at -78°C for another 0.5 h, then warmed to -20°C for 45 minutes. The mixture was cooled to -40°C, treated with n-BuLi (289 mL, 0.46 mol), stirred at -40°C for 1.5 h, then cooled to -78°C. The cold mixture was added via syringe to a solution of 12 (187.8 g, 0.74 mol) in THF at -78°C, stirred at -78°C for 0.5 h, then warmed to 0°C. The mixture was quenched with satd. NaS2O3, the organic layer washed with brine, dried over Na2SO4, concentrated under reduce pressure, and purified by chromatography. The resulting solid was washed with pet ether to afford 4-iodo-2-methoxynicotinaldehyde (22 g, 23percent). ‘H NMR (400 MHz, CDC13): 5 10.20 (s, 1 H), 7.84 (d, J = 5.6 Hz, 1 H), 7.53 (d, J = 5.2 Hz, 1 H), 3.99 (s, 3 H).

Reference： [1] Patent: WO2014/145004, 2014, A1, . Location in patent: Paragraph 0105

8
[ 1628-89-3 ]
[ 1634-04-4 ]
[ 105669-53-2 ]
[ 158669-26-2 ]

Reference： [1] Patent: US6063923, 2000, A,
[2] Patent: US5491237, 1996, A,

[ 158669-26-2 ] Synthesis Path-Downstream 1~88

1
[ 1628-89-3 ]
[ 105669-53-2 ]
[ 158669-26-2 ]

Yield	Reaction Conditions	Operation in experiment
29%		Synthesis of Difluoro Compound General Scheme; [00632] 4-Iodo-2-methoxynicotinic aldehyde: To a solution of t-BuLi (1.7 M, 7.36 niL, 12.51 mmol) in 20 niL THF at -78 C was added dropwise 2-bromomesitylene (0.91 niL, 5.95 mmol). After stirred for 1 h, 2-methoxypyridine (0.48 mL, 4.58 mmol) was added dropwise, and the mixture was warmed to 0 C and stirred for 2 h. The solution was cooled to -78 C and JV-formyl-iV, iV,7V-trimethylethylenediamine (0.7 mL, 5.06 mmol) was added. The mixture was stirred at -78 C for 30 min and then warmed to -23 C. A hexane solution of W-BuLi (2.5 M, 2.75 mL, 6.87 mmol) was added dropwise, and the resulting yellow mixture was stirred for 3 h. The mixture was cooled to -78 C and transferred via a double- tipped needle to a solution of iodine (2.17 g, 8.23 mmol) in 30 mL of THF at -78 C. After stirred at -78 C for 30 min, the cooling bath was removed and the reaction mixture was allowed to warm to the room temperature. After the reaction mixture was cooled to -5 C, aqueous solution OfNH4Cl (20 mL) was added dropwise and stirred for 15 min. The reaction mixture was poured into brine (300 mL) and extracted with EtOAc (5 xlOO mL). The combined extracts were washed with brine (2 x 50 mL), dried over Na2SO4 and concentrated. The residue was purified by chromatography (25:1 hexanes/EtOAc) to afford the title <n="345"/>compound (350 mg, 29%). 1H NMR (CDCl3) delta 4.05 (s, 3H, CH3), 7.53 (d, J= 6 Hz, IH, ArH), 7.85 (d, J= 6 Hz, IH, ArH), 10.20 (s, IH, CHO).
		A 5-liter three-necked round bottom flask was equipped with an overhead mechanical stirrer under nitrogen, the flask was charged with THF (1 L) and cooled to -78 C. To this stirred solution was added tert-butyllithium (1.7 M solution in pentane) (800 mL, 1.36 mol) via canula followed by 2-methoxypyridine (132.2 g, 1.21 mol) at -78 C. The mixture was stirred for 1 h at -78 C. To the mixture was added N-formyl-N, N', N'-trimethylethylenediamine (176 mL, 1.37 mol) dropwise at -78 C. The reaction mixture was stirred for ca. 30 min at -78 C. before warming to -23 C. over ca. 30 min. To the mixture at -23 C. was added ethylene glycol dimethyl ether (1 L) followed by n-butyllithium (2.5 M solution in hexane) (800 mL, 2.0 mol). The resulting mixture was stirred for ca. 2 h during which time the reaction mixture turned deep green. A 12-L 4-necked round flask was charged with iodine (571 g, 2.25 mol) and ethylene glycol dimethyl ether (2 L) and the resultant solution was cooled to -78 C. The contents of the 5-L flask were transferred via canula to the mixture of iodine and ethylene glycol dimethyl ether in the 12-L flask at -78 C. After the addition was complete, the reaction mixture was stirred for an additional 1 h at -78 C. The cooling bath was removed and the mixture was allowed to warm to about 0 C. and treated with 2 L of water and 2 L of 1 N hydrochloric acid. Methyl t-butyl ether (2L) was added and the layers were separated. The aqueous layer was extracted with 2×1 L of methyl t-butyl ether. The combined organic layers were washed with saturated Na2S2O3 (1.2 L), brine (1.2 L), dried over Na2SO4. After concentration in vacuo, the thick slurry was diluted with hexane (1 L). The mixture was cooled with an ice/water bath for ca. 30 min. The precipitate was filtered and dried in vacuum to yield the title compound as a light yellow solid. 1H NMR (300 MHz, CDCl3) delta 10.22 (s, 1H), 7.86 (1H, d, J=5.3 Hz), 7.54 (1H, d, J=5.3 Hz), 4.06 (3H, s). LCMS (M+H)+ m/z 364 (t=2.26 min.).

Reference： [1]Tetrahedron,2002,vol. 58,p. 6329 - 6341
[2]Patent: WO2007/56155,2007,A1 .Location in patent: Page/Page column 341-343
[3]Journal of Organic Chemistry,1994,vol. 59,p. 6142 - 1643
[4]Patent: US2004/44203,2004,A1 .Location in patent: Page 26

2
[ 504-61-0 ]
[ 158669-26-2 ]
[ 158669-27-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylsilane; trifluoroacetic acid;	3-(But-2-enyloxymethyl)-4-iodo-2-methoxy-pyridine (Formula (XII)) A 500 mL 3-necked round-bottom flask is equipped with an overhead mechanical stirrer under nitrogen, the flask is charged with 4-iodo-2-methoxy-pyridine-3-carbaldehyde (Intermediate 1, 75.0 g, 0.29 mol), crotyl alcohol (75 mL, 0.88 mol), and triethylsilane (70 mL, 0.44 mol). To the stirred suspension at 0 C. is added trifluoroacetic acid (175 mL, 2.27 mol) dropwise via an addition funnel. The resulting solution is stirred at about 22 C. for approximately 12 hours. The reaction mixture is slowly poured into a rapidly stirring saturated sodium bicarbonate solution (2 L). The mixture is extracted with 3*500 mL of hexane. The combined organic layers are dried over sodium sulfate, filtered, and concentrated in vacuo to give an oil. Purification of this oil by vacuum distillation (about 0.4 mm Hg, about 120-130 C.) yields 3-(but-2-enyloxymethyl)-4-iodo-2-methoxypyridine as a pale yellow oil: 1 H-NMR (400 MHz, CDCl3) d 7.69 (d, J=5 Hz, 1H), 7.34 (d, J=5 Hz, 1H), 5.71 (m, 2H), 4.58 (s, 2H), 4.02 (d, J=1 Hz, 2H), 3.94 (s, 3H), 1.72 (d, J=6 Hz, 3H); IR (neat) 2948, 2859, 1561, 1459, 1381, 1361, 1301, 1233, 1169, 1094, 1052 cm-1; Elemental analysis: calculated for C11 H14 NO2 I: C 41.40, H 4.42, N 4.39, I 39.76; Found: C 41.31, H 4.45, N 4.37, I 39.71.
	With triethylsilane; trifluoroacetic acid;	EXAMPLE 2 3-(but-2-enyloxymethyl)-4-iodo-2-methoxy-pyridine A 500 mL 3-necked round-bottom flask equipped with an overhead mechanical stirrer and under nitrogen, is charged with 4-iodo-2-methoxy-pyridine-3-carbaldehyde (75.0 g, 0.29 mol) as prepared in example 1, crotyl alcohol (75 mL, 0.88 mol), and triethylsilane (70 mL, 0.44 mol). To the stirred suspension at 0 C. is added trifluoroacetic acid (175 mL, 2.27 mol) dropwise via an addition funnel. The resulting solution is stirred at about 22 C. for approximately 12 hr. The reaction mixture is slowly poured into a rapidly stirring saturated sodium bicarbonate solution (2 L). The mixture is extracted with 3*500 mL of hexane. The combined organic layers are dried over sodium sulfate, filtered, and concentrated in vacuo to give an oil. Purification of this oil by vacuum distillation (ca. 0.4 mm Hg, ca. 120-130 C.) yields 3-(but-2-enyloxymethyl)-4-iodo-2-methoxy-pyridine as a pale yellow oil: 1 H-NMR (400 MHz, CDCl3) delta7.69 (d, J=5 Hz, 1H), 7.34 (d, J=5 Hz, 1H), 5.71 (m, 2H), 4.58 (s, 2H), 4.02 (d, J=1 Hz, 2H), 3.94 (s, 3H), 1.72(d, J=6 Hz, 3H); IR (neat) 2948, 2859, 1561, 1459, 1381, 1361, 1301, 1233, 1169, 1094, 1052 cm-1; Elemental analysis: calculated for C11 H14 NO2 I: C 41.40, H 4.42, N 4.39, I 39.76; Found: C 41.31, H 4.45, N 4.37, I 39.71.

Reference： [1]Journal of Organic Chemistry,1994,vol. 59,p. 6142 - 1643
[2]Patent: US6063923,2000,A
[3]Patent: US5491237,1996,A

3
3-methyl-5-morpholin-4-yl-benzene-1,2-diamine [ No CAS ]
[ 158669-26-2 ]
[ 468741-21-1 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 0 - 20℃;	2-Methyl-4-morpholin-4-yl-6-nitro-phenylamine (15.2 g, 64 mmol) was suspended in methanol (200 ml) in a PARR flask. Palladium on carbon (1.0 g, 10% Pd) was added and the suspension shaken under 60 psi of hydrogen overnight. The mixture was filtered through a pad of celite (under argon) into a 3-neck flask, the celite rinsed with methanol and the filtrate diluted with methanol to a total volume of 500 ml and cooled to 0 C. A solution of <strong>[158669-26-2]4-Iodo-2-methoxy-pyridine-3-carbaldehyde</strong> (14.6 g, 55.5 mmol) in methanol (500 ml) was added slowly (during 3 hours). After addition of of the solution the system was opened to air and stirred over the weekend, thereby reaching room temperature. The reaction mixture was concentrated in vacuo, filtered through a pad of silica (eluent: methylenechloride-ethyl acetate-methanol 55-40-5) then crystallized from ethyl acetate. The title compound was isolated as brown solid (12.68 g, 51%). Flash column chromatography of the mother liquor (gave additional 2.90 g (12%). [pack column with methylene chloride, elute compound with methylene chloride-ethyl acetate 6-4, then methylenechloride-ethyl acetate-methanol 58-40-2]. LCMS (M+H)+ m/z 451 (t=1.03 min.). 1H NMR (500 MHz, CDCl3) delta 7.76 (1H, d, J=5.3 Hz),), 7.42 (1H, d, J=5.3 Hz), 6.85 (1H, broad s), 6.82 (1H, s), 3.86 (4H, t, J=4.5 Hz), 3.79 (3H, s), 3.12 (4H, t, J=4.5 Hz), 2.60 (3H, s), 2.21 (3H, s).

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 5639 - 5643
[2]Patent: US2004/44203,2004,A1 .Location in patent: Page 32

4
[ 131885-95-5 ]
[ 158669-26-2 ]
[ 468740-99-0 ]

Yield	Reaction Conditions	Operation in experiment
60%	In methanol; at 0 - 20℃; for 3.5h;	To a solution of 5-imidazol-1-yl-3-methyl-benzene-1,2-diamine (175 mg, 0.93 mmol) in methanol (8 mL) was added a solution of 4-iodo-2-methoxy-pyridine-3-carbaldehyde (245 mg, 0.93 mmol) in methanol (5 mL) at 0 C. The reaction mixture was stirred at 0 C. for 1.5 h and then at room temperature for 2 h. After concentration, the residue was purified by flash column chromatography (10% MeOH/CH2Cl2) to give the title compound (291 mg, 60%). 1H NMR (300 MHz, CD3OD) delta 8.13 (1H, s), 7.98 (1H, d, J=5.4 Hz), 7.62 (1H, d, J=5.4 Hz), 7.59 (2H, s), 7.33 (1H, s), 7.16 (1H, s), 3.90 (3H, s), 2.67 (3H, s). LCMS (M+H)+ m/z 432 (t=0.99 min.).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 2317 - 2321
[2]Patent: US2004/44203,2004,A1 .Location in patent: Page 26
[3]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 974 - 977

5
[ 100568-79-4 ]
[ 158669-26-2 ]
2-(4-iodo-2-methoxy-pyridin-3-yl)-7,7-dimethyl-5,7-dihydro-3H-imidazo[4,5-f]indol-6-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	In methanol; at 0 - 20℃;	To a solution of 5,6-Diamino-3,3-dimethyl-l,3-dihydro-indol-2-one (200 mg, 1.04 mmol) in methanol (3 mL) was added at 0 0C a suspension of 4-Iodo-2-methoxy- pyridine-3-carbaldehyde (247 mg, 0.94 mmol) in MeOH (2 mL). The unclosed flask was stirred over night at room temperature. Concentration and purification by silica column chromatography followed. The resulting solid was dissolved in ethyl acetate and then precipitated with heptane, filtered and dried. This gave the title compound as a light brown solid. Yield: 200 mg (44 %).1H-NMR (400 MHz, D^-DMSO): delta= 12.44 (d, IH, NH, benzimidazole), 10.26 (d, IH, NH, indolone), 7.98 (m, IH, 5-H-pyridine), 7.64 (m, IH, 6-H-pyridine), 7.57 (s, 0.59H, Ar-H, 4-H-benzimidazole, tautomeric form), 7.42 (s, 0.41H, Ar-H, 4-H- benzimidazole, tautomeric form), 7.03 (s, 0.52H, Ar-H, 8-H-benzimidazole, tautomeric form), 6.89 (s, 0.59H, Ar-H, 8-H-benzimidazole, tautomeric form), 3.80(s, 3H, CH3, methoxy), 1.31 (s, 6H, CH3). MS: M = 435.1 (ESI+)

Reference： [1]Patent: WO2008/22747,2008,A1 .Location in patent: Page/Page column 29

6
[ 17876-76-5 ]
[ 158669-26-2 ]
[ 1010399-94-6 ]

Yield	Reaction Conditions	Operation in experiment
81%	With tetrabutyl ammonium fluoride; In tetrahydrofuran; at 20℃; for 0.5h;	b) l-(4-Iodo-2-methoxy-pyridin-3-yl)-2-(2-nitro-phenyl)-ethanol; To a solution of trimethyl-(2-nitro-benzyl)-silane (3.9 g, 18.63 mmol) and 4-iodo- 2-methoxypyridine-3-carboxaldehyde (4.9 g, 18.63 mmol) in THF (39 ml) is added <n="27"/>tetrabutylammonium fluoride (2.8 ml of a 1 M solution in THF, 2.8 mmol = 0.15 equivalents) at ambient temperature under inert gas atmosphere. Stirring is continued at ambient temperature until completion of the reaction (typically ca. 30 minutes). The reaction mixture is treated with saturated aqueous ammonium chloride solution (5 ml), extracted with dichloromethane and worked up. The product is used without any additional purification for the next step. Yield: 7.78 g (81 %).1H-NMR (400 MHz, D6-DMSO): delta= 7.87 (d, IH), 7.62 (d, IH), 7.52 (m, IH), 7.44 (m, IH), 7.33 (d, IH), 7.24 (d, IH), 5.26 (d, 1H),5.14 (m, IH), 3.83 (s, 3H), 3.54 (m, IH), 3.34 (m, IH)MS: M = 400.85 (ESI+)

Reference： [1]Patent: WO2008/25526,2008,A1 .Location in patent: Page/Page column 25-26

7
[ 1010399-99-1 ]
[ 158669-26-2 ]
[ 1010400-00-6 ]

Yield	Reaction Conditions	Operation in experiment
55%	With tetrabutyl ammonium fluoride; In tetrahydrofuran; at 20℃; for 1h;	b) l-(4-Iodo-2-methoxy-pyridin-3-yl)-2-(5-methoxy-2-nitro-4-trifluoromethyl- phenyl)-ethanol; To a solution of (5-methoxy-2-nitro-4-trifluoromethyl-benzyl)-trimethyl-silane (0.7 g, 2.28 mmol) and <strong>[158669-26-2]4-iodo-2-methoxypyridine-3-carboxaldehyde</strong> (0.6 g, 2.28 mmol) in THF (8 ml) is added tetrabutylammonium fluoride (0.34 ml of a 1 M solution in THF, 0.34 mmol = 0.15 equivalents) at ambient temperature under inert gas atmosphere. Stirring is continued at ambient temperature until completion of the reaction (typically ca. one hour). The reaction mixture is treated with saturated aqueous ammonium chloride solution (2 ml), extracted with dichloromethane and worked up. The product is purified by silica gel chromatography.Yield: 0.63 g (55 %).1H-NMR (400 MHz, D6-DMSO): delta= 8.16 (d, IH), 7.66 (d, IH), 7.37 (d, IH), 7.07 (s, IH), 5.41 (d, IH), 5.19 (m, IH), 3.88 (s, 3H), 3.86 (s, 3H), 3.66 (m, IH), 3.55(m, IH)MS: M = 499.1 (ESI+)

Reference： [1]Patent: WO2008/25526,2008,A1 .Location in patent: Page/Page column 28

8
[ 916851-24-6 ]
[ 158669-26-2 ]

Yield	Reaction Conditions	Operation in experiment
54%		Synthesis of 4-iodo-2-methoxypyridine-3-carbaldehyde (DeTMS-PM) t-Butyllithium (1.5 M in n-pentane, 6.9 mL, 9.16 * 1.1 mmol) was added dropwise to a dry THF (7.5 mL) solution of 2-methoxypyridine (1.00 g, 9.16 mmol) between -75C and -60C and stirred at the same temperature for 1 hour. A dry THF (10 mL) solution of FEO (1.44 g, 9.16 * 1.2 mmol) was added dropwise at the same temperature and stirred for 30 minutes. The temperature was raised to around -23C, ethylene glycol dimethyl ether (DME, organic synthesis grade, 7.5 mL) was added, and subsequently n-butyllithium (1.6 M in n-hexane, 9.9 mL, 9.16 * 1.7 mmol) was added dropwise at between -15C and -25C and stirred at around -23C for 2 hours. The mixture was cooled to around -70C, a DME (10 mL) solution of iodine (4.42 g, 9.16 * 1.9 mmol) was added at one-portion, and stirred at around -70C for 30 minutes. The temperature was raised to room temperature, 10% Na2SO3 (appropriate amount, until the iodine color disappeared) was added and it was stirred for 10 minutes, followed by adding water, brine, and ethyl acetate (50 mL). The organic layer was separated, dried over Na2SO4, filtered, and then concentrated to dryness. The residue (brown solid) was dissolved in chloroform and purified by medium pressure silica gel column chromatography (n-hexane:ethyl acetate = 1000:1 ? 100:1). Desired fractions were concentrated to dryness, and DeTMS-PM (1.31 g, 4.98 mmol, 54%) was obtained as a yellow solid. 1H-NMR (400 MHz, CDCl3) delta: 4.05 (3H, s, MeO), 7.54 (1H, d, J = 5.4 Hz, aromatic-H), 7.85 (1H, d, J = 5.4 Hz, aromatic-H), 10.21 (1H, s, CHO). IR (KBr) (cm-1): 2943, 1697 (CHO), 1543, 1458, 1362, 1015. EI-MS (m/z): 263 [M]+ (100%)

Reference： [1]Patent: EP1900740,2008,A1 .Location in patent: Page/Page column 14-15

9
[ 468741-03-9 ]
[ 158669-26-2 ]
[ 468741-04-0 ]

Yield	Reaction Conditions	Operation in experiment
46%		To a solution of 3,4-diamino-5-methyl-benzonitrile (2.00 g, 13.6 mmol) in MeOH (40 mL) was added 4-iodo-2-methoxy-pyridine-3-carbaldehyde (3.6 g, 13.6 mmol) in MeOH (20 mL) at 0 C. The resulting slurry was stirred at 0 C. for 1 h. Iodine (1.73 g, 8.8 mmol) in MeOH (10 mL) was added dropwise via a dropping funnel to the reaction mixture at 0 C. The reaction mixture was stirred at room temperature for 14 h. After removal of MeOH, the residue was diluted with saturated Na2S2O3 and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4. The crude product was purified by flash column chromatography (3% MeOH/CH2Cl2) to yield the title compound (1.81 g, 46%). 1H NMR (300 MHz, CDCl3) delta 7.90 (1H, s), 7.49 (1H, d, J=5.4 Hz), 7.46 (1H, s), 7.41 (1H, d, J=5.3 Hz), 3.78 (3H, s), 2.68 (3H, s). LCMS (M+H)+ m/z 391 (t=1.27 min.).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 3072 - 3076
[2]Patent: US2004/44203,2004,A1 .Location in patent: Page 27

10
[ 76153-06-5 ]
[ 158669-26-2 ]
[ 468741-06-2 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of 5-bromo-3-methyl-1,2-phenylenediamine (4 g, 19.9 mmol) in methanol (80 mL) was added 4-iodo-2-methoxy-pyridine-3-carbaldehyde (5.23 g, 19.9 mmol) in methanol (20 mL) dropwise at 0 C. The resulting slurry was stirred for 30 min at room temperature. Then iodine (2.53 g, 9.95 mmol) in methanol (20 mL) was added via a dropping funnel. After 14 h, the reaction mixture was concentrated in vacuo, diluted with 5% Na2S2O3, and extracted with ethyl acetate. The combined organic layers were washed with water, brine, and dried over Na2SO4. After removal of solvent, the residue was purified by careful flash chromatography (20% EtOAc/hexane) to yield the title compound (4.05 g, 46%) as a yellow foam. 1H NMR (300 MHz, CDCl3) delta 7.86 (1H, d, J=5.31 Hz), 7.53 (IH, d, J=5.3 Hz), 7.26 (2H, broad s), 3.91 (3H, s), 2.63 (3H, s). LCMS (M+H)+ m/z 444 (t=1.39 min.).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 3072 - 3076
[2]Patent: US2004/44203,2004,A1 .Location in patent: Page 28

11
[ 158669-26-2 ]
[ 221054-70-2 ]

Reference： [1]Tetrahedron,2002,vol. 58,p. 6329 - 6341

12
[ 158669-26-2 ]
[ 500726-35-2 ]

Reference： [1]Tetrahedron,2002,vol. 58,p. 6329 - 6341

13
[ 158669-26-2 ]
[ 472958-55-7 ]

Reference： [1]Tetrahedron,2002,vol. 58,p. 6329 - 6341

14
[ 158669-26-2 ]
[ 472958-57-9 ]

Reference： [1]Tetrahedron,2002,vol. 58,p. 6329 - 6341

15
[ 158669-26-2 ]
[ 472958-60-4 ]

Reference： [1]Tetrahedron,2002,vol. 58,p. 6329 - 6341

16
[ 158669-26-2 ]
[ 472958-58-0 ]

Reference： [1]Tetrahedron,2002,vol. 58,p. 6329 - 6341

17
[ 158669-26-2 ]
[ 472958-59-1 ]

Reference： [1]Tetrahedron,2002,vol. 58,p. 6329 - 6341

18
[ 158669-26-2 ]
[ 472958-56-8 ]

Reference： [1]Tetrahedron,2002,vol. 58,p. 6329 - 6341

19
[ 158669-26-2 ]
[ 472958-61-5 ]

Reference： [1]Tetrahedron,2002,vol. 58,p. 6329 - 6341

20
[ 158669-26-2 ]
4-Eth-(Z)-ylidene-8-methoxy-3,4-dihydro-1H-pyrano[3,4-c]pyridine [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1994,vol. 59,p. 6142 - 1643

21
[ 158669-26-2 ]
[ 158669-25-1 ]

Reference： [1]Journal of Organic Chemistry,1994,vol. 59,p. 6142 - 1643
[2]Journal of Organic Chemistry,1994,vol. 59,p. 6142 - 1643

22
[ 158669-26-2 ]
(3S,4R)-4-Ethyl-8-methoxy-3,4-dihydro-1H-pyrano[3,4-c]pyridine-3,4-diol [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1994,vol. 59,p. 6142 - 1643
[2]Journal of Organic Chemistry,1994,vol. 59,p. 6142 - 1643

23
[ 158669-26-2 ]
3(R)-4(S)-4-ethyl-8-methoxy-3,4-dihydro-1H-pyrano[3,4-c]pyridine-3,4-diol [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1994,vol. 59,p. 6142 - 1643
[2]Journal of Organic Chemistry,1994,vol. 59,p. 6142 - 1643

24
[ 105669-53-2 ]
[ 158669-26-2 ]

Yield	Reaction Conditions	Operation in experiment
		4-IODO-2-METHOXY-PYRIDINE-3-CARBALDEHYDE (WO 95/29917): A 5-liter three-necked round bottom flask was equipped with an overhead mechanical stirrer under nitrogen, the flask was charged with THF (1 L) and cooled TO-78C. To this stirred solution was added tert-butyllithium (1.7 M solution in pentane) (800 mL, 1.36 mol) via canula followed by 2-methoxypyridine (132.2 g, 1.21 mol) AT-78C. The mixture was stirred for 1 h AT-78C. To the mixture was added N-FORMYL-N, N', N'- trimethylethylenediamine (176 mL, 1.37 mol) dropwise AT-78C. The reaction mixture was stirred for ca. 30 min at-78C before warming TO-23C over ca. 30 min. To the mixture AT-23C was added ethylene glycol dimethyl ether (1 L) followed by M-butyllithium (2.5 M solution in hexane) (800 ML, 2.0 mol). The resulting mixture was stirred for ca. 2 h during which time the reaction mixture turned deep green. A 12-L 4-necked round flask was charged with iodine (571 g, 2.25 mol) and ethylene glycol dimethyl ether (2 L) and the resultant solution was cooled TO-78C. The contents of the 5-L flask were transferred via canula to the mixture of iodine and ethylene glycol dimethyl ether in the 12-L flask AT-78C. After the addition was complete, the reaction mixture was stirred for an additional 1 h AT-78C. The cooling bath was removed and the mixture was allowed to warm to about 0C and treated with 2 L of water and 2 L of 1 N hydrochloric acid. Methyl t-butyl ether (2L) was added and the layers were separated. The aqueous layer was extracted with 2 x 1 L of methyl t-butyl ether. The combined organic layers were washed with saturated Na2S203 (1.2 L), brine (1.2 L), dried OVER NA2S04. After concentration in vacuo, the thick slurry was diluted with hexane (1 L). The mixture was cooled with an ice/water bath for ca. 30 min. The precipitate was filtered and dried in vacuum to yield the title compound as a light yellow solid NMR (300 MHz, CDC13) 5 10.22 (s, 1H), 7.86 (1H, d, J= 5.3 Hz), 7.54 (1H, d, J= 5. 3 Hz), 4.06 (3H, s). LCMS (M+H) + M/Z 364 (t = 2.26 min.).
		4-Iodo-2-methoxy-pyridine-3-carbaldehyde (WO 95/29917): A 5-liter three-necked round flask was equipped with an overhead mechanical stirrer under nitrogen, the flask was charged with THF (1 L) and cooled to -78 C. To this stirred solution was added tert-butyllithium (1.7 M solution in pentane) (800 mL, 1.36 mol) via canula followed by 2-methoxypyridine (132.2 g, 1.21 mol) at -78 C. The mixture was stirred for 1 h at -78 C. To the mixture was added N-formyl-N,N',N'-trimethylethylenediamine (176 mL, 1.37 mol) dropwise at -78 C. The reaction mixture was stirred for ca. 30 min at -78 C. before warming to -23 C. over ca. 30 min. To the mixture at -23 C. was added ethylene glycol dimethyl ether (1 L) followed by n-butyllithium (2.5 M solution in hexane) (800 mL, 2.0 mol). The resulting mixture was stirred for ca. 2 h during which time the reaction mixture turned deep green. A 12-L 4-necked round flask was charged with iodine (571 g, 2.25 mol) and ethylene glycol dimethyl ether (2 L) and the resultant solution was cooled to -78 C. The contents of the 5-L flask were transferred via canula to the mixture of iodine and ethylene glycol dimethyl ether in the 12-L flask at -78 C. After the addition was complete, the reaction mixture was stirred for an additional 1 h at -78 C. The cooling bath was removed and the mixture was allowed to warm to about 0 C. and treated with 2 L of water and 2 L of 1 N hydrochloric acid. Methyl t-butyl ether (2 L) was added and the layers were separated. The aqueous layer was extracted with 2×1 L of methyl t-butyl ether. The combined organic layers were washed with saturated Na2S2O3 (1.2 L), brine (1.2 L), dried over Na2SO4. After concentration in vacuo, the thick slurry was diluted with hexane (1 L). The mixture was cooled with an ice/water bath for ca. 30 min. The precipitate was filtered and dried over vacuum to yield the title compound as a light yellow solid. 1H NMR (300 MHz, CDCl3) delta 10.22 (s, 1H), 7.86 (1H, d, J=5.3 Hz), 7.54 (1H, d, J=5.3 Hz), 4.06 (3H, s). LCMS (M+H)+ m/z 364 (t=2.26 min.).

Reference： [1]Patent: WO2004/63151,2004,A2 .Location in patent: Page 37-38
[2]Patent: US2005/187218,2005,A1 .Location in patent: Page/Page column 11

25
[ 158669-26-2 ]
[ 726206-50-4 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 20℃; for 12h;	6- (4-LODO-2-METHOXY-PYRIDIN-3-YL)-3, 5-DIHYDRO-IH-BENZO [1, 2-D ; 4, 5-DL DIIMIDAZOL- 2-one: A 250 mg (1.0 mml) of the dianiline, and 281 mg (1.0 mml) of the iodoaldehyde were taken in 5 mL of methanol, and the reaction mixture was stirred at room temperature for 12 hr, solvent was evaporated to dryness, and the residue was chromatographed to FURNISH the product. LRMS [M+H] + 408; 1H NMR (400MHZ, CD30D) 0 8.13 (d, J=5. 4 Hz, 2H), 7.73 (d, J=5.4 Hz, 2H), 7.42 (s, 2H), 3.96 (s, 3H).

Reference： [1]Patent: WO2004/63151,2004,A2 .Location in patent: Page 39

26
[ 158669-26-2 ]
[ 726206-55-9 ]

Yield	Reaction Conditions	Operation in experiment
67%	With sodium chlorite; sodium dihydrogenphosphate; 2-methyl-but-2-ene; In tetrahydrofuran; water; tert-butyl alcohol; at 20℃; for 1h;	4-IODO-2-METHOXY-NICOTINIC acid: To a solution of 4-iodo-2-methoxy-pyridine-3- CARBALDEHYDE (4.96 g, 18.9 mmol) in 22 mL tert. -butanol was added in this order 2- METHYL-2-BUTENE (30 mL of a 2 M solution in THF, 60 mmol), natriumdihydrogen- phosphate (5.7 g, 47.5 MMOL), water (15 mL) and sodiumchlorite (3.9 g, 43 mmol). The mixture was stirred at ambient temperature for 1 hour, then poured on dilute aqueous formic acid. The mixture was extracted with ethyl acetate, the organic layer washed with water and brine and concentrated. The residue was dissolved in diisopropylether + dichloromethane (1+1) and extracted 3 times with half- concentrated aqueous NAOH solution. The combined aqueous layers were acidified with cone. HC1 and extracted with ethyl acetate. The organic layers were washed with water and brine, then dried over sodium sulfate and concentrated to give 3.462 g of the title compound as a white solid (67%). 1H NMR (500MHZ, CD30D) 8 7.83 (d, J= 5.4 Hz, 1H), 7.43 (d, J= 5.4 Hz, 1H), 3.94 (s, 3H);
54%		2-Methyl-2-butane (1.0ml), sodium dihydrogenphosphate (l.Og, 7.4mmol), water (7ml) and sodium chlorite (0.6g, 6.6mmol) were added to a stirred solution of 4-iodo-2-methoxy-pyridine-3-carbaldehyde (0.74g, 2.9mmol) in tert-butanol (10ml) at 00C. After 10 minutes the reaction was poured into an aqueous solution of formic acid (IM, 50ml) and extracted with ethyl acetate (50ml). The organic layer was extracted with NaOH (IM, 50ml) and the aqueous layer acidified to pH 3 with HCl (cone). The acidic layer was extracted with ethyl acetate (3 x 30ml) and <n="29"/>the organic layer dried (MgSO4) and concentrated to give the desired product as a yellow solid (0.43g, 54%).
		Example Ia: 4-Iodo-2-methoxynicotinic acid <n="110"/>[000247] To a solution of <strong>[158669-26-2]4-iodo-2-methoxynicotinaldehyde</strong> (1 g, 3.58 mmol) in /-BuOH (6 mL), cooled at 25 0C, is added 2-methyl-2-butene (6 mL, 2 M solution), Na2HPO4 (1.2 g) and water (3 mL). The reaction mixture is stirred for 5 minutes and sodium chlorite (800 mg, 8.9 mmol) is added slowly. Stirring of the mixture is continued until the aldehyde is completely consumed (3 hours, monitored by LCMS). The reaction is quenched with aq. formic acid. The mixture is partitioned between ethyl acetate (100 mL) and the organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated. The white powder was used for the next reaction without any further purification. 1H NMR 400 MHz (DMSO-

Reference： [1]ACS Medicinal Chemistry Letters,2016,vol. 7,p. 100 - 104
[2]Patent: WO2004/63151,2004,A2 .Location in patent: Page 40
[3]Patent: WO2009/24332,2009,A1 .Location in patent: Page/Page column 27-28
[4]Patent: WO2009/97287,2009,A1 .Location in patent: Page/Page column 108-109

27
[ 111157-98-3 ]
[ 158669-26-2 ]
[ 726206-64-0 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 0 - 20℃; for 144h;	N5- (4-IODO-2-METHOXY-PYRIDIN-3-YLMETHYLENE)-6-METHYL-2-MORPHOLIN-4-YL- pyrimidine-4,5-diamine : To 4-AMINO-6-METHYL-2-MORPHOLIN-4-YL-5NITROPYRIMIDINE (500 mg, 2.09 mmol) and 10% palladium on carbon (100 mg) were added methanol (10 mL) under nitrogen. The reaction mixture was stirred under hydrogen atmosphere (hydrogen balloon) for 22 hours. The solution was filtered through a pad of celite and the filtercake was washed with a small amount OF MEOH. The product in MEOH was used for the next step without purification; LCMS (+ ESI, M+H+) m/z 210; HPLC: 97% (220 NM). To the crude diamino in MEOH (50 mL) was added a solution of 4- iodo-2-methoxy-pyridine-3-carbaldehyde (604 mg, 2.30 mmol) in MEOH (10 mL) at 0 C and stirred for 0.5 hour. The resulting mixture was allowed to warm to ambient temperature and stirred for 6 days in an open system exposed to air. The reaction mixture was cooled to 0 C to afford a crystalline yellow solid, which was collected by filtration to give the title compound (830 mg, 87%) : 1H NMR (400 MHz, DMSO) 8 8.43 (s, 1H), 7.85 and 7.62 (d, J = 5.3, 1H), 6.23 (br s, 2H), 3.91 (s, 3H), 3.61 (s, 8H), 2.26 (s, 3H); LCMS (+ESI, M+H+) M/Z 455.

Reference： [1]Patent: WO2004/63151,2004,A2 .Location in patent: Page 44

28
C₁₄H₂₄N₆O₂ [ No CAS ]
[ 158669-26-2 ]
[ 726206-66-2 ]

Yield	Reaction Conditions	Operation in experiment
53%		4- [8- (4-IODO-2-METHOXY-PYRIDIN-3-YL)-6-METHYL-9H-PURIN-2-YL]-PIPERAZINE-L- carboxylic acid tert-butyl ester: To a stirred solution of 4- (5-AMINO-4-METHYL-6- nitro-pyrimidin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (3.18 g, 9.4 mmol) in methanol (200 mL) and 10% palladium on carbon (180 mg) were added methanol (10 mL) under nitrogen. The reaction mixture was stirred under hydrogen atmosphere (hydrogen balloon) for 18 hours. The solution was filtered through a pad of celite and the filtercake was washed with a small amount OF MEOH. This solution was cooled to 0 C and the 4-iodo-2-methoxy-pyridine-3-carbaldehyde (2.47 g, 9.4 mmol) in methanol (50 mL) was added to the reaction mixture and stirred at 23 C for 18 hours. Then iodobenzene diacetate (3.03 g, 9.4 mmol) was added and the reaction mixture was stirred at 23 C for 5 hours. MEOH was evaporated in vacuo and the crude material was purified on silica gel column using EtOAc: Hex (1: 2 to 1: 1 gradient) to give the title compound as a yellow solid. (2.75 g, 53%). HPLC 98%. LCMS (+ ESI, M+H+) m/z 552; IR (KBr, CM-1) 3177,2976, 1699,1558, 1223 ; 1H NMR (400 MHz, DMSO) 8 12.92 (s, 1H), 8.0 (d, J= 5.1 Hz, 1H), 7.64 (d, J= 5.6 Hz, 1H), 3.81 (s, 3H), 3.73 (br s, 4H), 3.43 (br s, 4H), 2.57 (s, 3H), 1.44 (s, 9H).

Reference： [1]Patent: WO2004/63151,2004,A2 .Location in patent: Page 45

29
[ 726206-71-9 ]
[ 158669-26-2 ]
[ 726206-70-8 ]

Yield	Reaction Conditions	Operation in experiment
80%	In methanol; at 0 - 50℃; for 144h;	2- (4-IODO-2-METHOXY-PYRIDIN-3-YL)-4-METHYL-6-MORPHOLIN-4-YL-LH-IMIDAZO [4,5- pyridine (Scheme IX): To 2-methyl-6-morpholin-4-yl-3-nitro-pyridin-4-ylamine (220 mg, 0.924 mmol) and 10% palladium on carbon (50 mg) were added methanol (10 mL) under nitrogen. The reaction mixture was stirred under hydrogen atmosphere (hydrogen balloon) for 18 hours. The solution was filtered through a pad of celite and the filtercake was washed with a small amount OF MEOH. The product in MEOH was concentrated and used for the next step without purification; LCMS (+ ESI, M+H) m/z 209. To the crude diamino in MEOH (5 mL) was added a solution of 4-iodo-2- METHOXY-PYRIDINE-3-CARBALDEHYDE (267 mg, 1.02 mmol) in MEOH (5 mL) at 0 C and stirred for 0.5 hour. The resulting mixture was allowed to warm to ambient temperature and stirred for 4 days in an open system exposed to air. The reaction mixture was then heated to 50 C and stirred for 2 days. MEOH was evaporated in vacuo and the crude was purified on silica gel column using CH2C12 : MEOH (95: 5 gradient) to give the title compound as a yellow solid (332 mg, 80 %): IR (KBr, CM-1) 1624,1554, 1458,1378 ; 1H NMR (400 MHz, DMSO) 6 12.46 (s, 1H), 8.00 and 7.64 (d, J = 5. 5, 1H), 6.54 (s, 1H), 3.80 (s, 3H), 3.74-3. 72 (M, 4H), 3.38-3. 36 (M, 4H), 2.58 (s, 3H); LCMS (+ ESI, M+H+) m/z 452; HPLC: 97% (220 NM).

Reference： [1]Patent: WO2004/63151,2004,A2 .Location in patent: Page 47-48

30
[ 7404-68-4 ]
[ 158669-26-2 ]
[ 726206-52-6 ]

Yield	Reaction Conditions	Operation in experiment
63%	In methanol; at 20℃;	6-(2-IODO-6-METHOXY-PHENYL)-1, 7-DIHYDRO-1, 2,5, 7-tetraaza-s-indacene : To a solution of LH-INDAZOLE-5, 6-diamine (250 mg, 1.69 mmol) in methanol (80 mL) was added 2-hydroxy-4-iodo-pyridine-3-carbaldehyde (445 mg, 1.69 mmol). The reaction mixture was stirred at room temperature overnight. Concentration in vacuo, the residue was purified by prep. HPLC to yield the titled compound (416 mg, 63%). LCMS (T = 0.81 min), [M+H] + 392

Reference： [1]Patent: WO2004/63151,2004,A2 .Location in patent: Page 39

31
[ 1723-25-7 ]
[ 158669-26-2 ]
[ 863012-42-4 ]

Yield	Reaction Conditions	Operation in experiment
47%	With ammonium acetate; In acetic acid; at 65℃; for 3h;	2-(4-Iodo-2-methoxy-pyridin-3-yl)-5-methyl-3H-imidazole-4-carboxylic acid ethyl ester: To a slurry of ammonium acetate (0.837 g, 10.9 mmol) in acetic acid (10 mL) was added 2,3-dioxo-butyric acid ethyl ester (0.176 g, 1.086 mmol) (J. Org. Chem., 60 (25), p. 8231 (1995)) followed by 4-iodo-2-methoxy-pyridine-3-carbaldehyde (0.286 g, 1.086 mmol). The mixture was stirred at 65 C. for 3 hours. The solution was cooled to room temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title material (0.199 g, 47%) as a yellow solid. LCMS (+ESI, M+H+) m/z 388; 1H NMR (400 MHz, methanol-d4) delta (ppm)(mixture of tautomers): 1.27 and 1.29 (3H, 2t, J=7.1 Hz), 2.39 and 2.46 (3H, 2s), 3.77 and 3.79 (3H, 3s), 4.20 and 4.25 (2H, 2q, J=7.1 Hz), 7.56 and 7.58 (1H, 2d, J=5.6 and 5.3 Hz), 7.94 and 7.95 (1H, 2d, J=5.6 and 5.3 Hz), 12.58 and 12.82 (1H, 2s).

Reference： [1]Patent: US2005/187218,2005,A1 .Location in patent: Page/Page column 13

32
[ 468741-11-9 ]
[ 158669-26-2 ]
[ 468741-12-0 ]

Yield	Reaction Conditions	Operation in experiment
66%	In methanol; at 20℃; for 14h;	To a solution of 1-[4-(3,4-diamino-5-methyl-phenyl)-piperazin-1-yl]-ethanone (4.00 g, 16.18 mmol) in methanol (100 mL) was added 4-iodo-2-methoxy-pyridine-3-carbaldehyde (4.25 g, 16.18 mmol). The reaction mixture was stirred at room temperature for 14 h. After concentration, the residue was purified by flash column chromatography (10% MeOH/CH2Cl2) to yield the title compound (5.25 g, 66%). 1H NMR (400 MHz, CD3OD) delta 7.81 (1H, d, J=5.4 Hz), 7.48 (1H, d, J=5.4 Hz), 7.26 (1H, s), 6.85 (1H, s), 3.85 (3H, s), 3.78 (2H, t, J=5.0 Hz), 3.64 (2H, t, J=5.0 Hz), 3.16 (2H, t, J=5.2 Hz), 3.11 (2H, t, J=5.2 Hz), 2.62 (3H, s), 2.13 (3H, s). LCMS (M+H)+ m/z 492 (t=1.71 min.).

Reference： [1]Patent: US2004/44203,2004,A1 .Location in patent: Page 29

33
[ 468741-25-5 ]
[ 158669-26-2 ]
[ 468741-26-6 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 0 - 20℃;	To a stirred solution of 4-(3,4-Diamino-5-methyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (44.6 mmol-assuming 100% conversion in previous step) in methanol (ca 2700 mL) at 0 oC under a nitrogen atmosphere was slowly added (2 h) via addition funnel, a solution of 4-iodo-2-methoxy-pyridine-3-carbaldehyde (15.0 g, 57.1 mmol) in anhydrous methanol (225 mL). The resulting solution was then stirred at 0 C. for an additional 30 min,. the cooling bath was removed, and the reaction mixture was allowed to stir at room temperature in the presence of air for 72 h. The resulting solution was concentrated in vacuo and the residue was dissolved in dichloromethane (1500 mL) and the solvent removed in vacuo (repeated 3×). The resulting dark foamy solid was dried under high vacuum. 1H NMR (500 MHz, CDCl3) delta 7.82 (d, 1H, J=5.4 Hz), 7.50 (d, 1H, J=5.4 Hz), 6.98 (brs, 1H), 6.90 (brs, 1H), 4.05 (s, 3H), 3.67-3.58 (m, 4H), 3.18-3.09 (m, 4H), 2.63 (s, 3H), 1.49 (s, 9H);. LCMS (M+H)+ m/z 550.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 3182 - 3185
[2]Patent: US2004/44203,2004,A1 .Location in patent: Page 33

34
C₁₇H₂₈N₄O₂ [ No CAS ]
[ 158669-26-2 ]
[ 468741-31-3 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 0 - 20℃;	[1-(3-Amino-5-methyl-4-nitro-phenyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (1.54 g, 4.4 mmol) was dissolved in methanol (100 ml). Palladium on carbon (0.3 g, 10% Pd) was added and the suspension stirred vigorously under a balloon pressure of hydrogen overnight. The mixture was filtered through a pad of celite (under argon) into a 3-neck flask, the celite rinsed with methanol and the filtrate cooled to 0 C. A solution of <strong>[158669-26-2]4-Iodo-2-methoxy-pyridine-3-carbaldehyde</strong> (1.21 g, 4.6 mmol) in methanol (50 ml) was added slowly (during 2 hours). The mixture was stirred overnight under air at ambient temperature, then concentrated in vacuo. Flash column chromatography on silica (eluent hexanes-ethyl acetate -methanol 5-4-1 gave the title compound. (0.79 g, 32%). LCMS (M+H)+ m/z 564 (t=1.31 min.).

Reference： [1]Patent: US2004/44203,2004,A1 .Location in patent: Page 34, 35

35
[ 25994-02-9 ]
[ 158669-26-2 ]
[ 863012-33-3 ]

Yield	Reaction Conditions	Operation in experiment
80%	With ammonium acetate; In acetic acid; for 2h;Heating / reflux;	4-Ethyl-2-(4-iodo-2-methoxy-pyridin-3-yl)-5-phenyl-imidazol-1-ol: To a stirred solution of 1-phenyl-butane-1,2-dione 2-oxime (0.200 g, 1.13 mmol) in acetic acid (6 mL) was added 4-iodo-2-methoxy-pyridine-3-carbaldehyde (0.297 g, 1.13 mmol) followed by ammonium acetate (0.435 g, 5.65 mmol). The mixture was refluxed for 2 hours, then the solvent was evaporated and the residue was purified by Prep HPLC (ammonium acetate/water/acetonitrile) to give the title material (0.379 g, 80%). HPLC 98% (220 nm), LCMS (+ESI, M+H+) m/z 422; 1H NMR (400 MHz, methanol-d4) delta (ppm): 1.34 (3H, t, J=7.6 Hz), 2.93 (2H, qa, J=7.6 Hz), 3.95 (3H, s) 7.41-7.43 (1H, m), 7.51 (2H, t, J=7.6 Hz), 7.63-7.59 (3H, m), 8.00 (1H, d, J=5.3 Hz).

Reference： [1]Patent: US2005/187218,2005,A1 .Location in patent: Page/Page column 11

36
[ 1628-89-3 ]
[ 1634-04-4 ]
[ 105669-53-2 ]
[ 158669-26-2 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; n-butyllithium; iodine; tert.-butyl lithium; sodium thiosulfate; In tetrahydrofuran; 1,2-dimethoxyethane; hexane; water; pentane;	4-Iodo-2-methoxy-pyridine-3-carbaldehyde (Formula (XIII)) A 5 liter 3-necked round bottom flask is equipped with an overhead mechanical stirrer under nitrogen, the flask is charged with tetrahydrofuran (1 L) and cooled to -78 C. To this stirred solution is added tert-butyllithium (1.7 M in pentane, 800 mL, 1.36 mol) via canula followed by 2-methoxypyridine (132.2 g, 1.21 mol) at -78 C. The mixture is allowed to stir for one hour at -78 C. To the mixture is added N-formyl-N,N',N'-trimethylethylenediamine (176 mL, 1.37 mol) dropwise at -78 C. described as in Comins, D. L.; Baevsky, M. F.; Hong, H. J. Am. Chem. Soc. 1992, 114, 10972. The reaction mixture is stirred for about 30 min at -78 C. before warming to -23 C. over about 30 min. To the mixture at -23 C. is added ethylene glycol dimethyl ether (1 L) followed by n-butyllithium (2.5 M in hexanes, 800 mL, 2.0 mol). The resultant mixture is stirred for about 2 hours during which time the reaction mixture turns deep green. A 12 liter 4-neck round bottom flask is equipped with an overhead mechanical stirrer under nitrogen, the 12 liter flask is charged with iodine (571 g, 2.25 mol) and ethylene glycol dimethyl ether (2 L) and the resultant solution is cooled to -78 C. The contents of the 5 liter flask are transferred via canula to the mixture of iodine and ethylene glycol dimethyl ether in the 12 liter flask at -78 C. After the addition is complete, the reaction mixture is stirred for an additional 1 hour at -78 C. The cooling bath is removed and the mixture is allowed to warm to about 0 C. then treated with 2 L of water and 2 L of 1N hydrochloric acid. Methyl t-butyl ether (2 L) is added and the layers are separated. The aqueous layer is extracted with 2*1 L of methyl t-butyl ether. The combined organic extracts are washed with 1.2 L of saturated sodium thiosulfate solution followed by 1.2 L of saturated sodium chloride solution. The organic extracts are dried over sodium sulfate, filtered, and concentrated in vacuo to give a thick slurry. To the slurry is added 1 L of hexane resulting in the generation of additional precipitate. The mixture is cooled in an ice/water bath for about 30 min then filtered yielding 4-iodo-2-methoxypyridine-3-carbaldehyde. The filtrate is reconcentrated to a slurry and treated with hexane to generate additional precipitate again yielding 4-iodo-2-methoxypyridine-3-carbaldehyde. Chromatography (silica gel, 10% ethyl acetate/hexane) yields an analytical sample as a bright yellow solid: mp 98-99 C. 1H-NMR (400 MHz, CDCl3) 10.21 (s, 1H), 7.86 (d, J=5 Hz, 1H), 7.54 (d, J=5 Hz, 1H), 4.06 (s, 3H); IR (CHCl3) 1710, 1560, 1470, 1380, 1305, 1260, 1025 cm-1; Elemental analysis: calculated for C7 H6 NO2 I: C 31.97%, H 2.30, N 5.32, I 48.25; Found: C 32.06, H 2.35; N 5.25, I 48.35.
	With hydrogenchloride; n-butyllithium; iodine; tert.-butyl lithium; sodium thiosulfate; In tetrahydrofuran; 1,2-dimethoxyethane; hexane; water; pentane;	EXAMPLE 1 4-Iodo-2-methoxy-pyridine-3-carbaldehyde A 5-liter 3-necked round-bottom flask equipped with an overhead mechanical stirrer and under nitrogen, is charged with tetrahydrofuran (1 L) and cooled to -78 C. To this stirred solution is added tert-butyllithium (1.7M in pentane, 800 mL, 1.36 mol) via canula followed by 2-methoxypyridine (132.2 g, 1.21 mol) in tetrahydrofuran at -78 C. The mixture is allowed to stir for one hr at -78 C. To the mixture is added N-formyl-N,N',N'-trimethylethylenediamine (176 mL, 1.37 mol) dropwise at -78 C. (prepared as in Comins, D. L.; Baevsky, M. F.; Hong, H. J. Am. Chem. Soc. 1992, 114, 10972). The reaction mixture is stirred for ca. 30 min at -78 C. before warming to -23 C. over ca. 30 min. To the mixture at -23 C. is added ethylene glycol dimethyl ether (1 L) followed by n-butyllithium (2.5M in hexanes, 800 mL, 2.0 mol). The resultant mixture is stirred for ca. 2 h during which time the reaction mixture turns deep green. A 12 liter 4-neck round bottom flask is equipped with an overhead mechanical stirrer under nitrogen, the 12 liter flask is charged with iodine (571 g, 2.25 mol) and ethylene glycol dimethyl ether (2 L) and the resultant solution is cooled to -78 C. The contents of the 5 liter flask are transferred via canula to the mixture of iodine and ethylene glycol dimethyl ether in the 12 liter flask at -78 C. After the addition is complete, the reaction mixture is stirred for 1 hr at -78 C. The cooling bath is removed and the mixture is allowed to warm to ca. 0 C. then treated with 2 L of water and 2 L of 1N hydrochloric acid. Methyl t-butyl ether (2 L) is added and the layers are separated. The aqueous layer is extracted with 2*1 L of methyl t-butyl ether. The combined organic extracts are washed with 1.2 L of saturated sodium thiosulfate solution followed by 1.2 L of saturated sodium chloride solution. The organic extracts are dried over sodium sulfate, filtered, and concentrated in vacuo to give a thick slurry. To the slurry is added 1 L of hexane resulting in the generation of additional precipitate. The mixture is cooled in an ice/water bath for ca. 30 min then filtered yielding 4-iodo-2-methoxy-pyridine-3-carbaldehyde. The filtrate is reconcentrated to a slurry and treated with hexane to generate additional precipitate again yielding 4-iodo-2-methoxy-pyridine-3-carbaldehyde. Chromatography (silica gel, 10% ethyl acetate/hexane) yields an analytical sample as a bright yellow solid: mp 98-99 C. 1H-NMR (400 MHz, CDCl3) 10.21 (s, 1H), 7.86 (d, J=5 Hz, 1H), 7.54 (d, J=5 Hz, 1H), 4.06 (s, 3H); IR (CHCl3) 1710, 1560, 1470, 1380, 1305, 1260, 1025 cm-1; Elemental analysis: calculated for C7 H6 NO2 I: C 31.97%, H 2.30, N 5.32, 1 48.25; Found: C 32.06, H 2.35; N 5.25, I 48.35.

Reference： [1]Patent: US6063923,2000,A
[2]Patent: US5491237,1996,A

37
[ 107-21-1 ]
[ 158669-26-2 ]
[ 936939-79-6 ]

Yield	Reaction Conditions	Operation in experiment
99%		3-[l,3]DioxoIan-2-yI-4-iodo-2-methoxy-pyridine; To a solution of 4-iodo-2- methoxynicotinic aldehyde (5.26 g, 20.0 mmol) and ethylene glycol (2.48 g, 40 mmol) in toluene (400 rnL) was added jp-toluenesulfonic acid monohydrate (95 mg, 0.5 mmol). After it was refluxed under N2 for 6 h, the reaction mixture was concentrated and the residue was diluted with 300 niL EtOAc and washed with 2 x 100 mL 10% Na2CO3 solution. The aqueous solution was extracted with EtOAc (3 x 50 mL) and the combined EtOAc extracts were washed with brine and dried over Na2SO4. Evaporation of solvent afforded the title product (6.07 g, 99%). 1HNMR (CDCl3) delta 3.95 (s, 3H), 4.07 (m, 2H), 4.33 (m, 2H), 6.25 (s, IH), 7.40 (d, J= 6Hz, IH), 7.70 (d, J= 6Hz, IH). ESI-MS mlz 308.4 (MH+).

Reference： [1]Patent: WO2007/56155,2007,A1 .Location in patent: Page/Page column 343

38
[ 124-41-4 ]
[ 113975-22-7 ]
[ 109-94-4 ]
[ 158669-26-2 ]

Yield	Reaction Conditions	Operation in experiment
94%		A mixture of DIPA (3.5 mL, 25 mmol) in THF (100 mL) was cooled to -20 C and nBuLi (2.7 M in heptane, 9.2 mL, 25 mmol) was added dropwise. After stirring 10 mm, the r.m. was cooled to -75 C and 2-fluoro-3-iodopyridine (5.55 g, 25 mmol) in THF (50 mL) was added dropwise. Stirring was continued for 2 h at -65 C. The r.m. was cooled to -75 C and ethyl formate (2.3 mL, 28 mmol) in THF (25 mL) was added dropwise. After 10 mill sodium methoxide (5.8 mL, 0.95 g/mL, 25 mmol, 25% purity) was added dropwise. The cooling bath was removed and the r.m. was allowed to come to r.t. and treated with brine (50 mL), Et20 (100 mL) and the layers were separated. The aq. layer was extracted with Et20 (100 mL) and the combined organic layers weretreated with brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo to afford intermediate 1 (6.15 g, 94%), which was used as such in the next reaction step.
64%		To a solution of diisopropylamine (345 mL, 249 g, 2.46 mol) in anhydrous THF (5 L) at -8 to -10 C. under a blanket of N2 was added n-BuLi (880 mL, 158 g, 2.46 mol) dropwise via cannula. The mixture was stirred at -10 C. for 30 min, cooled to -78 C. and treated with a solution of 2-fluoro-3-iodopyridine (500 g, 2.24 mol) in dry THF (2 L) dropwise. After the addition, the reaction mixture was warmed to -60 C. and this temperature was maintained for 2 h. The mixture was then cooled to -78 C., treated with ethyl formate (183 g, 2.47 mol) dropwise, followed by sodium methoxide (149 g, 2.75 mol) in MeOH (1.5 L) and warmed to ambient temperature. The reaction mixture was quenched with ice water and extracted with EtOAc. The layers were separated and the organic phase was washed with water and brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to afford 4-iodo-2-methoxynicotinaldehyde (380 g, 64%) as a solid.
44 g		Under the stream of nitrogen, a THF (500 mL) solution of diisopropylamine (25 g) was added into a 2L-fourneckedflask. The solution was cooled to -25C, and n-butyl lithium - hexane solution (1.57 mol/L) (157 mL) was droppedto the solution for 20 minutes (-25C ? -15C), and the solution was stirred at -10C for 30 minutes. The resulting solutionwas cooled to -66C, and a THF (200 mL) solution of 2-fluoro-3-iodopyridine (CAS registration No.: 113975-22-7) (50g) was dropped thereto for 25 minutes, and stirred at -60C for two hours. The resulting solution was cooled to -66C,and ethyl formate (18.3 g) was dropped thereto for 10 minutes. Then, 28% solution of sodium methoxide methanolsolution (53.2 g) in methanol (100 mL) was dropped, and lifted up from dry ice bath. The resulting product was naturallycooled to room temperature, and ice water (100 mL) was dropped thereto. A saturated saline solution (1 L) was addedthereto. The resulting solution was extracted with ethyl acetate (1 L), and washed with water (700 mL) and a saturatedsaline solution (700 mL). The water layer was combined and extracted with ethyl acetate (500 mL 3 2), and washedwith water (500 mL) and a saturated saline solution (500 mL). The organic layer was combined and dried over anhydroussodium sulfate, and the solvent was removed by evaporation under reduced pressure. The obtained residue was purifiedby column chromatography on silica gel (hexane : ethyl acetate = 9:1 ? 6:1 ? 5:1 ? 4:1 ? 3:1) to obtain the titlecompound (44 g) having the following physical property values

Reference： [1]Patent: WO2018/162444,2018,A1 .Location in patent: Page/Page column 25; 26
[2]Patent: US2008/114033,2008,A1 .Location in patent: Page/Page column 7
[3]Patent: EP3067356,2016,A1 .Location in patent: Paragraph 0375

39
[ 158669-26-2 ]
[ 726206-53-7 ]

Yield	Reaction Conditions	Operation in experiment
90%		4-Iodo-2-methoxynicotinaldehyde (25 g, 95 mmol) and sodium iodide (31.0 g, 285 mmol, Aldrich) were stirred together in 500 mL of acetonitrile. To this solution was added chlorotrimethylsilane (36.0 mL, 285 mmol, Aldrich 99%) dropwise over 15 minutes. The reaction mixture was stirred for 2 h at room temperature and then concentrated under vacuum. The product was suspended in ethyl acetate, water, and saturated aqueous sodium bicarbonate, then filtered to give a dark brown solid. This solid was triturated with acetonitrile to yield 4-iodo-2-oxo-1,2-dihydropyridine-3-carbaldehyde (21.3 g, 90%) as a yellow solid (mixture of tautomers). MS (ESI+) m/z 250.04 (M+H)+.
51%	With chloro-trimethyl-silane; sodium iodide; In acetonitrile; at 20℃; for 2.25h;	[0106j A mixture of <strong>[158669-26-2]4-iodo-2-methoxynicotinaldehyde</strong> (25 g, 83 mmol) and sodium iodide (37.0 g, 249 mmol) in MeCN (500 mL) was treated drop-wise with chlorotrimethylsilane (31.4 mL, 249 mmol) over 15 minutes. The reaction mixture was stirred at RT for 2 h, then to dryness. The residue was suspended in EtOAc, water, and satd. NaHCO3, the solid collected via filtration, triturated with MeCN and dried to afford 4-iodo-2- oxo-1,2-dihydropyridine-3-carbaldehyde (12 g, 51%) as a yellow solid. MS (ESI) mlz: 250.0 (M+Hj.
50.5%	With chloro-trimethyl-silane; sodium iodide; In acetonitrile; at 15 - 25℃; for 2.25h;	4-Iodo-2-methoxynicotinaldehyde (25 g, 83 mmol, prepared according to W095/29917) and sodium iodide (37.0 g, 249 mmol) were combined in MeCN (500 mL). Chlorotrimethylsilane (31.4 mL, 249 mmol) was added dropwise over 15 min. The reaction mixture was stirred at RT for 2 h and then concentrated under vacuum. The crude product was suspended in a mixture of EtOAc, water, and saturated aqueous NaHC03, then filtered to give a dark brown solid. This solid was triturated with MeCN to yield 4-iodo-2-oxo-l ,2- dihydropyridine-3-carbaldehyde (12 g, yield 50.5%) as a yellow solid. MS (ESI) m/z: 250.0 (M+H+).

27 g

Under the stream of nitrogen, an acetonitrile (600 mL) solution of the compound (44 g) produced in Example82 was added into a 1L-four-necked flask. Then, sodium iodide (75 g) was added thereto for two minutes. The mixturewas stirred at room temperature for 15 minutes. Then, trimethylchlorosilane (54 g) was dropped for 25 minutes, and themixture was stirred at room temperature for four hours. Under reduced pressure, the solvent was distilled off underreduced pressure, and ethyl acetate (100 mL), a saturated aqueous solution of sodium hydrogen carbonate (200 mL),and water (100 mL) were added thereto. Then resulting product was subjected to ultrasonic treatment, and then filteredto obtain a title compound (14 g). The filtrate was extracted with ethyl acetate (500 mL 3 2) and THF (500 mL 3 2), andwashed with saturated saline solution (500 mL). The resulting solution was dried over anhydrous sodium sulfate, andthen the solvent was removed by evaporation under reduced pressure and washed with ethyl acetate (100 mL) to obtainthe title compound (12 g). The title compound (27 g) was obtained together

Reference： [1]Patent: US2008/114033,2008,A1 .Location in patent: Page/Page column 7
[2]Journal of Medicinal Chemistry,2009,vol. 52,p. 1251 - 1254
[3]Patent: WO2014/145004,2014,A1 .Location in patent: Paragraph 0106
[4]Patent: WO2013/78295,2013,A2 .Location in patent: Paragraph 00187
[5]Patent: EP3067356,2016,A1 .Location in patent: Paragraph 0376

40
[ 1008450-65-4 ]
[ 158669-26-2 ]
[ 1008450-67-6 ]

Yield	Reaction Conditions	Operation in experiment
47%	With acetic acid; In methanol; at 60℃;	To a solution of 5,6-Diamino-4-methyl-2-(1-methyl-piperidin-4-yl)-isoindole-1,3-dione (1.7 g, 5.90 mmol) in MeOH (50 mL) were added AcOH (3 mL) and <strong>[158669-26-2]4-iodo-2-methoxynicotinaldehyde</strong> (1.55 g, 5.90 mmol) and the resulting mixture was heated at 60 C. for overnight. The reaction mixture was evaporated in vacuo and the residue was purified by flash chromatography (5-10% (6% NH3 in MeOH)/CHCl3) to afford 2-(4-Iodo-2-methoxy-pyridin-3-yl)-4-methyl-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione (1.48 g, 47%) as a yellow solid.

Reference： [1]Patent: US2008/171769,2008,A1 .Location in patent: Page/Page column 123

41
[ 1008452-98-9 ]
[ 158669-26-2 ]
[ 1008453-02-8 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 20 - 75℃; for 22h;	To a solution of 5-amino-2-(1-methyl-piperidin-4-yl)-6-nitro-isoindole-1,3-dione (1.216 g, 4.0 mmol) in MeOH (47.5 mL) was added 120 mg of Pd/C (10%) (the solution was purged with N2 before adding Pd/C) and AcOH (2.5 mL). After it was stirred under atmospheric H2 for 5 h, the reaction mixture was filtered through Celite. To the filtrate was added <strong>[158669-26-2]4-iodo-2-methoxynicotinic aldehyde</strong> (1.052 g, 4.0 mmol) and the resulting mixture was stirred at the room temperature for 17 h, heated at 80 C. for 5 h, and then evaporated to dryness under reduced pressure. The residue was mixed with 4 M HCl/dioxane (40 mL) and H2O (3 mL), heated at 70 C. for 3 h and was evaporated under reduced pressure. The chromatography of the crude residue (150:10:1 CH2Cl2/MeOH/28% aqueous NH4OH) afforded the title compound (688 mg, 42% for 3 steps). 1H NMR (DMSO-d6) delta 1.65 (m, 2H), 2.05 (m, 2H), 2.24 (s, 3H), 2.40 (m, 2H), 2.92 (m, 2H), 4.01 (m, 1H), 6.60 (d, 1H, J=6.9 Hz), 7.70 (d, J=6.9 Hz, 1H), 8.03 (s, 1H), 8.05 (s, 1H); ESI-MS m/z 412.4 (MH+).

Reference： [1]Patent: US2008/171769,2008,A1 .Location in patent: Page/Page column 153-154

42
[ 1008453-07-3 ]
[ 158669-26-2 ]
[ 1008453-08-4 ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid; In methanol; at 20 - 75℃; for 22h;	To a solution of 5-amino-6-nitro-2-[(S)-1-(tetrahydro-furan-2-yl)methyl]-isoindole-1,3-dione (29.1 mg, 0.1 mmol) in MeOH (30 mL) was added 3 mg of Pd/C (10%) (the solution was purged with N2 before adding Pd/C). After it was stirred under atmospheric H2 for 2 h, the reaction mixture was filtered through Celite. To the filtrate was added AcOH (1.5 mL) and <strong>[158669-26-2]4-iodo-2-methoxynicotinic aldehyde</strong> (26.3 mg, 0.1 mmol) and the resulting mixture was stirred at the room temperature for 18 h and heated at 75 C. for 4 h, and then evaporated to dryness under reduced pressure. The residue was mixed with 4 M HCl/dioxane (8 mL) and H2O (0.6 mL), heated at 70 C. for 4 h and evaporated to dryness under reduced pressure. The residue was subjected to HPLC purification to furnish the corresponding chloropyridone intermediate, which was then mixed with (S)-2-amino-1-(3-chloro-phenyl)-ethanol (7 mg, 0.02 mmol) and Et3N (10 mg, 0.1 mmol) in EtOH (1.5 mL). After it was heated at 100 C. for 17 h, the reaction mixture was concentrated and subjected to HPLC purification to furnish the title compound (15.8 mg, 30% for 4 steps). 1H NMR (DMSO-d6) delta 1.50-1.99 (4H), 3.52-3.79 (6H), 4.13 (m, 1H), 4.99 (m, 1H), 6.00 (br s, 1H, NH), 6.20 (d, J=6 Hz, 1H), 7.30-7.39 (3H), 7.50 (d, J=6 Hz, 1H), 7.63 (s, 1H), 7.88 (s, 1H), 8.14 (s, 1H); 10.90 (br s, 1H, NH), 11.29 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 534.2 (MH+).

Reference： [1]Patent: US2008/171769,2008,A1 .Location in patent: Page/Page column 162-163

43
C₁₂H₁₉N₃O [ No CAS ]
[ 158669-26-2 ]
[ 1056877-83-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4075 - 4080

44
C₁₃H₂₁N₃O [ No CAS ]
[ 158669-26-2 ]
[ 1056877-80-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4075 - 4080

45
C₁₅H₂₅N₃O₂ [ No CAS ]
[ 158669-26-2 ]
[ 1056877-81-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4075 - 4080

46
C₁₄H₂₃N₃O₂ [ No CAS ]
[ 158669-26-2 ]
[ 1056877-82-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4075 - 4080

47
C₁₄H₂₁N₃O₂ [ No CAS ]
[ 158669-26-2 ]
[ 1056877-68-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4075 - 4080

48
C₁₂H₂₀N₄ [ No CAS ]
[ 158669-26-2 ]
[ 1056877-84-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4075 - 4080

49
[ 158669-26-2 ]
[ 3694-52-8 ]
[ 1095321-45-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sulfur; at 160℃; for 1h;	2-(4-Iodo-2-methoxy-pyridin-3-yl)-7-nitro-lH-benzoimidazole3-Nitro-benzene-l,2-diamine (0.153 g, 1.0 mmol), 4-Iodo-2-methoxy-pyridine-3- carbaldehyde (0,263 g, 1.0 mmol) and sulfur (0.032 g, 1.0 mmol) were heated at160 for 60 min. The resulting slurry was purred on ice water (100 ml). Precipitates were collected by filtration and dried in vacuum to yield the desired product (0.40 g, quant.) which was used without any further purification.

Reference： [1]Patent: WO2009/489,2008,A1 .Location in patent: Page/Page column 24

50
[ 1628-89-3 ]
N-(2-dimethylaminoethyl)-N-methylformamidine [ No CAS ]
[ 158669-26-2 ]

Yield	Reaction Conditions	Operation in experiment
19%		A solution of 2-methoxypyridine (2.18 g, 20 mmol) in 100 ml THF is cooled to -78 0C and t-BuLi (13 ml of 1.7 M solution) is added which results in a color shift of the solution from clear to yellow/orange. Stirring at same temperature is continued for 30 min and at -60 0C for another 30 min. After cooling down to -78 0C, N- (2-Dimethylaminoethyl)-N-methylformimidine (3.08 ml, 22 mmol) is added within a few minutes. Stirring is continued for another 30 min at -78 0C and 45 min at -20 0C. The reaction mixture is now cooled to -40 0C, n-BuLi (15.6 ml of a 1.6 M solution) is added and stirring at that temperature is continued for 90-120 min. After cooling the reaction mixture to -78 0C, a pre-cooled solution of iodine (10.1 g, 40 mmol) in 100 ml THF is added via syringe until de-colorization stops to occur. Stirring at -78 0C is continued for another 30 min, and the reaction mixture is allowed to warm up to 00C before the mixture is quenched with 150 ml of saturatedNa2S2O3-solution and 100 ml of water. The formed precipitate is dissolving and the solution is loosing its color slowly during stirring overnight at RT. Purification is accomplished by phase separation and extraction of the aqueous phase with diethylether. The combined organic phases are washed with IN aqueous HCl, saturated aqueous sodium bicarbonate and brine. After drying and evaporation of solvent, 3.5 g of raw product is furnished. The product is purified by flash chromatography using a heptan/ethyl acetate (9:1) eluent yielding 1.0 g (19%) of the desired product. Thoroughly dried glass ware is needed as well as inert gas atmosphere has to be applied for all reactions.

Reference： [1]Patent: WO2009/24332,2009,A1 .Location in patent: Page/Page column 27

51
[ 1206831-77-7 ]
[ 158669-26-2 ]
[ 1054315-50-2 ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 5897 - 5900

52
[ 1008451-69-1 ]
[ 158669-26-2 ]
[ 1008451-70-4 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of 5,6-diamino-4-chloro-2-(l-methyl- piperidin-4-yl)-isoindole-1,3-dione (62.0 mg, 0.2 mmol), <strong>[158669-26-2]4-iodo-2-methoxynicotinic aldehyde</strong> (34.3 mg, 0.2 mmol) and HOAc (1 mL) in MeOH was stirred at the room temperature for 14 h, heated at 80 C for 4.5 h, and concentrated to result a residue which was then mixed with HCl in dioxane (4 M, 10 mL) and H2O (0.8 mL) and heated for 1.7 h at 70 C for 1.5 h. The reaction mixture was evaporated, diluted with diluted with a mixed solvent of DCM/MeOH (1 :5), basified with aqueous NH4OH solution (28%) and evaporated. Chromatography of the residue with mixed solvent OfCH2Cl2 <n="139"/>/MeOH/28% aqueous NH4OH (40: 10: 1) afforded the title compound (70.2 mg, 78% for2 steps). ESI-MS mlz 446.5 (MH+).

Reference： [1]Patent: WO2009/117097,2009,A1 .Location in patent: Page/Page column 136-138

53
[ 1008452-94-5 ]
[ 158669-26-2 ]
[ 1008449-01-1 ]

Yield	Reaction Conditions	Operation in experiment
	at 20 - 80℃; for 17h;open to air;	Pd/C (250 mg) was added to a solution of crude 3b in MeOH/AcOH ( 100 mL/5 mL) and hydrogenated for 5 h. The mixture was filtered through Celite and the filtrate was treated with <strong>[158669-26-2]4-iodo-2-methoxynicotinaldehyde</strong> (3.2 g, 12.07 mmol) and stirred at ambient temperature open to air for 12 h and at 80 C for 5h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to dryness. Purification by flash chromatography gave the title phthalimide 6b as a solid (2.02 g, 32% over 4 steps). 1H NMR (MeOD): delta 8.15 (s, 2H), 8.01-8.08 (t, J=3 Hz 1H), 7.64 (t, J=3 Hz, 1H), 3.89-3.78 (m, 2H), 3.41-3.22 (m, 2H), 2.95-2.81 (m, 6H), 2.15-1.82 (m, 7H). ESMS (m/z) 532 (M+H)+.

Reference： [1]Patent: WO2009/117097,2009,A1 .Location in patent: Page/Page column 104-105

54
[ 158669-26-2 ]
[ 1025721-07-6 ]

Reference： [1]Patent: WO2013/78295,2013,A2
[2]Patent: WO2014/145004,2014,A1
[3]Patent: EP3067356,2016,A1

55
[ 158669-26-2 ]
[ 1025721-10-1 ]

Reference： [1]Patent: WO2013/78295,2013,A2
[2]Patent: WO2014/145004,2014,A1
[3]Patent: EP3067356,2016,A1

56
[ 158669-26-2 ]
[ 1025721-21-4 ]

Reference： [1]Patent: WO2013/78295,2013,A2
[2]Patent: WO2014/145004,2014,A1

57
[ 158669-26-2 ]
[ 1439876-98-8 ]

Reference： [1]Patent: WO2013/78295,2013,A2

58
[ 158669-26-2 ]
[ 1439878-75-7 ]

Reference： [1]Patent: WO2013/78295,2013,A2

59
[ 158669-26-2 ]
[ 1439878-82-6 ]

Reference： [1]Patent: WO2013/78295,2013,A2

60
[ 158669-26-2 ]
[ 1439877-05-0 ]

Reference： [1]Patent: WO2013/78295,2013,A2

61
[ 1604803-38-4 ]
[ 158669-26-2 ]
[ 1604803-39-5 ]

Yield	Reaction Conditions	Operation in experiment
91%		To a solution of methyl-(3-nitro-4-trimethylsilanylmethyl-phenyl)-carbamic acid tert- butyl ester (0.75 g, 1.10 mmol) and <strong>[158669-26-2]4-iodo-2-methoxynicotinaldehyde</strong> (1.17 g, 4.43 mmol) in THF (10 mL) was added tetra-butylammonium fluoride (174 mg, 665 muiotaetaomicron) at 25 C. Upon addition, the color of the solution changed to dark blue. The reaction mixture was stirred at 25C for 30 min. To the reaction mixture was then added 2,2,2-trifluoroacetic anhydride (1.37g, 6.52 mmol) at 25 C resulting in a color change to dark blue. The reaction was allowed to stir at 25C for 30 min. To the reaction mixture was then added 8-diazabicyclo[5.4.0]undec-7-ene (1.64 g, 10.8 mmol) at 25C . The reaction was allowed to stir at 70C for 3 h. The reaction mixture was cooled to 25 C and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (80/20 hexanes/ethyl acetate) afforded {4-[(E)-2-(4-iodo-2- methoxy-pyridin-3-yl)-vinyl]-3-nitro-phenyl}-methyl-carbamic acid tert-butyl ester (1.0 g, 91%) as an oil. MH+ 512.0

Reference： [1]Patent: WO2014/60328,2014,A1 .Location in patent: Page/Page column 17

62
[ 1604803-41-9 ]
[ 158669-26-2 ]
[ 1604803-42-0 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrabutyl ammonium fluoride; In tetrahydrofuran; at 25℃; for 0.5h;	solution of (2-methoxy-5-nitro-4-trimethylsilanylmethyl-phenyl)-carbamic acid tert- butyl ester (0.75 g, 2.12 mmol) and <strong>[158669-26-2]4-iodo-2-methoxynicotinaldehyde</strong> (557 mg, 2.12 mmol) in THF (10 mL) was added tetra-butyl ammonium fluoride (83 mg, 317 muiotaetaomicron) at 25C, the color of the solution changed to dark blue after the addition. The reaction mixture was stirred at 25 C for 30 min. The solution of crude {4-[2-hydroxy-2-(4-iodo- 2-methoxy-pyridin-3-yl)-ethyl] -2-methoxy-5-nitro-phenyl } -carbamic acid tert-butyl ester (crude 1.18 g, 2.12) was used directly for next step. M+H 546.0

Reference： [1]Patent: WO2014/60328,2014,A1 .Location in patent: Page/Page column 19-20

63
[ 1604803-28-2 ]
[ 158669-26-2 ]
[ 1604803-29-3 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrabutyl ammonium fluoride; In tetrahydrofuran; at 25℃; for 0.5h;	A solution of (3-nitro-4-trimethylsilanylmethyl-phenyl)-carbamic acid tert-butyl ester (1.00 g, 3.08 mmol) and <strong>[158669-26-2]4-iodo-2-methoxynicotinaldehyde</strong> (811 mg, 3.08 mmol, Eq: 1.00) in THF (10 mL) was added tetra-butylammonium fluoride (121 mg, 462 mupiiotaomicron) at 25C, the color of the solution changed to dark blue after the addition. The reaction mixture was stirred at 25C for 30 min. The solution of crude {4-[2-hydroxy-2-(4-iodo- 2-methoxy-pyridin-3-yl)-ethyl]-3-nitro-phenyl}-carbamic acid tert-butyl ester (crude 1.59 g, 3.08 mmol) was used directly for next step. M+H 515.9.

Reference： [1]Patent: WO2014/60328,2014,A1 .Location in patent: Page/Page column 12-13

64
[ 107582-20-7 ]
[ 158669-26-2 ]
2-(4-iodo-2-methoxypyridin-3-yl)-3H-benzoimidazole-4-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		In a 250 mL round-bottomed flask, methyl 2,3-diaminobenzoate (1.5 g, 9.03 mmol) was combined with methanol (25 mL) to give a yellow solution that was stirred under nitrogen and cooled in a water/dry ice bath. To this was added drop wise <strong>[158669-26-2]4-iodo-2-methoxynicotinaldehyde</strong> (2.37 g, 9.03 mmol) dissolved in methanol (15 mL) and DMF (10 mL). During the addition more methanol (25.0 mL) was added to the reaction. The reaction was kept in the water/dry ice bath for 2.5 hr, allowed to warm to room temperature over 3 hr, and then cooled in a water/dry ice bath. To this was added drop wise iodine (1.49 g, 5.87 mmol) dissolved in methanol (15 mL) and then the reaction was allowed to warm to room temperature overnight. The reaction was concentrated, diluted with ethyl acetate (200 mL) and saturated Na2S203 (200 mL) and mixed. Significant insoluble material was present and the mixture was filtered. The resulting solid was washed with ethyl acetate and water. The filtrate was separated and the resulting aqueous layer was extracted with ethyl acetate (100 mL) and DCM (3 x 150 mL). The organic layers were washed with saturated Na2S203 and brine, combined, dried over MgS04, and concentrated as a red oil/solid. The insoluble solid from the original extract was washed with DCM (5 x 100 mL) and the filtrate was concentrated as a dark red/black solid. The liquid extracted crude and the solid extract crude were dissolved in minimal DCM, combined, and purified by flash chromatography (silica gel, 120 g, 0% to 60% ethyl acetate in hexanes) to give 2-(4-iodo-2- methoxy-pyridin-3-yl)-3- H-benzoimidazole-4-carboxylic acid methyl ester, as a purple solid, 0.73 g LC/MS calcd for C15Hi2lN303 (m/e) 409.0, obsd 410.0 (M+H); 1H NMR (DMSO-d6) delta: 12.68 (s, 1H), 8.05 (d, J = 5.5 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.88 - 7.95 (m, 1H), 7.67 (d, J = 5.3 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 3.96 (s, 3H), 3.82 (s, 3H). The original insoluble solid remaining after being extracted with DCM was subsequently extracted with boiling methanol (5 x 20 ml). The methanol filtrate was concentrated and dried, yielding additional product (83 % pure by LCMS), as the sodium salt (assumed) and as a dark purple solid, 0.57g. The remaining original insoluble solid after the DCM and methanol extractions yielded additional product (90% pure by LCMS), as the sodium salt (assumed) and as a purple solid, 0.88 g. The combined yield was 59 %.

Reference： [1]Patent: WO2014/140058,2014,A1 .Location in patent: Page/Page column 25; 26

65
[ 158669-26-2 ]
2-[4-((S)-2-hydroxy-2-phenylethylamino)-2-oxo-1,2-dihydropyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Patent: WO2014/140058,2014,A1

66
[ 158669-26-2 ]
2-[4-((S)-2-hydroxy-2-phenylethylamino)-2-oxo-1,2-dihydropyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2014/140058,2014,A1

67
[ 158669-26-2 ]
C₂₈H₂₄FN₅O₃ [ No CAS ]

Reference： [1]Patent: WO2014/140058,2014,A1

68
[ 158669-26-2 ]
2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-3H-benzoimidazole-4-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Patent: WO2014/140058,2014,A1

69
[ 1628-89-3 ]
N-(2-dimethylaminoethyl)-N-methylformamidine [ No CAS ]
[ 158669-26-2 ]

Yield	Reaction Conditions	Operation in experiment
23%		Example A5: A -78C solution of 2-methoxypyridine (40 g, 0.37 mol) in THF (1 L) was treated with t-BuLi (163 mL, 0.41 mol), stirred at -78C for 0.5 h, treated with N-(2-dimethylaminoethyl)-N-methylformamidine (52.9 g, 0.41 mol) over 10 mm, stirred at -78C for another 0.5 h, then warmed to -20C for 45 minutes. The mixture was cooled to -40C, treated with n-BuLi (289 mL, 0.46 mol), stirred at -40C for 1.5 h, then cooled to -78C. The cold mixture was added via syringe to a solution of 12 (187.8 g, 0.74 mol) in THF at -78C, stirred at -78C for 0.5 h, then warmed to 0C. The mixture was quenched with satd. NaS2O3, the organic layer washed with brine, dried over Na2SO4, concentrated under reduce pressure, and purified by chromatography. The resulting solid was washed with pet ether to afford 4-iodo-2-methoxynicotinaldehyde (22 g, 23%). ?H NMR (400 MHz, CDC13): 5 10.20 (s, 1 H), 7.84 (d, J = 5.6 Hz, 1 H), 7.53 (d, J = 5.2 Hz, 1 H), 3.99 (s, 3 H).

Reference： [1]Patent: WO2014/145004,2014,A1 .Location in patent: Paragraph 0105

70
[ 158669-26-2 ]
1-(4-fluoro-phenyl)-4-iodo-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid {2,5-difluoro-4-[2-(1-methyl-1H-pyrazol-4-yl)-pyridin-4-yloxy]-phenyl}-amide [ No CAS ]

Reference： [1]Patent: WO2014/145004,2014,A1

71
[ 158669-26-2 ]
N-(2,5-difluoro-4-((2-( 1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-4-(methylamino)-2-oxo-1,2-dihydropyridine-3-carboxamide [ No CAS ]

Reference： [1]Patent: WO2014/145004,2014,A1

72
[ 158669-26-2 ]
N-(2,5-difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-4-(ethylamino)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide [ No CAS ]

Reference： [1]Patent: WO2014/145004,2014,A1

73
tert-butyl 4-(5,6-diamino-1,3-dioxoisoindolin-2-yl)piperidine-1-carboxylate [ No CAS ]
[ 158669-26-2 ]
tert-butyl 4-(2-(4-iodo-2-methoxypyridin-3-yl)-5,7-dioxoimidazo[4,5-f]isoindol-6(1H,5H,7H)-yl)piperidine-1-carboxylate [ No CAS ]

Reference： [1]Journal of Heterocyclic Chemistry,2016,vol. 53,p. 1430 - 1438

74
[ 158669-26-2 ]
C₁₆H₂₂N₆O₂ [ No CAS ]