Name: 319460-85-0|(E)-N-Methyl-2-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)benzamide|98%
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1
[ 319460-85-0 ]
[ 67-63-0 ]
6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]indazole isopropanol solvate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	for 0.5h;Heating / reflux;	Polymorphic Form VI of Compound 1 (102 mg) was suspended in 20 mL isopropyl alcohol, refluxed for 30 min, and cooled to room temperature. Solids were collected by filtration, washed with isopropyl alcohol, and dried under vacuum. Polymorphic Form VII of Compound 1 is an isopropanol solvate.

Reference： [1]Patent: US2006/94763,2006,A1 .Location in patent: Page/Page column 18

2
[ 100-69-6 ]
[ 319460-85-0 ]

Reference： [1]Beilstein Journal of Organic Chemistry,2018,vol. 14,p. 786 - 795

3
[ 100-69-6 ]
[ 885126-34-1 ]
[ 319460-85-0 ]

Yield	Reaction Conditions	Operation in experiment
70.68%		Take N-methylpyrrolidone (379.11 ml), Palladium (II) acetate (3.64 g, 0.0162 mol) andXantphos (9.32 g, 0.Ol6lmol) into a RB flask at 25-30 C in nitrogen atmosphere. Charged2-((3-iodo-1H-indazol-6-yl)thio)-N methylbenzamide (HPLC Purity: 99.29%; 165.0 g,0.4031mo1) and diisopropylethylamine(156.62 g, 1.21 mol)under stirring. The reaction was heated to 50C. Acetic anhydride (83.77 g, 0.8 195 mol) was slowly added and stirred for 2-3 hrs at 50C. 2-Vinylpyridine (254.97 g, 2.4250 mol) was added slowly, raised the temperature of reaction mass to 90-95C and maintained for about 12 hrs. Cooled the reaction mixture to 50C under stirring, diluted with THF (495 ml) and filtered. To the reaction mass1,2-diaminopropane (120.20 g) was added. Stirred at 50C for 30 mm. Water (1815 ml) was added slowly for 30 mm followed by maintaining temperature 50C under stirring for 12 hrs. Reaction mass cooled to 15C and further maintained for 2 hrs, filtered the solid, washed with purified water (495 ml) and THF (163.69 ml). The obtained solid was dried under vacuum to afford crude Axitinib. Yield: ii0 g (70.68%) Chromatographic Purity (By HPLC): 96.3%;XRPD resembles with Fig. II
	With tris-(o-tolyl)phosphine; lithium bromide;palladium diacetate; In 2,4-dichlorophenoxyacetic acid dimethylamine; at 110℃; for 25h;Product distribution / selectivity;	2-(3-lodo-1H-indazol-6-ylsulfanyl)-N-methyl-benzamide (239.19 g), 2-vinyIpyridine (75.7 mL, 702 Mmol), Pd(OAc)2 (6.56 g), P(O-ToI)3 (23.12 g), Proton Sponge (187.82 g), LiBr (314.59 g), and DMA (3.1 L, 3.5 mL/g) were added to a 5 L 3-neck flask, equipped with a mechanical stirrer and a temperature probe. The mixture was degassed three times by alternately connecting to house vacuum and nitrogen. The mixture was then heated to 110 0C in one hour and the temperature was maintained at 110 0C for 24 hours, at which time all of the 2-(3-lodo-1 H-indazol- 6-ylsulfanyl)-N-methyl-benzamide was consumed (HPLC). After cooling, the mixture was transferred to a 22 L extractor and followed by the addition of 5.5 L of CH2CI2, 5.5 L of water and 275 mL of 37% aqueous HCI. After agitation and partitioning, the organic phase was extracted twice with 2.0 L of water and 100 mL of 37% HCI. At this stage, the organic phase (HPLC) did not contain any significant amount of the final product (HPLC), and was discarded. The combined aqueous layers were treated with 2.2 L of toluene, followed by the addition of 1.05 L of 28% NH4OH over 45 minutes of time (via addition funnel). A thick precipitate formed at this stage. The resulting mixture was allowed to stir for approximately 48 hours. The mixture was then filtered and sucked dry. The cake was triturated with 3.5 L of toluene, stirred overnight, filtered and sucked dry. The cake was then transferred to a glass dish and dried at 50 C under house vacuum overnight to afford 160.20 g of the final product.
	With N,N,N',N'-tetramethyl-1,8-diaminonaphthalene; tris-(o-tolyl)phosphine; lithium bromide;palladium diacetate; In DMA; at 110℃; for 25h;Inert atmosphere;Product distribution / selectivity;	2-(3-lodo-1H-indazol-6-ylsulfanyl)-N-methyl-benzamide (239.19 g), 2-vinylpyridine (75.7 mL, 702 Mmol), Pd(OAc)2 (6.56 g), P(o-Tol)3 (23.12 g), Proton Sponge (187.82 g), LiBr (314.59 g), and DMA (3.1 L, 3.5 mL/g) were added to a 5 L 3 -neck flask, equipped with a mechanical stirrer and a temperature probe. The mix ture was degassed three times by alternately connecting to house vacuum and nitrogen. The mixture was then heated to 110 C in one hour and the temperature was maintained at 110 C for 24 hours, at which time all of the 2-(3-lodo-1H-indazol-6-ylsulfanyl)-N-methyl-benzamide was consumed (HPLC). After cooling, the mixture was transferred to a 22 L extractor and followed by the addition of 5.5 L of CH 2Cl2, 5.5 L of water and 275 mL of 37% aqueous HCI. After agitation and partitioning, the organic phase was extracted twice with 2.0 L of water and 100 mL of 37% HCI. At this stage, the organic phase (HPLC) did not contain any significant amount of the final product (HPLC), and was discarded. The combined aqueous layers were treated with 2.2 L of toluene, foll owed by the addition of 1.05 L of 28% NH 4OH over 45 minutes of time (via addition funnel). A thick precipitate formed at this stage. The resulting mixture was allowed to stir for approximately 48 hours. The mixture was then filtered and sucked dry. The cake was triturated with 3.5 L of toluene, stirred overnight, filtered and sucked dry. The cake was then transferred to a glass dish and dried at 50 C under house vacuum overnight to afford 160.20 g of the final productproduct. 1H NMR, 300 MHz, (DMSO -D6), ppm; 13.35 (1 H, s), 8.61 (1 H, d, J=3.8 Hz), 8.39 (1 H, q, J=4.4 Hz), 8.21 (1 H, d, J=8.8 Hz), 7.96 (1 H, d, J=16.4 Hz), 7.85 -7.76 (1 H, m), 7.66 (1 H, d, J=7.8 Hz), 7.61 (1 H, s), 7.58 (1 H, d, J=16.5 Hz), 7.50 (1 H, dd, J=5.7 Hz), 7.36 -7.23 (3 H, m), 7.192 (1 H, dd, J=8.4, 1.2 Hz), 7.05 (1 H, dd, J=7.5, 1.5 Hz), 2.78 (3 H, d, J=4.5 Hz).

		Example 1 Preparation of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(Pyridine-2-yl)ethenyl]indazole 2-(3-Iodo-1H-indazol-6-ylsulfanyl)-N-methyl-benzamide (239.19 g), 2-vinylpyridine (75.7 mL, 702 Mmol), Pd(OAc)2 (6.56 g), P(o-Tol)3 (23.12 g), Proton Sponge (187.82 g), LiBr (314.59 g), and DMA (3.1 L, 3.5 mL/g) were added to a 5 L 3-neck flask, equipped with a mechanical stirrer and a temperature probe. The mixture was degassed three times by alternately connecting to house vacuum and nitrogen. The mixture was then heated to 110 C. in one hour and the temperature was maintained at 110 C. for 24 hours, at which time all of the 2-(3-Iodo-1H-indazol-6-ylsulfanyl)-N-methyl-benzamide was consumed (HPLC). After cooling, the mixture was transferred to a 22 L extractor and followed by the addition of 5.5 L of CH2Cl2, 5.5 L of water and 275 mL of 37% aqueous HCl. After agitation and partitioning, the organic phase was extracted twice with 2.0 L of water and 100 mL of 37% HCl. At this stage, the organic phase (HPLC) did not contain any significant amount of the final product (HPLC), and was discarded. The combined aqueous layers were treated with 2.2 L of toluene, followed by the addition of 1.05 L of 28% NH4OH over 45 minutes of time (via addition funnel). A thick precipitate formed at this stage. The resulting mixture was allowed to stir for approximately 48 hours. The mixture was then filtered and sucked dry. The cake was triturated with 3.5 L of toluene, stirred overnight, filtered and sucked dry. The cake was then transferred to a glass dish and dried at 50 C. under house vacuum overnight to afford 160.20 g of the final productproduct. 1H NMR, 300 MHz, (DMSO-D6), ppm; 13.35 (1 H, s), 8.61 (1 H, d, J=3.8 Hz), 8.39 (1 H, q, J=4.4 Hz), 8.21 (1 H, d, J=8.8 Hz), 7.96 (1 H, d, J=16.4 Hz), 7.85-7.76 (1 H, m), 7.66 (1 H, d, J=7.8 Hz), 7.61 (1 H, s), 7.58 (1 H, d, J=16.5 Hz), 7.50 (1 H, dd, J=5.7 Hz), 7.36-7.23 (3 H, m), 7.192 (1 H, dd, J=8.4, 1.2 Hz), 7.05 (1 H, dd, J=7.5, 1.5 Hz), 2.78 (3 H, d, J=4.5 Hz).
		N-1 Boc 2-(3-Iodo-1H-indazol-6-ylsulfanyl)-N-methyl-benzamide (510 mg), and 2-vinylpyridine (0.14 mL, 1.3 Mmol) were added to a 100 mL 3-neck flask, equipped with a stirring bar and a temperature probe. The mixture was then degassed three times by alternately connecting to house vacuum and nitrogen. The mixture was allowed to stir for two hours, after which an aliquot indicated that only the starting material was present (HPLC). Initially, Pd[P(t-Bu)3]2 was used as a catalyst (9.28 g), along with 20 mL of DMF, and 124 mL of Cy2NMe (711 Mmol) at room temperature for 2 hours, but the reaction did not work. Subsequently, it was found that when Pd(OAc)2 was used as the catalyst, along with P(o-Tol)3, the reaction worked. However, the role of the Pd[P(t-Bu)3]2 catalyst in the overall reaction could not be excluded. Accordingly, 22 mg of Pd(OAc)2 and 91 mg of P(o-Tol)3 were then added to the flask and the mixture was degassed again by alternately connecting to house vacuum and nitrogen three times. The mixture was heated to 100 C. and the temperature was maintained at 100 C. overnight, at which time all the starting material was consumed (HPLC). TFA (1.0 mL, 13.0 Mmol) was added to remove the Boc protecting group. After cooling, the mixture was poured into a mixture of 100 mL of water and 100 mL of EtOAc. After partitioning, the aqueous layer was extracted twice with 50 mL of EtOAc. The combined organic layers were washed twice with water, dried over MgSO4 and concentrated. The residue was pre-adsorbed onto silica and subjected to gradient flash chromatography (Hexanes/EtOAc, 1:3, 1:4, EtOAc, EtOAc/MeOH, 100:1, 50/1) to yield 155 mg of the final productproduct.
		A 3 L 3-neck flask was equipped with a mechanical stirrer, temperature probe, and a nitrogen inlet. 2-(3-Iodo-1H-indazol-6-ylsulfanyl)-N-methyl-benzamide (200 g), as prepared in Example 12, was charged to the flask followed by Pd(OAc)2 (5.48 g), P(o-tol)3 (19.3 g), proton sponge (104.7 g) and NMP (1.0 L). Note this initial mixing was slightly endothermic, with the temperature dropping from 22.8 C. to 20.9 C. Also note, it is possible to use less Pd(OAc)2 (e.g. as little as 1 to 2%) if Xantphos is also added. In addition, it is possible to replace proton sponge as the base and instead use bases such as N-methyl-piperidine or N,N-diisopropylethylamine (Hunig's base). After stirring had started, LiBr (262 g) was added. This addition was exothermic, the temperature rose from 20.9 C. to 68 C. in 15 min, then began to fall. 2-vinyl pyridine (69 mL) was then added. The mixture was degassed three times by alternately connecting to house vacuum and nitrogen. The mixture was heated at 110 C. over one hour and the temperature was maintained at 110 C. for 18 h. The reaction was monitored by HPLC until all of the 2-(3-Iodo-1H-indazol-6-ylsulfanyl)-N-methyl-benzamide was was consumed. Heating was then discontinued and the reaction was allowed to cool to room temperature. In a separate operation, 250 mL of concentrated HCl (0.25 L) was carefully added to 2750 mL deionized water to prepare the required 3.0 L of 1.0 N hydrochloric acid solution to be used in the next step. To the reaction mixture was added 1 N aqueous HCl (2L) while continuing to stir. Note, the HCl addition is mildly exothermic. Methyl-isobutyl ketone (MIBK, 2L) was then added and the mixture was agitated vigorously (300-400 RPM) for 2 hours. During this partitioning step, some solids were formed. The solids were removed via filtration through a 1 pad of celite. The filter cake was washed with both 1N HCl (200 mL) and MIBK (200 mL). Note, this filtration may possibly be slow on scale-up. At present scale, 2.5+ L passed through 2 L sinterglass funnel in less than 4 minutes. The collected solids were mostly proton sponge and dimeric impurity by HPLC. As standard precaution, the identity of the solids should be confirmed by HPLC before discarding. The filtrate was agitated via vigorous mechanical stirring and then allowed to separate into organic (upper) and aqueous (lower) layers. The lower aqueous layer was drained (3.6 L) and the organic layer was extracted twice with 1 N HCl (500 mL then 300 mL). The acidic aqueous extracts were pooled and washed once with MIBK (1 L). The final volume for the lower aqueous layer was 4.3 L; upper MIBK layer volume was 1.1 L. Based on subsequent experiments it is recommended that further agitation should not be carried out since phase mixing is accomplished as described previously. Further agitation requires more time to allow for phase re-separation and is not necessary. The initial MIBK extract may be very close in color to the aqueous phase and difficult to distinguish; measured volumes are given above. To the combined aqueous layer was added toluene (1 L) and the mixture was transferred to a reaction flask with an overhead stirrer and pH meter. The mixture was stirred rapidly (400 rpm) while 28% NH4OH (300 mL) was slowly added over 20 to 30 minutes via addition funnel. Since the target pH is 9, extra reagent should be on hand because slightly more or less base may need to be added to reach the desired pH endpoint. Slow addition of NH4OH was necessary to prevent formation of gummy (unfilterable) solids; toluene helped to prevent formation of this gummy product by dissolving proton sponge as it was deposited during basification. Solids were then collected by filtration. The filter cake was washed with water (1 L) and toluene (400 mL). Note, on 2L sintered-glass Buchner funnel, initial filtration and washes (total volume 7.5L) were completed within 9 minutes. The cake was then transferred to a glass dish and dried at 60 C. under house vacuum for 24 hours to afford 148.2 g (78% yield) of crude 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridine-2-yl)ethenyl]indazole as a light orange solid. Note, the reaction was monitored via HPLC (TFASH method, details contained herein). Sample preparation was as follows: 1 drop of the reaction mixture was diluted with 1 mL of methanol and 1 mL of 80/20 0.1N HCl/ACN was added; sample shaken. Product assay was carried out as above with 0.5 mg sample. Typical purity was 83-87%. The product contained NMP, which was visible by 1H NMR.

Reference： [1]Patent: WO2016/178150,2016,A1 .Location in patent: Page/Page column 18
[2]Patent: WO2006/48745,2006,A1 .Location in patent: Page/Page column 28
[3]Patent: EP2163544,2010,A1 .Location in patent: Page/Page column 31; 23
[4]Patent: US2006/94881,2006,A1 .Location in patent: Page/Page column 21
[5]Patent: US2006/94881,2006,A1 .Location in patent: Page/Page column 23; 24
[6]Patent: US2006/94881,2006,A1 .Location in patent: Page/Page column 27

4
[ 100-69-6 ]
N-1 Boc 2-(3-iodo-1H-indazol-6-ylsulfanyl)-N-methyl-benzamide [ No CAS ]
[ 319460-85-0 ]

Yield	Reaction Conditions	Operation in experiment
		N-1 Boc 2-(3-lodo-1H-indazol-6-ylsulfanyl)-N-methyl-benzamide (510 mg), and 2- vinylpyridine (0.14 mL, 1.3 Mmol) were added to a 100 mL 3-neck flask, equipped with a stirring bar and a temperature probe. The mixture was then degassed three times by alternately connecting to house vacuum and nitrogen. The mixture was allowed to stir for two hours, after which an aliquot indicated that only the starting material was present (HPLC). Initially, Pd[P(t- Bu)3J2 was used as a catalyst (9.28 g), along with 20 mL of DMF, and 124 mL of Cy2NMe (711 Mmol) at room temperature for 2 hours, but the reaction did not work. Subsequently, it was found that when Pd(OAc)2 was used as the catalyst, along with P(O-ToI)3, the reaction worked. However, the role of the Pd[P(t-Bu)3]2 catalyst in the overall reaction could not be excluded. Accordingly, 22 mg of Pd(OAc)2 and 91 mg of P(O-ToI)3 were then added to the flask and the EPO <DP n="33"/>mixture was degassed again by alternately connecting to house vacuum and nitrogen three times. The mixture was heated to 100 0C and the temperature was maintained at 100 0C overnight, at which time all the starting material was consumed (HPLC). TFA (1.0 mL, 13.0 Mmol) was added to remove the Boc protecting group. After cooling, the mixture was poured into a mixture of 100 mL of water and 100 mL of EtOAc. After partitioning, the aqueous layer was extracted twice with 50 mL of EtOAc. The combined organic layers were washed twice with water, dried over MgSO4 and concentrated. The residue was pre-adsorbed onto silica and subjected to gradient flash chromatography (Hexanes/EtOAc, 1 :3, 1 :4, EtOAc, EtOAc/MeOH, 100:1 , 50/1) to yield 155 mg of the final product.

Reference： [1]Patent: WO2006/48745,2006,A1 .Location in patent: Page/Page column 31-32

Yield	Reaction Conditions	Operation in experiment
	With cysteine-silica; In tetrahydrofuran; DMA; at 20℃;Purification / work up;	To a 12 L 3-neck flask, equipped with a mechanical stirrer, was adde d 160.20 g of 6-[2-(methylcarbamoyl)phenylsulfanyl] -3-E-[2-(pyridine-2-yl)ethenyl]indazole and 1.6 L of DMA and 1.6 L of THF. After stirring for 20 minutes, the mixture became homogeneous. To the clear solution was added 800.99 g of 10% cysteine -silica and the resulting mixture was allowed to stir at room temperature overnight. The mixture was filtered through a medium sintered glass fritted funnel, and the cake was washed with a solution of 500 mL of DMA and 500 mL of THF. The cake was further washed wi th 2.0 L of THF and the filtrate was collected into a separate flask. The volatile parts in the latter filtrate were removed in vacuo and the residue was combined with the main filtrate. The combined filtrate was recharged back into the 12 L flask, followed by 800 g of 10% cysteine -silica. The flask was equipped with a mechanical stirrer and stirred over the weekend at room temperature. The mixture was then filtered through a medium sintered glass fritted funnel and the silica was washed with a mixture o f solvents of 500 mL of DMA ans 500mL of THF followed by 3.0 L of THF. The volatile parts in the filtrate were removed in vacuo and the remaining solution was transferred to a 22 L 3 -neck flask and treated with 12 L of water (added over a 20 minute peri od of time), a thick precipitate formed at this stage. After stirring overnight, the mixture was filtered and the cake was washed with 2.0 L of water and sucked dry. The cake was charged to a 5 L 3 -neck flask, followed by 1.6 L of THF and 160 mL of DMF. The flask was equipped with a mechanical stirrer, a reflux condenser and the mixture was heated at reflux for 8 hours. After cooling overnight, the mixture was filtered through sharkskin filter paper and sucked dry. The cake was charged to a 5 L 3 -neck flask and 1.6 L of MeOH was added. The flask was equipped with a mechanical stirrer, a water condenser and the contents were heated at reflux for 6 hours. After cooling overnight, the mixture was filtered through sharkskin filter paper and sucked dry. The cake was dissolved into 1.6 L of HOAc with the assistance of gentle heating in the water bath of a rotary evaporator. The solution was filtered through No.3 filter paper and the total volume of the filtrate was reduced to -500 mL in volume on the rotary eva porator at 60 C/60 mmHg. At this stage, the bulk of the mixture remained a yellow solution and a small amount of precipitate formed. To the flask was charged 500 mL of xylenes (precipitate formed) and the total volume was reduced to -500 mL in volume on the rotary evaporator at 60 C/60 mmHg. The process was repeated two more times. After cooling, the mixture was filtered, the cake was washed with 500 mL of xylenes and sucked dry. The cake was transferred to a glass dish and further dried at 80 C/27 inch vacuum overnight. The cake was off-white in color and weighed 108.38g. X -ray powder diffraction analysis indicated that a crystalline form was present, which was characterized as Form IV by a powder X-ray diffraction pattern comprising peaks at the fol lowing approximate diffraction angles (2theta): 8.9, 12.0, 14.6, 15.2, 15.7, 17.8, 19.2, 20.5, 21.6, 23.2, 24.2, 24.8, 26.2, and 27.5.
	With 10% cysteine-silica; In tetrahydrofuran; ISOPROPYLAMIDE; at 20℃;Purification / work up;	To a 12 L 3-neck flask, equipped with a mechanical stirrer, was added 160.20 g of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridine-2-yl)ethenyl]indazole and 1.6 L of DMA and 1.6 L of THF. After stirring for 20 minutes, the mixture became homogeneous. To the clear solution was added 800.99 g of 10% cysteine-silica and the resulting mixture was allowed to stir at room temperature overnight. The mixture was filtered through a medium sintered glass fritted funnel, and the cake was washed with a solution of 500 mL of DMA and 500 mL of THF. The cake was further washed with 2.0 L of THF and the filtrate was collected into a separate flask. The volatile parts in the latter filtrate were removed in vacuo and the residue was combined with the main filtrate. The combined filtrate was recharged back into the 12 L flask, followed by 800 g of 10% cysteine-silica. The flask was equipped with a mechanical stirrer and stirred over the weekend at room temperature. The mixture was then filtered through a medium sintered glass fritted funnel and the silica was washed with a mixture of solvents of 500 mL of DMA and 500 mL of THF, followed by 3.0 L of THF. The volatile parts in the filtrate were removed in vacuo and the remaining solution was transferred to a 22 L 3-neck flask and treated with 12 L of water (added over a 20 minute period of time), a thick precipitate formed at this stage. After stirring overnight, the mixture was filtered and the cake was washed with 2.0 L of water and sucked dry. The cake was charged to a 5 L 3-neck flask, followed by 1.6 L of THF and 160 mL of DMF. The flask was equipped with a mechanical stirrer, a reflux condenser and the mixture was heated at reflux for 8 hours. After cooling overnight, the mixture was filtered through sharkskin filter paper and sucked dry. The cake was charged to a 5 L 3-neck flask and 1.6 L of MeOH was added. The flask was equipped with a mechanical stirrer, a water condenser and the contents were heated at reflux for 6 hours. After cooling overnight, the mixture was filtered through sharkskin filter paper and sucked dry. The cake was dissolved into 1.6 L of HOAc with the assistance of gentle heating in the water bath of a rotary evaporator. The solution was filtered through No.3 filter paper and the total volume of the filtrate was reduced to 500 mL in volume on the rotary evaporator at 60 C./60 mmHg. At this stage, the bulk of the mixture remained a yellow solution and a small amount of precipitate formed. To the flask was charged 500 mL of xylenes (precipitate formed) and the total volume was reduced to 500 mL in volume on the rotary evaporator at 60 C./60 mmHg. The process was repeated two more times. After cooling, the mixture was filtered, the cake was washed with 500 mL of xylenes and sucked dry. The cake was transferred to a glass dish and further dried at 80 C./27 inch vacuum overnight. The cake was off-white in color and weighed 108.38 g. X-ray powder diffraction analysis indicated that a crystalline form was present, which was characterized as Form IV by a powder X-ray diffraction pattern comprising peaks at the following approximate diffraction angles (20): 8.9, 12.0, 14.6, 15.2, 15.7, 17.8, 19.2, 20.5, 21.6, 23.2, 24.2, 24.8, 26.2, and 27.5.

6
[ 319460-85-0 ]
6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]indazole hydrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With water; at 20℃; for 144h;	Polymorphic Form II of Compound 1, which is a hydrate, was generated by placing polymorphic Form I of Compound 1 (37 mg) in a 93% relative humidity chamber at room temperature for six days. (HPLC purity >98.5%). FIG. 2A is an X-ray powder diffractogram of polymorph Form II of Compound 1. Polymorphic Form II of Compound 1 was further characterized by differential scanning calorimetry. FIG. 2B is a differential scanning calorimetry (DSC) profile of a sample of polymorphic Form II of Compound 1. Form II displayed endotherms with onset at 102, 152, and 202 C., followed by an exotherm at 206 C. and another exotherm at 210 C. at a scan rate of 10 C./min.

Reference： [1]Patent: US2006/94763,2006,A1 .Location in patent: Page/Page column 16

7
(E)-N-methyl-2-[3-(2-(pyridin-2-yl)ethenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl]thio}benzamide [ No CAS ]
[ 319460-85-0 ]

Yield	Reaction Conditions	Operation in experiment
99%	With toluene-4-sulfonic acid; In neat (no solvent); for 0.75h;Milling;	A mixture of 7 (5 mmol), p-TsOH (20 mmol), and silica gel (4.0 g) was placed in a 80 mL stainless-steel vessel, along with 207 stainless-steel balls (dMB = 6 mm, MB = 0.293). The reaction mixture was then ball-milled at 500 rpm for 45 min. At the end of the experiment, the reaction mixture was scratched off from the vessel and directly purified by column chromatography on silica gel eluting with (petroleum ether/EtOAc 1:1) to provide 1.917 g (99%) of axitinib.
98%	With toluene-4-sulfonic acid; In methanol; water; at 64℃; for 1 - 5h;Product distribution / selectivity;	6-(2-mercapto-N-methylbenzamide)-3-((E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyroan-2-yl)- 1H-indazole (20.2 Kg), p-toluene sulfonic acid monohydrate (40 Kg), methanol (111 Kg) and water (20 Kg) are combined and agitated for 1 to 5 hours at 640C (until the deprotection is complete by HPLC analysis). The mixture is then cooled to 220C and concentrated under reduced pressure to volume of ca. 90 L. Methanol (111 Kg) is added and the mixture is agitated for 1 hour at 640C. Water (71 Kg) is added and the mixture is cooled to 22C and concentrated under reduced pressure to a volume of ca. 100 L. The process is repeated to drive the reaction to completion by evaporation of the side-product (DHP) with water. Methanol (1 11 Kg) is added and the mixture is agitated for 1 hour at 640C, diluted with water (71 Kg) and the mixture is agitated for 1 hour at O0C. The mixture is filtered and the solids are washed with cold methanol (61 Kg). The solids are transferred to a reactor and ethyl acetate (61 Kg) is added. The mixture is agitated for 30 minutes at 650C, cooled to 30C, and the solids are filtered and washed with cold ethyl acetate (61 Kg). This sequence removes any residual methanol since trace amounts of methanol may prevent the formation of the desired polymorph form III during the neutralization step. The solids are transferred to a reactor, diluted with ethyl acetate (82 Kg), agitated for 3 minutes at O0C, and neutralized by addition of 5% aqueous sodium bicarbonate solution (175 Kg) (aqueous phase pH ? 7). Caution: carbon dioxide is evolved. The slurry is agitated for 2 hours at 220C and a sample is withdrawn (60 ml_) to check the pH and to test for polymorph form. If the DSC indicates that the conversion of polymorph form Vl to polymorph form III (~ Vz ethyl acetate solvate) is not complete, continue the agitation at 220C and check DSC every 4 hours until the formation of polymorph form III is confirmed. A long period of agitation (ca. 16 hours) may be required for the complete polymorph conversion. Once the DSC indicates the formation of form III, the solids are filtered, washed with ethyl acetate (61 Kg), water (61 Kg), and ethyl acetate (61 Kg), and dried in a vacuum oven for 24 to 48 hours (4O0C and 25 mm Hg) to provide 17.8 Kg of 6- (2-mercapto-N-methylbenzamide)-3-((E)-2-pyridin-2-yl-vinyl)-1-H-indazole (98% yield with a purity of 98.8% by HPLC). The product is light sensitive and should be stored in the dark at O0C.
95.4%	With toluene-4-sulfonic acid; In methanol; water; at 65℃; for 4h;Inert atmosphere;	(5) Synthesis of axitinib In a 2L reaction flask was added (E)-N-methyl-2-[3-(2-(pyridin-2-yl)ethenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl]thio}benzamide (150.0g, 0.32mol), p-toluenesulfonic acid monohydrate (303.2g, 1.59mol), methanol (800mL) and water (150mL), under nitrogen, was heated to 65 deg. C for 4 hours, rotary evaporated to dryness, added ethanol (800mL), stirred at 65 for one hour, the ethanol was removed by rotary evaporation, then repeated three times, the reaction was monitored by TLC (petroleum ether: ethyl acetate = 1: 1). After completion of the reaction, the solution was cooled to room temperature, rotary evaporated to dryness, added to a 500 mL of water, stirred for one hour, filtered, the filter cake was washed with methanol and ice, and then the reaction vessel was charged with 450mL of ethyl acetate, stirred at 65 for 30 minutes, cooled to room temperature, suction filtered, the filter cake was washed with ethyl acetate and ice, washed with water, and dried 50 deg. C under vacuum for 12 hours to give a white solid 117.5g, axitinib (II), yield 95.4%, HPLC purity 98.8%.

95.1%	With toluene-4-sulfonic acid; In methanol; for 4h;Reflux;	Example 2 The dried solid obtained in Example 1 was added into a flask with methanol (20 mL, 4 vol.) and p-toluenesulfonic acid (4.28 g, 2 eq.), and then heated at reflux for about 4 hours. After cooling, the resulting solid was isolated by filtration and washed with methanol (20 mL, 4 vol.) and water (20 mL, 4 vol.) to afford Axitinib (3.87 g, 95.1% weight yield).
92.5%	With toluene-4-sulfonic acid; In methanol; at 65℃; for 4h;Heating / reflux;Product distribution / selectivity;	N-1 THP 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridine-2-yl)ethenyl]indazole (355 g) was suspended in 2,485 ml_ of methanol, after which p-toluenesulfonic acid monohydrate (718 g) was added. The mixture was then heated to 65 0C (hard reflux) for 4 hours under argon while the reaction was monitored by HPLC (gluco method). Heating continued until less than 1% of the N-1 THP protected starting material persisted. The heating was then removed and the reaction was cooled to room temperature. The solid was filtered and the wet cake was washed with methanol (2 volumes, 710 mL) then the solids were rinsed with ethyl acetate (2 volumes, 710 mL). The wet cake was transferred to a reactor containing sodium bicarbonate (126.84 g), deionized water (1800 mL), and ethyl acetate (975 mL), which was then stirred for 2 hours at 2O0C. The solids were filtered and washed with 5 volumes of deionized water (1800 mL), then with 2 volumes of ethyl acetate (760 mL), and then dried in a vacuum oven at 400C for 16 hours. The isolated yield for the reaction was 92.5% (274 g). The isolated material was identified as crystalline Form III free base (0.5 ethyl acetate solvate). 1H NMR, 300 MHz, (DMSO-D6), ppm; 13.35 (1 H, s), 8.60 (1 H, d, J=3.8 Hz), 8.39 (1 H, m), 8.23 (1 H, d, J=8.5 Hz), 7.95 (1 H, d, J=16.4 Hz), 7.82 (1 H, ddd, J=7.7, 7.6, 1.8 Hz), 7.67 (1 H, d, J=7.8 Hz), 7.60 (a H, s), 7.57 (1 H, d, J=16.4 Hz), 7.49 (1 H, dd, J=7.1 , 1.6 Hz), 7.35-7.26 (3 H, m), 7.19 (1 H, d, J=8.4 Hz), 7.04 (1 H, d, J=7.8 Hz), 2.77 (3 H, d, J=4.6 Hz). 13C NMR, 75 MHz, (DMSO-D6) ppm: 168.23, 155.18, 149.81 , 142.35, 142.22, 137.31 , 136.00, 132.89, 130.64, 130.36, 129.51 , 128.14, 126.50, 125.93, 124.08, 123.01 , 122.85, 122.12, 120.642, 115.08, 26.45.
92.5%		N-1 THP 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridine-2-yl)ethenyl]indazole (355 g) was suspended in 2,485 mL of methanol, after which p-toluenesulfonic acid monohydrate (718 g) was added. The mixture was then heated to 65 C. (hard reflux) for 4 hours under argon while the reaction was monitored by HPLC (gluco method). Heating continued until less than 1% of the N-1 THP protected starting material persisted. The heating was then removed and the reaction was cooled to room temperature. The solid was filtered and the wet cake was washed with methanol (2 volumes, 710 mL) then the solids were rinsed with ethyl acetate (2 volumes, 710 mL). The wet cake was transferred to a reactor containing sodium bicarbonate (126.84 g), deionized water (1800 mL), and ethyl acetate (975 mL), which was then stirred for 2 hours at 20 C. The solids were filtered and washed with 5 volumes of deionized water (1800 mL), then with 2 volumes of ethyl acetate (760 mL), and then dried in a vacuum oven at 40 C. for 16 hours. The isolated yield for the reaction was 92.5% (274 g). The isolated material was identified as crystalline Form III free base (0.5 ethyl acetate solvate). 1H NMR, 300 MHz, (DMSO-D6), ppm; 13.35 (1 H, s), 8.60 (1 H, d, J=3.8 Hz), 8.39 (1 H, m), 8.23 (1 H, d, J=8.5 Hz), 7.95 (1 H, d, J=16.4 Hz), 7.82 (1 H, ddd, J=7.7, 7.6, 1.8 Hz), 7.67 (1 H, d, J=7.8 Hz), 7.60 (1 H, s), 7.57 (1 H, d, J=16.4 Hz), 7.49 (1 H, dd, J=7.1, 1.6 Hz), 7.35-7.26 (3 H, m), 7.19 (1 H, d, J=8.4 Hz), 7.04 (1 H, d, J=7.8 Hz), 2.77 (3 H, d, J=4.6 Hz). 13C NMR, 75 MHz, (DMSO-D6) ppm: 168.23, 155.18, 149.81, 142.35, 142.22, 137.31, 136.00, 132.89, 130.64, 130.36, 129.51, 128.14, 126.50, 125.93, 124.08, 123.01, 122.85, 122.12, 120.642, 115.08, 26.45.

Reference： [1]Beilstein Journal of Organic Chemistry,2018,vol. 14,p. 786 - 795
[2]Patent: WO2006/48745,2006,A1 .Location in patent: Page/Page column 25
[3]Patent: CN103570696,2016,B .Location in patent: Paragraph 0080; 0081; 0082; 0083
[4]Patent: US2016/318898,2016,A1 .Location in patent: Paragraph 0054
[5]Patent: WO2006/48745,2006,A1 .Location in patent: Page/Page column 30
[6]Patent: US2006/94881,2006,A1 .Location in patent: Page/Page column 22; 23
[7]Organic Process Research and Development,2015,vol. 19,p. 849 - 857

8
1,2-bis(diphenylphosphino)ethane; 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridine-2-yl)ethenyl]indazole; mixture of [ No CAS ]
[ 319460-85-0 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; at 20 - 65℃; for 18h;Purification / work up;	To a 250 mL round bottom flask under a nitrogen atmosphere was charged crude 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridine-2-yl)ethenyl]indazole (35 g)-as prepared in Example 13-DIPHOS, NMP (175 mL) and then 1,2-diaminopropane with mechanical stirring. The mixture became an orange solution after about 10 minutes. The solution was then stirred at room temperature for 2.5 hours. To the mixture was then added methanol (1400 mL) over 5 to 10 minutes. During addition, the solution became cloudy. After a few minutes, a precipitate formed. Stirring (250 RPM or less, moderate stir rate) was continued for 18 hours. Note, after MeOH was added, granulation was carried out for 18 h. Use of a shorter granulation time has been shown to reduce yield. Use of a longer granulation time does not increase yield but may be carried out without any adverse effect. The granular solid was then collected by filtration. The solids were washed with 105 mL (3 volumes) of MeOH. The solids were pulled dry via suction on a filter. The cake was transferred to a glass dish and dried at 65 C. under house vacuum for 18 hours to afford 26 g of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-12-(pyridine-2-yl)ethenyl]indazole as an off-white, granular solid (74% recovery by weight; purity-corrected recovery is 89%). The product was 97+% pure by HPLC (TFASH method) but contained DIPHOS, visible by NMR that was removed in the next steps. The product thus obtained contained 16 ppm residual palladium metal (the original Pd content before treatment was 1189 ppm). A portion of the product (21.2 g) was charged to a flask and tetrahydrofuran (210 mL, 10 mL/g) was added under an atmosphere of nitrogen. The mixture was heated to 65 C., under 250 rpm stirring, for 15 h. The mixture remained a suspension of solids throughout the reslurry. The mixture was cooled to room temperature and stirred for 3 h. The solids were collected by filtration, washed with 42 mL (2 volumes) of THF and then were pulled dry on the filter via suction. Note, the small wash volume of THF was used because the THF appeared to wash some product into the filtrate. It is recommended to not use more than 2 volumes for the wash or for rinsing forward material. The solids were then dried in a vacuum oven at 65 C. for 18 h. The resulting white solid weighed 16 g (76% recovery by weight; purity-corrected recovery was 77%) and was 98+% pure by HPLC (TFASH method). Pd content was 7 ppm. A portion of the product (13 g) was charged to a flask and methanol (130 mL) was added while stirring under an atmosphere of nitrogen. The mixture was heated to 65 C., and mechanically stirred for 10 h. The mixture remained a suspension of solids throughout the reslurry. Note, about 5 to 10 minutes after MeOH was added, an apparent physical form change took place, resulting in a rapid change from a thin slurry to a very thick one that did not stir well at room temperature (the slurry itself was not actually thicker, but the new form solids appeared to be needle-like crystals and thus their volume expanded considerably). Stirring quickly improved on heating and the mixture remained an easily stir-able slurry both at elevated temperature and on cooling back to 25 C. The mixture was then cooled to room temperature and stirred for 3 h. The solids were collected by filtration and were pulled dry on the filter via suction. The filter cake was not washed. The solids were dried in a vacuum oven at 65 C. for 18 h. The resulting white solid weighed 12.2 g (94% recovery by weight; purity-corrected recovery was 95%) and was 99+% pure by HPLC (TFASH method). Pd content was 7 ppm.

Reference： [1]Patent: US2006/94881,2006,A1 .Location in patent: Page/Page column 28

9
6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]indazole ethylacetate solvate [ No CAS ]
[ 319460-85-0 ]

Yield	Reaction Conditions	Operation in experiment
92%	In methanol; acetic acid; at 60℃;	Polymorphic Form IV of Compound 1 was prepared from polymorphic Form III of Compound 1. A sample of polymorphic Form III of Compound 1 (1.015 kg) was dissolved in 3 L of methanol and 5 L of acetic acid at 60 C. The solution was then filtered and concentrated by medium vacuum. 6 L of xylenes were added at 60 C. and then removed by full vacuum. 4 L of xylenes were added and then removed under full vacuum, followed by treatment with an additional 4 L of xylenes. Xylenes were then removed under full vacuum to yield polymorphic Form IV of Compound 1 in 92% Yield. HPLC analysis showed greater than 98.5% purity.
		Polymorphic Fom III of Compound 1, (2 g) was suspended in 15 mL ethanol. 4 g of para-toluenesulfonic acid monohydrate was added and the mixture heated to 82 C. for 14 hr. After cooling to room temperature, 25 mL of saturated NaHCO3 solution was added and the suspension stirred for 2 hr. Solids were collected by filtration, washed with 50 mL water and dried under lab vacuum at 45 C. overnight (HPLC purity>99%).

Reference： [1]Patent: US2006/94763,2006,A1 .Location in patent: Page/Page column 16-17
[2]Patent: US2006/94763,2006,A1 .Location in patent: Page/Page column 18

10
6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]indazole p-toluene sulfonic acid salt [ No CAS ]
[ 319460-85-0 ]

Yield	Reaction Conditions	Operation in experiment
92%	In NaHCO3; ethyl acetate; at 65℃;	A crystalline form of Compound A, designated as polymorphic Form IV, was prepared using the following procedure. Unless otherwise indicated, all temperatures in the following description are in degrees Celsius (0C) and all parts and percentages are by weight, unless indicated otherwise.Polymorphic Form IV of Compound A was prepared from a different polymorphic form of Compound A, which is designated as polymorphic Form III. Polymorphic Form III of Compound A was prepared by neutralizing a p-toluenesulfonic acid salt derivative of Compound A in ethyl acetate followed by drying under vacuum at 65C. The p-toluene sulfonic EPO <DP n="35"/>acid salt of Compound A (421g) was suspended in 1800 mL of 0.84 M NaHCO3 and 1800 mL ethylacetate and stirred at 65C for 2 hrs. Solids were collected by filtration, washed with 1800 mL water and with 800 mL ethylacetate, and dried under lab vacuum at 5O0C overnight to yield the polymorphic Form III of Compound A, which is an ethylacetate solvate. Yield: 92% (HPLC purity was greater than 99%). A sample of polymorphic Form III of Compound A (1.015 kg) was then dissolved in acetic acid at 6O0C. The solution was then filtered and concentrated by medium vacuum. 6 L of xylenes were added at 600C and then removed by full vacuum. 4 L of xylenes were added and then removed under full vacuum, followed by treatment with an additional 4 L of xylenes. Xylenes were then removed under full vacuum to yield polymorphic Form IV of Compound A in 92% yield. HPLC analysis showed greater than 98.5% purity.A sample of crystalline Compound A in polymorphic Form IV was examined using powder x-ray diffraction (PXRD) with a Bruker AXS D8 Advance diffractometer. Samples (approximately 100 mg) were packed in Lucite sample cups fitted with Si(511) plates as the bottom of the cup to give no background signal. Samples were spun in the phi plane at a rate of 30 rpm to minimize crystal orientation effects. The x-ray source (KCualpha, lambda = 1.54 A) was operated at a voltage of 45 kV and a current of 40 mA. Data for each sample were collected over a period of 27 minutes in continuous detector scan mode at a scan speed of 1.8 seconds/step and a step size of 0.04/step. Diffractograms were collected over the 2Theta range of 4 to 30. FIG. 1 gives the PXRD diffractogram of polymorphic Form IV of Compound A.

Reference： [1]Patent: WO2006/123223,2006,A1 .Location in patent: Page/Page column 33-34

11
N-methyl-2-((3-((1E)-2-(pyridin-2-yl)ethenyl)-1H-indazol-6-yl)sulfanyl)benzamide [ No CAS ]
[ 319460-85-0 ]

Yield	Reaction Conditions	Operation in experiment
	With trifluoroacetic acid; In N,N-dimethyl-formamide;	N-1 Boc 2-(3-lodo-1H-indazol-6-ylsulfanyl)-N-methyl-benzamide (510 mg), and 2-vinylpyridine (0.14 mL, 1.3 Mmol) were added to a 100 mL 3 -neck flask, equipped with a stirring bar and a temperature probe. The mixture was then degassed three times by alternately connecting to house vacuum and nitrogen. The mixture was allowed to stir for two hours, after which an aliquot indicated that only the starting material was present (HPLC). Initially, Pd[P(t-Bu)3]2 was used as a catalyst (9.28 g), along with 20 mL of DMF, and 124 mL of Cy2NMe (711 Mmol) at room temperature for 2 hours, but the reaction did not work. Subsequently, it was found that when Pd(OAc)2 was used as the catalyst, along with P(o-Tol)3, the reaction worked. However, the role of the Pd[P(t -Bu)3]2 catalyst in the overall reaction could not be excluded. Accordingly, 22 mg of Pd(OAc)2 and 91 mg of P(o-Tol)3 were then added to the flask and the mixture was degassed again by alternately connecting to house vacuum and nitrogen three times. The mixtur e was heated to 100 C and the temperature was maintained at 100 C overnight, at which time all the starting material was consumed (HPLC). TFA (1.0 mL, 13.0 Mmol) was added to remove the Boc protecting group. After cooling, the mixture was poured into a mixture of 100 mL of water and 100 mL of EtOAc. After partitioning, the aqueous layer was extracted twice with 50 mL of EtOAc. The combined organic layers were washed twice with water, dried over MgSO4 and concentrated. The residue was pre -adsorbed onto silica and subjected to gradient flash chromatography (Hexanes/EtOAc, 1:3, 1:4, EtOAc, EtOAc/MeOH, 100:1, 50/1) to yield 155 mg of the final productproduct.

Reference： [1]Patent: EP2163544,2010,A1 .Location in patent: Page/Page column 33-34; 27

12
[ 319460-85-0 ]
C₂₂H₁₈N₄O₃S [ No CAS ]
axitinib sulfone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5%; 30%	With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; for 7h;	MCPBAwas added to 200 mg of <strong>[319460-85-0]axitinib</strong> suspended in 10 ml of methylene chloride at0C. The reaction mixture was stirred at room temperature for 7 hours. Afterremoval of solvent, the crude products were purified by silica gel chromatographyusing methylene chloride/acetone/methanol (10:1:1) as eluent to afford M15 (63mg, 30%) and M9 (11 mg, 5%). The structures of M9, M12, and M15 wereelucidated using 1H and 13C NMR methods by dissolving the compounds intoDMSO-d6. The chromatographic profiles and 1H and 13C NMRs of M9, M12,and M15 are presented in Supplemental Figs. S1-S7.

Reference： [1]Drug Metabolism and Disposition,2014,vol. 42,p. 918 - 931

13
[ 319460-85-0 ]
Axitinib sulfoxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30 mg	With Cunninghamella echinulata; for 192h;Microbiological reaction;	Authentic metabolitestandards of M9, M12, and M15 were prepared either using microbes orchemically using meta-chloroperbenzoic acid (MCPBA) in support of definitivestructure determination. For microbial synthesis, 40 fungi and 40 bacteria, themajority obtained from the American Type Culture Collection (Manassas, VA)920 Smith et al.and a few from in-house sources (Pfizer Inc., Groton, CT), were screened forM12 formation. The bacteria and fungi were grown in 20 g glucose, 5 g soy flour,5 g yeast extract, 5 g K2HPO4, 5 g NaCl, and 1 g MgSO4×7H2O, adjusted toa final volume of 1 liter with water, adjusted to pH 7.2, and sterilized. All strainswere grown at 28C and 250 rpm on a rotary shaker. After 2 and 3 days, 0.2 mgof <strong>[319460-85-0]axitinib</strong> from a 10% ethanol solution was added. After 3 and 6 days, thereactions were analyzed by LC-MS using a Cosmosil 5PYE column (150 4.6mm) with a mobile phase of acetonitrile/50 mM ammonium acetate (pH 4.5), ata flow rate of 1.0 ml/min and UV detection at 254 nm. For positive-mode MSdetection, the mobile phase consisted of 20 mM ammonium acetate in wateradjusted to pH 4.0 with acetic acid and acetonitrile. Among all strains screened,Cunninghamella echinulata and Streptomyces griseus showed the highestoxygenation activity. M12 was produced in abundance of .80%, and this wasused to prepare a large batch of the metabolite.For preparative transformation, C. echinulata obtained from the American TypeCulture Collection was grown from an agar plate into a 100-ml preculture using thescreening medium and conditions. After 2 days, 10 ml of the preculture wasinoculated into 1 liter of culture on a 4-liter shake flask ( 5 liters). The culture wasgrown for 24 hours, and then <strong>[319460-85-0]axitinib</strong> was added (0.2 g/l substrate for each 1 liter ofculture). Oxidation was followed by reverse-phase HPLC, and the reaction wasstopped after 8 days. The mycelium was removed from the culture by filtration, andthe oxidation products were extracted three times with one volume of chloroformused each time. After removal of CHCl3 in vacuo, crude product (;500 mg) wasobtained. The crude product was purified by silica gel flash chromatography, usingCH2C12/acetone/MeOH (10:1:1) as eluent to afford 30 mg of the sulfoxide M12.For preparative transformation of <strong>[319460-85-0]axitinib</strong> to M12 by S. griseus, the microbe wasgrown from an agar plate into a 100-ml preculture using the screening medium andconditions. After 2 days, 10 ml of the preculture was inoculated into 1 liter ofculture in a 4-liter shake flask ( 10 liters). The culture was grown for 24 hours, and<strong>[319460-85-0]axitinib</strong> was added (0.1 g/l substrate for each 1 liter of culture). Oxidation wasfollowed by reverse-phase HPLC and the reaction stopped after 8 days. Themycelium was removed from the culture by filtration, and the oxidation productswere extracted three times with one volume of chloroform each. After removal ofCHCl3 in vacuo, the crude product (1.5 g) was obtained. The crude product waspurified by silica gel flash chromatography using CH2Cl2/acetone/MeOH (10:1:1)as eluent to afford 80 mg of sulfoxide and yielded 8-9 mg pure sulfoxide.

Reference： [1]Drug Metabolism and Disposition,2014,vol. 42,p. 918 - 931

14
[ 261953-36-0 ]
[ 319460-85-0 ]

Reference： [1]Organic Process Research and Development,2014,vol. 18,p. 266 - 274

15
[ 944835-85-2 ]
[ 319460-85-0 ]

Reference： [1]Organic Process Research and Development,2014,vol. 18,p. 266 - 274

16
[ 885126-34-1 ]
[ 319460-85-0 ]

Reference： [1]Organic Process Research and Development,2014,vol. 18,p. 266 - 274

17
[ 1639137-80-6 ]
[ 319460-85-0 ]

Reference： [1]Organic Process Research and Development,2014,vol. 18,p. 266 - 274

18
[ 20054-45-9 ]
[ 319460-85-0 ]

Reference： [1]Organic Process Research and Development,2014,vol. 18,p. 266 - 274

19
[ 319460-85-0 ]
(E)-2-((1-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazine-1-carbonyl)-3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)-N-methylbenzamide [ No CAS ]

Reference： [1]Patent: WO2015/38649,2015,A1

20
[ 319460-85-0 ]
[ 7693-46-1 ]
(E)-4-nitrophenyl 6-((2-(methylcarbamoyl)phenyl)thio)-3-(2-(pyridin-2-yl)vinyl)-1H-indazole-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	In tetrahydrofuran;Reflux;	(E)-N-methyl-2-((3-(2-(pyridin-2-yl)vinyl)- lH-indazol-6-yl)thio)benzamide (100 mg, 0.258 mmol) and 4-nitrophenyl carbonochloridate (63 mg, 0.31 mmol) were taken in THF (8 mL). The suspension was heated to reflux overnight. The resulting yellow solid was filtered, washed with ethyl acetate and dried to get the product (110 mg, 75%).

Reference： [1]Patent: WO2015/38649,2015,A1 .Location in patent: Paragraph 001722

21
[ 319460-85-0 ]
axitinib hydrobromic acid salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With hydrogen bromide; In isopropyl alcohol; at 20 - 50℃;	Example 5 Preparation of salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole and hydrobromic acid 250 mg (0.647 mmol) of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole was dissolved in 5 mL of 2-propanol by heating to 50C. 75 mu (0.647 mmol) of hydrobromic acid (48% solution) was diluted with 0.5 mL of 2-propanol at room temperature and the solution of the counterion was drop-wise added to the solution of the API of 50C. The solution at 50C is stirred for 1 hour in closed vial, cooled back to room temperature and stirred overnight. The resulting suspension was filtered off and dried at laboratory conditions.Yield: 253 mg (84%)Determination of the bromide ion concentration by titration confirmed the presence of bromide ion.

Reference： [1]Patent: WO2015/67224,2015,A1 .Location in patent: Page/Page column 18

22
[ 319460-85-0 ]
axitinib hydrochloric acid salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With hydrogenchloride; In isopropyl alcohol; at 20 - 50℃;	Example 6 Preparation of salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole and hydrochloric acid 250 mg (0.647 mmol) of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole was dissolved in 5 mL of 2-propanol by heating to 50C. 57 mu (0.647 mmol) of hydrochloric acid (35% solution) was diluted with 0.5 mL of 2-propanol at room temperature and the solution of the counterion was drop-wise added to the solution of the API of 50C.The solution at 50C is stirred for 1 hour in closed vial, cooled back to room temperature and stirred overnight. The resulting suspension was filtered off and dried at laboratory conditions.Yield: 227 mg (83%)Determination of the chloride ion concentration by titration confirmed the presence of chloride ion.

Reference： [1]Patent: WO2015/67224,2015,A1 .Location in patent: Page/Page column 18

23
[ 319460-85-0 ]
axitinib sulfuric acid salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With sulfuric acid; In isopropyl alcohol; at 20 - 50℃;	Example 7 Preparation of salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole and sulphuric acid 250 mg (0.647 mmol) of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole was dissolved in 5 mL of 2-propanol by heating to 50C. 36 mu (0.647 mmol) of sulphuric acid (96% solution) was dissolved in 0.5 mL of 2-propanol at room temperature and the solution of the counterion was drop-wise added to the solution of the API of 50C. The solution at 50C is stirred for 1 hour in closed vial, cooled back to room temperature and stirred overnight. The resulting suspension was filtered off and dried at laboratory conditions.Yield: 230 mg (73%)

Reference： [1]Patent: WO2015/67224,2015,A1 .Location in patent: Page/Page column 18; 19

24
[ 319460-85-0 ]
[ 98-11-3 ]
axitinib benzenesulphonic acid salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	In isopropyl alcohol; at 20 - 50℃;	Example 1 Preparation of salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole and benzenesulphonic acid 250 mg (0.647 mmol) of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole was dissolved in 5 mL of 2-propanol by heating to 50C. 105 mg (0.663 mmol) of benzenesulphonic acid was dissolved in 0.5 mL of 2-propanol at room temperature and the solution of the counterion was drop-wise added to the solution of the API of 50C.The solution at 50C is stirred for 1 hour in closed vial, cooled back to room temperature and stirred overnight. The resulting suspension was filtered off and dried at laboratory conditions.Yield: 265 mg (75%)1H-NMR analysis showed a 1:1 stoichiometry of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E- [2-(pyridin-2-yl)ethanyl]indazole and benzenesulphonic acid.

Reference： [1]Patent: WO2015/67224,2015,A1 .Location in patent: Page/Page column 16

25
[ 319460-85-0 ]
[ 98-66-8 ]
axitinib 4-chlorobenzenesulphonic acid salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	In isopropyl alcohol; at 20 - 50℃;	Example 2 Preparation of salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole and 4-chlorobenzenesulphonic acid 250 mg (0.647 mmol) of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole was dissolved in 5 mL of 2-propanol by heating to 50C. 125 mg (0.649 mmol) of 4- chlorobenzenesulphonic acid was dissolved in 0.5 mL of 2-propanol at room temperature and the solution of the counterion was drop-wise added to the solution of the API of 50C.The solution at 50C is stirred for 1 hour in closed vial, cooled back to room temperature and stirred overnight the resulting suspension was filtered off and dried at laboratory condition. Yield: 277 mg (74%)1H-NMR analysis showed a 1:1 stoichiometry of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E- [2-(pyridin-2-yl)ethanyl]indazoleand 4-chlorobenzenesulphonic acid.

Reference： [1]Patent: WO2015/67224,2015,A1 .Location in patent: Page/Page column 17

26
[ 319460-85-0 ]
[ 75-75-2 ]
axitinib methanesulfonic acid salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	In isopropyl alcohol; at 20 - 50℃;	Example 3 Preparation of salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole and methanesulphonic acid 250 mg (0.647 mmol) of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole was dissolved in 5 mL of 2-propanol by heating to 50C. 63 mu (0.663 mmol) of methanesulphonic acid was dissolved in 0.5 mL of 2-propanol at room temperature and the solution of the counterion was drop-wise added to the solution of the API of 50C.The solution at 50C is stirred for 1 hour in closed vial, cooled back to room temperature and stirred overnight. The resulting suspension was filtered off and dried at laboratory conditions.Yield: 253 mg (81%)^-NMR analysis complies with 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2- yl)ethanyl]indazole and methanesulphonic acid.

Reference： [1]Patent: WO2015/67224,2015,A1 .Location in patent: Page/Page column 17

27
[ 319460-85-0 ]
[ 104-15-4 ]
axitinib para-toluenesulphonic acid salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	In isopropyl alcohol; at 20 - 50℃;	Example 4 Preparation of salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole and p-toluenesulphonic acid 250 mg (0.647 mmol) of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole was dissolved in 5 mL of 2-propanol by heating to 50C. 123 mg (0.647 mmol) of p- toluenesulphonic acid was dissolved in 0.5 mL of 2-propanol at room temperature and the solution of the counterion was drop-wise added to the solution of the API of 50C.The solution at 50C is stirred for 1 hour in closed vial, cooled back to room temperature and stirred overnight. The resulting suspension was filtered off and dried at laboratory conditions.Yield: 249 mg (67%) l-NMR analysis showed a 1:0.9 stoichiometry of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E- [2-(pyridin-2-yl)ethanyl]indazole and p-toluenesulphonic acid.

Reference： [1]Patent: WO2015/67224,2015,A1 .Location in patent: Page/Page column 17; 18

28
(E)-6-nitro-3-[(2-pyridin-2-yl)vinyl]-1H-indazole [ No CAS ]
[ 319460-85-0 ]

Reference： [1]Organic Process Research and Development,2015,vol. 19,p. 849 - 857

29
[ 886230-75-7 ]
[ 319460-85-0 ]

Reference： [1]Organic Process Research and Development,2015,vol. 19,p. 849 - 857
[2]Patent: CN103570696,2016,B

30
[ 886230-76-8 ]
[ 319460-85-0 ]

Reference： [1]Organic Process Research and Development,2015,vol. 19,p. 849 - 857
[2]Patent: CN103570696,2016,B

31
[ 7597-18-4 ]
[ 319460-85-0 ]

Reference： [1]Organic Process Research and Development,2015,vol. 19,p. 849 - 857
[2]Patent: CN103570696,2016,B

32
(Ε)-6-iodo-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole [ No CAS ]
[ 20054-45-9 ]
[ 319460-85-0 ]

Reference： [1]Organic Process Research and Development,2015,vol. 19,p. 849 - 857

33
[ 119-80-2 ]
[ 319460-85-0 ]

Reference： [1]Organic Process Research and Development,2015,vol. 19,p. 849 - 857

34
[ 19602-82-5 ]
[ 319460-85-0 ]

Reference： [1]Organic Process Research and Development,2015,vol. 19,p. 849 - 857

35
[ 2527-58-4 ]
[ 319460-85-0 ]

Reference： [1]Organic Process Research and Development,2015,vol. 19,p. 849 - 857

36
[ 70315-70-7 ]
[ 319460-85-0 ]

Reference： [1]Organic Process Research and Development,2015,vol. 19,p. 849 - 857

37
1-acetyl-3-iodine-6-nitroindazole [ No CAS ]
[ 319460-85-0 ]

Reference： [1]Organic Process Research and Development,2015,vol. 19,p. 849 - 857

38
[ 108-36-1 ]
[ 319460-85-0 ]

Reference： [1]Advanced Synthesis and Catalysis,2016,vol. 358,p. 926 - 939

39
[ 33243-33-3 ]
[ 319460-85-0 ]

Reference： [1]Advanced Synthesis and Catalysis,2016,vol. 358,p. 926 - 939

40
(E)-1-(2,4-dibromophenyl)-3-(pyridin-2-yl)prop-2-en-1-one [ No CAS ]
[ 319460-85-0 ]

Reference： [1]Advanced Synthesis and Catalysis,2016,vol. 358,p. 926 - 939

41
C₂₁H₁₆BrN₃O₂S [ No CAS ]
[ 319460-85-0 ]

Reference： [1]Advanced Synthesis and Catalysis,2016,vol. 358,p. 926 - 939

42
C₂₁H₁₇Br₂N₃O₂S [ No CAS ]
[ 319460-85-0 ]

Reference： [1]Advanced Synthesis and Catalysis,2016,vol. 358,p. 926 - 939

43
[ 20054-45-9 ]
(E)-6-bromo-3-(2-(pyridin-2-yl)vinyl)-1H-indazole [ No CAS ]
[ 319460-85-0 ]

Reference： [1]Advanced Synthesis and Catalysis,2016,vol. 358,p. 926 - 939

44
[ 150187-67-0 ]
[ 319460-85-0 ]

Reference： [1]Patent: CN103570696,2016,B

45
[ 886230-74-6 ]
[ 319460-85-0 ]

Reference： [1]Patent: CN103570696,2016,B

46
[ 319460-85-0 ]
[ 110-17-8 ]
C₂₂H₁₈N₄OS*C₄H₄O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99.9%	With palladium; In 1-methyl-pyrrolidin-2-one; ethanol; at 65 - 75℃; for 1h;	Add 150 ml of ethanol at room temperature, 10 ml of N-methylpyrrolidone and acesteribine crude (according to Organic Process Research & Development 2014, 18, 266-274, HPLC test data as shown in Table 5 or Figure 5, HPLC purity(10 g, 0.0259 mol) was added to the reaction flask and fumaric acid (3.3 g, 0.0284 mol) was added under stirring. Heating to 65 ~ 75 C for 1 hour; then cooled to room temperature , its filter, the end of pumping, the wet goods were put Vacuum drying at 80 C to 60 C and 80 C to 100 C, respectively. The X-ray diffraction pattern of powder was measured by X-ray diffraction pattern. Fumarate ethanol (vacuum at 50 C to 60 C), see Figure 9 for acitinib fumarate Form A (vacuum Drying temperature is 80 C to 100 C). A total of 13.0 g of acitinib fumarate was obtained in a yield of 99.9%, HPLC 99.9%, palladium Residual 6.8 ppm. The HPLC test data are shown in Table 6 or Figure 6.

Reference： [1]Patent: CN106467512,2017,A .Location in patent: Paragraph 0061; 0062; 0070; 0071; 0078; 0079; 0090; 0091

47
C₂₂H₁₈N₄OS*C₄H₄O₄ [ No CAS ]
[ 319460-85-0 ]

Yield	Reaction Conditions	Operation in experiment
95%	With 1,2-diaminopropan; In 1-methyl-pyrrolidin-2-one; at 40 - 70℃; for 1h;	In the four bottles of 45g N-methyl pyrrolidone, put into the stirring10g acitinib fumarate, warming up to40 to 70 C, add 1. 8 g of 1,2-propanediamine and stir for 1 hour.Filtrate with a little N-methylpyrrolidone. filtrateStir to warm to 40-70 C, add 350g water, slowly down to room temperature, pumping, rinse with 10g of water. Wet product at 50 ~ 60 CDry in a vacuum oven for less than 12 hours to give an off-white solid axitinib 7. 3g, yield 95%, HPLC 99.8%, palladium residue2. lppm. HPLC detection data are shown in Table 7 or Figure 7:

Reference： [1]Patent: CN106467512,2017,A .Location in patent: Paragraph 0086; 0087

48
[ 319460-85-0 ]
[ 24424-99-5 ]
N-methyl-2-((3-((1E)-2-(pyridin-2-yl)ethenyl)-1H-indazol-6-yl)sulfanyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
4.1 g	With triethylamine; In N,N-dimethyl-formamide; for 1h;	4.0 g of acetidine was added to 10 ml of DMF, 2.0 g of triethylamine was added with stirring, 1.5 g of Bocic anhydride was added, reacted for 1 h, 20 ml of water was added and the compound 1 was filtered to dry under reduced pressure to give 4.1 G. Compound 2 was added to 10 ml of acetonitrile and 1,8 g was addedChloromethyl isopropyl carbonate, reacted at 80 C for 30 h, concentrated to an oil which was chromatographed to give 3.2 g of formula B.
4.1 g	With triethylamine; In N,N-dimethyl-formamide; for 1h;	Add <strong>[319460-85-0]axitinib</strong> 4.0g to 10ml of DMF,Add 2.0g of triethylamine with stirringInto 1.5 g of Boc anhydride,Reaction 1h,Add 20ml of water,Filtered to give compound 1,After drying under reduced pressure,4.1g M-1;4.1 g M-1 was added to 10 ml DMF,Add 37ml formalin 5ml,0.05 ml triethylamine,80 degrees reaction 20h,Add water,E A extraction,After concentration, 2.5 g of an oil was obtained by column chromatography,Add 10 ml EA,1.0 g of triethylamine was added,Add 1.3 g of acid chloride,After overnight reaction at room temperature,Concentration column chromatography gave 2.3 g of M-2.M-2 was added to 15 ml of acetonitrile,Add 1.5 g of chloromethyl acetate,80 degrees reaction 40h,After concentration, 1.6 g of M-3 was obtained by column chromatography,Added to 20ml of methanol,2 ml of 1N hydrochloric acid was added,Reflux 0.5h,Add water,EA extraction was concentrated,Column chromatography gave 0.9 g of the title compound.
4.1 g	With triethylamine; In N,N-dimethyl-formamide; for 1h;	Add <strong>[319460-85-0]axitinib</strong> 4.0g to 10ml of DMF,Under stirring, 2.0 g of triethylamine,1.5 g Boc anhydride,Reaction 1h,Add 20ml of water, filtered to give compound 1,After drying under reduced pressure, 4.1 g was obtained.Compound 2 was added to 10 ml of acetonitrile, 1 was added,8g chloromethyl isopropyl carbonate,80 degrees reaction 30h, concentrated to give an oil,Column chromatography gave 3.2 g of formula B.

Reference： [1]Patent: CN106317017,2017,A .Location in patent: Paragraph 0011
[2]Patent: CN106478596,2017,A .Location in patent: Paragraph 0012
[3]Patent: CN106336397,2017,A .Location in patent: Paragraph 0011

49
[ 319460-85-0 ]
[ 98298-66-9 ]
C₂₈H₂₉N₄O₄S⁽¹⁺⁾*Cl^(1-) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3.2 g	In acetonitrile; at 80℃; for 30h;	4.0 g of acetidine was added to 10 ml of DMF, 2.0 g of triethylamine was added with stirring, 1.5 g of Bocic anhydride was added, reacted for 1 h, 20 ml of water was added and the compound 1 was filtered to dry under reduced pressure to give 4.1 G. Compound 2 was added to 10 ml of acetonitrile and 1,8 g was addedChloromethyl isopropyl carbonate, reacted at 80 C for 30 h, concentrated to an oil which was chromatographed to give 3.2 g of formula B.

Reference： [1]Patent: CN106317017,2017,A .Location in patent: Paragraph 0011

50
[ 319460-85-0 ]
C₃₈H₄₇N₄O₅S⁽¹⁺⁾*Cl^(1-) [ No CAS ]

Reference： [1]Patent: CN106478596,2017,A

51
[ 319460-85-0 ]
C₄₀H₅₀N₄O₅S [ No CAS ]

Reference： [1]Patent: CN106478596,2017,A

52
[ 319460-85-0 ]
C₃₅H₄₂N₄O₃S [ No CAS ]

Reference： [1]Patent: CN106478596,2017,A

53
[ 319460-85-0 ]
C₃₆H₄₄N₄O₄S [ No CAS ]

Reference： [1]Patent: CN106478596,2017,A

54
[ 319460-85-0 ]
C₃₆H₄₅N₄O₇PS [ No CAS ]

Reference： [1]Patent: CN106478596,2017,A

55
[ 319460-85-0 ]
C₂₈H₂₈N₄O₄S [ No CAS ]

Reference： [1]Patent: CN106478596,2017,A

56
[ 319460-85-0 ]
C₂₈H₂₉N₄O₇PS [ No CAS ]

Reference： [1]Patent: CN106478596,2017,A

57
[ 319460-85-0 ]
C₂₃H₂₁N₄O₅PS [ No CAS ]

Reference： [1]Patent: CN106478596,2017,A

58
[ 319460-85-0 ]
C₄₃H₅₅N₄O₇S⁽¹⁺⁾*Cl^(1-) [ No CAS ]

Reference： [1]Patent: CN106478596,2017,A

59
3,6-dibromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole [ No CAS ]
[ 319460-85-0 ]

Reference： [1]Beilstein Journal of Organic Chemistry,2018,vol. 14,p. 786 - 795

60
[ 79762-54-2 ]
[ 319460-85-0 ]

Reference： [1]Beilstein Journal of Organic Chemistry,2018,vol. 14,p. 786 - 795

61
3,6-dibromo-1H-indazole [ No CAS ]
[ 319460-85-0 ]

Reference： [1]Beilstein Journal of Organic Chemistry,2018,vol. 14,p. 786 - 795

62
[ 108-86-1 ]
[ 1663-39-4 ]
[ 319460-85-0 ]

Reference： [1]Green Chemistry,2015,vol. 17,p. 225 - 230

63
C₇H₆NOS^(1-)*Na⁽¹⁺⁾ [ No CAS ]
[ 319460-85-0 ]