Name: 404950-80-7|(E)-N-Hydroxy-3-(4-(((2-(2-methyl-1H-indol-3-yl)ethyl)amino)methyl)phenyl)acrylamide|98%
Brand: Ambeed
SKU: A165763
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1
[ 404950-80-7 ]
[ 64-19-7 ]
[ 67-64-1 ]
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide acetate acetone solvate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	at 20℃;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 1. A stoichiometric amount of acetic acid was <n="16"/>- 15 -subsequently added to the suspension. The mixture was stirred at either 60C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.Table 1[0055] The salt forming reaction in acetone produced a highly crystalline salt, with the ratio ofN-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2- propenamide to acetate of 1 : 1 , identified as a stoiciometric acetone solvate SA- The salt forming reaction in isopropyl alcohol and ethyl acetate at 60C produced the same crystalline, non-solvated acetate salt (form A). The accompanied weight loss above 105C is either due to the loss of water (if the salt is a hydrate) or loss of acetic acid or both.

Reference： [1]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 14; 15

2
[ 404950-80-7 ]
[ 64-19-7 ]
[ 960055-50-9 ]

Yield	Reaction Conditions	Operation in experiment
	In isopropyl alcohol; at 60℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 1. A stoichiometric amount of acetic acid was <n="16"/>- 15 -subsequently added to the suspension. The mixture was stirred at either 60C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.Table 1[0055] The salt forming reaction in acetone produced a highly crystalline salt, with the ratio ofN-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2- propenamide to acetate of 1 : 1 , identified as a stoiciometric acetone solvate SA- The salt forming reaction in isopropyl alcohol and ethyl acetate at 60C produced the same crystalline, non-solvated acetate salt (form A). The accompanied weight loss above 105C is either due to the loss of water (if the salt is a hydrate) or loss of acetic acid or both.
	In ethyl acetate; at 60℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 1. A stoichiometric amount of acetic acid was <n="16"/>- 15 -subsequently added to the suspension. The mixture was stirred at either 60C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.Table 1[0055] The salt forming reaction in acetone produced a highly crystalline salt, with the ratio ofN-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2- propenamide to acetate of 1 : 1 , identified as a stoiciometric acetone solvate SA- The salt forming reaction in isopropyl alcohol and ethyl acetate at 60C produced the same crystalline, non-solvated acetate salt (form A). The accompanied weight loss above 105C is either due to the loss of water (if the salt is a hydrate) or loss of acetic acid or both.
	In acetone; at 4 - 20℃;Product distribution / selectivity;	EXAMPLE 1; Preparation of Acetate Salt; About 40 to 50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 ml of a solvent as listed in Table 1. A stoichiometric amount of acetic acid was subsequently added to the suspension. The mixture was stirred at either 60 C. or ambient temperature (where a clear solution formed, stirring continued at 4 C.). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.; The salt forming reaction in acetone produced a highly crystalline salt, with the ratio of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide to acetate of 1:1, identified as a stoichiometric acetone solvate SA. The salt forming reaction in isopropyl alcohol and ethyl acetate at 60 C. produced the same crystalline, non-solvated acetate salt (form A). The accompanied weight loss above 105 C. is either due to the loss of water (if the salt is a hydrate) or loss of acetic acid or both.

In acetone; at 4 - 20℃;Product distribution / selectivity;

About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 1. A stoichiometric amount of acetic acid was subsequently added to the suspension. The mixture was stirred at either 60 C. or ambient temperature (where a clear solution formed, stirring continued at 4 C.). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. TABLE 1 LOD, % Physical CrystallinityTdecomposition Solvent T, C. Appearance and Form(Tdesolvation)1H-NMR Acetone Ambient FFP Excellent 13.5 (107.9) 1.89 (acetate, 3H) SA 147.9 2.08 (acetone, 6H) 3.74 (Hbz) IPA 60 FFP Good A ~10.5 (72.5) - 148.7 AcOEt 60 FFP Good A 9.3 (105.1) 1.89 (acetate, 3H) 147.93.73 (Hbz) The salt forming reaction in acetone produced a highly crystalline salt, with the ratio of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide to acetate of 1:1 identified as a stoichiometric acetone solvate SA. The salt forming reaction in isopropyl alcohol and ethyl acetate at 60 C. produced the same crystalline, non-solvated acetate salt (form A). The accompanied weight loss above 105 C. is either due to the loss of water or loss of acetic acid or both.

Reference： [1]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 14; 15
[2]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 14; 15
[3]Patent: US2009/187029,2009,A1 .Location in patent: Page/Page column 4-5
[4]Patent: US2009/192210,2009,A1 .Location in patent: Page/Page column 7

3
[ 404950-80-7 ]
[ 64-17-5 ]
[ 65-85-0 ]
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide benzoate ethanol hemisolvate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In water; at 20℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 2. A stoichiometric amount of benzoic acid was subsequently added to the suspension. The mixture was stirred at ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. <n="17"/>- 16 -Table 2?Isothermal hold at 1200C for 10 minutes[0057] The salt forming reaction in ethanol alone and with water produced the same ethanol solvate SA. The stoichiometry of the protonated base:benzoate:ethanol is 1 : 1 :0.5 by NMR. Solvent loss and decomposition are closely spaced events at the heating rate of 10C/min., and the ethanol content could not be determined initially. Eventually, it was determined by holding at 1200C for 10 min. The LOD of 5.2 % corresponds to 0.5 moles of ethanol per formula unit. Isopropyl alcohol alone and with water produced the same isopropanol (IPA) solvate SB. The stoichiometry of the protonated base:benzoate is 1 :1 by NMR. Solvent loss and decomposition are closely spaced at the heating rate of 10C/min., and the isopropanol content could not be determined initially. Eventually, it was determined by holding at 1200C for 10 min. The 6.3% LOD corresponds to 0.5 moles of IPA per formula unit. Based on solvent content and XRPD patterns, the two solvates SA and SB appeared to be isostructural. The salt forming reaction in acetone produced benzoate salt that did not contain any solvent or water, a 1 :1 stoichiometric salt of excellent crystallinity and high decomposition temperature (form A).
	at 20℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 2. A stoichiometric amount of benzoic acid was subsequently added to the suspension. The mixture was stirred at ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. <n="17"/>- 16 -Table 2?Isothermal hold at 1200C for 10 minutes[0057] The salt forming reaction in ethanol alone and with water produced the same ethanol solvate SA. The stoichiometry of the protonated base:benzoate:ethanol is 1 : 1 :0.5 by NMR. Solvent loss and decomposition are closely spaced events at the heating rate of 10C/min., and the ethanol content could not be determined initially. Eventually, it was determined by holding at 1200C for 10 min. The LOD of 5.2 % corresponds to 0.5 moles of ethanol per formula unit. Isopropyl alcohol alone and with water produced the same isopropanol (IPA) solvate SB. The stoichiometry of the protonated base:benzoate is 1 :1 by NMR. Solvent loss and decomposition are closely spaced at the heating rate of 10C/min., and the isopropanol content could not be determined initially. Eventually, it was determined by holding at 1200C for 10 min. The 6.3% LOD corresponds to 0.5 moles of IPA per formula unit. Based on solvent content and XRPD patterns, the two solvates SA and SB appeared to be isostructural. The salt forming reaction in acetone produced benzoate salt that did not contain any solvent or water, a 1 :1 stoichiometric salt of excellent crystallinity and high decomposition temperature (form A).

Reference： [1]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 15; 16
[2]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 15; 16

4
[ 404950-80-7 ]
[ 67-63-0 ]
[ 65-85-0 ]
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide benzoate 2-propanol hemisolvate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In water; at 20℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 2. A stoichiometric amount of benzoic acid was subsequently added to the suspension. The mixture was stirred at ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. <n="17"/>- 16 -Table 2?Isothermal hold at 1200C for 10 minutes[0057] The salt forming reaction in ethanol alone and with water produced the same ethanol solvate SA. The stoichiometry of the protonated base:benzoate:ethanol is 1 : 1 :0.5 by NMR. Solvent loss and decomposition are closely spaced events at the heating rate of 10C/min., and the ethanol content could not be determined initially. Eventually, it was determined by holding at 1200C for 10 min. The LOD of 5.2 % corresponds to 0.5 moles of ethanol per formula unit. Isopropyl alcohol alone and with water produced the same isopropanol (IPA) solvate SB. The stoichiometry of the protonated base:benzoate is 1 :1 by NMR. Solvent loss and decomposition are closely spaced at the heating rate of 10C/min., and the isopropanol content could not be determined initially. Eventually, it was determined by holding at 1200C for 10 min. The 6.3% LOD corresponds to 0.5 moles of IPA per formula unit. Based on solvent content and XRPD patterns, the two solvates SA and SB appeared to be isostructural. The salt forming reaction in acetone produced benzoate salt that did not contain any solvent or water, a 1 :1 stoichiometric salt of excellent crystallinity and high decomposition temperature (form A).
	at 20℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 2. A stoichiometric amount of benzoic acid was subsequently added to the suspension. The mixture was stirred at ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. <n="17"/>- 16 -Table 2?Isothermal hold at 1200C for 10 minutes[0057] The salt forming reaction in ethanol alone and with water produced the same ethanol solvate SA. The stoichiometry of the protonated base:benzoate:ethanol is 1 : 1 :0.5 by NMR. Solvent loss and decomposition are closely spaced events at the heating rate of 10C/min., and the ethanol content could not be determined initially. Eventually, it was determined by holding at 1200C for 10 min. The LOD of 5.2 % corresponds to 0.5 moles of ethanol per formula unit. Isopropyl alcohol alone and with water produced the same isopropanol (IPA) solvate SB. The stoichiometry of the protonated base:benzoate is 1 :1 by NMR. Solvent loss and decomposition are closely spaced at the heating rate of 10C/min., and the isopropanol content could not be determined initially. Eventually, it was determined by holding at 1200C for 10 min. The 6.3% LOD corresponds to 0.5 moles of IPA per formula unit. Based on solvent content and XRPD patterns, the two solvates SA and SB appeared to be isostructural. The salt forming reaction in acetone produced benzoate salt that did not contain any solvent or water, a 1 :1 stoichiometric salt of excellent crystallinity and high decomposition temperature (form A).

Reference： [1]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 15; 16
[2]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 15; 16

5
[ 404950-80-7 ]
[ 65-85-0 ]
[ 960055-51-0 ]

Yield	Reaction Conditions	Operation in experiment
	In acetone; at 20℃;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 2. A stoichiometric amount of benzoic acid was subsequently added to the suspension. The mixture was stirred at ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. <n="17"/>- 16 -Table 2?Isothermal hold at 1200C for 10 minutes[0057] The salt forming reaction in ethanol alone and with water produced the same ethanol solvate SA. The stoichiometry of the protonated base:benzoate:ethanol is 1 : 1 :0.5 by NMR. Solvent loss and decomposition are closely spaced events at the heating rate of 10C/min., and the ethanol content could not be determined initially. Eventually, it was determined by holding at 1200C for 10 min. The LOD of 5.2 % corresponds to 0.5 moles of ethanol per formula unit. Isopropyl alcohol alone and with water produced the same isopropanol (IPA) solvate SB. The stoichiometry of the protonated base:benzoate is 1 :1 by NMR. Solvent loss and decomposition are closely spaced at the heating rate of 10C/min., and the isopropanol content could not be determined initially. Eventually, it was determined by holding at 1200C for 10 min. The 6.3% LOD corresponds to 0.5 moles of IPA per formula unit. Based on solvent content and XRPD patterns, the two solvates SA and SB appeared to be isostructural. The salt forming reaction in acetone produced benzoate salt that did not contain any solvent or water, a 1 :1 stoichiometric salt of excellent crystallinity and high decomposition temperature (form A).
	In ethanol; water; at 4 - 20℃;Product distribution / selectivity;	EXAMPLE 2; Preparation of Benzoate Salt; About 40 to 50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 ml of a solvent as listed in Table 2. A stoichiometric amount of benzoic acid was subsequently added to the suspension. The mixture was stirred at ambient temperature (where a clear solution formed, stirring continued at 4 C.). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.; The salt forming reaction in ethanol alone and with water produced the same ethanol solvate SA. The stoichiometry of the protonated base:benzoate:ethanol is 1:1:0.5 by NMR. Solvent loss and decomposition are closely spaced events at the heating rate of 10 C./min, and the ethanol content could not be determined initially. Eventually, it was determined by holding at 120 C. for 10 min. The LOD of 5.2% corresponds to 0.5 moles of ethanol per formula unit. Isopropyl alcohol alone and with water produced the same isopropanol (IPA) solvate SB. The stoichiometry of the protonated base:benzoate is 1:1 by NMR. Solvent loss and decomposition are closely spaced at the heating rate of 10 C./min, and the isopropanol content could not be determined initially. Eventually, it was determined by holding at 120 C. for 10 min. The 6.3% LOD corresponds to 0.5 moles of IPA per formula unit. Based on solvent content and XRPD patterns, the two solvates SA and SB appeared to be isostructural. The salt forming reaction in acetone produced benzoate salt that did not contain any solvent or water, a 1:1 stoichiometric salt of excellent crystallinity and high decomposition temperature (form A).
	In ethanol; water; at 4 - 20℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 2. A stoichiometric amount of benzoic acid was subsequently added to the suspension. The mixture was stirred at ambient temperature (where a clear solution formed, stirring continued at 4 C.). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. TABLE 2 Physical Crystallinity LOD, % Solvent T, C. Appearance and FormTdecomposition 1H-NMR EtOH:H2O Ambient FFP Excellent 1.5 - (1:0.05) SA prior to dec. at 110 C.IPA:H2O Ambient FFP Excellent 6.3* 1.02 (IPA, 6H) (1:0.05) SB (isothermal3.83 (Hbz) at 120 C.) EtOH Ambient FFP Excellent 5.2* 1.04 (EtOH, 5H) SA (isothermal 3.43 (EtOH, 1H) at 120 C.) 7.93 (benzoate, 2H) 3.85 (Hbz) IPA Ambient FFP Excellent 1.5% prior - SB dec. at 100 C. Acetone Ambient FFP Excellent A 0.5% 7.93 (benzoate, 160.2 2H) 3.84 (Hbz) *Isothermal hold at 120 C. for 10 minutesThe salt forming reaction in ethanol alone and with water produced the same ethanol solvate SA. The stoichiometry of the protonated base:benzoate:ethanol is 1:1:0.5 by NMR. Solvent loss and decomposition are closely spaced events at the heating rate of 10 C./min, and the ethanol content could not be determined initially. Eventually, it was determined by holding at 120 C. for 10 minutes. The LOD of 5.2% corresponds to 0.5 moles of ethanol per formula unit. Isopropyl alcohol alone and with water produced the same isopropanol (IPA) solvate SB. The stoichiometry of the protonated base:benzoate is 1:1 by NMR. Solvent loss and decomposition are closely spaced at the heating rate of 110 C./min., and the isopropanol content could not be determined initially. Eventually, it was determined by holding at 120 C. for 10 minutes. The 6.3% LOD corresponds to 0.5 moles of IPA per formula unit. Based on solvent content and XRPD patterns, the two solvates SA and SB appeared to be isostructural. The salt forming reaction in acetone produced benzoate salt that did not contain any solvent or water, a 1:1 stoichiometric salt of excellent crystallinity and high decomposition temperature (form A).

Reference： [1]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 15; 16
[2]Patent: US2009/187029,2009,A1 .Location in patent: Page/Page column 5
[3]Patent: US2009/192210,2009,A1 .Location in patent: Page/Page column 7-8

6
[ 404950-80-7 ]
[ 960055-52-1 ]

Yield	Reaction Conditions	Operation in experiment
96.2%	With hydrogenchloride; In ethanol; water;	3.67 g (10 mmol) of the free base monohydrate (N-hydroxy-3-[4-[[[2-(2-methyl-lH- indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide) and 40 mL of absolute ethanol were charged in a 250 mL 3-neck flask equipped with a magnetic stirrer and an addition funnel. To the stirred suspension were added dropwise 7.5 mL of 2 M HCl (15 mmol, 50% excess), affording a clear solution. A white solid precipitated out within 10 minutes, and stirring continued at ambient for an additional 2 hours. The mixture was cooled in an ice bath for approximately 30 minutes, and the white solid was recovered by filtration. It was washed <n="37"/>- 36 -once with cold ethanol (10 mL) and dried overnight under vacuum to yield 3.72 g of the chloride salt of N-hydroxy-3 - [4- [ [ [2-(2-methyl- 1 H-indol-3 -yl)ethyl]amino]methyl]phenyl] - 2E-2-propenamide (96.2%).[00102] It should be noted that HCl was used in excess to improve the yield, although equimolar amounts afforded yields of greater than 80%. Di-salt formation via protonation of the methyl- 1 H-indol-3 -yl ring does not occur even when HCl is used in large excess. Reactions with 1, 1.5 and 2 equivalents of HCl afforded the same monochloride salt as a product. In addition, NMR data show no shifts for any of the protons in the vicinity of the ring, as it would have happened upon protonation.
	With hydrogenchloride; In ethanol; water; at 60℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base was suspended in 1 mL of a solvent as listed in Table 3. A stoichiometric amount of hydrochloric acid was subsequently added to the suspension. The mixture was stirred at either 6O0C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.Table 3[0059] All the above five reactions produced the same crystalline salt. The salt was anhydrous and decomposed at high temperature.
	With hydrogenchloride; In ethyl acetate; at 20℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base was suspended in 1 mL of a solvent as listed in Table 3. A stoichiometric amount of hydrochloric acid was subsequently added to the suspension. The mixture was stirred at either 6O0C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.Table 3[0059] All the above five reactions produced the same crystalline salt. The salt was anhydrous and decomposed at high temperature.

	With hydrogenchloride; In isopropyl alcohol; at 20℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base was suspended in 1 mL of a solvent as listed in Table 3. A stoichiometric amount of hydrochloric acid was subsequently added to the suspension. The mixture was stirred at either 6O0C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.Table 3[0059] All the above five reactions produced the same crystalline salt. The salt was anhydrous and decomposed at high temperature.
	With hydrogenchloride; In ethanol; at 20℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base was suspended in 1 mL of a solvent as listed in Table 3. A stoichiometric amount of hydrochloric acid was subsequently added to the suspension. The mixture was stirred at either 6O0C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.Table 3[0059] All the above five reactions produced the same crystalline salt. The salt was anhydrous and decomposed at high temperature.
	With hydrogenchloride; In acetone; at 20℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base was suspended in 1 mL of a solvent as listed in Table 3. A stoichiometric amount of hydrochloric acid was subsequently added to the suspension. The mixture was stirred at either 6O0C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.Table 3[0059] All the above five reactions produced the same crystalline salt. The salt was anhydrous and decomposed at high temperature.
	With hydrogenchloride; In ethanol; water; at 4 - 60℃;Product distribution / selectivity;	EXAMPLE 3; Formation of Hydrochloride Salt; About 40 to 50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base was suspended in 1 ml of a solvent as listed in Table 3. A stoichiometric amount of hydrochloric acid was subsequently added to the suspension. The mixture was stirred at either 60 C. or ambient temperature (where a clear solution formed, stirring continued at 4 C.). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.; All the above five reactions produced the same crystalline salt. The salt was anhydrous and decomposed at high temperature.

Reference： [1]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 35; 36
[2]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 17
[3]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 17
[4]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 17
[5]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 17
[6]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 17
[7]Patent: US2009/187029,2009,A1 .Location in patent: Page/Page column 5-6
[8]Patent: US2009/192210,2009,A1 .Location in patent: Page/Page column 15

7
[ 404950-80-7 ]
[ 77-92-9 ]
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide hemicitrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In water; isopropyl alcohol; at 60℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base was suspended in 1 mL of a solvent as listed in Table 4. A stoichiometric amount of citric acid was subsequently added to the suspension. The mixture was stirred at either 600C or ambient temperature (where a clear <n="19"/>- 18 -solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.Table 4[0061] Heating to 60C (acetone and ethanol), as well as the introduction of water (isopropyl alcohol and water, acetone and water at 60C) yielded a highly crystalline salt that does not contain any solvent or water. A high LOD value for acetone at ambient/60C is due to the presence of amorphous material within the crystalline powder. The stoichiometry of the salt could not be determined by 1H-NMR in DMSO-d6, since the expected peak for the citrate ion coincides with that of the solvent. However, 13C-NMR spectroscopy indicated the presence of two 13C = O signals at 177.3 and 171.6 ppm. The former is due to the protonated carboxylic group and the latter to the unprotonated carboxylate.
	In ethanol; at 60℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base was suspended in 1 mL of a solvent as listed in Table 4. A stoichiometric amount of citric acid was subsequently added to the suspension. The mixture was stirred at either 600C or ambient temperature (where a clear <n="19"/>- 18 -solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.Table 4[0061] Heating to 60C (acetone and ethanol), as well as the introduction of water (isopropyl alcohol and water, acetone and water at 60C) yielded a highly crystalline salt that does not contain any solvent or water. A high LOD value for acetone at ambient/60C is due to the presence of amorphous material within the crystalline powder. The stoichiometry of the salt could not be determined by 1H-NMR in DMSO-d6, since the expected peak for the citrate ion coincides with that of the solvent. However, 13C-NMR spectroscopy indicated the presence of two 13C = O signals at 177.3 and 171.6 ppm. The former is due to the protonated carboxylic group and the latter to the unprotonated carboxylate.
	In water; acetone; at 60℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base was suspended in 1 mL of a solvent as listed in Table 4. A stoichiometric amount of citric acid was subsequently added to the suspension. The mixture was stirred at either 600C or ambient temperature (where a clear <n="19"/>- 18 -solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.Table 4[0061] Heating to 60C (acetone and ethanol), as well as the introduction of water (isopropyl alcohol and water, acetone and water at 60C) yielded a highly crystalline salt that does not contain any solvent or water. A high LOD value for acetone at ambient/60C is due to the presence of amorphous material within the crystalline powder. The stoichiometry of the salt could not be determined by 1H-NMR in DMSO-d6, since the expected peak for the citrate ion coincides with that of the solvent. However, 13C-NMR spectroscopy indicated the presence of two 13C = O signals at 177.3 and 171.6 ppm. The former is due to the protonated carboxylic group and the latter to the unprotonated carboxylate.

In acetone; at 20 - 60℃;Product distribution / selectivity;

About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base was suspended in 1 mL of a solvent as listed in Table 4. A stoichiometric amount of citric acid was subsequently added to the suspension. The mixture was stirred at either 600C or ambient temperature (where a clear <n="19"/>- 18 -solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.Table 4[0061] Heating to 60C (acetone and ethanol), as well as the introduction of water (isopropyl alcohol and water, acetone and water at 60C) yielded a highly crystalline salt that does not contain any solvent or water. A high LOD value for acetone at ambient/60C is due to the presence of amorphous material within the crystalline powder. The stoichiometry of the salt could not be determined by 1H-NMR in DMSO-d6, since the expected peak for the citrate ion coincides with that of the solvent. However, 13C-NMR spectroscopy indicated the presence of two 13C = O signals at 177.3 and 171.6 ppm. The former is due to the protonated carboxylic group and the latter to the unprotonated carboxylate.

Reference： [1]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 17; 18
[2]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 17; 18
[3]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 17; 18
[4]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 17; 18

8
[ 404950-80-7 ]
[ 110-17-8 ]
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide hemi-fumarate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; at 20℃;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl] amino] methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in1 mL of a solvent as listed in Table 5. A stoichiometric amount of fumaric acid was <n="20"/>- 19 -subsequently added to the suspension. The mixture was stirred at either 600C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.Table 5[0063] The salt forming reactions in isopropyl alcohol and acetone at ambient temperature produced fumarate salts of stoichiometry 2:1 (protonated base:fumarate), i.e., hemi-fumarate salts. Although none of them was a solvate, they had poor crystallinity and a low decomposition temperature. The LOD for isopropyl alcohol at ambient temperature was most likely associated with the loss of water. The salt forming reaction in ethanol, ethanol and water, and isopropyl alcohol and water, all at ambient temperature or 60C, produced a fumarate salt of stoichiometry 2:1 (protonated base: fumarate), i.e., hemi-fumarate salt. The salt forming reaction in ethanol and water and isopropyl alcohol and water (1:0.05), ambient or 6O0C, produced identical XRPD spectra (anhydrous form A). The spectrum of the salt <n="21"/>- 20 -formed by ethanol at ambient temperature, albeit similar, displays some small differences and it may represent a unique, hemi-fumarate polymorph (form B) of similar structure.
	In water; isopropyl alcohol; at 20 - 60℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl] amino] methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in1 mL of a solvent as listed in Table 5. A stoichiometric amount of fumaric acid was <n="20"/>- 19 -subsequently added to the suspension. The mixture was stirred at either 600C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.Table 5[0063] The salt forming reactions in isopropyl alcohol and acetone at ambient temperature produced fumarate salts of stoichiometry 2:1 (protonated base:fumarate), i.e., hemi-fumarate salts. Although none of them was a solvate, they had poor crystallinity and a low decomposition temperature. The LOD for isopropyl alcohol at ambient temperature was most likely associated with the loss of water. The salt forming reaction in ethanol, ethanol and water, and isopropyl alcohol and water, all at ambient temperature or 60C, produced a fumarate salt of stoichiometry 2:1 (protonated base: fumarate), i.e., hemi-fumarate salt. The salt forming reaction in ethanol and water and isopropyl alcohol and water (1:0.05), ambient or 6O0C, produced identical XRPD spectra (anhydrous form A). The spectrum of the salt <n="21"/>- 20 -formed by ethanol at ambient temperature, albeit similar, displays some small differences and it may represent a unique, hemi-fumarate polymorph (form B) of similar structure.
	In isopropyl alcohol; at 20℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl] amino] methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in1 mL of a solvent as listed in Table 5. A stoichiometric amount of fumaric acid was <n="20"/>- 19 -subsequently added to the suspension. The mixture was stirred at either 600C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.Table 5[0063] The salt forming reactions in isopropyl alcohol and acetone at ambient temperature produced fumarate salts of stoichiometry 2:1 (protonated base:fumarate), i.e., hemi-fumarate salts. Although none of them was a solvate, they had poor crystallinity and a low decomposition temperature. The LOD for isopropyl alcohol at ambient temperature was most likely associated with the loss of water. The salt forming reaction in ethanol, ethanol and water, and isopropyl alcohol and water, all at ambient temperature or 60C, produced a fumarate salt of stoichiometry 2:1 (protonated base: fumarate), i.e., hemi-fumarate salt. The salt forming reaction in ethanol and water and isopropyl alcohol and water (1:0.05), ambient or 6O0C, produced identical XRPD spectra (anhydrous form A). The spectrum of the salt <n="21"/>- 20 -formed by ethanol at ambient temperature, albeit similar, displays some small differences and it may represent a unique, hemi-fumarate polymorph (form B) of similar structure.

	In ethanol; water; at 20 - 60℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl] amino] methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in1 mL of a solvent as listed in Table 5. A stoichiometric amount of fumaric acid was <n="20"/>- 19 -subsequently added to the suspension. The mixture was stirred at either 600C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.Table 5[0063] The salt forming reactions in isopropyl alcohol and acetone at ambient temperature produced fumarate salts of stoichiometry 2:1 (protonated base:fumarate), i.e., hemi-fumarate salts. Although none of them was a solvate, they had poor crystallinity and a low decomposition temperature. The LOD for isopropyl alcohol at ambient temperature was most likely associated with the loss of water. The salt forming reaction in ethanol, ethanol and water, and isopropyl alcohol and water, all at ambient temperature or 60C, produced a fumarate salt of stoichiometry 2:1 (protonated base: fumarate), i.e., hemi-fumarate salt. The salt forming reaction in ethanol and water and isopropyl alcohol and water (1:0.05), ambient or 6O0C, produced identical XRPD spectra (anhydrous form A). The spectrum of the salt <n="21"/>- 20 -formed by ethanol at ambient temperature, albeit similar, displays some small differences and it may represent a unique, hemi-fumarate polymorph (form B) of similar structure.
	In ethanol; at 4 - 20℃;Product distribution / selectivity;	EXAMPLE 5; Formation of Hemi-Fumarate Salt; About 40 to 50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 ml of a solvent as listed in Table 5. A stoichiometric amount of fumaric acid was subsequently added to the suspension. The mixture was stirred at either 60 C. or ambient temperature (where a clear solution formed, stirring continued at 4 C.). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.; The salt forming reaction in isopropyl alcohol and acetone at ambient temperature produced fumarate salts of stoichiometry 2:1 (protonated base:fumarate), i.e., hemi-fumarate salts. Although none of them was a solvate, they had poor crystallinity and a low decomposition temperature. The LOD for isopropyl alcohol at ambient temperature was most likely associated with the loss of water (most likely HA form). The salt forming reaction in ethanol, ethanol and water, and isopropyl alcohol and water, all at ambient temperature or 60 C., produced a fumarate salt of stoichiometry 2:1 (protonated base:fumarate) ), i.e., hemi-fumarate salt. The salt forming reaction in ethanol and water and isopropyl alcohol and water (1:0.05), ambient or 60 C., produced identical XRPD spectra (anhydrous Form A). The spectrum of the salt formed by ethanol at ambient temperature, albeit similar, displays some small differences and it may represent a unique, hemi-fumarate polymorph (Form B) of similar structure.

Reference： [1]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 18; 19; 20
[2]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 18; 19; 20
[3]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 18; 19; 20
[4]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 18; 19; 20
[5]Patent: US2009/187029,2009,A1 .Location in patent: Page/Page column 6-7

9
[ 404950-80-7 ]
[ 490-79-9 ]
[ 960055-55-4 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; water; at 60℃;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl] amino] methyl]phenyl]-2E-2-propenamide free base was suspended in 1 mL of a solvent as listed in Table 6. A stoichiometric amount of 2,5-dihydroxybenzoic acid (gentisic acid) was subsequently added to the suspension. The mixture was stirred at either 60C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.Table 6[0065] The gentisate salt prepared was highly crystalline, anhydrous, and decomposed at a very high temperature. The stoichiometry of the salt is 1 : 1 by NMR.
	In ethanol; water; at 4 - 60℃;	EXAMPLE 6; Formation of Gentisate Salt; About 40 to 50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base was suspended in 1 ml of a solvent as listed in Table 6. A stoichiometric amount of 2,5-dihydroxybenzoic acid (gentisic acid) was subsequently added to the suspension. The mixture was stirred at either 60 C. or ambient temperature (where a clear solution formed, stirring continued at 4 C.). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.; The gentisate salt prepared was highly crystalline. anhydrous, and decomposed at a very high temperature. The stoichiometry of the salt is 1:1 by NMR.

Reference： [1]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 20
[2]Patent: US2009/187029,2009,A1 .Location in patent: Page/Page column 7

10
[ 849585-22-4 ]
[ 404950-80-7 ]
[ 960055-68-9 ]

Yield	Reaction Conditions	Operation in experiment
	In isopropyl alcohol; at 4 - 20℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl] amino] methyl]phenyl]-2E-2-propenamide free base was suspended in 1 mL of a solvent as listed in Table 7. A stoichiometric amount of lactic acid was subsequently added to the suspension. The mixture was stirred at ambient temperature and when a clear solution formed, stirring continued at 4C. Solids were collected by filtration and analyzed by XRPD, TGA and 1H-NMR. <n="22"/>- 21 -Table 7[0067] The salt forming reaction in isopropyl alcohol and acetone at 4C produced a stoichiometric (1:1) DL-lactate salt, a monohydrate. The salt is crystalline, begins to dehydrate above 77C, and decomposes above 150C.
	In acetone; at 4 - 20℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl] amino] methyl]phenyl]-2E-2-propenamide free base was suspended in 1 mL of a solvent as listed in Table 7. A stoichiometric amount of lactic acid was subsequently added to the suspension. The mixture was stirred at ambient temperature and when a clear solution formed, stirring continued at 4C. Solids were collected by filtration and analyzed by XRPD, TGA and 1H-NMR. <n="22"/>- 21 -Table 7[0067] The salt forming reaction in isopropyl alcohol and acetone at 4C produced a stoichiometric (1:1) DL-lactate salt, a monohydrate. The salt is crystalline, begins to dehydrate above 77C, and decomposes above 150C.

Reference： [1]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 20; 21
[2]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 20; 21

11
[ 404950-80-7 ]
[ 110-16-7 ]
[ 960055-57-6 ]

Yield	Reaction Conditions	Operation in experiment
90.5%	In acetone; at 45℃;	3.67 g (10 mmol) of the free base monohydrate (N-hydroxy-3-[4-[[[2-(2-methyl-lH- indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide) and 75 mL of acetone were charged in a 250 mL 3-neck flask equipped with a mechanical stirrer and an addition funnel. The mixture was heated to 450C, and to the hot suspension were added dropwise 1.16 g (10 mmol) of maleic acid dissolved in 25 mL acetone. Although the addition was slow, the salt precipitated out as a soft gummy solid hindering stirring. Stirring continued overnight at 45 C and during that time the solid converted to a white free-flowing powder. The mixture was cooled to room temperature and placed in an ice bath for approximately 30 minutes. The white solid was recovered by filtration, washed once with cold acetone (15 mL), and dried overnight under vacuum to yield 4.21 g of the maleate salt of N-hydroxy-3-[4-[[[2-(2-methyl- lH-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide (90.5%).[00108] It is noted that a more preferable solvent for synthesis is 2-propanol. During optimization, however, it was observed that, in addition to the desired form, another polymorph with a low decomposition temperature (118.9C) could be isolated from 2-propanol as a yellow powder.
90.5%	In acetone; at 0 - 45℃;Cooling with ice;Product distribution / selectivity;	3.67 g (10 mmol) of the free base monohydrate (N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide) and 75 mL of acetone were charged in a 250 mL 3-neck flask equipped with a mechanical stirrer and an addition funnel. The mixture was heated to 45 C., and to the hot suspension were added dropwise 1.16 g (10 mmol) of maleic acid dissolved in 25 mL acetone. Although the addition was slow, the salt precipitated out as a soft gummy solid hindering stirring. Stirring continued overnight at 45 C. and during that time the solid converted to a white free-flowing powder. The mixture was cooled to room temperature and placed in an ice bath for approximately 30 minutes. The white solid was recovered by filtration, washed once with cold acetone (15 mL), and dried overnight under vacuum to yield 4.21 g of the maleate salt of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide (90.5%).It is noted that a more preferable solvent for synthesis is 2-propanol. During optimization, however, it was observed that, in addition to the desired form, another polymorph with a low decomposition temperature (118.9 C.) could be isolated from 2-propanol as a yellow powder.
	In isopropyl alcohol; at 60℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]arnino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 8. A stoichiometric amount of maleic acid was subsequently added to the suspension. The mixture was stirred at either 60C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.Table 8 <n="23"/>- 22 -[0069] The salt forming reaction in isopropyl alcohol and acetone at 6O0C produced highly crystalline, anhydrous solids that decompose above ~180C. Maleic acid was the only dicarboxylic acid that produced a 1 :1 salt with N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenarnide. Its 1H-NMR spectrum displays a resonance at 6.01 ppm, corresponding to the two olefinic protons, and a resonance at 10.79 ppm due to one unprotonated carboxylic acid. Maleic acid also formed a salt with high water content that is lost under mild heating conditions. It is likely that the salt forming reaction in ethanol (RT to 4C) produced a hydrate (form HA).

	In acetone; at 60℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]arnino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 8. A stoichiometric amount of maleic acid was subsequently added to the suspension. The mixture was stirred at either 60C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.Table 8 <n="23"/>- 22 -[0069] The salt forming reaction in isopropyl alcohol and acetone at 6O0C produced highly crystalline, anhydrous solids that decompose above ~180C. Maleic acid was the only dicarboxylic acid that produced a 1 :1 salt with N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenarnide. Its 1H-NMR spectrum displays a resonance at 6.01 ppm, corresponding to the two olefinic protons, and a resonance at 10.79 ppm due to one unprotonated carboxylic acid. Maleic acid also formed a salt with high water content that is lost under mild heating conditions. It is likely that the salt forming reaction in ethanol (RT to 4C) produced a hydrate (form HA).
	In isopropyl alcohol; at 4 - 60℃;Product distribution / selectivity;	EXAMPLE 8; Formation of Maleate Salt; About 40 to 50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 ml of a solvent as listed in Table 8. A stoichiometric amount of maleic acid was subsequently added to the suspension. The mixture was stirred at either 60 C. or ambient temperature (where a clear solution formed, stirring continued at 4 C.). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.; The salt forming reaction in isopropyl alcohol and acetone at 60 C. produced highly crystalline, anhydrous solids that decompose above 180 C. Maleic acid was the only dicarboxylic acid that produced a 1:1 salt with N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide. Its 1H-NMR spectrum displays a resonance at 6.01 ppm, corresponding to the two olefinic protons, and a resonance at 10.79 ppm due to one unprotonated carboxylic acid. Maleic acid also formed a salt with high water content that is lost under mild heating conditions. It is likely that the salt forming reaction in ethanol (RT to 4 C.) produced a hydrate (form HA).

Reference： [1]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 38
[2]Patent: US2009/192210,2009,A1 .Location in patent: Page/Page column 13
[3]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 21; 22
[4]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 21; 22
[5]Patent: US2009/187029,2009,A1 .Location in patent: Page/Page column 7

12
[ 404950-80-7 ]
[ 617-48-1 ]
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide hemi-malate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; water; at 20 - 60℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 9. A stoichiometric amount of malic acid was subsequently added to the suspension. The mixture was stirred at either 60C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances H-NMR.Table 9 <n="24"/>- 23 -[0071] The salt forming reaction in ethanol and water, ethanol and isopropyl alcohol produced the same crystalline and anhydrous hemi-malate salt. The difference in LOD between ethanol and water (1:0.05) and ethanol may reflect varying amounts of amorphous material in the two samples. The salt forming reaction in acetone afforded a different hemi- malate salt that continuously loses weight above ~95C. This salt is an acetone solvate (form SA). Solvent loss and decomposition are closely spaced thermal events.
	In isopropyl alcohol; at 60℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 9. A stoichiometric amount of malic acid was subsequently added to the suspension. The mixture was stirred at either 60C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances H-NMR.Table 9 <n="24"/>- 23 -[0071] The salt forming reaction in ethanol and water, ethanol and isopropyl alcohol produced the same crystalline and anhydrous hemi-malate salt. The difference in LOD between ethanol and water (1:0.05) and ethanol may reflect varying amounts of amorphous material in the two samples. The salt forming reaction in acetone afforded a different hemi- malate salt that continuously loses weight above ~95C. This salt is an acetone solvate (form SA). Solvent loss and decomposition are closely spaced thermal events.
	In ethanol; at 60℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 9. A stoichiometric amount of malic acid was subsequently added to the suspension. The mixture was stirred at either 60C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances H-NMR.Table 9 <n="24"/>- 23 -[0071] The salt forming reaction in ethanol and water, ethanol and isopropyl alcohol produced the same crystalline and anhydrous hemi-malate salt. The difference in LOD between ethanol and water (1:0.05) and ethanol may reflect varying amounts of amorphous material in the two samples. The salt forming reaction in acetone afforded a different hemi- malate salt that continuously loses weight above ~95C. This salt is an acetone solvate (form SA). Solvent loss and decomposition are closely spaced thermal events.

In ethanol; water; at 4 - 60℃;Product distribution / selectivity;

EXAMPLE 9; Formation of Hemi-Malate Salt; About 40 to 50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 ml of a solvent as listed in Table 9. A stoichiometric amount of malic acid was subsequently added to the suspension. The mixture was stirred at either 60 C. or ambient temperature (where a clear solution formed, stirring continued at 4 C.). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.; The salt forming reaction in ethanol and water, ethanol and isopropyl alcohol produced the same crystalline and anhydrous hemi-malate salt. The difference in LOD between ethanol and water (1:0.05) and ethanol may reflect varying amounts of amorphous material in the two samples. The salt forming reaction in acetone afforded a different hemi-malate salt that continuously loses weight above 95 C. This salt is an acetone solvate (form SA). Solvent loss and decomposition are closely spaced thermal events.

Reference： [1]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 22; 23
[2]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 22; 23
[3]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 22; 23
[4]Patent: US2009/187029,2009,A1 .Location in patent: Page/Page column 7-8

13
[ 404950-80-7 ]
[ 141-82-2 ]
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide hemi-malonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; at 60℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base was suspended in 1 mL of a solvent as listed in Table 10. A stoichiometric amount malonic acid was subsequently added to the suspension. The mixture was stirred at either 60C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.Table 10[0073] All reactions afforded the same hemi-malonate salt. The crystallinity is usually good, although an amorphous halo could be seen in all the XRPD spectra. The water associated with these materials is likely due to increased moisture sorption by the amorphous component. Ambient conditions during synthesis appear to produce a better quality salt.
	In isopropyl alcohol; at 60℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base was suspended in 1 mL of a solvent as listed in Table 10. A stoichiometric amount malonic acid was subsequently added to the suspension. The mixture was stirred at either 60C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.Table 10[0073] All reactions afforded the same hemi-malonate salt. The crystallinity is usually good, although an amorphous halo could be seen in all the XRPD spectra. The water associated with these materials is likely due to increased moisture sorption by the amorphous component. Ambient conditions during synthesis appear to produce a better quality salt.
	In acetone; at 20 - 60℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base was suspended in 1 mL of a solvent as listed in Table 10. A stoichiometric amount malonic acid was subsequently added to the suspension. The mixture was stirred at either 60C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.Table 10[0073] All reactions afforded the same hemi-malonate salt. The crystallinity is usually good, although an amorphous halo could be seen in all the XRPD spectra. The water associated with these materials is likely due to increased moisture sorption by the amorphous component. Ambient conditions during synthesis appear to produce a better quality salt.

In isopropyl alcohol; at 4 - 60℃;Product distribution / selectivity;

EXAMPLE 10; Formation of Hemi-Malonate Salt; About 40 to 50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base was suspended in 1 ml of a solvent as listed in Table 10. A stoichiometric amount malonic acid was subsequently added to the suspension. The mixture was stirred at either 60 C. or ambient temperature (where a clear solution formed, stirring continued at 4 C.). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.; All reactions afforded the same hemi-malonate salt. The crystallinity is usually good, although an amorphous halo could be seen in all the XRPD spectra. The water associated with these materials is likely due to increased moisture sorption by the amorphous component. Ambient conditions during synthesis appear to produce a better quality salt.

Reference： [1]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 23
[2]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 23
[3]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 23
[4]Patent: US2009/187029,2009,A1 .Location in patent: Page/Page column 8

14
[ 404950-80-7 ]
[ 75-75-2 ]
[ 960055-60-1 ]

Yield	Reaction Conditions	Operation in experiment
98.3%	In ethyl acetate; at 50℃;	3.67 g (10 mmol) of the free base monohydrate (N-hydroxy-3-[4-[[[2-(2-methyl-lH- indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide) and 75 mL of ethyl acetate were charged in a 250 mL 3-neck flask equipped with a mechanical stirrer and an addition funnel. To the stirred suspension were added dropwise 0.65 mL (10 mmol) of methane sulfonic acid dissolved in 20 mL of ethyl acetate, affording a stirrable suspension of a free flowing yellow powder. The mixture was heated to 50C and kept there overnight, and during that time the yellow powder converted to a white solid. The suspension was cooled to room temperature and the white solid was recovered by filtration. It was washed once with cold ethyl acetate (15 mL) and dried overnight under vacuum to yield 4.38 g of the mesylate salt of N-hydroxy- 3-[4-[[[2-(2-methyl-lH-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide (98.3%).[00106] It is noted that the initially formed yellow powder is a polymorph of the mesylate salt that contains more than the equimolar amount of methane sulfonic acid. As a result, this solid is very highly hygroscopic. Upon gentle heating to 4O0C or 500C and within 2-4 hours, the yellow powder converts to a white crystalline solid that contains the equimolar amount of the methane sulfonic acid. This salt is non-hygroscopic. It is also advised that addition of the methane sulfonic acid is done at ambient temperature and the temperature increased afterwards. It was observed that addition at higher temperature afforded the immediate precipitation of the salt as a soft and gummy material.
98.3%	In ethyl acetate; at 50℃;Product distribution / selectivity;	3.67 g (10 mmol) of the free base monohydrate (N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide) and 75 mL of ethyl acetate were charged in a 250 mL 3-neck flask equipped with a mechanical stirrer and an addition funnel. To the stirred suspension were added dropwise 0.65 mL (10 mmol) of methane sulfonic acid dissolved in 20 mL of ethyl acetate, affording a stirrable suspension of a free flowing yellow powder. The mixture was heated to 50 C. and kept there overnight, and during that time the yellow powder converted to a white solid. The suspension was cooled to room temperature and the white solid was recovered by filtration. It was washed once with cold ethyl acetate (15 mL) and dried overnight under vacuum to yield 4.38 g of the mesylate salt of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide (98.3%).It is noted that the initially formed yellow powder is a form of the mesylate salt that contains more than the equimolar amount of methane sulfonic acid. As a result, this solid is very highly hygroscopic. Upon gentle heating to 40 C. or 50 C. and within 2-4 hours the yellow powder converts to a white crystalline solid that contains the equimolar amount of the methane sulfonic acid. This salt is non-hygroscopic. It is also advised that addition of the methane sulfonic acid is done at ambient temperature and the temperature increased afterwards. It was observed that addition at higher temperature afforded the immediate precipitation of the salt as a soft and gummy material.
	In ethyl acetate; at 20 - 50℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 11. A stoichiometric amount of methanesulfonic acid was subsequently added to the suspension. The mixture was stirred at either 6O0C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.Table 11[0075] The salt forming reaction in ethyl acetate afforded a yellow salt, upon stirring at room temperature. The salt (form A) is crystalline, displays a 2-step weight loss and, by NMR, does not contain any solvent but appears to have more than one molecule of methanesulfonate (mesylate). The salt forming reaction in acetone afforded isolation of a white powder after heating at 6O0C. It displayed excellent crystallinity but may be a composite of more than one polymorphic form (forms A and B). By NMR, it does not contain any solvent but appears to contain more than one molecule of methanesulfonate. Another salt forming reaction in ethyl acetate, in which reaction is initiated at ambient temperature and then the obtained yellowish powder suspension is heated to 500C, afforded isolation of a new form B, as shown in Figure 5.

In ethyl acetate; at 4 - 20℃;Product distribution / selectivity;

About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 6. A stoichiometric amount of methanesulfonic acid was subsequently added to the suspension. The mixture was stirred at either 60 C. or ambient temperature (where a clear solution formed, stirring continued at 4 C.). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. TABLE 6 Physical Crystallinity LOD, % Solvent T, C. Appearance and FormTdecomposition 1H-NMR Acetone 60 SAM to FFP Excellent 1.64.22 (Hbz) A + B ? 172.8 2.33 (~5H, methane sulfonate) AcOEt Ambient FFP Excellent A 1.3 + 1.34.22 (Hbz) (2-step) 2.36 (~5H, 170.9 methane sulfonate) The salt forming reaction in ethyl acetate afforded a yellow salt, upon stirring at room temperature. The salt (form A) is crystalline, displays a 2-step weight loss and, by NMR, does not contain any solvent but appears to have more than one molecule of methanesulfonate (mesylate). The salt forming reaction in acetone afforded isolation of a white powder after heating at 60 C. It displayed excellent crystallinity but may be a composite of more than one polymorphic form (forms A and B). By NMR, it does not contain any solvent but appears to contain more than one molecule of methanesulfonate. Another salt forming reaction in ethyl acetate, in which reaction is initiated at ambient temperature and then the obtained yellowish powder suspension is heated to 50 C., afforded isolation of a new form B, as shown in FIG. 4.

Reference： [1]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 37
[2]Patent: US2009/192210,2009,A1 .Location in patent: Page/Page column 12-13
[3]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 24
[4]Patent: US2009/192210,2009,A1 .Location in patent: Page/Page column 9-10

15
[ 404950-80-7 ]
[ 64-17-5 ]
[ 86119-84-8 ]
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide phosphate ethanol hemisolvate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	at 20℃;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 13. A stoichiometric amount of phosphoric acid was subsequently added to the suspension. The mixture was stirred at either 600C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. <n="27"/>- 26 -Table 13[0079] The salt forming reaction in ethanol and isopropyl alcohol gave ethanol and isopropanol hemi-solvates (forms SA and SB, respectively). In ethanol and water, only traces of ethanol were detected by NMR, in spite of the large LOD. The material is either hygroscopic or a hydrate (form HA) that loses water upon gentle heating and vacuum conditions (the loss of water measured by TGA is complete in by -60C at 10C/min.). The salt forming reaction in acetone and ethyl acetate produced the same crystalline and anhydrous phosphate salt (form A). The stoichiometry is most likely 1:1. The salt displays a high decomposition temperature.

Reference： [1]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 25; 26

16
[ 404950-80-7 ]
[ 86119-84-8 ]
[ 67-63-0 ]
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide phosphate isopropanol hemisolvate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	at 20℃;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 13. A stoichiometric amount of phosphoric acid was subsequently added to the suspension. The mixture was stirred at either 600C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. <n="27"/>- 26 -Table 13[0079] The salt forming reaction in ethanol and isopropyl alcohol gave ethanol and isopropanol hemi-solvates (forms SA and SB, respectively). In ethanol and water, only traces of ethanol were detected by NMR, in spite of the large LOD. The material is either hygroscopic or a hydrate (form HA) that loses water upon gentle heating and vacuum conditions (the loss of water measured by TGA is complete in by -60C at 10C/min.). The salt forming reaction in acetone and ethyl acetate produced the same crystalline and anhydrous phosphate salt (form A). The stoichiometry is most likely 1:1. The salt displays a high decomposition temperature.

Reference： [1]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 25; 26

17
[ 404950-80-7 ]
[ 86119-84-8 ]
[ 960055-62-3 ]

Yield	Reaction Conditions	Operation in experiment
	In acetone; at 20 - 60℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 13. A stoichiometric amount of phosphoric acid was subsequently added to the suspension. The mixture was stirred at either 600C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. <n="27"/>- 26 -Table 13[0079] The salt forming reaction in ethanol and isopropyl alcohol gave ethanol and isopropanol hemi-solvates (forms SA and SB, respectively). In ethanol and water, only traces of ethanol were detected by NMR, in spite of the large LOD. The material is either hygroscopic or a hydrate (form HA) that loses water upon gentle heating and vacuum conditions (the loss of water measured by TGA is complete in by -60C at 10C/min.). The salt forming reaction in acetone and ethyl acetate produced the same crystalline and anhydrous phosphate salt (form A). The stoichiometry is most likely 1:1. The salt displays a high decomposition temperature.
	In ethyl acetate; at 20 - 60℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 13. A stoichiometric amount of phosphoric acid was subsequently added to the suspension. The mixture was stirred at either 600C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. <n="27"/>- 26 -Table 13[0079] The salt forming reaction in ethanol and isopropyl alcohol gave ethanol and isopropanol hemi-solvates (forms SA and SB, respectively). In ethanol and water, only traces of ethanol were detected by NMR, in spite of the large LOD. The material is either hygroscopic or a hydrate (form HA) that loses water upon gentle heating and vacuum conditions (the loss of water measured by TGA is complete in by -60C at 10C/min.). The salt forming reaction in acetone and ethyl acetate produced the same crystalline and anhydrous phosphate salt (form A). The stoichiometry is most likely 1:1. The salt displays a high decomposition temperature.

Reference： [1]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 25; 26
[2]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 25; 26

18
[ 404950-80-7 ]
[ 802294-64-0 ]
[ 67-63-0 ]
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide propionate isopropanol hemisolvate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	at 60℃;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 14. A stoichiometric amount of propionic acid was subsequently added to the suspension. The mixture was stirred at either 60C or ambient temperature (where a clear solution formed, stirring continued at 40C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. <n="28"/>- 27 -Table 14[0081] A salt forming reaction in ethanol afforded the unreacted free base (most likely form HB). Isopropyl alcohol produced an IPA solvate of the propionate salt (form SA). Based on NMR, the IPA content is -0.5. The salt shows a weight loss of 15%, which corresponds to the loss of IPA plus an unidentified component. The salt forming reaction in acetone and ethyl acetate produced the same crystalline and unsolvated salt (form A). A weight loss of 6.3-7%, that starts at ~100C, is due to water (if the salt is a hydrate), propionic acid or a decomposition product. Upon completion of weight loss (~140C), the salt decomposes. It should be pointed out that when the material is dissolved in DMSO for NMR, free propionic acid and only traces of propionate were detected.

Reference： [1]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 26; 27

19
[ 404950-80-7 ]
[ 802294-64-0 ]
[ 960055-63-4 ]

Yield	Reaction Conditions	Operation in experiment
	In acetone; at 60℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 14. A stoichiometric amount of propionic acid was subsequently added to the suspension. The mixture was stirred at either 60C or ambient temperature (where a clear solution formed, stirring continued at 40C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. <n="28"/>- 27 -Table 14[0081] A salt forming reaction in ethanol afforded the unreacted free base (most likely form HB). Isopropyl alcohol produced an IPA solvate of the propionate salt (form SA). Based on NMR, the IPA content is -0.5. The salt shows a weight loss of 15%, which corresponds to the loss of IPA plus an unidentified component. The salt forming reaction in acetone and ethyl acetate produced the same crystalline and unsolvated salt (form A). A weight loss of 6.3-7%, that starts at ~100C, is due to water (if the salt is a hydrate), propionic acid or a decomposition product. Upon completion of weight loss (~140C), the salt decomposes. It should be pointed out that when the material is dissolved in DMSO for NMR, free propionic acid and only traces of propionate were detected.
	In ethyl acetate; at 60℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 14. A stoichiometric amount of propionic acid was subsequently added to the suspension. The mixture was stirred at either 60C or ambient temperature (where a clear solution formed, stirring continued at 40C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. <n="28"/>- 27 -Table 14[0081] A salt forming reaction in ethanol afforded the unreacted free base (most likely form HB). Isopropyl alcohol produced an IPA solvate of the propionate salt (form SA). Based on NMR, the IPA content is -0.5. The salt shows a weight loss of 15%, which corresponds to the loss of IPA plus an unidentified component. The salt forming reaction in acetone and ethyl acetate produced the same crystalline and unsolvated salt (form A). A weight loss of 6.3-7%, that starts at ~100C, is due to water (if the salt is a hydrate), propionic acid or a decomposition product. Upon completion of weight loss (~140C), the salt decomposes. It should be pointed out that when the material is dissolved in DMSO for NMR, free propionic acid and only traces of propionate were detected.
	In isopropyl alcohol; at 4 - 60℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 8. A stoichiometric amount of propionic acid was subsequently added to the suspension. The mixture was stirred at either 60 C. or ambient temperature (where a clear solution formed, stirring continued at 4 C.). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. TABLE 8 T, Physical Crystallinity LOD, % Solvent C. Appearance and FormTdecomposition 1H-NMR IPA 60 FFP Excellent 15.1 0.97 (3H, SA propionic) 1.02 (~4H, IPA) 3.73 (Hbz) Acetone 60 FFP Excellent A 7.0 0.97 (3H, 98.9 propionic) 3.73 (Hbz) AcOEt 60 FFP Excellent A 6.3 - ~100 A salt forming reaction in ethanol afforded the unreacted free base (most likely form HB). Isopropyl alcohol produced an IPA solvate of the propionate salt (form SA). Based on NMR, the IPA content is 0.5. The salt shows a weight loss of 15%, which corresponds to the loss of IPA plus an unidentified component. The salt forming reaction in acetone and ethyl acetate produced the same crystalline and unsolvated salt (form A). A weight loss of 6.3-7%, that starts at 100 C., is due to water, propionic acid or a decomposition product. Upon completion of weight loss (140 C.), the salt decomposes. It should be pointed out that when the material is dissolved in DMSO for NMR, free propionic acid and only traces of propionate were detected.

Reference： [1]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 26; 27
[2]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 26; 27
[3]Patent: US2009/192210,2009,A1 .Location in patent: Page/Page column 10-11

20
[ 404950-80-7 ]
[ 67-63-0 ]
1.5C₃H₈O*C₂₁H₂₃N₃O₂*H₂O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; at 60℃;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 15. A stoichiometric amount of sulfuric acid was subsequently added to the suspension. The mixture was stirred at either 6O0C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. <n="29"/>- 28 -Table 15[0083] The salt forming reaction in isopropyl alcohol afforded isolation of a white crystalline salt. It was identified as an isopropanol solvate (form SA), containing 1.5 mol of IPA per formula unit. In DMSO, 0.5 mol of IPA is protonated. The salt forming reaction in ethyl acetate afforded isolation of a yellow hygroscopic powder (form A). During filtration, the sample visibly absorbed moisture, and its poor crystallinity is attributed to this effect.

Reference： [1]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 27; 28

21
[ 404950-80-7 ]
[ 960055-65-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; In ethyl acetate; at 20℃;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 15. A stoichiometric amount of sulfuric acid was subsequently added to the suspension. The mixture was stirred at either 6O0C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. <n="29"/>- 28 -Table 15[0083] The salt forming reaction in isopropyl alcohol afforded isolation of a white crystalline salt. It was identified as an isopropanol solvate (form SA), containing 1.5 mol of IPA per formula unit. In DMSO, 0.5 mol of IPA is protonated. The salt forming reaction in ethyl acetate afforded isolation of a yellow hygroscopic powder (form A). During filtration, the sample visibly absorbed moisture, and its poor crystallinity is attributed to this effect.

Reference： [1]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 27; 28

22
[ 404950-80-7 ]
[ 110-15-6 ]
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide hemi-succinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; water; at 60℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 16. A stoichiometric amount of succinic acid was subsequently added to the suspension. The mixture was stirred at either 60C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. <n="30"/>- 29 -Table 16[0085] Four distinctly different hemi-succinate salts were isolated: a monohydrate (form A) (ethanol at ambient), a hemi-solvate of isopropanol (form SA) (isopropyl alcohol), and two unsolvated forms A and B. Form A displays higher crystallinity, minimal weight loss up to 200C, and higher decomposition temperature. In addition, it could be synthesized reproducibly, as demonstrated in ethanol and ethanol and water at 60C.
	In ethanol; at 20 - 60℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 16. A stoichiometric amount of succinic acid was subsequently added to the suspension. The mixture was stirred at either 60C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. <n="30"/>- 29 -Table 16[0085] Four distinctly different hemi-succinate salts were isolated: a monohydrate (form A) (ethanol at ambient), a hemi-solvate of isopropanol (form SA) (isopropyl alcohol), and two unsolvated forms A and B. Form A displays higher crystallinity, minimal weight loss up to 200C, and higher decomposition temperature. In addition, it could be synthesized reproducibly, as demonstrated in ethanol and ethanol and water at 60C.
	In ethanol; water; at 4 - 60℃;Product distribution / selectivity;	EXAMPLE 16; Formation of Hemi-Succinate Salt; About 40 to 50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 ml of a solvent as listed in Table 16. A stoichiometric amount of succinic acid was subsequently added to the suspension. The mixture was stirred at either 60 C. or ambient temperature (where a clear solution formed, stirring continued at 4 C.). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.; Four distinctly different hemi-succinate salts were isolated: a monohydrate (form A) (ethanol at ambient), a hemi-solvate of isopropanol (form SA) (isopropyl alcohol), and two unsolvated forms A and B. Form A displays higher crystallinity, minimal weight loss up to 200 C., and higher decomposition temperature. In addition, it could be synthesized reproducibly, as demonstrated in ethanol and ethanol and water at 60 C.

Reference： [1]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 28; 29
[2]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 28; 29
[3]Patent: US2009/187029,2009,A1 .Location in patent: Page/Page column 10

23
[ 404950-80-7 ]
[ 110-15-6 ]
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide hemi-succinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethyl acetate; at 20℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 16. A stoichiometric amount of succinic acid was subsequently added to the suspension. The mixture was stirred at either 60C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. <n="30"/>- 29 -Table 16[0085] Four distinctly different hemi-succinate salts were isolated: a monohydrate (form A) (ethanol at ambient), a hemi-solvate of isopropanol (form SA) (isopropyl alcohol), and two unsolvated forms A and B. Form A displays higher crystallinity, minimal weight loss up to 200C, and higher decomposition temperature. In addition, it could be synthesized reproducibly, as demonstrated in ethanol and ethanol and water at 60C.
	In acetone; at 20℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 16. A stoichiometric amount of succinic acid was subsequently added to the suspension. The mixture was stirred at either 60C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. <n="30"/>- 29 -Table 16[0085] Four distinctly different hemi-succinate salts were isolated: a monohydrate (form A) (ethanol at ambient), a hemi-solvate of isopropanol (form SA) (isopropyl alcohol), and two unsolvated forms A and B. Form A displays higher crystallinity, minimal weight loss up to 200C, and higher decomposition temperature. In addition, it could be synthesized reproducibly, as demonstrated in ethanol and ethanol and water at 60C.
	In water; isopropyl alcohol; at 4 - 60℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 10. A stoichiometric amount of succinic acid was subsequently added to the suspension. The mixture was stirred at either 60 C. or ambient temperature (where a clear solution formed, stirring continued at 4 C.). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. TABLE 10 Physical Crystallinity LOD, % Solvent T, C. Appearance and FormTdecomposition 1H-NMR EtOH:H2O 60 SAM to FFP Excellent A 1.1 2.31 (2H, (1:0.05) 203.7 succinate) 3.86 (Hbz)IPA:H2O 60 SAM to FFP Excellent 4.6 2.31 (2H, (1:0.05) HA succinate) 3.85 (Hbz) EtOH Ambient FFP to SAM Excellent A 1.1 2.31 (2H, to FFP 194.6 succinate) 3.85 (Hbz) IPA Ambient FFP Good 2.8 + 4.6 1.02 (~3H, IPA) SA (90.6) (2- 2.32 (2H, step) succinate) 155.83.88 (Hbz) Acetone Ambient FFP Good B 1.5 + 1.3 (2- 2.31 (2H, step) succinate) 162.33.86 (Hbz) AcOEt Ambient FFP Good B 1.3 + 2.9 - 154.5 EtOH 60 SAM to FFP Excellent A - -EtOH:H2O 60 SAM to FFP Excellent A 1.0 2.31 (2H, (1:0.025) 197.3 succinate) 3.85 (Hbz)EtOH:H2O 60 SAM to FFP Excellent A - - (1:0.05) Four distinctly different hemi-succinate salts were isolated: a monohydrate (form A) (ethanol at ambient), a hemi-solvate of isopropanol (form SA) (isopropyl alcohol), and two unsolvated forms A and B. Form A displays higher crystallinity, minimal weight loss up to 200 C., and higher decomposition temperature. In addition, it could be synthesized reproducibly, as demonstrated in ethanol and ethanol and water at 60 C.

Reference： [1]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 28; 29
[2]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 28; 29
[3]Patent: US2009/192210,2009,A1 .Location in patent: Page/Page column 11-12

24
[ 404950-80-7 ]
[ 110-15-6 ]
[ 67-63-0 ]
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide hemisuccinate isopropanol hemisolvate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	at 20℃;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 16. A stoichiometric amount of succinic acid was subsequently added to the suspension. The mixture was stirred at either 60C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. <n="30"/>- 29 -Table 16[0085] Four distinctly different hemi-succinate salts were isolated: a monohydrate (form A) (ethanol at ambient), a hemi-solvate of isopropanol (form SA) (isopropyl alcohol), and two unsolvated forms A and B. Form A displays higher crystallinity, minimal weight loss up to 200C, and higher decomposition temperature. In addition, it could be synthesized reproducibly, as demonstrated in ethanol and ethanol and water at 60C.

Reference： [1]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 28; 29

25
[ 404950-80-7 ]
[ 110-15-6 ]
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide hemisuccinate monohydrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In water; isopropyl alcohol; at 60℃;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 16. A stoichiometric amount of succinic acid was subsequently added to the suspension. The mixture was stirred at either 60C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. <n="30"/>- 29 -Table 16[0085] Four distinctly different hemi-succinate salts were isolated: a monohydrate (form A) (ethanol at ambient), a hemi-solvate of isopropanol (form SA) (isopropyl alcohol), and two unsolvated forms A and B. Form A displays higher crystallinity, minimal weight loss up to 200C, and higher decomposition temperature. In addition, it could be synthesized reproducibly, as demonstrated in ethanol and ethanol and water at 60C.

Reference： [1]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 28; 29

26
[ 404950-80-7 ]
[ 87-69-4 ]
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide hemi-tartarate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; water; at 20 - 60℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 17. A stoichiometric amount of tartaric acid was subsequently added to the suspension. The mixture was stirred at either 600C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.Table 17[0087] The salt forming reaction of the free base with tartaric acid required heating to elevated temperatures. A highly crystalline, anhydrous salt that decomposed above 200C was isolated as a hemi-tartarate and was labeled as form A. Form B was isolated once in isopropyl alcohol and water at 60C and, although very similar in structure with A, significant differences were seen in its XRPD pattern.
	In water; isopropyl alcohol; at 60℃;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 17. A stoichiometric amount of tartaric acid was subsequently added to the suspension. The mixture was stirred at either 600C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.Table 17[0087] The salt forming reaction of the free base with tartaric acid required heating to elevated temperatures. A highly crystalline, anhydrous salt that decomposed above 200C was isolated as a hemi-tartarate and was labeled as form A. Form B was isolated once in isopropyl alcohol and water at 60C and, although very similar in structure with A, significant differences were seen in its XRPD pattern.
	In ethanol; at 60℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 17. A stoichiometric amount of tartaric acid was subsequently added to the suspension. The mixture was stirred at either 600C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.Table 17[0087] The salt forming reaction of the free base with tartaric acid required heating to elevated temperatures. A highly crystalline, anhydrous salt that decomposed above 200C was isolated as a hemi-tartarate and was labeled as form A. Form B was isolated once in isopropyl alcohol and water at 60C and, although very similar in structure with A, significant differences were seen in its XRPD pattern.

In ethanol; water; at 4 - 60℃;Product distribution / selectivity;

EXAMPLE 17; Formation of Hemi-Tartarate Salt; About 40 to 50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 ml of a solvent as listed in Table 17. A stoichiometric amount of tartaric acid was subsequently added to the suspension. The mixture was stirred at either 60 C. or ambient temperature (where a clear solution formed, stirring continued at 4 C.). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.; The salt forming reaction of the free base with tartaric acid required heating to elevated temperatures. A highly crystalline anhydrous salt that decomposed above 200 C. was isolated as a hemi-tartarate and was labeled as form A. Form B was isolated once in isopropyl alcohol and water at 60 C. and, although very similar in structure with A, significant differences were seen in its XRPD pattern.

Reference： [1]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 30
[2]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 30
[3]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 30
[4]Patent: US2009/187029,2009,A1 .Location in patent: Page/Page column 10

27
[ 404950-80-7 ]
[ 960055-70-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In methanol; at 50℃;	About 50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of methanol. A stoichiometric amount of sodium hydroxide was subsequently added to the suspension. The mixture was stirred at 5O0C. Once a clear solution formed, stirring continued at 4C. Solids were collected by filtration and analyzed by XRPD and TGA. The sodium salt ofN-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3-yl)ethyl]amino]methyl]phenyl]-2E- 2-propenamide was isolated as a yellow highly hygroscopic powder, which absorbed moisture during filtration.

Reference： [1]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 34

28
[ 404950-80-7 ]
[ 960055-71-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; In methanol; at 50℃;	About 50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of methanol. A stoichiometric amount of potassium hydroxide was subsequently added to the suspension. The mixture was stirred at 500C. Once a clear solution formed, stirring continued at 4C. Solids were collected by filtration and analyzed by XRPD and TGA. The potassium salt of N-hydroxy-3 - [4- [ [ [2-(2-methyl- 1 H-indol-3 -yl)ethyl] amino] methyl]phenyl] - 2E-2-propenamide was isolated as a yellow highly hygroscopic powder, which absorbed moisture during filtration.

Reference： [1]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 34

29
[ 404950-80-7 ]
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide calcium salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		About 50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in <n="36"/>- 35 -1 mL of methanol. A stoichiometric amount of sodium hydroxide was subsequently added to the suspension. The mixture was stirred at 5O0C. Once a clear solution formed, a stoichiometric amount of calcium dichloride was added causing an immediate precipitation of yellowish solid. Solids were collected by filtration and analyzed by XRPD and TGA. The calcium salt of N-hydroxy-3 - [4- [[[2-(2 -methyl- 1 H-indol-3-yl)ethyl]amino]methyl]phenyl] - 2E-2-propenamide was less hygroscopic than the sodium or potassium salt of N-hydroxy-3 - [4-[[[2-(2-methyl-lH-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide and could be readily isolated.

Reference： [1]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 34; 35

30
[ 404950-80-7 ]
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide zinc salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		About 50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of methanol. A stoichiometric amount of sodium hydroxide was subsequently added to the suspension. The mixture was stirred at 500C. Once a clear solution formed, a stoichiometric amount of zinc sulfate was added causing an immediate precipitation of yellowish solid. Solids were collected by filtration and analyzed by XRPD and TGA. The zinc salt of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2- propenamide was less hygroscopic than the sodium or potassium salt of N-hydroxy-3-[4-[[[2- (2-methyl-lH-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide and could be readily isolated.

Reference： [1]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 35

31
[ 404950-80-7 ]
[ 87-69-4 ]
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide hemi-L-tartarate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96.6%	In ethanol; at 60℃; for 2h;	3.67 g (10 mmol) of the free base monohydrate (N-hydroxy-3 -[4- [[[2-(2-methyl- IH- indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide) and 50 mL of absolute ethanol were charged in a 250 mL 3-neck flask equipped with a magnetic stirrer and an addition funnel. The mixture was heated to 60C, and to the hot suspension were added dropwise 0.83 g (5.5 mmol, 10% excess) of L-tartaric acid dissolved in 15 mL absolute ethanol. Initially, large yellow agglomerates formed that prevented adequate stirring, but overtime these were converted to free flowing and stirrable yellow powder. Stirring continued at 60C for 2 hours. The mixture was subsequently cooled to room temperature and placed in an ice bath for approximately 30 minutes. The yellow powder was recovered by filtration and washed once by cold absolute ethanol (10 mL). It was dried overnight under vacuum to yield 4.1 g of the L-tartarate (hemi-tartarate) salt of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide (96.6%).
96.6%	In ethanol; at 60℃;Product distribution / selectivity;	EXAMPLE 27; Formation of L-Tartarate Salt; 3.67 g (10 mmol) of the free base monohydrate (N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl) ethyl]amino]methyl]phenyl]-2E-2-propenamide) and 50 ml of absolute ethanol were charged in a 250 ml 3-neck flask equipped with a magnetic stirrer and an addition funnel. The mixture was heated to 60 C., and to the hot suspension were added dropwise 0.83 g (5.5mmol, 10% excess) of 1-tartaric acid dissolved in 15 ml absolute ethanol. Initially, large yellow agglomerates formed that prevented adequate stirring, but overtime these were converted to free flowing and stirrable yellow powder. Stirring continued at 60 C. for 2 hours. The mixture was subsequently cooled to room temperature and placed in an ice bath for approximately 30 min. The yellow powder was recovered by filtration and washed once by cold absolute ethanol (10 ml). It was dried overnight under vacuum to yield 4.1 g of the 1-tartarate (hemi-tartarate) salt of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide (96.6%).

Reference： [1]Patent: WO2007/146715,2007,A1 .Location in patent: Page/Page column 36
[2]Patent: US2009/187029,2009,A1 .Location in patent: Page/Page column 12

32
[ 441741-66-8 ]
[ 404950-80-7 ]

Yield	Reaction Conditions	Operation in experiment
94.6%		To a 250 ml four-necked flask was added (E) -3- [4 - [[2- (2-methyl-1H-indol-3-yl)(15 g, 0.039 mol), methanol (75 ml), cooled at -10 C to 15 C with stirring, and rapidly precipitated with sodium hydroxide (4.68 g, 0.71 m 1 ) In methanol solution, drop the mixture, stir lOmin, dropping hydroxylamine solution (32. 52g 50% aqueous solution corresponding to hydroxylamine hydrochloride 16.268,0.234111001), dropping finished at -10 (: - 15 (temperature insulation Stir for 2 hours.The reaction mixture was warmed to 0 C, kept at 0-5 C for 30 min, then warmed to 20 C, kept at 20-25 C for 1 hour, drop in water 38 ml, stir l0 min, Filtered and rinsed with 38 ml of water. The resulting filtrate was adjusted to pH 10 with an aqueous solution of hydrochloric acid (about 18. 5 g of an aqueous solution of 2 mol / L) to 10. The crystals were stirred at 20-25 C and treated with hydrochloric acid (About 15.5 g of 2 mol / L of aqueous solution), continue to adjust the PH value of the solution to 8-9, stirring at 20-25 C for 1 hour, continue to adjust the pH of the solution to 3-4, stirring for 1 hour , The solid was filtered and the filter cake was rinsed with 50 ml of a methanolic water mixture (nu / nu = 1: 1) and dried to a constant weight in a 50 hot air oven to give a solid 12. 89 g, yield 94. 6% :
73%	With hydroxylamine; potassium hydroxide; In methanol; at 0℃; for 4h;Inert atmosphere;	A solution of potassium hydroxide (1.17 g, 21 mmol) in methanol (5 mL) was added to a stirred solution of hydroxylamine hydrochloride (0.97 g, 14 mmol) in methanol (10 mL) at 0 C. The mixture was stirred at 0 C for 15 min. The precipitate was removed by filtration and the filtrate was collected to provide fresh hydroxylamine solution. The ester (0.48 g, 1.4 mmol) was added to the above freshly prepared hydroxylamine solution at 0 C. The reaction mixture was then stirred at this temperature under a nitrogen atmosphere for 4 h. After the reaction was completed, the mixture was diluted with water and neutralised with NH4Cl aqueous solution to pH = 7-8. The precipitate that formed was collected by filtration, washed with water and recrystallised from MeOH/H2O to give the title compound as: Off-white solid; yield 0.35 g (73%); m.p. 89-91 C (lit. 1286-88 C); 1H NMR (600 MHz, DMSO-d6): delta 2.31 (s, 3H), 2.69 (t, J= 7.5 Hz, 2H), 2.81 (t, J= 7.5 Hz, 2H), 3.77 (s, 2H), 6.45 (d, J= 15.8 Hz, 1H), 6.90 (m, 1H), 6.95 (m, 1H), 7.22 (d, J= 8.0 Hz, 1H), 7.38 (m, 3H), 7.44 (d, J= 15.8 Hz, 1H), 7.49 (d, J= 8.0 Hz, 2H), 10.70 (brs, 1H); 13C NMR (150 MHz, DMSO-d6): delta 11.7, 24.7, 50.0, 52.8, 108.5, 110.8, 117.8, 118.4, 118.8, 120.3, 127.7, 128.8, 128.9, 132.2, 133.6, 135.6, 138.6, 142.7, 163.2; MS (ESI) m/z [M + H]+: 350.0; HRMS m/z calcd for C21H23O2N3[M + H]+: 350.1863; found: 350.1864.
	With sodium hydroxide; hydroxylamine hydrochloride; In water; at 0℃; for 6h;	A suspension of LiAIH4 (17 g, 445 mmol) in dry THF(IOOO mL) is cooled to 0 0C and 2- methylindole-3-gryoxylamide (30 g, 148 mmol) is added in portions over 30 min. The mixture is stirred at room temperature for 30 min. and then maintained at reflux for 3 h. The reaction is cooled to 0 0C and treated with H2O (17ml), 15% NaOH (aq., 17ml) and H2O (51 ml). The mixture is treated with MgSO4, filtered and the filtrate evaporated to give 2-methyltryptamine which is dissolved in MeOH. Methyl 4-formylcinnamate (16.9 g, 88.8 mmol) is added to the solution, followed by NaBH3CN (8.4 g) and AcOH (1 equiv.). After 1 h the reaction is diluted with NaHCO3 (aq.) and extracted with EtOAc. The organic extracts are dried (MgSO4), filtered and evaporated. The residue is purified by chromatography to give 3-(4-[2-(2-methyl-1 /-/-indo.-3-yl)-ethylamino]-methyl}-phenyl)-(2£)-2-propenoic acid methyl ester. The ester is dissolved in MeOH, 1.0 M HCI/dioxane (1 - 1.5 EPO <DP n="27"/>eqiv.) is added followed by Et2O. The resulting precipitate is filtered and the solid washed with Et2O and dried thoroughly to give 3-(4-[2-(2-methyl-1 /-/-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2£)-2- propenoic acid methyl ester hydrochloride. 1.0 M NaOH (aq., 85 mL) is added to an ice cold solution of the methyl ester hydrochloride (14.9 g, 38.6 mmoi) and HONH2 (50% aq. solution, 24.0 mL, ca. 391.2 mmol). After 6 h, the ice cold solution is diluted with H2O and NH4CI (aq., 0.86 M, 100 mL). The resulting precipitate is filtered, washed with H2O and dried to afford Lambda/-hydroxy-3-[4-[[[2-(2- methyl-1 W-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide (m/z 350 [MH+]).

EXAMPLE 31; Formation of the Lactate Salt; The manufacture of LBH589 lactate (6) drug substance is via a convergent synthesis; the point of convergence is the condensation of indole-amine Z3a with aldehyde 3.The synthesis of indole-amine Z3a involves reaction of 5-chloro-2 pentanone (Z3b) with phenylhydrazine (Z3c) in ethanol at reflux (variation of Fischer indole synthesis).Product isolation is by an extractive work-up followed by crystallization. Preparation of aldehyde 3 is by palladium catalyzed vinylation (Heck-type reaction; Pd(OAc)2/P(o-Tol)3/Bu3N in refluxing CH3CN) of 4-bromo-benzyladehyde (1) with methyl acrylate (2) with product isolation via precipitation from dilute HCl solution. Intermediates Z3a and 3 are then condensed to an imine intermediate, which is reduced using sodium borohydride in methanol below 0 C. (reductive amination). The product indole-ester 4, isolated by precipitation from dilute HCl, is recrystallized from methanol/water, if necessary. The indole ester 4 is converted to crude LBH589 free base 5 via reaction with hydroxylamine and sodium hydroxide in water/methanol below 0 C. The crude LBH589 free base 5 is then purified by recrystallization from hot ethanol/water, if necessary. LBH589 free base 5 is treated with 85% aqueous racemic lactic acid and water at ambient temperature. After seeding, the mixture is heated to approximately 65 C., stirred at this temperature and slowly cooled to 45-50 C. The resulting slurry is filtered and washed with water and dried to afford LBH589 lactate (6).If necessary the LBH589 lactate 6 may be recrystallised once again from water in the presence of 30 mol % racemic lactic acid. Finally the LBH589 lactate is delumped to give the drug substance. If a rework of the LBH589 lactate drug substance 6 is required, the LBH589 lactate salt is treated with sodium hydroxide in ethanol/water to liberate the LBH589 free base 5 followed by lactate salt formation and delumping as described above.All starting materials, reagents and solvents used in the synthesis of LBH589 lactate are tested according to internal specifications or are purchased from established suppliers against a certificate of analysis.A flow diagram for the synthesis of LBH589 lactate is provided in FIG. A. A nomenclature reference index of the intermediates is provided below in the Nomenclature Reference Index;

Reference： [1]Patent: CN106674079,2017,A .Location in patent: Paragraph 0089; 0090; 0091
[2]Journal of Chemical Research,2018,vol. 42,p. 471 - 473
[3]Patent: WO2007/21682,2007,A1 .Location in patent: Page/Page column 25-26
[4]Patent: US2009/187029,2009,A1 .Location in patent: Page/Page column 13-14

33
[ 404950-80-7 ]
[ 144-62-7 ]
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide oxalate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; water; at 4 - 60℃;Product distribution / selectivity;	EXAMPLE 12; Formation of Oxalate Salt; About 40 to 50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base was suspended in 1 ml of a solvent as listed in Table 12. A stoichiometric amount of salt forming agent oxalic acid was subsequently added to the suspension. The mixture was stirred at either 60 C. or ambient temperature (where a clear solution formed, stirring continued at 4 C.). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.; Oxalate salts, although precipitated immediately upon addition of oxalic acid to suspensions of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide, were hard to isolate and appear to absorb water during filtration.

Reference： [1]Patent: US2009/187029,2009,A1 .Location in patent: Page/Page column 8

34
[ 404950-80-7 ]
[ 75-75-2 ]
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide mesylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethyl acetate; at 4 - 20℃;Product distribution / selectivity;	EXAMPLE 11; Formation of Mesylate Salt; About 40 to 50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 ml of a solvent as listed in Table 11. A stoichiometric amount of methanesulfonic acid was subsequently added to the suspension. The mixture was stirred at either 60 C. or ambient temperature (where a clear solution formed, stirring continued at 4 C.). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.; The salt forming reaction in ethyl acetate afforded a yellow salt, upon stirring at room temperature. The salt (form A) is crystalline, displays a 2-step weight loss and, by NMR, does not contain any solvent but appears to have more than one molecule of methanesulfonate (mesylate). The salt forming reaction in acetone afforded isolation of a white powder after heating at 60 C. It displayed excellent crystallinity but may be a composite of more than one polymorphic form (forms A and B). By NMR, it does not contain any solvent but appears to contain more than one molecule of methanesulfonate. Another salt forming reaction in ethyl acetate, in which reaction is initiated at ambient temperature and then the obtained yellowish powder suspension is heated to 50 C., afforded isolation of a new form B, as shown in FIG. 5.

Reference： [1]Patent: US2009/187029,2009,A1 .Location in patent: Page/Page column 8

35
[ 849585-22-4 ]
[ 404950-80-7 ]
[ 960055-56-5 ]

Yield	Reaction Conditions	Operation in experiment
86.2%	In water; acetone; at 0 - 20℃;Cooling with ice;Product distribution / selectivity;	3.67 g (10 mmol) of the free base form HA (N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide) and 75 mL of acetone were charged in a 250 mL 3-neck flask equipped with a magnetic stirrer and an addition funnel. To the stirred suspension were added dropwise 10 mL of 1 M lactic acid in water (10 mmol) dissolved in 20 mL acetone, affording a clear solution. Stirring continued at ambient and a white solid precipitated out after approximately 1 hour. The mixture was cooled in an ice bath and stirred for an additional hour. The white solid was recovered by filtration and washed once with cold acetone (15 mL). It was subsequently dried under vacuum to yield 3.94 g of the DL-lactate monohydrate salt of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide (86.2%).
	In isopropyl alcohol; at 4℃;Product distribution / selectivity;	EXAMPLE 7; Formation of Monohydrate Lactate Salt; About 40 to 50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base was suspended in 1 ml of a solvent as listed in Table 7. A stoichiometric amount of lactic acid was subsequently added to the suspension. The mixture was stirred at ambient temperature and when a clear solution formed, stirring continued at 4 C. Solids were collected by filtration and analyzed by XRPD, TGA and 1H-NMR.; The salt forming reaction in isopropyl alcohol and acetone at 4 C. produced a stoichiometric (1:1) lactate salt, a monohydrate. The salt is crystalline, begins to dehydrate above 77 C., and decomposes above 150 C.

Reference： [1]Patent: US2009/192210,2009,A1 .Location in patent: Page/Page column 14
[2]Patent: US2009/187029,2009,A1 .Location in patent: Page/Page column 7

36
[ 404950-80-7 ]
[ 77-92-9 ]
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide citrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In water; isopropyl alcohol; at 4 - 60℃;Product distribution / selectivity;	EXAMPLE 4; Formation of Hemi-Citrate Salt; About 40 to 50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base was suspended in 1 ml of a solvent as listed in Table 4. A stoichiometric amount of citric acid was subsequently added to the suspension. The mixture was stirred at either 60 C. or ambient temperature (where a clear solution formed, stirring continued at 4 C.). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.; Heating to 60 C. (acetone and ethanol), as well as the introduction of water (isopropyl alcohol and water, acetone and water at 60 C.) yielded a highly crystalline salt that does not contain any solvent or water. A high LOD value for acetone at ambient/60 C. is due to the presence of amorphous material within the crystalline powder. The stoichiometry of the salt could not be determined by 1H-NMR in DMSO-d6, since the expected peak for the citrate ion coincides with that of the solvent. However, 13C-NMR spectroscopy indicated the presence of two 13C=O signals at 177.3 and 171.6 ppm. The former is due to the protonated carboxylic group and the latter to the unprotonated carboxylate. Therefore, the salt stoichiometry is either 2:1 (most likely) or 1:1.

Reference： [1]Patent: US2009/187029,2009,A1 .Location in patent: Page/Page column 6

37
[ 404950-80-7 ]
[ 802294-64-0 ]
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide propionate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In acetone; at 4 - 60℃;Product distribution / selectivity;	EXAMPLE 14; Formation of Propionate Salt; About 40 to 50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 ml of a solvent as listed in Table 14. A stoichiometric amount of propionic acid was subsequently added to the suspension. The mixture was stirred at either 60 C. or ambient temperature (where a clear solution formed, stirring continued at 4 C.). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.; A salt forming reaction in ethanol afforded the unreacted free base (most likely form HB). Isopropyl alcohol produced an IPA solvate of the propionate salt (form SA). Based on NMR, the IPA content is 0.5. The salt shows a weight loss of 15%, which corresponds to the loss of IPA plus an unidentified component. The salt forming reaction in acetone and ethyl acetate produced the same crystalline and unsolvated salt (form A). A weight loss of 6.3 to 7%, that starts at 100 C., is due to water (if the salt is a hydrate), propionic acid or a decomposition product. Upon completion of weight loss (140 C.), the salt decomposes. It should be pointed out that when the material is dissolved in DMSO for NMR, free propionic acid and only traces of propionate were detected.

Reference： [1]Patent: US2009/187029,2009,A1 .Location in patent: Page/Page column 9

38
[ 404950-80-7 ]
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide phosphate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With phosphoric acid; In ethanol; water; at 4 - 60℃;Product distribution / selectivity;	EXAMPLE 13; Formation of Phosphate Salt; About 40 to 50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 ml of a solvent as listed in Table 13. A stoichiometric amount of phosphoric acid was subsequently added to the suspension. The mixture was stirred at either 60 C. or ambient temperature (where a clear solution formed, stirring continued at 4 C.). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.; The salt forming reaction in ethanol and isopropyl alcohol gave ethanol and isopropanol hemi-solvates (forms SA and SB, respectively). In ethanol and water, only traces of ethanol were detected by NMR, in spite of the large LOD. The material is either hygroscopic or a hydrate (form HA) that loses water upon gentle heating and vacuum conditions (the loss of water measured by TGA is complete in by -60 C. at 10 C./min). The salt forming reaction in acetone and ethyl acetate produced the same crystalline and anhydrous phosphate salt (form A). The stoichiometry is most likely 1:1. The salt displays a high decomposition temperature.

Reference： [1]Patent: US2009/187029,2009,A1 .Location in patent: Page/Page column 9

39
[ 404950-80-7 ]
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide sulfate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; In isopropyl alcohol; at 4 - 60℃;Product distribution / selectivity;	EXAMPLE 15; Formation of Sulfate Salt; About 40 to 50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 ml of a solvent as listed in Table 15. A stoichiometric amount of sulfuric acid was subsequently added to the suspension. The mixture was stirred at either 60 C. or ambient temperature (where a clear solution formed, stirring continued at 4 C.). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.; The salt forming reaction in isopropyl alcohol afforded isolation of a white crystalline salt. It was identified as an isopropanol solvate (form SA), containing 1.5 mol of IPA per formula unit. In DMSO, 0.5 mol of IPA is protonated. The salt forming reaction in ethyl acetate afforded isolation of a yellow hygroscopic powder (form A). During filtration, the sample visibly absorbed moisture, and its poor crystallinity is attributed to this effect.

Reference： [1]Patent: US2009/187029,2009,A1 .Location in patent: Page/Page column 9-10

40
[ 404950-80-7 ]
[ 87-69-4 ]
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide hemi-L-tartarate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96.6%	In ethanol; at 0 - 60℃;Cooling with ice;Product distribution / selectivity;	3.67 g (10 mmol) of the free base monohydrate (N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide) and 50 mL of absolute ethanol were charged in a 250 mL 3-neck flask equipped with a magnetic stirrer and an addition funnel. The mixture was heated to 60 C., and to the hot suspension were added dropwise 0.83 g (5.5 mmol, 10% excess) of L-tartaric acid dissolved in 15 mL absolute ethanol. Initially, large yellow agglomerates formed that prevented adequate stirring, but overtime these were converted to free flowing and stirrable yellow powder. Stirring continued at 60 C. for 2 hours. The mixture was subsequently cooled to room temperature and placed in an ice bath for approximately 30 minutes. The yellow powder was recovered by filtration and washed once by cold absolute ethanol (10 mL). It was dried overnight under vacuum to yield 4.1 g of the L-tartarate (hemi-tartarate) salt of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide (96.6%).

Reference： [1]Patent: US2009/192210,2009,A1 .Location in patent: Page/Page column 12

41
[ 404950-80-7 ]
[ 110-17-8 ]
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide hemi-fumarate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; at 4 - 20℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 3. A stoichiometric amount of fumaric acid was subsequently added to the suspension. The mixture was stirred at either 60 C. or ambient temperature (where a clear solution formed, stirring continued at 4 C.). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. TABLE 3 Physical Crystallinity LOD, % Solvent T, C. Appearance and FormTdecomposition 1H-NMR EtOH Ambient FFP to SAM excellent B 1.1 + 1.7 (2-3.93 (Hbz) to FFP step) 6.50 (1H, 213.2 fumarate) IPA Ambient FFP consists of 3.4 + 6.0 (2-3.91 (Hbz) one intense step) 6.50 (1H, peak 159.8 fumarate) HA only small amount of IPAEtOH:H2O Ambient FFP to SAM Excellent A 0.73.90 (Hbz) (1:0.05) to FFP 217.4 6.49 (1H, fumarate)IPA:H2O Ambient FFP Excellent A 1.5 - (1:0.05) 208.2IPA:H2O Ambient FFP Excellent A - - (1:0.05)EtOH:H2O Ambient FFP to SAM Poor A 0.7 - (1:0.025) to FFP 154.8EtOH:H2O Ambient FFP to SAM Excellent A 0.93.90 (Hbz) (1:0.05) to FFP 217.1 6.49 (1H, fumarate) The salt forming reactions in isopropyl alcohol and acetone at ambient temperature produced fumarate salt of stoichiometry 2:1 (protonated base:fumarate), i.e., hemi-fumarate salts. Although none of them was a solvate, they had poor crystallinity and a low decomposition temperature. The LOD for isopropyl alcohol at ambient temperature was most likely associated with the loss of water (most likely HA form). The salt forming reaction in ethanol, ethanol and water, and isopropyl alcohol and water, all at ambient temperature or 60 C., produced a fumarate salt of stoichiometry 2:1 (protonated base:fumarate)), i.e., hemi-fumarate salt. The salt forming reaction in ethanol and water and isopropyl alcohol and water (1:0.05), ambient or 60 C., produced identical XRPD spectra (anhydrous form A). The spectrum of the salt formed by ethanol at ambient temperature, albeit similar, displays some small differences and it may represent a unique, hemi-fumarate polymorph (form B) of similar structure.

Reference： [1]Patent: US2009/192210,2009,A1 .Location in patent: Page/Page column 8-9

42
[ 404950-80-7 ]
[ 617-48-1 ]
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide hemi-malate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; water; at 4 - 60℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 5. A stoichiometric amount of malic acid was subsequently added to the suspension. The mixture was stirred at either 60 C. or ambient temperature (where a clear solution formed, stirring continued at 4 C.). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. TABLE 5 Physical Crystallinity LOD, % Solvent T, C. Appearance and FormTdecomposition 1H-NMR EtOH:H2O (1:0.05) 60 SAM to FFP Excellent A 1.93.96 (Hbz) 206.0 3.83 (0.5H, malate) EtOH 60 SAM to FFP Excellent A 0.4 - 199.3 IPA 60 SAM to FFP Excellent A - - Acetone 60 SAM to FFP Excellent 0.63.97 (Hbz) SA 95 3.84 (0.5H, malate)EtOH:H2O (1:0.05) Ambient SAM to FFP Excellent A - - The salt forming reaction in ethanol and water, ethanol and isopropyl alcohol produced the same crystalline and anhydrous hemi-malate salt. The difference in LOD between ethanol and water (1:0.05) and ethanol may reflect varying amounts of amorphous material in the two samples. The salt forming reaction in acetone afforded a different hemi-malate salt that continuously loses weight above 95 C. This salt is an acetone solvate (form SA). Solvent loss and decomposition are closely spaced thermal events.

Reference： [1]Patent: US2009/192210,2009,A1 .Location in patent: Page/Page column 9

43
[ 404950-80-7 ]
[ 7664-93-9 ]
[ 960055-65-6 ]

Yield	Reaction Conditions	Operation in experiment
	In ethyl acetate; at 4 - 20℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 9. A stoichiometric amount of sulfuric acid was subsequently added to the suspension. The mixture was stirred at either 60 C. or ambient temperature (where a clear solution formed, stirring continued at 4 C.). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. TABLE 9 Physical Crystallinity and LOD, % Solvent T, C. Appearance FormTdecomposition 1H-NMR IPA 60 SAM to FFP Excellent 8.9 to 12 1.02 (6H, IPA) SA 1621.10 (3H, IPA+) 4.22 (Hbz) AcOEt Ambient FFP Poor A ~6.74.22 (Hbz) ~160 The salt forming reaction in isopropyl alcohol afforded isolation of a white crystalline salt. It was identified as an isopropanol solvate (form SA), containing 1.5 mol of IPA per formula unit. In DMSO, 0.5 mol of IPA is protonated. The salt forming reaction in ethyl acetate afforded isolation of a yellow hygroscopic powder (form A). During filtration, the sample visibly absorbed moisture, and its poor crystallinity is attributed to this effect.

Reference： [1]Patent: US2009/192210,2009,A1 .Location in patent: Page/Page column 11

44
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide hemi-L-tartarate [ No CAS ]
[ 404950-80-7 ]

Reference： [1]Patent: US2009/192210,2009,A1 .Location in patent: Page/Page column 15

45
[ 404950-80-7 ]
[ 960055-62-3 ]

Yield	Reaction Conditions	Operation in experiment
	With phosphoric acid; In ethanol; water; at 4 - 60℃;Product distribution / selectivity;	About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 7. A stoichiometric amount of phosphoric acid was subsequently added to the suspension. The mixture was stirred at either 60 C. or ambient temperature (where a clear solution formed, stirring continued at 4 C.). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. TABLE 7 Physical Crystallinity LOD, % Solvent T, C. Appearance and FormTdecomposition 1H-NMR EtOH:H2O 60 FFP Excellent 7.03.94 (Hbz) (1:0.05) HA 179.6 EtOH Ambient FFP Good ~6.6 1.1 (~1.5H, SA EtOH) 4.00 (Hbz) IPA Ambient FFP Excellent ~7.0 1.02 (3-4H, IPA) SB 4.00 (Hbz) Acetone RT to 60 SAM to FFP Excellent A 1.04.00 (Hbz) 187.4 AcOEt RT to 60 SAM to FFP Good A 1.2 - 175.5 The salt forming reaction in ethanol and isopropyl alcohol gave ethanol and isopropanol hemi-solvates (forms SA and SB respectively). In ethanol and water, only traces of ethanol were detected by NMR, in spite of the large LOD. The material is either hygroscopic or a hydrate (form HA) that loses water upon gentle heating and vacuum conditions (the loss of water measured by TGA is complete in by 0 C. at 10 C./min.). The salt forming reaction in acetone and ethyl acetate produced the same crystalline and anhydrous phosphate salt (form A). The stoichiometry is most likely 1:1. The salt displays a high decomposition temperature.

Reference： [1]Patent: US2009/192210,2009,A1 .Location in patent: Page/Page column 10

46
[ 960058-93-9 ]
[ 404950-80-7 ]

Yield	Reaction Conditions	Operation in experiment
		(E)-3-(4-[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]-phenyl)-acrylic acid methyl ester hydrochloride salt (90 g, 233.8 mmole) is placed in a 4-necked reaction flask and methanol (475 g) is added. The suspension is cooled to -15 C. A solution of sodium hydroxide (28.2 g, 705 mmole) in methanol (419.2 g) is added to the suspension at -15 C. (addition time ca. 30 minutes), followed by the addition of the hydroxylamine solution (100.3 g of a 50% solution in water, corresponding to 50.15 g hydroxylamine, 1518 mmole) at this temperature (addition time ca. 30 minutes). Caution: it is important to use different addition funnels for the sodium hydroxide and hydroxylamine solutions respectively. Stirring is continued at -15 C. for an additional 7 hours until a conversion of >99.5 area % is achieved according to HPLC. The reaction mixture is warmed to 0 C., stirred for 5 hours at 0-5 C., warmed to 20 C. and stirring is continued for 8 hours at 20-25 C. De-mineralized water (225 g) is added to the suspension at 20-25 C. during 30 minutes to obtain a solution. The solution is filtered and the filter as well as the filter pipeline are washed with de-mineralized water (225 g). The pH of the solution is adjusted to 10.3-10.7 by the addition of an aqueous hydrochloric acid solution (ca. 140 g of a 7.8 m/m % solution in water). Seed crystals are added as a suspension of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base (80 mg) in water (5 g) and the mixture is stirred for ca. 30 minutes at 20-25 C., until a suspension is formed. The pH of the suspension is then adjusted to 8.5-9.0 by addition of an aqueous hydrochloric acid solution (ca. 108 g of a 7.8 m/m % solution in de-mineralized water) at 20-25 C. and stirring is continued for at least 30 minutes at 20-25 C. The solid product is isolated by filtration and the filter cake is washed with a 1:1 (v/v) mixture of demineralized water and methanol (140 mL). The wet product is dried at 45-50 C./5 mbar for 24 hours to obtain N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide. Yield: 81.15 g; 99.3% of the theory. HPLC analysis indicated 97.6 area % purity for the product, which comprised 3.2% w/w of water. The hydroxylamine content was found to be 345 ppm, which is sufficient for the preparation of the corresponding lactate salt with <5 ppm hydroxylamine.

Reference： [1]Patent: US2009/306405,2009,A1 .Location in patent: Page/Page column 5

47
[ 849585-22-4 ]
[ 404950-80-7 ]
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]acrylamide DL-lactate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	In water; at 60 - 90℃;	The DL - lactic acid (4.0g, 85% of the aqueous solution, corresponding to the 3.4g pure DL - lactic acid, 0.0378 muM) water 27.2g dilution, and heating the solution to the 90 C4 more than 24 hours, cooled to room temperature, the spare.In 250 ml bottle into four (E)- N - hydroxy -3 - [4 - [[ [2 - (2 - methyl - 1H - indole -3 - yl) ethyl] amino] methyl] phenyl] acrylamide (10.0g, 0 . 0286 muM), adding water to 110 ml, raising the temperature to 60 - 70 C stirring suspension, at this temperature dropping the DL - lactic acid solution, suspension dissolved into solution, in the 60 - 70 C lower heat insulating 30min, lowering the temperature to 40 - 50 C, crystallization 1 hour, then lowering the temperature to 30 - 35 C insulation stirring 1 hour, the suspension is again raising the temperature to 60 - 70 C after, slow cooling to 30 - 35 C, thermal insulation 1 hour later, then slowly cooling to 0 - 5 C, thermal insulation 2 hours. Filtering, cold water for 30 ml washing the filter cake, filtration cake 45 C vacuum drying to constant weight, to obtain the crystalline product, 11.44g, yield 91%

Reference： [1]Patent: CN106674079,2017,A .Location in patent: Paragraph 0092; 0093; 0094; 0095

48
[ 404950-80-7 ]
(E)-trifluoro(((4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)(methyl)(2-(2-methyl-1H-indol-3-yl)ethyl)ammonio)methyl)borate [ No CAS ]