[ CAS No. 16689-34-2 ] {[proInfo.proName]}

Name: 16689-34-2|tert-Butyl 2-(propan-2-ylidene)hydrazinecarboxylate|95%
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Quality Control of [ 16689-34-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 16689-34-2 ]

CAS No. :	16689-34-2	MDL No. :	MFCD07636643
Formula :	C₈H₁₆N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XCMYPTLLFDFJAE-UHFFFAOYSA-N
M.W :	172.22	Pubchem ID :	11435207
Synonyms :

Calculated chemistry of [ 16689-34-2 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.75
Num. rotatable bonds :	4
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	48.77
TPSA :	50.69 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.56 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.34
Log Po/w (XLOGP3) :	1.12
Log Po/w (WLOGP) :	1.91
Log Po/w (MLOGP) :	1.34
Log Po/w (SILICOS-IT) :	0.84
Consensus Log Po/w :	1.51

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.35
Solubility :	7.7 mg/ml ; 0.0447 mol/l
Class :	Very soluble
Log S (Ali) :	-1.78
Solubility :	2.87 mg/ml ; 0.0167 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.69
Solubility :	3.48 mg/ml ; 0.0202 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.87

Safety of [ 16689-34-2 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P261-P280-P301+P312-P302+P352-P305+P351+P338	UN#:
Hazard Statements:	H302-H315-H319-H335	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 16689-34-2 ]

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

Upstream synthesis route of [ 16689-34-2 ]
Downstream synthetic route of [ 16689-34-2 ]

[ 16689-34-2 ] Synthesis Path-Upstream 1~1

1
[ 16689-34-2 ]
[ 16689-35-3 ]

Yield	Reaction Conditions	Operation in experiment
77%	With bromocresol green; sodium cyanoborohydride; toluene-4-sulfonic acid In tetrahydrofuran at 20℃; for 2 h;	Alternatively, tert-Butyl 2-(propan-2-ylidene)hydrazinecarboxylate 2 (0.51 g, 3.0 mmol) was dissolved in 20 mL of THF, treated with NaBCN (0.19 g, 3.0 mmol) and a few mg of bromocresol green, followed by a solution of p-toluenesulfonic acid (0.57 g, 3.0 mmol) in 1.5 mL of THF which was added dropwise over approximately 1 h to maintain the reaction pH between 3.5-5.0. After stirring at room temperature for an additional hour, the solvent was removed by rotary evaporation, and the residue was partitioned between EtOAc (30 mL) and brine. The organic phase was extracted with sat. NaHCC>3, 20 mL and brine, evaporated to a residue and dissolved in 10 mL of ethanol. The ethanolic solution was treated with 3.6 mL of 1M NaOH solution (3.6 mmol) and left to stir at rt for 30 min. The solvent was removed by rotary evaporation and the residue was taken up into ethyl acetate and extracted with water. The organic layer was evaporated under reduced pressure and the residue was purified by column chromatography using 5 percent MeOH in DCM as eluent to collect tert-butyl 2- isopropylhydrazinecarboxylate 3 (0.4 g, 77 percent yield): mp = 47-49 °C; Rf = 0.44 (5 percent MeOH in DCM); IH NMR 300 MHz (CDC13) d 6.03 (s, N-H, IH), 3.92 (s, N-H, IH), 3.14 (m, IH), 1.46 (s, 9H), 1.02 (d, 6H, J = 6 Hz); 13C NMR 300 MHz (CDC13) d 157.2, 80.8, 51.2, 28.7, 21.0.
70%	With hydrogen In methanol at 20℃; for 1.75 h;	To a solution of isopropylidine hydrazine (2.94 g, 17.1 MMOL) in MEOH at rt under argon was added 5percent PT/C (290 mg). Hydrogen gas was bubbled through the black suspension for 15 min and then the reaction was left under an atmosphere of hydrogen for 1.5 h. After this time, the suspension was filtered and the collected solids were washed with ADDITIONAL MEOH. The combined filtrate and washings were concentrated under reduced pressure. The crude material that remained was then redissolved in EtOAc and washed with sat. NaHCO3. The organic layer was separated, washed with sat. NaCI, dried (MGS04), filtered and concentrated under reduced pressure. Purification by chromatography on silica eluting with 50percent EtOAc/hexanes gave the title compound as colourless crystals (2.08 g, 70percent). 1 H- NMR; δ (CDCI3), 6.34 (1H, s NHBoc), 3.50 (1H, br, NH) 3.13 (1H, sept, J=6.5Hz, CH (CH3) 2), 1.46 (9H, s, (CH3) 3), 1.02 (6H, d, J=6.5Hz, (CH3) 2CH). LRMS: +ve ion: 197 [M+23], 175 [M+1], 161.
61%	With lithium borohydride; chloro-trimethyl-silane In tetrahydrofuran at 20℃; for 2 h; Inert atmosphere	The title compound can be prepared by the method of Dutta et ( J . C:S Perkin /1975,1712-1720) Or from the following method: A mixture of 13.2 g (0.1 mol) of t-butyl carbazate and 6 g (0.103 mol) of acetone and 12.58 g (0.1 mol) of anhydrous magnesium sulfate in 100 ml of dichloromethane was stirred at room temperature for 12 hours. After removal of the desiccant by filtration, the filtrate was evaporated under reduced pressure and crystallized from cyclohexane to give 16.9 g of the corresponding hydrazone having a melting point of 104-105 ° C. intoo a suspension solution of 2.04 g (0.094 mol) of lithium borohydride in 100 ml of anhydrous tetrahydrofuran was added 12 ml (0.094 mol) of trimethylchlorosilane in a greenhouse under a nitrogen atmosphere. After 30 minutes at room temperature the 13.45 g (0.078 mol) of hydrazone was slowly added and stirring was continued for 2 hours. Then, 50 ml of methanol was carefully added and the mixture was evaporated to dryness under reduced pressure. The residue was partitioned between ether (150 ml) and water (50 ml). The organic phase was dried over anhydrous magnesium sulfate and filtered,the hydrogen chloride was dried through the filtrate and the resulting white solid was removed by filtration then washed with a portion of fresh ether and dried to give the Hydrochloric acid of the title compound(10.5g).then it was converted to its free base form through partitioning between hexane (150 ml) and 20percent aqueous potassium hydroxide solution to give 8.3 g (61percent) of product.

10%

With sodium tris(acetoxy)borohydride In tetrahydrofuran; methanol at 25℃; for 18 h; Reflux; Inert atmosphere

To a solution of tert-butyl 2-(propan-2-ylidene)hydrazine-1-carboxylate (3.90 g, 22.7 mmol) in THF (22 mL) and MeOH (22 mL) was added NaBH(OAc)₃ (4.80 g, 22.7 mmol) portionwise. The resulted mixture was refluxed under N₂ balloon for 2 h and then cooled to 25° C. for 16 hours. The mixture was concentrated. The crude was purified by column chromatograph on silica gel (petroleum ether:ethyl acetate=4:1). The product was recrystallized by ethyl acetate and petroleum ether to give tert-butyl 2-isopropylhydrazine-1-carboxylate (400 mg, 2.30 mmol, 10percent yield). ¹H NMR (CDCl₃ 400 MHz): δ 6.67 (br. s, 1H), 5.99-5.98 (m, 1H), 3.54-3.48 (m, 1H), 1.51 (s, 9H), 1.26 (d, J=6.8 Hz, 6H).

Reference： [1] Polish Journal of Chemistry, 2002, vol. 76, # 12, p. 1693 - 1697
[2] Journal of the American Chemical Society, 2004, vol. 126, # 21, p. 6759 - 6764
[3] Patent: WO2014/140073, 2014, A1, . Location in patent: Page/Page column 24
[4] Chemistry - A European Journal, 2018, vol. 24, # 33, p. 8325 - 8330
[5] Patent: WO2004/56751, 2004, A1, . Location in patent: Page 18-19
[6] Organic and Biomolecular Chemistry, 2012, vol. 10, # 12, p. 2439 - 2446
[7] Patent: CN104628771, 2016, B, . Location in patent: Paragraph 0182-0184
[8] Patent: US2017/291901, 2017, A1, . Location in patent: Paragraph 0194; 0195; 0196
[9] Journal of the American Chemical Society, 1963, vol. 85, p. 4040 - 4041
[10] Journal of the Chemical Society. Perkin transactions 1, 1975, # 17, p. 1712 - 1720
[11] Journal of Organic Chemistry, 2013, vol. 78, # 8, p. 3541 - 3552
[12] Patent: US2015/191473, 2015, A1, . Location in patent: Paragraph 0236
[13] European Journal of Inorganic Chemistry, 2018, vol. 2018, # 3, p. 517 - 524
[14] New Journal of Chemistry, 2018, vol. 42, # 20, p. 17062 - 17072
[15] Patent: WO2007/135417, 2007, A1, . Location in patent: Page/Page column 54

[ 16689-34-2 ] Synthesis Path-Downstream 1~87

1
[ 16689-34-2 ]
[ 16689-35-3 ]

Yield	Reaction Conditions	Operation in experiment
77%	With bromocresol green; sodium cyanoborohydride; toluene-4-sulfonic acid; In tetrahydrofuran; at 20℃; for 2h;pH 3.5 - 5;	Alternatively, tert-Butyl 2-(propan-2-ylidene)hydrazinecarboxylate 2 (0.51 g, 3.0 mmol) was dissolved in 20 mL of THF, treated with NaBCN (0.19 g, 3.0 mmol) and a few mg of bromocresol green, followed by a solution of p-toluenesulfonic acid (0.57 g, 3.0 mmol) in 1.5 mL of THF which was added dropwise over approximately 1 h to maintain the reaction pH between 3.5-5.0. After stirring at room temperature for an additional hour, the solvent was removed by rotary evaporation, and the residue was partitioned between EtOAc (30 mL) and brine. The organic phase was extracted with sat. NaHCC>3, 20 mL and brine, evaporated to a residue and dissolved in 10 mL of ethanol. The ethanolic solution was treated with 3.6 mL of 1M NaOH solution (3.6 mmol) and left to stir at rt for 30 min. The solvent was removed by rotary evaporation and the residue was taken up into ethyl acetate and extracted with water. The organic layer was evaporated under reduced pressure and the residue was purified by column chromatography using 5 % MeOH in DCM as eluent to collect tert-butyl 2- isopropylhydrazinecarboxylate 3 (0.4 g, 77 % yield): mp = 47-49 C; Rf = 0.44 (5 % MeOH in DCM); IH NMR 300 MHz (CDC13) d 6.03 (s, N-H, IH), 3.92 (s, N-H, IH), 3.14 (m, IH), 1.46 (s, 9H), 1.02 (d, 6H, J = 6 Hz); 13C NMR 300 MHz (CDC13) d 157.2, 80.8, 51.2, 28.7, 21.0.
70%	With hydrogen;platinum on carbon; In methanol; at 20℃; for 1.75h;	To a solution of isopropylidine hydrazine (2.94 g, 17.1 MMOL) in MEOH at rt under argon was added 5% PT/C (290 mg). Hydrogen gas was bubbled through the black suspension for 15 min and then the reaction was left under an atmosphere of hydrogen for 1.5 h. After this time, the suspension was filtered and the collected solids were washed with ADDITIONAL MEOH. The combined filtrate and washings were concentrated under reduced pressure. The crude material that remained was then redissolved in EtOAc and washed with sat. NaHCO3. The organic layer was separated, washed with sat. NaCI, dried (MGS04), filtered and concentrated under reduced pressure. Purification by chromatography on silica eluting with 50% EtOAc/hexanes gave the title compound as colourless crystals (2.08 g, 70%). 1 H- NMR; delta (CDCI3), 6.34 (1H, s NHBoc), 3.50 (1H, br, NH) 3.13 (1H, sept, J=6.5Hz, CH (CH3) 2), 1.46 (9H, s, (CH3) 3), 1.02 (6H, d, J=6.5Hz, (CH3) 2CH). LRMS: +ve ion: 197 [M+23], 175 [M+1], 161.
61%	With lithium borohydride; chloro-trimethyl-silane; In tetrahydrofuran; at 20℃; for 2h;Inert atmosphere;	The title compound can be prepared by the method of Dutta et ( J . C:S Perkin /1975,1712-1720) Or from the following method: A mixture of 13.2 g (0.1 mol) of t-butyl carbazate and 6 g (0.103 mol) of acetone and 12.58 g (0.1 mol) of anhydrous magnesium sulfate in 100 ml of dichloromethane was stirred at room temperature for 12 hours. After removal of the desiccant by filtration, the filtrate was evaporated under reduced pressure and crystallized from cyclohexane to give 16.9 g of the corresponding hydrazone having a melting point of 104-105 C. intoo a suspension solution of 2.04 g (0.094 mol) of lithium borohydride in 100 ml of anhydrous tetrahydrofuran was added 12 ml (0.094 mol) of trimethylchlorosilane in a greenhouse under a nitrogen atmosphere. After 30 minutes at room temperature the 13.45 g (0.078 mol) of hydrazone was slowly added and stirring was continued for 2 hours. Then, 50 ml of methanol was carefully added and the mixture was evaporated to dryness under reduced pressure. The residue was partitioned between ether (150 ml) and water (50 ml). The organic phase was dried over anhydrous magnesium sulfate and filtered,the hydrogen chloride was dried through the filtrate and the resulting white solid was removed by filtration then washed with a portion of fresh ether and dried to give the Hydrochloric acid of the title compound(10.5g).then it was converted to its free base form through partitioning between hexane (150 ml) and 20% aqueous potassium hydroxide solution to give 8.3 g (61%) of product.

61%	With lithium borohydride; chloro-trimethyl-silane; In tetrahydrofuran; at 20℃; for 2h;Inert atmosphere; Green chemistry;	The title compound can be prepared by the method of Dutta et al. (J. C: S. Perkin/1975, 1712-1720) or by the following method:in room temperature,A mixture of 13.2 g (0.1 mol) of tert-butyl carbazate and 6 g (0.103 mol) of acetone and 12.5 g (0.1 mol) of anhydrous magnesium sulfate in 100 ml of dichloromethane was stirred for 12 hours.After removing the desiccant by filtration,The filtrate was evaporated under reduced pressure untilAfter crystallization from cyclohexane,Yielding 16.9 g (98% yield) of corresponding hydrazine,Its melting point is 104-105 C.Under the greenhouse in a nitrogen atmosphere,To a suspension of 2.04 g (0.094 mol) of lithium borohydride in 100 ml of anhydrous tetrahydrofuran was added 12 ml (0.094 mol) of trimethylchlorosilane.After 30 minutes,13.45 g (0.078 mol) of hydrazine was slowly added at room temperature.Stirring was continued for 2 hours.Then, carefully add 50 ml of methanol,And the mixture was evaporated to dryness under reduced pressure.The residue was partitioned between diethyl ether (150 ml) and water (50 ml).The organic phase was dried over anhydrous magnesium sulfate and filtered.Dry hydrogen chloride through the filtrate and remove the formed white solid by filtration.Wash with a portion of fresh ether.Drying gave (10.5 g) of the title compound.It was converted to its free base form by partitioning between hexane (150 ml) and 20% aqueous potassium hydroxide.8.3 g (61%) of product.
10%	With sodium tris(acetoxy)borohydride; In tetrahydrofuran; methanol; at 25℃; for 18h;Reflux; Inert atmosphere;	To a solution of tert-butyl 2-(propan-2-ylidene)hydrazine-1-carboxylate (3.90 g, 22.7 mmol) in THF (22 mL) and MeOH (22 mL) was added NaBH(OAc)3 (4.80 g, 22.7 mmol) portionwise. The resulted mixture was refluxed under N2 balloon for 2 h and then cooled to 25 C. for 16 hours. The mixture was concentrated. The crude was purified by column chromatograph on silica gel (petroleum ether:ethyl acetate=4:1). The product was recrystallized by ethyl acetate and petroleum ether to give tert-butyl 2-isopropylhydrazine-1-carboxylate (400 mg, 2.30 mmol, 10% yield). 1H NMR (CDCl3 400 MHz): delta 6.67 (br. s, 1H), 5.99-5.98 (m, 1H), 3.54-3.48 (m, 1H), 1.51 (s, 9H), 1.26 (d, J=6.8 Hz, 6H).
	With methanol; sodium cyanoborohydride; In tetrahydrofuran; for 0.166667h;Inert atmosphere; Reflux;	Step 2: Intermediate 44-c [0236] To a solution of intermediate 44-b (9.90 g, 57.5 mmol) in THF (57.5 mL) and MeOH (57.5 mL) was added sodium cyanoborohydride (4.34 g, 69.0 mmol) portion wise. The reaction was refluxed under nitrogen for 10 minutes, and then cooled to room temperature. 6N HCl (30 mL) was added, the mixture was refluxed for 3 hours, cooled to room temperature and stirred overnight. The reaction was filtered to remove inorganic insoluble material and the filtrate was concentrated under reduced pressure and azeotroped three times with toluene for complete water removal. The residue was dissolved in hot isopropanol, cooled to room temperature, diluted with ether and then cooled to 0 C. A precipitate formed and was collected by filtration to provide intermediate 44-c.HCl as a white solid.
		A mixture of tert-butylcarbazate (13.2g, lOOmmol), MgSO4 (19g) and HOAc (0.57mL, 9.99mmol) in acetone (30OmL) was heated at reflux for 8h. The solvent was evaporated and the residue was dissolved in EtOAc (20OmL). The organic phase was washed with 10% aqueous K2CO3 (15OmL), 10% aqueous KHSO4 (15OmL), brine (15OmL) and dried (MgSO4). Filtration and evaporation of the solvent gave a residue which was dissolved in 50% aqueous HOAc (30OmL) and treated with NaCNBH3 (9.43 g, 150mmol). The reaction mixture was stirred at ambient temperature for 2h. The solvent was evaporated and the residue was dissolved in EtOAc (20OmL), washed successively with 10% K2CO3 solution (15OmL), brine (15OmL) and dried (MgSO4). Filtration and evaporation of the solvent afforded the product (15.69g, 90%). 1H NMR (CDCl3) 6.05 (IH, br s), 3.87 (IH, br s), 3.17-3.09 (IH, m), 1.47 (9H, s), 1.04-1.02 (6H, m).

Reference： [1]Polish Journal of Chemistry,2002,vol. 76,p. 1693 - 1697
[2]Journal of the American Chemical Society,2004,vol. 126,p. 6759 - 6764
[3]Patent: WO2014/140073,2014,A1 .Location in patent: Page/Page column 24
[4]Chemistry - A European Journal,2018,vol. 24,p. 8325 - 8330
[5]ChemBioChem,2019,vol. 20,p. 241 - 246
[6]Patent: WO2004/56751,2004,A1 .Location in patent: Page 18-19
[7]Organic and Biomolecular Chemistry,2012,vol. 10,p. 2439 - 2446
[8]Patent: CN104628771,2016,B .Location in patent: Paragraph 0182-0184
[9]Patent: CN108997421,2018,A .Location in patent: Paragraph 0106
[10]Patent: US2017/291901,2017,A1 .Location in patent: Paragraph 0194; 0195; 0196
[11]Journal of the American Chemical Society,1963,vol. 85,p. 4040 - 4041
[12]Journal of the Chemical Society. Perkin transactions I,1975,p. 1712 - 1720
[13]Journal of Organic Chemistry,2013,vol. 78,p. 3541 - 3552
[14]Patent: US2015/191473,2015,A1 .Location in patent: Paragraph 0236
[15]European Journal of Inorganic Chemistry,2018,vol. 2018,p. 517 - 524
[16]New Journal of Chemistry,2018,vol. 42,p. 17062 - 17072
[17]Patent: WO2007/135417,2007,A1 .Location in patent: Page/Page column 54

2
[ 870-46-2 ]
[ 67-64-1 ]
[ 16689-34-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	for 4h; Heating;
100%	at 50℃;	B Boohydrazine (1a) (50 g, 0.385 mmoi) was dissolved in acetone (500 mL) and the reaction mixture was stirred at 50 0C overnight. Then, the solvent was removed under reduced pressure, and the residue was re-suspended in Et2O and filtered. A white precipitate was obtained with quantity yield
100%	at 60℃;	144.1; 153.1 Example 144: 4-chloro-N-(4-chlorophenyl)-3-methyl- 1-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide The solution of hydrazinecarboxylic acid tert-butyl ester (10 g, 75.6 mmol) in acetone was stirred at 60 °C overnight. The solvent was removed in vacuum to give N’-isopropylidene-hydrazinecarboxylic acid tertbutyl ester (13 g, yield: 100%) as a white solid.

100%	In diethyl ether at 20℃; for 24h;
99%	at 20℃; for 16h;	tert-butyl 2-(propan-2-ylidene)hydrazine-1-carboxylate A solution of tert-butyl hydrazinecarboxylate (3.0 g, 23 mmol) in acetone (20 mL) was stirred at 20° C. for 16 hours. The mixture was concentrated to give tert-butyl 2-(propan-2-ylidene)hydrazine-1-carboxylate (3.9 g, 23 mmol, 99% yield). 1H NMR (CDCl3 400 MHz): δ 7.33 (br. s, 1H), 2.02 (s, 3H), 1.80 (s, 3H), 1.50 (s, 9H).
98%	With magnesium sulfate; acetic acid at 56℃; for 1h; Inert atmosphere;
98%	With magnesium sulfate; acetic acid for 2.5h; Reflux;	1 Example 1 tert-butyl 2-(propan-2-ylidene)hydrazinecarboxylate 2 To a solution of tert-butyl hydrazinecarboxylate 1 (CAS Reg. No. 870-46-2) (25.1 g, 0.190 mol) in acetone (185 mL) was added the magnesium sulfate (6 g) and 12 drops acetic acid (Wu et al (2012) Jour. Med. Chem. 55(6):2724-2736; WO 2007/056170; Zawadzki et al (2003) Polish Jour. Chem. 77(3):315-319). The mixture was heated to reflux for 2.5 h and cooled to rt and filtered. The filtrate was concentrated to give tert-butyl 2-(propan-2- ylidene)hydrazinecarboxylate 2 (CAS Reg. No. 16689-34-2) as an off-white solid (32 g, 98%) (used in the next step without further purification). LC-MS [M+H]+ = 172.9, RT = 2.11 min. 1H NMR 300 MHz (CDC13) d 7.35 (br s, 1H, NH), 2.04 (s, 3H), 1.82 (s, 3H), 1.54 (s, 9H); 13C NMR 300 MHz (CDC13) d 152.9, 149.7, 80.7, 28.1, 25.3, 15.9.
98%	With magnesium sulfate; acetic acid for 0.25h; Reflux; Inert atmosphere;
98%	In toluene at 20℃; for 18h;
98%	With magnesium sulfate In dichloromethane at 20℃; for 12h;	1.A Step A: Preparation of tert-butyl 3-isopropylcarbazinate The title compound can be prepared by the method of Dutta et al. (J. C: S. Perkin/1975, 1712-1720) or by the following method:in room temperature,A mixture of 13.2 g (0.1 mol) of tert-butyl carbazate and 6 g (0.103 mol) of acetone and 12.5 g (0.1 mol) of anhydrous magnesium sulfate in 100 ml of dichloromethane was stirred for 12 hours.After removing the desiccant by filtration,The filtrate was evaporated under reduced pressure untilAfter crystallization from cyclohexane,Yielding 16.9 g (98% yield) of corresponding hydrazine,Its melting point is 104-105 ° C.Under the greenhouse in a nitrogen atmosphere,To a suspension of 2.04 g (0.094 mol) of lithium borohydride in 100 ml of anhydrous tetrahydrofuran was added 12 ml (0.094 mol) of trimethylchlorosilane.After 30 minutes,13.45 g (0.078 mol) of hydrazine was slowly added at room temperature.Stirring was continued for 2 hours.Then, carefully add 50 ml of methanol,And the mixture was evaporated to dryness under reduced pressure.The residue was partitioned between diethyl ether (150 ml) and water (50 ml).The organic phase was dried over anhydrous magnesium sulfate and filtered.Dry hydrogen chloride through the filtrate and remove the formed white solid by filtration.Wash with a portion of fresh ether.Drying gave (10.5 g) of the title compound.It was converted to its free base form by partitioning between hexane (150 ml) and 20% aqueous potassium hydroxide.8.3 g (61%) of product.
97%	With magnesium sulfate; acetic acid for 1h; Heating;
97%	In diethyl ether at 20℃; for 16h;
95%	With magnesium sulfate; acetic acid for 2h; Reflux;	22.a a) tert-Butyl ester of 2-isopropylidene-hydrazinecarboxylic acid (2); To a solution of Boc-hydrazine (4 g, 30.3 mmol, 1 eq.) in 55 mL of acetone are added 1.35 g of anhydrous MgSO4 and 4 drops of acetic acid. The mixture is refluxed for 2 hours. The magnesium sulfate is filtered off and the solvent is then evaporated off to give 4.96 g of a white solid (yield 95%).1H NMR 300 MHz (CDCl3): δ (ppm)=1.53 (s, 9H, COOC(CH3)3); 1.80 (s, 3H, CH3); 2.05 (s, 3H, CH3); 7.37 (s, 1H, NH).IR (KBr): νNH=3348 cm-1; νCsp3=2981 cm-1 and 2920 cm-1; νCO=1725 cm-1; νCN=1648 cm-1.Melting point: 87° C.
94%	With magnesium sulfate; acetic acid for 1h; Reflux;	4.1.24 1-(Pivaloyloxy)-2-(propan-2-ylidene) hydrazine (33) A suspension of t-butyl carbazate (1 g, 7.56 mmol) and magnesium sulfate (182 mg, 1.51 mmol) in anhydrous acetone (7.5 mL) with catalytic amount of acetic acid (18.4 mg, 0.36 mmol) was refluxed for 1 h. The reaction mixture was then cooled to rt and filtered. The organic filtrate was evaporated under reduced pressure to afford white crystalline solid 33 (1.23 mg, 7.14 mmol, yield 94%). 1H NMR (CDCl3) δ 1.41 (s, 9H), 1.74 (s, 3H), 1.93 (s, 3H), 7.51 (s, br, 1H).4.1.25
93%	In hexane Reflux;
92%	With magnesium sulfate; acetic acid for 1h; Heating / reflux;	78.1 Step 1: Hydrazinecarboxylic acid tert-butyl ester To a solution of tert-butyl carbazate (10.0 g, 75.6 mmol) in acetone (75 mL, 1.0 mol) was added anhydrous magnesium sulfate (~2.0 g) and 10 drops of glacial acetic acid. The solution was heated to reflux in a preheated oil bath (~85° C.) for 1 h. The solution was cooled to room temperature, filtered and concentrated in vacuo to provide hydrazine-carboxylic acid tert-butyl ester as a white solid (12.0 g, 92%). Mass spectrum: m/z: 173.3 (M+1).
92%	In hexane Inert atmosphere; Reflux;
92%	In diethyl ether at 20℃; for 12h;
92%	With magnesium sulfate; acetic acid at 70℃; for 2h;	2-tert-Butyl 2-(propan-2-ylidene)hydrazinecarboxylate (46b) To a solution of tert-butyl hydrazinecarboxylate (46a, 60.0 g, 454 mmol) in 96 mL of acetone wasadded magnesium sulfate (12.0 g, 100 mmol) and glacial acetic acid (96.0 mL, 12.5 g, 209 mmol).The resulting white suspension was heated to 70 °C for 2 h, cooled to room temperature andvacuum filtered through a medium fritted funnel. The filtrate was concentrated under reducedpressure and dried under high vacuum for 18 h to afford tert-butyl 2-(propan-2-ylidene)hydrazinecarboxylate (46b) as a white solid (75.0 g, 92%) that was suitable for usewithout further purification: 1H NMR (300 MHz, CDCl3) 7.39 (br s, 1H), 2.04 (s, 3H), 1.82 (s, 3H),1.51 (s, 9H).
89%	In toluene for 12h; Ambient temperature;
85%	With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 16h;	1.A Step A:; ISOPROPYLIDINE hydrazine To a solution of test-butyl carbazate (2.64 g, 20 MMOL) in THF (50 ML) at rt under argon was added acetone (1.61 ml, 22 MMOL) and sodium TRIACETOXYBOROHYDRIDE (4.45 g, 22 MMOL). The resulting suspension was stirred for 16 h. After this time the mixture was concentrated under reduced pressure and the crude product was partitioned between EtOAc and sat. NAHCO3. The organic layer was separated, washed with sat. NaCI, dried (MGSO4), filtered and concentrated under reduced pressure to give a pale yellow oil. This oil was purified by chromatography on silica eluting with 50% EtOAc/hexanes to give the title compound as a white solid (2.95 g, 85%). 1 H-NMR ; δ (CDCI3), 7.34 (1 H, s, NH), 2.04 (3H, s, CH3), 1.81 (3H, s, CH3), 1.51 (9H, S, (CH3) 3). LRMS: +ve ion: 195 [M+23], 117.
79%	With magnesium sulfate; acetic acid for 3.5h; Heating / reflux;	A.1 Step 1 : Preparation of fe/t-Butyl 2-isopropylidenehvdrazinecarboxylateTo a mechanically stirred solution of te/f-butylcarbazate (450 g, 3.4 mol) in acetone (2.5 L) was added magnesium sulfate (100 g, 0.83 mol) and 100 drops of acetic acid. The mixture was warmed to reflux and stirred for 3.5 h. After being cooled to rt, the mixture was filtered and partially concentrated, at which point the product crystallized from the supersaturated solvent. The crystals were filtered and dried in a vacuum oven overnight to provide the title compound as colorless needles (463 g, 79%): 1H NMR (300 MHz, Cf6-DMSO) δ 1.40 (s, 9H), 1.75 (s, 3H)1 1.83 (s, 3H).
79%	With acetic acid In methanol Reflux;
77%	at 20℃;
73%	at 20℃; for 12h;
	In tetrahydrofuran
	With magnesium sulfate for 1h; Reflux;	B.24.a To a solution of te/t-butylcarbazate (50.0 g, 378 mmol) in 40 mL acetone is added 1O g MgSO4 and 5 mL acetic acid and the reaction mixture is stirred at reflux temperature for I h. The reaction mixture is filtered and concentrated in vacuo. The residue is crystallized from diethyl ether/cyclohexane. Yield: 49.4 g.
	In ethanol
	at 20℃;	44; 1 Step 1: Intermediate 44-b Step 1: Intermediate 44-b tert-Butyl hydrazinecarboxylate (7.60 g, 57.5 mmol) was added to acetone (50 mL) and the reaction was stirred overnight at room temperature. Volatiles were removed under reduced pressure to provide intermediate 44-b as a white solid.
7.087 g	In hexane at 20℃; for 0.166667h;	P7 The mixture of tert-butyL carbazate (7.690 g, 58.20 mmol) and acetone (8.634 ml, 116.40 mmol) in hexane (50 ml) was stirred for 10 minutes at roomtemperature. Obtained aqueous Layer was separated, and organic layer was dried with sodium suLphate and concentrated to obtain 7.087 g of the intermediate compound (Schiff’s base). To this compound 1 .01 eq. of 1M borane solution in tetrahydrofuran were added to obtain a clear mixture. The whole was stirred at room temperature until cease of hydrogen evolution (10 minutes).Then 6 eq. of 6M HCI were added and the mixture was heated at reflux for 60 minutes. The whole was concentrated, obtained solid was washed with dioxane/tetrahydrofuran mixture and fiLtered. 3.770 g of the title product in the form of a white powder were obtained (yield 58.6%). 1H NMR (300MHz, DMSO-d6): δ 7.43 (s, broad, 3H), 3.30-3.12 (m, 1H), 1.16 (d, J = 6.5 Hz, 6H). 13C NMR (75 MHz, DMSO-d6): δ 52.42, 17.66.
1.23 g	With magnesium sulfate; acetic acid for 1h; Reflux;	9 1-(Pivaloyloxy)-2-(propan-2-ylidene) hydrazine (33). A suspension of f-butyl carbazate (1000 mg) and magnesium sulfate (182 mg) in anhydrous acetone (7.5 mL) with catalytic amount of acetic acid (18 mg) was refluxed for 1 h. The reaction mixture was then cooled to room temperature and filtered. Organic filtrate was evaporated under reduced pressure to afford white crystalline solid 33 (1.23 g).
	at 20℃;	1 Step 1: Intermediate 44-b Step 1: Intermediate 44-b [0235] tert-Butyl hydrazinecarboxylate (7.60 g, 57.5 mmol) was added to acetone (50 mL) and the reaction was stirred overnight at room temperature. Volatiles were removed under reduced pressure to provide intermediate 44-b as a white solid.
16.9 g	With magnesium sulfate In dichloromethane at 20℃; for 12h;	1.A Preparation of tert-butyl 3-isopropylhydrazinate The title compound can be prepared by the method of Dutta et ( J . C:S Perkin /1975,1712-1720) Or from the following method: A mixture of 13.2 g (0.1 mol) of t-butyl carbazate and 6 g (0.103 mol) of acetone and 12.58 g (0.1 mol) of anhydrous magnesium sulfate in 100 ml of dichloromethane was stirred at room temperature for 12 hours. After removal of the desiccant by filtration, the filtrate was evaporated under reduced pressure and crystallized from cyclohexane to give 16.9 g of the corresponding hydrazone having a melting point of 104-105 ° C. intoo a suspension solution of 2.04 g (0.094 mol) of lithium borohydride in 100 ml of anhydrous tetrahydrofuran was added 12 ml (0.094 mol) of trimethylchlorosilane in a greenhouse under a nitrogen atmosphere. After 30 minutes at room temperature the 13.45 g (0.078 mol) of hydrazone was slowly added and stirring was continued for 2 hours. Then, 50 ml of methanol was carefully added and the mixture was evaporated to dryness under reduced pressure. The residue was partitioned between ether (150 ml) and water (50 ml). The organic phase was dried over anhydrous magnesium sulfate and filtered,the hydrogen chloride was dried through the filtrate and the resulting white solid was removed by filtration then washed with a portion of fresh ether and dried to give the Hydrochloric acid of the title compound(10.5g).then it was converted to its free base form through partitioning between hexane (150 ml) and 20% aqueous potassium hydroxide solution to give 8.3 g (61%) of product.
	With acetic acid In tetrahydrofuran at 20℃; Inert atmosphere;
	Stage #1: t-butoxycarbonylhydrazine; acetone With magnesium sulfate; acetic acid for 8h; Heating / reflux; Stage #2: With potassium carbonate In water; ethyl acetate	1.b A mixture of tert-butylcarbazate (13.2g, lOOmmol), MgSO4 (19g) and HOAc (0.57mL, 9.99mmol) in acetone (30OmL) was heated at reflux for 8h. The solvent was evaporated and the residue was dissolved in EtOAc (20OmL). The organic phase was washed with 10% aqueous K2CO3 (15OmL), 10% aqueous KHSO4 (15OmL), brine (15OmL) and dried (MgSO4). Filtration and evaporation of the solvent gave a residue which was dissolved in 50% aqueous HOAc (30OmL) and treated with NaCNBH3 (9.43 g, 150mmol). The reaction mixture was stirred at ambient temperature for 2h. The solvent was evaporated and the residue was dissolved in EtOAc (20OmL), washed successively with 10% K2CO3 solution (15OmL), brine (15OmL) and dried (MgSO4). Filtration and evaporation of the solvent afforded the product (15.69g, 90%). 1H NMR (CDCl3) 6.05 (IH, br s), 3.87 (IH, br s), 3.17-3.09 (IH, m), 1.47 (9H, s), 1.04-1.02 (6H, m).
65.1 g	With magnesium sulfate; acetic acid for 2h; Reflux;	11.i Process (i): A mixture of compound I (50 g), acetic acid (0.4 mL), magnesium sulfate (10 g) and acetone (375 mL) was stirred with heating under reflux for 2 hours. The room temperature reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain compound II (65.1 g).

Reference： [1]Zawadzki; Zwierzak [Polish Journal of Chemistry, 2003, vol. 77, # 3, p. 315 - 319]
[2]Current Patent Assignee: LANTHEUS MI HOLDINGS INC - WO2010/118367, 2010, A2 Location in patent: Page/Page column 70
[3]Current Patent Assignee: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE - WO2016/123392, 2016, A2 Location in patent: Paragraph 00445; 00461
[4]Santos, Marilia S.; Nortcliffe, Andrew; Lewis, William; Bradshaw, Tracey D.; Moody, Christopher J. [Chemistry - A European Journal, 2018, vol. 24, # 33, p. 8325 - 8330]
[5]Current Patent Assignee: H. Lundbeck A/S; Juhl, Karsten; Jessing, Mikkel; Langgård, Morten; Vital, Paulo Jorge Vieira; Marigo, Mauro; Kehler, Jan; Rasmussen, Lars Kyhn - US2017/291901, 2017, A1 Location in patent: Paragraph 0191-0193
[6]Wu, Xiongyu; Öhrngren, Per; Joshi, Advait A.; Trejos, Alejandro; Persson, Magnus; Arvela, Riina K.; Wallberg, Hans; Vrang, Lotta; Rosenquist, Åsa; Samuelsson, Bertil B.; Unge, Johan; Larhed, Mats [Journal of Medicinal Chemistry, 2012, vol. 55, # 6, p. 2724 - 2736]
[7]Current Patent Assignee: ROCHE HOLDING AG - WO2014/140073, 2014, A1 Location in patent: Page/Page column 9; 23
[8]Chan, Chun-Ming; Zhou, Zhongyuan; Yu, Wing-Yiu [Advanced Synthesis and Catalysis, 2016, vol. 358, # 24, p. 4067 - 4074]
[9]Kumar, Varun; Shova, Sergiu; Maurel, Vincent; Novitchi, Ghenadie; Train, Cyrille [European Journal of Inorganic Chemistry, 2018, vol. 2018, # 3, p. 517 - 524]
[10]Current Patent Assignee: CHENGDU CHUANGPU BIO TECH - CN108997421, 2018, A Location in patent: Paragraph 0106
[11]Meyer, Kevin G. [Synlett, 2004, # 13, p. 2355 - 2356]
[12]Melendez, Rosa E.; Lubell, William D. [Journal of the American Chemical Society, 2004, vol. 126, # 21, p. 6759 - 6764]
[13]Current Patent Assignee: CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE; UNIVERSITY OF LYON - US2012/10161, 2012, A1 Location in patent: Page/Page column 19
[14]Purohit, Meena K.; Chakka, Sai Kumar; Scovell, Iain; Neschadim, Anton; Bello, Angelica M.; Salum, Norue; Katsman, Yulia; Bareau, Madeleine C.; Branch, Donald R.; Kotra, Lakshmi P. [Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 9, p. 2739 - 2752]
[15]Location in patent: experimental part Matveeva; Podrugina; Kolesnikova; Prisyazhnoi; Karateev; Zefirov [Russian Chemical Bulletin, 2010, vol. 59, # 2, p. 418 - 424]
[16]Current Patent Assignee: ROCHE HOLDING AG - US2007/225280, 2007, A1 Location in patent: Page/Page column 59
[17]Giampietro, Natalie C.; Wolfe, John P. [Journal of the American Chemical Society, 2008, vol. 130, p. 12907 - 12911]
[18]Yepremyan, Akop; Mehmood, Arshad; Asgari, Parham; Janesko, Benjamin G.; Simanek, Eric E. [ChemBioChem, 2019, vol. 20, # 2, p. 241 - 246]
[19]Barnes, Keith D.; Buckle, Ronald N.; Chen, Xinchao; Herr, R. Jason; Johnson, Graham; Lin, Juinn H.; Mayhew, Nicholas J.; Mobley, William C.; Nguyen, Phuong; Paquette, William D.; Rynearson, Kevin D.; Sakwa, Samuel A.; Tanzi, Rudolph E.; Wagner, Steven L.; Yang, Jinhai [Bioorganic and Medicinal Chemistry, 2020, vol. 28, # 22]
[20]Calabretta; Gallina; Giordano [Synthesis, 1991, # 7, p. 536 - 539]
[21]Current Patent Assignee: LIGAND PHARMACEUTICALS INC - WO2004/56751, 2004, A1 Location in patent: Page 18-19
[22]Current Patent Assignee: BAYER AG - WO2008/141731, 2008, A2 Location in patent: Page/Page column 63
[23]Clavette, Christian; Gan, Wei; Bongers, Amanda; Markiewicz, Thomas; Toderian, Amy B.; Gorelsky, Serge I.; Beauchemin, Andre M. [Journal of the American Chemical Society, 2012, vol. 134, # 39, p. 16111 - 16114,4]
[24]Wieczerzak; Kozlowska; Lankiewicz; Grzonka [Polish Journal of Chemistry, 2002, vol. 76, # 12, p. 1693 - 1697]
[25]Hui, Pramiti; Arif, Khaja Md.; Chandrasekar, Rajadurai [Organic and Biomolecular Chemistry, 2012, vol. 10, # 12, p. 2439 - 2446]
[26]Hess,H.-J. et al. [Journal of the American Chemical Society, 1963, vol. 85, p. 4040 - 4041]
[27]Dutta; Morley [Journal of the Chemical Society. Perkin transactions I, 1975, # 17, p. 1712 - 1720]
[28]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2009/112565, 2009, A1 Location in patent: Page/Page column 55
[29]Abo-Dya, Nader E.; Biswas, Suvendu; Basak, Akash; Avan, Ilker; Alamry, Khalid A.; Katritzky, Alan R. [Journal of Organic Chemistry, 2013, vol. 78, # 8, p. 3541 - 3552]
[30]Current Patent Assignee: GOSSAMER BIO INC - WO2013/177668, 2013, A1 Location in patent: Page/Page column 77
[31]Current Patent Assignee: CELON PHARMA SP. Z.O.O. - WO2014/16789, 2014, A1 Location in patent: Page/Page column 21; 22
[32]Current Patent Assignee: UNIVERSITY HEALTH NETWORK; CANADIAN BLOOD SERVICES - WO2014/138979, 2014, A1 Location in patent: Page/Page column 19
[33]Current Patent Assignee: GOSSAMER BIO INC - US2015/191473, 2015, A1 Location in patent: Paragraph 0235
[34]Current Patent Assignee: HESI XI AN BIOTECHNOLOGY - CN104628771, 2016, B Location in patent: Paragraph 0182-0184
[35]Bizet, Faustine; Tonali, Nicolo; Soulier, Jean-Louis; Oliva, Agostino; Kaffy, Julia; Crousse, Benoit; Ongeri, Sandrine [New Journal of Chemistry, 2018, vol. 42, # 20, p. 17062 - 17072]
[36]Current Patent Assignee: JAMES BLACK FOUNDATION; BLACK JAMES FOUNDATION - WO2007/135417, 2007, A1 Location in patent: Page/Page column 54
[37]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); Sumitomo Pharma (in: Sumitomo Chemical); SUMITOMO CHEMICAL COMPANY LIMITED - JP2015/129094, 2015, A Location in patent: Paragraph 0226-0228

3
[ 67-56-1 ]
[ 16689-34-2 ]
[ 154027-18-6 ]

Yield	Reaction Conditions	Operation in experiment
40%	With lead(IV) acetate at 0℃; for 2h;

Reference： [1]De Meijere, Armin; Kozhushkov, Sergei I.; Yufit, Dmitry S.; Boese, Roland; Haumann, Thomas; Pole, David L.; Sharma, Pradeep K.; Warkentin, John [Liebigs Annalen, 1996, # 4, p. 601 - 612]

Yield	Reaction Conditions	Operation in experiment
79%	With acetic acid In methanol Reflux;	1 General procedure: General procedure C (Berger, R.; Duff, K.; Leighton, J. L. J. Am. Chem. Soc. 2004, 126, 5686): To a round bottom flask were added the corresponding carbazate, ketone (2 equiv), methanol and a catalytic amount of AcOH (5-15 mol%). The reaction solution was refluxed overnight (10-14 h), then cooled to ambient temperature, concentrated under reduced pressure and purified by silica gel chromatography or direct recrystallization to give the corresponding products.
	Carbazinsaeure-tert-butylester, Aceton;

5
[ 109-65-9 ]
[ 16689-34-2 ]
[ 561067-09-2 ]

Yield	Reaction Conditions	Operation in experiment
86%	With tetrabutylammomium bromide; sodium hydride In tetrahydrofuran at 40 - 45℃; for 2h;

Reference： [1]Zawadzki; Zwierzak [Polish Journal of Chemistry, 2003, vol. 77, # 3, p. 315 - 319]

6
[ 74-96-4 ]
[ 16689-34-2 ]
[ 561067-07-0 ]

Yield	Reaction Conditions	Operation in experiment
93%	With tetrabutylammomium bromide; sodium hydride In tetrahydrofuran at 40 - 45℃; for 2h;
8.32 g	With potassium hydroxide; tetrabutylammonium bicarbonate In toluene at 50 - 80℃; for 2h;	1.1 Step 1: A mixture of t-butylcarbazate acetone hydrazine XII-5 (10.3 g), powdered KOH (4.4 g), tetrabutylammonium hydrogen carbonate (2.0 g) and 200 mL of toluene was stirred and warmed to 50 °C, at which temperature neat ethyl bromide (5.2 mL, 7.8 g) was added dropwise. When addition was complete, the reaction mixture was warmed to 80 °C for two hours, then cooled to room temperature and washed with water until the washings were neutral. The resulting toluene solution was dried over magnesium sulfate and evaporated at reduced pressure to give 12.5 g crude product as an oil. Chromatography (silica gel, cyclohexane-ethyl acetate gradient) provided 8.32 g of pure N-ethyl carbazate XIII-5 as an oil; 1H-NMR (CDCl3): δ = 1.1 (3H, triplet), 1.4 (9H, singlet), 1.8 (3H, singlet), 2.0 (3H, singlet), 3.6 (2H, quartet). Such compounds did not give M+1 peaks in the mass spectrometer used.

Reference： [1]Zawadzki; Zwierzak [Polish Journal of Chemistry, 2003, vol. 77, # 3, p. 315 - 319]
[2]Current Patent Assignee: BASF SE - EP2700634, 2014, A1 Location in patent: Paragraph 0258

7
[ 16689-34-2 ]
[ 100-39-0 ]
[ 561067-10-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	With tetrabutylammomium bromide; sodium hydride In tetrahydrofuran at 40 - 45℃; for 2h;
93%	With potassium hydroxide; tetra(n-butyl)ammonium hydrogensulfate In toluene at 80℃;

Reference： [1]Zawadzki; Zwierzak [Polish Journal of Chemistry, 2003, vol. 77, # 3, p. 315 - 319]
[2]Meyer, Kevin G. [Synlett, 2004, # 13, p. 2355 - 2356]

8
[ 16689-34-2 ]
[ 106-94-5 ]
[ 561067-08-1 ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium hydroxide; tetra(n-butyl)ammonium hydrogensulfate In toluene at 80℃;
80%	With tetrabutylammomium bromide; sodium hydride In tetrahydrofuran at 40 - 45℃; for 2h;
77%	With sodium hydroxide In toluene Reflux;	144.2 Example 144: 4-chloro-N-(4-chlorophenyl)-3-methyl- 1-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide To a solution of tert-butyl 2-(propan-2-ylidene)hydrazine-1-carboxylate (6.3 g, 36.6 mmol) in toluene (100 mL) was added 1-bromopropane (5.7 g, 47.2 mmol) and NaOH (2.2 g 54.9 mmol), it was then refluxed overnight. Resultant was concentrated to dryness and the cmde mixture was purified by flash column (EA in PE: 0 to 20%) directly to afford tert-butyl 2-(propan-2-ylidene)-1-propylhydrazine-1-carboxylate (6 g, yield: 77%) as white solid. ‘HNMR (300 MHz, DMSO-d6): = 3.35-3.32 (m, 2H), 1.96 (s, 3H), 1.77 (s, 3H), 1.37 (s, 11H), 0.82 (t,J= 7.5 Hz, 3H);

Reference： [1]Meyer, Kevin G. [Synlett, 2004, # 13, p. 2355 - 2356]
[2]Zawadzki; Zwierzak [Polish Journal of Chemistry, 2003, vol. 77, # 3, p. 315 - 319]
[3]Current Patent Assignee: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE - WO2016/123392, 2016, A2 Location in patent: Paragraph 00446

9
[ 16689-34-2 ]
[ 106-95-6 ]
[ 561067-11-6 ]

Yield	Reaction Conditions	Operation in experiment
79%	With tetrabutylammomium bromide; sodium hydride In tetrahydrofuran at 40 - 45℃; for 2h;

Reference： [1]Zawadzki; Zwierzak [Polish Journal of Chemistry, 2003, vol. 77, # 3, p. 315 - 319]

10
[ 762-49-2 ]
[ 16689-34-2 ]
[ 809282-56-2 ]

Yield	Reaction Conditions	Operation in experiment
93%	Stage #1: tert-butyl isopropylidenecarbazate With tetra(n-butyl)ammonium hydrogensulfate; potassium hydroxide In toluene at 50℃; for 0.166667h; Stage #2: 2-fluoroethyl bromide In toluene at 80℃; for 18h;	tert-Butyl 1-(2-fluoroethyl)-2-(propan-2-ylidene)hydrazinecarboxylate (46c) To a solution of tert-butyl 2-(propan-2-ylidene)hydrazinecarboxylate (46b, 28.3 g, 164 mmol) intoluene (540 mL) was added powdered potassium hydroxide (11.9 g, 213 mmol) andtetrabutylammonium hydrogen sulfate (5.56 g, 16.4 mmol). The mixture was vigorously stirred at50 °C for 10 minutes, then 2-fluoroethyl bromide (25 g, 196 mmol) was added in one portion, andthe resulting mixture stirred at 80 °C for 18 h. The resulting yellow suspension was cooled to roomtemperature, and water (1.2 L) was added. The organic layer was separated and dried oversodium sulfate, filtered and concentrated under reduced pressure. The residue was dried underhigh vacuum for 18 h to afford tert-butyl 1-(2-fluoroethyl)-2-(propan-2-ylidene)hydrazinecarboxylate (46c) as a yellow oil (33.3 g, 93%) that was suitable for use withoutfurther purification: 1H NMR (300 MHz, CDCl3) 4.48 (dt, J = 47.1, 5.1 Hz, 2H), 3.83 (dt, J = 25.5,5.1 Hz, 2H), 2.08 (s, 3H), 1.91 (s, 3H), 1.46 (s, 9H).
83%	With potassium hydroxide; tetra(n-butyl)ammonium hydrogensulfate In toluene at 80℃;

Reference： [1]Barnes, Keith D.; Buckle, Ronald N.; Chen, Xinchao; Herr, R. Jason; Johnson, Graham; Lin, Juinn H.; Mayhew, Nicholas J.; Mobley, William C.; Nguyen, Phuong; Paquette, William D.; Rynearson, Kevin D.; Sakwa, Samuel A.; Tanzi, Rudolph E.; Wagner, Steven L.; Yang, Jinhai [Bioorganic and Medicinal Chemistry, 2020, vol. 28, # 22]
[2]Meyer, Kevin G. [Synlett, 2004, # 13, p. 2355 - 2356]

11
[ 592-55-2 ]
[ 16689-34-2 ]
[ 809282-58-4 ]

Yield	Reaction Conditions	Operation in experiment
77%	With potassium hydroxide; tetra(n-butyl)ammonium hydrogensulfate In toluene at 80℃;

Reference： [1]Meyer, Kevin G. [Synlett, 2004, # 13, p. 2355 - 2356]

12
[ 16689-34-2 ]
[ 7051-34-5 ]
[ 809282-57-3 ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium hydroxide; tetra(n-butyl)ammonium hydrogensulfate In toluene at 80℃;
11.1 g	With potassium hydroxide; tetrabutylammonium bicarbonate In toluene at 50 - 80℃; for 3h;	2.1 Step 1: A mixture of t-butylcarbazate acetone hydrazone XII-18 (10.0 g), powdered KOH (4.24 g), tetrabutylammonium hydrogen carbonate (1.97 g) and 100 mL of toluene was stirred and warmed to 50 °C, at which temperature neat bromomethylcyclopropane (7.02 mL, 9.41 g) was added dropwise. When addition was complete, the reaction mixture was warmed to 80 °C for three hours, then cooled to room temperature and washed with water until the washings were neutral. The resulting toluene solution was dried over magnesium sulfate and evaporated at reduced pressure to give 11.1 g of the N-cyclopropylmethyl carbazate XIII-18; 1H-NMR (CDCl3): δ = 0.2 (2H, multiplet), 0.4 (2H, multiplet), 1.0 (1H, multiplet), 1.4 (9H, singlet), 1.9 (3H, singlet), 2.1 (3H, singlet), 3.3 (2H, doublet). Such compounds did not give M+1 peaks in the mass spectrometer used.

Reference： [1]Meyer, Kevin G. [Synlett, 2004, # 13, p. 2355 - 2356]
[2]Current Patent Assignee: BASF SE - EP2700635, 2014, A1 Location in patent: Paragraph 0221

13
[ 16689-34-2 ]
[ 106-96-7 ]
[ 809282-59-5 ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium hydroxide; tetra(n-butyl)ammonium hydrogensulfate In toluene at 80℃;

Reference： [1]Meyer, Kevin G. [Synlett, 2004, # 13, p. 2355 - 2356]

14
[ 36865-41-5 ]
[ 16689-34-2 ]
[ 950859-79-7 ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium hydroxide; tetra(n-butyl)ammonium hydrogensulfate In toluene at 50 - 80℃; for 3.75h;	78.2 Step 2: N'-Isopropylidene-N-(3-methoxypropyl)-hydrazinecarboxylic acid tert-butyl ester To a solution of hydrazinecarboxylic acid tert-butyl ester (4.67 g, 27.16 mmol) in toluene (90 mL) was added pulverized potassium hydroxide (1.98 g, 35.3 mmol) and tetrabutylammonium hydrogensulfate (904 mg, 2.72 mmol). The solution was heated to 50° C. in a preheated oil bath and 1-bromo-3-methoxypropane (3.67 mL, 32.6 mmol) was added drop-wise over 45 minutes. The solution was then heated to 80° C. for 3 h. The solution was cooled to room temperature and washed with water (3*150 mL) until the water layer was neutral. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to provide N'-isopropylidene-N-(3-methoxypropyl)-hydrazinecarboxylic acid tert-butyl ester as a viscous oil (6.49 g, 98%), which was used without further purification. Mass spectrum: m/z: 245.4 (M+1).
70%	With tetra-(n-butyl)ammonium iodide; potassium hydroxide at 60℃;	153.2 Example 153: 4-Chloro-1-(3-methoxypropyl)-3-methyl-1H-pyrazolo[3,4-b] pyridine-5-carboxylic acid (4-trifluoromethylphenyl)amide To a solution of N’-isopropylidene-hydrazinecarboxylic (7 g, 4i mmol) in THF (iOO mL) was added TBAI (i.5 g, 4 mmol), KOH (2.98 g, 53 mmol), i-bromo-3-methoxy-propane (6.885 g, 45 mmol). The mixture was then stirred at 60 oC overnight. The solvent was removed in vacuum. The resultant was added to water (50 mL) and the aqueous phase was extracted with EA (50 mL x3). The organic layer was washed with water (iOO mL x3) and dried over Na2SO4. The solvent was removed in vacuum. The resulting solid was purified by column chramatoghraphy (PE: EA i 0: i to 7: i). The solvent was removed in vacuum to afford N’isopropylidene-N-(3-methoxy-propyl)-hydrazinecarboxylic acid tert-butyl ester (7g, yield: 70%) as a yellow oil.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2007/225280, 2007, A1 Location in patent: Page/Page column 59
[2]Current Patent Assignee: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE - WO2016/123392, 2016, A2 Location in patent: Paragraph 00462

15
[ 24424-99-5 ]
[ 16689-34-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 78.1 percent / hydrazine monohydrate / propan-2-ol / 0.33 h / 20 °C 2: 97 percent / diethyl ether / 16 h / 20 °C

Reference： [1]Melendez, Rosa E.; Lubell, William D. [Journal of the American Chemical Society, 2004, vol. 126, # 21, p. 6759 - 6764]

16
[ 16689-34-2 ]
Boc-AzaVal-Gly-OH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 77 percent / NaBH₃CN; p-toluenesulfonic acid / tetrahydrofuran / 2 h / 20 °C / pH 3.5 - 5.0 2: 72 mg / diisopropylethylamine / CH₂Cl₂; toluene / 16 h / 20 °C 3: 93 percent / H₂ / Pd/C / ethanol / 0.5 h / 760 Torr

Reference： [1]Melendez, Rosa E.; Lubell, William D. [Journal of the American Chemical Society, 2004, vol. 126, # 21, p. 6759 - 6764]

17
[ 16689-34-2 ]
[ 714251-87-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 77 percent / NaBH₃CN; p-toluenesulfonic acid / tetrahydrofuran / 2 h / 20 °C / pH 3.5 - 5.0 2: 72 mg / diisopropylethylamine / CH₂Cl₂; toluene / 16 h / 20 °C

Reference： [1]Melendez, Rosa E.; Lubell, William D. [Journal of the American Chemical Society, 2004, vol. 126, # 21, p. 6759 - 6764]

18
[ 16689-34-2 ]
[ 561067-12-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 93 percent / NaH; tetrabutylammonium bromide / tetrahydrofuran / 2 h / 40 - 45 °C 2: 70 percent / LiAlH₄ / tetrahydrofuran / 5 h / Heating

Reference： [1]Zawadzki; Zwierzak [Polish Journal of Chemistry, 2003, vol. 77, # 3, p. 315 - 319]

19
[ 16689-34-2 ]
[ 561067-13-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 80 percent / NaH; tetrabutylammonium bromide / tetrahydrofuran / 2 h / 40 - 45 °C 2: 70 percent / LiAlH₄ / tetrahydrofuran / 5 h / Heating

Reference： [1]Zawadzki; Zwierzak [Polish Journal of Chemistry, 2003, vol. 77, # 3, p. 315 - 319]

20
[ 16689-34-2 ]
[ 561067-16-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 79 percent / NaH; tetrabutylammonium bromide / tetrahydrofuran / 2 h / 40 - 45 °C 2: 69 percent / LiAlH₄ / tetrahydrofuran / 5 h / Heating

Reference： [1]Zawadzki; Zwierzak [Polish Journal of Chemistry, 2003, vol. 77, # 3, p. 315 - 319]

21
[ 16689-34-2 ]
[ 561067-14-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 86 percent / NaH; tetrabutylammonium bromide / tetrahydrofuran / 2 h / 40 - 45 °C 2: 82 percent / LiAlH₄ / tetrahydrofuran / 5 h / Heating

Reference： [1]Zawadzki; Zwierzak [Polish Journal of Chemistry, 2003, vol. 77, # 3, p. 315 - 319]

22
[ 16689-34-2 ]
[ 561067-15-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 95 percent / NaH; tetrabutylammonium bromide / tetrahydrofuran / 2 h / 40 - 45 °C 2: 74 percent / LiAlH₄ / tetrahydrofuran / 5 h / Heating

Reference： [1]Zawadzki; Zwierzak [Polish Journal of Chemistry, 2003, vol. 77, # 3, p. 315 - 319]

23
[ 16689-34-2 ]
[ 57699-60-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 99 percent / NaBH₃CN; p-toluenesulfonic acid; bromocresol green / tetrahydrofuran / 4.5 h 2: 94 percent / Et₃N / ethyl acetate / 0 °C
	Multi-step reaction with 2 steps 1: H₂ / Pd-C / tetrahydrofuran 2: Et₃N / CHCl₃

Reference： [1]Wieczerzak; Kozlowska; Lankiewicz; Grzonka [Polish Journal of Chemistry, 2002, vol. 76, # 12, p. 1693 - 1697]
[2]Dutta; Morley [Journal of the Chemical Society. Perkin transactions I, 1975, # 17, p. 1712 - 1720]

24
[ 16689-34-2 ]
[ 57699-67-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: H₂ / Pd-C / tetrahydrofuran 2: aq. HCl / dioxane

Reference： [1]Dutta; Morley [Journal of the Chemical Society. Perkin transactions I, 1975, # 17, p. 1712 - 1720]

25
[ 16689-34-2 ]
[ 104-81-4 ]
[ 26177-51-5 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: tert-butyl isopropylidenecarbazate; 4-Methylbenzyl bromide With sodium hydride In acetonitrile at 80℃; Stage #2: With hydrogenchloride In ethanol; water; ethyl acetate	169 Example 169 The intermediate (1.76 g) obtained in Step 1 of Example 168, 4-methylbenzylbromide (1.85 g) and sodium hydride (300 mg) are stirred overnight in acetonitrile (30 ml) at 80C. Water is added and the mixture is extracted with ethyl acetate. After drying over sodium sulfate, the solvent is evaporated. The obtained residue is stirred overnight in 4 Mol hydrochloric acid-ethyl acetate solution (10 ml) at room temperature, and the solvent is evaporated. The obtained residue is dissolved in ethanol (20 ml) and conc. hydrochloric-acid (5 ml) is added. The mixture is stirred overnight at room temperature, concentrated to dryness and washed with ethyl acetate to give 4-methylbenzylhydrazine hydrochloride (1.9 g). A compound of Example 169 was synthesized according to a method similar to the method of Example 3 from the obtained hydrazine hydrochloride. MS (ESI) m/z 272(M+H)+

Reference： [1]Current Patent Assignee: AJINOMOTO COMPANY INC - EP1396493, 2004, A1 Location in patent: Page 43

26
[ 592-55-2 ]
[ 16689-34-2 ]
[ 475094-51-0 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-Bromoethyl ethyl ether; tert-butyl isopropylidenecarbazate With sodium hydride In acetonitrile at 80℃; Stage #2: With hydrogenchloride In ethanol; water; ethyl acetate at 20℃; Stage #3: With hydrogenchloride In ethanol; water at 20℃;	168.2 Step 2 The intermediate (0.86 g) obtained in Step 1, 2-bromoethyl ethyl ether (0.77 g) and sodium hydride (250 mg) are stirred overnight in acetonitrile (30 ml) at 80C. Water is added and the mixture is extracted with ethyl acetate. After drying over sodium sulfate, the solvent is evaporated. The obtained residue is stirred overnight in 4 Mol hydrochloric acid-ethyl acetate solution (10 ml) at room temperature, and the solvent is evaporated. The obtained residue is dissolved in ethanol (20 ml) and conc. hydrochloric acid (5 ml) is added. The mixture is stirred overnight at room temperature, concentrated to dryness and washed with ethyl acetate to give 2-ethoxyethylhydrazine hydrochloride (0.4 g). A compound of Example 168 was synthesized according to a method similar to the method of Example 3 from the obtained hydrazine hydrochloride. MS (ESI) m/z 239 (M+H) +

Reference： [1]Current Patent Assignee: AJINOMOTO COMPANY INC - EP1396493, 2004, A1 Location in patent: Page 42-43

27
[ 870-46-2 ]
[ 77-76-9 ]
[ 16689-34-2 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol	168.1 Example 168; Step 1 t-Butyl carbazate (2.6 g), 2,2-dimethoxypropane (3 ml) and a catalytic amount of acetic acid are stirred overnight in ethanol (20 ml), and the solution is concentrated to give an isopropylidene-protected compound (3.4 g) as a solid.

Reference： [1]Current Patent Assignee: AJINOMOTO COMPANY INC - EP1396493, 2004, A1 Location in patent: Page 42

28
[ 16689-34-2 ]
[ 64-19-7 ]
[ 1133463-25-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen	91 N-(4,5-Dihydro-1H-imidazol-2-ylmethyl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)aniline fumarate 1-Methylethylidene-2-tert-butoxycarbonylhydrazine, glacial acetic acid (150 mL) and 10% palladium on carbon (2.0 g) were placed in a 500 mL Parr flask. The bottle was placed on a Parr apparatus, and after evacuating and flushing the bottle with nitrogen three times, the flask was charged with hydrogen to 40 psi. After hydrogen uptake ceased, the flask was evacuated and flushed with nitrogen. Filtration through celite, eluding with ethyl acetate, and concentration afforded the crude 1-(isopropyl)-2-tert-butoxycarbonylhydrazine as an acetic acid salt.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - US6884801, 2005, B1 Location in patent: Page/Page column 34

29
[ 16689-34-2 ]
[ 104-81-4 ]
[ 1085453-43-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; tetra(n-butyl)ammonium hydrogensulfate In toluene at 50 - 80℃; for 3h;	A.2 Step 2: Preparation of fert-Butyl 2-isopropylidene-1-(4-methylbenzyl)hvdrazine- carboxylateTo a mechanically stirred solution of tert-butyl 2-isopropylidene-1-(4-methylbenzyl)- hydrazinecarboxylate (Step 1 , 77.6 g, 450 mmol) in toluene (1800 ml_) was added powdered potassium hydroxide (32.8 g, 585 mmol) and tetrabutylammonium hydrogen sulfate (15.3 g, 45 mmol). The mixture was stirred vigorously and was warmed to 500C, at which point p-methylbenzyl bromide (91.7 g, 495 mmol) was added portionwise. The mixture was further warmed to 800C and was stirred for 3 h. After being cooled to rt, the mixture was washed with water (3 * 500 ml.) and brine (1 * 500 mL), was dried (MgSO4), filtered and concentrated to a light yellow oil that was carried on without additional purification: 1H NMR (300 MHz, Cf6-DMSO) δ 1.38 (s, 9H), 1.65 (s, 3H), 1.89 (s, 3H), 2.25 (s, 3H) 4.49 (s, 2H), 7.09-7.11 (m, 4H).

Reference： [1]Current Patent Assignee: BAYER AG - WO2008/141731, 2008, A2 Location in patent: Page/Page column 63-64

30
[ 16689-34-2 ]
[ 1730-25-2 ]
[ 1064138-79-9 ]

Yield	Reaction Conditions	Operation in experiment
51%	In tetrahydrofuran at 0 - 20℃; Inert atmosphere;

Reference： [1]Giampietro, Natalie C.; Wolfe, John P. [Journal of the American Chemical Society, 2008, vol. 130, p. 12907 - 12911]

31
[ 16689-34-2 ]
[ 6482-24-2 ]
[ 1187368-94-0 ]

Yield	Reaction Conditions	Operation in experiment
	With tetra(n-butyl)ammonium hydrogensulfate; potassium hydroxide In toluene at 50 - 80℃;	B.24.b B-24a (5.0 g, 29.0 mmol) is dissolved in 70 mL toluene and potassium hydroxide (2.12 g, 37.7 mmol) and tetrabutylammonium hydrogensulfate (986 mg, 2.90 mmol) are added. The reaction mixture is heated to 50 0C and 2-bromoethyl methyl ether (3.23 mL, 34.8 mmol) is added. Next the reaction mixture is heated to 80 0C and stirred for 2 h. The reaction mixture is washed with water, the organic phase is dried on MgSO4 and concentrated in vacuo. Yield: 4.35 g.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2009/112565, 2009, A1 Location in patent: Page/Page column 55

32
[ 2567-14-8 ]
[ 16689-34-2 ]
[ 1072137-90-6 ]
[ 1072137-89-3 ]

Yield	Reaction Conditions	Operation in experiment
	With tetra(n-butyl)ammonium hydrogensulfate; potassium hydroxide In toluene at 50 - 80℃;	18.1 Production Example 18; (1) To a mixture of 1.3 g of N'-isopropylidenehydrazinecarboxylic acid tert-butyl ester (a compound described in Synlett (2004), 2355-2356), 0.44 g of potassium hydroxide, 0.20 g of tetrabutyl ammonium sulfate and 20 mL of toluene, 1.05 g of 1,1,3-trichloro-2-propene was added dropwise at 50°C. The reaction mixture was stirred at 80°C for 3.5 hours and 0.44 g of 1,1,3-trichloro-2-propene was further added, followed by stirring at 80°C for 1 hour. After cooling and adding water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to column chromatography to obtain 0.74 g of a mixture of N-(3,3-dichloro-2-propenyl)-N'-isopropylidenehydrazinecarboxylic acid tert-butyl ester and N-(3,3-dichloro-2-propenyl)hydrazinecarboxylic acid tert-butyl ester. N-(3,3-dichloro-2-propenyl)-N'-isopropylidenehydrazinecarboxylic acid tert-butyl ester 1H-NMR (CDCl3) δ: 1.47 (9H, s), 1.88 (3H, s), 2.07 (3H, s), 4.18 (2H, d, J=7Hz), 6.02 (1H, t, J=7Hz) N-(3,3-dichloro-2-propenyl)hydrazinecarboxylic acid tert-butyl ester 1H-NMR (CDCl3) δ: 1.48 (9H, s), 4.01 (2H, brs), 4.11 (2H, d, J=7Hz), 5.99 (1H, t, J=7Hz)

Reference： [1]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - EP2143721, 2010, A1 Location in patent: Page/Page column 136

33
[ 16689-34-2 ]
[ 103-63-9 ]
[ 1251463-81-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide In toluene at 80℃;	B (3a) (15 g, 0.087 mol) was dissolved in touene (150 mL); KOH powder 14.6 g (0.267 mol), 2.105 g (0.0087 mol) BTEA-HOSO3 (10 mol %) and R-ethyl bromide 19.3 g (0.104 rnol) were added. The reaction mixture was stirred at 80 0C overnight. The solids were removed by filtration, and the filtrate was washed twice with the same volume of cold water. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Intermediate 4a contained about 20% elimination by-product, but was used in the next step without further purification.

Reference： [1]Current Patent Assignee: LANTHEUS MI HOLDINGS INC - WO2010/118367, 2010, A2 Location in patent: Page/Page column 70

34
[ 16689-34-2 ]
[ 762-04-9 ]
[ 1260118-58-8 ]

Yield	Reaction Conditions	Operation in experiment
65%	With [tetra(tert-butyl)phthalocyanine]aluminum chloride at 80℃; for 11h; Inert atmosphere;

Reference： [1]Location in patent: experimental part Matveeva; Podrugina; Kolesnikova; Prisyazhnoi; Karateev; Zefirov [Russian Chemical Bulletin, 2010, vol. 59, # 2, p. 418 - 424]

35
[ 16689-34-2 ]
[ 5437-45-6 ]
[ 1236324-62-1 ]

Yield	Reaction Conditions	Operation in experiment
92%	Stage #1: tert-butyl isopropylidenecarbazate With sodium hydride In N,N-dimethyl-formamide; mineral oil Inert atmosphere; Stage #2: Benzyl bromoacetate In N,N-dimethyl-formamide; mineral oil for 1h;	22.b b) Benzyl (1-tert-butoxycarbonyl-2-isopropylidenehydrazino)-acetate (3); 4.9 g of compound (2) (28.5 mmol, 1 eq.) are dissolved in 60 mL of anhydrous DMF, under N2. 1.4 g of NaH (60% in mineral oil, 34 mmol, 1.2 eq.) are introduced portionwise. Evolution of gas and setting to a solid are observed. In 60 mL of anhydrous DMF and then 5 mL of benzyl bromoacetate (31.4 mmol, 1.1 eq.) are added slowly. The solution turns dark orange. After one hour, the excess NaH is hydrolyzed by slow addition of water. The solution is extracted with twice 90 mL of EtOAc. The organic phases are washed with 90 mL of water and then 90 mL of saturated NaCl solution, dried over anhydrous Na2SO4 and then evaporated. The residue is chromatographed on silica gel, eluting with an EtOAc/P.E. mixture (1/2 by volume), to give 8.4 g of a yellow oil (yield 92%).1H NMR 300 MHz (CDCl3): δ (ppm)=1.45 (s, 9H, COOC(CH3)3); 1.95 (s, 3H, CH3); 2.05 (s, 3H, CH3); 4.35 (s, 2H, N-CH2); 5.20 (s, 2H, CH2); 7.37 (m, 5H, Harom).IR (NaCl): νCsp2 Harom=3066 cm-1 and 3034 cm-1; νCsp3=2977 cm-1 and 2932 cm-1; νCO=1754 cm-1 and 1710 cm-1.

Reference： [1]Current Patent Assignee: CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE; UNIVERSITY OF LYON - US2012/10161, 2012, A1 Location in patent: Page/Page column 19

36
[ 16689-34-2 ]
[ 589-15-1 ]
[ 1365541-45-2 ]
[ 1365541-44-1 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: tert-butyl isopropylidenecarbazate With tetra(n-butyl)ammonium hydrogensulfate; potassium hydroxide In toluene at 50℃; for 0.333333h; Inert atmosphere; Stage #2: 1-bromomethyl-4-bromobenzene In toluene at 100℃; for 3h; Inert atmosphere;

Reference： [1]Wu, Xiongyu; Öhrngren, Per; Joshi, Advait A.; Trejos, Alejandro; Persson, Magnus; Arvela, Riina K.; Wallberg, Hans; Vrang, Lotta; Rosenquist, Åsa; Samuelsson, Bertil B.; Unge, Johan; Larhed, Mats [Journal of Medicinal Chemistry, 2012, vol. 55, # 6, p. 2724 - 2736]

37
[ 16689-34-2 ]
[ 589-15-1 ]
(4-bromobenzyl)hydrazine dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
4 g	Stage #1: tert-butyl isopropylidenecarbazate With tetra(n-butyl)ammonium hydrogensulfate; potassium hydroxide In toluene at 50℃; for 0.333333h; Inert atmosphere; Stage #2: 1-bromomethyl-4-bromobenzene In toluene at 100℃; for 3h; Inert atmosphere; Stage #3: With hydrogenchloride; water In tetrahydrofuran; toluene at 68℃; for 3h; Inert atmosphere;

38
[ 498-66-8 ]
[ 16689-34-2 ]
(±)-exo-2-(propan-2-ylidene)-4-oxo-2,3-diazatricyclo[4,3,1⁶'⁹,0]decane-2-ium-3-ide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	at 150℃; for 3h; Sealed tube; Microwave irradiation;

Reference： [1]Clavette, Christian; Gan, Wei; Bongers, Amanda; Markiewicz, Thomas; Toderian, Amy B.; Gorelsky, Serge I.; Beauchemin, Andre M. [Journal of the American Chemical Society, 2012, vol. 134, # 39, p. 16111 - 16114,4]

39
[ 16689-34-2 ]
[ 1429433-22-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: acetic acid; sodium cyanoborohydride / tetrahydrofuran 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C