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Structure of Boc-DL-Ala-OH
CAS No.: 3744-87-4

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Synonyms: tert-Butoxycarbonyl-DL-alanine

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Quality Control of [ 3744-87-4 ] Purity: 95% SDS Specification

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Product Details of [ 3744-87-4 ]

CAS No. :	3744-87-4
Formula :	C₈H₁₅NO₄
M.W :	189.21
SMILES Code :	CC(OC(NC(C(O)=O)C)=O)(C)C
Synonyms :	tert-Butoxycarbonyl-DL-alanine
English Name :	Boc-DL-Ala-OH
MDL No. :	MFCD00063124
InChI Key :	QVHJQCGUWFKTSE-UHFFFAOYSA-N
Pubchem ID :	268471

Safety of [ 3744-87-4 ]

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Computational Chemistry of [ 3744-87-4 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	0
Fraction Csp3	0.75
Num. rotatable bonds	5
Num. H-bond acceptors	4.0
Num. H-bond donors	2.0
Molar Refractivity	46.86
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	75.63 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.79
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	0.92
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.98
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.51
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-0.17
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.81

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.26
Solubility	10.3 mg/ml ; 0.0546 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.09
Solubility	1.52 mg/ml ; 0.00805 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-0.64
Solubility	43.0 mg/ml ; 0.228 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.8 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.56

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.54

Application In Synthesis of [ 3744-87-4 ]

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

Downstream synthetic route of [ 3744-87-4 ]

[ 3744-87-4 ] Synthesis Path-Downstream 1~32

1
[ 6066-82-6 ]
[ 3744-87-4 ]
[ 34404-33-6 ]

Yield	Reaction Conditions	Operation in experiment
	With dicyclohexyl-carbodiimide; at 0℃;	General procedure: The general scheme for the synthesis of AA-CAMderivatives is shown in Fig. S1 and the details ofchemical synthesis are provided in the SupplementaryMethods section. CAM [(1R,2R)-2-amino-1-(4--nitrophenyl)propane-1,3-diol)] was prepared asdescribed previously [23]. Amino acids with protectedalpha- and side-chain amino groups wereactivated by reaction with N-hydroxysuccinimide inthe presence of N,N?-dicyclohexylcarbodiimide at0 C. The resulting succinimide-reactive esters wereused for the acylation of CAM in the presence ofdiisopropylethylamine as a base at room temperature.Subsequent deprotection was achieved bytreatment of the obtained amino-acid CAM derivativeswith trifluoroacetic acid and appropriate scavengers.Synthesized AA-CAM derivatives were purifiedby columnchromatography on silica gel using suitablesystems of solvents. For generating N-acetylatedvariants of AA-CAM, additional acetylation wasperformed by reacting the unprotected AA-CAMderivatives with the N-acetylsuccinimide. Purity andchemical structures of obtained compounds wereconfirmed by HPLC, LC-MS, and NMR spectroscopy(see Supplementary Methods).

References: [1]Journal of the Chemical Society. Chemical communications,1987,p. 1155 - 1156.
[2]Journal of the American Chemical Society,1996,vol. 118,p. 6975 - 6985.
[3]Journal of Molecular Biology,2018,vol. 430,p. 842 - 852.

2
[ 3744-87-4 ]
[ 74-88-4 ]
[ 91103-47-8 ]

Yield	Reaction Conditions	Operation in experiment
96%		Intermediate 57 Boc-D-AlaOMe Boc-D-AlaOH (10.0 g, 52.9 mmol) was dissolved in dry DMF (60 mL), then potassium carbonate (8.0 g, 58.0 mmol) was added, the mixture was stirred at rt for 15 min, and methyl iodide (6.58 mL, 106.0 mmol) was added dropwise. The stirring was maintained for 18h. Then, the mixture was concentrated in vacuo and the residue was dissolved in EtOAc (lOOmL). The organic layer was washed with water, brine, dried over MgSCU, filtered and concentrated. The crude product was purified by flash column chromatography (silica gel, DCM/MeOH 0 to 1%) to give 10.36 g (51.0 mmol, 96% yield) of the title compound. *Eta NMR (DMSO-d6) delta 7.46 (1H, d), 4.35 (1H, m), 3.66 (3H, s), 1.30 (9H, s), 1.18 (3H, d).
82%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	Example 452-tert-Butoxycarbonylamino-propionic acid methyl ester Boc-D-Ala-OH (4.0 g, 21 mmol) and potassium carbonate (11.7 g, 84.6 mmol) was dissolved in dimethylformamide (90 mL) and iodomethane (1.6 mL, 25 mmol) was added to the reaction mixture. The reaction was allowed to stir at room temperature. overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with portions of water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound as a colorless oil (3.53 g, 82%).1H NMR (300 MHz, CDCl3): delta (ppm) 5.14 (broad s, 1 h), 4.33 (broad s, 1H), 3.51 (s, 3H), 1.49 (s, 9H).

References: [1]Patent: WO2016/8946,2016,A1 .Location in patent: Page/Page column 72-73.
[2]Patent: US2007/259860,2007,A1 .Location in patent: Page/Page column 34.
[3]Journal of Organic Chemistry,1987,vol. 52,p. 1252 - 1255.
[4]Angewandte Chemie - International Edition,2012,vol. 51,p. 5239 - 5243.

3
[ 4530-20-5 ]
[ 6404-26-8 ]
[ 3744-87-4 ]
[ 55297-72-8 ]
Boc-Ala-OH [ No CAS ]
[ 76491-51-5 ]

References: [1]Collection of Czechoslovak Chemical Communications,1980,vol. 45,p. 1424 - 1446.

4
[ 4530-20-5 ]
[ 6404-26-8 ]
[ 3744-87-4 ]
[ 55297-72-8 ]
Boc-Ala-OH [ No CAS ]
[ 76491-50-4 ]

References: [1]Collection of Czechoslovak Chemical Communications,1980,vol. 45,p. 1424 - 1446.

5
[ 3744-87-4 ]
[ 6638-79-5 ]
[ 342603-65-0 ]

Yield	Reaction Conditions	Operation in experiment
98%	With Carbonyldiimidazole; triethylamine In dichloromethane
96%	With triethylamine; diethyl dicarbonate In dichloromethane at 20℃;
95%	With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine In dichloromethane at 0 - 20℃; for 24h;

95%	With N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine In dichloromethane at 0 - 20℃;	38 tert- butyl 1-carboxypropan-2-ylcarbamate (3.8 g, 20.0 mmol, 1.0 equiv. ) and N, O-dimethylhydroxyl amine-HCl (2.6 g, 26.1 mmol, 1. 33 equiv. ) were added to a 250 mL RBF followed by CH2Cl2 (100 mL). The mixture was cooled to 0 °C via an ice bath and TEA was added (4.7 mL, 33.4 mmol, 1.7 equiv. ). Next, EDC (4.6 g, 24.0 mmol, 1.2 equiv. ) and DMAP (240 mg, 2.0 mmol, 0.1 equiv. ) were added as solids and the solution warmed to rt gradually overnight. After stirring a total of 24 h the reaction solution was transferred to a separatory funnel with CH2Cl2 (100 mL). The mixture was washed with 1% HCl (2 x 50 mL), sat. NaHCO3 (1 x 50 mL), and sat. NaCl (1 x 50 mL). The organic layer was dried over Na2S04, concentrated on a rotary evaporator, and dried under vacuum to give 4.4 g (95%) of 39 as a white solid. mp = 150- 151 °C ; IR (KBr) 3296,2975, 1705,1660, 1541,1296, 1184 cm-1; 1H NMR (500 MHz, CDC13) 6 5.30 (br s, 1H, carbamate-N_), 4.73 (br s, 1H, Boc-NH- CH), 3.78 (s, 3H, N-OCH3), 3.19 (s, 3H, N-CH3), 1.44 (s, 9H, Boc-t-butyl- CH3), 1.31 (d, J= 6.5 Hz, 3H, CH-CH3) ; 13C NMR (125 MHz, CDCl3) 8 173. 8, 155.3, 79.6, 61.7, 46.6, 32.2, 28.5, 18.8 ; LRMS (ESI-MS 7n/z) : Mass calcd for CioH2oN2Na04Si [M+Na+], 232.28. Found 233. Spectroscopic data were consistent with the literature data for this compound.
95%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere;
94%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 25℃; for 12h;	33a; 33b; 33c; 33d; 35a; 35b; 35c; 35d; 40a; 40b; 40c; 40d; 41a; 41b; 41c; 41d; 46a; 46b; 46c; 46d; 47a; 47b; 47c; 47d; 48a; 48b; 48c; 48d (+/-)-tert-Butyl (1 -(methoxy(methyl)amino)- 1 -oxopropan-2-yl)carbamate N,O-dimethylhydroxylamine hydrochloride (38.7 g, 396.39 mmol) was added to (+/-)-2- ((tert-butoxycarbonyl)amino)propanoic acid (50 g, 264.26 mmol), HATU (111 g, 290.68mmol) and DIEA (138 mL, 792.77 mmol) in DMF (150 mL) at 25 °C under air. Theresulting mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated and diluted with EtOAc (1 L), and washed sequentially with water (200 mL) and saturated brine (600 mL). The organic layer was dried over Na2SO4, filtered and evaporated toafford crude product. The crude product was purified by flash silica chromatography,elution gradient 0 to 25% THF in petroleum ether. Pure fractions were evaporated todryness to afford (+/-)-tert-butyl (1 -(methoxy(methyl)amino)- 1 -oxopropan-2-yl)carbamate (58 g, 94 %) as a white solid. mlz (ES+), [M+H]+ = 233.
81%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0 - 20℃;
75%	Stage #1: N-t-butyloxycarbonyl-DL-alanine With 4-methyl-morpholine; 2-Chloro-4,6-dimethoxy-s-triazine In tetrahydrofuran at 20℃; for 1h; Stage #2: N,O-dimethylhydroxylamine*hydrochloride In tetrahydrofuran at 20℃; for 16h; Further stages.;
72%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide for 12.0833h;	^-(te/^-ButoxycarbonylJ-^-methoxy-^-methylalaninamide (Starting Material 6)To a solution of Boc-[DL]-Ala-Oη (25 g, 132 mmol) and N-methoxyl-N-methylamine hydrochloride salt (19.32 g, 198 mmol) in dry DMF (250 mL) was added DIPEA (117 mL, 673 mmol) under N2 atm. The resulting solution was stirred for 5 min and treated with HATU (60.2 g, 158.5 mmol). The reaction mixture was stirred for 12 h. Filtration of the reaction mixture gave crude amide that was purified by flash chromatography on silica gel. Yield: 22.1 g (72%).. 1H NMR (300 MHz, CDCl3) δ: 5.26-5.23 (m, IH), 4.66-4.63 (m, IH), 3.7 (s, 3H), 3.13 (s, 3H), 1.41 (s, 9H), 1.29 (d, J= 7.4 Hz, 3H). (M+l)/Z = 233.1.
70%	Stage #1: N-t-butyloxycarbonyl-DL-alanine With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 25℃; for 0.166667h; Stage #2: N,O-dimethylhydroxylamine*hydrochloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃; for 5h;	bor. 5: tert-butyl N-[1-methyl-2-oxo-2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y1)-2-pyridyl] ethyl] carbamate To a solution of 2-(tert-butoxycarbonylamino) propanoic acid 11.1 (10 g, 53 mmol,1.0 equiv) in DMF (100 mL) was added HATU (25 g, 66 mmol, 1.2 equiv), the reactionmixture was stirred at 25 for 10 min. Then the mixture was added DIEA (19 g, 0.14 mol,25 mL, 2.7 equiv) and N-methoxymethanamine (6.0 g, 62 mmol, 1.2 equiv, HCI). Themixture was stirred at 25 °C for another 5 h. The reaction mixture was extracted with EtOAc(400 mL) and H2O (300 mL). The combined organic layers were washed with saturatedaqueous NH4Cl (300 mL), saturated aqueous NaHCO3 (300 mL) and brine (300 mL), driedover Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified byflash chromatography (80 g column, Eluent of 0~50% EtOAc/PE gradient at 100 mL/min) togive tert-butyl N-[2-[methoxy(methyl)amino]-1-methyl-2-oxo-ethyl] carbamate 11.2 (9.0 g,37 mmol, 70% yield, 95% purity) as a white solid.
42%	With sodium hydrogencarbonate; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide for 48h; Under nitrogen;	13.A Preparation of 2-(2,4-Difluorophenyl)-4-(2-methylsulfanylethyl)-oxazole-5-carboxylic acid [1-methyl-2-(4-pyrimidin-2-yl-piperazin-1-yl)-ethyl]-amide (A) 2-t-butoxycarbonylamino-propionic acid (25 g, 132 mmole) was dissolved in dimethylformamide (DMF, 300 ml). N,O-dimethylhydroxylamine HCl (12.9 g, 132 mmol) was added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (26.6 g, 139.0 mmol), HOBT (17.8 g, 132 mmol), and NaHCO3 (44.4 g, 528 mmol). The reaction mixture was stirred under nitrogen for 48 h. The solution was then filtered, and the solvent evaporated under reduced pressure. The residue was dissolved in CH2Cl2 and washed with 2% aqueous HCl, saturated aqueous NaHCO3, and water. The organic layers were dried over sodium sulfate and evaporated under reduced pressure to provide [1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (intermediate XIIIa, 12.84 g, 42%). M+=233.
	With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine In chloroform at 0 - 20℃;
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at -5℃; for 1h;
	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In dichloromethane at 0℃; for 1h;
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 25℃; for 16h;	The first step At 0 °C, N-methoxymethylamine hydrochloride (8.83 g, 90.57 mmol) was added into a solution of the compound 6a (15.58 g, 82.34 mmol), HATU (32.87 g, 86.46 mmol) and diisopropylethylamine (22.35 g, 172.91 mmol) in 200 mL dichloromethane. The reaction mixture obtained was stirred at 25 °C for 16hrs. After completion of the reaction, 200 mL water was added into the reaction mixture, and the pH of the mixture was adjusted to 14 with 1 N aqueous sodium hydrochloride solution, then extracted with dichloromethane (200 mLx2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, the crude product was purified by silica gel column (PE/EtOAc = 100-0%) to give the compound 6b. 1H NMR (400MHz, CDCl3) δ 5.25 (s, 1H), 4.69 (s, 1H), 3.78 (s, 3H), 3.22 (s, 3H), 1.45 (s, 9H), 1.32 (d, J = 8.0 Hz, 3H).
	With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 0 - 25℃;	1.1 Step 1: 0°C to compound a (15.58g, 82.34mmol),HATU (32.87g, 86.45mmol) and diisopropylethylamine (22.35g, 172.92mmol)Add N-methoxymethylamine hydrochloride (8.83g, 90.57mmol) to 200mL of dichloromethane solution,The resulting reaction was warmed to 25°C and stirring was continued for 16 hours.Add 200mL water to the reaction solution after the reaction finishes,The pH was adjusted to 14 with 1N aqueous sodium hydroxide solution, extracted with dichloromethane (200 mL×2),The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated,The crude product was purified by silica gel column (petroleum ether/ethyl acetate=100-0%) to obtain compound b.
	With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 0 - 25℃;	1.1 Step 1: 0°C to compound a (15.58g, 82.34mmol),HATU (32.87g, 86.45mmol) and diisopropylethylamine (22.35g, 172.92mmol)Add N-methoxymethylamine hydrochloride (8.83g, 90.57mmol) to 200mL of dichloromethane solution,The resulting reaction was warmed to 25°C and stirring was continued for 16 hours.Add 200mL water to the reaction solution after the reaction finishes,The pH was adjusted to 14 with 1N aqueous sodium hydroxide solution, extracted with dichloromethane (200 mL×2),The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated,The crude product was purified by silica gel column (petroleum ether/ethyl acetate=100-0%) to obtain compound b.
98 %	Stage #1: N-t-butyloxycarbonyl-DL-alanine; N,O-dimethylhydroxylamine*hydrochloride With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 0 - 25℃; Inert atmosphere; Stage #2: Inert atmosphere;	1f.A Example 1f: Synthesis of (4R)-2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2 -fluorotetrahydro- 1H-pyrTohzin-7a(5H)-yl)methoxy)-4-(6-methylhexahydropyrrolo[3,4-b]pyrrol-l(2H)-yl)quinazolin-7-yl)-7-fluorobenzo [b] thiophene -3 -carbonitrile (121). Step A: N-methoxymethylamine hydrochloride (5.60 g, 57.73 mmol) was added at 0 °C to a solution of 6-1 (10.00 g, 52.91 mmol), HATU (21.11 g, 55.55 mmol) and diisopropylethylamine (20 mL) in 200 mL dichloromethane. The resulting mixture was stirred at 25 °C for 16 h, then 200 mL water was added and the pH of the mixture adjusted to 14 with 1 N aqueous sodium hydroxide solution. The product was extracted with dichloromethane (200 mL x 2) and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (PE/EtOAc = 100-0%) to give 6-2 (12 g, yield: 98%) as a white solid. ESI-MS m/z: (M+H)+= 233.2.

References: [1]Location in patent: scheme or table Cheung; Kuntz; Pobanz; Salovich; Wilson; Andrews III; Shewchuk; Epperly; Hassler; Leesnitzer; Smith; Smith; Lansing; Mook Jr. [Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 23, p. 6214 - 6217].
[2]Gomtsyan; Koenig; Lee [Journal of Organic Chemistry, 2001, vol. 66, # 10, p. 3613 - 3616].
[3]Myers, Michael C.; Wang, JinLing; Iera, Jaclyn A.; Bang, Jeong-Kyu; Saito, Shin'ichi; Hara, Toshiaki; Zambetti, Gerard P.; Appella, Daniel H. [Journal of the American Chemical Society, 2005, vol. 127, # 17, p. 6152 - 6153].
[4]Current Patent Assignee: NORTHWESTERN UNIVERSITY ILLINOIS - WO2005/42481, 2005, A2 Location in patent: Page/Page column 44.
[5]Zhang, Chenhao; Gao, Anthony Z.; Nie, Xin; Ye, Chen-Xi; Ivlev, Sergei I.; Chen, Shuming; Meggers, Eric [Journal of the American Chemical Society, 2021, vol. 143, # 33, p. 13393 - 13400].
[6]Current Patent Assignee: ASTRAZENECA - WO2016/162325, 2016, A1 Location in patent: Page/Page column 200.
[7]Fujimoto, Jun; Okamoto, Rei; Noguchi, Naoyoshi; Hara, Ryoma; Masada, Shinichi; Kawamoto, Tetsuji; Nagase, Hiroki; Tamura, Yumiko Okano; Imanishi, Mitsuaki; Takagahara, Shuichi; Kubo, Kazuki; Tohyama, Kimio; Iida, Koichi; Andou, Tomohiro; Miyahisa, Ikuo; Matsui, Junji; Hayashi, Ryouta; Maekawa, Tsuyoshi; Matsunaga, Nobuyuki [Journal of Medicinal Chemistry, 2017, vol. 60, # 21, p. 8963 - 8981].
[8]Gibson, Colin L.; Kennedy, Alan R.; Morthala, Raghavendar R.; Parkinson, John A.; Suckling, Colin J. [Tetrahedron, 2008, vol. 64, # 32, p. 7619 - 7625].
[9]Current Patent Assignee: ASTRAZENECA - WO2007/129019, 2007, A1 Location in patent: Page/Page column 60.
[10]Current Patent Assignee: DEWPOINT THERAPEUTICS - WO2025/147600, 2025, A1 Location in patent: Paragraph 0165.
[11]Current Patent Assignee: ROCHE PALO ALTO - US2007/37974, 2007, A1 Location in patent: Page/Page column 13.
[12]Location in patent: scheme or table Kameda, Minoru; Kobayashi, Kensuke; Ito, Hirokatsu; Miyazoe, Hiroshi; Tsujino, Toshiaki; Nakama, Chisato; Kawamoto, Hiroshi; Ando, Makoto; Ito, Sayaka; Suzuki, Tomoki; Kanno, Tetsuya; Tanaka, Takeshi; Tahara, Yoshio; Tani, Takeshi; Tanaka, Sachiko; Tokita, Shigeru; Sato, Nagaaki [Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4325 - 4329].
[13]Barluenga, Jose; Escribano, Maria; Aznar, Fernando; Valde, Carlos [Angewandte Chemie - International Edition, 2010, vol. 49, # 38, p. 6856 - 6859].
[14]Nguyen, T. Vu; Minrovic, Bradley M.; Melander, Roberta J.; Melander, Christian [ChemMedChem, 2019, vol. 14, # 9, p. 927 - 937].
[15]Current Patent Assignee: CHINA RESOURCES PHARMACEUTICAL HOLDINGS - EP3656772, 2020, A1 Location in patent: Paragraph 0111; 0112; 0113.
[16]Current Patent Assignee: CHINA MEDICINE RESEARCH AND DEVELOPMENT CENTER - CN115724846, 2023, A Location in patent: Paragraph 0111-0114.
[17]Current Patent Assignee: CHINA MEDICINE RESEARCH AND DEVELOPMENT CENTER - CN115724846, 2023, A Location in patent: Paragraph 0111-0114.
[18]Current Patent Assignee: KUMQUAT BIOSCIENCES - WO2024/138052, 2024, A1 Location in patent: Paragraph 231; 274-275.

6
[ 186581-53-3 ]
[ 3744-87-4 ]
[ 91103-47-8 ]

References: [1]Tetrahedron Letters,2002,vol. 43,p. 9691 - 9693.

7
[ 3744-87-4 ]
[ 1479-58-9 ]
(R)-{1-[4-bromo-2-(2-fluoro-benzoyl)-phenylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester [ No CAS ]
[ 2387-23-7 ]

Yield	Reaction Conditions	Operation in experiment
77%	With dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 8.5h;	{1-[4-Bromo-2-(2-fluorobenzoyl)-phenylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester 136; To a stirred solution of (2-amino-5-bromophenyl)-(2'-fluoro-phenyl)-methanone 115 (60 g, 204 mmol) and the N-Boc-D-alanine 129 (38.59 g, 204 mmol) in CH2Cl2 (500 mL) was added dicyclohexylcarbodiimide (DCC) (42.09 g, 204 mmol) in CH2Cl2 (200 mL) dropwise, over a 30 min period at 0° C. The reaction mixture was allowed to stir an additional 8 h at rt. The dicyclohexyl urea which formed was filtered off and the filtrate concentrated under reduced pressure. The crude solid product 136 was purified by recrystallization from hexane and EtoAc to afford 136 (73 g, 77percent). mp 158-159° C.; IR (KBr, cm-1) 3332, 2931, 255, 1694, 1643, 1613, 1582, 1537, 1450; 1H NMR (CDCl3) delta 11.68 (s, 1H), 8.71 (d, J=9.0 Hz, 1H), 7.69 (dd, J=9.0, 2.3 Hz, 1H), 7.55-7.62 (m, 2H), 7.46 (td, J=7.6, 1.4 Hz, 1H), 7.30 (t, J=7.5 Hz, 1H), 7.21 (t, J=9.1 Hz, 1H), 5.13 (b, 1H), 4.37 (b, 1H), 1.51 (d, J=7.2 Hz, 3H), 1.45 (S, 9H). MS (EI) m/e (relative intensity) 467 (M++2, 14), 466 (M++1, 44), 465 (M+, 14), 464 (42), 329 (15), 321 (60), 295 (100), 224 (26); [alpha]26D=59.6 (c 0.51, EtOAc).

References: [1]Patent: US2006/3995,2006,A1 .Location in patent: Page/Page column 65-66.

8
[ 3744-87-4 ]
[ 17664-93-6 ]
[ 1207335-46-3 ]

References: [1]Helvetica Chimica Acta,2009,vol. 92,p. 2698 - 2721.

9
[ 3744-87-4 ]
[ 1117-97-1 ]
[ 87694-49-3 ]
[ 146553-06-2 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-[(1-cyano-2-ethoxy-2-oxoethylideneaminooxy)-morpholinomethylene]dimethylammonium hexafluorophosphate.; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; for 2.83333h; Inert atmosphere; optical yield given as %ee;	(L)-N-tert-butyoxycarbonyl-(N'-methoxy-N'-methyl)alaninamide (5) General procedure: A mixture of DMF (120 mL) containing N,O-dimethylhydroxylamine hydrochloride (1.56 g, 0.016 mol) and redistilled diisopropylethylamine (6.16 g, 0.0477 mol) were cooled to 0 °C in an ice-bath under a nitrogen atmosphere. To the mixture was added alanine (3 g, 0.0159 mol) followed by COMU (0.016 mol). The solution immediately turned yellow and the solution was left stirring in the ice-bath for a further 20 min. The ice-bath was removed and the reaction mixture was allowed to reach ambient temperature. After about 2 h the colour of the reaction mixture became orange and stirring was continued for a further 30 min. The solution was diluted with H2O (200 mL) and extracted with Et2O (3 × 100 mL). The combined organic fractions were washed with dilute HCl (1 M) (20 mL), saturated Na2CO3 solution (3 × 20 mL) and finally a saturated brine solution (20 mL). The organic layer was dried over anhydrous MgSO4, filtered in vacuo and the solvent removed at the pump to afford the title compound as a white crystalline solid 2.32 g, 63%. Mp 147.2-148.6 °C, lit. 148-153 °C;25 [α]D -26, c 1, (MeOH), lit. [α]D -26, c 1, (MeOH);25 HRMS (EI, M+) calcd for C10H21O4N2 233.1496, found 233.1497; 1H NMR (CDCl3, 400 MHz) δ 5.18 (1H, br s, N-H), 4.62 (1H, br s, C-H), 3.70 (3H, s, O-CH3), 3.14 (3H, s, CH3), 1.37 (9H, s, CH3), 1.24 (3H, d J = 7.03 Hz, CH3); 13C (CDCl3 101 MHz) δ 18.69, 28.36, 32.16, 46.52, 61.61, 79.50. 155.12,26 173.69.2724 HPLC was determined using a (Chiralcel-OD-H column) with a Waters 996 photodiode array diode detector. Measurements were made at 230 nm at a flow rate of 0.5 ml/min. Solvent, hexane/IPA (98:2).

References: [1]Location in patent: experimental part Tyrrell, Elizabeth; Brawn, Peter; Carew, Mark; Greenwood, Iain [Tetrahedron Letters, 2011, vol. 52, # 3, p. 369 - 372].

10
[ 3744-87-4 ]
[ 74-88-4 ]
[ 13734-31-1 ]

References: [1]British Journal of Pharmacology,2016,p. 2657 - 2668.
[2]Helvetica Chimica Acta,2012,vol. 95,p. 973 - 982.

11
Fmoc-D-allo-MeIle-OH [ No CAS ]
[ 3744-87-4 ]
[ 35661-60-0 ]
[ 109425-51-6 ]
[ 104091-08-9 ]
C₅₄H₇₃N₇O₁₀ [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 7739 - 7741.

12
[ 3744-87-4 ]
[ 13130-79-5 ]
[ 1452573-04-4 ]

Yield	Reaction Conditions	Operation in experiment
94%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl acetamide; at 20℃; for 72h;	HATU (7.5 g, 19.7 mmol) is added to a mixture of l-bromoisoquinolin-3-amine (2.0 g, 9.0 mmol), 2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid (1.7 g, 9.0 mmol) and DIPEA (3.4 ml, 200 mmol) in DMA (10 ml). After stirring for 3 days at RT the mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 3.3 g (94%). HPLC-MS: M-H=392/394; tR=1.97 min (*Method_l).
94%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl acetamide; at 20℃; for 72h;	B4a) tert-butyl-N-[1-[(1-bromoisoquinolin-3-yl)amino]-1-oxopropan-2-yl]carbamate HATU (7.5 g, 19.7 mmol) is added to a mixture of <strong>[13130-79-5]1-bromoisoquinolin-3-amine</strong> (2.0 g, 9.0 mmol), 2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid (1.7 g, 9.0 mmol) and DIPEA (3.4 ml, 200 mmol) in DMA (10 ml). After stirring for 3 days at RT the mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 3.3 g (94%). HPLC-MS: M-H=392/394; tR=1.97 min (*Method-1).

References: [1]Patent: WO2013/127729,2013,A1 .Location in patent: Page/Page column 50; 51.
[2]Patent: US2013/225567,2013,A1 .Location in patent: Paragraph 0253; 0254.

13
[ 3744-87-4 ]
[ 1408076-36-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: triethylamine / tetrahydrofuran / 0.25 h / -15 - 0 °C 1.2: 3 h / 20 °C 2.1: triethylamine; rhodium(II) acetate / dichloromethane / 1 h / 0 °C
	Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine; isobutyl chloroformate / tetrahydrofuran / 4 h / 0 °C 1.2: 8 h / 0 - 250 °C 2.1: triethylamine; dirhodium tetraacetate / dichloromethane / 1 h / 0 °C
	Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 3 h / 0 °C 1.2: 19 h / 0 - 20 °C 2.1: triethylamine; dirhodium tetraacetate / dichloromethane / 16 h / 0 - 20 °C

References: [1]Current Patent Assignee: SHANGHAI PHARMATECHS - US2014/206663, 2014, A1.
[2]Current Patent Assignee: NANJING MINGDE NEW DRUG RESEARCH AND DEVELOPMENT - EP3567030, 2019, A1.
[3]Current Patent Assignee: BLACKSMITH MEDICINES - WO2024/36176, 2024, A1.

14
[ 3744-87-4 ]
[ 18107-18-1 ]
[ 91103-47-8 ]

References: [1]MedChemComm,2015,vol. 6,p. 300 - 305.

15
[ 3744-87-4 ]
[ 97682-44-5 ]
camptothecin [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 2690 - 2693.

16
[ 13734-41-3 ]
[ 13139-15-6 ]
[ 15761-38-3 ]
[ 3744-87-4 ]
[ 15260-10-3 ]
[ 13836-37-8 ]
C₁₀₆H₁₅₇ClN₁₉O₂₃PolS [ No CAS ]
[ 73821-95-1 ]
[ 18942-49-9 ]
[ 73821-97-3 ]
[ 6404-28-0 ]
[ 108-24-7 ]
[ 55260-24-7 ]
Boc-C^αMeLeu-OH [ No CAS ]
[ 25024-53-7 ]
cyclo(30−33)[D-Phe¹², Nle^21,38,D-Ala^27,40,Glu³⁰,Lys³³]-acetyl-{human/rat corticotropin releasing factor}(9−41) [ No CAS ]