Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:33])[C:13](=[O:32])[N:14]([C:15]4[C:16]([CH3:31])=[N:17][N:18]([CH2:21][CH2:22][O:23][Si](C(C)(C)C)(C)C)[C:19]=4[CH3:20])[C:5]=3[C:4]=2[CH:3]=1.[CH2:34]([NH:36][C:37]1[C:38]([CH3:52])=[N:39][CH:40]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:42]=1)[CH3:35]>>[CH2:34]([NH:36][C:37]1[CH:42]=[C:41]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:33])[C:13](=[O:32])[N:14]([C:15]5[C:16]([CH3:31])=[N:17][N:18]([CH2:21][CH2:22][OH:23])[C:19]=5[CH3:20])[C:5]=4[C:4]=3[CH:3]=2)[CH:40]=[N:39][C:38]=1[CH3:52])[CH3:35]
Reactant: CCNc1cc(B2OC(C)(C)C(C)(C)O2)cnc1C
Reactant: Cc1nn(CCO[Si](C)(C)C(C)(C)C)c(C)c1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CCNc1cc(-c2ccc3ncc4c(c3c2)n(-c2c(C)nn(CCO)c2C)c(=O)n4C)cnc1C

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-Bromo-1-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3,5-dimethyl-1H-pyrazol-4-yl}-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (stage 210.1.1) and ethyl-[2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine (Stage 87.1.1) to give the title compound as an off-white solid; deprotection of the silyl group occurred during the purification step. (HPLC: tR 2.16 min (Method A); M+H=472 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.96 (s, 1H), 8.10-8.06 (m, 1H), 7.94-7.90 (m, 1H), 7.85-7.82 (m, 1H), 7.55-7.52 (m, 1H), 6.83-6.80 (m, 1H), 5.21 (t, 1H), 4.92 (t, 1H), 4.21-4.03 (m, 2H), 3.81-3.67 (m, 2H), 3.59 (s, 3H), 3.24-3.14 (m, 2H), 2.32 (s, 3H), 2.09 (s, 3H), 1.94 (s, 3H), 1.24 (t, 3H))
Reaction SMILES: [CH2:1]([P:3]([OH:5])[OH:4])[CH3:2].[C:6]([O:9][CH:10]=[CH2:11])(=[O:8])[CH3:7].[O-]S(OOS([O-])(=O)=O)(=O)=O.[Na+].[Na+]>O>[CH2:1]([P:3]([CH2:11][CH2:10][O:9][C:6](=[O:8])[CH3:7])(=[O:5])[OH:4])[CH3:2]
Reactant: CCP(O)O
Reactant: C=COC(C)=O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCP(=O)(O)CCOC(C)=O
Temperature: 100 °C
Yield: 94.9 %

Procedure:
564 g (6 mol) of ethylphosphonous acid are dissolved in 860 g of water and initially charged to a 5 l five-neck flask equipped with thermometer, reflux condenser, high-performance stirrer and dropping funnel. After heating the reaction mixture to 100° C., 602 g (7 mol) of vinyl acetate and 500 g of a 5% strength sodium peroxodisulfate solution (1.5 mol % based on vinyl acetate) are added dropwise at atmospheric pressure over 1 h. The water is then distilled off in vacuo. The residue is taken up in tetrahydrofuran and the insoluble salts are filtered off. The solvent of the filtrate is removed in vacuo. Chromatographic purification leaves 1026 g (95% of theory) of ethyl(2-acetoxyethyl)phosphinic acid being obtained as oil.
Reaction SMILES: [OH:1][CH:2]([C:9]1[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=1)[C:3]#[C:4][C:5]([O:7][CH3:8])=[O:6]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:16][S:15][C:12]1[CH:11]=[CH:10][C:9]([C:2]([C:3]#[C:4][C:5]([O:7][CH3:8])=[O:6])=[O:1])=[CH:14][CH:13]=1
Reactant: COC(=O)C#CC(O)c1ccc(SC)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COC(=O)C#CC(=O)c1ccc(SC)cc1
Reaction time: 2 h

Procedure:
A solution of 11.6 g (49 mmol) of methyl 4-hydroxy-4-[4-(methylthio)phenyl]-2-butynoate in 300 ml of methylene chloride was added dropwise at 0° to a suspension of 124 g (1.42 mol) of manganese dioxide in 300 ml of methylene chloride. The reaction mixture was stirred at 0° for 2 hours filtered over magnesium sulphate and concentrated. Crystallization of the residue from ether/hexane yielded methyl 3-[4-(methylthio)benzoyl]propiolate of melting point 74°-76°.
Reaction SMILES: [OH:1][CH:2]1[C@@H:7]2[CH2:8][C@@H:4]([CH2:5][N:6]2[C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH2:3]1.CCN(CC)CC.S(=O)(=O)=O.N1C=CC=CC=1.CS(C)=O>C(Cl)Cl>[O:1]=[C:2]1[C@H:7]2[CH2:8][C@H:4]([CH2:5][N:6]2[C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH2:3]1
Reactant: N#Cc1ccc(N2C[C@H]3CC(O)[C@@H]2C3)cc1
Agent: O=S(=O)=O
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: N#Cc1ccc(N2C[C@@H]3CC(=O)[C@H]2C3)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To a round bottom flask was added 4-((1S,4R)-6-hydroxy-2-azabicyclo[2.2.1]heptan-2-yl)benzonitrile (329 mg, 1.535 mmol), Et3N (777 mg, 7.68 mmol) and CH2Cl2 (7.2 ml). The resulting solution was cooled to 0° C. In a separate vial, pyridine sulfur trioxide (1.22 gm, 7.68 mmol) and DMSO (2.4 gm, 30.7 mmol) were mixed until the solution turned clear. The resulting solution was then added to the reaction at 0° C. The reaction mixture was slowly warmed to rt and stirred for an additional 1 hr. After this time, the solution was diluted with CH2Cl2. The resulting solution was wash with water (2×) and saturated aqueous NaCl. The organic layer was separated, dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give product 4-((1R,4S)-6-oxo-2-azabicyclo[2.2.1]heptan-2-yl)benzonitrile (281 mg, 1.324 mmol, 86% yield) as colorless oil. Anal. Calcd. for C13H12N2O m/z 212.2, found: 213.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([C:11]1[CH:22]=[C:21]([CH3:23])[C:14]([O:15][CH2:16][C:17]([O:19]C)=[O:18])=[C:13]([CH3:24])[CH:12]=1)([C:7]([F:10])([F:9])[F:8])[C:3]([F:6])([F:5])[F:4].[OH-].[Na+]>C(O)C>[NH2:1][C:2]([C:11]1[CH:22]=[C:21]([CH3:23])[C:14]([O:15][CH2:16][C:17]([OH:19])=[O:18])=[C:13]([CH3:24])[CH:12]=1)([C:3]([F:6])([F:5])[F:4])[C:7]([F:10])([F:9])[F:8]
Reactant: COC(=O)COc1c(C)cc(C(N)(C(F)(F)F)C(F)(F)F)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(N)(C(F)(F)F)C(F)(F)F)cc(C)c1OCC(=O)O

Procedure:
Combine methyl 2-[4-(2-aminohexafluoro-2-propyl)-2,6-dimethylphenoxy]acetate (7.2 g=20 mmol) with 150 ml ethanol and 30 ml 1.0 N sodium hydroxide. Reflux 30 minutes and concentrate. Add 30 ml 1 N HCl and extract with ether. Dry and concentrate the ether. Sublime at 130° C./0.1 mm pressure to obtain as a while solid, 2-[4-(2-aminohexafluoro-2-propyl)-2,6-dimethylphenoxy]acetic acid, m.p. 138° C.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:23])[C:6]1[CH:11]=[C:10]([N:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH3:13])[N:9]=[C:8]([NH:18][C@H:19]([CH2:21][CH3:22])[CH3:20])[CH:7]=1>C1COCC1>[C@@H:19]([NH:18][C:8]1[CH:7]=[C:6]([CH:11]=[C:10]([N:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH3:13])[N:9]=1)[C:5]([OH:23])=[O:4])([CH2:21][CH3:22])[CH3:20]
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(N(C)S(C)(=O)=O)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC[C@H](C)Nc1cc(C(=O)O)cc(N(C)S(C)(=O)=O)n1
Reaction time: 2 h
Yield: 95.2 %

Procedure:
Add 1 N lithium hydroxide (19.5 mL, 19.5 mmol) to a solution of (S)-2-sec-butylamino-6-(methanesulfonyl-methylamino)-isonicotinic acid methyl ester (2.45 g, 7.77 mmol) in THF (10 mL) at 0° C. After 2 h at room temperature, acidify the mixture to about pH=2 and concentrate. Extract the residue with ethyl acetate (3×40 mL), wash the combined extracts with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound as a yellow solid (2.23 g, 95%).
Reaction SMILES: [C:1]([NH:6][CH2:7][C:8]([OH:10])=O)(=[O:5])[C:2]([CH3:4])=[CH2:3].Cl.[NH2:12][C:13]1[C:18]([OH:19])=[C:17]([Cl:20])[C:16]([CH3:21])=[C:15]([Cl:22])[CH:14]=1.N1C=CC=CC=1.S(Cl)(Cl)=O>O.C(OCC)(=O)C>[C:1]([NH:6][CH2:7][C:8]([NH:12][C:13]1[C:18]([OH:19])=[C:17]([Cl:20])[C:16]([CH3:21])=[C:15]([Cl:22])[CH:14]=1)=[O:10])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: Cc1c(Cl)cc(N)c(O)c1Cl
Reactant: C=C(C)C(=O)NCC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: C=C(C)C(=O)NCC(=O)Nc1cc(Cl)c(C)c(Cl)c1O
Yield: 54.9 %

Procedure:
To mixture composed of 68 g (0.48 mol) of N-methacryloyl glycine obtained in the above described manner and 46 g (0.2 mol) of 6-amino-2,4-dichloro-3-methylphenol hydrochloride were added 114 ml (1.44 mol) of pyridine and 1 liter of ethyl acetate and stirred under cooling. To the solution was added dropwise 29 ml (0.4 mol) of thionyl chloride. After the completion of the reaction, 300 ml of water was added to the reaction solution and extracted with ethyl acetate. The ethyl acetate solution was concentrated and to the residue was added acetonitrile. The crystals thus deposited were collected and recrystallized from acetonitrile to obtain 34.8 g of Monomer Coupler (2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])(C)([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OC(C)C)=O.C1(C)C=CC=CC=1>FC(F)(F)C(O)=O.ClCCl.O1CCCC1>[CH:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1
Agent: CC(C)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 60.9 %

Procedure:
A solution of 4-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 59; 400 mg, 0.84 mmol) in a mixture of trifluoroacetic acid (3 mL) and dichloromethane (7 mL) was stirred at room temperature for 45 min. The solvents were evaporated and the residue was co-evaporated three times with dichloromethane, dried under high vacuum, and then diluted with 1M aqueous sodium carbonate solution. The mixture was extracted twice with dichloromethane and twice with 10% methanol/chloroform. The combined organic layers were dried (sodium sulfate) and evaporated. A solution of the residue in tetrahydrofuran (6 mL) and triethylamine (0.23 mL, 1.65 mmol) was cooled to −20° C. under nitrogen and a solution of isopropyl chloroformate in toluene (1 M; 0.8 mL, 0.8 mmol) was added. The mixture was stirred at −10° C. to −20° C. for 45 min, then allowed to reach room temperature, and then filtered through a Millipore filter. The filter was washed with tetrahydrofuran and ethyl acetate and the combined filtrate and washings were evaporated. The crude material was purified on a flash silica column (30 mm×4″) eluting with 75-83% ethyl acetate/hexanes to give 4-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl ester (235 mg, 61%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.20 (d, 6H, J=6.3 Hz), 1.92-2.04 (m, 4H), 2.98-3.12 (m, 2H), 3.28-3.30 (m, methyl sulfone and water peak), 4.07-4.15 (m, 2H), 4.75-4.84 (m, 1H), 4.96-5.05 (m, 1H), 7.60-7.63 (m, 2H), 8.02-8.05 (m, 2H), 8.37 (s, 1H), 8.55 (s, 1H). Mass spectrum (ES) MH+=460.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH:17]([OH:18])[CH2:16][O:15][C:13]1=[O:14])C1C=CC=CC=1>C(O)C.C(O)(=O)C.[Pd]>[OH:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH:17]([OH:18])[CH2:16][O:15][C:13]1=[O:14]
Reactant: O=C1OCC(O)C1CCCOCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C1OCC(O)C1CCCO

Procedure:
A solution of 18.7 g of 2-(3-benzyloxypropyl)-3-hydroxy-γ-butyrolactone in 90 ml of ethanol-acetic acid (2:1) is hydrogenated over 640 mg of 10% palladium on carbon at 45 psi for 20 h. The catalyst is filtered and the filtrates are evaporated to give 2-(3-hydroxypropyl)-3-hydroxy-γ-butyrolactone as an oil.
Reaction SMILES: CC(OC([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][CH2:11][CH2:12][N:13]=[C:14]([NH:16][N+:17]([O-:19])=[O:18])[NH2:15])=O)(C)C.[Cl:23][C:24](OCC(C)C)=O.CN1CCOCC1.[ClH:38].C(O)C>O1CCCC1>[NH2:8][C@H:9]([C:20]([CH2:24][Cl:23])=[O:22])[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[NH:15])[NH:16][N+:17]([O-:19])=[O:18].[ClH:38]
Reactant: CC(C)COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN=C(N)N[N+](=O)[O-])C(=O)O
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CCO
Product: N=C(NCCC[C@H](N)C(=O)CCl)N[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Boc Arg(NO2)OH (5.0 g, 15.6 mmol) was dissolved in 60 ml of tetrahydrofuran (THF) and was allowed to react with isobutyl chloroformate (2.06 ml, 15.6 mmol) in the presence of N-methylmorpholine (1.72 ml, 15.6 mmol) for 10 min at -20° C. The mixed anhydride preparation was filtered, and the filtrate was added to 120 ml of ethereal diazomethane. After stirring the reaction solution for 30 min at 0° C., 80 ml of ether was added. The product crystallized from the reaction solution in the cold. The Boc-Arg(HO2)CHNH2 product was dissolved in a minimum volume of THF and was allowed to react with ethanol HCl (20 mmol) at room temperature until nitrogen evolution ceased.
Reaction SMILES: O[CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][C:4]([O:6]C(C)(C)C)=[O:5].[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[CH2:42][SH:43])[C:36]([OH:38])=[O:37].FC(F)(F)C(O)=O>C(Cl)Cl>[C:36]([C:35]1[CH:39]=[CH:40][C:41]([CH2:42][S:43][CH:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:3][C:4]([OH:6])=[O:5])=[C:33]([O:32][CH3:31])[CH:34]=1)([OH:38])=[O:37]
Reactant: COc1cc(C(=O)O)ccc1CS
Reactant: CC(C)(C)OC(=O)CC(O)c1ccccc1CCCCCCCCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)O)ccc1CSC(CC(=O)O)c1ccccc1CCCCCCCCc1ccccc1
Reaction time: 4 h

Procedure:
A solution of 0.54 g (1.32 mmol) of tert-butyl 3-hydroxy-3-[2-(8-phenyloctyl)phenyl]propionate and 0.52 gm, (2.64 mmol) of 3-methoxy-4-mercaptomethylbenzoic acid in 10 ml of methylene chloride at 0° was treated dropwise with 20 ml of trifluoroacetic acid. Stirring was continued at 0° for 4 hours and 221 for 1 hour, and all the solvents were thoroughly evaporated. The residue was crystallized first from H2O/MECN (1:4), and then from Me2CO/hexane, and to yield the product, 0.26 gm. nmr (CDCl3 /Me2CO/DMSO): 7.05-7.72(m, 12H), 4.52 (d of d, 1H), 4.83(d, 1H), 4.82(s,3H), 4.68(d.1H), 2.88-3.24(m, 2H), 2.36-2.74 (m, 4H), 1.10-1.75(m,12H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][N:23]=2)=[CH:15][CH:14]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][N:23]=2)=[CH:15][CH:14]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCCc1ccc(CCOc2ncnc3ccccc23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: OCCCCc1ccc(CCOc2ncnc3ccccc23)cc1

Procedure:
To 4-(2-(4-(4-tert-butyldimethylsilyloxybutyl) phenyl) ethoxy) quinazoline (0.4 g, 0.916 mmol) is added tetrabutylammonium fluoride solution (1M TBAF in THF, 4.58 ml, 4.58 mmol). The solution is stirred for 2 hours after which water is added to the reaction and this is extracted in ethyl acetate. The organic layer is then washed with water, dried and concentrated. The residue obtained is purified by flash chromatography (silica gel; ethyl acetate/hexanes)
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:3]([OH:5])=[O:4].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Cl)=[CH:33][CH:32]=1.P(=O)(O)(O)O>CC(O)C.CCCCCC>[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][O:4][C:3](=[O:5])[C:2](=[O:1])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:33][CH:32]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C(O)CCC(=O)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P(O)(O)O
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCCCCC
Product: COc1ccc(COC(=O)C(=O)CCC(=O)O)cc1

Procedure:
2-Ketoglutaric acid (98.5%, 1.484 g, 10.0 mmol) was suspended in 2-propanol (25 mL), cooled in ice and neutralized with a 40% aqueous solution of tetrabutylammonium hydroxide (5.9 mL, 9.0 mmol). The resulting solution was diluted with hexane (7 mL), dried in vacuo (below 30° C.), dissolved in a mixture of 2-propanol (15 mL) and hexane (5 mL) and dried as above to a viscous syrup (4.834 g). The residue was protected with argon, dissolved in N,N-dimethylacetamide (5 mL), and p-methoxybenzyl chloride (1.25 mL, 9.0 mmol) was added. The mixture was allowed to react at room temperature under argon protection for 65 h. An 0.8 M aqueous solution of phosphoric acid (40 mL) was added, the mixture was extracted with ethyl acetate, the organic layer was washed with 0.8 M phosphoric acid, with water, and dried. The crude monoester (2.266 g) was purified by flash chromatography (silica-gel, chloroform-ethyl acetate, 100:0 to 1:1, containing 0.2% of acetic acid) and crystallized from ethyl acetate-hexane. Yield of 3: 1.330 g (56%), 1H NMR (CDCl3) detected 60% of the open tautomer 3a and 40% of the cyclic tautomer 3b.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[O:3]1.Cl[C:18]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[O:19].CN1CCOCC1>O1CCCC1>[CH3:24][O:23][CH2:22][CH2:21][O:20][C:18](=[O:19])[NH:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: COCCOC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COCCOC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
107 mg of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenylamine (0.48 mmol) were dissolved in tetrahydrofuran. 96 mg of 2-methoxyethyl chloroformate (0.68 mmol) and 79 mg of N-methylmorpholine (0.78 mmol) were added at room temperature. The mixture was left to stir at room temperature for 1 day, precipitated solid was filtered off and the solvent was removed under reduced pressure. This gave a yellowish oil which was used without further purification in the next reaction.
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:68])[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[C:64]([F:67])([F:66])[F:65])[CH2:53][CH2:52]1)=[O:50]>CN(C=O)C.C(OCC)(=O)C.O>[O:50]=[C:49]([N:51]1[CH2:52][CH2:53][N:54]([C:57](=[O:68])[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[C:64]([F:67])([F:66])[F:65])[CH2:55][CH2:56]1)[CH2:48][NH:47][C:20](=[O:22])[C:19]1[CH:18]=[CH:17][C:16]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][N:10]=2)=[CH:24][CH:23]=1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1ccc(-c2cnccn2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2cnccn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
DIPEA (96 mg, 0.12 mL, 0.74 mmol) was added to a stirred solution of 4-pyrazin-2-yl-benzoic acid (50 mg, 0.24 mmol) in DMF (2 mL). HOBT (40 mg, 0.23 mmol) and EDCI (57 mg, 0.29 mmol) were then added at room temperature. After 2 minutes 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (105 mg, 0.29 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and then extrated with ethyl acetate. The organic layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure to afford 78 mg (63.4%) of N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-4-pyrazin-2-yl-benzamide. LCMS Purity: 96.69%. 1H NMR (DMSO-d6): δ 9.4-9.3 (d, 1H), 8.8-8.7 (m, 2H), 8.7-8.6 (d, 1H), 8.3-8.2 (d, 1H), 8.1-8.0 (d, 2H), 7.9-7.6 (m, 3H), 7.6-7.5 (bt, 1H), 4.3-4.1 (m, 2H), 3.8-3.54 (m, 4H), 3.54-3.4 (m, 2H), 3.2-3.04 (m, 2H).
Reaction SMILES: [C:1]1(=[O:5])[O:4][CH2:3][CH2:2]1.Cl.[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:1](=[O:5])[CH2:2][CH2:3][OH:4])=[CH:26][CH:25]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1CCO1
Reactant: Nc1ccc(CCCc2ccccc2OCc2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCO)Nc1ccc(CCCc2ccccc2OCc2ccccc2)cc1
Reaction time: 18 h

Procedure:
Propiolactone (0.23 ml) was added to a mixture of 4-[3-(2-benzyloxyphenyl]propyl]benzeneamine hydrochloride (1.26 g) and triethylamine (0.5 ml) in methylene chloride (10 ml) and the mixture was stirred for 18 hours. A further equivalent of propiolactone (0.23 ml) was added and stirring continued for a further 24 hours. The reaction mixture was concentrated and the residue was subjected to flash chromatography on silica eluted with a stepwise gradient of methanol in methylene chloride. The fractions eluting with 5% methanol in methylene chloride were collected, concentrated and subjected to chromatography again, eluting with ethyl acetate to give, after crystallisation from dichloromethane/hexane (1:20 v/v) 4-[3-(2-benzyloxyphenyl)propyl]-N-(3-hydroxypropionyl]benzene amine m.p. 109°-110°, 0.22 g (15%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([NH:8][CH2:9][CH3:10])=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1.[C:16]([C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1)#[N:17].O>O1CCCC1>[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([N:8]([CH2:9][CH3:10])[S:24]([C:21]2[CH:20]=[CH:19][C:18]([C:16]#[N:17])=[CH:23][CH:22]=2)(=[O:26])=[O:25])=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1
Reactant: CCNc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(c1ccc(Cl)cc1[N+](=O)[O-])S(=O)(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Yield: 64.6 %

Procedure:
To a suspension of sodium hydride (60%, 0.10 g (2.50 mmol)) in tetrahydrofuran (THF)(3.0 ml), 4-chloro-N-ethyl-2-nitroaniline (0.40 g (1.99 mmol)) was added with stirring at room temperature. To the mixture, after stirring for 30 minutes at room temperature, 4-cyanobenzenesulfonyl chloride (0.50 g (2.48 mmol)) was added and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:2) as eluent, to give 0.47 g (64%) of the title compound as pale yellow crystals.
Reaction SMILES: C([NH:8][C@@H:9]([CH2:13][C:14]1[CH:21]=[C:19]([OH:20])[C:17]([OH:18])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])(OC(C)(C)C)=O.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.CN(C=O)C.C(OCC)C>[O:11]=[C:10]([C@H:9]([CH2:13][C:14]1[CH:21]=[C:19]([OH:20])[C:17]([OH:18])=[CH:16][CH:15]=1)[NH2:8])[OH:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOCC
Product: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.1 g of p(EG1k-Asp) (1.77 mmol —NH2) was dissolved in 30 mL of DCM and 15 mL of DMF. 842 mg of N-Boc-DOPA (2.83 mmol), 382 mg of HOBt (2.83 mmol), HBTU (2.83 mmol), and 595 μL of Et3N (4.25 mmol) were added. The mixture was stirred for 1 hr at room temperature and added to 450 mL ethyl ether. The polymer was further precipitated in cold MeOH and dried in vacuum to yield 1.9 g of PEE-1 (GPC: Mw=33,800, PD=1.3; UV-vis: 7.7±1.3 wt % DOPA).