Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[O:6]1[CH2:10][C@H:9]([OH:11])[C@H:8]([OH:12])[CH2:7]1.CCN(CC)CC>C(Cl)Cl>[CH3:1][S:2]([O:12][C@H:8]1[C@@H:9]([O:11][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:10][O:6][CH2:7]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@@H]1COC[C@@H]1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1COC[C@H]1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Methanesulfonyl chloride (1.642 mL, 21.13 mmol) in DCM (5 mL) was added to a solution of (3R,4S)-tetrahydrofuran-3,4-diol (0.787 mL, 9.61 mmol) and Et3N (4.05 mL, 28.8 mmol) in DCM (10 mL) at 0° C. After stirring at 0° C. for 1 h, the mixture was diluted with DCM. The organic layer was washed with saturated aqueous NaHCO3, dried, and concentrated in vacuo to give the title compound as a yellowish white solid (2.5 g, 100%). 1H NMR (400 MHz, CDCl3) δ ppm 3.09-3.20 (m, 6H), 3.90-4.07 (m, 2H), 4.10-4.22 (m, 2H), 5.19 (ddd, J=5.31, 3.54, 1.77 Hz, 2H).
Reaction SMILES: C(NC1CCCCC1)(C)C.C([Li])CCC.[CH3:16][O:17][C:18](=[O:28])[CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27].[Cl:29][C:30]1[N:35]=[C:34]([Cl:36])[C:33]([CH2:37]I)=[CH:32][N:31]=1>O1CCCC1.C(OCC)(=O)C>[CH3:16][O:17][C:18](=[O:28])[CH:19]([C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27])[CH2:37][C:33]1[C:34]([Cl:36])=[N:35][C:30]([Cl:29])=[N:31][CH:32]=1
Reactant: Clc1ncc(CI)c(Cl)n1
Reactant: COC(=O)Cc1c(Cl)cccc1Cl
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1cnc(Cl)nc1Cl)c1c(Cl)cccc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-isopropylcyclohexylamine (1.44 g, 10.0 mmol) (Aldrich) in dry tetrahydrofuran (20 mL) was added n-butyllithium (2.5 M in hexanes, 4.0 mL, 10.0 mmol) (Aldrich) at −78° C. under argon. After 30 minutes, a solution of 2,6-dichloro-phenylacetic acid methyl ester (2.19 g, 10.0 mmol) (TCI-US) in tetrahydrofliran (5 mL) was added by injection via a syringe and the reaction mixture was stirred at −78° C. for another 30 minutes. To this reaction mixture was added a solution of 2,4-dichloro-5-iodomethyl-pyrimidine (1.45 g, 5.0 mmol) (from Example 1c supra) in tetrahydrofuran (5 mL) at −78° C. and the reaction mixture was stirred at the same temperature for 1 hour then slowly allowed to warm up to −30° C. and stirred for 10 minutes. The reaction mixture was diluted with ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (100 mL), water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to give 2-(2,6-dichloro-phenyl)-3-(2,4-dichloro-pyrimidin-5-yl)-propionic acid methyl ester as a colorless oil. (Yield 1.57 g, 82.6%).
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH:11][C:12]([CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=O)=[C:9]([C:21]#[N:22])[C:8]([CH2:23][CH3:24])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:25](C)[Na].OO>C(O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([CH2:14][C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)=[N:22][C:21](=[O:25])[C:9]3=[C:8]([CH2:23][CH3:24])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CO[Na]
Reactant: CCc1nn(C2CCCC2)c(NC(=O)Cc2ccncc2)c1C#N
Agent: OO
Solvent: CCO
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccncc3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 15.1 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-4-cyano-5-[(4-pyridinylmethyl)carbonylamino]-1H-pyrazole (2.8 g, 8.6 mmol), ethanol (50 ml), NaOCH3 (1.0 g, 18 mmol) and 30% H2O2 (4.5 ml) was stirred at room temperature for 20 minutes, then was heated at reflux for 3.5 hours. Additional 30% H2O2 (3 ml) was added and the reaction mixture was heated at reflux for 2 more hours. The reaction mixture was concentrated in vacuo, the residue was partitioned between CHCl3 (100 ml) and 10% aqueous NaHCO (50 ml), and the organic layer was separated. The organic layer was concentrated in vacuo, and the residue was crystallized from cyclohexane and a solid was collected by filtration. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with ether to 10% methanol/ether, followed by recrystallization from ether, to afford 420 mg of 1-cyclopentyl-3-ethyl-6-(4-pyridinylmethyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 162°-164° C.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][O:16][CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[C:30]([F:36])[CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC>C(N(CC)CC)C>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@@H:15]([O:16][CH2:17][CH3:18])[C@@H:32]([C:31]1[CH:34]=[CH:35][C:28]([O:27][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:29][C:30]=1[F:36])[OH:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1F
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(CC)CC
Product: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCc2ccccc2)cc1F

Procedure:
In analogy to the procedure described in example 17 a], (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one (for the preparation of (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one see: D. Haigh, H. C. Birrell, B. C. C. Canteilo, D. S. Eggleston, R. C. Haltiwanger, R. M. Hindley, A. Ramaswamy, N. C. Stevens, Tetrahedron: Asymmetry 1999, 10, 1353-1367) was reacted with 4-benzyloxy-2-fluoro-benzaldehyde in the presence of triethylamine and di-n-butylboron triflate to give (S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-fluoro-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-one as colorless foam. According to 1H-NMR spectroscopy, one of the four isomers is strongly predominating. The configuration was tentatively assigned as 2S,3R according to D. Haigh et al., Tetrahedron: Asymmetry 1999, 10, 1353-1367.
Reaction SMILES: [O:1]=[C:2]([C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:20]=1)[CH2:3][C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6]CC(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[OH:6][C:5]1[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=1[CH2:3][C:2]([C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:20]=1)=[O:1]
Reactant: CCCCCn1cc(C(=O)Cc2ccccc2OCC(=O)OC(C)(C)C)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCn1cc(C(=O)Cc2ccccc2O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
t-Butyl 2-(2-(2-oxo-2-(1-pentyl-1H-indol-3-yl)ethyl)phenoxy)acetate (O-desmethyl JWH-250 t-butyl 2-CME) 6 (1.09 g, 2.50 mmol) was dissolved in dichloromethane (20 ml) and trifluoroacetic acid (10 ml) was added and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was purified by column chromatography (Biotage Isolera 4, SNAP-50 g, 50% ethyl acetate in hexane) to give 512 mg (54%) of O-desmethyl JWH-250 2-CME (Hapten 1) as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[OH:9][C@@H:10]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([O:9][C@@H:10]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccnc(Cl)n2)C1
Temperature: 140 °C

Procedure:
2,4-Dichloropyrimidine (3.95 g, 26.5 mmol), tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (4.14 g, 22.11 mmol), and cesium carbonate (18 g, 55.3 mmol) were taken up in DMSO (44 ml). The reaction mixture was heated to 140° C. for 40 min, cooled to room temperature, and diluted with ethyl acetate. The mixture was washed with water (×2) and brine. The combined organics were dried over sodium sulfate, concentrated, and purified by Combiflash (ethyl acetate/hexanes) to afford tert-butyl (3R)-3-[(2-chloropyrimidin-4-yl)oxy]pyrrolidine-1-carboxylate.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][C:5]([O:7]CC)=[O:6].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26](Cl)(=[O:28])=[O:27].CCN(CC)CC>C(Cl)Cl>[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26]([NH:2][C@@H:3]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:4][C:5]([OH:7])=[O:6])(=[O:27])=[O:28]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CCOC(=O)C[C@@H](N)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)C[C@@H](NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
To a solution of (R)-ethyl 3-amino-3-phenylpropanoate hydrochloride (5.04 g, 21.9 mmol) and naphthalene-2-sulfonyl chloride (4.97 g, 21.9 mmol) in CH2Cl2 (60 mL) was added a solution of Et3N (7.65 mL, 54.9 mmol) in CH2Cl2 (60 mL) at 0° C. over a period of 45 min. The reaction mixture was stirred at room temperature for 42 h and then washed with aqueous 1 M HCl (300 mL). The organic layer was dried (Na2SO4) and evaporated to dryness, which gave 8.05 g (96%) of S9-1 as a light pink solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14].CO.[CH2:17]([N:19]1[C:25](=[O:26])[C:24]([CH3:28])([CH3:27])[C:23](=[O:29])[N:22]([CH3:30])[C:21]2[CH:31]=[C:32]([CH:35]=O)[CH:33]=[CH:34][C:20]1=2)[CH3:18].[BH4-].[Na+]>O>[CH2:17]([N:19]1[C:25](=[O:26])[C:24]([CH3:27])([CH3:28])[C:23](=[O:29])[N:22]([CH3:30])[C:21]2[CH:31]=[C:32]([CH2:35][NH:1][CH2:2][CH2:3][N:4]3[CH:13]=[CH:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]3=[O:14])[CH:33]=[CH:34][C:20]1=2)[CH3:18]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C=O)ccc21
Reactant: NCCn1ccc2ccccc2c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNCCn3ccc4ccccc4c3=O)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
2-(2-Aminoethyl)-2H-isoquinolin-1-one (1.0 g) was added to a methanol solution (15 ml) of 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde (1.46 g). The mixture was stirred for 0.5 hours at room temperature. Sodium borohydride (0.23 g) was added to the mixture, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using dichloromethane. The organic layer was washed with water and saturated saline, dried with magnesium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1→8:2). The purified product was condensed under reduced pressure to give the title compound (1.92 g) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7]Cl.[Na].[OH:10][CH2:11][C:12]1([CH3:20])[O:16][C:15]([CH3:19])([C:17]#[N:18])[CH2:14][CH2:13]1>CN(C)C=O>[CH3:19][C:15]1([C:17]#[N:18])[CH2:14][CH2:13][C:12]([CH3:20])([CH2:11][O:10][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[O:16]1
Reactant: CC1(C#N)CCC(C)(CO)O1
Reactant: ClCc1ccccn1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC1(C#N)CCC(C)(COCc2ccccn2)O1

Procedure:
Freshly liberated 2-picolinyl chloride was secured by extracting a mixture of 1.48 g potassium carbonate and 1.64 g 2-picolinyl chloride in 10 ml water with methylene chloride. The extract was dried (MgSO4) and concentrated (rotary evaporator). To the residue was added 10 ml dry dimethylformamide and the remaining methylene chloride was removed by further evaporation. The resulting solution was then added to a mixture of 10 mmol of the sodium salt of tetrahydro-5-(hydroxymethyl)-2,5-dimethyl-2-furancarbonitrile as a mixture of cis-trans isomers in 10 ml dry dimethylformamide prepared as described in Embodiment 10 above. The reaction progress and workup also followed the procedure for Embodiment 10 with the exception that crude product was secured from both pentane and ether extraction of the ice-quenched mixture. The crude product, which consisted of both cis- and trans-isomers, was purified and isomerically separated by preparative hplc using a silica gel column and ethyl acetate:pentane (60:40) as eluent. The cis (Z)-isomer amounted to 0.69 g bp not determined.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10]Cl)=[CH:7][C:6]=2[CH:12]=1.[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C)C=O.C(=O)(O)[O-].[Na+]>[N:13]([CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:12][C:6]=2[CH:7]=1)=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: ClCc1cc2cc(Cl)ccc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cc2cc(Cl)ccc2o1
Temperature: 70 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
To a solution of 5-chloro-2-(chloromethyl)-1-benzofuran (500 mg, 2.49 mmol) in N,N-dimethylformamide (10 ml) was added NaN3 (320 mg, 4.92 mmol) and the contents were stirred overnight at 70° C. The resulting solution was diluted with saturated aqueous sodium bicarbonate (150 ml) and extracted with dichloromethane (3×70 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with petroleum ether to afford 2-(azidomethyl)-5-chloro-1-benzofuran as light brown oil (500 mg, 97%). 1H NMR (300 MHz, CDCl3): δ 7.54 (s, 1H), 7.40 (d, J=9.0 Hz, 1H), 7.25 (d, J=9.0 Hz, 1H), 6.66 (s, 1H), 4.50 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=[O:21])=[CH:16][CH:15]=1.I[CH3:32]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]([CH3:32])[CH2:23][C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(CNC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1
Reactant: CI
Product: Cc1ccc(CN(C)C(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1

Procedure:
2′-Methyl-N-methyl-N-(4-methylbenzyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4carboxamide was prepared from 2′-methyl-N-(4-methylbenzyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide and iodomethane using method L. NMR; δH [2H6]—DMSO 7.88,(1H, d), 7.75,(1H, s), 7.55-7.47,(5H, m), 7.25-7.08,(4H, m), 4.65-4.49,(2H, m), 2.88,(3H, m), 2.55,(3H, s), 2.32,(6H, m). LCMS; retention time 3.60 min, MH+ 412.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][N:11]=[C:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].[Cl:19]Cl>C(Cl)(Cl)(Cl)Cl>[Cl:19][C:12]([N:11]=[N:10][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=1[Cl:9])([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: ClCl
Reactant: CCOC(=O)C(C)=NNc1c(Cl)cc(Cl)cc1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C)(Cl)N=Nc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
A solution consisting of 9.0 g. ethyl pyruvate (2,4,6-trichlorophenyl)hydrazone (mixed isomers) and 100 ml. carbon tetrachloride was chilled to minus 10° (-10° ) C. and 5 ml. chlorine gas was added. After allowing the reaction mixture to warm up to about 25° C., the carbon tetrachloride was removed by evaporation under reduced pressure. The oily residue that remained was dissolved in a mixture of benzene and technical hexane (1 part of benzene to 4 parts of the latter). This solution was poured onto a 50 cm. × 5 cm. column of silica gel and the chromatogram was developed with the solvent mixture. The first portion of eluate was discarded and the fractions containing the orange-red azo compound were saved. After removal of the solvents by evaporation at 100° C. and 10 mm. mercury pressure 6.9 g. ethyl 2-chloro-2-[(2,4,6-trichlorophenyl)azo]propionate was obtained.
Reaction SMILES: C[C@@]12[C@H]3[C@@H](O)C[C@]4(C)[C@@](O)(C(CO)=O)CC[C@H]4[C@@H]3CCC1=CC(=[O:6])CC2.C(N(CC)C(=O)COCC(O)=O)C.[CH:40]1([N:46]=[C:47]=[N:48][CH:49]2[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>N1C=CC=CC=1>[C:47]([NH:46][CH:40]1[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]1)([NH:48][CH:49]1[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1)=[O:6]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Agent: CCN(CC)C(=O)COCC(=O)O
Solvent: c1ccncc1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
To a solution of hydrocortisone (5.12 g, 0.014 mole) and N,N-diethyl-3-oxaglutaramic acid (2.57 g, 0.015 mole) in 15 ml pyridine was added dicyclohexylcarbodiimide (3.06 g, 0.015 mole). After the reaction was stirred 10 minutes, 25 ml CH2CH2 was added to it to keep the suspension which had formed sufficiently fluid for stirring. The reaction was stirred overnight at room temperature then filtered. The residue was washed twice with CH2Cl2 and dried to give 2.6 g (89% yield) dicyclohexylurea. The filtrate was concentrated in vacuo to give a foam which was suspended in 20 ml hot dichloromethane and allowed to cool. The suspension was filtered and the filtrate was concentrated in vacuo to give a residue which was dissolved in 20 ml THF; the solution was then diluted to 100 ml with Et2O. Crystals formed overnight and were filtered to give 2.69 g of product which TLC showed to be contaminated with hydrocortisone. These crystals were in turn recrystallized from THF-Et2O (20:80). After 5 days, 2.14 g (29% yield) of light brown needles were filtered which were the etherate of the desired product: mp 95°-97.5° C., NMR (CDCl3) δ5.67 (s, 1, O=C--CH=), 5.07 (s, 2, O=C--CH2O--C=O), 4.48 (m, 3, CHOH,--OH), 4.35 (s, 2, --OCOCH2O--), 4.30 (s, 2, NCOCH2O--), 3.48 (q, 4, O(CH2CH3)2, J=5 Hz), 3.34 (m, 4, N(CH2CH3)2), 1.44 (s, 3, C--CH3), 1.18 (t, 6, O(CH2CH3)2, J=5 Hz), 0.93 (s, 3, C--CH3), 2.9-0.9 (m, 23, CH, CH2); IR (KBr) 3400 cm-1 (s) OH and 1730, 1710 and 1640 cm-1 (s) (C=O); TLC (silica gel, 10% MeOH/Et2O) Rf 0.36; [α]23D=+117° (C=0.5, dioxane).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](O)=[CH:3][C:2]=1[OH:12].[CH2:13]([NH2:18])[C:14]([CH3:17])([CH3:16])[CH3:15].Cl.CN1C(=O)CCC1>C(O)(C)C>[CH3:15][C:14]([CH3:17])([CH3:16])[CH2:13][NH:18][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[C:2]([OH:12])[CH:3]=1
Reactant: Oc1cc(O)c2ccccc2n1
Reactant: CC(C)(C)CN
Agent: Cl
Solvent: CC(C)O
Solvent: CN1CCCC1=O
Product: CC(C)(C)CNc1cc(O)nc2ccccc12
Temperature: 180 °C
Reaction time: 1 h

Procedure:
2,4-Quinolinediol (15 g, 93 mmol), neopentyl amine (33 mL, 280 mmol), 6 N HCl in isopropanol (15 mL), and 40 mL NMP were place in a sealed tube and heated to 180° C. for 40 h. The reaction was then poured onto water (800 mL), stirred for 1 h and filtered. The cake was washed with water, collected and dried in vacuo (50 mTorrr, 60° C.) to afford 17.85 g (81.5%). 1H NMR (360 MHz, DMSO): 0.97 (s, 9H), 3.02(d, 2H, J=6.06 Hz), 5.41(s, 1H), 6.58(t, 1H, J=6.06 Hz), 7.08(t, 1H, J=7.67 Hz), 7.21(d, 1H, J=8.07 Hz), 7.43(dd, 1H, J=7.67, 7.27 Hz), 8.03(d, 1H, J=8.07 Hz), 10.73(s, 1H).
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC(OC)=O)C=CC=1OC.[CH2:27]([C:29]1[CH:30]=[C:31]([C:37](=O)[C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH3:47])[CH:39]=2)[CH:32]=[CH:33][C:34]=1[CH2:35][CH3:36])[CH3:28].C(OP([CH2:57][C:58]#[N:59])(=O)OCC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>CCCCCC>[CH2:27]([C:29]1[CH:30]=[C:31]([C:37]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH3:47])[CH:39]=2)=[CH:57][C:58]#[N:59])[CH:32]=[CH:33][C:34]=1[CH2:35][CH3:36])[CH3:28]
Reactant: CCc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1CC
Reactant: CCOP(=O)(CC#N)OCC
Agent: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Product: CCc1ccc(C(=CC#N)c2ccc(OC)c(OC)c2)cc1CC

Procedure:
3-(3,4-Diethylphenyl)-3-(3,4-dimethoxyphenyl)acrylonitrile was prepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3′,4′-diethyl-3,4-dimethoxybenzophenone (0.51 g, 1.7 mmol), diethylcyanomethylphosphonate (0.31 mL, 1.9 mmol) and lithium hexamethyldisilazide (1.4 mL, 1.9 mmol, 1.3M) with a reaction time of 60 hours at room temperature. The crude product was purified by chromatography (silica gel, 1% ethyl acetate/methylene chloride) to afford an oil which was stirred in hexane until it solidified. The resulting slurry was filtered, the solid washed with hexane, air dried, and dried in vacuo to afford 0.31 g (57%) of a mixture of the E and Z isomers as an off white solid: mp 78–82° C.; 1H NMR (CDCl3) δ 7.30–6.75 (m, 12H), 5.61 (s, 1H), 5.60 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H), 3.83 (s, 3H), 2.80–2.59 (m, 8H), 1.35–1.14 (m, 12H); 13C NMR (CDCl3) δ 163.0, 163.0, 151.0, 150.5, 148.8, 148.6, 144.6, 143.9, 142.1, 141.8, 136.8, 134.5, 131.9, 129.7, 128.6, 128.5, 128.2, 127.3, 126.3, 123.2, 122.2, 118.7, 118.6, 112.8, 111.3, 110.7, 92.5, 92.2, 56.1, 56.0, 25.5, 25.4, 25.4, 25.3, 15.3, 15.2, 15.0, 14.9; Anal. Calcd for C21H23NO2. Theoretical: C, 78.47; H, 7.21; N, 4.36. Found: C, 77.80; H, 7.25; N, 4.68.
Reaction SMILES: [N:1]1([C:30](OC(C)(C)C)=[O:31])[CH2:29][CH2:28][CH2:27][C@@H:2]1[C:3]([NH:5][C@H:6]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:16])[NH:12][N+:13]([O-:15])=[O:14])=[O:4].Cl.CCOC(C)=O.[NH:44]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C@H:45](C(O)=O)[CH2:46][O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CCN(CC)CC>[NH:44]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C@H:45]([C:30]([N:1]1[CH2:29][CH2:28][CH2:27][C@@H:2]1[C:3]([NH:5][C@H:6]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:16])[NH:12][N+:13]([O-:15])=[O:14])=[O:4])=[O:31])[CH2:46][O:47][CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)N1CCC[C@@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1

Procedure:
The desired compound was prepared as an oily product from 12 g of Boc-D-Pro-Arg(NO2)-OBzl, 60 ml of 4 N HCl-AcOEt, 3.3 ml of Et3N, 7 g of Boc-Ser(Bzl)-OH, 4.2 g of HOBt and 5.1 g of DCC in the same manner as in Example 7-(2).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[C:3]=1[C:4]([OH:6])=[O:5].N1C=CC=CC=1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>C1(C)C=CC=CC=1>[Br:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([NH:1][C:20](=[O:21])[CH2:19][Cl:18])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1cccc(Br)c1C(=O)O
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(CCl)Nc1cccc(Br)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
To a stirred solution of 2-amino-6-bromo-benzoic acid (6) (3.06 g, 14.2 mmol) in toluene (75 mL) cooled to 0° C. in an ice-bath was added pyridine (0.60 mL, 7.10 mmol) followed by a solution of chloroacetyl chloride (2.26 mL, 28.4 mmol) in toluene (75 mL) drop-wise over 1 hr. The reaction mixture was allowed to warm to RT, and was heated at 115° C. for 3 hr and then allowed to cool to RT. The solvent volume was reduced by half by evaporation in vacuo. Upon standing overnight, the product precipitated and was collected by filtration to afford 2-bromo-6-(2-chloroacetamido)benzoic acid (7a) (1.44 g) as a white solid: m/z 290/292 (M+H)+ (ES+). The filtrate was concentrated in vacuo and the residue triturated with ethanol/heptane to afford 2-bromo-6-(2-hydroxyacetamido)benzoic acid (7b) (1.02 g, combined yield, 59%): m/z 274/276 (M+H)+ (ES+). Both 7a and 7b can be used without further purification in the next step.