Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:9][C@H:7]([OH:8])[CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].C1CCN2C(=NCCC2)CC1.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>CN(C=O)C>[CH2:13]([O:12][C:10]([N:1]1[CH2:9][CH:7]([O:8][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:6][CH:2]1[C:3]([OH:5])=[O:4])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CC(C(=O)O)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 140.6 %

Procedure:
A solution of Z-Hyp-OH (1, 300 g, 1.13 mol), TEA (395 mL, 2.83 mol), and DBU (17.2 g, 1.13 mol) in DMF (1.25 L) was stirred in a cold water bath while a suspension of TBS-Cl (188 g, 1.24 mol) in DMF (270 mL) was added slowly at 21-26° C. [Note: moderately exothermic]. The resulting thin suspension was stirred for 22 h at ambient temperature. The reaction mixture was cooled to 2° C. and quenched with water (1.54 L) at 26° C. [Note: the pH of the aqueous layer was 8.5-9.0]. MTBE (3 L) was added and the mixture was acidified to pH 3-4 with conc. HCl (168 g) at 17-19° C. The organic layer was separated and washed with water (2×1.5 L). The organic layer was concentrated in vacuo and dried by additional MTBE distillation. Toluene (2×500 mL) was added and distilled to remove moisture to provide 603 g of 2 as a light yellow-colored oil [Note: the water content by KF analysis was 508 ppm]. Based on drying a small sample of 2 to a solid, the contained weight of 2 was 412 g (96% yield, not corrected for purity). 1H NMR (300 MHz, CDCl3): δ7.34 (m, 3H), 7.29 (m, 2H), 5.24-5.11 (m, 2H), 4.52 (m, 1H), 4.43 (m, 1H), 3.64-3.42 (m, 2H), 2.27-2.09 (m, 2H), 0.85 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H) ppm; 13C NMR (75 MHz, d6-DMSO), mixture of rotomers: δ178.7, 178.4, 159.3, 158.9, 141.9, 141.8, 133.4, 133.3, 132.8, 132.6, 132.3, 131.9, 75.3, 74.6, 71.0, 71.0, 62.8, 62.3, 60.1, 59.7, 44.4, 43.4, 30.6, 30.6, 22.6, 22.6, 0.1, 0.0 ppm. Mass spectrum (ESI), m/z 379.5 [(M)+; calcd for C19H29NO5Si: 379.5].
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.F[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27].C(OCC)(=O)C.CCOCC>CN(C)C1C=CN=CC=1.CN(C=O)C>[N+:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CN1CCN(c2cccc3ccc(N)cc23)CC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CN1CCN(c2cccc3ccc(Nc4ccccc4[N+](=O)[O-])cc23)CC1
Yield: 7.1 %

Procedure:
The title product was obtained following the procedure of example 27 by reacting 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.225 g, 0.93 mmol), 2-fluoronitrobenzene (0.255 g, 1.8 mmol), and 4-dimethylaminopyridine (0.167 g, 1.37 mmol) in dry DMF (5 mL) with an overnight reflux. The product was isolated by silica gel flash chromatography and recrystallization from ethyl acetate/ether to yield 0.024 g (7%) of the title compound as orange crystals: mp 87°-94° C.; 1H NMR δ 9.70 (br s, 1H), 8.26 (dd, J=1.5, 8.5 Hz, 1H), 8.07 (d, J=2 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.57 (s, J=8 Hz, 1H), 7.44-7.32 9m, 4H), 7.16 (dd, J=1,7.5 Hz, 1H), 6.82 (dd, J=6.5, 8.5 Hz, 1H), 3.15 (br s, 4H), 2.70 (br s, 4H), 2.41 (s, 3H). HRMS m/e calculated for C21H22N4O2 ; 362.1738. Observed m/e: 362.1736.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][C@H:3]1[F:15].[O-]S([O-])(=O)=O.[Na+].[Na+].[N:23]1[C:31]2[C:26](=[N:27][CH:28]=[C:29]([CH:32]=O)[CH:30]=2)[S:25][N:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCO>[F:15][C@@H:3]1[C@H:2]([NH:1][CH2:32][C:29]2[CH:30]=[C:31]3[N:23]=[N:24][S:25][C:26]3=[N:27][CH:28]=2)[CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](F)C1
Reactant: O=Cc1cnc2snnc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: F[C@H]1CNCC[C@H]1NCc1cnc2snnc2c1
Temperature: 25 °C

Procedure:
A solution of cis-4-amino-1-tert-butoxycarbonyl-3-fluoropiperidine (1a) (1.00 mmole) in CH2Cl2 (5 mL) and EtOH (0.5 mL) is treated with anhydrous Na2SO4 (280 mg) and [1,2,3]thiadiazolo[5,4-b]pyridine-6-carboxaldehyde (1b) (1.10 mmole). The resulting solution is stirred at room temperature, then sodium triacetoxy borohydride (320 mg, 1.50 mmole) is added. The mixture is quenched by the addition of water (2 mL) and the volatiles removed in vacuo. Purification gives the desired compound.
Reaction SMILES: [C:1]([O-:5])(=[O:4])[CH:2]=O.[Na+].C([O-])(=O)C.[NH4+:11].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[CH:14]1[C:15]([CH:2]([NH2:11])[C:1]([OH:5])=[O:4])=[CH:16][CH:17]=[C:12]([OH:18])[CH:13]=1
Reactant: [NH4+]
Reactant: O=CC(=O)[O-]
Reactant: Oc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: NC(C(=O)O)c1ccc(O)cc1
Yield: 42.3 %

Procedure:
36.9 g of sodium glyoxylate are added to 130 ml of water, and 75 g of ammonium acetate and 60 g of phenol are added thereto under stirring. The mixture is stirred at 30° to 35° C. for 48 hours. After the reaction, the crystalline precipitates are collected by filtration under cooling, and then successively washed with water and methanol. 27.2 g of DL-p-hydroxyphenylglycine are thereby obtained as white crystals.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29]C)=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C1COCC1.CO.O>[C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([OH:29])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The compound of example 97 (130 mg, 0.294 mmol) was taken in THF (4 mL) and MeOH (1 mL). To this reaction mixture, 1 N LiOH (61.89 mg, 1.475 mmol) was added and stirred at room temperature for 2-3 h. After completion of the reaction, the solvent was evaporated and the residue obtained was dissolved in water and acidified with 1 N HCl to obtain the title compound, which was filtered and dried.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]([F:26])([F:25])[C:14]1[CH:24]=[CH:23][C:17]2[N:18]=[C:19]([S:21][CH3:22])[NH:20][C:16]=2[CH:15]=1>C(Cl)Cl>[F:26][C:13]([F:25])([F:12])[C:14]1[CH:24]=[CH:23][C:17]2[N:18]=[C:19]([S:21]([CH3:22])=[O:6])[NH:20][C:16]=2[CH:15]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2ccc(C(F)(F)F)cc2[nH]1
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(C(F)(F)F)cc2[nH]1
Reaction time: 1 h

Procedure:
2.6 g (0.013 mole) of commercially available 85% strength m-chloroperoxybenzoic acid are added dropwise to a suspension, cooled to -20° C., of 3.0 g (0.013 mole) of 5-trifluoromethyl-2-methylthio-benzimidazole in 50 ml of methylene chloride in the course of 30 minutes. The mixture is then stirred for a further 60 minutes and is then extracted twice with, each time, 20 ml of an aqueous potassium carbonate solution. The solvent is stripped off in vacuo and the solid residue which remains is recrystallized from acetonitrile. 1.8 g of 5-trifluoromethyl-2-methylsulfinyl-benzimidazole of m.p. 135° C. are obtained. Deprotonation of this compound with n-butyllithium and reaction with 2-chloro-4-methoxypyridine in dry benzene yields the title compound of m.p. 166° C. (decomposition).
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Br:14])[CH:5]1[CH2:15][C:16]([O:18]C)=O)(=[O:3])[CH3:2].C([N:23]1C=CC2C(=CC=CC=2Br)C1CC(OC)=O)(=O)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCCl>[Br:14][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH2:12][CH2:13][N:4]1[C:1](=[O:3])[CH2:2][NH:23][C:16](=[O:18])[CH:15]=[C:5]12
Reactant: COC(=O)CC1c2cccc(Br)c2C=CN1C(C)=O
Reactant: COC(=O)CC1c2cccc(Br)c2CCN1C(C)=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: O=C1C=C2c3cccc(Br)c3CCN2C(=O)CN1
Temperature: 25 °C

Procedure:
methyl 2-(2-acetyl-5-bromo-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate. A stirred solution of methyl 2-(2-acetyl-5-bromo-1,2-dihydroisoquinolin-1-yl)acetate (147 g, 453 mmol), triethylsilane (388 g, 3333 mmol) and trifluoroacetic acid (266 mL, 3446 mmol) in 1,2-dichloroethane (1100 mL) was stirred at 80° C. for 3 h. The reaction mixture was cooled to rt and the solvent was evaporated under reduced pressure. The remaining volatile components were evaporated under high vacuo and 40° C. bath temperature. To the resulting yellow residue saturated aqueous NaHCO3 (500 mL) was added while stirring and the mixture was extracted with DCM (3×400 mL). The organic layer was washed with saturated aqueous NaHCO3 (300 mL) and brine (300 mL). The organic layer was treated with charcoal, then dried with sodium sulfate, filtered through a pad of Hyflo and the solvent was removed under reduced pressure. The crude product was crystallized from diethyl ether (300 mL) to yield the title compound as white crystals (90 g). UPLC-MS: MS 326.0/328.0 (M+H+); UPLC rt 0.94 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:13](Cl)(=[O:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[C:13]([C:7]1[C:6]([CH3:8])=[CH:5][C:4]([NH:9][C:10](=[O:12])[CH3:11])=[CH:3][C:2]=1[Cl:1])(=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: CC(=O)Nc1cc(C)cc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)Nc1cc(C)c(C(C)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
A dry CS2 solution (30 mL) containing N-(3-chloro-5-methyl-phenyl)acetamide (5.0 g, 27 mmol) and acetyl chloride (2.9 ml, 40.8 mmol) was slowly mixed with aluminum chloride (9.1 g, 68 mmol). The reaction mixture was heated at reflux for 30 min, cooled to room temperature, and allowed to stand for 4.0 h. The CS2 was decanted and the remaining syrup was poured into icy HCl. The resultant solids were collected, re-dissolved in EtOH, and decolorized with charcoal. The solution was filtered and the filtrate was concentrated under vacuum to give N-(4-acetyl-3-chloro-5-methylphenyl)acetamide (5.2 g) as light yellow solids in 85% yield: 1H NMR (500 MHz, CDCl3) δ 7.48 (s, 1 H), 7.26 (s, 1 H), 7.21 (s, 1 H), 2.52 (s, 3 H), 2.24 (s, 3 H), 2.18 (s, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([OH:18])[CH2:10]2)=[CH:4][CH:3]=1.[Cl:19][C:20]([C:30]([F:33])([F:32])[F:31])=[CH:21][C@@H:22]1[C@H:24]([C:25](Cl)=[O:26])[C:23]1([CH3:29])[CH3:28].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:19][C:20]([C:30]([F:31])([F:32])[F:33])=[CH:21][C@@H:22]1[C@H:24]([C:25]([O:18][C@H:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@H:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:10]2)=[O:26])[C:23]1([CH3:29])[CH3:28]
Reactant: O[C@@H]1C[C@@H](Cc2ccc(F)cc2)c2ccccc21
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)O[C@@H]1C[C@@H](Cc2ccc(F)cc2)c2ccccc21
Yield: 86.7 %

Procedure:
In the manner of Example 4, the reaction of 1.00 g (0.004 mole) of trans-3-[(4-fluorophenyl)methyl]-1-indanol (96% trans, 4% cis) and 1.07 g (0.004 mole) of cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride in the presence of 0.32 g (0.004 mole) of pyridine and 50 mL of toluene gave 1.62 g of trans-3-[(4-fluorophenyl)-methyl]-1-indanyl cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate. The ir and nmr spectra were consistent with the proposed structure.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][C:12]([NH:35][C:36]1[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][C:37]=1[CH3:43])=[N:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:27][CH:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][NH:11][C:12]([NH:35][C:36]1[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][C:37]=1[CH3:43])=[N:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:27][CH:28]3[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]3)=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1
Reactant: COc1cc2c(N=C(NCCNC(=O)OC(C)(C)C)Nc3c(C)cccc3C)ncnc2cc1OCC1CCN(C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(N=C(NCCN)Nc3c(C)cccc3C)ncnc2cc1OCC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62.1 %

Procedure:
A mixture of N-(2-tert-butoxycarbonylaminoethyl)-N′-(2,6-dimethylphenyl)-N″-[6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazolin-4-yl]guanidine (0.31 g), trifluoroacetic acid (1 ml) and methylene chloride (1 ml), was stirred at ambient temperature for 20 minutes. The reaction mixture was evaporated and the residue was dissolved in water (4 ml) and the solution was basified to pH10 by the addition of 10N aqueous potassium hydroxide solution. The mixture was extracted with a 19:1 mixture of methylene chloride and methanol. The organic extract was dried over magnesium sulphate and evaporated. There was thus obtained the title compound (0.16 g); NMR Spectrum: (DMSOd6) 1.2–1.4 (m, 2H), 1.65–1.94 (m, 5H),2.12 (s, 3H), 2.21 (s, 6H), 2.7–2.9 (m, 4H), 3.22 (br s, 3H), 3.4–3.8 (m, 4H), 3.91 (d, 2H), 7.0 (s, 1H), 7.13 (s, 3H), 8.4 (s, 1H); Mass Spectrum: M+H+ 492.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([N:6]([CH2:8][CH2:9][O:10][CH3:11])[CH3:7])=[O:5].COC[CH2:19][NH:20]C.C12[C:28](=[CH:29]C=CC=1)[NH:27][C:26](=O)OC2=O>>[NH:27]1[CH2:26][CH2:19][N:20]=[C:28]1[CH2:29][NH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([N:6]([CH2:8][CH2:9][O:10][CH3:11])[CH3:7])=[O:5]
Reactant: CNCCOC
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: COCCN(C)C(=O)c1ccccc1N
Product: COCCN(C)C(=O)c1ccccc1NCC1=NCCN1

Procedure:
2-Amino-N-(2-methoxyethyl)-N-methylbenzamide (prepared from N-(2-methoxyethyl)methylamine and isatoic anhydride, using the methods described in Example 17) and CMI were reacted using conditions described in the general procedure for CMI coupling to give 2-[(4,5-dihydro-1H-imidazol-2-ylmethyl)amino]-N-(2-methoxyethyl)-N-methylbenzamide.
Reaction SMILES: [O-]S([O-])(=O)=O.[Mg+2].OS(O)(=O)=O.[Br:12][C:13]1[S:17][C:16]([C:18]([OH:20])=[O:19])=[CH:15][CH:14]=1.[C:21](O)([CH3:24])([CH3:23])[CH3:22]>C(Cl)Cl>[C:21]([O:19][C:18]([C:16]1[S:17][C:13]([Br:12])=[CH:14][CH:15]=1)=[O:20])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(O)c1ccc(Br)s1
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(Br)s1
Reaction time: 0.25 h
Yield: 94.4 %

Procedure:
To a mixture of anhydrous MgSO4 (11.60 g, 96.4 mmol) in 100 mL CH2Cl2 was added concentrated H2SO4 (1.45 mL, 24.1 mmol) and the mixture was stirred for 15 minutes followed by addition of 5-bromo-thiophene-2-carboxylic acid (5.0 g, 24.1 mmol). After stirring for 1 minute, tert-butanol (11.6 g, 20 mmol) was added and the reaction was stirred at room temperature for 18 h. The reaction was quenched with saturated NaHCO3. The layers were separated, the aqueous layer was extracted with CH2Cl2, and the combined organic layers were dried over MgSO4. The organic solution was concentrated to give a clear oil which was purified via medium pressure chromatography (3% EtOAc in hexanes) to afford the title compound (4.97 g). 1H NMR (400 MHz, CDCl3) δ 7.45 (d, 1H), 7.02 (d, 1H), 1.54 (s, 9H).
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][Cl:32])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCO>[ClH:32].[CH2:19]([O:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:31][S:18][C:9]2[NH:8][C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C@H:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:10]=2)=[CH:33][CH:34]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Solvent: CCO
Product: Cl
Product: c1ccc(COc2ccc(CSC3=N[C@@H](c4ccccc4)[C@@H](c4ccccc4)N3)cc2)cc1
Temperature: 25 °C
Yield: 50.7 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 4-benzyloxybenzyl chloride (365 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 194 mg of the product 224. 1H NMR (DMSO-d6) δ 11.28 (s, 2 H), 7.60-7.25 (m, 7 H), 7.20-6.95 (m, 8 H), 6.95-6.70 (m, 4 H), 5.75 (s, 2 H), 5.25 (s, 2 H), 4.80 (s, 2 H); MS: m/z 451 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH2:10])=[N:7][N:6]=1.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27](O)=[O:28])[CH2:26][CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH:10][C:27]([C:24]2([C:22]3[CH:21]=[CH:20][C:19]4[O:15][CH2:16][O:17][C:18]=4[CH:23]=3)[CH2:26][CH2:25]2)=[O:28])=[N:7][N:6]=1
Reactant: Nc1nnc(Cc2ccccc2Cl)s1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1nnc(Cc2ccccc2Cl)s1)C1(c2ccc3c(c2)OCO3)CC1
Reaction time: 16 h
Yield: 14 %

Procedure:
5-(2-Chloro-benzyl)-[1,3,4]thiadiazol-2-ylamine (23 mg, 0.10 mmol) and 1-benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (21 mg, 0.10 mmol) were dissolved in acetonitrile (1.5 mL) containing triethylamine (42 L, 0.30 mmol). Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 49 mg, 0.11 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography to yield the pure product (5.7 mg, 0.014 mmol, 14%). ESI-MS m/z calc. 413.1. found; 414.3 (M+1)+ Retention time 3.38 minutes.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]([C:12]1[CH:17]=[C:16]([SH:18])[CH:15]=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]=1[OH:23])([CH3:11])[CH3:10].[CH:24]([CH:26]=[CH2:27])=[O:25]>CO>[CH3:11][C:9]([C:12]1[CH:17]=[C:16]([S:18][CH2:27][CH2:26][CH:24]=[O:25])[CH:15]=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]=1[OH:23])([CH3:8])[CH3:10]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C=CC=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)c1cc(SCCC=O)cc(C(C)(C)C)c1O
Reaction time: 0.5 h

Procedure:
Triethylamine (1.1 ml, 0.0076 mole) was added to a solution of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (18.2 g, 0.076 mole) in methyl alcohol (200 ml) and stirred for 30 minutes. Freshly distilled acrolein (12.8 g, 0.23 mole) was added and the solution stirred at room temperature. The product was purified by chromatography on silica and characterized by its NMR and IR spectra and m.p. ca. 75° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[C:7]([C:24](O)=[O:25])=[CH:6]2)#[N:2].[NH2:27][CH2:28][CH:29]([OH:32])[CH2:30][CH3:31]>>[OH:32][CH:29]([CH2:30][CH3:31])[CH2:28][NH:27][C:24]([C:7]1[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:22])([F:21])[F:23])[CH:14]=2)[C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)=[O:25]
Reactant: CCC(O)CN
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Product: CCC(O)CNC(=O)c1cc2cc(C#N)ccc2n1Cc1cccc(OC(F)(F)F)c1

Procedure:
The title compound was prepared using 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid [prepared from 3-(trifluoromethoxy)benzyl bromide and ethyl 5-cyanoindole-2-carboxylate] and 1-amino-2-butanol in a manner similar to that described in Example 11.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1(=[O:20])[N:10]([CH2:11][C:12]([OH:14])=[O:13])[C:9](=[O:15])[C:8]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:7]12.[N+:21]([O-])([OH:23])=[O:22]>>[N+:21]([C:17]1[CH:16]=[C:8]2[C:9](=[O:15])[N:10]([CH2:11][C:12]([OH:14])=[O:13])[C:6](=[O:20])[C:7]2=[CH:19][CH:18]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)CN1C(=O)c2ccccc2C1=O
Agent: O=S(=O)(O)O
Product: O=C(O)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Temperature: 25 °C

Procedure:
To a mixture of concentrated sulfuric acid (350 ml) and fuming nitric acid (d=1.52)(60 ml) was added 2-phthalimidoacetic acid (70 g) with stirring and under ice-cooling. The mixture was stirred for 1 hour under ice-cooling and for 2 hours at room temperature, and poured into ice-water (2 l). The resultant precipitate was collected by filtration and recrystallized from a mixture of water (2 l) and ethanol (1 l) to give the title compound (60 g) as light yellow sharp-pointed needles.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-])=O)=[CH:9][CH:10]=2)[C:5](=[O:15])[CH2:4][CH2:3]1>CCOC(C)=O>[CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([NH2:12])=[CH:9][CH:10]=2)[C:5](=[O:15])[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(=O)c2cc([N+](=O)[O-])ccc21
Solvent: CCOC(C)=O
Product: CC1(C)CCC(=O)c2cc(N)ccc21

Procedure:
A solution of 230.0 mg (1.05 mmol) 3,4-dihydro-4,4-dimethyl-7-nitro-1(2H)-naphthalenone (Compound Y) in 5.0 ml of EtOAc was stirred at room temperature with a catalytic amount of 10% Pd--C under 1 atm of H2 for 24 hours. The catalyst was removed by filtration through a pad of Celite, and the filtrate concentrated under reduced pressure to give the title compound as a dark green oil. 1H NMR (CDCl3): δ 7.30 (1H, d, J=2.7 Hz), 7.22 (1H, d, J=8.4 Hz), 6.88 (1H, dd, J=2.7, 8.5 Hz), 2.70 (2H, t, J=6.6 Hz), 1.97 (2H, t, J=6.6 HZ), 1.34 (6H, s).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=O)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C1(C)C(S(O)(=O)=O)=CC=CC=1.[CH2:22]([O:29][C:30](=[O:37])[C@@H:31]1[CH:35]([Br:36])[CH2:34][CH2:33][NH:32]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C=O)C.ClCCl>[CH2:22]([O:29][C:30](=[O:37])[C@@H:31]1[CH:35]([Br:36])[CH2:34][CH2:33][N:32]1[C:8](=[O:10])[C@H:2]([CH2:3][CH2:4][C:5](=[O:6])[OH:7])[NH2:1])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(OCc1ccccc1)[C@H]1NCCC1Br
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N[C@@H](CCC(=O)O)C(=O)N1CCC(Br)[C@H]1C(=O)OCc1ccccc1

Procedure:
A solution of 20 mmoles of pyro-L-glutamic acid and 20 mmoles of 3-bromo-proline benzyl ester toluene sulfonic acid, neutralized with N-ethyl morpholine, in dichloromethane: DMF(4:1) is cooled in an ice bath with stirring. A solution of 20 mmoles of dicyclohexylcarbodiimide in dichloromethane is ddded to the above reaction mixture. The reaction mixture is stirred in an ice water bath for one hour and then at room temperature overnight. Dicyclohexylurea is removed by filtration and the product is washed in ethyl acetate. Solvents of the combined filtrates are removed under reduced pressure with a rotary evaporator at 40° C. Ethyl acetate is added to the residue and the organic solution is washed until neutral. The organic phase is dried over anhydrous MgSO4, filtered and then the solvent is removed with a rotary evaporator. The material is crystallized from isopropanol and ether yielding the named product.