Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[O:3]([CH3:15])[CH:4]1[O:12][C@@H:11]([CH2:13][OH:14])[C@H:9]([OH:10])[C@@H:7]([OH:8])[C@@H:5]1[OH:6].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCOCC1>[CH2:16]([O:6][C@H:5]1[C@H:7]([O:8][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:9]([O:10][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:11]([CH2:13][O:14][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@H:4]1[O:3][CH3:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC1O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: ClCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CO[C@@H]1O[C@@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 4 h

Procedure:
Powdered potassium hydroxide (25 g.) was added to a magnetically stirred solution of syrupy methyl L-glucopyranoside (4.8 g.) in dry 1,4-dioxane (30 ml.). This stirred solution was gently heated on an oil bath (reflux), and freshly distilled benzyl chloride (32 ml.) was added dropwise over a 1 hour period. Heating and stirring were continued for an additional 4 hour period, at which time the dioxane was distilled and the resultant mixture cooled, diluted with water (200 ml.) and extracted with chloroform (3×75 ml.). The chloroform extracts were then washed with dilute hydrochloric acid and then with water. The chloroform layer was dried over sodium sulfate and then concentrated at reduced pressure to a syrup (17 g.) which was seen to contain three components (t.l.c., benzene/ethyl acetate 10:1 v/v) having Rf values of approximately 0.4, 0.48, and 0.73. T.L.C. comparison (benzene/ethyl acetate 10:1 v/v) of this mixture with the previously prepared methyl 2,3,4,6-tetra-O-benzyl-D-glucopyranosides and also with benzyl ether showed that the component with the greatest mobility was benzyl ether whereas the one having the least mobility was likely the α-anomer and the middle component the β-anomer. A small portion of this reaction mixture was purified by column chromatography on silica gel by eluting first with benzene to remove benzyl ether and then with a 10:1 mixture of benzene-ethyl acetate to give methyl 2,3,4,6-tetra-O-benzyl-α-L-glucopyranoside as a syrup having [α]D -25.4° (c 3.8, chloroform) as compared with [α]D +23.8° (c 3.42, chloroform), or [α]D +18.7° (c 1.5, chloroform) for methyl 2,3,4,6-tetra-O-benzyl-α-D-glucopyranoside, and crystalline methyl 2,3,4,6-tetra-O-benzyl-β-L-glucopyranoside having m.p. 69.5°-70°, [α]D -12.1° (c 4.2, dioxane) as compared to m.p. 68°-69°, [α]D +11° (c 5.3, dioxane) for methyl 2,3,4,6-tetra-O-benzyl-β-D-glucopyranoside.
Reaction SMILES: C([Mg]Br)C.CCOCC.[CH:10]1([C:13]#[CH:14])[CH2:12][CH2:11]1.[C:15]([O:21][C@H:22]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[C:33](=[O:38])[C:34]([F:37])([F:36])[F:35])=[O:24])(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[C:15]([O:21][C@H:22]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[C@@:33]([OH:38])([C:14]#[C:13][CH:10]1[CH2:12][CH2:11]1)[C:34]([F:36])([F:37])[F:35])=[O:24])(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: C#CC1CC1
Reactant: CC(C)(C)C(=O)O[C@@H](C(=O)Nc1ccc(Cl)cc1C(=O)C(F)(F)F)c1ccccc1
Agent: CC[Mg]Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)C(=O)O[C@@H](C(=O)Nc1ccc(Cl)cc1[C@@](O)(C#CC1CC1)C(F)(F)F)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethylmagnesium bromide 3 M in ether (2 mL, 6.2 mmol) was added slowly to a solution of cyclopropyl acetylene (0.41 g, 6.2 mmol) in THF (5 mL) in an ice-bath under argon. The mixture was stirred at 0° C. for 1 hour and then 40° C. for 2 hours. Then (R)-2-(4-chloro-2-(2,2,2-trifluoroacetyl)phenylamino)-2-oxo-1-phenylethyl pivalate (12, 0.55 g, 1.24 mmol) in THF (2 mL) was added slowly in an ice-bath. The mixture was stirred at 0° C. for 1.5 hours. 10% Citric acid was added to quench the reaction. The organic layer was washed with water and then evaporated to dryness to give (R)-2-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phe nylamino)-2-oxo-1-phenylethyl pivalate (13). This solid was shown to be 35.9% de by chiral HPLC. The pure product was isolated by chromatography.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[Li]CCCC.CN([CH:20]=[O:21])C>O1CCCC1>[CH:20]([C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])=[O:21]
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)O)cc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a stirred solution of 3-bromo-4-methylbenzoic acid (2.14 g, 10.0 mmol) in tetrahydrofuran (30 mL) under nitrogen at -78° C. was added n-BuLi (10 mL, 2.5 M in THF, 25 mmol) drop-wise. The mixture was stirred for 1 h below −70° C., then DMF (5 mL) was slowly added. The resulting solution was slowly warmed to room temperature and stirred for 1 h, then carefully quenched by slow addition of water (50 mL). The pH was adjusted to −3-4 using aqueous HCl (6 M) and the resulting mixture was extracted with ethyl acetate (2×50 mL). The combined organics was dried (Na2SO4), filtered, and concentrated under reduced pressure to yield the title compound as a yellow solid (1.6 g, 98%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH2:6][NH:7][C:8]([NH2:10])=[O:9].[C:16]([N:24]=[C:25]=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH2:6][NH:7][C:8](=[O:9])[NH:10][C:25]([NH:24][C:16](=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[S:26]
Reactant: NC(=O)NCc1cccc(C(F)(F)F)c1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: O=C(NCc1cccc(C(F)(F)F)c1)NC(=S)NC(=O)c1ccccc1
Reaction time: 18 h

Procedure:
(3-Trifluoromethyl-benzyl)-urea (218 mg; 1.0 mmol) and 163 mg (1.0 mmol) benzoylisothiocyanate were dissolved in acetone and the mixture was heated to reflux. After 18 h of reflux HPLC-MS revealed almost complete conversion to expected product in a very clean reaction. The solvent was evaporated and the residue was dissolved in EtOAc (40 mL). Wash with 2M HCl (5 mL), water (2×5 mL) and brine (5 mL), and the organic phase was dried over MgSO4 and concentrated in vacuo to give 347 mg of a light yellow solid. HPLC-MS indicates a purity of approximately 90%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C:9]2=[O:21])=[CH:4][CH:3]=1.[ClH:22].O1CCOCC1>ClCCl>[ClH:22].[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]2=[O:21])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(F)cc2)C(=O)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1CNCCN1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To the solution of tert-butyl 4-(4-fluorophenyl)-3-oxopiperazine-1-carboxylate (2 g, 6.80 mmol) in dichloromethane (5 ml) was added slowly hydrogenchloride in 1,4-dioxane (16.99 ml, 68.0 mmol) at 0° C. and reaction was stirred for 3 h at 25° C. After completion of the reaction, the solvent was evaporated under reduced pressure to obtained salt was triturated with diethyl ether (2×10 ml) decanted it and dried to give 1-(4-fluorophenyl)piperazin-2-one hydrochloride (1.2 g, 5.20 mmol, 77%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[O:12][C:11](=[O:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1.C(Cl)(Cl)Cl>CC(C)=O>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:16][CH:17]=2)[O:12][C:11](=[O:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(CCBr)cc1
Reactant: O=c1cc(OCc2ccccc2)c2ccc(O)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: O=c1cc(OCc2ccccc2)c2ccc(OCCc3ccc(F)cc3)cc2o1

Procedure:
A mixture of 4-benzyloxy-7-hydroxycoumarin (5.36; 0.02 mole) anhydrous potassium carbonate (4.0 g) and 1-bromo-2-(4-fluorophenyl) ethane (4.06 g) in acetone (100 ml) was stirred at reflux for 20 hours and the inorganic material filtered off. Evaporation of the filtrate in vacuo gave an oil which rapidly set solid on scratching. Chloroform (200 ml) was added and the mixture filtered to remove unchanged 4-benzyloxy-7-hydroxycoumarin. Reevaporation of the filtrate afforded a white solid, 3.34 g (43%) of m.p. 120°, νmax (mull) 1715, 1675, 1620 cm-1 ; τ(CDCl3); 6.93 (2H, t, J 6.7 Hz); 5.80 (2H, t, J 6.7 Hz); 4.87 (2H, S); 4.38 (1H, ); 3.29-2.49 (6H, m) 2.32 (1H, d, J 10 Hz); (Found C, 73.75 H, 5.14 C24H19FO4 requires; C, 73.84; H, 4.91%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:15](=[O:21])[N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C@H:10]([CH3:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:34][C:35]1[CH:40]=[C:39]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[CH:38]=[CH:37][C:36]=1[C:46](=[N:48]O)[NH2:47]>ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:10]([C:11]1[O:13][N:48]=[C:46]([C:36]2[CH:37]=[CH:38][C:39]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])=[CH:40][C:35]=2[Cl:34])[N:47]=1)[CH3:14])[C:15]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:21])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](C(=O)O)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC1
Reactant: CS(=O)(=O)Nc1ccc(C(N)=NO)c(Cl)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: C[C@H](c1nc(-c2ccc(NS(C)(=O)=O)cc2Cl)no1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the product from Step B (132.0 mg, 0.44 mmol) in dichloromethane (5 mL) was added 1,1′-carbonyldiimidazole (148.0 mg, 0.91 mmol). After stirring at room temperature for 1 h, 2-chloro-N′-hydroxy-4-[(methylsulfonyl)amino]benzenecarboximidamide (Intermediate 6, 145.0 mg, 0.55 mmol) was added. After stirring at room temperature for 2 h, the reaction was quenched with saturated aqueous ammonium chloride solution. The organic phase was then dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was dissolved in 10 mL of toluene and heated at 110° C. for 12 h. The toluene was removed under reduced pressure and the residue was then purified by preparative thin layer chromatography (silica gel, 30:70 hexanes/ethyl acetate) to give the desired product.
Reaction SMILES: CC([O-])(C)C.[K+].O.Cl[C:9]([C:20]1[C:24]([CH3:25])=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[N:22]([CH3:33])[N:21]=1)=[C:10]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1)C=O.C(=O)(O)[O-]>C1COCC1>[Cl:19][C:15]1[CH:14]=[C:13]([C:10]#[C:9][C:20]2[C:24]([CH3:25])=[C:23]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[N:22]([CH3:33])[N:21]=2)[CH:18]=[CH:17][N:16]=1
Reactant: Cc1c(C(Cl)=C(C=O)c2ccnc(Cl)c2)nn(C)c1-c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C#Cc2ccnc(Cl)c2)nn(C)c1-c1ccc(F)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To 11 ml of THF cooled to 0° C. were added 0.26 g of Potassium tert-butylate and 20 μl of water. Then a solution of 0.40 g 3-Chloro-2-(2-chloro-pyridin-4-yl)-3-[5-(4-fluoro-phenyl)-1,4-dimethyl-1H-pyrazol-3-yl]-propenal in 7 ml of THF was added at 0°. After stirring for 1 h at 5° C., 10 ml of 5% Bicarbonate solution were added and the aqueous phase was extracted twice with Ethyl acetate. The combined organic phases were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product (0.28 g, yellow oil) was purified by chromatography on silica gel (Heptane/Ethyl acetate 4:1). The desired product was obtained as a white solid (0.275 g, 82%), MS: m/e=326.0 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.I[CH:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH:13]([CH3:15])[CH3:14])[CH:7]=1
Reactant: CC(C)I
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]

Procedure:
A mixture of 5-fluoro-2-nitrophenol (2.5 g, 15.9 mmol), 2-iodopropane (5.4 g, 31.8 mmol), and potassium carbonate (4.2 g, 39.8 mmol) in acetone (40 mL) was heated to reflux for 16 hours. The mixture was cooled and evaporated under vacuum, and the residue was partitioned between ethyl acetate (100 mL) and water (150 mL), and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic layers were washed with water (3×150 mL), dried (MgSO4), and evaporated, providing 3.2 g, in quantitative yield; 1H NMR (CDCl3) δ 1.42 (d, J=6.0 Hz, 6H), 4.63 (septet, J=6.0 Hz, 6H), 6.64-6.72 (m, 1H), 6.76 (dd, J=9.8 Hz, J=2.5 Hz, 1H), 7.88 (dd, J=8.9 Hz, J=6.1 Hz, 1H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[F:7][C:8]([F:18])([F:17])[O:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[F:7][C:8]([F:17])([F:18])[O:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH:12][C:2](=[O:3])[O:4][CH2:5][CH3:6]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccccc1OC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)Nc1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Ethyl chloroformate (4.4 mL, 0.046 mol) was added to a mixture of 2-(trifluoromethoxy)aniline (8.25 g, 0.0466 mol), sodium carbonate (15 g, 0.14 mol), 1,4-dioxane (70 mL) and water (70 mL) at 0° C. and the reaction mixture stirred at room temperature overnight. The reaction mixture was then washed with ether, acidified (pH 3) and the product extracted into EtOAc (3×40 mL). The combined extracts were washed with water (40 mL) and brine (40 mL), dried over Na2SO4 and the solvent removed in vacuo to give the desired product in a 84% yield. 1H NMR (400 MHz, CDCl3): δ 1.33 (t, J=5.2 Hz, 3H), 4.25 (q, J=6.8 Hz, 2H), 6.91 (br, 1H), 7.04 (m, 1H), 7.23 (m, 1H), 7.28 (m, 1H) and 8.2 (m, 1H). MS (ES+): m/z 250.12 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([CH:10]=[O:11])[C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[NH:16][C:17](=[O:19])[CH3:18].[CH2:21]([Mg]Cl)[CH2:22][CH3:23]>CCOCC>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([CH:10]([OH:11])[CH2:21][CH2:22][CH3:23])[C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[NH:16][C:17](=[O:19])[CH3:18]
Reactant: CCC[Mg]Cl
Reactant: COC(=O)c1cc(C=O)c(C(F)(F)F)cc1NC(C)=O
Solvent: CCOCC
Product: CCCC(O)c1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F
Temperature: 20 °C
Reaction time: 1 h
Yield: 23.3 %

Procedure:
To a solution of 2-acetylamino-5-formyl-4-trifluoromethyl-benzoic acid methyl ester (1.52 g, 5.26 mmol) in absolute Et2O (52 mL), under argon, was added a solution of propylmagnesium chloride (2.0 M in Et2O, 5.3 mL, 11 mmol) over 5 min at 20° C. An immediate crystallisation occurred along with an exotherm. The reaction mixture was cooled to 20° C. using an ice/water bath. The reaction mixture was stirred at r.t. for 1 h then poured onto sat. aq NH4Cl and EtOAc. The pH was adjusted to 7 with sat. aq NH4Cl and the layers were separated. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (25 g silica gel, hexanes/EtOAc (1:0→7:3)) to give product as colorless crystals (409 mg, 23%). m.p.: 97-101° C., ESI-MS: m/z 334 [M+H]+, m/z 332 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:12][OH:13])[CH:7]=[C:8]([CH2:10][OH:11])[CH:9]=1)[CH3:2]>C(Cl)Cl.O=[Mn]=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([CH2:10][OH:11])[CH:9]=1)[CH:12]=[O:13])[CH3:2]
Reactant: CCOc1cc(CO)cc(CO)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCOc1cc(C=O)cc(CO)c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 47.9 %

Procedure:
MnO2 (8.37 g, 96.3 mmol) was added to a solution of (3-ethoxy-5-hydroxymethyl-phenyl)-methanol (17.55 g, 96.3 mmol) in CH2Cl2 (175 ml) and the mixture was stirred for 64 h. at room temperature. Thereafter, further MnO2 (8.37 g, 96.3 mmol) was added and the mixture was stirred for 6 h. The mixture was filtered over Celite and the filtrate was concentrated. The product was purified by chromatography. There were obtained 8.32 g (48%) of 3-ethoxy-5-hydroxymethyl-benzaldehyde as a colorless oil.
Reaction SMILES: C([NH:4][C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:18][CH3:19])[CH:6]=1)(=O)C.Cl.[CH2:21](O)C>>[NH2:4][C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:8]([C:9]([O:11][CH2:12][CH3:21])=[O:10])=[C:7]([O:18][CH3:19])[CH:6]=1
Reactant: CCO
Reactant: COC(=O)c1cc([N+](=O)[O-])c(NC(C)=O)cc1OC
Agent: Cl
Product: CCOC(=O)c1cc([N+](=O)[O-])c(N)cc1OC
Yield: 91 %

Procedure:
To a solution of methyl 4-acetamido-2-methoxy-5-nitrobenzoate (135 mg, 0.50 mmol) in ethanol 10 ml) was added concentrated hydrochloric acid (0.5 ml) dropwise and the mixture refluxed under nitrogen overnight. The reaction mixture was then cooled, the solvents removed and the residue purified by column chromatography (silica gel), eluting with 1:1 ethyl acetate/hexane to give ethyl 4-amino-2-methoxy-5-nitrobenzoate as a yellow solid (110 mg, 91%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1>>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: Oc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Product: FC(F)(F)c1ccc(Oc2ccc(N3CCN(Cc4ccccc4)CC3)cc2)cc1
Yield: 29.1 %

Procedure:
The title compound (120 mg, 25%) was prepared from 4-(4-benzyl-piperazin-1-yl)-phenol (268 mg, 1 mmol) and 1-iodo-4-trifluoromethyl-benzene (270 mg, 1 mmol) by the procedure described in step 2 of Example 17: MS (ESI) m/z 413 (M+H): 1H NMR (400 MHz, CDCl3) δ 2.63 (br, 4H), 3 18 (br, 4H), 3.58 (s, 2H), 6.92-6.98 (m, 6H), 7.32-7.35 (m, 5H), 7.52 (d, J=7.2 Hz, 2H).
Reaction SMILES: [NH:1]([C:39]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@H:2]([C:24]([NH:26][C@H:27]([C:35]([O:37]C)=[O:36])[CH2:28][S:29][CH2:30][NH:31][C:32]([CH3:34])=[O:33])=[O:25])[CH2:3][S:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[OH-].[Na+].Cl>O1CCOCC1>[NH:1]([C:39]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C@H:2]([C:24]([NH:26][C@H:27]([C:35]([OH:37])=[O:36])[CH2:28][S:29][CH2:30][NH:31][C:32]([CH3:34])=[O:33])=[O:25])[CH2:3][S:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](CSCNC(C)=O)NC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)NCSC[C@H](NC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5.63 g of Trt-Cys(Trt)-Cys(Acm)-OMe are dissolved in 75 ml of dioxane and 17.5 ml of water and 3.71 ml of 2 N sodium hydroxide solution are cautiously added thereto. After 1 hour at 20°C, the mixture is cooled to 0°C, 3.71 ml of 2 N hydrochloric acid are added and the solution is concentrated under reduced pressure, at room temperature, to approx. 30 ml and is then diluted with 200 ml of chloroform. The solution is washed three times with water and is dried over sodium sulphate. On evaporating off the solvent, the product, which is pure according to thin layer chromatography, is obtained as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([N+:14]([O-:16])=[O:15])=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[CH:17]1([C:23]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([N+:14]([O-:16])=[O:15])=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([N:28]1[CH2:27][CH2:26][CH:25]([C:23]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[O:24])[CH2:30][CH2:29]1)=[O:8]
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OC
Reactant: O=C(C1CCCCC1)C1CCNCC1
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(C(=O)C3CCCCC3)CC2)c([N+](=O)[O-])cc1OC

Procedure:
10.3 g of 3,4-dimethoxy-6-nitrobenzoic acid was converted to the corresponding acid chloride as described in Example 43. It was added to a solution containing 8.83 g of 4-cyclohexylcarbonylpiperidine and 4.58 g oftriethylamine in 300 ml of dichloromethane. Yield 16.4 g (90%), m.p. 120°-125° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[NH:28][C:29](=[O:31])[CH3:30].[CH3:32][C:33]([OH:37])([C:35]#[CH:36])[CH3:34].C(N(CC)CC)C>[Cu]I>[F:27][C:25]1[CH:24]=[CH:23][C:22]([NH:28][C:29](=[O:31])[CH3:30])=[C:21]([C:36]#[C:35][C:33]([OH:37])([CH3:34])[CH3:32])[CH:26]=1
Reactant: C#CC(C)(C)O
Reactant: CC(=O)Nc1ccc(F)cc1Br
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(F)cc1C#CC(C)(C)O
Temperature: 85 °C

Procedure:
0.32 g (1.2 mmol, purity 99%) triphenylphosphine, 0.085 g (0.12 mmol, purity 99%) bis-triphenylphosphine palladium dichloride, and 0.14 g (0.72 mmol, purity 98%) copper(I)iodide are added to a mixture of 56.8 g (0.24 mol, purity 98%) N-(2-bromo-4-fluorophenyl)acetamide, 30.9 g (0.264 mol, purity 98%) 2-methylbut-3-yn-2-ol and 121.4 g (1.2 mol) triethylamine and the mixture is heated for 6 hours while stirring at 85° C. The surplus triethylamine is distilled off in a vacuum, approximately 170 ml toluene is added, the same quantity of water is added, and the phases are separated at ˜70° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[N:10]([O-])=[O:11].[Na+]>C(O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[C:7]=1[N:10]=[O:11]
Reactant: Cc1cc(C)cc(O)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(O)cc(C)c1N=O
Temperature: 0 °C
Yield: 71.6 %

Procedure:
750 ml of concentrated HClare added to a solution of 3,5-dimethyl phenol (80.6 g) in 750 ml of 95% ethyl alcohol. The mixture is cooled to 0° C. in an ice/methanol bath. While maintaining the temperature of the reaction mixture below 5° C. a solution of NaNO2 (69.0 g) in 150 ml of H2O is added dropwise to the reaction mixture. The mixture is stirred at 0° C. for more than an hour and then poured into 9 liters of water. The aqueous mixture is filtered to give a yellow solid which is recrystallized from hot methanol and filtered to give 71.45 grams of a yellow solid, M.P. 180°-181° C. (dec).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][S:10][C:11](=S)[S:12]C>C(#N)C.C(OCC)C>[CH3:9][S:10][C:11]([N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[NH2:8])=[S:12]
Reactant: NNc1ccccc1
Reactant: CSC(=S)SC
Solvent: CCOCC
Solvent: CC#N
Product: CSC(=S)N(N)c1ccccc1
Reaction time: 18 h

Procedure:
To a stirred solution of phenylhydrazine (30 mmol, 1 equiv) in dry acetonitrile (20 mL) was added trithiocarbonic acid dimethyl ester (30 mmol, 1 equiv) slowly at ice bath temperature. The mixture was stirred for 18 hours and diluted with diethylether (30 mL). The resulting white solid was filtered and was washed with ether and dried under nitrogen to afford title compound.