Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[Na+].[C:3](=[O:11])([O:7][CH:8]([CH3:10])[CH3:9])OCCl.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[C:20]1[CH:24]=[C:23]([C:25]2[CH:30]=[C:29]([NH2:31])[CH:28]=[CH:27][N:26]=2)[O:22][N:21]=1.[CH3:32][C:33](C)=O>>[Cl:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([Cl:12])[C:14]=1[C:20]1[CH:24]=[C:23]([C:25]2[CH:30]=[C:29]([NH:31][CH2:32][CH2:33][C:3]([O:7][CH:8]([CH3:9])[CH3:10])=[O:11])[CH:28]=[CH:27][N:26]=2)[O:22][N:21]=1
Reactant: CC(C)=O
Reactant: CC(C)OC(=O)OCCl
Reactant: Nc1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Agent: [I-]
Agent: [Na+]
Product: CC(C)OC(=O)CCNc1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Sodium iodide (1.4 g, 9.3 mmol) was added to a solution of chloromethyl isopropyl carbonate (750 mg, 4.8 mmol) in acetone (5 mL). The resulting mixture was stirred at room temperature for 2.5 h, followed by addition of 2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-amine (500 mg, 1.6 mmol). The reaction mixture was then stirred at room temperature for 7 d. The reaction mixture was concentrated under reduced pressure to provide isopropyl 3-(2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-ylamino)propanoate, which was carried forward without further purification. 1H NMR (CDCl3): 8.56 (d, 1H), 7.96 (s, 1H), 7.62 (m, 1H), 7.42-7.30 (m, 4H), 7.01 (s, 1H), 6.26 (d, 2H), 5.02 (m, 1H), 1.31 ppm (d, 6H).
Reaction SMILES: [NH:1]1[C:11]2C(=CC=CC=2)C(=O)C1=O.C1C=CC(N[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:20])=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].[N+:32](C1C=CC=CC=1)([O-])=O>>[N:21]1([NH2:32])[C:22]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:11]([NH2:1])[C:19]1=[O:20]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: O=C(Nc1ccccc1)Nc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: NC1C(=O)N(N)c2ccccc21
Temperature: 0 °C

Procedure:
In a most preferred embodiment of the process of this invention, a solution of 0.05 equivalents of the isatin derivative, 0.06 mole equivalents of the carbanilide, and 0.30 moles of aluminum chloride in 200 ml. of nitrobenzene are maintained at 100° C for about 12 hours. The cooled solution is poured into one liter of ice water and 600 ml. of hexane to precipitate the product. After filtering, the product is suspended in 200 ml. of acetic acid, 5 ml. of water, and 20 ml. of sulfuric acid. This solution is refluxed for approximately 24 hours, cooled and filtered. This refluxing hydrolyzes the reacted anilide and yields the desired oxindole diamine derivative. The filtrate containing the oxindole diamine derivative is neutralized with sodium carbonate and the solution concentrated in vacuo and taken in about 300 ml. of boiling 1N hydrochloric acid. This solution is diluted in about 300 ml. of water, cooled to about 5° C, filtered, and made basic with ammonia to precipitate the product. The product is collected and may be recrystallized from a dioxane hexane solution to yield the pure oxindole diamine derivative.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH:9]([C:14]([F:17])([F:16])[F:15])[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7]2)(=O)[CH3:2].ClCCl.C([SiH](CC)CC)C>O>[CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH:9]([C:14]([F:15])([F:16])[F:17])[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7]2)[CH3:2]
Reactant: CCOC(=O)C1=Cc2cc(C(C)=O)ccc2OC1C(F)(F)F
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1=Cc2cc(CC)ccc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 50 mL single-neck round bottom flask was charged with ethyl 6-acetyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate (1.465 g, 4.662 mmole), dichloromethane (4 mL), and triethyl silane (1.71 mL, 1.25 g, 10.72 mmole) and stirred at RT overnight. The crude reaction was poured into water and extracted several times with dichloromethane. The combined organics were washed with water, then with aqueous 10% sodium carbonate solution, dried over MgSO4, filtered and concentrated in vacuo to yield a colorless oil. This oil was purified by silica chromatography (9 hexane: 1 ethyl acetate) yielding the title compound as a clear, colorless oil (1.25 g, 89%): 1H NMR (acetone-d6/300 MHz) 7.84 (s, 1H), 7.30 (d, 1H, J=2.0 Hz), 7.26 (dd, 1H, J=8.3, 2.0 Hz), 6.93 (d, 1H, J=8.3 Hz), 5.79 (q, 1H, J=7.3 Hz), 4.37-4.24 (m, 2H), 2.60 (q, 2H, J=7.6 Hz), 1.32 (t, 3H, J=7.3 Hz), 1.20 (t, 3H, J=7.6 Hz). GCMS m/z 300 (M+).
Reaction SMILES: O=[C:2]1[NH:7][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:5][C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]1[CH:20]([CH2:25][CH2:26][CH3:27])[C:21]([O:23][CH3:24])=[O:22].P(Cl)(Cl)([Cl:30])=O.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:30][C:2]1[C:3]([CH:20]([CH2:25][CH2:26][CH3:27])[C:21]([O:23][CH3:24])=[O:22])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCC(C(=O)OC)c1c(-c2ccccc2)nc(N2CCCCC2)[nH]c1=O
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: CCCC(C(=O)OC)c1c(Cl)nc(N2CCCCC2)nc1-c1ccccc1

Procedure:
To a suspension of methyl 2-(6-oxo-4-phenyl-2-(piperidin-1-yl)-1,6-dihydropyrimidin-5-yl)pentanoate (1.74 g; 4,71 mmol) in dry toluene (10 mL) under nitrogen atmosphere were carefully added phosphorus oxychloride (4.38 mL; 47.1 mmol) and dimethylaniline (0.476 mL; 3.77 mmol) and the reaction mixture was heated to reflux for 3 h. The volatiles were removed under reduced pressure (while the reaction mixture was still at elevated temperature), the residue was cooled in an ice-bath and quenched by adding crushed ice and a saturated solution of sodium hydrogen carbonate until neutralization. The aqueous layer was extracted with ethyl acetate, the organics were collected, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (1-10%) in heptane furnished 0.040 g (1.6%, over 3 last steps) of the title compound as a yellow oil.
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:23])[C@@H:8]([NH:15]C(OC(C)(C)C)=O)[CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)Cl>[CH:1]1([O:6][C:7](=[O:23])[C@@H:8]([NH2:15])[CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)OC1CCCC1)C1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](C(=O)OC1CCCC1)C1CCCCC1
Reaction time: 1.5 h
Yield: 96.2 %

Procedure:
(S)-tert-butoxycarbonylamino-cyclohexyl-acetic acid cyclopentyl ester (1.17 g, 3.60 mmol) was dissolved in a TFA/DCM mixture (1:1, 10 ml) at 0° C. The solution was stirred for 90 minutes, the solvent removed in vacuo. The residue was azetroped with a DCM/heptane mixture (2×) to give a gum. The gum was redissolved in DCM (10 ml) and washed with saturated aqueous NaHCO3 solution (3×10 ml), dried (MgSO4) and filtered. The solvent of the filtrate was removed in vacuo to give the product as an oil (0.780 g, 78% yield). 1H NMR (300 MHz, CDCl3), δ: 1.00-1.40 (10H, m, CH×10), 1.50-2.00 (8H, m, CH×8), 3.25 (1H, d, CH, J=7.2Hz), 5.20 (1H, m, CH).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[N:10][OH:11])[C:2]1=[N:12][OH:13].[H-].[Na+].S(OC)(O[CH3:20])(=O)=O.O>CN(C)C=O>[CH3:20][O:11][N:10]=[C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][C:2]1=[N:12][OH:13]
Reactant: ON=C1Oc2ccccc2C1=NO
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CON=C1C(=NO)Oc2ccccc21
Reaction time: 1 h
Yield: 6.1 %

Procedure:
A solution of 11 g (0.0617 mol) of benzofuran-2,3-dione dioxime in 50 ml of dimethylformamide is added dropwise to a suspension of 2.4 g (0.06 mol) of 60% strength sodium hydride in 25 ml of dimethylformamide, and stirring is effected at 20° C. for one hour. 7.55 g (0.06 mol) of dimethyl sulphate are then added dropwise and stirring is continued at 20° C. for a further 16 hours. The reaction mixture is poured into water and the resulting mixture is extracted with ethyl acetate, the organic phase is dried over sodium sulphate and concentrated under reduced pressure. The residue is chromatographed over silica gel using hexane/acetone (7:3). Stirring the residue with diethyl ether affords 0.7 g of benzofuran-2,3-dione3-(O-methyl-oxime)2-oxime (VIII-1) as a mixture of stereoisomers consisting of 90.6% of isomer A and 9% of isomer B (HPLC).
Reaction SMILES: [F:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:31]=[CH:30][C:20]([O:21][C:22]2[CH:23]=[CH:24][C:25]([F:29])=[C:26]([OH:28])[CH:27]=2)=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].[C:37]([O:41][CH2:42][CH3:43])(=[O:40])[CH2:38]O>>[F:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:31]=[CH:30][C:20]([O:21][C:22]2[CH:23]=[CH:24][C:25]([F:29])=[C:26]([CH:27]=2)[O:28][CH2:38][C:37]([O:41][CH2:42][CH3:43])=[O:40])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15]
Reactant: CCOC(=O)CO
Reactant: Cc1c(N(Cc2ccc(Oc3ccc(F)c(O)c3)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Product: CCOC(=O)COc1cc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)ccc1F

Procedure:
The product from Example 305G and ethyl glycolate were processed as described in Example 62A to provide the title compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]2[O:18][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=3)[N:19]=2)=[CH:15][CH:14]=1
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: NC(=O)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2coc(-c3ccc(Br)cc3)n2)cc1
Temperature: 160 °C

Procedure:
A mixture of 2-bromo-4′-methylacetophenone (152 mg, 0.7 mmol) and 4-bromobenzamide (200 mg, 1.0 mmol) was heated to 160° C. for 3 hours, cooled to room temperature, dissolved in ethyl acetate (20 mL), and treated with 5% sodium bicarbonate (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 50% ethyl acetate/hexanes to provide the desired product. MS (DCI) m/e 314, 316 (M−H)−, (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.00-7.97 (m, 2H), 7.79-7.76 (m, 2H), 7.77-7.74 (m, 2H), 7.29-7.27 (m, 2H), 2.34 (s, 31).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([C:12]1[C:13]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[N:14][C:15]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][C:17]=1[CH3:18])(=[O:11])[CH3:10].C(Cl)(Cl)(Cl)Cl>C(O)C>[C:9]([C:12]1[C:13]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[N:14][C:15]([NH:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[C:16]([Br:1])[C:17]=1[CH3:18])(=[O:11])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1c(C)cc(NC(C)(C)C)nc1NC(C)(C)C
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: CC(=O)c1c(NC(C)(C)C)nc(NC(C)(C)C)c(Br)c1C
Reaction time: 8 h

Procedure:
534 mg. (3 mmol.) of N-bromosuccinimide (recrystallized from water) were added in small portions to a solution of 831 mg. (3 mmol.) of 3-acetyl-2,6-di-t-butylamino-4-methylpyridine (Compound V) in 20 ml. of carbon tetrachloride and 5 ml. of ethanol, and the reaction mixture was allowed to stand overnight at room temperature. The reaction mixture was evaporated down at reduced pressure, and the residue was partitioned between ether and water. The organic phase was dried over anhydrous sodium sulfate and evaporated at reduced pressure to obtain yellow crystals. Recrystallization from methanol/water gave the product (990 mg.), m.p. 99°-100° C.
Reaction SMILES: [CH3:1][C@@:2]12[CH2:19][CH2:18][C@@H:17]3[C@:12]([CH3:22])([CH2:13][CH2:14][CH2:15][C:16]3([CH3:21])[CH3:20])[C@H:11]1[CH2:10][S:9](=[O:24])(=[O:23])[C:8]1[C:3]2=[C:4]([C:28]([OH:30])=O)[CH:5]=[C:6]([C:25](O)=[O:26])[CH:7]=1.[CH3:31][N:32](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:55][N:56]1CCOCC1>C1COCC1.CN(C=O)C>[CH3:1][C@@:2]12[CH2:19][CH2:18][C@@H:17]3[C@:12]([CH3:22])([CH2:13][CH2:14][CH2:15][C:16]3([CH3:21])[CH3:20])[C@H:11]1[CH2:10][S:9](=[O:24])(=[O:23])[C:8]1[C:3]2=[C:4]([C:28]([NH:56][CH3:55])=[O:30])[CH:5]=[C:6]([C:25]([NH:32][CH3:31])=[O:26])[CH:7]=1
Reactant: CC1(C)CCC[C@]2(C)[C@H]3CS(=O)(=O)c4cc(C(=O)O)cc(C(=O)O)c4[C@]3(C)CC[C@@H]12
Reactant: CN1CCOCC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(C(=O)NC)c2c(c1)S(=O)(=O)C[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 18 h
Yield: 38 %

Procedure:
A mixture of (1R,10R,11S,16S)-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3,5-dicarboxylic acid (85) (0.07 g, 0.2 mmol), HATU (0.25 g, 0.65 mmol) and 4-methylmorpholine (0.07 mL, 1 mmol) in THF (10 mL) and DMF (2.0 mL) was stirred at room temperature for 18 h in a sealed vessel. The mixture was concentrated under reduced pressure and the residue was triturated with water. The resulting solid was collected by filtration to give (1R,10R,11S,16S)-1,3-N,5-N,11,15,15-hexamethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3,5-dicarboxamide (86) (0.035 g, 47%) as a white solid. 1H NMR (CD3OD): δ 8.38 (d, 1H), 7.88 (d, 1H), 3.54 (m, 2H), 2.90 (d, 6H), 2.67 (d, 1H), 2.18 (d, 1H), 1.90-1.48 (m, 9H), 1.46-1.14 (m, 3H), 1.06-0.93 (m, 4H), 0.90 (s, 3H), 0.87 (s, 3H). MS m/z 461 (C25H36N2O4S+H+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8]1[N:14]([CH3:26])[C:15](=[O:25])[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)=[CH:17][C:7]2=1)(=[O:3])[CH3:2].[C:27](OCC)(=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH2:31]([O:30][C:28](=[O:29])[C:27](=[O:33])[CH2:2][C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8]1[N:14]([CH3:26])[C:15](=[O:25])[C:16]([C:18]3[CH:19]=[CH:20][C:21]([Br:24])=[CH:22][CH:23]=3)=[CH:17][C:7]2=1)=[O:3])[CH3:32]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Br)cc3)c(=O)n(C)c1n2C
Product: CCOC(=O)C(=O)CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Br)cc3)c(=O)n(C)c1n2C

Procedure:
The process is carried out as in Example 80 above, with the compound from Example 60B, 6-acetyl-3-(4-bromophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and diethyl oxalate.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CCCC)=[N+:2]=[N-:3].C1(/C=C/CC(Cl)=O)C=CC=CC=1.N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8]/[CH:9]=[CH:10]/[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Agent: O=C(Cl)C/C=C/c1ccccc1
Agent: [N-]=[N+]=NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCCNC(=O)C/C=C/c1ccccc1
Yield: 55 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, (E)-4-phenylbut-3-enoyl chloride (0.198 g, 1.19 mmol) was reacted with 2-azidoethanamine (0.114 g, 1.19 mmol) and triethylamine (0.239 g, 2.37 mmol) in dichloromethane (5 mL) to give (E)-N-(2-azidoethyl)-4-phenylbut-3-enamide (0.168 g, 55%). 1H NMR (300 MHz, CDCl3) δ 7.68 (d, 1H), δ 7.45 (d, 2H), δ 7.29 (m, 3H), δ 7.04 (t, 1H), δ 6.59 (d, 1H), δ 3.55 (q, 2H), δ 3.47 (t, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 166.9, 141.6, 134.9, 130.1, 129.1, 128.1, 120.8, 51.1, 39.4 ppm; HRMS (ESI) calcd for C11H12N4O (M+) 216.1011, found 216.1005.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C@:3]([OH:9])([CH3:8])[C:4](OC)=[O:5].O.[NH2:13][NH2:14]>>[F:1][C:2]([F:11])([F:10])[C@:3]([OH:9])([CH3:8])[C:4]([NH:13][NH2:14])=[O:5]
Reactant: COC(=O)[C@](C)(O)C(F)(F)F
Reactant: NN
Solvent: O
Product: C[C@](O)(C(=O)NN)C(F)(F)F
Temperature: 130 °C

Procedure:
To a solution of methyl(2S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoate (3.26 g, 19.0 mmol) was added hydrazine monohydrate (2.1 ml). The mixture was heated at 130° C. for 90 min and cooled down to room temperature. After evaporation to dryness, the residue was purified on a small bed of silica gel (100% EtOAc) to afford the title compound.
Reaction SMILES: Cl.N(OCCC(C)C)=O.[CH2:10]([O:17][C:18]([NH:20][C@H:21]([C:24]([NH:26][C@H:27]([C:36]([N:38]=[N+]=[N-])=[O:37])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)=[O:25])[CH2:22][OH:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.[CH3:42][O:43][C:44](=[O:55])[C@H:45]([CH2:51][CH:52]([CH3:54])[CH3:53])[NH:46][C:47](=[O:50])[CH2:48]N>O1CCCC1.C(N(CC)CC)C.CN(C)C=O>[CH3:42][O:43][C:44](=[O:55])[C@H:45]([CH2:51][CH:52]([CH3:53])[CH3:54])[NH:46][C:47](=[O:50])[CH2:48][NH:38][C:36](=[O:37])[C@H:27]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[NH:26][C:24](=[O:25])[C@H:21]([CH2:22][OH:23])[NH:20][C:18]([O:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:19]
Reactant: [N-]=[N+]=NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)CN
Agent: CC(C)CCON=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 7.49 g. of N-benzyloxycarbonyl-L-seryl-L-tyrosyl hydrazide [this compound is reported in Helv. Chim. Acta, 41, 1852 (1958)] in 50 ml. of N,N-dimethylformamide, cooled to -30° C., is first added 16.9 ml. of 3.607 N hydrogen chloride in tetrahydrofuran and then 2.7 ml. of isoamyl nitrite, and the resulting mixture is stirred at -30° C. for 30 minutes. The mixture, which contains N-benzyloxycarbonyl-L-seryl-L-tyrosyl azide, is next cooled to -60° C., and to it are added first 8.57 ml. of triethylamine, then 4.297 g. of glycyl-L-leucine methyl ester hydrochloride and finally 2.52 ml. more of triethylamine. The stirred mixture is allowed to warm to 0° C. during one hour and is stirred at 0° C. for one hour and kept at -5° C. for 48 hours. It is then filtered, and the filtrate is evaporated under reduced pressure at 40°-50° C. The gummy residue is partitioned between dilute hydrochloric acid and ethyl acetate, and the organic layer is separated, washed with saturated aqueous sodium bicarbonate and with saturated aqueous sodium chloride, dried, and evaporated to give a solid residue of N-benzyloxycarbonyl-L-seryl-L-tyrosylglycyl-L-leucine methyl ester; m.p. 166°-167° C., following two crystallizations from ethyl acetate-ether; [α]D25 -25.4° (2% in N,N-dimethylformamide); [α]D25 -38.2° (2.09% in methanol).
Reaction SMILES: C([O-])C.[Na+].C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH:16]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:14][C:13]=2[CH:23]=1)(=O)C>C(O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH:16]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:14][C:13]=2[CH:23]=1
Reactant: CCOC(=O)C1=COc2ccc(OC(C)=O)cc2O1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=COc2ccc(O)cc2O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
Add 0.5 cm3 of a molar solution of sodium ethanolate in ethanol to a solution of 1 g (3.78 mmol) of ethyl 7-acetoxy-1,4-benzodioxin-2-carboxylate in 15 cm3 of anhydrous ethanol under a nitrogen atmosphere. Stir for 18 hours at room temperature and then neutralise with Dowex X-8 resin, acid form, which has been washed beforehand with ethanol. After filtration and concentration to dryness under partial pressure, the crude product obtained is purified by chromatography on a silica column (eluant: petroleum ether/diethyl ether, 80:20). Ethyl 7-hydroxy-1,4-benzodioxin-2-carboxylate is thereby obtained in a yield of 96%. Melting point: 160° C. ##STR43##
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:20][C:21](Cl)=[O:22].[NH2:24][CH2:25][CH2:26][SH:27].[Na]>ClCCl.C(O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:21](=[O:22])[CH2:20][S:27][CH2:26][CH2:25][NH2:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCS
Reactant: O=C(Cl)CCl
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Agent: [Na]
Solvent: CCO
Solvent: ClCCl
Product: NCCSCC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 92.4 %

Procedure:
There was dissolved 15.0 g (0.0604 mol) of 3-[3-(piperidinomethyl)phenoxy]propylamine in 150 ml of dichloromethane and added dropwise 6. 82 g (0.0604 mol) of chloroacetyl chloride under cooling with ice. After dropping, the mixture was stirred for 3.5 hours under cooling with ice and then the solvent was removed under reduced pressure. The residue was dissolved in 150 ml of ethanol and this solution was added to a solution which was prepared by adding 4.65 g (0.0604 mol) of 2-aminoethanethiol to a solution of 3.06 g (0.1329 mol) of sodium 150 ml of ethanol and stirring for 30 minutes at room temperature, and the obtained mixture was refluxed with heating for 3 hours. After being allowed to cool at room temperature, the precipitate was filtrated off, and the solvent was removed under reduced pressure. The obtained residue was dissolved in ethyl acetate and washed with water, and dried over Glauber's salt. Then the solvent was removed under reduced pressure to give 20.4 g of the titled compound as oily matter.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.Br.[CH3:27][NH:28][CH2:29][CH:30]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)[OH:31].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:28]([CH2:29][CH:30]([OH:31])[C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)[CH3:27])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: CNCC(O)c1cccnc1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Agent: Br
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN(C)CC(O)c2cccnc2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 30 h
Yield: 68.1 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 2-(methylamino)-1-pyridin-3-ylethanol hydrobromide (Arch. Pharm. 1961, 294 453-68)(89 mg, 0.38 mmol) and diisopropylethylamine (134 μL, 0.76 mmol) in dry DMF (5.0 mL) was stirred for 30 hours at room temperature. The solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (10 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (87 mg) as a white solid.