Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@:2]1([CH3:18])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]1=[O:17].N1C=NN=N1.C(N([CH:31]([O:39][P:40]([O-])[O-:41])N(C(C)C)C(C)C)C(C)C)(C)C>N1C=CC=CC=1.C(#N)C>[F:1][C@:2]1([CH3:18])[C@@H:6]2[O:7][P@:40]([O:39][CH3:31])(=[O:41])[O:9][CH2:8][C@H:5]2[O:4][C@H:3]1[N:10]1[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]1=[O:17]
Reactant: CC(C)N(C(C)C)C(OP([O-])[O-])N(C(C)C)C(C)C
Reactant: C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Agent: c1nnn[nH]1
Solvent: c1ccncc1
Solvent: CC#N
Product: CO[P@@]1(=O)OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@](C)(F)[C@@H]2O1
Reaction time: 2 h

Procedure:
To a stirred solution of 1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (730 mg, 2.8 mmol) in dry pyridine (15 mL) was added a 0.45M solution of tetrazole in acetonitrile (15 mL) followed by bis(N,N-diisopropylamino)methylphosphite (0.971 mL, 3.3 mmol) at room temperature. After 2 h, TLC indicated disappearance of the starting material and two non-polar products. The reaction mixture was concentrated under reduced pressure at room temperature and the residue was triturated with EtOAc (30 mL). Tetrazole salts precipitated were filtered off and the filtrate was concentrated under reduced pressure. The residue was chromatographed using 0-40% EtOAc/hexanes gradient to give pure product 2 (92 mg) and mixture of product 1&2 (102 mg). 1H NMR confirmed that the product 2 is a single isomer of the required compound. Stereochemistry is not determined.
Reaction SMILES: [CH2:1]([N:4]([CH2:7][CH:8]=[CH2:9])[C:5]#[N:6])[CH:2]=[CH2:3].[C-]#N.[K+].[CH3:13][OH:14]>O>[CH2:1]([N:4]([CH2:7][CH:8]=[CH2:9])[C:5](=[NH:6])[O:14][CH3:13])[CH:2]=[CH2:3]
Reactant: CO
Reactant: C=CCN(C#N)CC=C
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: C=CCN(CC=C)C(=N)OC
Yield: 67 %

Procedure:
The following reactants were combined in a 1-liter, round-bottom flask: 24.4 g (0.2 mole) diallylcyanamide, 13 g (0.2 mole) KCN and 500 ml methanol. The mixture was heated under reflux for 24 hours, then stripped in vacuo. The residue was dissolved in 250 ml H2O, which was subsequently extracted with three 200 ml portions of diethyl ether. The organic phases were combined, washed with 200 ml of H2O and dried with MgSO4. The solvent was evaporated to yield 20.7 g (67% yield) of N,N-diallyl-O-methylisourea.
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[CH2:9](O)[CH2:10][OH:11].C(OCC)(OCC)OCC.C(OCC)(=O)C>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH3:2][C:1]1([C:4]2[O:5][CH:6]=[CH:7][CH:8]=2)[O:11][CH2:10][CH2:9][O:3]1
Reactant: CC(=O)c1ccco1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOC(OCC)OCC
Product: CC1(c2ccco2)OCCO1
Yield: 46.4 %

Procedure:
A mixture of 4 mL (139.6 mmol) 2-acetylfuran, 8.7 mL (156 mmol) of ethylene glycol, 198 mg (1 mmol) of p-toluenesulfonic acid monohydrate, and 22 mL (132.3 mmol) of triethyl orthoformate was reacted at room temperature under N2 for 3 days. The reaction mixture was poured into a mixture of ethyl acetate (100 mL) and water (100 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL), and the combined organic layer was washed with water (100 mL), sodium bicarbonate solution (150 mL), and brine (100 mL). The organic layer was dried over MgSO4, concentrated in vacuo, and the residue was distilled under reduced pressure (1.5 torr) to afford 9.98 g (50%) of 2-(2-methyl-1,3-dioxolan-2-yl)-furan, as a clear oil, b.p. 24° C./1.5 mm.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[O:5][N:4]=1.[C:14]1([C@@H:20]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:21]([O:23][C@@H:24]2[CH:29]3[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]3)[CH2:25]2)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC#N.O>CCOC(C)=O>[Cl-:1].[C:14]1([C@@H:20]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:21]([O:23][C@@H:24]2[CH:29]3[CH2:28][CH2:27][N+:26]([CH2:2][C:3]4[N:7]=[C:6]([C:8]5[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=5)[O:5][N:4]=4)([CH2:31][CH2:30]3)[CH2:25]2)=[O:22])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ClCc1noc(-c2ccncc2)n1
Reactant: O=C(O[C@H]1CN2CCC1CC2)[C@H](Nc1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: O=C(O[C@H]1C[N+]2(Cc3noc(-c4ccncc4)n3)CCC1CC2)[C@H](Nc1ccccc1)c1ccccc1
Product: [Cl-]
Temperature: 80 °C
Yield: 40.5 %

Procedure:
3-(Chloromethyl)-5-(pyridin-4-yl)-1,2,4-oxadiazole (I51) (45.0 mg, 0.23 mmol) was added to a solution of (R)—((R)-quinuclidin-3-yl) 2-phenyl-2-(phenylamino)acetate (diastereomer 1 of I2) (50 mg, 0.15 mmol) in EtOAc (2 ml). The reaction mixture was heated under microwave irradiation at 80° C. for 3 hours. The solvent was evaporated, and the residue was triturated with Et2O, filtered and dried. The product was purified by flash-chromatography (DCM/MeOH=97/3 to 9/1) and then by preparative HPLC (eluents: CH3CN/H2O) to obtain (R)-3-((R)-2-phenyl-2-(phenylamino)acetoxy)-1-((5-(pyridin-4-yl)-1,2,4-oxadiazol-3-yl)methyl)-1-azoniabicyclo[2.2.2]octane chloride (32.3 mg, 29.0% yield).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][S:18][C:12]=3[NH:11][C:10]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]2[N:38]=[C:37](C(Cl)(Cl)Cl)[O:36][N:35]=2)=[CH:24][CH:23]=1.C(=O)([O-])[O-:44].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[O:44]=[C:37]1[O:36][N:35]=[C:34]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:25]2[CH:26]=[CH:27][C:22]([CH2:21][N:11]3[C:12]4[S:18][CH:17]=[CH:16][C:13]=4[C:14](=[O:15])[N:9]([CH2:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:10]3=[O:19])=[CH:23][CH:24]=2)[NH:38]1
Reactant: O=C([O-])[O-]
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: O=c1[nH]c2sccc2c(=O)n1CCc1ccccc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1[nH]c(-c2ccccc2-c2ccc(Cn3c(=O)n(CCc4ccccc4)c(=O)c4ccsc43)cc2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.9 %

Procedure:
A mixture of 3-(2-phenylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (4.0 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (6.3 g), potassium carbonate (2 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (15 mL) and methanol (15 mL). 1N Aqueous sodium hydroxide solution (15 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 4 with water and 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (0.75 g, 10%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(OCC)(=O)C.O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]([CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[S:32]([CH3:31])(=[O:34])=[O:33])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(NCc2cccnc2)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)N(Cc1cccnc1)c1cccc([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
A 3.2 g. portion of 3-(3-nitrophenylaminomethyl)pyridine was dissolved in 15 ml. of toluene, and 2.7 g. of potassium carbonate and 1.6 ml. of methanesulfonyl chloride were added. The mixture was heated to a gentle boil and stirred overnight under reflux. Twenty-five ml. of water and 25 ml. of ethyl acetate were added, and the organic phase was dried and evaporated under vacuum. The residue was triturated with diethyl ether, filtered and dried to obtain 2.4 g. of the desired product, m.p. 131°-133°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][N:11]3[CH:20]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].S(OCC)(O[CH2:27][CH3:28])(=O)=O>C(O)C>[CH2:27]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][N:11]3[CH:20]=2)[CH:5]=[CH:6][CH:7]=1)[CH3:28]
Reactant: CCOS(=O)(=O)OCC
Reactant: Oc1cccc(-c2cn3ccc4ccccc4c3n2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cccc(-c2cn3ccc4ccccc4c3n2)c1
Temperature: 25 °C

Procedure:
2-(3-Hydroxyphenyl)imidazo[2,1-a]isoquinoline (2.07 g.) is added to 0.63 g. of 85 percent potassium hydroxide in 25 ml. of ethanol. To this mixture, 1.56 ml. of diethyl sulfate in 5 ml. of ethanol is added at 0° to 5° C. The mixture is maintained for 16 hours at room temperature, then is refluxed for 30 minutes. After cooling, the solution is evaporated to dryness and the residue is washed thoroughly with water. Crystallization of the solid from ethanol yields 1 g. of the title product, melting at 102°-3° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([N:15]2[C:16]3[C:12](=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:17]=3)[CH:13]=[CH:14]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(COc2ccc3cc[nH]c3c2)cc1
Reactant: Ic1ccccc1
Product: c1ccc(COc2ccc3ccn(-c4ccccc4)c3c2)cc1

Procedure:
Prepared by Procedure C and Scheme O using 6-(benzyloxy)-1H-indole and iodobenzene: ESMS m/e: 300.0 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=2[O:22][CH3:23])[CH2:9]1)C1C=CC=CC=1.[Cl:24]C(OC(Cl)C)=O>ClCCCl>[ClH:24].[C:20]([C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[C:14]([C@@H:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:19]=1)#[N:21]
Reactant: CC(Cl)OC(=O)Cl
Reactant: COc1ccc(C#N)cc1[C@H]1CN(Cc2ccccc2)CCO1
Solvent: ClCCCl
Product: COc1ccc(C#N)cc1[C@H]1CNCCO1
Product: Cl
Yield: 90.6 %

Procedure:
To a solution of (2S)-4-benzyl-2-(5-cyano-2-methoxyphenyl)-morpholine (10.8 g, 35.0 mmol) in 1,2-dichloroethane (80 ml) was added 1-chloroethyl chloroformate (5.73 ml, 52.5 mmol) at room temperature. Upon disappearance of the starting material, the reaction mixture was concentrated under reduced pressure. The residue was then dissolved in methanol (100 ml) and refluxed for 30 minutes. The solvents were removed in vacuo and the residue was filtered and washed with ethyl acetate to afford (2S)-2-(5-cyano-2-methoxyphenyl)-morpholine hydrochloride (8.08 g, 91%) as white solids.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][OH:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:27][CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][O:23][CH2:27][CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: BrCCOC1CCCCO1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(CO)nc3N21
Agent: [H-]
Agent: [Na+]
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(COCCOC4CCCCO4)nc3N21

Procedure:
This compound was prepared in analogy to Example 15 intermediate c), from (4R,9aR)-6-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester, sodium hydride and 2-(2-bromoethoxy)tetrahydro-2H-pyran.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([C:12](=[N:14][OH:15])[NH2:13])=[CH:10][CH:11]=1)=[O:4].[C:16]1(=O)[O:21][C:19](=[O:20])[CH2:18][CH2:17]1>CN(C)C=O.O>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:16]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[O:15][N:14]=2)=[N:8][CH:7]=1)=[O:4]
Reactant: NC(=NO)c1ccc(NC(=O)CCl)cn1
Reactant: O=C1CCC(=O)O1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CCc1nc(-c2ccc(NC(=O)CCl)cn2)no1

Procedure:
A mixture of compound of example 4 (0.228 g, 1 mmol) and succinic anhydride was stirred in dimethyl formamide (5 mL), at a temperature in the range of 115-120° C. for a period of 16 hours. The reaction mixture was cooled, diluted with water, and extracted with ethyl acetate (3×50 mL). The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude product obtained was purified over silica gel using ethyl acetate as eluent. The pure fractions were concentrated and crystallized using ethyl acetate/petroleum ether, to obtain the title compound.
Reaction SMILES: C(OC(N1[C:12](=[O:13])[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[N:16]=2)([CH3:14])[N:10](C(OC(C)(C)C)=O)C1=O)=O)(C)(C)C.[OH-:30].[Na+]>CCOC(C)=O.CO>[NH2:10][C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[N:16]=1)([CH3:14])[C:12]([OH:13])=[O:30]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1C(=O)N(C(=O)OC(C)(C)C)C(C)(c2cccc(Br)n2)C1=O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(N)(C(=O)O)c1cccc(Br)n1
Reaction time: 0.5 h

Procedure:
A solution of 4-(6-bromo-pyridin-2-yl)-4-methyl-2,5-dioxo-imidazolidine-1,3-dicarboxylic acid di-tert-butyl ester (31.53 g, 67.0 mmol) in 2.5M aq. NaOH soln. (215 ml) was refluxed for 40 h. The reaction mixture was diluted with EtOAc (100 ml) and filtered. The filtrates were separated and the org. layer was washed with H2O. The combined aq. layers were evaporated to dryness to leave a solid that was suspended in MeOH (350 ml) and stirred for 30 min. The suspension was filtered and the white precipitate was washed with MeOH. The filtrates were evaporated to leave a pale orange solid which was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]3[C:14](=[C:15]([C:21](OC)=[O:22])[C:16]=2[C:17](OC)=[O:18])[CH2:13][CH2:12][CH2:11]3)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].[H-].O>ClCCl.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]3[C:14](=[C:15]([CH2:21][OH:22])[C:16]=2[CH2:17][OH:18])[CH2:13][CH2:12][CH2:11]3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1c(C(=O)OC)c(-c2ccc(Cl)c(Cl)c2)n2c1CCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: OCc1c(CO)c(-c2ccc(Cl)c(Cl)c2)n2c1CCC2
Yield: 19.8 %

Procedure:
A solution of dimethyl 2,3-dihydro-5-(3,4-dichlorophenyl)-1H-pyrrolizine-6,7-dicarboxylate (57.8 g, 0.157 mol) in dry dichloromethane (250 mL) was added dropwise, over a 30-min period, to a mechanically stirred mixture of lithium aluminum hydride (14.04 g, 2.35 equiv) in anhydrous ether (400 ml) heated under reflux. The stirred mixture was heated at reflux for 1 h after the addition was completed and cooled in an ice bath. The excess hydride was decomposed with wet ether and then with water until the salts were white. The mixture was filtered (through sintered glass) and the inorganic residue was washed with several portions (ca. 100 mL) of hot dichloromethane until the total filtrate volume was 1.2 L. The filtrate was concentrated in vacuo to a volume of 500 mL, warmed to boiling, and diluted with slow addition of 350 mL of petroleum ether. Compound 2,3-Dihydro-5-(3',4'-dichlorophenyl)-6,7-bis(hydroxy-methyl)-1H-pyrrolizine precipitated as clear, white, chunky prisms (33.8 g); the concentrated mother liquor, after similar treatment, gave an additional 9.71 g of 2,3-dihydro-5-(3',4'-dichlorophenyl)-6,7-bis(hydroxymethyl)-1H-pyrrolizine to a total yield of 89%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([C:9]([F:12])([F:11])[F:10])[C:5]([O:7][CH3:8])=[O:6].[CH:14]([C:16]([CH3:18])=[O:17])=[CH2:15].C(N(CC)CC)C.N1C=CC=CC=1>O>[F:10][C:9]([F:11])([F:12])[C:4]([C:5]([O:7][CH3:8])=[O:6])([C:3]([O:2][CH3:1])=[O:13])[CH2:15][CH2:14][C:16](=[O:17])[CH3:18]
Reactant: COC(=O)C(C(=O)OC)C(F)(F)F
Reactant: C=CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)C(CCC(C)=O)(C(=O)OC)C(F)(F)F
Temperature: 70 °C
Yield: 73.5 %

Procedure:
A mixture of dimethyl(trifluoromethyl)malonate (4.0 g, 20 mmol), methyl vinyl ketone (1.54 g, 22 mmol), triethylamine (0.30 g, 3 mmol), and pyridine (20 ml) was heated for 4 h at 70° C. The reaction mixture was poured into water and worked up as usual. The adduct, dimethyl 1,1,1-trifluoro-5-oxo-2,2-hexanedicarboxylate (3.97 g), b.p. 88°-89° C./0.2 mmHg, was obtained and identified in a similar way.
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:30][C@H:31]([C:36]([NH:38][C@H:39]([C:43]([OH:45])=[O:44])[CH:40]([CH3:42])[CH3:41])=[O:37])[CH2:32][CH:33]([CH3:35])[CH3:34].[C:46]([O:50][C:51]([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][NH-:60])=[O:52])([CH3:49])([CH3:48])[CH3:47].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CO>[NH:1]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:30][C@H:31]([C:36]([NH:38][C@H:39]([C:43]([OH:45])=[O:44])[CH:40]([CH3:41])[CH3:42])=[O:37])[CH2:32][CH:33]([CH3:34])[CH3:35])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[C:46]([O:50][C:51]([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][NH-:60])=[O:52])([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)C[C@H](N)C(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(C)OC(=O)CCCCCCC[NH-]
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)O)C(C)C

Procedure:
In a manner analogous to that discribed in Example 1, using as starting materials 81 mg of BOC-Phe-His-OH, 79 mg of H-Leu-Val-7-tert.-butoxycarbonyl-heptyl amide, 28 mg of HOBt and 57 mg of DCCI, the title compound is obtained in the form of a colourless powder after flash chromatography (30 g of silica gel 60, 40-63 μm, system: methylene chloride/methanol/concentrated ammonia 800:50:1). Rf (methylene chloride/methanol/concentrated ammonia 500:50:1)=0.33.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].O.O.Cl[Sn]Cl>CCO>[NH2:13][C:11]1[CH:10]=[CH:9][C:3]([C:4]([N:6]([CH3:8])[CH3:7])=[O:5])=[C:2]([F:1])[CH:12]=1
Reactant: CN(C)C(=O)c1ccc([N+](=O)[O-])cc1F
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CN(C)C(=O)c1ccc(N)cc1F
Temperature: 85 °C
Yield: 104 %

Procedure:
To a 50 mL round bottom flask was added 2-fluoro-N,N-dimethyl-4-nitro benzamide (2.8 g, 0.0132 mol) and EtOH (20 mL). To the same flask, SnCl2.2H2O (11.9 g, 0.0528 mol) was added and the reaction mixture was maintained at 85° C. for 2 h. The reaction mass was cooled to room temperature and the volatiles were evaporated under reduced pressure. The residue was dissolved in water and ethyl acetate. Aqueous saturated sodium bicarbonate was added to adjust to a pH of 7.0. The reaction mixture was filtered through a pad of Celite® reagent and washed with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the title compound [2.5 g, 100%]. 1H NMR (300 MHz, CDCl3): δ 7.21 (t, J=7.8 Hz, 1H), 6.46 (dd, J′=8.4 Hz, J″=2.4 Hz, 1H), 6.34 (d, J′=11.4 Hz, J″=1.8 Hz, 1H), 3.95 (brs, 2H), 3.08 (s, 3H), 2.95 (d, J=1.8 Hz, 3H); LC-MS (ESI): Calculated mass: 182.1; Observed mass: 183.1 (RT: 0.17 min).
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].[CH2:6]([O:8][CH2:9][CH2:10][NH2:11])[CH3:7]>C(O)(C)C>[CH2:6]([O:8][CH2:9][CH2:10][NH:11][CH2:1][CH:2]([OH:3])[CH2:4][OH:5])[CH3:7]
Reactant: OCC1CO1
Reactant: CCOCCN
Solvent: CC(C)O
Product: CCOCCNCC(O)CO
Reaction time: 15 h
Yield: 69.2 %

Procedure:
A solution of glycidol (15 g, 0.2 mol) in isopropanol (50 ml) was added dropwise under N2 at 70° C. to a solution of 2-ethoxyethylamine (53 g, 0.6 mol) in isopropanol (125 ml). After 15 hours, the isopropanol was removed under reduced pressure (20 mm) and the residue distilled at 120°-5° C. at 0.4 mm to yield 22.6 g (69%) of 1.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1.[Br:23][C:24]1[CH:29]=[C:28]([CH2:30]Br)[CH:27]=[CH:26][C:25]=1[F:32].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Br:23][C:24]1[CH:29]=[C:28]([CH:27]=[CH:26][C:25]=1[F:32])[CH2:30][C:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1
Reactant: Fc1ccc(CBr)cc1Br
Reactant: CC(C)(C)OC(=O)C1CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(Cc2ccc(F)c(Br)c2)CC1
Temperature: -50 °C
Reaction time: 4 h

Procedure:
Under argon, 199.5 ml (1.42 mol) of diisopropylamine were initially charged in 1300 ml of dry THF and cooled to −50° C. 569.1 ml (1.42 mol) of n-butyllithium solution (2.5 M in hexane) were slowly added dropwise. The resulting mixture was warmed to 0° C. and then cooled to −70° C. A solution of 161.9 g (1.14 mol) of tert-butyl cyclopropanecarboxylate in 380 ml THF was added to the reaction solution, with the temperature being kept below −60° C. After 4 h of stirring at −78° C., a solution of 262 g (0.95 mol) of 2-bromo-4-(bromomethyl)-1-fluorobenzene in 480 ml of THF was added, the temperature again being kept below −60° C. The reaction mixture was then slowly warmed to RT overnight, after which 1.5 liters of saturated aqueous ammonium chloride solution and 3.0 liters of ethyl acetate were carefully added. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on 3 kg of silica gel (mobile phase cyclohexane/dichloromethane 9:1, then 5:1). 189.9 g (50.4% of theory) of the title compound were thus obtained.