Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:17])=[CH:4][C:5]([O:13][CH2:14][O:15][CH3:16])=[C:6]([CH:12]=1)[C:7](OCC)=[O:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[C:3]([Cl:17])=[CH:4][C:5]([O:13][CH2:14][O:15][CH3:16])=[C:6]([CH:12]=1)[CH2:7][OH:8]
Reactant: CCOC(=O)c1cc(Br)c(Cl)cc1OCOC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCOc1cc(Cl)c(Br)cc1CO
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
In THF (800 ml) was dissolved ethyl 5-bromo-4-chloro-2-methoxymethoxybenzoate (161.4 g). To the solution was added lithium aluminum hydride (19.2 g) at 0° C. over a period of 30 minutes, and the mixture was stirred for further 30 minutes. The reaction mixture was poured into a saturated aqueous saline solution, to which was added ethyl acetate, followed by subjecting the mixture to filtration with celite. The organic layer was washed with a saturated aqueous saline solution, dried (anhydrous magnesium sulfate), and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane) to give 5-bromo-4-chloro-2-methoxymethoxybenzyl alcohol (137.9 g) (Compound B-34). The physical properties are shown in Table 8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH2:9][CH2:10]2)=[CH:5][CH:4]=1.[N+](=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N-]>C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6](=[CH:5][CH:4]=1)[CH:7]1[CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]1[CH2:9][CH2:10]2
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: COc1ccc2c(c1)CCC=C2
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)C1C2CCc3cc(OC)ccc3C21

Procedure:
7-Methoxy-1,2-dihydronaphthalene (8.8 g, 0.055 mol) was mixed with 10 ml of degassed absolute methylene chloride and 20 mg of rhodium acetate (appr. 0.1 mol %). The reaction mixture was bubbled with nitrogen and ethyl diazoacetate (2 eq, 50% solution in degassed abs. methylene chloride) was added slowly through the syringe (flow rate about 1 ml/hour) to the stirred solution at ambient temperature. Gas evolution started upon the addition. The reaction was monitored by GC. Additional amount of catalyst was added during the reaction (about 20 mg). GC-ratio of cis/trans isomers was 21:48.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:11]1[CH:28]=[CH:27][C:14]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:26])[CH2:24][NH2:25])[CH2:18][CH2:17]2)=[CH:13][CH:12]=1.C(N(CC)CC)C.N>C(Cl)(Cl)Cl>[C:1]([NH:25][CH2:24][C:23]([NH:22][CH:19]1[CH2:18][CH2:17][N:16]([CH2:15][C:14]2[CH:13]=[CH:12][CH:11]=[CH:28][CH:27]=2)[CH2:21][CH2:20]1)=[O:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC(=O)NC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=C(Cl)c1ccccc1
Agent: N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(CNC(=O)c1ccccc1)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of benzoyl chloride (0.060 mmol) in chloroform (0.4 mL) was added to a solution of 1-(4-chlorobenzyl)-4-(glycylamino)piperidine (0.050 mmol) and triethylamine (0.070 mmol) in chloroform (1.0 mL). After the reaction mixture was agitated at room temperature for 2.5 h, (aminomethyl)polystyrene resin (1.04 mmol/g, 50 mg, 50 mmol) was added and the mixture was agitated at room temperature for 12 h. The reaction mixture was filtered and the resin was washed with dichloromethane (0.5 mL). The filtrate and washing were combined, dichloromethane (4 mL) was added, and the solution was washed with 2 N aqueous NaOH solution (0.5 mL) to give 4-(N-benzoylglycyl)amino-1-benzylpiperidine (compound No. 386) (11.3 mg, 64%): The purity was determined by RPLC/MS (94%); ESI/MS m/e 352.0 (M++H, C21H25N3O2).
Reaction SMILES: [CH2:1]([NH:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10])[CH2:2][CH3:3].Cl.Cl[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.C1(O)C=CC=CC=1>ClCCl>[CH2:1]([N:4]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10])[CH2:2][CH3:3]
Reactant: Clc1ccncc1
Reactant: CCCNN1CCCC1=O
Agent: Cl
Solvent: Oc1ccccc1
Solvent: ClCCl
Product: CCCN(c1ccncc1)N1CCCC1=O
Temperature: 143 °C
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
A slurry consisting of 1-(propylamino)-2-pyrrolidinone (7.96 g), 4-chloropyridine hydrochloride (6.31 g) and phenol (20.9 g) was heated in a 143° C. oil bath under nitrogen. After 30 min., the resulting solution was treated with additional 4-chloropyridine hydrochloride (6.30 g) and heated for an additional 30 minutes. The mixture was cooled to room temperature and diluted with dichloromethane. The organic layer was washed with dilute aqueous sodium bicarbonate and the combined aqueous layers back-extracted with dichloromethane and ether. The combined organic layers were washed with brine and dried (K2CO3). Filtration, concentration, and purification via flash column chromatography (silica gel, 10% MeOH/DCM) and preparative HPLC afforded 3.65 g (30%) of 1-(propyl-4-pyridinylamino)-2-pyrrolidinone as an oil. The oxalate was prepared with 1.0 eq. oxalic acid in absolute ethanol, m.p. 194°-195.5° C.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([CH3:24])[C:5]([CH2:6][NH:7][C:8]2[C:9]3[N:10]([C:15](C(O)=O)=[C:16]([CH3:18])[N:17]=3)[CH:11]=[C:12]([CH3:14])[CH:13]=2)=[C:4]([CH3:25])[CH:3]=1.C1(OC2C=CC=CC=2)C=CC=CC=1.[Cl-]>C(OCC)C>[CH3:18][C:16]1[N:17]=[C:9]2[C:8]([NH:7][CH2:6][C:5]3[C:4]([CH3:25])=[CH:3][C:2]([F:1])=[CH:23][C:22]=3[CH3:24])=[CH:13][C:12]([CH3:14])=[CH:11][N:10]2[CH:15]=1
Reactant: Cc1cc(NCc2c(C)cc(F)cc2C)c2nc(C)c(C(=O)O)n2c1
Agent: [Cl-]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Product: Cc1cc(NCc2c(C)cc(F)cc2C)c2nc(C)cn2c1
Yield: 55.5 %

Procedure:
A mixture of 8-(4-fluoro-2,6-dimethylbenzylamino)-2-methyl-6-methylimidazo[1,2-a]pyridine 3-carboxylic acid (0.35 g, 1.03 mmol) and diphenyl ether and refluxed for 10 min. Petroleum ether 40-60 was added at room temperature followed by hydrogene chloride in diethyl ether. The petroleum ether diphenlether layer was removed from the formed precipitate. The precipitate was washed with petroleum ether thereafter dissolved in methylene chloride and basified with sodium hydroxide (2M). The layers were separated and the organic layer was washed with water. The solvent was evaporated and the residue was chromatographed (hexane:ethyl acetate, 2:1) giving 0.17 g (50%) of the title compound.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]1[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][C:17]([O-:19])=[O:18])=O)(C)(C)C.[CH2:27](O)[CH3:28].[ClH:30]>>[ClH:30].[NH2:8][CH2:9][CH2:10][C:11]1[CH:23]=[CH:22][C:21]([CH:24]([CH3:25])[CH3:26])=[CH:20][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:27][CH3:28])=[O:18]
Reactant: CCO
Reactant: CC(C)c1ccc(CCNC(=O)OC(C)(C)C)c(OCCCC(=O)[O-])c1
Agent: Cl
Product: CCOC(=O)CCCOc1cc(C(C)C)ccc1CCN
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-[2-(2-tert-Butoxycarbonylaminoethyl)-5-isopropylphenoxy]butyrate (0.283 g) was deissolved in 10 mL of 35% hydrogen chloride ethanol solution, and the mixture was stirred at room temperature for 5 hours. The solvent was removed under reduced pressure to give 0.235 g of ethyl 4-[2-(2-aminoethyl)-5-isopropylphenoxy]butyrate hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[O:21][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:19][C:18]=1[CH2:28][CH2:29]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:29][CH2:28][C:18]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:21][C:17]=2[CH3:16])=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(NC(=O)OC(C)(C)C)cc1
Reaction time: 16 h
Yield: 79.6 %

Procedure:
To a solution of 5.00 g of (4-hydroxy-phenyl)-carbamic acid tert-butyl ester, 7.28 g of 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethan-1-ol and 9.40 g of triphenylphosphine in 100 ml of THF was added at 0° C. a solution of 7.25 g of diisopropyl azodicarboxylate in 50 ml of THF over 30 min and stirring was continued at 22° C. for 16 h. A further portion of 1.88 g of triphenylphosphine and 1.45 g of diisopropyl azodicarboxylate in 10 ml of THF was added at 0° C. and stirring was continued at 22° C. for 2 h after which time conversion was complete. The mixture was evaporated and the residue purified by chromatography (SiO2, n-hexane/AcOEt 4:1) to give 7.5 g of the title compound as a colorless solid. MS: (M+H)− 395.4.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[C:12]([NH:14][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]1[O:9][CH2:8]1)#[N:2].[CH:22]([NH2:25])([CH3:24])[CH3:23]>C(O)C>[C:1]([C:3]1[CH:13]=[C:12]([NH:14][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]([OH:9])[CH2:8][NH:25][CH:22]([CH3:24])[CH3:23])#[N:2]
Reactant: CC(C)N
Reactant: CCCCCC(=O)Nc1ccc(OCC2CO2)c(C#N)c1
Solvent: CCO
Product: CCCCCC(=O)Nc1ccc(OCC(O)CNC(C)C)c(C#N)c1

Procedure:
Ten grams (0.035 mol) of 1-(2-cyano-4-hexanoylamino-phenoxy)-2,3-epoxypropane were dissolved in 100 ml of ethanol and, after the addition of 8.3 gm (0.14 mol) of isopropylamine, the mixture was refluxed for one hour. The solvent was evaporated in vacuo, and the remaining residue solidified. It was recrystallized twice from acetonitrile. The white crystalline base was recovered by suction filtration and dried.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].CO[C:11]1[C:12](OC)=CC2[Te]C(C)=[N+](CC#C)C=2[CH:23]=1.[CH3:26][C:27]1[Te:28][C:29]2[CH:35]=[C:34]([CH3:36])[C:33]([CH3:37])=[CH:32][C:30]=2[N:31]=1>>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[CH3:26][C:27]1[Te:28][C:29]2[CH:35]=[C:34]([CH3:36])[C:33]([CH3:37])=[CH:32][C:30]=2[N+:31]=1[CH2:12][C:11]#[CH:23]
Reactant: C#CC[n+]1c(C)[te]c2cc(OC)c(OC)cc21
Reactant: Cc1nc2cc(C)c(C)cc2[te]1
Agent: O=S(=O)([O-])C(F)(F)F
Product: C#CC[n+]1c(C)[te]c2cc(C)c(C)cc21

Procedure:
This compound was prepared in the same way and on the same molar scale as the compound of Example 46, except that 2,5,6-trimethylbenzotellurazole (Example 22) was used in place of 5,6-dimethoxy-2-methylbenzotellurazole. Yield 1.10 g (72% of theory) cream colored powder, m.p. 189°-192° C. dec. The infrared, nuclear magnetic resonance, and mass spectra were in agreement with that expected for the structural formula.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.[CH:15]1([NH2:19])[CH2:18][CH2:17][CH2:16]1>ClCCl.O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:19][CH:15]2[CH2:18][CH2:17][CH2:16]2)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: NC1CCC1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(NC2CCC2)c([N+](=O)[O-])c1
Yield: 148.8 %

Procedure:
To a solution of 4-fluoro-3-nitro-benzoic acid methyl ester (14.51 g, 50.9 mmol) in dichloromethane (150 ml) was added cyclobutylamine (14 ml, 164 mmol) slowly with cooling on an ice bath. After 2 hours at 23° C. the reaction was diluted with water and extracted with dichloromethane. The organic layer was dried with sodium sulfate and concentrated in vacuo to give 18.95 g of 4-cyclobutylamino-3-nitro-benzoic acid methyl ester.
Reaction SMILES: [NH2:1][CH:2]([C:8]#[N:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C=CC=CC=1.[F:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:18]=1[C:19](Cl)=[O:20]>ClCCl.C(OCC)(=O)C>[C:8]([CH:2]([NH:1][C:19](=[O:20])[C:18]1[C:17]([F:16])=[CH:25][CH:24]=[CH:23][C:22]=1[F:26])[C:3]([O:5][CH2:6][CH3:7])=[O:4])#[N:9]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CCOC(=O)C(N)C#N
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)NC(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a solution of ethyl 2-amino-2-cyanoacetate (1 eq) in 6 mL of dichloromethane was added pyridine (1.5 eq) and 2,6-difluorobenzoyl chloride (1 eq) at 0° C. The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate, washed with brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc:hexanes=1:1) to give the titled compound (84%). LC/MS (m/z): 269.1 (MH+), Rt: 0.69 min.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:9][O:10][C:11](=[O:16])[NH:12][CH2:13][CH2:14]Cl.[F:17][C:18]1[CH:19]=[C:20]([CH:29]=[C:30]([F:32])[CH:31]=1)[O:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>CN(C)C=O>[CH3:9][O:10][C:11](=[O:16])[NH:12][CH2:13][CH2:14][O:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][C:20]2[CH:29]=[C:30]([F:32])[CH:31]=[C:18]([F:17])[CH:19]=2)=[CH:27][CH:26]=1
Reactant: COC(=O)NCCCl
Reactant: Oc1ccc(Oc2cc(F)cc(F)c2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)NCCOc1ccc(Oc2cc(F)cc(F)c2)cc1

Procedure:
21.3 g of potassium carbonate powder, 1.5 g of finely powdered potassium iodide and 16 g of 2-chloroethylcarbamic acid methyl ester are added to a solution of 17.1 g of 4-(3,5-difluorophenoxy)-phenol in 100 ml of dimethylformamide, and the reaction mixture is heated at +95° C. for 15 hours. The reaction mixture is then cooled, poured onto ice-water and extracted repeatedly with ether. The combined ether phases are washed with water and dried over sodium sulfate. The solvent is distilled off completely. The crude product is purified further by chromatography over silica gel (eluant: petroleum ether (40° C.-65° C.)/diethyl ether, 5:1), yielding 2-[4-(3,5-difluorophenoxy)-phenoxy]-ethylcarbamic acid methyl ester, n21D : 1.5394.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][S:7]([CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=1)[CH3:11])(=[O:9])=[O:8].C[Li].[CH3:27]C(C)=O.C([O:33][CH2:34][CH3:35])C>C1COCC1>[Br:18][C:14]1[CH:13]=[C:12]([C:10]([S:7]([NH2:6])(=[O:8])=[O:9])([C:34]([OH:33])([CH3:35])[CH3:27])[CH3:11])[CH:17]=[CH:16][CH:15]=1
Reactant: CCOCC
Reactant: COc1ccc(CNS(=O)(=O)C(C)c2cccc(Br)c2)c(OC)c1
Reactant: CC(C)=O
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(C)(O)C(C)(c1cccc(Br)c1)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Under inert gas, 2.82 g of N-(2,4-dimethoxybenzyl)-1-(3-bromophenyl)ethanesulfonamide was initially charged in 40 ml of THF, and then, at a temperature of −76° C., 10.00 ml of a 1.6 N methyllithium solution in diethyl ether were added dropwise and the mixture was stirred at constant temperature for 5 minutes. Subsequently, 1.50 ml of acetone were added. After stirring for 5 minutes, the reaction solution was allowed to warm up to room temperature, and the solvent was removed under reduced pressure. The residue was dissolved in 30 ml of dichloromethane, 2 ml of trifluoroacetic acid were added and the mixture was stirred at room temperature for 90 minutes. The conversion was checked by LCMS, a further 2 ml of trifluoroacetic acid were added and the mixture was stirred for 75 minutes. Then, 40 ml of water were added while stirring vigorously, the phases were separated and the aqueous phase was washed again with 2×30 ml of dichloromethane. The combined organic phases were concentrated by rotary evaporation and coevaporated twice with toluene. The crude product was purified by means of normal phase chromatography using a Flashmaster with a dichloromethane/methanol gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (1.10 g) with a molecular weight of 322.2 g/mol (C11H16BrNO3S); MS (ESI): m/e=341 (M+H2O+H+).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[I-].[K+].Cl[CH2:26][CH2:27][CH2:28][C:29]#[CH:30]>CS(C)=O>[F:7][C:8]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:9]=1[O:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:30][CH2:29][CH2:28][C:27]#[CH:26])=[CH:15][CH:16]=1
Reactant: Oc1ccc(Oc2ccc(F)cc2F)cc1
Reactant: C#CCCCCl
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: C#CCCCOc1ccc(Oc2ccc(F)cc2F)cc1
Temperature: 25 °C

Procedure:
With cooling, a solution of 4.2 g of potassium tert-butoxide in 20 ml of anhydrous dimethyl sulfoxide is added to a solution of a 8 g of 4-(2,4-difluorophenoxy)phenol in 20 ml of anhydrous dimethyl sulfoxide and 0.3 g of finely powdered potassium iodide. With stirring, a solution of 4,4 g of 1-chloro-4-pentine in 5 ml of dimethyl sulfoxide is added dropwise at 10°-15° C. to the above mixture. After 2 hours the reaction mixture is warmed to room temperature (20°-23° C.) and stirred for 24 hours at this temperature. The reaction mixture is then poured into ice-water and extracted repeatedly with a 1:2 mixture of diethyl ether/hexane. The combined organic phases are washed until neutral with cold 10% aqueous sodium hydroxide and then with water and dried over sodium sulfate. The solvent is removed by vacuum distillation and the residue is further purified by chromatography over silica gel 60 (eluant: 1:9 mixture of diethyl ether/n-hexane), affording the pure 1-[4-(2,4-difluorophenoxy)phenoxy]-4-pentine with a refractive index nD22 =1.5392.
Reaction SMILES: [C:1]([C:4]1[CH:40]=[CH:39][C:7]([O:8][CH2:9][CH:10]([OH:38])[CH2:11][O:12][C:13]2[C:14]([C:36]#[N:37])=[C:15]([NH:19][C:20]([C:22]3[N:26](CC4C=CC(OC)=CC=4)[N:25]=[N:24][N:23]=3)=[O:21])[CH:16]=[CH:17][CH:18]=2)=[C:6]([CH2:41][CH2:42][CH3:43])[C:5]=1[OH:44])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[C:1]([C:4]1[CH:40]=[CH:39][C:7]([O:8][CH2:9][CH:10]([OH:38])[CH2:11][O:12][C:13]2[C:14]([C:36]#[N:37])=[C:15]([NH:19][C:20]([C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[O:21])[CH:16]=[CH:17][CH:18]=2)=[C:6]([CH2:41][CH2:42][CH3:43])[C:5]=1[OH:44])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCC(O)COc2cccc(NC(=O)c3nnnn3Cc3ccc(OC)cc3)c2C#N)ccc(C(C)=O)c1O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCCc1c(OCC(O)COc2cccc(NC(=O)c3nnn[nH]3)c2C#N)ccc(C(C)=O)c1O

Procedure:
A solution of 7.1 g (11.8 mmol) of N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-2-hydroxypropoxy]-2-cyanophenyl}-1-(4-methoxybenzyl)tetrazole-5-carboxamide in 150 ml of trifluoroacetic acid and 15 ml of anisole is heated at reflux temperature for 30 minutes. The reaction mixture is concentrated under reduced pressure, about 200 ml of ether and 300 ml of petroleum ether are added to the residue, and the crystals are filtered off. The N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-2-hydroxypropoxy]-2-cyanophenyl}-1H-tetrazole-5-carboxamide of melting point 210°-213° thus obtained is dissolved in 50 ml of hot acetone, and one equivalent of triethanolamine in 20 ml of acetone is added. Crystallisation sets in after ether has been addded. This gives the triethanolammonium salt of N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-2-hydroxypropoxy]-2-cyanophenyl}-1H-tetrazole-5-carboxamide of melting point 80°-82°.
Reaction SMILES: [CH3:1][C@H:2]1[O:6][C:5](=[O:7])[NH:4][C@@H:3]1[C:8]([OH:10])=O.[N+]([O-])(O)=O.[N+:15]([O:18][CH2:19][CH2:20][NH2:21])([O-:17])=[O:16]>>[N+:15]([O:18][CH2:19][CH2:20][NH:21][C:8]([C@@H:3]1[C@@H:2]([CH3:1])[O:6][C:5](=[O:7])[NH:4]1)=[O:10])([O-:17])=[O:16]
Reactant: NCCO[N+](=O)[O-]
Reactant: C[C@H]1OC(=O)N[C@@H]1C(=O)O
Solvent: O=[N+]([O-])O
Product: C[C@H]1OC(=O)N[C@@H]1C(=O)NCCO[N+](=O)[O-]
Yield: 14.2 %

Procedure:
A procedure similar to that described in Example 19 was repeated, but using 180 mg of (4S,5R)-5-methyl-2-oxooxazolidine-4-carboxylic acid and 230 mg of N-(2-nitrooxyethyl)amine nitrate, after which the product was recrystallized from methylene chloride, to obtain 41 mg of the title compound as colorless needles, melting at 81.5°-82.5° C.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[N:6]=[CH:7][N:8]([C@H]3C[C@@H](CO)[C@H](O)[C@@H]3O)[C:9]=2[N:10]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.[OH-].[Na+]>CS(C)=O.CO>[NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[N:6]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:7]=[N:8][C:9]=2[N:10]=1
Reactant: Nc1nc2c(ncn2[C@H]2C[C@@H](CO)[C@H](O)[C@@H]2O)c(=O)[nH]1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Product: Nc1nc2ncn(Cc3ccccc3)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.4 %

Procedure:
A mixture of 2-amino-9-[(1S,2R,3S,4S)-2,3-dihydroxy-4-(hydroxymethyl)-cyclopentyl]-1,9-dihydro-6H-purin-6-one (60.0 g, 0.213 mol) and benzyl bromide (60.9 mL, 0.512 mol) in DMSO (300 mL) was stirred at room temperature for 18 h. Concentrated HCl aqueous solution (150 mL) was added to the reaction mixture and stirring was continued for 45 min. The resulting mixture was poured into MeOH (1800 ml). The solution was neutralized with 2 M NaOH solution. The resulting white precipitate was collected by filtration, washed with water, and dried under vacuum to afford the product (48 g, 93.3%). LCMS calculated for C12H12N5O (M+H): 242.1. found: 242.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH3:9].C1C(=O)N(Br)C(=O)C1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(Cl)(Cl)(Cl)Cl.CCO>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:22]1[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]1
Reactant: Cc1ccc(I)cc1F
Reactant: CN1CCNCC1
Agent: O=C1CCC(=O)N1Br
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Product: CN1CCN(Cc2ccc(I)cc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
To a mixture of 2-fluoro-4-iodotoluene (0.94 g, 4.0 mmol) in CCl4 (40 mL) were added BPO (0.02 g, 0.08 mmol) and NBS (0.78 g, 4.4 mmol) under N2. The reaction mixture was refluxed for 5 h, then cooled and concentrated in vacuo. To the residue was added a solution of methylpiperazine (2.00 g, 20 mmol) in EtOH (40 mL) under N2. The mixture was stirred at rt overnight and concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=10:1) to give the title compound as a white solid (0.69 g, 52%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C([Cl:15])=O>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([Cl:15])=[O:8]
Reactant: Cc1ccc(Br)cc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(Br)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The above 5-bromo-2-methylbenzoic acid (10.0 g) was suspended in dichloromethane (100 ml), and thereto were added oxalyl chloride (8.1 ml) and N,N-dimethylformamide (2 drops). The mixture was stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure to give 5-bromo-2-methylbenzoyl chloride. This benzoyl chloride was dissolved in dichloromethane (200 ml), and thereto was added N,O-dimethylhydroxylamine hydrochloride (12.3 g). To the mixture was added dropwise triethylamine (20 ml) at 0° C., and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate, and washed successively with water, 10% aqueous hydrochloric acid solution, water, a saturated aqueous sodium hydrogen carbonate solution, and brine. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give N-methoxy-N-methyl-5-bromo-2-methylbenzamide (12.25 g) as oil. APCI-Mass m/Z 258/260 (M+H).