Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:19]=[CH:20][C:21](=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[O:27]=[C:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:20][CH2:19][NH:1][CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CCCCCCC(N)C(=O)OCC
Reactant: C=CC(=O)CCCCC
Product: CCCCCC(=O)CCNC(CCCCCCC(=O)OCC)C(=O)OCC
Reaction time: 3 h

Procedure:
The above aminodiester was alternatively prepared in the following manner. Diethyl 2-aminononanedioate (10.40 g) and oct-1-en-3-one (5.04 g) were mixed slowly at 0° C. with stirring, and set aside at room temperature for 3 hours, giving diethyl 2-(3-oxooctylamino)nonanedioate as a colourless oil, δ2.3(4H, multiplet, -CH2 -CO2Et and NCH2CH2CO-), 3.16(1H, triplet, EtO2C-CHR-N), 4.11(2H, quartet, --O--CH2 --CH3), 4.17(2H, quartet, -O-CH2 -CH3). A stirred solution of this ketone (13.5 g) in absolute ethanol (140 ml) was treated dropwise at 0° C. with sodium borohydride (665 mg) in absolute ethanol (70 ml), then kept for 31/2 hours at room temperature and concentrated at 40° C. in vacuo. The residue, dissolved in water, was brought to pH 5 with N-hydrochloric acid and extracted thoroughly with chloroform, the extract was washed with water, dried, and evaporated, giving diethyl 2-(3-hydroxy-octylamino)nonanedioate as a colourless oil. Without further purification, the latter was dissolved in dihydropyran (14.0 ml), treated with ether (10 ml) followed by p-toluenesulphonic acid (6.72 g) in portions, and set aside at room temperature for 18 hours. The reaction solution was diluted with ether, washed with aqueous sodium carbonate then water, dried, and evaporated, and the residue was purified by column chromatography on silica in 1:4 hexane/ether, giving diethyl 2-(3-(tetrahydropyran-2-yloxy)octylamino)nonanedioate identical (n.m.r., i.r. mixed t.l.c.) with that prepared previously.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5]Cl)[CH3:2].[C:8]([O:12][CH2:13][CH3:14])(=[O:11])[CH:9]=[CH2:10].[H-].[Na+]>CN(C=O)C>[C@@H:9]1([C:8]([O:12][CH2:13][CH3:14])=[O:11])[CH2:10][C@H:5]1[C:4]([O:3][CH2:1][CH3:2])=[O:7]
Reactant: CCOC(=O)CCl
Reactant: C=CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1C[C@H]1C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl-2-chloroacetate (147 g, 1.20 mol) was added to a stirred solution of ethyl prop-2-enoate (150 g, 1.50 mol) in DMF (700 mL) at 0° C. Sodium hydride (60% w/w, 48.0 g, 1.20 mol) was added portion-wise to the reaction mixture at 0° C. over a period of 2 hours. The reaction mixture was allowed to warm to room temperature. After 16 hours, the reaction mixture was quenched with ice water (500 mL) and extracted with ethyl acetate (2×1.0 L). The organic layers were combined, washed with water (500 mL) and then brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (10-20% ethyl acetate/petroleum ether, linear gradient) to afford diethyl rel-(1R,2R)-cyclopropane-1,2-dicarboxylate. 1H NMR (300 MHz, CDCl3) δ 4.20-4.10 (m, 4H), 2.10-2.05 (m, 2H), 1.48-1.40 (m, 2H), 1.35-1.20 (m, 6H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:12]([F:21])[CH:11]=1.C(=O)([O-])O.[Na+].C1(C)C=CC=CC=1>C(O)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:21][C:12]1[CH:11]=[C:10]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:15]=[CH:14][C:13]=1[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCc1ccc(Br)cc1F
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(-c2cccs2)cc1F
Temperature: 80 °C

Procedure:
A mixture of 40.0 g (0.31 mol) of thiophen-2-ylboronic acid, 80.0 g (0.32 mol) of 4-bromo-2-fluoro-1-pentylbenzene, 18.0 g (15.6 mmol) of tetrakis(triphenylphosphine)palladium(0) and 400 ml of 2 M sodium hydrogencarbonate solution in 1000 ml of ethanol/toluene=3:2 is heated at 80° C. for 19 h. Toluene and water are added to the mixture, and the organic phase is separated off. The aqueous phase is extracted with toluene, and the combined organic phases are washed with sat. sodium chloride solution. The solution is dried using sodium sulfate and evaporated to dryness. The residue is purified by column chromatography (SiO2, n-heptane). 2-(3-Fluoro-4-pentylphenyl)thiophene is obtained as a colourless liquid.
Reaction SMILES: [CH2:1]([C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][C:11]2[O:12][CH:13]=[C:14]([OH:18])[C:15](=[O:17])[CH:16]=2)=[CH:7][CH:6]=1)[C:2]([CH3:4])=O.[NH2:21][C:22]1[C:27]([Cl:28])=[CH:26][C:25]([CH:29]([OH:32])[CH2:30][NH2:31])=[CH:24][C:23]=1[Cl:33]>C1C=CC=CC=1>[NH2:21][C:22]1[C:23]([Cl:33])=[CH:24][C:25]([CH:29]([OH:32])[CH2:30][NH:31][CH:2]([CH3:4])[CH2:1][C:5]2[CH:20]=[CH:19][C:8]([O:9][CH2:10][C:11]3[O:12][CH:13]=[C:14]([OH:18])[C:15](=[O:17])[CH:16]=3)=[CH:7][CH:6]=2)=[CH:26][C:27]=1[Cl:28]
Reactant: CC(=O)Cc1ccc(OCc2cc(=O)c(O)co2)cc1
Reactant: NCC(O)c1cc(Cl)c(N)c(Cl)c1
Solvent: c1ccccc1
Product: CC(Cc1ccc(OCc2cc(=O)c(O)co2)cc1)NCC(O)c1cc(Cl)c(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-[4-acetonylphenoxymethyl]-5-hydroxy-4H-pyran-4-one (1.0 g) and 2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethylamine (0.75 g) in benzene, was heated to reflux for 3 hours under a Dean and Stark head. After cooling, the solvent was removed in vacuo, the residue dissolved in methanol, treated with sodium cyanoborohydride (0.25 g) and then stirred at ambient temperature for 18 hours. The solvent was evaporated under reduced pressure and the residue taken up in ethyl acetate and washed with water (2×50ml), brine (1×50 ml) and dried (MgSO4). After filtration and evaporation of solvent the residue was purified by column chromatography on silica using 3% methanol:chloroform as eluent to give 2-[4-[2-[(4-amino-3,5-dichloro-β-hydroxyphenethyl)amino]propyl]phenoxymethyl]-5-hydroxy-4H-pyran-4-one as a (40:60) mixture of diastereoisomers.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:29]=[C:28]([CH3:30])[N:27]([CH3:31])[N:26]=4)=[CH:21][C:20]=3[CH3:32])=[C:6]([N:10]3[C:14](=[O:15])[N:13]([CH3:16])[N:12]=[N:11]3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[Cl:33]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH:1]1([C:4]2[C:5]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:29]([Cl:33])=[C:28]([CH3:30])[N:27]([CH3:31])[N:26]=4)=[CH:21][C:20]=3[CH3:32])=[C:6]([N:10]3[C:14](=[O:15])[N:13]([CH3:16])[N:12]=[N:11]3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(-c2cc(C)n(C)n2)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Solvent: ClC(Cl)Cl
Product: Cc1cc(-c2nn(C)c(C)c2Cl)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Temperature: 25 °C

Procedure:
A mixture of 1-{3-cyclopropyl-2-(2-methyl-4-(1,5-dimethyl-1H-pyrazol-3-yl)-phenoxymethyl]-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one (described in Preparation example 15) (Present compound 15) 0.37 g, N-chlorosuccinimide 0.12 g and chloroform 5 ml was stirred at room temperature for twelve hours. The resulting mixture was extracted with chloroform and was washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-{3-cyclopropyl-2-(2-methyl-4-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)-phenoxymethyl]-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one (hereinafter, referred to as “Present compound 36”) 0.13 g.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[Na].[CH2:22]([CH:24]1[O:29][CH2:28][CH2:27][N:26]([C:30]2[N:31]=[C:32]([CH2:37][C:38](O)=[O:39])[NH:33][C:34](=[O:36])[CH:35]=2)[CH2:25]1)[CH3:23]>CN(C)C=O.N1C=CC=CC=1>[CH2:22]([CH:24]1[O:29][CH2:28][CH2:27][N:26]([C:30]2[N:31]=[C:32]([CH2:37][C:38]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=3)=[O:39])[NH:33][C:34](=[O:36])[CH:35]=2)[CH2:25]1)[CH3:23]
Reactant: Nc1ccc(F)cc1
Reactant: CCC1CN(c2cc(=O)[nH]c(CC(=O)O)n2)CCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCC1CN(c2cc(=O)[nH]c(CC(=O)Nc3ccc(F)cc3)n2)CCO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4 ml of pyridine, 472 mg of 4-fluoroaniline and 815 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are successively added to a solution of 410 mg of the sodium salt of [4-(2-ethylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetic acid in 4 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 16 hours, and then concentrated under reduced pressure. The residue is taken up in 25 ml of water and then the pH is brought back to about 7 with a 2M hydrochloric acid solution. 30 ml of ethyl acetate are added and then the resulting mixture is allowed to stir at ambient temperature for 1 hour. The precipitate formed is filtered off, and then rinsed successively with water and diethyl ether. 300 mg of (±)-2-[4-(2-ethylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-(4-fluorophenyl)-acetamide are thus obtained in the form of an off-white powder, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([C:17]4[CH:18]([CH3:24])[CH2:19][C:20](=[O:23])[NH:21][N:22]=4)[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(O)C>O>[Cl:1][C:2]1[C:7]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([C:17]4[CH:18]([CH3:24])[CH2:19][C:20](=[O:23])[NH:21][N:22]=4)[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:5]=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:3]=1
Reactant: C1COCCN1
Reactant: CC1CC(=O)NN=C1c1ccc2nc(-c3ccc(Cl)nc3Cl)oc2c1
Solvent: CCO
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc2nc(-c3ccc(N4CCOCC4)nc3Cl)oc2c1

Procedure:
1.1 g (2.9 mmol) 6-[2-(2,6-dichloro-pyridin-3-yl)-benzoxazol-6-yl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one, 1 ml morpholine and 50 ml of ethanol are refluxed together for 3 h, then the solv. is eliminated by rotary evaporation i.V., the residue is stirred with water and filtered off. The crude product is recrystallised from aqueous isopropanol.
Reaction SMILES: [CH:1]([C@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[CH2:6][N:5]([C@@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[CH2:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:4]1)=O.Cl.Cl.[CH2:34]([N:37]([CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)[C:38]1[N:43]=[CH:42][CH:41]=[CH:40][N:39]=1)[CH:35]=[CH2:36].C(N(CC)CC)C>ClCCl.CCOC(C)=O>[CH2:34]([N:37]([CH:44]1[CH2:49][CH2:48][N:47]([CH2:1][C@@H:3]2[C@@H:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=3)[CH2:6][N:5]([C@@H:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]3[CH2:21][C:22]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])[CH2:4]2)[CH2:46][CH2:45]1)[C:38]1[N:43]=[CH:42][CH:41]=[CH:40][N:39]=1)[CH:35]=[CH2:36]
Reactant: C=CCN(c1ncccn1)C1CCNCC1
Reactant: O=C[C@@H]1CN([C@@H]2CCCCC2CC(=O)OCc2ccccc2)C[C@@H]1c1cccc(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN(c1ncccn1)C1CCN(C[C@H]2CN([C@@H]3CCCCC3CC(=O)OCc3ccccc3)C[C@@H]2c2cccc(F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
The title compound was prepared from 2-(R)-(3-(S)-formyl-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-cyclohexaneacetic acid, benzyl ester 83 mg, 0.195 mmol; prepared above as Aldehyde 6), 4-(N-allyl-N-(pyrimid-2-yl)-amino)piperidine dihydrochloride (64 mg, 0.219mmol, from Step A), 104 mg (0.49 mmol) NaHB(OAc)3, and 0.035 ml (0.25 mmol) triethylamine in 3 ml dichloromethane. The mixture was stirred overnight at room temperature. The reaction was diluted with 100 ml EtOAc and washed with 1M NaOH and saturated NaCl. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The material was purified using flash chromatography (5% EtOAc in hexane) to provide 83 mg of the title compound. RF: 0.3 (5% EtOAc/hexane). HPLC (Zorbax SB-C8 column, 4.6 mm×7.5 cm, Gradient: 90 H2O:10 CH3CN to 0 H2O:100 CH3CN over 7.5 minutes then hold at 100 CH3CN:0 H2O for 45 seconds, 2.25 mL/min, 220 nm): Retention Time: 4.6 minutes.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])[S:7](=[O:26])(=[O:25])[C:8]2[CH:24]=[CH:23][CH:22]=[CH:21][C:9]=2[C:10]=1[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=1)=[O:4].O.[OH-].[Li+]>CO.O>[CH3:18][O:17][C:15]1[CH:16]=[C:11]([C:10]2[C:9]3[CH:21]=[CH:22][CH:23]=[CH:24][C:8]=3[S:7](=[O:26])(=[O:25])[N:6]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:34])[F:35])[C:5]=2[C:3]([OH:4])=[O:2])[CH:12]=[C:13]([O:19][CH3:20])[CH:14]=1
Reactant: COC(=O)C1=C(c2cc(OC)cc(OC)c2)c2ccccc2S(=O)(=O)N1c1ccccc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(OC)cc(C2=C(C(=O)O)N(c3ccccc3C(F)(F)F)S(=O)(=O)c3ccccc32)c1
Yield: 66 %

Procedure:
The solution of 4-(3,5-dimethoxy-phenyl)-2-(2-trifluoromethyl-phenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester (1.29 g, 2.5 mmol) and lithium hydroxide monohydrate (0.3 g 12.5 mmol) in 30 mL of MeOH and 15 mL water was refluxed for 2.5 hours and evaporated to an oil. The residue was dissolved in water, washed with ethyl ether, and the aqueous layer decanted. The aqueous layer was acidified to pH 1 with concentrated HCl and extracted into ethyl ether, washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to a foam. The residue was chromatographed on 50 g silica gel eluted with chloroform, and the appropriate fractions were concentrated in vacuo and evaporated from ethyl ether giving a solid foam. 1.4 g, 66% yield. NMR spectra and elemental analysis were consistent with the structure.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[CH:3]=1.[CH:20]1([NH2:23])[CH2:22][CH2:21]1.[CH2:24](N(CC)CC)C.C(#N)C>O>[CH:20]1([NH:23][C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([CH2:11][CH2:12][C:13]3[CH:24]=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]#[N:16])[CH:3]=2)[CH2:22][CH2:21]1
Reactant: N#Cc1cccc(Cc2cc(Cl)n3nccc3n2)c1
Reactant: CCN(CC)CC
Reactant: NC1CC1
Solvent: O
Solvent: CC#N
Product: N#Cc1ccccc1CCc1cc(NC2CC2)n2nccc2n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To the reaction flask, 3((7-chloropyrazolo[1,5-a]pyrimidin-5-yl)methyl)benzonitrile (400 mg, 1.5 mmol) was added along with cyclopropylamine (115 μL, 1.6 mmol), triethylamine (230 μL, 1.6 mmol), and acetonitrile (3 mL). The reaction was stirred at room temperature for 8 hours at 80° C. then cooled to room temperature, diluted with water, filtered and washed with water. The product, 3-((7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)benzonitrile, was collected as a solid in 83% yield after drying under vacuum overnight. LCMS (M+1=290)
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[NH2:11][C:12]1[N:17]=[C:16](F)[CH:15]=[C:14]([F:19])[N:13]=1.O>CO.CN1CCCC1=O>[NH2:11][C:12]1[N:13]=[C:14]([F:19])[CH:15]=[C:16]([O:10][C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=2)[N:17]=1
Reactant: Nc1nc(F)cc(F)n1
Reactant: Oc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CO
Product: Nc1nc(F)cc(Oc2ccc(Cl)cc2)n1
Temperature: 140 °C
Reaction time: 4 h

Procedure:
2.52 g (0.038 mol) of 85% sodium hydroxide were dissolved in 50 ml of methanol, 4.9 g (0.0382 mol) of 4-chlorophenol were added, and the mixture was evaporated to dryness. The residue of salt obtained in this way was taken up in 50 ml of N-methyl-2-pyrrolidone and, at 25° C., 5.0 g (0.0382 mol) of 2-amino-4,6-difluoropyrimidine were added, and the mixture was stirred at 140° C. for 4 hours. After the reaction mixture had been cooled to 25° C. it was stirred into 500 ml of water, and the resulting precipitate was isolated. 7.4 g (81% of theory) of the title compound of melting point 223°-226° C. were obtained in this way.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:17][C:18]([CH3:23])([CH3:22])[C:19](Br)=[O:20].C(=O)C1C=CC=CC=1>C1COCC1>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][C:19](=[O:20])[C:18]([Br:17])([CH3:23])[CH3:22])=[CH:3][CH:4]=1)=[O:7]
Reactant: CC(C)(Br)C(=O)Br
Reactant: O=Cc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: O=Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(Br)C(=O)Oc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 48 %

Procedure:
A solution of 4-hydroxy benzaldehyde (6.1 g, 0.050 mol) and triethylamine (6.1 g, 0.060 mol) was stirred in THF (200 mL) in a round-bottom flask. Bromoisobutyryl bromide (13.6 g, 0.060 mol) was added slowly to the stirring benzaldehyde solution, and the reaction mixture was stirred at room temperature for five hours. The white precipitate that appeared was removed by filtration, and the solvent was removed by rotary evaporation. Purification by column chromatography (eluting with 12% EtOAc in hexane) provided the desired aldehyde (6.5 g) as a white solid. 1H NMR (CDCl3) δ=2.09 (s, 6H), 7.33 (d, J=7.2 Hz, 2H), 7.96 (d, J=7.99 Hz, 2H), 10.02 (s, 1H) ppm; 13C NMR (CDCl3) δ (ppm) 30.4, 55.3, 121.5, 131.3, 134.2, 155.3, 169.6, 175.7, 190.9 ppm.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8].O[C:15]1[C:16]([O:23][CH3:24])=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19].C(=O)([O-])[O-:26].[K+].[K+].CN(C)C=O>O>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:5]1[O:6][C:7]([CH3:8])=[C:3]([CH2:2][O:26][C:22]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[C:16]([O:23][CH3:24])[CH:15]=2)[N:4]=1
Reactant: O=C([O-])[O-]
Reactant: COc1c(O)cccc1C=O
Reactant: Cc1oc(-c2ccco2)nc1CCl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OCc2nc(-c3ccco3)oc2C)ccc1C=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
A mixture of 4-chloromethyl-2-(2-furyl)-5-methyl-1,3-oxazole (3.28 g), 3-hydroxy-2-methoxybenzaldehyde (2.10 g), potassium carbonate (1.91 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1:2, v/v) to give 4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-2-methoxybenzaldehyde as colorless crystals (3.35 g, yield 78%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 111-112° C.
Reaction SMILES: [Cl:1][C:2]([F:9])([N+:6]([O-:8])=[O:7])[C:3]([OH:5])=[O:4].OS(O)(=O)=O.O=S(=O)=O.[N+:19]([O-:22])(O)=[O:20].[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[Cl:30][C:31]([F:35])=[C:32]([F:34])[Cl:33]>>[Cl:1][C:2]([F:9])([N+:6]([O-:8])=[O:7])[C:3]([OH:5])=[O:4].[F:23][C:24]([F:29])([F:28])[C:25]([O:27][C:31]([Cl:30])([F:35])[C:32]([Cl:33])([F:34])[N+:19]([O-:22])=[O:20])=[O:26]
Reactant: FC(Cl)=C(F)Cl
Reactant: O=C(O)C(F)(F)F
Reactant: O=[N+]([O-])O
Agent: O=C(O)C(F)(Cl)[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=C(OC(F)(Cl)C(F)(Cl)[N+](=O)[O-])C(F)(F)F

Procedure:
The yield of chlorofluoronitroacetic acid in the nitration reaction was increased to 44% by replacing sulfuric acid with oleum. When a mixture of oleum, nitric acid and trifluoracetic acid was reacted with 1,2-dichlorodifluoroethylene, chlorofluoronitroacetic acid was obtained in 63% yield along with 14% of the 1,2-addition product, 1,2-dichloro-1,2-difluoro-2-nitroethyl trifluoroacetate, bringing the total yield of the nitration reaction to 77%. Apparently the 1,2-addition product was formed first and then was hydrolyzed in situ, to give the acetic acid derivative. The lower boiling point and diminished water sensitivity of the 1,2-addition product makes it a potentially attractive alternative to chlorofluoronitroacetic acid in subsequent nitration reactions.
Reaction SMILES: [Cl:1][C:2]1[O:11][C:5]2=[C:6]([NH2:10])[N:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:12].[I:13]N1C(=O)CCC1=O>CC#N>[Cl:1][C:2]1[O:11][C:5]2=[C:6]([NH2:10])[N:7]=[CH:8][C:9]([I:13])=[C:4]2[C:3]=1[CH3:12]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1c(Cl)oc2c(N)nccc12
Solvent: CC#N
Product: Cc1c(Cl)oc2c(N)ncc(I)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
2-chloro-3-methylfuro[2,3-c]pyridin-7-amine (1.0 g, 5.5 mmol) in MeCN (30 mL) was treated with N-iodosuccinimide (1.70 g, 7.52 mmol), added portionwise over a 5 min period. The mixture was stirred at RT for overnight. The reaction was quenched with 20% aqueous Na2S2O3 and stirred for 10 min. EtOAc (100 mL) was added and the phases separated. The organic phase was washed with 20% aqueous Na2S2O3, then water and finally with brine. After drying over Na2SO4, the organic extracts were filtered and concentrated in vacuo. The material was purified using flash chromatography (30% EtOAc:DCM) to afford 1.15 g (68%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 4.73 (br s, 2H), 2.33 (s, 3H).
Reaction SMILES: Cl[Si](C)(C)C.C([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O)(=O)C1C=CC=CC=1>>[N:23]1[C:15]([NH2:14])=[C:16]2[C:20]([N:19]=[CH:18][NH:17]2)=[N:21][CH:22]=1
Reactant: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O)c1ccccc1
Agent: C[Si](C)(C)Cl
Product: Nc1ncnc2nc[nH]c12

Procedure:
N6 -Benzoyl-9-(2'-fluoro-b-D-ribofuranosyl) adenine was prepared from 9-β-D-arabinofuranosyladenine in a five-step synthesis using a modification of a procedure reported by Ikehara at al. [Nucleosides and Nucleotides, 2, 373-385 (1983)]. The N6 -benzoyl derivative was obtained in good yield utilizing the method of transient protection with chlorotrimethylsilane. Jones [J. Am. Chem. Soc., 104, 1316 (1982)]. Selective protection of the 3' and 5'-hydroxyl groups of N6 -Benzoyl-9-β-D-arabinofuranosyladenine with tetrahydropyranyl (THP) was accomplished by modification of the literature procedure according to Butke et al. [Nucleic Acid Chemistry, Part 3, p.149, L. B. Townsend and R. S. Tipson, Eds., J. Wiley and Sons, New York, 1986], to yield N6 -Benzoyl-9-[3',5'-di-O-tetrahydropyran-2-yl)-β-D-arabino-furanosyl]adenine in good yield. Treatment of N6 -Benzoyl-9-[3',5 -di-O-tetrahydropyran-2-yl)-β-D-arabino-furanosyl]adenine with trifluoromethanesulfonic anhydride in dichloromethane gave the 2'-triflate derivative N6 -Benzoyl-9-[2'-O-trifluoromethylsulfonyl-3',5'-di-O-tetrahydropyran-2-yl)-β-D-arabinofuranosyl] adenine which was not isolated due to its lability. Displacement of the 2'-triflate group was effected by reaction with tetrabutylammonium fluoride in tetrahydrofuran to obtain a moderate yield of the 2'-fluoro derivative N6 -Benzoyl-9-[2'-fluoro-3',5'-di-O-tetrahydropyran-2-yl)-β-D-arabinofuranosyl]adenine. Deprotection of the THP groups of N6 -Benzoyl-9-[2'-fluoro-3',5'-di-O-tetrahydro-pyran-2-yl)-β-D-arabinofuranosyl]adenine was accomplished by treatment with Dowex-SOW in methanol to yield N6 -benzoyl-9-(2'-deoxy-2'-fluoro-β-D-ribofuranosyl)adeninein moderate yield. The 1H-NMR spectrum was in agreement with the literature values. [Ikehara and Miki, Chem. Pharm. Bull., 26, 2449 (1978)]. Standard methodologies were employed to obtain the 5'-dimethoxytrityl-3'-phosphoramidite intermediates N6 -Benzoyl-9-[2'-fluoro-5'-O-(4,4'-dimethoxytrityl)-β-D-ribofuranosyl]adenine and N6 -Benzoyl-[2'-deoxy-2'-fluoro -5'-O-(4,4'-dimethoxytrityl)]adenosine-3'-O-(N,N-diisopropyl-β-cyanoethylphosphoramidite. [Ogilyie, Can J. Chem., 67, 831-839 (1989)].