Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:11][S:12][C:13]([C:16]2[C:25]([O:26][Si](C(C)(C)C)(C)C)=[N:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[O:34][CH3:35])[N:17]=2)=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(O)(=O)C>[OH:8][CH2:9][C:10]1[S:11][S:12][C:13]([C:16]2[C:25]([OH:26])=[N:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[O:34][CH3:35])[N:17]=2)=[CH:14][CH:15]=1
Reactant: COc1cccc2nc(C3=CC=C(CO[Si](C)(C)C(C)(C)C)SS3)c(O[Si](C)(C)C(C)(C)C)nc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cccc2nc(C3=CC=C(CO)SS3)c(O)nc12
Reaction time: 3 h
Yield: 51.7 %

Procedure:
To a stirred solution of the 3-[(tert-butyldimethylsilyloxy)methyl]-6-[methyloxy[3-(tert-butyldimethylsilyloxy)quinoxalin-2-yl]]-1,2-dithiin obtained above (50 mg, 0.09 mmol) in 1 mL of THF was added a mixture of 1.2 mL of 1M tetrabutylammonium fluoride in THF and 0.7 mL of acetic acid. The reation mixture was stirred for 3 h until TLC analysis showed the reaction to be complete, and then concentrated in vacuo. The residue was partitioned between 20 mL of water and 30 mL of ethyl acetate. The organic phase was washed with dilute aqueous sodium bicarbonate, water, dried over sodium sulfate, and then evaporated to a small volume. The residue was purified by flash chromatography (ethyl acetate-hexane, 1:1) to yield 15 mg (51.7%) of the title compound. Further purification was accomplished by reverse phase HPLC (acetonitrile:water 1:1, PRP-1 column); 1H-NMR (CD3OD) 5.68 (d, J=8.0, 1 H), 7.47 (m, 2 H), 7.37 (m, 1 H), 6.66 (d, J=5.6, 1 H), 6.42 (d, J=6.0, 1 H), 5.16 (s, 2 H), 4.17 (s, 2 H); MS (EI) 319.1 (M+).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([Cl:12])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:2]2[C:3]3[C:10]([CH3:11])=[C:9]([Cl:12])[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:15][CH2:16]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1c(Cl)sc2ncnc(Cl)c12
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: Cc1c(Cl)sc2ncnc(NC3CCN(C(=O)OC(C)(C)C)CC3)c12

Procedure:
The title compound was prepared (611 mg, 82%) from 4,6-dichloro-5-methylthieno[2,3-d]pyrimidine (425 mg, 1.94 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (582 mg, 2.9 mmol) by following the general procedure described for Preparation 9. 1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 5.25 (d, 1H), 4.35 (m, 1H), 4.30 (m, 2H), 3.00 (m, 2H), 2.55 (s, 3H), 2.15 (m, 2H), 1.45 (s, 9H), 1.35-1.55 (m, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:20])[C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]([CH3:20])[C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)=[CH:24][CH:23]=1
Reactant: Cc1cc(OCCCCCl)cc2c1NC(=O)OC2(C)C
Reactant: Sc1ccc(Cl)cc1
Product: Cc1cc(OCCCCSc2ccc(Cl)cc2)cc2c1NC(=O)OC2(C)C

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4,8-trimethyl-4H-3,1-benzoxazin-2-one and 4-chloro-thiophenol.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH2:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([O:13]C)[C:7]=1[C:15](=[O:18])[CH2:16]Cl.Cl.CO>ClCCl>[NH2:5][C:6]1[C:7]2[C:15](=[O:18])[CH2:16][O:13][C:8]=2[CH:9]=[CH:10][C:11]=1[Cl:12]
Reactant: COc1ccc(Cl)c(N)c1C(=O)CCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: Nc1c(Cl)ccc2c1C(=O)CO2
Temperature: 25 °C
Yield: 132.9 %

Procedure:
To a stirred suspension of aluminum chloride (77.6 g) in dry dichloromethane (300 ml) was added dropwise a solution of Intermediate 20 (45 g) in dichloromethane (250 ml). The mixture was heated under reflux for 6 h and then cooled to room temperature. The mixture was decomposed by the dropwise addition of 2M hydrochloric acid, then methanol and dichloromethane were added and the organic layer collected. The aqueous layer was extracted with dichloromethane and the combined organic layers dried over sodium sulphate and concentrated in vacuo. The residue was dissolved in boiling methanol and an excess of triethylamine added. The solvent was removed in vacuo and the residue absorbed onto silica gel. Purification by chromatography on silica gel eluting with a gradient of 20% to 50% ethyl acetate in cyclohexane gave the title compound as an orange/brown solid (46.9 g).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[F:14])[CH3:5].CS(O[CH:20]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21]1)(=O)=O.O>CN(C=O)C>[CH3:5][N:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:20]2[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23]2)=[CH:9][C:8]=1[F:14])[CH3:3]
Reactant: CN(C)Cc1ccc(O)cc1F
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)Cc1ccc(OC2CN(C(=O)OC(C)(C)C)C2)cc1F
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
A mixture of NaH (55-65% disp. in oil, 0.31 g, 7.7 mmol) in dry DMF (10 mL) under nitrogen was cooled by an ice-bath. A solution of 26A (1.0 g, 5.9 mmol) in DMF (10 mL) was added drop-wise over 10 minutes. The mixture was stirred for 30 minutes and then tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (1.63 g, 6.5 mmol) in DMF (10 mL) was added. The mixture was heated to 80° C. over night and then cooled to RT. Water (100 mL) was added and the mixture was extracted three times with EtOAc (50 mL). The combined organic phases were filtered through a phase separator and the solvent was removed by evaporation. The residue was purified by preparative chromatography on a Kromasil C8 column (10 μm 250×20 ID mm) using a gradient of 10-50% acetonitrile in water/acetonitrile/formic acid (95/5/0.2), 100 mL/min. Fractions were collected, pooled and concentrated in vacuo. DCM was added and the solution was filtered through a phase separator and concentrated by evaporation. There was obtained 1.2 g (55%) of 26B as a solid. 1H NMR (500 MHz, CDCl3): δ 1.45 (s, 9H), 2.58 (s, 6H), 3.90 (s, 2H), 3.95-4.05 (m, 2H), 4.25-4.35 (m, 2H), 4.81-4.92 (m, 1H), 6.45-6.65 (m, 2H), 7.35-7.45 (m, 1H), 8.42 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:12]1([CH:18]([CH2:22][CH3:23])[C:19](O)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(=O)(O)[O-].[Na+]>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:19](=[O:20])[CH:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:22][CH3:23])=[CH:8][CH:7]=1
Reactant: ClCCCOc1ccccc1
Reactant: CCC(C(=O)O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCC(C(=O)c1ccc(OCCCCl)cc1)c1ccccc1
Reaction time: 16 h

Procedure:
3-Chloropropoxybenzene (8g, 47 mmol) was added to a stirred solution of 2-phenylbutyric acid (8.5 g, 52 mmol) in trifluoroacetic anhydride (7.5 ml, 52 mmol) and stirring continued for 16 h. The mixture was poured into saturated sodium bicarbonate solution (100 ml), neutralized by addition of sodium bicarbonate, and extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with water (2×50 ml), dried (MgSO4), and concentrated in vacuo. The residues were distilled to give the title compound as a white waxy solid (12.01 g, 81%) bp 200° C. at 0.1 mm Hg.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:60])([F:59])[C:12]([F:58])([F:57])[O:13][C:14]([F:56])([F:55])[C:15]([F:54])([C:50]([F:53])([F:52])[F:51])[O:16][C:17]([F:49])([F:48])[C:18]([F:47])([F:46])[O:19][C:20]([F:45])([C:41]([F:44])([F:43])[F:42])[C:21]([F:40])([F:39])[O:22][C:23]([F:38])([F:37])[C:24]([F:36])([F:35])[C:25]2[CH:30]=[CH:29][C:28]([O:31]C(=O)C)=[CH:27][CH:26]=2)=[CH:7][CH:6]=1)(=O)C.Cl.O>CO>[OH:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]([F:35])([F:36])[C:23]([F:37])([F:38])[O:22][C:21]([F:39])([F:40])[C:20]([F:45])([C:41]([F:42])([F:43])[F:44])[O:19][C:18]([F:46])([F:47])[C:17]([F:48])([F:49])[O:16][C:15]([F:54])([C:50]([F:51])([F:52])[F:53])[C:14]([F:55])([F:56])[O:13][C:12]([F:58])([F:57])[C:11]([F:60])([F:59])[C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=2)=[CH:30][CH:29]=1
Reactant: CC(=O)Oc1ccc(C(F)(F)C(F)(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)OC(F)(C(F)(F)F)C(F)(F)OC(F)(F)C(F)(F)c2ccc(OC(C)=O)cc2)C(F)(F)F)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: Oc1ccc(C(F)(F)C(F)(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)OC(F)(C(F)(F)F)C(F)(F)OC(F)(F)C(F)(F)c2ccc(O)cc2)C(F)(F)F)cc1
Yield: 32 %

Procedure:
To a solution of 4-iodophenyl acetate (7.86 g, 0.030 mole) and 1,14-diiodoerfluoro-5,10-dimethyl-3,6,9,12-tetraoxatetradecane (9.20 g, 0.010 mole) in 45 ml of N,N-dimethylformamide was added copper bronze (5.08 g, 0.080 g atom). This slurry was stirred under nitrogen at 115°-117° C for 96 hours. The cooled reaction mixture was added to a stirred mixture of 150 ml of ether and 200 ml of water. The cuprous salts and excess copper were filtered off and the ether layer was washed repeatedly with water until free from the reaction solvent. The ethereal solution was evaporated to dryness to give a brown oil which was refluxed in 20 ml of acetic anhydride for 15 minutes. The excess acetic anhydride was distilled off and the residue was distilled under reduced pressure to give 3.40 g of 1,14-bis (4-acetoxyphenyl)perfluoro-5,10-dimethyl-3,6,9,12-tetraoxatetradecane, b.p. 180°-185° C/0.30 mm. This water-white oil was refluxed for an hour in a solution of 10 ml of concentrated hydrochloric acid (0.12 mole) in 100 ml of methanol. The solvent was evaporated under reduced pressure and the resultant tan residue was taken up in 600 ml of hexane. This solution was treated with charcoal, filtered, and reduced in volume to give 2.72 g (32% yield) of product (III) as a viscous water-white oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]2[CH:14]=[CH:15][S:16][C:12]=2[CH:11]=[C:10]([C:17]([OH:19])=O)[N:9]=1.[CH2:20]([N:22](CC)[CH2:23][CH3:24])[CH3:21].ClC(OCC)=O.C(NCC)C>C(Cl)(Cl)Cl>[CH2:20]([N:22]([CH2:23][CH3:24])[C:17]([C:10]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:13]2[CH:14]=[CH:15][S:16][C:12]=2[CH:11]=1)=[O:19])[CH3:21]
Reactant: O=C(O)c1cc2sccc2c(-c2ccccc2Cl)n1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCNCC
Product: CCN(CC)C(=O)c1cc2sccc2c(-c2ccccc2Cl)n1
Yield: 60.8 %

Procedure:
Operations are carried out as for example 7, starting from 2.9 g of 4-(2-chloro phenyl) thieno[3,2-c]pyridine 6-carboxylic acid, 1.17 g of triethylamine, 1.25 g of ethyl chloroformate and 0.94 g of diethylamine in 100 ml of chloroform. 2.1 g of N,N-diethyl 4-(2-chloro phenyl) thieno[3,2-c]pyridine 6-carboxamide, melting at 119° C., are obtained.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH:5]([C:11]1[C:16]([Cl:17])=[N:15][CH:14]=[CH:13][N:12]=1)C(OCC)=O)C.[OH-].[Na+].Cl.C(OCC)C>C(O)C>[Cl:17][C:16]1[C:11]([CH2:5][C:4]([OH:18])=[O:3])=[N:12][CH:13]=[CH:14][N:15]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1nccnc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: O=C(O)Cc1nccnc1Cl
Temperature: 60 °C
Yield: 68.7 %

Procedure:
To a solution of 2-(3-chloro-pyrazin-2-yl)-malonic acid diethyl ester (10.0 g) in ethanol (100 ml) was added 2M sodium hydroxide (100 ml) and the reaction mixture heated to 60° C. for 4 hours. The reaction mixture was cooled to ambient temperature then poured onto water and 1M hydrochloric acid followed by extraction with ethyl acetate (3×). The combined organic layers were dried (magnesium sulfate), filtered and the filtrate concentrated to give the crude title compound as a yellow solid. The solid was slurried with diethylether to give (3-chloro-pyrazin-2-yl)-acetic acid (4.35 g). MH+=173, RT=0.72 min (Method A).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]2([C:23](=[O:27])[CH2:24][CH2:25][CH3:26])[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO.Cl.O>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]2([CH:23]([CH2:24][CH2:25][CH3:26])[OH:27])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]3[C:22]2=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC(=O)C1(CCCc2ccccc2)c2ccccc2-c2ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCC(O)C1(CCCc2ccccc2)c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of Example 189 compound (400 mg, 1.13 mmol) in 25 ml of methanol was cooled to 0° C. under an argon atmosphere. Sodium borohydride (93 mg, 2.45 mmol) was added portion wise over 10 minutes and the mixture was then stirred for 30 min. longer at 0° C. The reaction was diluted with 0.1 N hydrochloric acid to pH 4. The reaction mixture was diluted with 30 ml of water and extracted with ethyl acetate (3×20 ml). The ethyl acetate extract was washed with water, brine and dried over sodium sulfate. The crude product was purified on a Merck EM silica column eluting with 10% ethyl acetate/hexane yielding 345 mg (86%) of title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:10]#[CH:11])=[CH:4][N:3]=1.[F:12][C:13]([F:22])([F:21])[C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1.C(N(CC)CC)C>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:10]#[C:11][C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:22])([F:21])[F:12])=[CH:15][CH:16]=2)=[CH:4][N:3]=1
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: C#Cc1cnc(N)c(C#N)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1nc(C#Cc2ccc(C(F)(F)F)cc2)cnc1N

Procedure:
A solution of 3.2 grams (0.022 mole) of 2-amino-3-cyano-5-ethynylpyrazine, 8.4 grams (0.031 mole) of 4-trifluoromethylphenyl iodide, 10.7 grams (0.077 mole) of triethylamine, 0.5 gram (catalyst) of bis(triphenylphosphine)palladium(II) chloride, and 0.5 gram (catalyst) of copper iodide in 100 mL of acetonitrile is stirred at ambient temperature for about 18 hours. After this time the reaction mixture is concentrated under reduced pressure to a residue. The residue is partitioned between ethyl acetate and aqueous 1N hydrochloric acid. The two-layered mixture is filtered to remove a solid. The aqueous layer and the organic layer are separated, and the aqueous layer is washed with ethyl acetate. The ethyl acetate wash is combined with the organic layer, and the combination is washed with an aqueous solution of 10% lithium chloride. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue is triturated with methylene chloride and filtered. The filtrate is subjected to column chromatography on silica gel. Elution is accomplished using methanol/methylene chloride combinations. The product-containing fractions are combined and concentrated under reduced pressure, yielding 2-amino-3-cyano-5-[(4-trifluoromethylphenyl)ethynyl]pyrazine.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:21](C2C=CC=CC=2)[NH2:22])[CH:18]=[CH:19][CH:20]=1.[C:29](Cl)(=[O:39])[O:30][C@@H:31]1[CH:36]2[CH2:37][CH2:38][N:33]([CH2:34][CH2:35]2)[CH2:32]1.O>N1C=CC=CC=1>[N:33]12[CH2:38][CH2:37][CH:36]([CH2:35][CH2:34]1)[C@@H:31]([O:30][C:29](=[O:39])[N:22]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:2]3[O:1][CH2:5][CH2:4][O:3]3)[CH:16]=1)[CH2:32]2
Reactant: O=C(Cl)O[C@H]1CN2CCC1CC2
Reactant: NC(c1ccccc1)c1cccc(OCCCCCCCCC2OCCO2)c1
Solvent: c1ccncc1
Solvent: O
Product: O=C(O[C@H]1CN2CCC1CC2)N(Cc1cccc(OCCCCCCCCC2OCCO2)c1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 154.1 %

Procedure:
To a stirred solution of (3-(8-(1,3-dioxolan-2-yl)octyloxy)phenyl)-(phenyl)-methanamine (0.62 g, 1.62 mmol) in pyridine (10 mL) at 0° C., (R)-quinuclidin-3-yl carbonochloridate (0.48 g, 2.1 mmol) was added. The reaction was stirred at 0° C. for 1 hour and then allowed to warm to RT for 16 hours. Water was added to the reaction mixture and extracted with ethyl acetate (×3). The combined extracts were washed with brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. The crude material was purified by chromatography on a KP-NH Biotage cartridge eluting with 0-20% methanol in ethyl acetate to afford the title compound (0.67 g, 78%).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:14]([O-])([OH:16])=[O:15]>FC(F)(F)C(O)=O>[N+:14]([C:3]1[CH:2]=[CH:1][C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=1)([O-:16])=[O:15]
Reactant: c1ccc2c(c1)oc1ccccc12
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc2c(c1)oc1ccccc12
Temperature: 0 °C
Yield: 80.4 %

Procedure:
To 80 mL trifluoroacetic acid in a 250 mL round bottom flask was added dibenzofuran (7.06 g, 42 mmol) and stirred vigorously to dissolve the content at room temperature. The solution was then cooled on ice and 1.2 equivalent 70% HNO3 (4.54 g, 50.40 mmol) in 20 mL trifluoroacetic acid was poured into the stirred solution slowly. After stirring for 30 minutes contents from the flask was poured into 150 mL ice-water and stirred for another 15 minutes. Off white color precipitate was then filtered out and finally washed with 2M NaOH and water. Moist material was then recrystallized from 1.5 L boiling ethanol in the form of light yellow color crystal. 7.2 g of product was isolated.
Reaction SMILES: S(=O)(=O)(O)O.[N:6]1[CH:11]=[CH:10][C:9]([OH:12])=[N:8][C:7]=1[OH:13].[N+:14]([O-])([OH:16])=[O:15]>>[N+:14]([C:10]1[C:9]([OH:12])=[N:8][C:7]([OH:13])=[N:6][CH:11]=1)([O-:16])=[O:15]
Reactant: Oc1ccnc(O)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cnc(O)nc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 3-necked roundbottom flask was charged with sulfuric acid (5400 ml) and the solution was cooled to 0° C. Pyrimidine-2,4-diol (1.0 kg, 8.93 mol) was added in several batches. The resulting solution was allowed to react, with stirring, for 30 minutes. To the above was added nitric acid (1800 ml) dropwise with stirring, while the temperature was maintained at 0° C. The resulting solution was allowed to react, with stirring, for 2 hours. The reaction mixture was then quenched by adding ice water and a precipitate formed. The solid was collected by filtration and dried in an oven under reduced pressure to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.Br[CH2:11][CH:12]1[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][CH:12]2[CH2:14][CH2:13]2)=[C:4]([I:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1I
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(OCC2CC2)c(I)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
A mixture of 4-bromo-2-iodophenol (5.00 g, 16.7 mmol), bromomethylcyclopropane (2.26 g, 16.7 mmol) and cesium carbonate (6.54 g, 20.1 mmol) in 15 mL dimethylformamide was stirred at 50° C. overnight. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with water, saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to the provide title compound (5.84 g, 99% yield).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[NH:7][CH:8]=[N:9]2)[CH2:2][CH3:3].[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:16]=1[CH2:17]Cl>>[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:16]=1[CH2:17][N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][CH:12]=[N:13][C:5]=2[NH:4][CH2:1][CH2:2][CH3:3]
Reactant: ClCc1c(Cl)cccc1Cl
Reactant: CCCNc1ncnc2nc[nH]c12
Product: CCCNc1ncnc2c1ncn2Cc1c(Cl)cccc1Cl

Procedure:
Exploying N6 -n-propyladenine prepared in Example 16 and 2,6-dichlorobenzyl chloride, the same procedures as in Example 39, (1) were repeated to give a crude 9-(2,6-dichlorobenzyl)-N6 -n-propyladenine, in which the purity was 72.6% by weight and the content of the 3-isomer was 27.4% by weight.
Reaction SMILES: N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:13][C:14]1[CH2:15][S:16][C@@H:17]2[C@H:24]([NH:25]C(=O)CC3C=CC=CC=3)[C:23](=[O:35])[N:18]2[C:19]=1[C:20]([OH:22])=[O:21]>C(Cl)Cl.P([O-])([O-])([O-])=O>[NH2:25][C@@H:24]1[C:23](=[O:35])[N:18]2[C:19]([C:20]([OH:22])=[O:21])=[C:14]([CH3:13])[CH2:15][S:16][C@H:17]12
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=P([O-])([O-])[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reaction time: 0.42 h

Procedure:
Dry pyridine (2.0 ml. 2.4 × 10-2 mole) was added dropwise over 1 minute to a stirred suspension of phosphorus pentachloride (5.12g, 2.4 × 10-2 mole) in methylene chloride (50 ml.) and the mixture stirred at 25°-30° for 25 minutes and then cooled to -10°. The polymer ester of (6R,7R)-3-methyl-7-phenylacetamidoceph-3-em-4-carboxylic acid (10.5g, containing 1.04 × 10-2 mole cephalosporin moiety) prepared as in example 8, was then added and washed in with methylene chloride (30 ml.). The slurry was stirred at room temperature for 90 minutes, cooled to -10° and treated with methanol (5.0 ml) such that the temperature did not rise above 0°. After stirring for 10 minutes further methanol (8 ml) was added and the mixture was stirred at room temperature for 30 minutes. The mixture was then filtered directly with no water treatment and the polymer was washed with methylene chloride (4 × 50 ml), and pulled dry. The damp polymer was slurried directly in 98% formic acid (25 ml) and the mixture poured into a glass column. The polymer was eluted with a mixture of methylene chloride/formic acid (140 ml, 1:1) containing toluene-4-sulphonic acid (4.2g). The combined eluate was evaporated and the residue worked-up as in example 21 to afford the title acid (0.815g, 36.8%) as an off-white crystalline solid. The IR and NMR spectra and t.l.c. of the product were identical with those of an authentic sample. [a]D20 150° (c. 0.5 in 0.2M, pH 7.0 phosphate buffer).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].[CH2:11]([O:13][C:14](=[O:22])[CH2:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:11]([O:13][C:14](=[O:22])[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:18][CH2:17]1)[CH3:12]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCOC(=O)CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCN(c2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To a solution of 1.00 g (7.09 mmol) of 2-nitrofluorobenzene in N,N-dimethylformamide (50 mL) is added 1.3 g (7.6 mmol) of 2-(piperdin-4-yl)-acetic acid ethyl ester followed by 1.0 g (7.2 mmol) of potassium carbonate. The mixture is stirred at room temperature for 2 hours. The mixture is diluted with water and washed with ethyl acetate. The combined organic phase is washed with water followed by brine then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to provide 1.85 g (89%) of [1-(2-nitro-phenyl)-piperidin-4-yl]-acetic acid ethyl ester as an orange oil.