Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([NH2:13])=[O:12])=[C:5]([F:18])[C:4]=1F)#[N:2].Cl.[NH2:21][C:22]1[S:26][N:25]=[C:24]([CH3:27])[CH:23]=1.[H-].[Na+].[OH2:30]>CS(C)=O.CCOC(C)=O>[NH2:13][C:11](=[O:12])[C@H:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]([NH2:2])=[O:30])=[C:4]([NH:21][C:22]2[S:26][N:25]=[C:24]([CH3:27])[CH:23]=2)[C:5]=1[F:18])[CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)C[C@@H](Nc1ccc(C#N)c(F)c1F)C(N)=O
Reactant: O
Reactant: Cc1cc(N)sn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2c(C(N)=O)ccc(N[C@H](CC(C)C)C(N)=O)c2F)sn1
Reaction time: 0.5 h

Procedure:
To a solution of (R)-2-(4-cyano-2,3-difluorophenylamino)-4-methylpentanamide (113 mg, 0.423 mmol) and 5-amino-3-methylisothiazole hydrochloride (70 mg, 0.464 mmol) in DMSO (3 mL), NaH (60% in mineral oil, 100 mg, 2.50 mmol) was added. H2 gas evolved. The mixture was stirred at 130 C for 30 min. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. To a solution of the residue in EtOH (2 mL) and DMSO (0.5 mL), 1N aq. NaOH (0.5 mL) and H2O2 (50% aq., 0.5 mL) were added. After being stirred at room temperature for 30 min, the mixture was concentrated in vacuo. The residue was acidified with HOAc (0.5 mL), and then was purified by HPLC to give the titled compound (36 mg). MS 380.4 (M+H); UV 202.2, 280.5 nm
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH2:9][CH3:10])=[O:8])[CH:2]=1.[Br:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].C1(CCN2CCCC(C(C)=O)=C2)C=CC=CC=1>>[Br-:11].[CH3:15][CH:14]([CH3:16])[CH2:13][CH2:12][N+:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[O:8])[CH2:9][CH3:10])[CH:2]=1
Reactant: CCC(=O)c1cccnc1
Reactant: CC(C)CCBr
Agent: CC(=O)C1=CN(CCc2ccccc2)CCC1
Product: CCC(=O)c1ccc[n+](CCC(C)C)c1
Product: [Br-]

Procedure:
Ethyl 3-pyridyl ketone was reacted with 1-bromo-3-methylbutane according to the procedure of Parb (a) of Example 6 to give 1-(3-methylbutyl)-3-propionyl pyridinium bromide as a pale brown crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH2:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][Cl:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: O=C(Cl)CCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CCCCl)C1
Reaction time: 16 h
Yield: 88.6 %

Procedure:
A mixture of 3-aminoazetidine-1-carboxylic acid tert-butyl ester (730 mg, 4.24 mmol) and triethylamine (1.74 mL, 1.29 g, 12.72 mmol) in DCM (10 mL) was cooled to 0° C. before the addition of 4-chlorobutyrylchloride (523 μL, 657 mg, 4.66 mmol). The resulting mixture was stirred for 16 h then quenched with H2O and extracted with DCM. The combined organic extracts were washed with brine then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 30-70%) affording 3-(4-Chlorobutyrylamino)azetidine-1-carboxylic acid tert-butyl ester as a brown oil (1.04 g, 89%).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:8]N1C(=O)N(O)C(=O)N(O)C1=O.[C:20]([OH:23])(=[O:22])[CH3:21].O=O>C([O-])(=O)C.[Co+2].C([O-])(=O)C.O>[C:20]([OH:23])(=[O:22])[C:21]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1.[CH:7](=[O:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)O
Reactant: O=c1n(O)c(=O)n(O)c(=O)n1O
Reactant: Cc1ccccc1
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: O
Product: O=C(O)c1ccccc1
Product: O=Cc1ccccc1

Procedure:
A mixture of 0.276 g of toluene, 0.005 g of hexahydro-1,3,5-trihydroxy-1,3,5-triazine-2,4,6-trione (1% by mole relative to toluene), 5 g of acetic acid and 0.004 g of cobalt (II) acetate.4 H2O was stirred at 60° C. in an atmosphere of oxygene gas (1 atm=0.1 MPa) for 6 hours. The resulting product in the reaction mixture was analyzed by gas chromatography and was found to yield benzoic acid and benzaldehyde in 49% and 3% yields, respectively, at 53% conversion of toluene.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=C(C#N)[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].[OH-:17].[K+].[CH2:19]([OH:21])[CH3:20]>>[CH2:1]([C:3]1[CH:8]=[C:20]([C:19]([OH:17])=[O:21])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: [OH-]
Reactant: CCO
Reactant: CCc1cc(C#N)ccc1-c1ccccc1
Agent: [K+]
Product: CCc1cc(C(=O)O)ccc1-c1ccccc1
Temperature: 25 °C

Procedure:
To the solution of 2-ethyl-biphenyl-4-carbonitrile (0.95 g, 4.58 mmol) in ethanol (50 mL) is added solid KOH (2.56 g, 45.8 mmol). The resulting mixture is heated at reflux for 12 h. After cooling to room temperature, the solvent is evaporated to dryness under reduced pressure. H2O (100 mL) is added and aqueous HCl (2N) is slowly added until the pH is adjusted to ca. pH=1. The mixture is extracted with EtOAc (3×50 mL). The combined organic layers are washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated. The obtained crude 2-ethyl-biphenyl-4-carboxylic acid is dissolved in methanol (20 mL). Concentrated aqueous HCl (5 mL) is added and the mixture is heated at reflux for 4 h. After cooling to room temperature, the reaction mixture is concentrated under reduced pressure. The residue obtained is dissolved in diethyl ether and washed with saturated aqueous NaHCO3 (3×10 mL). The organic layer is separated and dried over Na2SO4 After concentration, the crude 2-ethyl-biphenyl-4-carboxylic acid methyl ester is dissolved in THF (5 mL) and added dropwise to the mixture of LAH (200 mg, 5.2 mmol) in THF (15 mL, anhydrous) at 0° C. After 1 h, the reaction is quenched by the slow addition of H2O, followed by the addition of aqueous HCl (1N, 20 mL). The mixture is extracted with EtOAc (3×40 mL). The combined organic layers are washed with saturated aqueous NaHCO3, saturated aqueous NaCl, and dried over Na2SO4. After concentration, the crude product is purified by silica gel chromatography (20% EtOAc in hexanes) to give (2-ethyl-biphenyl-4-yl)-methanol as a colorless oil.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].O.[CH2:6]([NH:12][C:13](=[S:16])SC)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>C(O)C>[CH2:6]([N:12]1[C:13]([SH:16])=[N:3][N:2]=[N:1]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCNC(=S)SC
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCCn1nnnc1S
Temperature: 90 °C
Yield: 103 %

Procedure:
Sodium azide (155.9 g.) and water (0.8 l.) were added under stirring to a solution of methyl N-hexyldithiocarbamate (430 g.) in ethanol (1.7 l.) and the resulting mixture was refluxed for 3.5 hours at 90° C. Ethanol was distilled off from the reaction mixture and the residue was washed with diethyl ether (1 l.), adjusted to pH 2.0 with conc. hydrochloric acid and extracted with diethyl ether (1 l.). The extract was washed with water, dried over magnesium sulfate and concentrated to give an oil of 1-hexyl-1H-tetrazole-5-thiol (431.3 g.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][O:43][C:44]([C@H:46]1[CH2:51][C@@H:50](O)[CH2:49][CH2:48][N:47]1[C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])=[O:45]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([O:19][C@@H:50]4[CH2:49][CH2:48][N:47]([C:53]([O:55][C:56]([CH3:57])([CH3:58])[CH3:59])=[O:54])[C@@H:46]([C:44]([O:43][CH3:42])=[O:45])[CH2:51]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O
Reactant: COC(=O)[C@H]1C[C@@H](O)CCN1C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
DTAD (7.26 g, 31.5 mmol) dissolved in 50 ml of DCM was added over a period of 10 minutes to a stirred suspension of 4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-ol (5.00 g, 15.7 mmol), triphenylphosphine (8.57 g, 62.6 mmol) and (2R,4S)—N-(tert-butoxycarbonyl)-4-hydroxypiperidine-2-carboxylic acid methyl ester (ex ACROS, 5.42 g, 20.9 mmol) in DCM (150 ml) at −15° C. (acetone/ice). The reaction mixture was allowed to warm to room temperature and stirred for 2 hours, concentrated to approximately 50 ml and purified directly by flash chromatography (silica gel, eluting with a gradient from 100% DCM to DCM/EtOAc (80/20) to DCM/EtOAc (50/50) to give 1-tert-butyl 2-methyl (2R,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-1,2-dicarboxylate (5.5 g, 81%) as a white foam; 1H NMR Spectrum: (DMSO d6) 1.47-1.53 (m, 11H), 1.86-1.91 (m, 1H), 2.25-2.36 (m, 1H), 2.95-3.13 (m, 1H), 3.70 (s, 3H), 3.95 (s, 3H), 3.98-4.04 (m, 1H), 4.45 (m, 1H), 4.86-4.94 (m, 1H), 7.31 (t, 1H), 7.51-7.64 (m, 3H), 7.80 (s, 1H), 8.39 (s, 1H), 9.54 (s, 1H); Mass Spectrum: (M+H)+ 561.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[Br:11]Br.Br.[OH-].[K+]>CC(O)=O.O>[Br:11][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([O:2][CH3:1])[C:9]=1[F:10]
Reactant: BrBr
Reactant: COc1c(N)cccc1F
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1c(N)ccc(Br)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
To a solution of 2-methoxy-3-fluoroaniline (2.18 g, 15.46 mmol) in AcOH (10 mL) was added a solution of bromine (1.98 g, 12.37 mmol) in AcOH (2 mL) dropwise. The reaction mixture was stirred at room temperature for 30 minutes. The resulting solid was filtered and washed with acetic acid to give the title and a di-bromo-compound as the HBr salt. The solid (2.53 g) was dissolved in water, basified by addition of KOH, and extracted with EtOAc. The organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was purified by Biotage silica gel column chromatography eluting with 15% EtOAc in cyclohexanes to give the title compound as white solid (1.24 g, 36%).
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:22][O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:5]([NH:7][CH:8]1[C:20](=[O:21])[N:10]2[C:11]([C:17]([OH:19])=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]12)=[O:6].[NH2:30][C:31]([NH2:33])=[S:32].C([O-])(=O)C.[Na+].Cl>O>[NH2:33][C:31]1[S:32][CH:2]=[C:3]([C:4](=[N:22][O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:5]([NH:7][CH:8]2[C:20](=[O:21])[N:10]3[C:11]([C:17]([OH:19])=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]23)=[O:6])[N:30]=1
Reactant: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OC)C(=O)CCl)[C@H]2SC1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OC)c3csc(N)n3)[C@H]2SC1
Yield: 90.6 %

Procedure:
To a suspension of 7-(4-chloro-2-methoxycarbonylmethoxyimino-3-oxobutyramido)-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (2.0 g) in water (20 ml) were added thiourea (0.683 g) and sodium acetate (1.84 g) at 40° C. with stirring. The reaction mixture was stirred at the same temperature for 1.5 hours. The resultant solution was adjusted to pH 2.8 with 10% hydrochloric acid and stirred under ice-cooling for 20 minutes. The precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 7-[2-(2-aminothiazol-4-yl)-2-methoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer)(1.9 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]([CH2:8][CH2:9][CH2:10][CH:11]=[O:12])[CH:7]=1.[CH:15]([Mg]Br)=[CH:16][CH2:17][CH3:18].[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]([CH2:8][CH2:9][CH2:10][CH:11]([OH:12])[CH2:18][CH2:17][CH:16]=[CH2:15])[CH:7]=1
Reactant: COc1ccc(F)cc1CCCC=O
Reactant: CCC=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCCC(O)CCCc1cc(F)ccc1OC
Yield: 63.7 %

Procedure:
To a solution of 4-(5′-fluoro-2′-methoxyphenyl)butyraldehyde (1.30 g, 6.6 mmol) in THF (15 mL) at 0° C. was added a solution 1-butenylmagnesium bromide (0.5 M in THF, 15 mL, 7.5 mmol) dropwise for 5 min. Then the reaction mixture was poured to a solution of saturated ammonium chloride (60 mL) in a separatory funnel. The organics were extracted with ethyl acetate (3×50 mL) and the combined organic layers were washed with brine (40 mL) and dried over sodium sulfate. The solvent then was removed in vacuo and crude product thus obtained was purified by a flash column chromatography (12.5% EtOAc in hexane, Rf=0.15) to give the product as a colorless oil (1.06 g, 61%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8](O)=[O:9].[C:12]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].CN(C([O:30][N:31]1[N:39]=[N:38][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([NH:20][C:8]([C:7]2[CH:6]=[C:5]([Cl:11])[N:4]=[N:3][C:2]=2[O:30][N:31]2[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[N:38]=[N:39]2)=[O:9])=[CH:21][CH:22]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(NC(=O)c2cc(Cl)nnc2On2nnc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3,6-dichloropyridazine-4-carboxylic acid (1.00 g, 5.18 mmol), 4-tert-butylaniline (0.92 ml, 5.60 mmol), TBTU (1.75 g, 5.44 mmol), and DIEA (1.80 ml, 10.4 mmol) in 7.5 ml of anhydrous DMF was stirred at RT under N2 overnight. The mixtrue was diluted with H2O, extracted with EtOAc, and the combined organic portions were washed with brine, dried with Na2SO4, filtered, and condensed. The crude compound was purified by flash column chromatography (hexanes/EtOAc/CH2Cl2, 9:0:1 to 7:2:1), to provide the desired compound as a light yellowish solid. MS (ES+): 423.0 (M+H)+. Calc'd for C21H19ClN6O2—422.87.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([C:11]2[CH:29]=[CH:28][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=3)=[O:16])=[CH:13][CH:12]=2)=[N:7][CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[Li]CCCC.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>O1CCCC1>[C:1]([N:4]([S:36]([CH3:35])(=[O:38])=[O:37])[C:5]1[C:6]([C:11]2[CH:29]=[CH:28][C:14]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([CH3:25])([CH3:27])[CH3:26])=[CH:22][CH:23]=3)=[O:16])=[CH:13][CH:12]=2)=[N:7][CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccnc1-c1ccc(C(=O)Nc2ccc(C(C)(C)C)cc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)N(c1cccnc1-c1ccc(C(=O)Nc2ccc(C(C)(C)C)cc2)cc1)S(C)(=O)=O
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
The product from Example 5 (610 mg, 1.58 mmol) in tetrahydrofuran (10 mL) was treated with n-BuLi (1.1 mL, 1.6 M in hexanes, 1.76 mmol) dropwise at −10° C. The reaction mixture was stirred at −10° C. for 15 minutes and then treated with methanesulfonyl chloride (0.13 mL, 1.68 mmol). The mixture was allowed to gradually warm to room temperature and stir overnight, quenched with H2O (10 mL), and diluted with ethyl acetate (50 mL). The layers were separated and the organic layer was washed with H2O (2×10 mL) and brine (10 mL), dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluant gradient from 99:1 CH2Cl2:CH3OH to 97:3 CH2Cl2:CH3OH) to provide the title compound as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.81 (dd, J=4.7 Hz, 1.7 Hz, 1H), 8.15 (dd, J=8.2 Hz, 1.7 Hz, 1H), 8.07 (m, 2H), 7.62–7.73 (m, 5H), 7.35–7.40 (m, 2H), 3.30 (s, 3H), 2.01 (s, 3H), 1.29 (s, 9H); MS (ESI+) m/zδ 466 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[F:16][C:17]([F:29])([F:28])[O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>CCOCC.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>[F:16][C:17]([F:28])([F:29])[O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:7]=[C:6]([C:8]3[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: O=Cc1ccc(-c2cccc(Br)n2)cc1
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: [K+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2cccc(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Yield: 75.2 %

Procedure:
4-(6-Bromo-pyridin-2-yl)-benzaldehyde (0.31 mmol), 4-trifluoromethoxyphenyl boronic acid (0.46 mmol), tetrakis(triphenylphosphine)palladium(0) (0.003 mmol), 2M potassium carbonate (0.31 mL) and dioxane (2 mL) were combined in a vial and irradiated by microwave for 10 min at 150° C. The reaction mixture was taken up in ether and washed with brine. The organic layer was dried over magnesium sulfate, was filtered and the solvent removed in vacuo. Purification by silica gel chromatography (EtOAc/hexanes) yielded the product (80 mg) as an off-white solid: mp 109-112° C.; 1H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 8.32 (d, J=8.5 Hz, 2H), 8.19 (d, J=8.1 Hz, 2H), 8.03 (d, J=8.4 Hz, 2H), 7.89 (t, J=7.9 Hz, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.35 (d, J=8.3 Hz, 2H); EIMS m/z 343 (M+).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7](OP(Cl)O[C:4]2=[CH:3][CH:2]=1)=O.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:19](Cl)Cl>CC[N+](CC)(CC)CC.[Br-]>[CH:6]1[C:5]2[C:4](=[N:13][C:18]3[C:17]([CH:7]=2)=[CH:16][CH:15]=[CH:14][CH:19]=3)[CH:3]=[CH:2][CH:1]=1
Reactant: ClCCl
Reactant: O=C1OP(Cl)Oc2ccccc21
Reactant: c1ccncc1
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Product: c1ccc2nc3ccccc3cc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a cold, stirring methylene chloride solution (30 ml; 0° C.) of 2-chloro-4H-1,2,3-benzodioxaphosphorin-4-one (2.4 ml of 1M methylene chloride solution; 2.4 mmol) and pyridine (0.2 g; 2.4 mmol) was added the DMT-protected pseudonucleoside of Example 2, paragraph A (0.55 g; 0.8 mmol). After stirring at 0° C. for 1 hour, the reaction mixture was poured into 1M TEAB aqueous solution (60 ml). The organic solution was separated, dried, concentrated. The residue was purified by flash column chromatography, eluted with 1% Et3N/CH2Cl2, 1% Et3N/1%CH3OH/CH2Cl2. The combined fraction of the product was washed with 1M TEAB aqueous solution, dried over Na2SO4, and concentrated, affording 0.19 g, 65% of the phosphorylated DMT-protected acridine pseudonucleotide.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=O)[CH:3]=[CH:2]1.[NH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].C1(C)C=CC=CC=1>C(O)(=O)C>[C:11]([CH2:10][CH2:9][N:8]1[C:1](=[O:7])[CH:2]=[CH:3][C:4]1=[O:6])([OH:13])=[O:12]
Reactant: O=C1C=CC(=O)O1
Reactant: NCCC(=O)O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=C(O)CCN1C(=O)C=CC1=O
Temperature: 140 °C
Yield: 54.9 %

Procedure:
To a solution of maleic anhydride (33.6 g, 377 mmol) and β-alanine (36.96 g, 377 mmol) in 400 mL of acetic acid was added 52 mL toluene, the mixture was an opaque suspension. Heating to 140° C. provided a clear solution, which was refluxed for 5 hours. To the solution was added 50 mL toluene and reflux was continued. In the next 4 hours 31 mL acetic acid/water mixture was separated by distillation using a Dean-Stark apparatus. The reaction mixture was cooled to 90° C. and solvent was removed via distillation with water aspiration. The residue viscous oil was taken up in 200 mL acetone and concentrated. The crude product was purified through a flash chromatography on silica gel with a gradient eluent of 5-12% methanol in dichloromethane to afford 35 g of 1 as white solid. 1H NMR (CDCl3) δ 6.70 (s, 2H), 3.81 (t, 7.2 Hz, 2H), 2.68 (t, 7.2 Hz, 2H), 2.14 (s, 1H).
Reaction SMILES: [C:1]1([CH:7]2O[CH:10]([CH2:12][CH2:13][OH:14])[C:9](=[C:15]=[CH2:16])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:17].[C:18]([O:21][CH2:22][CH3:23])(=[O:20])C>CO.Cl[Pd]Cl>[C:1]1([CH:7]2[O:17][CH:10]3[CH2:12][CH2:13][O:14][C:9]3([C:15](=[CH2:16])[C:18]([O:21][CH2:22][CH3:23])=[O:20])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O
Reactant: C=C=C1CC(c2ccccc2)OC1CCO
Reactant: CCOC(C)=O
Agent: Cl[Pd]Cl
Solvent: CO
Product: C=C(C(=O)OCC)C12CC(c3ccccc3)OC1CCO2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(5-phenyl-3-vinylidene-tetrahydrofuran-2-yl)ethanol (39 mg, 0.18 mmol) was dissolved in 2 mL of methanol, and then was filled with CO gas (1 atm), followed by addition of PdCl2 (2.4 mg, 0.014 mmol) and CuCl2 (73 mg, 0.54 mmol). The solution was stirred for 4 hours at room temperature. When the reaction was completed, H2O was added and the solution was stirred for 5 minutes. The mixture was diluted with ethyl acetate, washed with H2O and NaCl. Organic layer was separated and dried with anhydride MgSO4. Solvent was removed under reduced pressure, and the remnant was purified through silica gel tube chromatography (EtOAc:n-Hexane=1:25, v/v), thus providing products (47 mg, 91%)
Reaction SMILES: O[CH:2]1[CH:6]2[O:7][C:8](=[O:18])[CH:9]3[CH:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:3]1[CH2:4][CH:5]23.C(N(CC)CC)C.[C:26](Cl)(=[O:30])[C:27]([CH3:29])=[CH2:28].C(=O)([O-])O.[Na+]>C(#N)C>[C:26]([CH:2]1[CH:6]2[O:7][C:8](=[O:18])[CH:9]3[CH:10]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH:3]1[CH2:4][CH:5]23)(=[O:30])[C:27]([CH3:29])=[CH2:28]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)C1C2CC3C(OC(=O)C31)C2O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)C1C2CC3C1OC(=O)C3C2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
In 2,500 ml of acetonitrile were dissolved 500 g of tert-butyl 6-hydroxy-2-oxohexahydro-3,5-methano-2H-cyclopenta[b]furan-7-carboxylate and 318 g of triethylamine. To the solution below 15° C., 288 g of methacrylic chloride was added dropwise. The solution was stirred at room temperature for 2 hours, another 32 g of methacrylic chloride added, and the solution stirred overnight. A saturated aqueous solution of sodium hydrogen carbonate, 500 ml, was added to the reaction solution, followed by ordinary work-up. Recrystallization from hexane yielded 437 g of the title compound (yield 69%).