Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([C@@:8]2([F:25])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([C:21](Cl)=[O:22])[C:9]2=[O:24])[CH:7]=1.N1C=CC=CC=1.[C:34]([O:38]CC1C=CC=CC=1)(=[O:37])[CH2:35][OH:36]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([C@@:8]2([F:25])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=3)[N:10]([C:21]([O:36][CH2:35][C:34]([OH:38])=[O:37])=[O:22])[C:9]2=[O:24])[CH:7]=1
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(C(=O)Cl)c2cc(C(F)(F)F)ccc21
Reactant: O=C(CO)OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(C(=O)OCC(=O)O)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C

Procedure:
To a solution of (S)-XI in toluene and methylene chloride was added 0.6 mL of pyridine followed by the addition of benzyl glycolate (0.878 mL). The resulting mixture was stirred at room temperature for an hour. This reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and condensed by rotary evaporation. The residue was chromatographed on a silica gel flash column packed with ethyl acetate: hexane (v/v, 10:1) and washed with dichloromethane to afford 1.32 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[CH:5]=[C:4]([O:12]B(O)O)[CH:3]=1.OO>C(O)(=O)C>[OH:12][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[CH:5]=1
Reactant: Cc1cc(OB(O)O)cc2oc(=O)[nH]c12
Agent: OO
Solvent: CC(=O)O
Product: Cc1cc(O)cc2oc(=O)[nH]c12
Reaction time: 1 h

Procedure:
77 mg (0.40 mmol) 4-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-ylboric acid were dissolved in 2.0 mL glacial acetic acid and mixed with 0.20 mL (2.3 mmol) hydrogen peroxide solution (35% in water) and stirred briefly. The reaction mixture was left to stand for 1 h at RT. The precipitate formed was suction filtered, washed with water and dried i. vac.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:16][C:13]([CH2:14][Cl:15])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:17][C@H:18]([NH:26][CH3:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CO.Cl>C1C=CC=CC=1>[ClH:15].[CH3:27][N:26]([CH2:14][C:13]1[O:16][C:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:11][CH:12]=1)[CH:18]([CH3:17])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccc(CCl)o2)cc1
Reactant: CN[C@@H](C)Cc1ccccc1
Agent: Cl
Solvent: c1ccccc1
Solvent: CO
Product: CC(Cc1ccccc1)N(C)Cc1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Reaction time: 8 h
Yield: 67.2 %

Procedure:
A solution of 11.9 g (0.05 mole) of 5-(4-nitrophenyl)furfuryl chloride and 14.9 g (0.10 mole) of d-N,a-dimethylphenethylamine in 60 ml of benzene was heated under reflux for 7 hrs. After standing overnight, the solid N,a-dimethylphenethylamine hydrochloride (9 g, 97%) was collected by filtration and washed with benzene. The benzene filtrate was washed with 10% Na2CO3 and water and dried over MgSO4. The solvent was removed on a rotary evaporator, and the residual oil was dissolved in 100 ml of anhydrous ether and 35 ml of nhydrous MeOH. The solution was treated with 20 ml of ethereal HCl and diluted with ether to give an oil. The solvent was removed on a rotary evaporator, and the residual oil was dissolved in ethyl acetate with heating. Cooling gave an oil which was dissolved by the addition of MeOH and 10 ml of etheral HCl. After cooling and dilution with ether, the yellow solid which was deposited was collected by filtration to give 13 g (67%) of N-methyl-5-(4-nitrophenyl)-N-(a-methylphenethyl)furfurylamine hydrochloride; m.p. 168°-175°.
Reaction SMILES: ClN1C(=O)CCC1=O.[F:9][C:10]([F:22])([F:21])[O:11][C:12]1[CH:20]=[CH:19][C:15]([CH:16]=[N:17][OH:18])=[CH:14][CH:13]=1.[NH2:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[CH2:29])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl.N1C=CC=CC=1>[F:9][C:10]([F:21])([F:22])[O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[CH2:29][CH:28]([C:27]3[CH:30]=[CH:31][C:24]([NH2:23])=[CH:25][CH:26]=3)[O:18][N:17]=2)=[CH:14][CH:13]=1
Reactant: ON=Cc1ccc(OC(F)(F)F)cc1
Reactant: C=Cc1ccc(N)cc1
Agent: O=C1CCC(=O)N1Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Nc1ccc(C2CC(c3ccc(OC(F)(F)F)cc3)=NO2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
To a stirred solution of N-chlorosuccinimide (0.634 mmol, 85 μL) and pyridine (4 μL) in 2.5 mL of chloroform was added p-trifluoromethoxybenzaldehyde oxime (130 mg, 0.634 mmol). The reaction was heated at 50° C. for 3 h. 4-Aminostyrene (0.793 mmol, 93 μL) was then added followed by a solution of triethylamine (0.666 mmol, 93 μL) dissolved in 0.5 mL of CHCl3 dropwise. The reaction was stirred at 50° C. for 3 h. The cooled solution was diluted with chloroform (15 mL) and washed with water (2×10 mL). The organic phase was then dried over MgSO4, filtered and concentrated. The residue was purified via radial chromatography using a 2:1 hexane/EtOAc solution as the eluent (Rf=0.18) to afford 4-[3-(4-trifluoromethoxyphenyl)-4,5-dihydro-isoxazol-5-yl]-phenylamine (125 mg; 61%). 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=8.2 Hz, 2H), 7.25 (d, J=8.2 Hz, 2H), 7.17 (d, J=8.2 Hz, 2H), 6.68 (d, J=8.2 Hz, 2H), 5.65 (dd, J=10.9, 8.9 Hz, 1H), 3.55-3.75 (bs, 2H), 3.67 (dd, J=16.8, 10.9 Hz, 1H), 3.30 (dd, J=16.8, 8.9 Hz, 1H); EIMS 322 (M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=1.Br[C:23]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][C:24]=1[CH2:25][O:26][C:27](=[O:38])[N:28]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:29][CH3:30]>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:6]=[C:7]([C:23]2[CH:42]=[CH:41][C:40]([C:43]([F:44])([F:45])[F:46])=[CH:39][C:24]=2[CH2:25][O:26][C:27](=[O:38])[N:28]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:29][CH3:30])[C:8]([F:11])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(F)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCN(Cc1ccccc1)C(=O)OCc1cc(C(F)(F)F)ccc1Br
Product: CCN(Cc1ccccc1)C(=O)OCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1F

Procedure:
Prepared according to the procedure described in Example 15, Step 3, using the following starting materials: [4-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester and benzyl-ethyl-carbamic acid 2-bromo-5-trifluoromethyl-benzyl ester.
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6][CH:5]=1)(=[O:3])[CH3:2].C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>>[CH3:17][N:18]([CH3:20])[CH:19]=[CH:2][C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6][CH:5]=1)=[O:3]
Reactant: CCOC(OCC)N(C)C
Reactant: CC(=O)c1cncc2ccccc12
Product: CN(C)C=CC(=O)c1cncc2ccccc12

Procedure:
2.0 g (11.6 mmol) of 4-acetylisoquinoline [J. Chem. Soc., Perkin Trans. 1, (7), 1503-8]are stirred in 50 ml of dimethyl formamide diethyl acetal for 1 hour at 110° C. The reaction mixture is concentrated under reduced pressure and the residue is chromatographed (methylene chloride:methanol=95:5), giving 3-dimethylamino-1-(4-isoquinolinyl)-2-propen-1-one; 1H-NMR (dimethyl sulfoxide): 2.9 (3H,s), 3.1 (3H,s), 5.52 (1H,d), 7.7-8.2 (m,5H), 8.6 (1H,s), 9.35 (1H,s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([C:16]([O:18]CC)=O)[C:11]([O:13]CC)=O.Cl.[NH2:22][C:23]1[NH:24][CH:25]=[CH:26][N:27]=1.C1CCN2C(=NCCC2)CC1.CN(C)C=O>O.C(Cl)(Cl)Cl>[OH:18][C:16]1[N:24]2[CH:25]=[CH:26][N:27]=[C:23]2[N:22]=[C:11]([OH:13])[C:10]=1[C:3]1[C:4]([F:9])=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: Nc1ncc[nH]1
Reactant: CCOC(=O)C(C(=O)OCC)c1c(F)cc(F)cc1F
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: Oc1nc2nccn2c(O)c1-c1c(F)cc(F)cc1F
Temperature: 100 °C
Yield: 78.3 %

Procedure:
A mixture of 2.90 g of diethyl (2,4,6-trifluorophenyl)malonate, 2.39 g of 2-aminoimidazole hydrochloride, 4.57 g of DBU and 10 ml of N,N-dimethylformamide was heated at 100° C. for 6 hours. After allowing the reaction mixture to cool to room temperature, chloroform and water were added thereto. The separated water layer was concentrated, the residue was diluted with water and conc. hydrochloric acid was added thereto under ice-cooling. The precipitation was filtered and dried to give 2.2 g of 5,7-dihydroxy-6-(2,4,6-trifluorophenyl)imidazo[1,2-a]pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[C:10](=[CH:15][N:16](C)C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:19]N>CCO>[NH:19]1[C:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]=2[CH:15]=[N:16]1
Reactant: NN
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2[nH]ncc2C1

Procedure:
To a solution of tert-butyl-3-[(dimethylamino)methylene]-4-oxopiperidine-1-carboxylate (63.6 g, 250 mmol) in EtOH (200 mL) is added hydrazine (9.6 mL, 305 mmol) and the mixture is heated at reflux for 2 hr. Solvent is evaporated in vacuo and residue is purified by flash column with 5% MeOH in DCM to give the title compound as a white solid. MS (M+1): 224.1.
Reaction SMILES: [Br-:1].[K+].[N+]([O-])(O)=O.[Br:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.ClC(Cl)C>[Br:1][C:13]1[CH:14]=[C:9]([CH2:8][Br:7])[CH:10]=[CH:11][C:12]=1[O:15][CH3:16]
Reactant: [Br-]
Reactant: COc1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Solvent: CC(Cl)Cl
Solvent: O=[N+]([O-])O
Product: COc1ccc(CBr)cc1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 26.6 %

Procedure:
To solution of potassium bromide (29.6 g, 248 mmol) in nitric acid (21% by volume, 149 g, 497 mmol), was added dichloroethane (188 mL) and tetrabutylammonium chloride (1.04 g, 3.73 mmol) followed by 4-(bromomethyl)anisol (25.0 g, 124 mmol) in dichloroethane (62 mL), and the reaction was stirred at room temperature for 5 h. The organic layer was separated, washed with water (2×100 mL, 2×150 mL), 2% aqueous potassium carbonate (150 mL), dried over sodium sulfate, and the solvent removed under vacuum. The residue was purified by being run through a flash silica gel plug (10% ethyl acetate in hexanes) to give the title compound (I-42) (9.22 g, 26% yield). 1H NMR (400 MHz, CDCl3) δ: 7.59 (d, 1H), 7.30 (dd, J=8.2, 2.2 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 4.44 (s, 2H), 4.44 (s, 3H).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:7])[CH2:4][CH2:5][CH3:6].[H-].[Na+].CO[C:12](=O)[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][Si](C(C)(C)C)(C)C)=[C:17]([O:29][Si](C(C)(C)C)(C)C)[CH:16]=1>O1CCCC1>[CH2:4]([C:3]1[N:7]=[C:12]([CH:13]=[CH:14][C:15]2[CH:16]=[C:17]([OH:29])[C:18]([OH:21])=[CH:19][CH:20]=2)[O:1][N:2]=1)[CH2:5][CH3:6]
Reactant: CCCC(=N)NO
Reactant: COC(=O)C=Cc1ccc(O[Si](C)(C)C(C)(C)C)c(O[Si](C)(C)C(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1noc(C=Cc2ccc(O)c(O)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of N-hydroxy-butyramidine (0.24 g, 2.34 mmol) in tetrahydrofuran (5 mL) was added slowly into the suspension of 60% sodium hydride (0.14 g, 3.5 mmol) in dry tetrahydrofuran (5 mL) under nitrogen atmosphere at 0° C. to 10° C. The mixture was stirred for 30 min at room temperature. 3-[3,4-Bis-(tert-butyl-dimethyl-silanyloxy)-phenyl]-acrylic acid methyl ester (compound of Example 1, Step 1; 0.5 g, 1.18 mmol) in dry tetrahydrofuran (5 mL) was added into the reaction mixture and heated at 60° C. for 8 h. The reaction mixture was cooled at 0° C. and quenched with methanol (2 mL) to destroy excess sodium hydride. The reaction mixture was extracted with ethyl acetate (2×10 mL) and the combined organic layers were washed with water (2×10 mL) followed by brine (10 mL). The organic phase obtained was dried over anhydrous sodium sulphate and concentrated to dryness. The crude product obtained was purified by column chromatography (silica gel, chloroform-methanol) to afford the title compound.
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=[C:2]1[NH2:3].[C:12](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C[Si](N[Si](C)(C)C)(C)C>[C:12]([NH:3][C:2]1[NH:1][C:10](=[O:11])[C:9]2[N:8]=[CH:7][N:6]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:5]=2[N:4]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: O=c1[nH]c(NC(c2ccccc2)(c2ccccc2)c2ccccc2)nc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 71.8 %

Procedure:
Freshly activated guanine (0.45 g, 3 mmol) and (NH4)2SO4 (60 mg) were stirred in HMDS (50 mL) under reflux for 24 h to give a clear solution. Volatiles were evaporated in vacuo, and the residue was dissolved in dried CH3CN (50 mL). Trityl chloride (3.5 g, 12.6 mmol) was added, and the solution was stirred under reflux for 48 h. Volatiles were evaporated in vacuo, and the residue was dissolved in CH2Cl2 (10 mL). NH3/H2O (28-30%, 30 mL) was added, and precipitation was observed immediately. The mixture was stirred at ambient temperature overnight. Volatiles were evaporated in vacuo, and the residue was washed (H2O, CH2Cl2) to give 2-N,9-bistritylguanine as a solid (1.37 g, 72%), which was further purified by dissolving in MeOH/CH2Cl2 (1:15) and filtering: 1H NMR (500 MHz, DMSO-d6) δ 10.75 (s, 1H), 7.35 (s, 1H), 7.08-7.19 (m, 19H), 6.87 (d, J=7.4 Hz, 6H), 6.81 (d, J=7.3 Hz, 6H); 13C NMR (125 MHz, DMSO-d6) δ 157.3, 151.8, 151.0, 145.3, 142.4, 139.6, 129.6, 128.8, 128.5, 128.3, 127.6, 126.9, 120.3, 75.4, 71.1; HRMS m/z 635.2675 (M+[C43H33N5O]=635.2685).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH:16]3[CH2:18][CH:13]1[CH2:14][N:15]3[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:7][N:6]=[CH:5]2.[CH:26]1([NH:29][C:30](=[O:47])[C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:32]=2)[CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.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>[CH:26]1([NH:29][C:30]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([N:12]3[CH2:17][CH:16]5[CH2:18][CH:13]3[CH2:14][N:15]5[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[N:7][N:6]=[CH:5]4)[CH:32]=2)=[O:47])[CH2:27][CH2:28]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2c1nncc2cc(Br)ccc12
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: COCCOC
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CC4CC3CN4C(=O)OC(C)(C)C)nncc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
A mixture of tert-butyl 5-(6-bromophthalazin-1-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylate (0.18 g, 0.44 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.14g, 0.44 mmol), tetrakis(triphenylphosphine)palladium (25 mg, 0.022 mmol) and 2 M potassium carbonate (0.66 mL, 1.32 mmol) in 5 mL DME/EtOH (4:1) was stirred at 90° C. for 2 h. The mixture was transferred directly to a column and purified via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOH/DCM to 10% 2M ammonia in MeOH/DCM to give tert-butyl 5-(6-(5-(cyclopropylcarbamoyl)-2-methylphenyl) phthalazin-1-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylate (0.20 g) as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][C:5]1=[O:19].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]([C:30]2([C:33]3[CH:43]=[CH:42][C:36]4[O:37][C:38]([F:41])([F:40])[O:39][C:35]=4[CH:34]=3)[CH2:32][CH2:31]2)=[O:29])[CH:24]=[CH:23][C:22]=1[CH3:44]>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.C([O-])([O-])=O.[Na+].[Na+]>[F:41][C:38]1([F:40])[O:37][C:36]2[CH:42]=[CH:43][C:33]([C:30]3([C:28]([NH:27][C:25]4[CH:24]=[CH:23][C:22]([CH3:44])=[C:21]([C:7]5[CH:8]=[CH:9][N:4]([CH2:3][CH2:2][OH:1])[C:5](=[O:19])[CH:6]=5)[N:26]=4)=[O:29])[CH2:32][CH2:31]3)=[CH:34][C:35]=2[O:39]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: CC1(C)OB(c2ccn(CCO)c(=O)c2)OC1(C)C
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+]
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccn(CCO)c(=O)c1
Temperature: 120 °C

Procedure:
1-(2-Hydroxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (0.14 mmol) was added to a microwave vial containing N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (51 mg, 0.14 mmol) and Pd(PPh3)4 (8.0 mg, 0.0070 mmol). Saturated aqueous Na2CO3 (70 μL) was added and the reaction vial was flushed with N2 (g) and sealed. The reaction was heated in the microwave at 120° C. for 20 minutes before being filtered and concentrated. The residue was dissolved in DMSO and purified by reverse-phase HPLC to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-(1-(2-hydroxyethyl)-2-oxo-1,2-dihydropyridin-4-yl)-5-methylpyridin-2-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 469.1. found 470.5 (M+1)+. Retention time 1.58 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.63 (d, J=6.9 Hz, 1H), 7.56 (d, J=1.6 Hz, 1H), 7.41 (d, J=8.3 Hz, 1H), 7.34 (dd, J=1.7, 8.3 Hz, 1H), 6.39 (d, J=1.8 Hz, 1H), 6.26 (dd, J=1.9, 6.9 Hz, 1H), 3.96 (t, J=5.4 Hz, 2H), 3.63 (t, J=5.5 Hz, 2H), 2.26 (s, 3H), 1.52-1.50 (m, 2H), 1.19-1.16 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:28][O:29][CH2:30][CH:31]=[CH2:32])[C:13](=[O:14])[N:12]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=3)[C:11](=[O:27])[NH:10]2)=[CH:5][CH:4]=1)#[N:2].[C:33](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:28][O:29][CH2:30][CH:31]=[CH2:32])[C:13](=[O:14])[N:12]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:24])[F:25])[CH:16]=3)[C:11](=[O:27])[N:10]2[CH3:33])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C([O-])[O-]
Reactant: C=CCOCC1(c2ccc(C#N)cc2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCOCC1(c2ccc(C#N)cc2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 459 mg of 4-[4-(4-cyanophenyl)-2,5-dioxo-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-trifluoromethylbenzonitrile obtained in Step 4 in DMF (1.5 mL), 173 mg of potassium carbonate and 130 μL of methyliodide are added. The mixture is stirred 3 hours at rt, evaporated, washed with brine, extracted with ethyl acetate, dried over magnesium sulfate and concentrated to give the desired compound.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH:32]([C:38]([O:40][CH:41]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])[C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)/[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[NH2:68][CH:69]1[C:90](=[O:91])[N:71]2[C:72]([C:78]([O:80][CH2:81][C:82]3[CH:87]=[CH:86][C:85]([O:88][CH3:89])=[CH:84][CH:83]=3)=[O:79])=[C:73]([CH2:76][Cl:77])[CH2:74][S:75][C@H:70]12.N1C=CC=CC=1.Cl>ClCCl.O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH:32]([C:38]([O:40][CH:41]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:39])[C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)/[C:27]([NH:68][C@@H:69]2[C:90](=[O:91])[N:71]3[C:72]([C:78]([O:80][CH2:81][C:82]4[CH:87]=[CH:86][C:85]([O:88][CH3:89])=[CH:84][CH:83]=4)=[O:79])=[C:73]([CH2:76][Cl:77])[CH2:74][S:75][C@H:70]23)=[O:28])[N:25]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(N)C(=O)N23)cc1
Reactant: O=C(O)/C(=N\OC(C(=O)OC(c1ccccc1)c1ccccc1)c1ccsc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](NC(=O)/C(=N\OC(C(=O)OC(c4ccccc4)c4ccccc4)c4ccsc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
(Z)-2-(2-tritylamino-4-thiazolyl)-2-[(diphenylmethyloxycarbonyl)(3-thienyl)methyl]oxyiminoacetic acid (1.90 g, 2.58 mmol) and phosphorus pentoxide (0.564 g, 2.71 mmol) were added to dichloromethane (11 ml) under ice-cooling, and then the resulting mixture was stirred for 30 min. Thus obtained solution was added at -60° C. to the solution of 4-methoxybenzyl 7-amino-3-chloromethyl-3-cephem-4-carboxylate (1.046 g, 2.58 mmol) and pyridine (1.04 ml, 12.9 mmol) in dichloromethane (30 ml) at -40° C. The reaction solution was allowed to -20° C. over 40 min. The reaction solution was cooled to -40° C., and 1N hydrochloric acid (12.9 ml) was added thereto. Water was added to the reaction solution, the solution was extracted with dichloromethane (×3), the organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and then the solvent was evaporated to give a caramel (3.50 g). The caramel was subjected to silica gel column chromatography eluting with hexane-ethyl acetate to obtain (4-methoxybenzyl) 7β-[(Z)-2-(2-tritylamino-4-thiazolyl)-2-[[(R S)-(diphenylmethyloxycarbonyl)(3-thienyl)methoxy]imino]acetamido]-3-cloromethyl-3-cephem-4-carboxylate (2.62 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[OH:11][C:12]1[CH:21]=[C:20]([CH3:22])[C:15]2[NH:16][C:17](=[O:19])[O:18][C:14]=2[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([O:11][C:12]2[CH:21]=[C:20]([CH3:22])[C:15]3[NH:16][C:17](=[O:19])[O:18][C:14]=3[CH:13]=2)[CH:7]=1
Reactant: COc1nc(Cl)cc(Cl)n1
Reactant: Cc1cc(O)cc2oc(=O)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(Cl)cc(Oc2cc(C)c3[nH]c(=O)oc3c2)n1

Procedure:
0.19 g (1.01 mmol) 4,6-dichloro-2-methoxypyrimidine, 0.18 g (1.04 mmol) 6-hydroxy-4-methyl-3H-benzoxazol-2-one and 0.15 g (1.09 mmol) potassium carbonate in 1.5 mL DMF were stirred for 2 h at RT. Then water was added and the precipitate formed was suction filtered, washed and dried.