Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Yield: 57 %

Procedure:
A stirred solution of 1-benzylpiperazine (8.81 g, 50.0 mmol), 4-fluoronitrobenzene (5.31 mL, 50.0 mmol), and K2CO3 (6.90 g, 50.0 mmol) in ethanol is heated at reflux temperature under nitrogen for 18 h, cooled, diluted with water, and extracted with CH2Cl2. The combined extracts are dried over MgSO4 and concentrated in vacuo to give a solid residue. The solid is triturated with 20:80 ethyl acetate:hexanes and filtered. The filtercake is air-dried to afford the title compound as orange crystals, 8.45 g (57% yield), mp 218-219° C., characterized by NMR and mass spectral analyses.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:20]I.N1C=CN=C1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:42]=[CH:41][C:40]([CH2:43][CH2:44]O)=[CH:39][C:36]=2[C:37]#[N:38])=[CH:30][C:29]=1[C:46]([F:49])([F:48])[F:47]>C(Cl)Cl>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][I:20])=[CH:39][C:36]=2[C:37]#[N:38])=[CH:30][C:29]=1[C:46]([F:49])([F:48])[F:47]
Reactant: N#Cc1cc(CCO)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1cc(CCI)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
To a solution of Ph3P (1036 mg, 3.95 mmol) and iodine (1003 mg, 3.95 mmol) in DCM (5 mL), which was stirred at room temperature for 10 min, was added imidazole (448 mg, 6.58 mmol). After stirring for another 10 min, 2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-5-(2-hydroxyethyl)benzonitrile (900 mg, 2.63 mmol) was added. The mixture was stirred at room temperature for 1 h, and quenched by water, extracted with DCM. Purification via flash chromatography then afforded the title compound (1.0 g, 2.214 mmol, 84% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH2:16])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[H][H]>[Pd].C1(C)CCC(C(C)C)C(O)C1>[CH3:1][C:2]1[CH:14]=[C:13]([CH:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5]
Reactant: C=C(c1ccccc1)c1ccc(C(=O)OC(C)(C)C)c(C)c1
Reactant: [H][H]
Agent: [Pd]
Agent: CC1CCC(C(C)C)C(O)C1
Product: Cc1cc(C(C)c2ccccc2)ccc1C(=O)OC(C)(C)C
Yield: 88.5 %

Procedure:
The tert-butyl 2-methyl-4-(1-phenylvinyl)benzoate (1.8 g, 6.1 mmol), palladium 10% on carbon (0.61 mmol, 700 mg) and 30 mL menthol was stirred at room temperature under the atmosphere of hydrogen (4 atmosphere) for 24 hours. Then mixture was filtered, the filtrate was concentrated to give tert-butyl 2-methyl-4-(1-phenylethyl)benzoate (1.6 g, 90%) product. 1H-NMR (300 MHz, CD3OD) δ 7.67 (d, J=8.1 Hz, 1H), 7.24-7.08 (m, 7H), 4.02 (m, 1H), 2.48 (s, 3H), 1.59-1.61 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=4[Cl:26])=[CH:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:27]1[C:32]([C:33]([OH:35])=[O:34])=[CH:31][C:30]2[C:36]([O:38][C:39](=O)[C:29]=2[CH:28]=1)=[O:37]>>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=4[Cl:26])=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]=1[N:1]1[C:36](=[O:37])[C:30]2[C:29](=[CH:28][CH:27]=[C:32]([C:33]([OH:35])=[O:34])[CH:31]=2)[C:39]1=[O:38]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: COc1ccc(-c2nc3cc(-c4cccc(Cl)c4Cl)ccc3o2)cc1N
Product: COc1ccc(-c2nc3cc(-c4cccc(Cl)c4Cl)ccc3o2)cc1N1C(=O)c2ccc(C(=O)O)cc2C1=O

Procedure:
Prepared by the method of Example 1b), from 2-(3-amino-4-methoxyphenyl)-5-(2,3-dichlorophenyl)benzoxazole (238 mg, 0.60 mmol) and 1,2,4-benzenetricarboxylic anhydride (119 mg, 0.60 mmol) the title compound was obtained (191 mg, 57%). 1H NMR (DMSO) δ 8.46(dd, 1H), 8.35(m, 3H), 8.13(d, 1H), 7.84(m, 2H), 7.70(m, 1H), 7.47(m, 4H), 3.87(s, 3H). MS 560 m/z (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:17]=[CH:16][C:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][C:9]=3[CH:8]=2)=[CH:5][C:4]([CH3:18])=[N:3]1.[OH:19][CH2:20][CH2:21][C:22](=O)[CH3:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.C(O)(=O)C>[CH3:1][N:2]1[C:6]([C:7]2[CH:17]=[CH:16][C:10]3[CH2:11][CH2:12][N:13]([CH:22]([CH3:23])[CH2:21][CH2:20][OH:19])[CH2:14][CH2:15][C:9]=3[CH:8]=2)=[CH:5][C:4]([CH3:18])=[N:3]1
Reactant: Cc1cc(-c2ccc3c(c2)CCNCC3)n(C)n1
Reactant: CC(=O)CCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc3c(c2)CCN(C(C)CCO)CC3)n(C)n1
Yield: 38.5 %

Procedure:
To a stirred solution of 7-(1,3-dimethyl-1H-pyrazol-5-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine (0.5 g) (intermediate 3) in tetrahydrofuran (5 ml), at room temperature, 4-hydroxy-2-butanone (0.22 g), glacial acetic acid (0.12 ml) and sodium triacetoxyborohydride (0.53 g) were subsequently added. After stirring over night the mixture was made alkaline with 1N aqueous sodium hydroxide and extracted with dichloromethane. The organic phase was dried with sodium sulphate and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel with 70% cyclohexane-ethyl acetate to give the title compound (0.25 g) as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[CH3:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[O:29]=[C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:35]3[CH:36]=[CH:37][C:32]([CH3:31])=[CH:33][CH:34]=3)[CH:17]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]2)[NH:20]1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Product: Cc1ccc(-c2ccc3nc(-n4cc(C(=O)O)cn4)[nH]c(=O)c3c2)cc1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 4-methylphenylboronic acid in step C. MS (ESI): mass calcd. for C19H14N4O3, 346.1; m/z found, 347.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.03 (s, 1H), 12.92 (s, 1H), 8.98 (s, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 8.16 (d, J=7.9 Hz, 1H), 7.77 (s, 1H), 7.69 (d, J=8.0 Hz, 2H), 7.33 (d, J=7.9 Hz, 2H), 2.37 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[CH2:2].Cl[C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:16]=[CH:17][CH:18]=1.F[K].C(P)(C)(C)C>C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd].O1CCOCC1>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:17]2[CH:18]=[CH:13][CH:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:16]=2)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: Clc1cccc(-c2ccccn2)c1
Reactant: C=Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: CC(C)(C)P
Agent: F[K]
Solvent: C1COCCO1
Product: C=Cc1ccc(-c2cccc(-c3ccccn3)c2)cc1
Temperature: 80 °C
Yield: 45 %

Procedure:
This Example was carried out in the same manner as Example 10, except that 23.42 g (0.158 mol) of 4-vinyl-phenyl boronic acid, 20.0 g (0.1055 mol) of 2-(3-chloro-phenyl)pyridine, 500□ of 1,4-dioxane, 27.54 g (0.474 mol, 3.3 equivalent) of fluoro-potassium, 1.69 g (0.0084 mol, 5.3 mol %) of t-butylphosphine [P( t-Bu)3)], and 2.6 g (0.0028 mol, 1.8 mol %) of palladium tris(dibenzylidene acetone) [Pd2(dba)3] were used. Finally, after the resulting solution was heated to reflux at 80° C. for 24 hours, the 2-(4′-vinyl-biphenyl-3-yl)pyridine was isolated. The yield was 45%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9][CH3:10])=[CH:4][N:3]=1.N#CN.IC1C=CC=C(CC([O-])=[O:23])C=1CC([O-])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([CH3:10])=[O:23])=[CH:4][N:3]=1
Reactant: CSCc1ccc(Cl)nc1
Reactant: O=C([O-])Cc1cccc(I)c1CC(=O)[O-]
Agent: N#CN
Solvent: ClCCl
Product: CS(=O)Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.6 %

Procedure:
To a solution of sulfide (A) (3.5 g, 17 mmol) and cyanamide (1.4 mg, 34 mmol) in CH2Cl2 (30 mL) at 0° C. was added iodobenzenediacetate (11.0 g, 34 mmol) all at once. The reaction was stirred for 30 min, then allowed to warm to room temperature overnight. The mixture was diluted with CH2Cl2 (50 mL) and washed with H2O. The aqueous layer was extracted with ethyl acetate (4×50 mL), and the combined organic layers were dried over MgSO4 and concentrated. The crude product was triturated with hexanes and purified by chromatography (chromatotron, 60% acetone/hexanes) to furnish the sulfilimine (B) as a yellow gum (0.60 g, 14%). IR (film) 3008, 2924, 2143, 1693 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.8 (s, 1H), 8.0 (d, 1H), 7.8 (d, 1H), 4.5 (d, 1H), 4.3 (d, 1H), 2.9 (s, 3H); LC-MS (ESI): mass calcd for C9H9F3N3S [M+H]+ 248.04. Found 248.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([S:16]([N:19]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=2[CH3:31])[CH2:20][CH:21]([CH3:23])[CH3:22])(=[O:18])=[O:17])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[CH:32]1(B(O)O)[CH2:34][CH2:33]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:32]1([C:2]2[CH:3]=[C:4]([S:16]([N:19]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=3[CH3:31])[CH2:20][CH:21]([CH3:22])[CH3:23])(=[O:17])=[O:18])[CH:5]=[CH:6][C:7]=2[O:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH2:34][CH2:33]1
Reactant: OB(O)C1CC1
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCC3CCOCC3)c(Cl)c2)c(C)c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCC3CCOCC3)c(C3CC3)c2)c(C)c1
Temperature: 120 °C

Procedure:
To a suspension of 3-chloro-N-(2,4-dimethylphenyl)-N-isobutyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide (100 mg, 0.215 mmol), cyclopropylboronic acid (46.1 mg, 0.536 mmol), tricyclohexylphosphine (12.03 mg, 0.043 mmol) and tripotassium phosphate (137 mg, 0.644 mmol) in toluene (4 mL) and water (0.2 mL), was added palladium(II) acetate (approximately 4.82 mg, 0.021 mmol) ensuring all particles were below solvent level. The reaction vessel was sealed and heated by microwaves (Emrys Optimiser) to 120° C. for 30 minutes. After cooling, the reaction mixture was passed through a pre-packed silica column (500 mg) to remove palladium residues, eluting with methanol. The reaction solution was evaporated in vacuo to and purified by mass directed autoprep (formic acid modifier). The appropriate fractions were concentrated under a stream of nitrogen to give the required product, 34 mg. LCMS [LCMS1] Rt 1.55 min, m/z (ES+) 472 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:20]=[CH:19][C:7]([O:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:28][S:29]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:19][CH:20]=1)(=[O:31])=[O:30]
Reactant: CC(=O)Nc1nc(COc2ccc(CCO)cc2)cs1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(COc2ccc(CCOS(C)(=O)=O)cc2)cs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 104.6 %

Procedure:
To a solution of N-(4-{[4-(2-hydroxyethyl)phenoxy]methyl}-1,3-thiazol-2-yl)acetamide (310.0 mg, 1.060 mmol) in anhydrous dichloromethane (8 ml) were added triethylamine (0.27 ml, 1.91 mmol) and 4-dimethylaminopyridine (13.0 mg, 0.106 mmol), and the mixture was cooled to 0° C. Methanesulfonyl chloride (0.12 ml, 1.60 mmol) was added dropwise at 0° C. The mixture was warmed to room temperature and stirred for 1 hr. Iced water (20 ml) was added to the reaction mixture and the mixture was stirred for 20 min, extracted 3 times with ethyl acetate. The combined organic layer was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-(4-{[2-(acetylamino)-1,3-thiazol-4-yl]methoxy}phenyl)ethyl methanesulfonate (410.8 mg, containing N-(4-{[4-(2-chloroethyl)phenoxy]methyl}-1,3-thiazol-2-yl)acetamide) as an orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:13][C:14]2[C:20]([Cl:21])=[C:19]([Cl:22])[CH:18]=[C:17]([S:23][C:24]#[N:25])[C:15]=2[N:16]=1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:11][C:12]2[S:13][C:14]3[C:20]([Cl:21])=[C:19]([Cl:22])[CH:18]=[C:17]([S:23][C:24]#[N:25])[C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: N#CSc1cc(Cl)c(Cl)c2sc(N)nc12
Solvent: CN(C)C=O
Product: N#CSc1cc(Cl)c(Cl)c2sc(NC(=O)Nc3ccc(Br)cc3)nc12
Reaction time: 2 h

Procedure:
p-Bromophenyl isocyanate (20 g., 0.10 mole) was added in portions to a solution of 27.6 g. (0.10 mole) of 2-amino-6,7-dichloro-4-thiocyanatobenzothiazole in 300 ml. of dimethylformamide. The solution was heated at 100° with stirring for 41/2 hours and cooled at 0° overnight. The solid was collected by filtration. The filtrate was poured into ice water and the solid was collected by filtration. The combined solids were recrystallized from a methanol-dimethylformamide-water mixture to give 22 g. (50%) of product. Recrystallization from ethanol gave an analytical sample, m.p. 243°-245° .
Reaction SMILES: [CH2:1]([O:10][C:11](=[O:44])[CH:12]([NH:36]C(OC(C)(C)C)=O)[CH2:13][C:14]1[CH:15]=[C:16]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[CH:17]=[C:18]([CH2:20][P:21]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22])[CH:19]=1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>FC(F)(F)C(O)=O>[CH2:1]([O:10][C:11](=[O:44])[CH:12]([NH2:36])[CH2:13][C:14]1[CH:15]=[C:16]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[CH:17]=[C:18]([CH2:20][P:21]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22])[CH:19]=1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOP(=O)(Cc1cc(CC(NC(=O)OC(C)(C)C)C(=O)OCC=Cc2ccccc2)cc(-c2ccc(Cl)cc2)c1)OCC
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(Cc1cc(CC(N)C(=O)OCC=Cc2ccccc2)cc(-c2ccc(Cl)cc2)c1)OCC

Procedure:
5.5 g of the product of step c) and 50 ml aqueous trifluoroacetic acid (70%) are stirred at room temperature 20 hours. To the mixture are added CH2CL2 and dropwise aqueous KHCO3 solution. The organic phase is dried (Na2SO4) and evaporated. The residue is taken up in diethyl ether, filtered and evaporated to dryness, to give the heading compound as an oil.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(OC=3C3C=CC=CC=3)=C3C(=CC=4)NN=C3)=CC=2)CCC1.C(OC(=O)[NH:38][C:39]1([C:43]2[CH:48]=[CH:47][C:46]([C:49]3[C:62](=[O:63])[C:61]4[C:52](=[C:53]5[C:58](=[CH:59][CH:60]=4)[NH:57][C:56](=[O:64])[CH2:55][O:54]5)[O:51][C:50]=3[C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[CH:45][CH:44]=2)[CH2:42][CH2:41][CH2:40]1)(C)(C)C>>[NH2:38][C:39]1([C:43]2[CH:44]=[CH:45][C:46]([C:49]3[C:62](=[O:63])[C:61]4[C:52](=[C:53]5[C:58](=[CH:59][CH:60]=4)[NH:57][C:56](=[O:64])[CH2:55][O:54]5)[O:51][C:50]=3[C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[CH:47][CH:48]=2)[CH2:42][CH2:41][CH2:40]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c5c(ccc4c3=O)NC(=O)CO5)cc2)CCC1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5[nH]ncc54)c3=O)cc2)CCC1
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c5c(ccc4c3=O)NC(=O)CO5)cc2)CCC1
Yield: 58 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-2-phenyl-7H-pyrano[2,3-e]indazol-4-one, {1-[4-(2,8-dioxo-6-phenyl-1,2,3,8-tetrahydro-4,5-dioxa-1-aza-phenanthren-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a white solid (31 mg, 58%). 1H NMR (400 MHz, DMSO-d6): δ 7.69 (d, J=8.8 Hz, 1H), 7.42-7.30 (m, 7H), 7.12-7.09 (m, 2H), 7.04 (d, J=8.8 Hz, 1H), 4.80 (s, 2H), 2.39-2.31 (m, 2H), 2.10-2.01 (m, 2H), 2.01-1.93 (m, 1H), 1.69-1.57 (m, 1H). LCMS (Method E): RT=3.03 min, [M+H]+=439.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:11](=[O:20])[CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][C:14]2=[O:19])=[CH:4][CH:3]=1.[CH3:21][C:22]1[C:30]2[CH2:29][O:28][C:27](=[O:31])[C:26]=2[CH:25]=[CH:24][C:23]=1[C@@H:32]1[CH2:34][O:33]1>CCO>[F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:11](=[O:20])[CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:34][C@H:32]([OH:33])[C:23]3[CH:24]=[CH:25][C:26]4[C:27](=[O:31])[O:28][CH2:29][C:30]=4[C:22]=3[CH3:21])[CH2:15][C:14]2=[O:19])=[CH:4][CH:3]=1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reactant: Cc1c(C(=O)CN2CCNCC2=O)ccc(F)c1C#N
Solvent: CCO
Product: Cc1c(C(=O)CN2CCN(C[C@H](O)c3ccc4c(c3C)COC4=O)CC2=O)ccc(F)c1C#N
Temperature: 140 °C

Procedure:
A mixture of 6-Fluoro-2-methyl-3-[(2-oxopiperazin-1-yl)acetyl]benzonitrile (40 mg, 0.14 mmol) and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (42 mg, 0.22 mmol) in EtOH (2 mL) was heated to 140° C. for 1 hour. The reaction mixture was concentrated to dryness, and dissolved in MeOH, filtered and shot into Mass-directed HPLC for separation to give the title product. LC-MS (IE, m/z): 466 [M+1]+.
Reaction SMILES: [Cl-].[OH:2][CH:3]([CH2:38][NH:39]C(OC(C)(C)C)=O)[CH2:4][N+:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][C:13]2[CH2:20][S:19][C@H:18]3[N:15]([C:16](=[O:34])[C@H:17]3[NH:21][C:22](=[O:33])[CH2:23][S:24][C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=3[Cl:32])[C:14]=2[C:35]([OH:37])=[O:36])=[CH:7][CH:6]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl-:31].[OH:2][CH:3]([CH2:38][NH2:39])[CH2:4][N+:5]1[CH:6]=[CH:7][C:8]([S:11][CH2:12][C:13]2[CH2:20][S:19][C@H:18]3[N:15]([C:16](=[O:34])[C@H:17]3[NH:21][C:22](=[O:33])[CH2:23][S:24][C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=3[Cl:32])[C:14]=2[C:35]([OH:37])=[O:36])=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)NCC(O)C[n+]1ccc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)CSc4cc(Cl)ccc4Cl)[C@H]3SC2)cc1
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: NCC(O)C[n+]1ccc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)CSc4cc(Cl)ccc4Cl)[C@H]3SC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 127.2 %

Procedure:
A slurry of 1-(2-hydroxy-3-t-butoxycarbonylamino-1-propyl)-4-[[(6R)trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5- thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium chloride (1.19 g, 1.58 mmol) in methylene chloride (22 mL) was cooled to 0° C. Anisole (3.4 mL) was added followed by trifluoroacetic acid (11 mL). The mixture was stirred for 30 min at 0° C. and 30 min at rt. The reaction mixture was concentrated in vacuo. The residue was stirred with ether until a yellow powder resulted. This solid was collected by filtration washing with ether. The crude product was stirred with ether (20 mL) for 45 min, and then the solid was collected by filtration. This was followed by similar treatments with acetone (1×10 mL) and then ether (1×20 mL). The final filtration gave 655 mg (54%) of the title compound as a yellow solid. 1H NMR (300 MHz, DMSO) δ2.80 (t, J=10, 1H), 3.06 (d, J=11, 1H), 3.31-3.44 (m, 1H), 3.60 (d, J=18, 1H), 3.90 (s, 2H), 4.10 (br s, 1H), 4.34-4.42 (m, 3H), 4.66 (d, J=12, 1H), 5.02 (d, J=5, 1H), 5.56 (t, J=6, 1H), 6.5-7.0 (br s, 1H), 7.21 (dd, J=2, 8, 1H), 7.41-7.46 (m, 2H), 8.12 (m, 2H), 8.30 (br s, 3H), 8.68 (m, 2H), 9.28 (m, 1H); MS (FIA) m/e 615 (MH+); Anal. calcd for C24H24 N4O5S3Cl2.HCl. HO2CCF3 : C, 40.71; H, 3.55; N, 7.30. Found: C, 40.70; H, 3.52; 7.38.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1.P(Br)(Br)[Br:20].C(=O)([O-])O.[Na+]>N1C=CC=CC=1.CCCCCC>[Br:20][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccccc1-c1ccc(CO)cc1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Reaction time: 2 h
Yield: 100.4 %

Procedure:
10.0 g (41 mmol) of methyl 2-(4'-hydroxymethylphenyl)benzoate was dissolved in 7.9 g of pyridine and n-hexane (100 ml). 8.3 g (31 mmol) of phosphorus tribromide was dropwise added thereto under cooling with ice, followed by stirring for 2 hours as such. The reaction liquid was added to an aqueous solution of sodium hydrogencarbonate, followed by the extraction with n-hexane. The organic phase was washed with water, dried and subjected to vacuum concentration. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) To give 9.5 g of the title compound (yield 75%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]([S:18][CH3:19])[N:8]=1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]([S:18]([CH3:19])=[O:33])[N:8]=1
Reactant: CCOC(=O)c1cnc(SC)nc1NCc1ccc(OC)c(F)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)c1cnc(S(C)=O)nc1NCc1ccc(OC)c(F)c1
Reaction time: 0.5 h

Procedure:
In DCM (50 mL) was dissolved ethyl 4-((3-fluoro-4-methoxybenzyl)amino)-2-(methylthio)pyrimidine-5-carboxylate (2.2 g, 6.3 mmol). m-CPBA (3-chloroperbenzoic acid, 1.1 g, 6.4 mmol) was added. The reaction was conducted at ambient temperature for 30 min. The reaction mixture was washed with water. The organic phase was dried over sodium sulfate and concentrated to give ethyl 4-((3-fluoro-4-methoxybenzyl)amino)-2-(methylsulfinyl)pyrimidine-5-carboxylate. The product was used in the subsequent procedure without further purification.
Reaction SMILES: [Br-].[K+].CC1(C)N([O])C(C)(C)CCC1.[Br:14][C:15]1[CH:16]=[C:17]([CH:25]=[C:26]([CH2:28][OH:29])[CH:27]=1)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].Cl[O-].[Na+].O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(=O)(O)[O-].[Na+].O.ClCCl>[Br:14][C:15]1[CH:16]=[C:17]([CH:25]=[C:26]([CH:28]=[O:29])[CH:27]=1)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(CO)c1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(Br)cc(C=O)c1
Temperature: 25 °C

Procedure:
To a suspension of potassium bromide (249.3 g, 2.095 mol), 2,2,6,6-tetramethylpiperidine 1-oxyl (3.27 g, 20.93 mmol) in saturated aqueous sodium bicarbonate (960 mL) and water (240 mL) were added tert-butyl 3-bromo-5-(hydroxymethyl)benzoate (119.7 g, 417 mmol) and dichloromethane (1200 mL). The mixture was cooled to <5° C. and sodium hypochlorite (850 mL, 12.53 mol) was added dropwise in 4 portions until the reaction completed. A solution of sodium thiosulfate pentahydrate (72 g) in water (250 mL) was added and the reaction mixture was warmed to ambient temperature. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated (119.0 g).