Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.C(N(CC)CC)C.[C:44]1([CH2:50][C:51](Cl)=[O:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>ClCCl>[OH:17][C@@H:16]1[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13][C@H:12]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][C:3]([CH2:2][NH:1][C:51](=[O:52])[CH2:50][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[N:4][C:5]=2[NH:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC(=O)Cc4ccccc4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A stirred solution of (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (220 mg, 0.45 mmol) in dichloromethane (10 ml) was treated with triethylamine (0.38 ml, 2.70 mmol) and phenylacetylchloride (280 mg, 1.80 mmol) at 0° C. and the resultant mixture stirred for 15 min. The mixture was then stirred at room temperature for 72 hr. The solvent was removed under reduced pressure and methanol (20 ml), saturated with ammonia gas, added. The resultant mixture was stirred at room temperature for 2 hr, treated with 2 molar aqueous sodium hydroxide (10 ml) and then left standing at room temperature for 24 hr. The methanol was removed under reduced pressure and the aqueous layer extracted with dichloromethane (×3). The combined organic layers were washed with water (×2), dried with anhydrous magnesium sulfate, filtered and the solvent removed under reduced pressure. The residue was dissolved in 1,4-dioxan (6 ml), 0.88 aqueous ammonia solution (8 ml) added and the mixture stirred at room temperature for 10 days. The 1,4-dioxan was removed under reduced pressure and the aqueous layer extracted with dichloromethane (×3).
Reaction SMILES: C([Li])CCC.C(P([CH2:12][S:13]([O:16][CH2:17][CH3:18])(=[O:15])=[O:14])(CC)=O)C.[CH3:19][C:20]1[S:24][C:23]([CH:25]=O)=[CH:22][CH:21]=1>C1COCC1>[CH3:25][C:23]1[S:24][C:20]([CH:19]=[CH:12][S:13]([O:16][CH2:17][CH3:18])(=[O:14])=[O:15])=[CH:21][CH:22]=1
Reactant: Cc1ccc(C=O)s1
Reactant: CCOS(=O)(=O)CP(=O)(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOS(=O)(=O)C=Cc1ccc(C)s1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
n-Butyl lithium (1.6 mL of a 2.5 M solution in hexanes, 4.0 mmol) was added dropwise to a solution of ethyl diethylphosphorylmethanesulfonate (1.0 g, 3.8 mmol), prepared as described in Tetrahedron, 1987, 43(21), 5125, at −78° C. in THF (15 mL). The mixture was stirred for 20 min. then 5-methyl-2-thiophenecarboxaldehyde (460 mg, 4.2 mmol) was slowly added. The mixture was stirred at −78° C. for 1 h. then allowed to warm to room temperature overnight. The bulk of the solvents were evaporated and the residue was treated with water (2 mL) and extracted with CH2CL2. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography eluting with CH2CL2 to give the title compound.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH3:16][O:17][C:18](=[O:32])[CH:19]([C:24]1[CH:29]=[C:28]([OH:30])[CH:27]=[C:26](O)[CH:25]=1)[CH2:20][CH:21]([CH3:23])[CH3:22].N1C=CC=CC=1>C(Cl)Cl>[CH3:16][O:17][C:18](=[O:32])[CH:19]([C:24]1[CH:29]=[C:28]([O:30][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:8])=[O:6])[CH:27]=[C:26]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[CH:25]=1)[CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(O)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(OS(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
Trifluoromethanesulfonic anhydride (208 μL, 1.26 mmol) was added dropwise to a stirred solution of 2-(3,5-dihydroxy-phenyl)-4-methyl-pentanoic acid methyl ester (50 mg, 0.21 mmol) and pyridine (195 μL, 2.52 mmol) in DCM (5 mL) at 0° C. then warmed to room temperature. After 1 h, the mixture washed with 1M HCl (2 mL), dried (MgSO4) and concentrated in vacuo to afford the title product as an orange oil (104 mg, 99%). The product was used without further purification in the next step
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.S(=O)(O)[O-].[Na+].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]=O>O.C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=3)=[N:9][C:4]=2[CH:3]=1
Reactant: O=Cc1ccccn1
Reactant: Nc1ccc(Br)cc1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Brc1ccc2[nH]c(-c3ccccn3)nc2c1
Temperature: 90 °C
Yield: 40.5 %

Procedure:
A mixture of 4-bromo-1,2-diaminobenzene (1.00 g, 5.35 mmol), sodium bisulfite (1.02 g) in water (8 mL) and ethanol (80 mL) and 2-pyridine carboxaldehyde (0.63 g, 5.88 mmol) was heated at 90° C. for 15 h. The reaction was cooled to room temperature and concentrated under vacuum. The residue was partitioned between water (60 mL) and chloroform (80 mL) and the aqueous phase was extracted with chloroform (2×50 mL). The organic extracts were combined, dried (MgSO4), filtered and concentrated under vacuum to give the crude product (1.36 g). The residue was purified by column chromatography eluting with EtOAc:hexaxes 0 to 50% to afford 594 mg of 5-bromo-2-(pyridin-2-yl)-1H-benzo[d]imidazole (40%).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[NH2:15][C:16]1[CH:17]=[C:18]([NH:22][S:23]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=1>CC(O)C>[C:11]([C:10]1[CH:13]=[CH:14][C:7]([C:4]2[O:3][C:2]([NH:15][C:16]3[CH:17]=[C:18]([NH:22][S:23]([CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=3)=[N:6][CH:5]=2)=[CH:8][CH:9]=1)#[N:12]
Reactant: N#Cc1ccc(-c2cnc(Cl)o2)cc1
Reactant: Nc1cccc(NS(=O)(=O)Cc2ccccc2)c1
Solvent: CC(C)O
Product: N#Cc1ccc(-c2cnc(Nc3cccc(NS(=O)(=O)Cc4ccccc4)c3)o2)cc1
Temperature: 80 °C

Procedure:
A mixture of 4-(2-chlorooxazol-5-yl)benzonitrile 2 (0.20 g, 0.98 mmol) and N-(3-aminophenyl)-1-phenylmethanesulfonamide 4 (0.256 g, 0.98 mmol) in 2-propanol (20 mL) was heated to 80° C. for 18 h with stirring. Upon cooling, a white solid precipitated out which was filtered off, washed with 2-propanol, and dried. This was then triturated with ether and filtered to yield the title product, a white solid, as the hydrochloride salt of 5 (0.15 g, 36%). Free amine containing filtrate was evaporated and silica column purified (Biotage) (Acetone/hexane as an eluent) to provide 5 (0.15 g, 36% yield) as pale yellow solid. MS (ES) m/z 431 (M+H+).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:9][C:10](=[O:18])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][CH2:3]1.Br[CH2:20][CH2:21][OH:22]>>[OH:22][CH2:21][CH2:20][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:9][C:10](=[O:18])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][CH2:3]1
Reactant: OCCBr
Reactant: O=c1[nH]c(C2CCNCC2)cc2ccccc12
Agent: Cl
Product: O=c1[nH]c(C2CCN(CCO)CC2)cc2ccccc12
Yield: 34.5 %

Procedure:
By the reaction in the same manner as in Example 2a, using 3-(piperidin-4-yl)-2H-isoquinolin-1-one hydrochloride (1.1 g) and 2-bromoethanol (1.0 g) as starting materials, 3-[1-(2-hydroxyethyl)piperidin-4-yl]-2H-isoquinolin-1-one (0.39 g) was obtained.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.[Li]CCCC.[C:17]1([C:23](Cl)=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C1COCC1.CCOC(C)=O>[Cl:11][C:9]1[C:10]2[C:2]([C:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:24])=[CH:3][NH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Clc1ncnc2[nH]cc(Br)c12
Reactant: O=C(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1c[nH]c2ncnc(Cl)c12
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a solution of 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.47 g, 6.38 mmol) in THF (60 mL) at −78° C. under N2 was added n-BuLi (2.5 M in hexane, 5.74 mL, 14.36 mmol) dropwise. After completion of addition, the mixture was stirred at −78° C. for additional 40 min. PhCOCl (0.88 mL) was added and the reaction was stirred for an additional 1 hour. Water (1 mL) was added to quench the reaction. The reaction mixture was then poured into water (100 mL). EtOAc (200 mL) was added for extraction. The organic layer was separated, dried (Na2SO4), filtered and concentrated to a residue. The residue was dissolved into small amount of DCM and a little MeOH. It was loaded to silica gel column. The purification was down by eluent with 1/1 DCM/EtOAc. The (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(phenyl)methanone was obtained as a white solid (0.49 g, 29%). 1H NMR (DMSO-d6, 400 MHz) 8.74 (s, 1H), 8.17 (s, 1H), 7.87 (m, 2H), 7.68 (m, 1H), 7.56 (m, 2H). LCMS [M+1]: 258.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:13]([NH:15][C@H:16]([C:22]([O:24][CH3:25])=[O:23])[CH2:17][CH2:18][CH2:19][CH:20]=O)=[O:14].FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl.O>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH:12]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:13]([N:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH:16]1[C:22]([O:24][CH3:25])=[O:23])=[O:14]
Reactant: COC(=O)[C@H](CCCC=O)NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CCC=CN1C(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Yield: 137 %

Procedure:
Transfer the solution of [2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-6-oxo-(S)-norleucine, methyl ester in methylene chloride (volume about 4.5 L) to a 12-liter flask and place under nitrogen atmosphere. Stir and add trifluoroacetic acid (440 mL, 5.71 mole) in one portion. Stir the resulting mixture at room temperature for one hour, then rapidly cool to about 0° C. Add a solution of sodium hydroxide (240 g, 6.0 mole) in water (3.4 L) in a slow stream to the vigorously stirred mixture at such a rate that the pot temperature stays at about 0° C. Separate the organic phase and extract the aqueous phase with methylene chloride (1 L). Combine the organic phases and dry (MgSO4). Filter and remove the solvent in vacuo to leave a residue (262 g, 137%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:22]([NH:24][C:25]2[S:26][CH:27]=[CH:28][N:29]=2)=[O:23])=[CH:4][CH:3]=1.[Sn](Cl)Cl.O.C(=O)([O-])[O-].[K+].[K+]>CO.Cl>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[NH:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[C:9]([C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[N:10]=2)=[CH:14][CH:15]=1
Reactant: Cc1ccc(-c2[nH]c(-c3ccc([N+](=O)[O-])cc3)nc2C(=O)Nc2nccs2)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2[nH]c(-c3ccc(N)cc3)nc2C(=O)Nc2nccs2)cc1
Yield: 68.7 %

Procedure:
5-(4-Methylphenyl)-2-(4-nitrophenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (0.44 g) obtained in Example 19 was suspended in methanol and ice-cooled. To the suspension was added a solution of tin(II) chloride 6 hydrate (1.0 g) in 6 M hydrochloric acid solution (10 ml) and the mixture was refluxed under heating for 2.5 hr. Water was added and the mixture was neutralized with potassium carbonate and extracted with ethyl acetate. The organic layer was washed with water and, after drying, the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethyl acetate and 1 M hydrochloric acid—ether solution (5 ml) was added. The precipitated crystals were collected by filtration, and the obtained crude crystals were recrystallized from methanol to give 2-(4-aminophenyl)-5-(4-methylphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide (0.28 g), melting point 244° C. (decomposition).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])(C)C)=[N:6][CH:7]=1.Cl.[CH3:17][CH2:18][O:19]C(C)=O>[O-]CC.[Na+]>[CH2:18]([O:19][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][CH2:11][CH3:14])=[N:6][CH:7]=1)[CH3:17]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cn1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: CCOC(=O)Nc1cnc(OCC)cn1
Temperature: 25 °C
Yield: 42.9 %

Procedure:
The mixed products from 1,1-dimethylethyl (5-chloro-2-pyrazinyl)carbamate were combined and refluxed in 24% sodium ethoxide for 5 days, then cooled to RT, neutralized with HCl, and the product extracted out with DCM. The DCM was washed with saturated NaHCO3, then concentrated to afford a black residue. Addition of EtOAc afforded solids that were filtered off, washed with EtOAc to give ethyl (5-ethoxypyrazin-2-yl)carbamate as a brown solid (3.5 g, 42.9%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[C:26]([NH:30][S:31]([C:34]1[CH:35]=[N:36][CH:37]=[C:38](Br)[CH:39]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][S:31]([C:34]1[CH:35]=[N:36][CH:37]=[C:38]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:39]=1)(=[O:33])=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)(C)NS(=O)(=O)c1cncc(Br)c1
Product: CC(C)(C)NS(=O)(=O)c1cncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 5-bromo-pyridine-3-sulfonic acid tert-butylamide (example B.3) (439 mg, 1.3 mmol) according to general procedure II. Obtained as an orange solid (390 mg, 70%). MS (ISP) 568.2 [(M+H)+]; mp 224° C.
Reaction SMILES: CC([O-])(C)C.[K+].[CH3:7][N:8]([CH3:40])[C:9]1[S:10][C@H:11]2[O:17][C@H:16]([CH:18]=O)[C@@H:15]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C@H:14]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[C@H:12]2[N:13]=1.C1[CH2:45][O:44][CH2:43]C1>>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C@@H:15]2[C@@H:16](/[CH:18]=[CH:43]/[O:44][CH3:45])[O:17][C@H:11]3[C@H:12]([N:13]=[C:9]([N:8]([CH3:40])[CH3:7])[S:10]3)[C@H:14]2[O:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)=[CH:23][CH:24]=1
Reactant: C1CCOC1
Reactant: COc1ccc(CO[C@@H]2[C@H]3N=C(N(C)C)S[C@H]3O[C@H](C=O)[C@H]2OCc2ccc(OC)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CO/C=C/[C@H]1O[C@@H]2SC(N(C)C)=N[C@@H]2[C@@H](OCc2ccc(OC)cc2)[C@@H]1OCc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 14 %

Procedure:
A solution of Ph3PCH2OCH3Br (2.0 g, 5.90 mmol) in THF (30 mL) was treated with t-BuOK (645 mg, 5.76 mmol) at −10° C. for 30 min, and followed by addition of (3aR,5S,6S,7R,7aR)-2-(dimethylamino)-6,7-bis(4-methoxybenzyloxy)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-5-carbaldehyde (700 mg, 1.37 mmol). After stirred for 3 h at 0° C., the resulting solution was quenched with ice-water (20 mL), and extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated to give a residue, which was purified by a silica gel column, eluted with 10-50% ethyl acetate in petroleum ether to give the product 37 as a yellow oil (100 mg, 14%). (ES, m/z) [M+H]+ 515.0; 1H NMR (300 MHz, CDCl3) δ 7.15-7.35 (m, 4H), 6.84-6.98 (m, 4H), 6.45 (d, J=7.8 Hz, 1H), 6.28 (d, J=6.3 Hz, 1H), 5.21 (m, 1H), 4.45-4.89 (m, 4H), 4.18 (t, J=5.7 Hz, 1H), 3.94 (t, J=4.8 Hz, 1H), 3.87-3.91 (m, 1H), 3.78 (s, 6H), 3.56-3.65 (m, 1H), 3.52 (s, 3H), 2.92 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH:10]=[CH2:11])[CH:3]=1.[Li]CCCC.CN(C)[CH:19]=[O:20]>O1CCCC1>[CH2:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:19]=[O:20])[CH2:9][CH:10]=[CH2:11]
Reactant: C=CCCc1cccc(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCCc1cccc(C=O)c1
Reaction time: 1 h
Yield: 79 %

Procedure:
To a mixture of 1-bromo-3-(but-3-en-1-yl)benzene (0.5 g, 2.369 mmol) in tetrahydrofuran (10 mL) at −78° C. was added BuLi (1.137 mL, 2.84 mmol) dropwise. It was then stirred at this temperature for 1 h, then N,N-dimethylformamide (0.208 g, 2.84 mmol) was added. The reaction mixture was stirred at −78° C. for 30 min, then rt for 3 h. It was then quenched with NH4Cl, extracted with ether. The organic layer was dried over MgSO4, filtered and concentrated to obtain 3-(but-3-en-1-yl)benzaldehyde (0.3 g, 79%) as an oil. 1H NMR (400 MHz, CDCl3) δ 10.03 (s, 1H), 7.77-7.72 (m, 2H), 7.51-7.46 (m, 2H), 5.86 (ddt, J=17.1, 10.3, 6.6 Hz, 1H), 5.10-5.00 (m, 2H), 2.86-2.79 (m, 2H), 2.48-2.39 (m, 2H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12](=[N:16][O:17][CH2:18][CH:19]=[CH2:20])[C:13]([OH:15])=O)[N:11]=1.C[Si](CC(N)=O)(C)C.[NH2:29][CH:30]1[C:40](=[O:41])[N:32]2[C:33]([C:37]([OH:39])=[O:38])=[CH:34][CH2:35][S:36][C@H:31]12.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[NH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12](=[N:16][O:17][CH2:18][CH:19]=[CH2:20])[C:13]([NH:29][CH:30]2[C:40](=[O:41])[N:32]3[C:33]([C:37]([OH:39])=[O:38])=[CH:34][CH2:35][S:36][C@H:31]23)=[O:15])[N:11]=1
Reactant: C=CCON=C(C(=O)O)c1csc(N)n1
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Reaction time: 0.33 h
Yield: 44.5 %

Procedure:
Phosphoryl chloride (0.84 g.) was added dropwise to a stirred suspension of 2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetic acid (syn isomer, 1.0 g.), tetrahydrofuran (10 ml.) and water (0.05 ml.) at 5° C., and stirred at the same temperature for 20 minutes. Trimethylsilylacetamide (0.66 g.), phosphoryl chloride (0.84 g.) and N,N-dimethylformamide (0.45 g.) were added to a solution, and stirred at 5° C. for an hour to prepare the activated acid solution. On the other hand, trimethylsilylacetamide (4.0 g.) was added to a suspension of 7-amino-3-cephem-4-carboxylic acid (0.88 g.) in tetrahydrofuran (10 ml.) at 40° C., and stirred for 30 minutes. To the solution was added all at once the activated acid solution obtained above at -20° C., and stirred at 0° C. for an hour. After water (20 ml.) was added to the resultant solution at -20° C., the solution was adjusted to pH 7.5 with an aqueous solution of sodium bicarbonate. Ethyl acetate was added to the solution, and the aqueous layer was separated. The solution was washed with ethyl acetate and diisopropyl ether in turn, adjusted to pH 5.0 and treated with activated charcoal. After the solution was adjusted to pH 3.0, the precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide to give 7-[2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.8 g.).
Reaction SMILES: [NH4+:1].C([O-])(=O)C.ClC(Cl)(Cl)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:13][C:12]=1[C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)=[O:9]>CS(C)=O>[Cl:34][C:30]1[CH:29]=[C:28]([C:27]2[C:12]3[C:11](=[CH:16][CH:15]=[C:14]([C:17](=[O:26])[C:18]4[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)[CH:13]=3)[NH:10][C:8](=[O:9])[N:1]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: COc1ccc(C(=O)c2ccc(NC(=O)C(Cl)(Cl)Cl)c(C(=O)c3cccc(Cl)c3)c2)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Product: COc1ccc(C(=O)c2ccc3[nH]c(=O)nc(-c4cccc(Cl)c4)c3c2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 77.3 %

Procedure:
Acetic acid, ammonium salt (0.107 mol) was added at room temperature to a mixture of intermediate 12 (0.0536 mol) in DMSO (250 ml). The mixture was stirred at 60° C. for 4 hours then brought to room temperature, poured out into ice water and stirred. The precipitate was filtered, washed with water and taken up in warm CH3CN. The precipitate was filtered, washed with diethyl ether and dried under a vacuo, yielding 16.2 g (77%) of intermediate 13. The mother layer was evaporated. The residue was purified by column chromatography over silica gel (15-40 μm) (eluent: DCM/MeOH/NH4OH; 95/5/0.1). The pure fractions were collected and the solvent was evaporated. The residue (1.2 g, 6%) was crystallized from 2-propanone. The precipitate was filtered off and dried, yielding 0.9 g (4%) of 4-(3-chlorophenyl)-6-(4-methoxybenzoyl)-2(1H)quinazolinone (intermediate 13), mp. 248° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([CH3:14])[N:11]([C:15]2[CH:16]=[C:17]3[C:26](=[CH:27][C:28]=2Br)[O:25][CH2:24][C:23]2[N:18]3[CH:19]([CH3:39])[C:20](=[O:38])[N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[N:22]=2)[CH2:10][C@@H:9]1[CH3:40])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([CH3:14])[N:11]([C:15]2[CH:16]=[C:17]3[C:26](=[CH:27][C:28]=2[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[F:41])[O:25][CH2:24][C:23]2[N:18]3[CH:19]([CH3:39])[C:20](=[O:38])[N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[N:22]=2)[CH2:10][C@@H:9]1[CH3:40])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1F
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(Br)c(N4C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]4C)cc3N21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(-c4ccccc4F)c(N4C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]4C)cc3N21
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 61.1 %

Procedure:
A mixture of (2S,5R)-4-[7-bromo-4-methyl-3-oxo-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.4 g, 0.626 mmol), 2-fluorophenylboronic acid (0.105 g, 0.752 mmol), K2CO3 (0.173 g, 1.253 mmol) and PdCl2(dppf)-CH2Cl2 adduct (0.101 g, 0.125 mmol) in dioxane (8 mL) and water (2 mL) was stirred at 90° C. for 2.5 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 0-20% EtOAc in petroleum ether) to give (2S,5R)-4-[7-(2-fluoro-phenyl)-4-methyl-3-oxo-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.250 g, 61%) as a solid. LC/MS (Table 1, Method 25) Rt=1.143 min.; MS m/z: 654 [M+H]+.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[CH2:11][O:12]2)=[CH:7][CH:6]=1)(=O)C.N1C=CN=C1.O1C2C(=CC=C(O)C=2)C=C(C2C=CC(O)=CC=2)C1>C(O)C>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[C:10]1[CH2:11][O:12][C:13]2[C:8]([CH:9]=1)=[CH:7][CH:6]=[C:5]([OH:4])[CH:14]=2
Reactant: COc1cccc(C2=Cc3ccc(OC(C)=O)cc3OC2)c1
Agent: Oc1ccc(C2=Cc3ccc(O)cc3OC2)cc1
Agent: c1c[nH]cn1
Solvent: CCO
Product: COc1cccc(C2=Cc3ccc(O)cc3OC2)c1

Procedure:
3′-MethoxyIsoflav-3-ene-7-ol was prepared from 7-acetoxy-3′-methoxyisoflav-3-ene (0.1 g, 0.3 mmol) and imidazole (0.15 g) in ethanol (2.0 ml) as described for isoflav-3-ene-4′,7-diol. Yield: (0.06 g, 70%) m.p. 75° C. 1H NMR (CDCl3): δ 3.84 (s, 3H, OMe), 5.12 (s, 2H, H2), 6.38 (d, 1H, J 2.0 Hz, H8), 6.40 (dd, 1H, J 2.0 Hz, 8.3 Hz, H6), 6.76 (bs, 1H, H4), 6.84 (dd, 1H, J 1.9 Hz, 8.3 Hz, ArH), 6.95 (m, 3H, ArH), 7.29 (t, 1H, J 8.3 Hz, ArH).