Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH2:3][CH2:2]1.FC(F)(F)S(O[C:22]1[CH:35]=[C:34]2[C:25]([O:26][C:27]3[CH:28]=[CH:29][C:30]([C:41]4[C:42]([F:47])=[N:43][CH:44]=[CH:45][CH:46]=4)=[CH:31][C:32]=3[C@:33]32[CH2:39][O:38][C:37]([NH2:40])=[N:36]3)=[C:24]([F:48])[CH:23]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>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.CN(C=O)C>[O:1]1[CH2:2][CH:3]=[C:4]([C:22]2[CH:23]=[C:24]([F:48])[C:25]3[O:26][C:27]4[C:32](=[CH:31][C:30]([C:41]5[C:42]([F:47])=[N:43][CH:44]=[CH:45][CH:46]=5)=[CH:29][CH:28]=4)[C@@:33]4([CH2:39][O:38][C:37]([NH2:40])=[N:36]4)[C:34]=3[CH:35]=2)[CH2:5][CH2:6]1
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(OS(=O)(=O)C(F)(F)F)cc12
Reactant: CC1(C)OB(C2=CCOCC2)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+]
Solvent: CN(C)C=O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(C3=CCOCC3)cc12
Temperature: 85 °C

Procedure:
A flask was charged with tetrakis(triphenylphosphine)palladium (29.3 mg, 0.025 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (106 mg, 0.506 mmol), (S)-2-amino-5′-fluoro-2′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl trifluoromethanesulfonate (130 mg, 0.253 mmol), sodium carbonate (saturated) (0.253 mL, 1.266 mmol) and DMF (2 ml). The solution was heated at 85° C. for 18 hours. The product was purified via Gilson HPLC (gradient elution 20-90% MeCN/H2O, 0.1% TFA) to afford (S)-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13]([CH:15]1[CH2:17][CH2:16]1)=[O:14])=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:15]1([C:13]([C:6]2[C:7]([CH3:12])=[N:8][C:9]3[C:4]([C:5]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:3][C:2]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:11][CH:10]=3)=[O:14])[CH2:17][CH2:16]1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1C(=O)C1CC1
Reactant: C1CCNCC1
Product: Cc1nc2ccc(N3CCCCC3)cc2c(-c2ccccc2)c1C(=O)C1CC1
Yield: 64 %

Procedure:
The title compound was prepared from [(6-Bromo-2-methyl-4-phenyl-quinolin-3-yl)-cyclopropyl-methanone [example 55] and piperidine according to the procedure of example 51. Yield: 64%; MS: m/z=371 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH:13]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:14]([NH2:16])=[O:15])[C:7]2=[O:12].CN(C)C=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[Cl:62][C:63]1[CH:68]=[CH:67][C:66]([C@H:69]([CH3:73])[C:70](O)=[O:71])=[CH:65][CH:64]=1>>[NH2:16][C:14](=[O:15])[CH:13]([N:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:70](=[O:71])[C@H:69]([C:66]2[CH:67]=[CH:68][C:63]([Cl:62])=[CH:64][CH:65]=2)[CH3:73])[C:7]1=[O:12])[C:17]1[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=1
Reactant: NC(=O)C(c1ccc(Cl)cc1)n1ccc2c(N)cccc2c1=O
Reactant: C[C@H](C(=O)O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](C(=O)Nc1cccc2c(=O)n(C(C(N)=O)c3ccc(Cl)cc3)ccc12)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A round bottom flask was charged with 2-(5-amino-1-oxoisoquinolin-2(1H)-yl)-2-(4-chlorophenyl)acetamide (100 mg, 0.3 mmol), N,N-dimethylformamide (1 mL, 10 mmol), N,N-diisopropylethylamine (0.1 mL, 0.6 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (200 mg, 0.6 mmol) and (S)-2-(4-chlorophenyl)propanoic acid (68 mg, 0.37 mmol) and the reaction stirred at room temperature over night. The solvent was removed and the residue purified by flash chromatography (12 g silica gel, 0-10% MeOH/DCM) followed by preparative HPLC (reverse phase) to obtain the product as an off white solid. MS m/z=477.1 (M+H). 1H NMR (400 MHz; DMSO-d6) δ 9.97 (s, 1H), 8.12-8.10 (d, J=8.18 Hz, 1H), 8.03 (s, 1H), 7.75-7.70 (dd, J=8.18&5.63 Hz, 1H), 7.59 (s, 1H), 7.501-7.34 (m, 9H), 7.03-7.00 (d, J=8.01 Hz, 1H), 6.71 (s, 1H), 6.40-6.38 (d, J=8.27 Hz, 1H), 4.00-3.94 (q, J=6.97 Hz, 1H), 1.44-1.41 (d, J=7.11 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH3:22]>CC(C)=O>[CH2:19]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[CH2:20][CH2:21][CH3:22]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCC1(C(=O)OCC)CCCC1=O
Yield: 83.9 %

Procedure:
Under vigorously agitation, 52.0 g (purity of 90%) of ethyl 2-oxocyclopentane carboxylate was added to 126.73 g (purity of 98%,) of ground anhydrous potassium carbonate, and after stirring for several minutes, to the mixture was added 100 ml of acetone. The reaction mixture was further stirred for about 15 minutes, then thereto was dropwise added 66.0 ml (purity of 98%,) of 1-bromo-n-butane. Upon the completion of the addition, the reaction mixture was heated for reflux for 5 hours. The reaction mixture was filtered under the reduced pressure, and the filter cake was washed with diethyl ether until its color was purely white. Pale yellow filtrate was collected and dried over anhydrous magnesium sulfate, then the solvent was removed. The residue was distilled under reduced pressure, and 53.39 g of colorless liquid as a distillate cut of 140-141° C./16 mmHg was collected. Yield: 83.9%. MS: m/e 212(M+′), 197(M+″—CH3), 184(M+′—CH2CH2), 167(M+′—OCH2CH3), 156(M+′—C4H9,base), 139(M+′—CO2CH2CH3), 127, 111, 55.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[NH:5][CH:6]=[O:7].Br[CH2:13][CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[N:5]([CH2:13][CH2:14][CH2:15][Cl:16])[CH:6]=[O:7]
Reactant: O=CNc1ccc(Cl)c(Cl)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: O=CN(CCCCl)c1ccc(Cl)c(Cl)c1
Yield: 76.9 %

Procedure:
To the mixture of 3,4-dichloro-N-formylaniline (133.0 g, 700 mmol), 1-bromo-3-chloropropane (132.3 g, 840 mmol) and acetone (700 mL) was added cesium carbonate (273.7 g, 840 mmol), and the mixture was stirred for under reflux. The reaction mixture was concentrated under reduced pressure, and to the concentrate was added ethyl acetate (500 mL). The organic layer was washed with water (300 mL) and saturated sodium chloride solution (100 mL×3), successively, dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel 500 g×2, hexane/ethyl acetate=1/0 to 9/1 to 4/1), and the desired fraction was concentrated under reduced pressure to give the titled compound (143.5 g, 538 mmol, Yield 77%) as pale yellow oily substance.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[C:15]([C:22]([F:25])([F:24])[F:23])[CH:14]=3)[N:9]=[C:8]([C:26]#[N:27])[C:7]=2[N:6]=[CH:5]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CN(C=O)C.CO>[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[N:9]=[C:8]([C:26]#[N:27])[C:7]3[N:6]=[CH:5][N:4]([CH2:3][CH2:2][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[C:12]=3[CH:11]=2)=[CH:14][C:15]=1[C:22]([F:25])([F:24])[F:23])[CH3:21]
Reactant: CCOc1ccc(-c2cc3c(ncn3CCBr)c(C#N)n2)cc1C(F)(F)F
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: CO
Product: CCOc1ccc(-c2cc3c(ncn3CCN3CCOCC3)c(C#N)n2)cc1C(F)(F)F
Temperature: 120 °C
Yield: 66.3 %

Procedure:
1-(2-Bromo-ethyl)-6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (92 mg, 0.21 mmol) was dissolved in DMF (2 ml) and morpholine (91 mg, 1.05 mmol) was added. The mixture was heated to 120° C. for 5 minutes in a Smith microwave. Mixture was diluted with methanol (5 ml) and passed through a 5 g SCX cartridge then eluted with 2M methanolic ammonia to afford 62 mg of 6-(4-ethoxy-3-trifluoromethyl-phenyl)-1-(2-morpholin-4-yl-ethyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile as a clear oil. 1H NMR (CDCl3) δ 8.26-8.15 (m, 3H), 7.87 (s, 1H), 7.08 (d, 1H), 4.35 (t, 2H), 4.20 (q, 2H), 3.69 (m, 4H), 2.82 (t, 2H), 2.52 (m, 4H), 1.48 (t, 3H). MS m/z 446.4 (M+1).
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.S(Cl)(Cl)=O.[O:14]1[CH2:19][CH2:18][CH2:17][O:16][CH:15]1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][C:28]3[C:33]([N:34]=2)=[CH:32][CH:31]=[C:30]([Sn](C)(C)C)[N:29]=3)=[C:22]([F:39])[CH:21]=1>C1(C)C=CC=CC=1>[O:16]1[CH2:17][CH2:18][CH2:19][O:14][CH:15]1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][C:28]3[C:33]([N:34]=2)=[CH:32][CH:31]=[C:30]([C:6]([CH:4]2[CH2:3][C:2]([F:1])([F:9])[CH2:5]2)=[O:8])[N:29]=3)=[C:22]([F:39])[CH:21]=1
Reactant: O=C(O)C1CC(F)(F)C1
Reactant: C[Sn](C)(C)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1)C1CC(F)(F)C1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of 3,3-difluorocyclobutanecarboxylic acid (542.6 mg, 3.99 mmol) in thionyl chloride (5.24 mL, 71.8 mmol) was heated at 70° C. for 1 h and then concentrated in vacuo. 2-(4-(1,3-Dioxan-2-yl)-2-fluorophenyl)-5-(trimethylstannyl)thiazolo[5,4-b]pyridine (1.08 g, 2.254 mmol) was added to the residue, and the mixture was taken up in toluene (20.0 mL) and stirred under argon at 80° C. for 16 h. The reaction mixture was then concentrated onto silica gel and chromatographically purified (0-60% EtOAc/hexanes) to provide (2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)thiazolo[5,4-b]pyridin-5-yl)(3,3-difluorocyclobutyl)methanone as an off-white solid. MS (ESI) m/z: Calculated: 434.1; Observed: 435.0 (M++1).
Reaction SMILES: O=[C:2]([CH3:11])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].Cl.[OH-].[NH4+:14]>CO>[NH2:14]/[C:2](/[CH3:11])=[CH:3]\[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: [NH4+]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: C/C(N)=C/C(=O)OC(C)(C)C
Yield: 100 %

Procedure:
A solution of 1,1-dimethylethyl 3-oxobutanoate (50 g, 0.32 mol) in MeOH (320 mL) and 30% ammonium hydroxide (280 mL) was stirred at ambient temperature overnight. The solution was neutralized carefully with conc. HCl (200 mL), partially concentrated at reduced pressure and extracted with EtOAc (2×300 mL). Combined organic phases were dried over Na2SO4, filtered and concentrated to afford 1,1-dimethylethyl (2Z)-3-amino-2-butenoate as an oil that crystallized on standing (54 g, 100% yield): 1H NMR (DMSO-d6) δ 7.63 (bs, 1H), 6.79 (bs, 1H), 4.18 (s, 1H), 1.74 (s, 3H), 1.35 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8](=[O:14])[C:9]([CH3:13])([CH3:12])[CH2:10][F:11])=[CH:4][CH:3]=1.[Br:17]Br.O>C(Cl)Cl>[Br:17][CH:7]([O:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:16][CH:15]=1)[C:8](=[O:14])[C:9]([CH3:12])([CH3:13])[CH2:10][F:11]
Reactant: CC(C)(CF)C(=O)COc1ccc(Cl)cc1
Reactant: BrBr
Solvent: O
Solvent: ClCCl
Product: CC(C)(CF)C(=O)C(Br)Oc1ccc(Cl)cc1
Yield: 78.3 %

Procedure:
175 g (0.71 mol) of 1-(4-chlorophenoxy)-3,3-dimethyl-4-fluoro-butan-2-one were dissolved in 500 ml of methylene chloride, and 114 g (0.71 mol) of bromine were added dropwise at 20° to 30° C., while stirring and cooling. The mixture was subsequently stirred at 20° C. for 2 hours, 200 ml of water were added carefully and the methylene chloride phase was washed several times with ice-water and dried over sodium sulphate. After distilling off the solvent in vacuo, the residue was recrystallized from cyclohexane. 180 g (78% of theory) of 1-bromo-1-(4-chlorophenoxy)-3,3-dimethyl-4-fluoro-butan-2-one of melting point 73°-75° C. were obtained. ##STR26##
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:34][CH:35]([CH3:37])[CH3:36])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([O:27][CH2:28][CH2:29][CH2:30][C:31](O)=[O:32])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:41]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.CN(C)C=O>O>[NH2:41][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][O:27][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([CH2:34][CH:35]([CH3:36])[CH3:37])[C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[C:19]2[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OCCCC(=O)O)cc23)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OCCCC(N)=O)cc23)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 4-{[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}butanoic acid (0.8 g, 1.6 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.34 g, 2.0 mmol), 1-hydroxy-1H-benzotriazole ammonium salt (0.24 g, 1.6 mmol) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 15 hrs. Water was added to the reaction mixture, and the mixture was extracted with a mixed solvent of ethyl acetate-tetrahydrofuran (2:1). The extract was washed successively with saturated aqueous sodium hydrogen carbonate, 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from isopropyl ether to give tert-butyl {[6-(4-amino-4-oxobutoxy)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (0.68 g, yield (84%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21]Cl.[CH3:23][C:24]1([CH3:34])[O:28][C:27]2[C:29]([OH:33])=[CH:30][CH:31]=[CH:32][C:26]=2[CH2:25]1>>[CH3:23][C:24]1([CH3:34])[O:28][C:27]2[C:29]([O:33][CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:3]3[C:4]([Cl:16])=[CH:5][C:6]([O:8][CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)=[CH:7][C:2]=3[Cl:1])=[CH:30][CH:31]=[CH:32][C:26]=2[CH2:25]1
Reactant: CC1(C)Cc2cccc(O)c2O1
Reactant: ClCCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Product: CC1(C)Cc2cccc(OCCCCOc3c(Cl)cc(OCc4ccccc4)cc3Cl)c2O1

Procedure:
In a first step as depicted in Scheme 1, an appropriately substituted phenol, for example, the known compound 2,6-dichloro-4-phenylmethoxyphenol, was reacted under basic conditions with a haloalkane derivative of a desired carbon chain length, for example 1-bromo-4-chlorobutane, to attach the bridging group B, thereby affording the corresponding 1,3-dichloro-2-(4-chlorobutoxy)-5-(phenylmethoxy)benzene (A). Intermediate (A) was then reacted under basic conditions with, for example, the known compound 2,2-dimethyl-2,3-dihydrobenzo[b]furan-7-ol, to attach moiety D, as well as the benzo-fused ring, affording the corresponding 2-[4-(2,2-dimethyl-(2,3-dihydrobenzo[2,3-b]furan-7-yloxy))butoxy]-1,3-dichloro-5-(phenylmethoxy)benzene (B). Intermediate (B), for example 2-[4-(2,2-dimethyl-(2,3-dihydrobenzo[2,3-b]furan-7-yloxy))butoxy]-1,3-dichloro-5-(phenylmethoxy)benzene, as set forth above, was then reduced with hydrogen gas in the presence of a catalyst, for example 10% palladium on carbon, providing the corresponding 4-[4-(2,2-dimethyl(2,3-dihydrobenzo[2,3-b]furan-7-yloxy))butoxy]-3,5-dichlorophenol (C). Intermediate (C) was then reacted under basic conditions with, for example, 1,1,1,3-tetrachloropropane, which simultaneously dehydrohalogenates, thereby introducing the moiety —E—G—C(R4)═C(R5)(R5) into the molecule to provide Compound 12, a novel compound of formula I. Example 1 set forth below, provides a detailed method to how Compound 12 shown in Scheme 1 was prepared.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:32](=[O:33])[C:31]4[CH:35]=[CH:36][CH:37]=[C:29]([Br:28])[CH:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: O=C(O)c1cccc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)c4cccc(Br)c4)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1-[4′-(4-Amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.181 g, 0.5 mmol), 3-bromo-benzoic acid (0.100 g, 0.5 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl uronium hexafluorophosphate (0.228 g, 0.6 mmol) and N-methylmorpholine (0.110 mL, 1.0 mmol) were combined in DMF and stirred at room temperature for 2 days. The reaction was submitted to standard aqueous workup and purified by silica gel chromatography to afford the title compound.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[O:19][CH2:20][CH3:21])[CH3:10].CCCCCC>C(#N)C>[Br:1][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:9][CH3:10])=[C:13]([O:19][CH2:20][CH3:21])[C:14]=1[F:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOc1cccc(F)c1OCC
Solvent: CC#N
Solvent: CCCCCC
Product: CCOc1ccc(Br)c(F)c1OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
A solution of N-bromosuccinimide (NBS) (153.72 g, 864 mmol) in acetonitrile (1.5 L) was added dropwise to a solution of 1,2-diethoxy-3-fluorobenzene (150.00 g, 814 mmol) in acetonitrile (900 mL) on ice, and this was stirred at room temperature overnight. After the solvent was distilled off, ethyl acetate was added to the residue and washed with water. The obtained aqueous layer was extracted again with ethyl acetate, and the extract was combined with the aforementioned organic layer. The organic layer was washed sequentially with water, saturated brine, and water again, and was dried over anhydrous magnesium sulfate. The solution was concentrated and an oily substance was obtained. Following hexane addition to the oily substance, crystals that have precipitated were removed by filtration. The remaining solution was concentrated to yield an oily substance, which was distilled under reduced pressure to obtain 205.65 g of the subject compound (yield: 96%).
Reaction SMILES: [OH:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:13]([N:14]3[C:18](=[O:19])[C:17]4=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]4[C:15]3=[O:24])[C:12](=[O:25])[N:6]2[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[N+](=[CH2:28])=[N-]>O1CCOCC1.CCOCC>[CH3:28][O:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:13]([N:14]3[C:18](=[O:19])[C:17]4=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]4[C:15]3=[O:24])[C:12](=[O:25])[N:6]2[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: C=[N+]=[N-]
Reactant: COC(=O)C1=C(O)CS[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N12
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)C1=C(OC)CS[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 3-oxo-7-phthalimidocephem-4-carboxylate (b) thus prepared by above methods is dissolved in dioxane, mixed with a solution of diazomethane in ether, and stirred for 1 hour at room temperature. The reaction mixture is evaporated under reduced pressure to give methyl 3-methoxy-7-phthalimido-3-cephem-4-carboxylate in nearly quantitative yield. Recrystallization from a mixture of acetone and ether gives pure crystals, m.p. 225°-227° C.
Reaction SMILES: [ClH:1].[NH2:2][C:3]([CH3:24])([CH2:6][CH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=1)[CH2:4][OH:5].S(=O)(=O)(O)[OH:26].[OH-].[Na+]>CO>[ClH:1].[NH2:2][C:3]([CH3:24])([CH2:6][CH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[O:26])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:12]=1)[CH2:4][OH:5]
Reactant: O=S(=O)(O)O
Reactant: CC(N)(CO)CCc1cc(C#CCCCc2ccccc2)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(N)(CO)CCc1cc(C(=O)CCCCc2ccccc2)cs1
Yield: 53 %

Procedure:
2-Amino-2-methyl-4-[4-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-ol hydrochloride (178 mg, 0.49 mmol) obtained in Example 26 (i) was dissolved in methanol (2 ml), and 6N sulfuric acid (2 ml) was added thereto followed by heating under reflux for 4 hours. After the reaction solution was made alkaline with a 1N aqueous sodium hydroxide solution, the resulting solution was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. The residue was dissolved in 1,4-dioxane (2 ml), and the dioxane solution of 4N hydrochloric acid was added thereto in an ice bath, and then the solvent was evaporated under reduced pressure. The obtained white solid was washed with ether, and dried to give the title compound (100 mg, 53% yield).
Reaction SMILES: B(Br)(Br)Br.[CH3:5][O:6][C:7](=[O:20])[CH2:8][C:9]1[C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18]C)[C:11]=2[S:12][CH:13]=1.[NH4+].[Cl-]>ClCCl>[CH3:5][O:6][C:7](=[O:20])[CH2:8][C:9]1[C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:11]=2[S:12][CH:13]=1
Reactant: COC(=O)Cc1csc2c(OC)cccc12
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: COC(=O)Cc1csc2c(O)cccc12
Reaction time: 0.5 h
Yield: 3 %

Procedure:
29 mL of boron tribromide (1M in dichloromethane) was added slowly dropwise to a stirred solution of compound 77A from the preceding step (4.5 g, 19 mmol) in 100 mL of dichloromethane under N2 at icebath temperature. An hour after the addition, 60 mL of 15% aq NH4Cl was added slowly dropwise, the mixture was stirred for an additional 30 min, then the layers allowed to separate. The organic layer was washed with water, then sat brine, then dried over MgSO4. The solvent was removed in vacuo, and the residue was chromatographed on a silica gel column in CHCl3/EtOAc (9:1) to afford a clear, amber oil. Crystallization began after several hours under vacuum. The product was recrystallized from 55–60 mL of chloroform/hexanes (1:1). After filtration to remove the first crop of regio-isomeric material, the mother liquor was stripped of solvent in vacuo, and the residue recrystallized from chloroform to yield 0.14 g (3% yield) of the title compound as a white powder, mp 147–148° C., of sufficient purity for use in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:13]([O:20][CH3:21])(=[O:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16]>C1(C)C=CC=CC=1>[CH3:18][O:17][C:15]([CH:14]([CH:6]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:12][CH:11]=1)[CH2:7][N+:8]([O-:10])=[O:9])[C:13]([O:20][CH3:21])=[O:19])=[O:16]
Reactant: COC(=O)CC(=O)OC
Reactant: Cc1ccc(C=C[N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)OC)C(C[N+](=O)[O-])c1ccc(C)cc1
Temperature: -20 °C
Reaction time: 48 h

Procedure:
[(S,S)-N-(pentamethylbenzenesulfonyl)-1,2-diphenyl-ethylenediamine](hexamethylbenzene)ruthenium (13.7 mg, 0.02 mmol, S/C=50), 4-methyl-β-nitrostyrene (1.0 mmol), dimethyl malonate (114 μl, 1.0 mmol) and toluene (1 ml) were added into Schlenk (20 ml) under an argon atmosphere, and stirred at −20° C. for 48 hours. The reaction solution was purified by flash column chromatography (hexane/acetone=80/20, SiO2), showing that the isolation yield of the product was 71%. The optical purity was measured by HPLC (CHIRALPACK AD manufactured by Daicel Co., Ltd., hexane:2-propanol=90:10, flow rate 0.5 ml/min, detection by 210 nm), resulting to 92% ee.