Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2]/[CH:3]=[C:4](\[CH3:9])/[C:5]([O:7][CH3:8])=[O:6].[CH3:10][NH:11][CH3:12]>O1CCCC1>[CH3:10][N:11]([CH3:12])[CH2:2]/[CH:3]=[C:4](\[CH3:9])/[C:5]([O:7][CH3:8])=[O:6]
Reactant: CNC
Reactant: COC(=O)/C(C)=C/CBr
Solvent: C1CCOC1
Product: COC(=O)/C(C)=C/CN(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To methyl(2E)-4-bromo-2-methylbut-2-enoate (643 mg, 3.33 mmol) in tetrahydrofuran (6.66 mL) was added dimethylamine (5.00 mL, 9.99 mmol, 2M in THF). The reaction was stirred at 25° C. overnight, then concentrated in vacuo and purified by silica chromatography using 1-8% DCM/MeOH (visualized with potassium permanganate stain). The product was collected and concentrated to afford the desired product as a colorless oil. LRMS (ESI) calc'd for C8H16NO2 [M+H]+: 158, found 158.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15]CC3C=CC=CC=3)[CH:13]=2)[N:8]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:7]=1)[CH3:3]>C(O)C.[OH-].[Pd+2].[OH-]>[CH3:1][N:2]([CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:24])=[O:25])[CH:7]=1)[CH3:3]
Reactant: CN(C)CCc1cn(S(=O)(=O)c2ccccc2)c2ccc(OCc3ccccc3)cc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CCc1cn(S(=O)(=O)c2ccccc2)c2ccc(O)cc12
Reaction time: 2.5 h

Procedure:
A solution of N,N-dimethyl 2-(1-benzenesulphonyl-5-benzyloxy-1H-indol-3-yl)ethylamine (2.25 g, 4.6 mmol) in absolute ethanol (100 ml) was hydrogenated at 40 psi over 20% palladium hydroxide (600 mg) for 4.5 h. Additional catalyst (1.6 g) was then added and hydrogenation was resumed at 45 psi for 2.5 h. The catalyst was removed by filtration, washed with a mixture of dichloromethane-methanol-ammonia (80:20:2; 3×70 ml), and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography (silica gel, dichloromethane-methanol-ammonia, 95:5:0.5) to give the title compound as a crystalline solid after trituration with diethyl ether (30 ml); mp 185°-188° C.; δH (360 MHz, DMSO-d6) 9.32 (1H, br s), 7.90-7.84 (2H, m), 7.69 (1H, d, J=8.7 Hz), 7.68-7.62 (1H, m), 7.55 (2H, t, J=8.0 Hz), 7.48 (1H, s), 6.82 (1H, d, J=2.2 Hz), 6.78 (1H, dd, H=8.8 and 2.2 Hz), 2.67 (2H, t, J=7.6 Hz), 2.47 (2H, t, J=7.6 Hz), 2.18 (6H, s); m/z (ES) 345 (M++1). (Found: C, 62.91; H, 5.86; N, 8.16. C18H20N2O3 requires: C, 62.77; H, 5.85; N, 8.13%).
Reaction SMILES: C([N:8]([CH2:45][CH2:46][O:47][CH3:48])[C:9]1[N:13]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]4)[N:20]3[CH3:23])=[C:16]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:15]=2)[C:12]2[CH:41]=[CH:42][CH:43]=[CH:44][C:11]=2[N:10]=1)C1C=CC=CC=1.C(O)(=O)C>[Pd].C(O)C>[CH3:48][O:47][CH2:46][CH2:45][NH:8][C:9]1[N:13]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([CH2:24][N:25]4[CH2:26][CH2:27][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:29][CH2:30]4)[N:20]3[CH3:23])=[C:16]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:15]=2)[C:12]2[CH:41]=[CH:42][CH:43]=[CH:44][C:11]=2[N:10]=1
Reactant: COCCN(Cc1ccccc1)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COCCNc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Temperature: 70 °C
Reaction time: 18 h
Yield: 28.2 %

Procedure:
A mixture of 2-(1-((2-(2-(benzyl(methoxyethyl)amino)-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (0.22 g, 0.34 mmol) and palladium on carbon (10 wt %, 0.2 g) and acetic acid (0.15 mL) in ethanol (10 mL) was stirred under a hydrogen atmosphere at 70° C. for 18 hours. The reaction mixture was then filtered though celite and concentrated. The crude product was purified by RP-HPLC to give 358 (54 mg, 28%). LCMS m/z: 564.4 (MH+)
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]([O:33][CH3:34])[CH2:6][C:7]1[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[C:10]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C1COCC1.CCO>[Cl:32][C:27]1[CH:26]=[C:25]([C:21]2[O:22][C:23]([CH3:24])=[C:19]([CH2:18][CH2:17][O:16][C:10]3[C:11]4[CH:15]=[CH:14][S:13][C:12]=4[C:7]([CH2:6][CH:5]([O:33][CH3:34])[C:4]([OH:35])=[O:3])=[CH:8][CH:9]=3)[N:20]=2)[CH:30]=[C:29]([Cl:31])[CH:28]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3cc(Cl)cc(Cl)c3)oc2C)c2ccsc12)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(Cc1ccc(OCCc2nc(-c3cc(Cl)cc(Cl)c3)oc2C)c2ccsc12)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
0.142 g of the above prepared [rac]-3-(4-{2-[2-(3,5-dichloro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-2-methoxy-propionic acid ethyl ester (0.27 mmol) was dissolved in 4 ml of THF/EtOH=1/1 and treated with 0.68 ml of 1N NaOH (2.5 eq.). The reaction mixture was stirred at ambient temperature and progress of the hydrolysis followed by TLC. After 2 h, the reaction mixture was poured onto crashed ice/HCl dil. and extracted twice with AcOEt. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated to dryness. Crystallization from AcOEt/hexane yielded finally 0.107 g of the title product as white crystals of mp. 160-61°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:30])([F:29])[C:12]3[CH:13]=[CH:14][C:15]4[N:16]([CH:18]=[C:19]([NH:21]C(=O)OC(C)(C)C)[N:20]=4)[N:17]=3)=[N:9][N:10]=2)[CH:7]=1>Cl.O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:29])([F:30])[C:12]3[CH:13]=[CH:14][C:15]4[N:16]([CH:18]=[C:19]([NH2:21])[N:20]=4)[N:17]=3)=[N:9][N:10]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cn2nc(C(F)(F)c3nnc4ccc(Br)cn34)ccc2n1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cn2nc(C(F)(F)c3nnc4ccc(Br)cn34)ccc2n1
Yield: 100.2 %

Procedure:
A solution of tert-butyl 6-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)imidazo[1,2-b]pyridazin-2-ylcarbamate (2.8 g, 5.83 mmol) in 4N HCl/dioxane (25 mL) was stirred at ambient temperature for 1 hr. The solvent was removed via rotary evaporation and the residue was dried under vacuum to provide the title compound, 6-((6-Bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)imidazo[1,2-b]pyridazin-2-amine 45M (2.2 g, 5.84 mmol, 92%), as HCl salt. This material was used without further purification. ESI-MS:m/z 380.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH2:15][CH3:16])=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9]C(=O)[C:7]2=[O:14])([O-:3])=[O:2].[OH:17]O.Cl>[OH-].[Na+]>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([NH2:9])=[C:6]([C:5]=1[CH2:15][CH3:16])[C:7]([OH:14])=[O:17])([O-:3])=[O:2]
Reactant: OO
Reactant: CCc1c([N+](=O)[O-])ccc2c1C(=O)C(=O)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCc1c([N+](=O)[O-])ccc(N)c1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of 1.0 g (4.5 mmoles) of 5-nitro-4-ethylisatin in 8.0 mL of 5% NaOH was slowly added 1.25 mL (11 mmoles) of 30% hydrogen peroxide over 10 minutes. A mild exotherm was detectable. The solution was stirred at room temperature for 60 minutes, then poured over crushed ice. The solution was acidified with 10% HCl until the `cloud point`. The suspension was extracted 3× with ethyl acetate. The combined organic extracts were washed 1× with water, dried over MgSO4, and concentrated in vacuo. There was obtained a dark oil, which upon standing at room temperature, became an orange-rust colored solid. 0.78 g (82% yield) of 5-nitro-6-ethyl-2-aminobenzoic acid was obtained. NMR(DMSO-d6): 1.16(t,3H,J=7.2 Hz), 2.88(q,2H,J=7.2 Hz), 3.34(bs,2H), 6.66(d,1H,J=9.3 Hz), 7.84(d,1H,J=9.3 Hz). MS(m/z): 210(M+).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10](Br)=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([OH:17])[CH:15]=[CH2:16].C([O-])(O)=O.[Na+]>CN(C=O)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:16][CH2:15][CH:14]=[O:17])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)s1
Reactant: C=CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(CCC=O)s1
Temperature: 65 °C

Procedure:
To a solution of 5-bromo-thiophene-2-carboxylic acid tert-butyl ester prepared of the method of Preparation 4, Step A (0.50 g, 1.89 mmol) in 5 mL DMF was added allyl alcohol (0.51 mL, 7.57 mmol) followed by NaHCO3 (0.397 g, 4.72 mmol), tetrabutylammonium chloride (0.525 g, 1.89 mmol), and palladium acetate (0.021 g, 0.094 mmol). The reaction was placed in an oil bath heated to 65° C. and was heated to 90° C. for 2 h. The mixture was diluted with EtOAc and 25 mL water and the solids were removed by filtration through Celite®. The layers were separated, and the organic solution was washed with water (4×), dried over MgSO4 and concentrated to a dark yellow oil which was purified via medium pressure chromatography (7:1 hexanes:EtOAc) to afford the title compound (0.190 g). 1H NMR (400 MHz, CDCl3) δ 9.80 (s, 1H), 7.51 (d, 1H), 6.78 (d, 1H), 3.14 (t, 2H), 2.86 (t, 2H), 1.54 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2Br)[CH:6]=1)[CH3:2].[F:19][C:20]([F:41])([F:40])[C:21]1[CH:22]=[CH:23][C:24]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[F:39])=[C:25](B(O)O)[CH:26]=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2[C:23]2[CH:22]=[C:21]([C:20]([F:40])([F:41])[F:19])[CH:26]=[CH:25][C:24]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[F:39])[CH:6]=1)[CH3:2]
Reactant: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccc(F)cc1F
Reactant: CCOC(=O)c1cc(C)cc(C2=C(Br)CCC2)c1
Product: CCOC(=O)c1cc(C)cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccc(F)cc3F)CCC2)c1

Procedure:
Prepared by general procedure B(iii) but using 3-(2-bromocyclopent-1-enyl)-5-methylbenzoic acid ethyl ester instead of 3-(2-bromo-cyclopent-1-enyl)-6-methyl benzoic acid ethyl ester and using [5-trifluoromethyl-2-(2,4-di-fluorobenzyloxy)phenyl]boronic acid instead of (5-chloro-2-benzyloxyphenyl)boronic acid.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:32])([CH3:31])[O:6][C:7]1[CH:12]=[C:11]([CH2:13][O:14][Si](C(C)(C)C)(C)C)[CH:10]=[CH:9][C:8]=1[CH2:22][P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])([CH3:4])[CH3:3].Cl.CCOC(C)=O.O>C(O)C>[CH3:1][C:2]([Si:5]([CH3:32])([CH3:31])[O:6][C:7]1[CH:12]=[C:11]([CH2:13][OH:14])[CH:10]=[CH:9][C:8]=1[CH2:22][P:23](=[O:30])([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])([CH3:4])[CH3:3]
Reactant: CCOP(=O)(Cc1ccc(CO[Si](C)(C)C(C)(C)C)cc1O[Si](C)(C)C(C)(C)C)OCC
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOP(=O)(Cc1ccc(CO)cc1O[Si](C)(C)C(C)(C)C)OCC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of diethyl [[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]methyl]phenyl]methyl]phosphonate (3.23 g, 6.4 mmol) from Preparation 17 in ethanol (30 mL) at 0° C. is treated with 1 mL of 1N HCl. The mixture is stirred at 0° C. for 2 hours. The solution is poured onto 500 mL EtOAc and water (50 mL). The organic phase is separated, dried (MgSO4), and concentrated. The residue is purified by silica gel chromatography (2.5% MeOH/CH2Cl2 followed by 5% MeOH/CH2Cl2). A colorless oil of diethyl [[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-(hydroxymethyl)phenyl]methyl]phosphonate is obtained (1.73 g, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([O:20]CC4C=CC=CC=4)=[CH:19][C:14]=3[O:13][CH2:12]2)=[O:10])=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29]>C1COCC1.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:14]=3[O:13][CH2:12]2)=[O:10])=[CH:4][C:3]=1[C:28]([F:30])([F:29])[F:31]
Reactant: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)N1COc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)N1COc2cc(O)ccc21

Procedure:
As a solution in 25 ml THF, 469 mg (1.04 mMol) 6-benzyloxy-benzooxazole-3-carboxylic acid (4-chloro-3-trifluoromethyl-phenyl)-amide are hydrogenated during 1 h in the presence of 267 mg Pd/C (10%). The catalyst is filtered off, washed with THF and the filtrate concentrated. Trituration with hexane gives the crystalline title compound, which is filtered off and washed with hexane: HPLC: tRet=14.3.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5].Cl[S:24]([C:27]1[CH:39]=[CH:38][C:30]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:29]([CH3:40])[CH:28]=1)(=[O:26])=[O:25].C(N(CC)CC)C>C(Cl)Cl>[CH3:40][C:29]1[CH:28]=[C:27]([S:24]([N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]2[CH:8]=[C:9]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=3)[CH:10]=[CH:11][CH:12]=2)(=[O:25])=[O:26])[CH:39]=[CH:38][C:30]=1[O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CCCCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCN(c1cccc(-c2ccc(C(F)(F)F)cc2)c1)S(=O)(=O)c1ccc(OCC(=O)OCC)c(C)c1
Yield: 58.6 %

Procedure:
To a solution of N-pentyl-N-[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amine (70.6 mg, 0.23 mmol) in CH2Cl2 (5 mL) under nitrogen at room temperature was added ethyl [4-(chlorosulfonyl)-2-methylphenoxy]acetate (101 mg, 0.35 mmol) and triethylamine (96 μL, 0.69 mmol). The resultant mixture was stirred for 24 h at room temperature. The reaction mixture was extracted with CH2Cl2 (15 mL) and water (10 mL). The organic solution was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification by SPE (5 g Silica cartridge) eluted with 1:49–1:19 EtOAc:cyclohexane afforded the title compound as a white crystalline solid (76 mg).
Reaction SMILES: FC(F)(S([O-])(=O)=O)CO.BrC(F)(F)C(OCC)=O.[Br:19][C:20]([F:24])([F:23])[CH2:21][OH:22].[C:25](Cl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>>[C:25]([O:22][CH2:21][C:20]([Br:19])([F:24])[F:23])(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: OCC(F)(F)Br
Reactant: CC(C)(C)C(=O)Cl
Agent: CCOC(=O)C(F)(F)Br
Agent: O=S(=O)([O-])C(F)(F)CO
Product: CC(C)(C)C(=O)OCC(F)(F)Br

Procedure:
On the other hand, the 1,1-difluoro-2-hydroxyethanesulfonate of the general formula (17) can be prepared by reducing ethyl bromodifluoroacetate to 2-bromo-2,2-difluoroethanol, esterifying the 2-bromo-2,2-difluoroethanol with pivaloyl chloride to form 2-bromo-2,2-difluoroethyl pivalate, sulfinating the 2-bromo-2,2-difluoroethyl pivalate to form 1,1-difluoro-2-(pivaloyloxy)ethanesulfinate, oxidizing the 1,1-difluoro-2-(pivaloyloxy)ethanesulfinate to 1,1-difluoro-2-(pivaloyloxy)ethanesulfonate, and then, saponifying the 1,1-difluoro-2-(pivaloyloxy)ethanesulfonate. Any known esterification technique can be adopted to react the carboxylic acid derivative of the general formula (16) and the 1,1-difluoro-2-hydroxyethanesulfonate of the general formula (17) for production of the polymerizable fluorine-containing sulfonate compound of the general formula (3) as indicated in SCHEME (1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][O:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=2[CH3:19])=[CH:4][CH:3]=1>O>[CH3:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[CH:9][O:10][C:11]=2[C:12]([CH3:19])=[C:13]([CH3:18])[CH:14]=1
Reactant: Cc1ccc(C(=O)COc2cc(C)cc(C)c2C)cc1
Solvent: O
Product: Cc1ccc(-c2coc3c(C)c(C)cc(C)c23)cc1
Temperature: 80 °C
Yield: 83 %

Procedure:
A mixture of 1-(4-methylphenyl)-2-(2,3,5-trimethylphenoxy)ethanone obtained in Reference Example 163 (1.0 g, 3.73 mmol) and polyphosphoric acid (6.0 g) was stirred at 80° C. for one and half hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with a saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain 770 mg (yield 83%) of the title compound. Melting point: 112-113° C. (ethyl acetate-methanol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([C@H:12]4[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH2:14][C@H:13]4[N:8]3[CH2:7][CH2:6][CH2:5]2)[CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:31][C:32]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O.P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:31][C:32]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=1[C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([C@H:12]4[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:15][CH2:14][C@H:13]4[N:8]3[CH2:7][CH2:6][CH2:5]2)[CH:11]=1
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(Br)cc3c1N2CCC3
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(-c3cccc(Cl)c3Cl)cc3c1N2CCC3
Temperature: 25 °C
Yield: 125.9 %

Procedure:
Tert-butyl(±)-cis-2-bromo-5,6,8,9,11,11a-hexahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (110 mg, 0.28 mmol) was dissolved in DME (4 mL). 2M aqueous sodium carbonate (0.75 ml) was added. 2,3-Dichlorophenylboronic acid (107 mg, 0.56 mmol) was added, followed by Pd2(dba)3(14.5 mg, 0.014 mmol). P(Ph)3(14.7 mg, 0.056 mmol) was added. The reaction flask was degassed and kept under a nitrogen atmosphere. The suspension was refluxed for 18 h cooled to rt. The reaction was concentrated in vacuo, after which water (10 mL) and EtOAc (10 mL) were added. The layers were separated and the aqueous phase was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (2×10 mL), dried, and concentrated to afford a crude brown amorphous solid (162 mg). The residue was purified by column chromatography (20–0% hexane/CH2Cl2) to afford the title compound (96.8 mg, 75%) as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 7.61–7.94 (m, 1H), 7.20 (s, 1H), 7.18 (d, 1H, 3.3 Hz), 7.00 (s, 1H), 6.93 (s, 1H), 3.70–3.74 (m, 1H), 3.45–60 (m, 1H), 3.15–3.35 (m, 4H), 2.65–2.80 (m, 4H), 2.10–2.20 (m, 2H), 1.80–2.00 (m, 2H), 1.46 (s, 9H) ppm.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[CH2:11][C:12]([S:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:16])[CH2:13][CH2:14][CH3:15])C.[NH4+].[Cl-]>CCOCC>[CH2:18]([S:17][C:12]([CH3:16])([CH2:13][CH2:14][CH3:15])[CH2:11][CH2:10][OH:9])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCC(C)(CC(=O)OCC)SCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: CCCC(C)(CCO)SCc1ccccc1
Reaction time: 1 h

Procedure:
At a temperature of 0° C. to a suspension of 6.8 g (0.18 mol) of LiAlH4 in 200 ml of Et2O was slowly added 50.0 9 (0.18 mol) of (rac)-3-benzylsulfanyl-3-methyl-hexanoic acid ethyl ester of step (b) under stirring such that the temperature did not exceed 10° C. Stirring was continued for 1 h and under cooling acetone and then 400 ml of a saturated NH4Cl solution was slowly added. The reaction mixture was extracted three times with 200 ml of Et2O, the combined organic layers were dried over Na2SO4 and concentrated in vacuo and gave 40.8 g of a yellowish oil. After drying in high vacuo (0.05 mbar/150° C.) 32.5 9 (75%) of (rac)-3-benzylsulfanyl-3-methyl-hexan-1-ol in form of a yellowish oil was obtained.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:11]=[O:12])=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C>C(Cl)Cl.CCCCCC>[CH2:13]([O:1][C:2]1[C:3]([CH:11]=[O:12])=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1cc2c(cc1O)CCO2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: ClCCl
Product: O=Cc1cc2c(cc1OCc1ccccc1)CCO2
Temperature: 0 °C
Yield: 78.7 %

Procedure:
A 2-liter, 3-neck flask equipped with a nitrogen inlet, internal thermometer, mechanical stirrer, and reflux condenser was charged with 5-hydroxy-2,3-dihydrobenzofuran-6-carboxaldehyde (50.00 g; 0.30 moles), benzylbromide (38.6 ml, 0.34 moles), and crushed anhydrous K2CO3 (165.84 g, 1.20 moles). The reaction mixture was refluxed for 16 hours, cooled to room termperature and suction filtered. The filtrate was concentrated in vacuo to afford a yellow solid. The solid was dissolved in methylene chloride (600 ml) and washed sequentially with 0.5 N sodium hydroxide solution (3×250 ml) and brine (2×250 ml). The organic phase was dried over MgSO4, suction filtered, and the filtrate concentrated in vacuo to yield a crude solid (85 g). The solid was dissolved in methylene chloride (300 ml)/n-hexane (200 ml), treated with charcoal and suction filtered through a bed of celite. The filtrate was evaporated in vacuo to approximately 300 ml and slowly cooled to 0° C. to produce yellowish flat needles (60 g, 78%).
Reaction SMILES: O=O.[O:3]=[O+][O-].[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O-:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[C:17]1([CH:23]([O:30][C:31]([C@@H:33]2[N:38]3[C:39](=[O:42])[C@@H:40]([NH2:41])[C@H:37]3[S:36][CH2:35][C:34]2=C)=[O:32])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CSC>CO>[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([O-:16])(=[O:15])=[O:14])=[CH:11][CH:12]=1.[C:24]1([CH:23]([O:30][C:31]([C@@H:33]2[N:38]3[C:39](=[O:42])[C@@H:40]([NH2:41])[C@H:37]3[S:36][CH2:35][C:34]2=[O:3])=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C=C1CS[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: O=[O+][O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=O
Solvent: CO
Solvent: CSC
Product: N[C@@H]1C(=O)N2[C@@H](C(=O)OC(c3ccccc3)c3ccccc3)C(=O)CS[C@H]12
Temperature: -12 °C
Reaction time: 0.08 h

Procedure:
A stream of oxygen and ozone (containing 0.35 mmol of ozone per minute) is passed for 4 minutes through a solution, cooled to -60° C., of 0.553 g of the 4-methylphenylsulphonate of 7β-amino-3-methylene-cepham-4α-carboxylic acid diphenylmethyl ester in 50 ml of methanol. After a further 5 minutes, the pale blue-coloured solution is treated with 0.3 ml of dimethyl sulphide. the mixture is stirred for 15 minutes at -70° C., for one hour at -12° C. and for one hour in an ice bath and is then evaporated. The residue is taken up in a small amount of methylene chloride, diethyl ether is then added until the mixture turns cloudy, and the mixture is left to stand. The microcrystalline, reddish-coloured pulverulent precipitate is filtered off and yields the 4-methylphenylsulphonate of 7β-amino-cepham-3-one-4α-carboxylic acid diphenylmethyl ester which is mainly present in the enol form as the 4-methylphenylsulphonate of 7β-amino-3-cephem-3-ol-4-carboxylic acid diphenylmethyl ester, melting point=143°-145° C. (with decomposition); thin layer chromatogram (silica gel) Rf~0.28 (system: ethyl acetate/pyridine/water, 85:10:5); ultraviolet absorption spectrum (in ethanol): λmax =262 mμ (ε=3,050) and 282 mμ (ε=3,020); infrared absorption spectrum (in methylene chloride): characteristic bands at 5.58μ, 5.77μ (shoulder), 6.02μ and 6.22μ.