Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COCCCN=C=O.[CH2:9]([C:16]1[NH:24][C:23]2[C:22](=[O:25])[N:21]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:20](=[O:31])[N:19]([CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([N+:40]([O-])=O)=[CH:36][CH:35]=3)[C:18]=2[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.NN.[H][H]>[Pd]>[NH2:40][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][CH2:32][N:19]2[C:18]3[N:17]=[C:16]([CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[NH:24][C:23]=3[C:22](=[O:25])[N:21]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:20]2=[O:31])=[CH:39][CH:38]=1
Reactant: [H][H]
Reactant: COCCCn1c(=O)c2[nH]c(Cc3ccccc3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Agent: [Pd]
Agent: COCCCN=C=O
Agent: NN
Solvent: O
Product: COCCCn1c(=O)c2[nH]c(Cc3ccccc3)nc2n(CCc2ccc(N)cc2)c1=O

Procedure:
By methods well known in the art 3-methoxypropyl isocyanate is converted into 8-benzyl-3-[2-(4-nitrophenyl)ethyl]-1-(3-methoxypropyl)xanthine, which in turn, is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-8-benzyl-1-(3-methoxypropyl)xanthine.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][O:11][C:12](=[O:33])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21](Cl)[C:22]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1>>[CH3:10][O:11][C:12](=[O:33])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:22]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(C(F)(F)F)sc3n2)cc1
Reactant: NCCc1ccccc1
Product: COC(=O)c1ccc(-c2nc(NCCc3ccccc3)c3cc(C(F)(F)F)sc3n2)cc1

Procedure:
The reaction procedure as above wherein phenethylamine is reacted with 4-(4-chloro-6-trifluoromethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-(4-phenethylamino-6-trifluoromethyl-thieno-[2,3-d]-pyrimidin-yl)-benzoic acid methylester.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:26]C(=O)C)([CH2:24][CH3:25])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=1)(=O)C.C(OC(=O)C(CC)C(OCC)=O)C>>[NH2:26][C:6]([CH2:24][CH3:25])([CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([OH:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:13][CH:14]=1)[CH2:5][OH:4]
Reactant: CCCCCCCC(=O)c1ccc(CCC(CC)(COC(C)=O)NC(C)=O)cc1
Agent: CCOC(=O)C(CC)C(=O)OCC
Product: CCCCCCCC(O)c1ccc(CCC(N)(CC)CO)cc1

Procedure:
In working example 77, 2-acetamido-2-ethyl-4-(4-octanoylphenyl)butyl acetate obtained by using ethylmalonic acid diethyl ester instead of propylmalonic acid diethyl ester, is treated in the same manners as working example 79 and then working example 80 to give the subject compound.
Reaction SMILES: [CH3:1][CH2:2][C:3]([NH:5][C@H:6]1[C@H:11]([OH:12])[CH2:10][C@H:9]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:7]12[CH3:8])[C:21]1[CH:20]=[CH:19][C:18]([OH:25])=[CH:17][C:16]=1[CH2:15][CH2:14]3)=[O:4].CC(C)=O.O.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>[OH-].[Na+]>[C:31]([O:25][C:18]1[CH:19]=[CH:20][C:21]2[C@@H:22]3[C@H:13]([C@H:9]4[C@@:7]([CH2:24][CH2:23]3)([CH3:8])[C@@H:6]([NH:5][C:3](=[O:4])[CH2:2][CH3:1])[C@H:11]([OH:12])[CH2:10]4)[CH2:14][CH2:15][C:16]=2[CH:17]=1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCC(=O)N[C@H]1[C@H](O)C[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@@]21C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCC(=O)N[C@H]1[C@H](O)C[C@H]2[C@@H]3CCc4cc(OC(=O)c5ccccc5)ccc4[C@H]3CC[C@@]21C
Reaction time: 0.17 h

Procedure:
17β-Methylacetamido-oestra-1,3,5(10)-triene-3,16α-diol (13.1 g) was dissolved in aqueous sodium hydroxide solution (260 ml; 2 N), acetone (260 ml) and water (260 ml). Benzoyl chloride (6.5 ml) was added and the mixture stirred vigorously for 10 min.; a further 6.5 ml of benzoyl chloride was added and the mixture was stirred vigorously for a further 10 min. Water (5 l) was added and the precipitated product was filtered, washed with water and dissolved in dichloromethane. The dichloromethane solution was washed with water, dried (Na2SO4) and evaporated to give a white froth (6.8 g), which was crystallised from dichloromethane-ether-light petroleum to give impure product (6.0 g). Acidification of the aqueous mother liquors provided unreacted starting material (7.8 g), which was treated as above to give a further quantity of impure product (2.3 g). Recrystallisation of the combined products from dichloromethane-ether afforded an isomeric mixture of 17β-methylacetamido-oestra-1,3,5(10)-triene-3,16α-diol 3-benzoates (4.68 g; 27%).
Reaction SMILES: [N+:1]([C:4]1[CH:39]=[CH:38][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][Si:13]([CH3:37])([CH3:36])[O:14][Si:15]([CH3:35])([CH3:34])[O:16][Si:17]([CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=2)([CH3:19])[CH3:18])=[CH:6][CH:5]=1)([O-])=O>[Pd]>[NH2:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][CH2:23][CH2:22][CH2:21][CH2:20][Si:17]([CH3:19])([CH3:18])[O:16][Si:15]([CH3:35])([CH3:34])[O:14][Si:13]([CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:39][CH:38]=2)([CH3:36])[CH3:37])=[CH:26][CH:27]=1
Reactant: C[Si](C)(CCCCOc1ccc([N+](=O)[O-])cc1)O[Si](C)(C)O[Si](C)(C)CCCCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Product: C[Si](C)(CCCCOc1ccc(N)cc1)O[Si](C)(C)O[Si](C)(C)CCCCOc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.9 %

Procedure:
1,5-bis[4-(4-nitrophenoxy)butyl]-1,1,3,3,5,5-hexamethyltrisiloxane (2.79 g; 4.69 mmol) (2c) and 15 mL of a 10 wt % Pd/C (0.0262 g) ethyl acetate solution was mixed, and stirred for 2 days in a nitrogen atmosphere at room temperature. The solution was filtrated by Celite and then concentrated to obtain a colorless oily material of 1,5-bis[4-(4-aminophenoxy)butyl]-1,1,3,3,5,5-hexamethyltrisiloxane (3b) (2.48 g, 99% of yield) represented by the following formula.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:21]1[O:25][C:24]2[CH:26]=[C:27]([OH:30])[CH:28]=[CH:29][C:23]=2[O:22]1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>[O:22]1[C:23]2[CH:29]=[CH:28][C:27]([O:30][C:2]3[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=3)=[CH:26][C:24]=2[O:25][CH2:21]1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CC(=O)c1c(C)cc(Cl)cc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CC(=O)c1c(C)cc(Oc2ccc3c(c2)OCO3)cc1C
Temperature: 100 °C
Yield: 61.6 %

Procedure:
To a solution of 1-(4-chloro-2,6-dimethylphenyl)ethanone (5.0 g, 27.4 mmol), K3PO4 (11.6 g, 54.7 mmol), sesamol (4.54 g, 32.9 mmol) in toluene (54.8 mL), was added 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (349 mg, 0.82 mmol), Pd(OAc)2 (259 mg, 1.15 mmol). The reaction was heated at 100° C. overnight under N2. The solution was cooled to room temperature and filtered through a small pad of diatomaceous earth. The cake was washed with ethyl acetate (50 mL) and combined filtrate was concentrated under reduced pressure. The residue was recrystallized in MeOH to give 1-(4-(benzo(d)(1,3)dioxol-5-yloxy)-2,6-dimethylphenyl)ethanone (4.80 g) as white solids in 62% yield: 1H NMR (500 MHz, CDCl3) δ 6.77 (d, J=8.5 Hz, 1H), 6.59 (s, 2 H), 6.56 (s, 1 H), 6.48 (m, 1 H), 5.98 (s, 2 H), 2.46 (s, 3 H), 2.21 (s, 6 H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([O:7][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@:3]1([CH3:26])[OH:25].[Cl:27][C:28]1[C:35]([CH3:36])=[C:34](F)[CH:33]=[CH:32][C:29]=1[C:30]#[N:31].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[Cl:27][C:28]1[C:35]([CH3:36])=[C:34]([NH:1][C@@H:2]2[CH2:6][CH2:5][C@H:4]([OH:7])[C@:3]2([OH:25])[CH3:26])[CH:33]=[CH:32][C:29]=1[C:30]#[N:31]
Reactant: CC(C)(C)[Si](O[C@H]1CC[C@@H](N)[C@]1(C)O)(c1ccccc1)c1ccccc1
Reactant: Cc1c(F)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(N[C@@H]2CC[C@H](O)[C@@]2(C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 6.4 %

Procedure:
The title compound is prepared by essentially following the procedure described in Example 1, using rel-(1S,2R,5 S)-2-amino-5-(tert-butyl(diphenyl)silyl)oxy-1-methyl-cyclopentanol (409 mg, 1.1 mmol, Preparation 43) and 2-chloro-4-fluoro-3-methyl-benzonitrile (142 mg, 0.84 mmol). A 0.2 M solution of the crude product in THF is treated with tetrabutylammonium fluoride (1.3 mL, 1.3 mmol, 1.0 M in THF) and stirred at room temperature for 16 h. The mixture is treated with water, concentrated in vacuo and extracted with EtOAc. The organic extracts are dried over magnesium sulfate, filtered, and concentrated. The resulting material is purified on silica gel (25-100% EtOAc/hexanes) to give the title compound as a pale yellow oil (15 mg, 6%). The relative stereochemistry is determined by NMR studies. 1H-NMR (400 MHz, DMSO-d6) δ 7.47 (d, J=8.8 Hz, 1H), 6.78 (d, J=8.8 Hz, 1H), 5.60-5.57 (m, 1H), 4.98 (d, J=4.2 Hz, 1H), 4.68 (s, 1H), 3.73-3.70 (m, 2H), 2.12 (s, 3H), 2.09-2.09 (m, 2H), 1.69-1.67 (m, 1H), 1.52-1.49 (m, 1H), 1.07 (s, 3H). LC-ES/MS m/z 281 (M+1).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Br:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].[C:20]([C:24]([C:27]([O:30][C:31]([C:37]([O:40][C:41]([CH2:47]O)([C:43]([F:46])([F:45])[F:44])[F:42])([F:39])[F:38])([C:33]([F:36])([F:35])[F:34])[F:32])([F:29])[F:28])([F:26])[F:25])([F:23])([F:22])[F:21]>O>[Br:14][CH2:15][CH2:16][C:17]([O:19][CH2:47][C:41]([O:40][C:37]([C:31]([O:30][C:27]([C:24]([C:20]([F:21])([F:22])[F:23])([F:25])[F:26])([F:28])[F:29])([C:33]([F:36])([F:35])[F:34])[F:32])([F:39])[F:38])([C:43]([F:46])([F:45])[F:44])[F:42])=[O:18]
Reactant: OCC(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Reactant: O=C(O)CCBr
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C(CCBr)OCC(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
A mixture comprising trifluoroacetic anhydride (25.6 g) and 3-bromopropionic acid (17.9 g) was stirred at room temperature under a nitrogen stream for 1 hour. CF3CF2CF2OCF(CF3)CF2OCF(CF3)CH2OH (55.9 g) was added dropwise thereto while cooling with water so that the internal temperature would be maintained to be 30° C. or lower over a period of 30 minutes. 3 hours later, the reaction liquid was directly concentrated and purified by silica gel column chromatography (eluent: mixed solvent comprising hexane (10): ethyl acetate (1)) to obtain the title compound (54.6 g). The yield: 80%.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[C:26]([OH:28])=[O:27])[C:19](Br)=[CH:18][CH:17]=1)[OH:15])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:37]([O:43][S:44]([C:47]1[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=1)(=[O:46])=[O:45])[CH2:38][CH2:39][CH2:40][C:41]#[CH:42]>CN(C)C=O.C(Cl)Cl.C1(P([Pd-4](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)C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[C:26]([OH:28])=[O:27])[C:19]([C:42]#[C:41][CH2:40][CH2:39][CH2:38][CH2:37][O:43][S:44]([C:47]2[CH:48]=[CH:49][C:50]([CH3:53])=[CH:51][CH:52]=2)(=[O:45])=[O:46])=[CH:18][CH:17]=1)[OH:15])([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(C(C)C)c1N=C(O)c1ccc(Br)c2cccc(C(=O)O)c12
Reactant: C#CCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCCCC#Cc2ccc(C(O)=Nc3c(C(C)C)cccc3C(C)C)c3c(C(=O)O)cccc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a degassed mixture of 0.50 g (1.15 mmoles) of N-(2,6-diisopropylphenyl)-4-bromo-naphthaline-1,8-dicarboxylic acid imide (synthesized according to WO2007062002) and 0.17 g (0.89 mmoles) of Cu(I) iodide in 20 ml anhydrous dimethylformamide (DMF) and 40 ml anhydrous methylene chloride were added 0.53 g (0.46 mmoles) of tetrakis(triphenylphosphino)-palladium (0), 0.58 g (0.80 ml, 5.5 mmol) triethylamine and a degassed solution of 0.48 g (1.90 mmol) p-toluensulfonic acid-5-hexinyl ester (synthesized according to (Y. Yang and T. M. Swager, Macromolecules 2006, 39, 2013-2015) in 2 ml methylene chloride. The reaction mixture was stirred for 60 minutes at room temperature, subsequently the solvent was evaporated until dryness and purified on silica gel ((60 Å, 60-200 μm), first with methylene chloride and afterwards with n-heptane/acetic acid (3:1) as free-flow agent. 0.6 g (86% of the theoretical yield) of a orange-yellow oil were obtained.
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:35])[C:11]2[C:6](=[CH:7][C:8]([CH:12]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:13])=[CH:9][CH:10]=2)[C:5]([CH3:34])([CH3:33])[CH2:4]1.[C:36]([C:39]1[CH:46]=[CH:45][C:42]([CH:43]=O)=[CH:41][CH:40]=1)(=[O:38])[CH3:37]>>[CH3:2][C:3]1([CH3:35])[C:11]2[C:6](=[CH:7][C:8](/[C:12](/[CH3:13])=[CH:43]/[C:42]3[CH:45]=[CH:46][C:39]([C:36](=[O:38])[CH3:37])=[CH:40][CH:41]=3)=[CH:9][CH:10]=2)[C:5]([CH3:34])([CH3:33])[CH2:4]1
Reactant: CC(=O)c1ccc(C=O)cc1
Reactant: CC(c1ccc2c(c1)C(C)(C)CC2(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CC3(C)C)cc1

Procedure:
In a manner analogous to that described in Example 1, from [1-(1,1,3,3-tetramethyl-5-indanyl)ethyl]-triphenylphosphonium bromide and 4-acetyl-benzaldehyde there can be obtained 4'-[(E)-2-(1,1,3,3-tetramethyl-5-indanyl)propenyl]-acetophenone of melting point 130°-131° C.
Reaction SMILES: [CH:1]1([C:4]2[C:15]3[O:14][C:11]4([CH2:13][CH2:12]4)[CH2:10][C:9]([CH3:17])([CH3:16])[C:8]=3[CH:7]=[C:6]([C:18]#[CH:19])[CH:5]=2)[CH2:3][CH2:2]1.[CH3:20][O:21][C:22](=[O:33])[C:23]([C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1)([CH3:25])[CH3:24]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[CH3:20][O:21][C:22](=[O:33])[C:23]([C:26]1[CH:27]=[CH:28][C:29]([C:19]#[C:18][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[C:15]3[O:14][C:11]4([CH2:13][CH2:12]4)[CH2:10][C:9]([CH3:16])([CH3:17])[C:8]=3[CH:7]=2)=[CH:30][CH:31]=1)([CH3:25])[CH3:24]
Reactant: COC(=O)C(C)(C)c1ccc(I)cc1
Reactant: C#Cc1cc(C2CC2)c2c(c1)C(C)(C)CC1(CC1)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1

Procedure:
Following General Procedure B and using 8-cyclopropyl-6-ethynyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane] (0.096 g, 0.38 mmol), methyl-2-(4-iodo phenyl)-2-methyl-propionate (Reagent 2, 0.127 g, 0.41 mmol), triethyl amine (3 mL), copper(I)iodide (0.040 g, 0.21 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.080 g, 0.11 mmol) followed by flash column chromatography over silica gel (230–400 mesh), the title compound was obtained as an oil (0.046 g, 47%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[C:17]([O:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=1[O:26]S(C(F)(F)F)(=O)=O>COCCOC>[Br:7][C:8]1[C:17]([O:18][S:19]([C:22]([F:23])([F:24])[F:25])(=[O:20])=[O:21])=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=1[OH:26]
Reactant: COC(=O)c1cc(OS(=O)(=O)C(F)(F)F)c(Br)c(OS(=O)(=O)C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: COC(=O)c1cc(O)c(Br)c(OS(=O)(=O)C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
In a 1-liter egg plant-type flask, cesium carbonate (24.8 g, 76.3 mmol) was added to a DME (200 mL) solution of methyl 4-bromo-3,5-bis{[(trifluoromethyl)sulfonyl]oxy}benzoate (26.0 g), and stirred at 60° C. for 3 hours. DME was removed under reduced pressure, the residue was diluted with ethyl acetate, washed with water and saturated saline water in that order, dried with sodium sulfate, filtered and concentrated to obtain a crude product as a brown solid. This was washed with a mixed solvent of toluene and hexane to obtain the title compound as a colorless solid.
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[N:8]=[C:9]3[C:22](=[O:23])[CH2:21][S:20](=[O:25])(=[O:24])[C:10]3=[C:11]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[C:6]2=[CH:5][CH:4]=1)[CH3:2]>O1CCCC1>[CH2:1]([C:3]1[N:7]2[N:8]=[C:9]3[CH:22]([OH:23])[CH2:21][S:20](=[O:24])(=[O:25])[C:10]3=[C:11]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[C:6]2=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc2c(-c3cccc(C#N)c3)c3c(nn12)C(=O)CS3(=O)=O
Solvent: C1CCOC1
Product: CCc1ccc2c(-c3cccc(C#N)c3)c3c(nn12)C(O)CS3(=O)=O
Reaction time: 1 h
Yield: 954.5 %

Procedure:
To a solution of 3-(6-ethyl-1,1-dioxido-3-oxo-2,3-dihydropyrrolo[1,2-b]thieno[2,3-e]pyridazin-9-yl)benzonitrile (60.0 mg) in tetrahydrofuran (0.2 mL) was added 1 M solution of borane-tetrahydrofuran complex in tetrahydrofuran (0.487 mL) under an ice-bath. After stirring for 1 hour, the reaction was quenched by adding 1N hydrochloric acid (1 mL). The mixture was partitioned between ethyl acetate (20 mL) and water (10 mL), and the organic layer was washed with brine, dried, and evaporated to give 3-(6-ethyl-3-hydroxy-1,1-dioxido-2,3-dihydropyrrolo[1,2-b]thieno[2,3-e]pyridazin-9-yl)-benzonitrile as an yellow foam (576 mg, 99.8%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:18]([O-])=O)[C:5]2[O:17][CH2:16][CH2:15][C:8]3([S:12][C:11](=[O:13])[NH:10][C:9]3=[O:14])[C:6]=2[CH:7]=1.C(Cl)(Cl)Cl>C(O)C.[Pt]=O>[F:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]2[O:17][CH2:16][CH2:15][C:8]3([S:12][C:11](=[O:13])[NH:10][C:9]3=[O:14])[C:6]=2[CH:7]=1
Reactant: O=C1NC(=O)C2(CCOc3c([N+](=O)[O-])cc(F)cc32)S1
Agent: O=[Pt]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Nc1cc(F)cc2c1OCCC21SC(=O)NC1=O
Reaction time: 2.5 h

Procedure:
755 mg of (±)-6-fluoro-8-nitro-2,3-dihydrospiro[4H-1-benzopyran-4,5'-thiazolidine]-2',4'-dione were hydrogenated at room temperature and normal pressure in the presence of 50 mg of platinum oxide in 50 ml of ethanol. An additional 100 mg of platinum oxide were added after 30 minutes. After 2.5 hours under hydrogen, some chloroform was added, the catalyst was filtered, the filtrate was concentrated and the residue was chromatographed on silica gel 60 with chloroform/methanol (19:1). (±)-6-Fluoro-8-amino-2,3-dihydrospiro[4H-1-benzopyran-4,5'-thiazolidine]-2',4'-dione was obtained in the form of a yellowish foam. The IR spectrum showed amine bands at 3383, 3202 and 2766 cm-1, in the mass spectrum the molecular ion appeared as a basic peak (m/e=268).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:20])=[C:4]([S:8]([NH:11][C:12]2[S:13][CH:14]=[C:15]([CH2:17][CH2:18]O)[N:16]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:41].O>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:20])=[C:4]([S:8]([NH:11][C:12]2[S:13][CH:14]=[C:15]([CH2:17][CH2:18][Cl:41])[N:16]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCO)cs1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCCl)cs1

Procedure:
A mixture of EXAMPLE 181A (100 mg, 0.30 mmol), triphenylphosphine (158 mg, 0.60 mmol) and carbontetrachloride (116 mg, 0.75 mmol) in DMF (2 mL) was stirred over night, and was then poured into water. The mixture was extracted with EtOAc, dried (Sodium sulfate) and the solvent was evaporated. The crude material was purified by flash chromatography on silica gel gradient eluting with 2-4% acetone in DCM giving a solid (25 mg, 24%). 1H NMR (CDCl3) δ 2.64 (s, 3H), 3.17 (t, 2H), 3.77 (t, 2H), 6.30 (s, 1H), 7.24 (m, 2H), 7.56 (d, 1H), 8.02 (d, 1H); MS (Ionspray, [M+H]+) m/z 350.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:34])[N:29]([CH3:33])[CH2:30][CH2:31]O)[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P([N:49]=[N+:50]=[N-:51])(C2C=CC=CC=2)=O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>O1CCCC1>[Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:34])[N:29]([CH2:30][CH2:31][N:49]=[N+:50]=[N-:51])[CH3:33])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CN(CCO)C(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CN(CCN=[N+]=[N-])C(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Yield: 100.8 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-{4-[N-methyl-N-(2-hydroxyethyl)carbamoyl]-1,3-thiazol-2-yl}azetidine (997.5 mg, 2.0 mmol) (obtained as described in Reference Example 58(1)) in tetrahydrofuran (50 ml) were added diphenylphosphoryl azide (0.65 ml, 3.02 mmol), triphenylphosphine (793 mg, 3.02 mmol), and a 40% solution of diethylazodicarboxylate in toluene (1.12 g, 3.04 mmol) in an ice bath under an atmosphere of nitrogen, and the mixture was stirred overnight under the same conditions. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using toluene:ethyl acetate (1:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-{4-[N-(2-azidoethyl)-N-methyl-carbamoyl]-1,3-thiazol-2-yl}azetidine (1.05 g, yield 100%) as a colorless and transparent syrup.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:28][O:29][CH2:30][CH3:31])[C:8]([NH:10][CH:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([OH:25])=[O:24])=[C:15](OS(C)(=O)=O)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.C[Si](NC(N[Si](C)(C)C)=O)(C)C.C([S:47]/[CH:48]=[CH:49]\[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)(=O)C.C[O-].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.O>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:28][O:29][CH2:30][CH3:31])[C:8]([NH:10][CH:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([OH:25])=[O:24])=[C:15]([S:47]/[CH:48]=[CH:49]\[C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CC(=O)S/C=C\c1ccccc1
Reactant: CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(OS(C)(=O)=O)CS[C@H]12)c1nsc(N)n1
Agent: C[O-]
Agent: C[Si](C)(C)NC(=O)N[Si](C)(C)C
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: O
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(S/C=C\c3ccccc3)CS[C@H]12)c1nsc(N)n1
Reaction time: 0.5 h
Yield: 50.9 %

Procedure:
To a suspension of 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-mesyloxy-3-cephem-4-carboxylic acid (syn isomer)(1 g) in tetrahydrofuran (30 ml) was added bis(trimethylsilyl)urea (444 mg) at ambient temperature. The mixture was stirred at 30°-35° C. for 30 minutes to give a clear solution. On the other hand, to a solution of (Z)-2-acetylthiovinylbenzene (780 mg) in tetrahydrofuran (6 ml) was added sodium methoxide (240 mg) at 0° C. The mixture was stirred for 30 minutes. This solution was added to the above-mentioned clear solution. The mixture was stirred for 2 hours at -20°~30° C. The mixture was poured into water (300 ml), and then the mixture was neutralized with sodium bicarbonate and washed with ethyl acetate. After stirring, the aqueous layer was separated. The aqueous solution was adjusted to pH 2.5 with 1N hydrochloric acid. To this solution was added ethyl acetate (200 ml). The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo to give a solid. The solid was triturated with diisopropyl ether to give 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-[(Z)-2-phenylvinylthio]-3-cephem-4-carboxylic acid (syn isomer)(550 mg).