Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11](I)=[C:10]([S:13][CH3:14])[N:9]=[C:8]([NH2:15])[N:7]=1.[C:16]1([C:22]#[CH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>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.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([C:23]#[C:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([S:13][CH3:14])[N:9]=[C:8]([NH2:15])[N:7]=1
Reactant: C#Cc1ccccc1
Reactant: CSc1nc(N)nc(-c2ccco2)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CSc1nc(N)nc(-c2ccco2)c1C#Cc1ccccc1
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
Following the method of Thorand and Krause (J. Org. Chem. 1998, 63, 8551), to a stirred solution of 500 mg (1.50 mmol) 4-furan-2-yl-5-iodo-6-methylsulfanyl-pyrimidin-2-ylamine in 10 ml dry degassed THF under argon at room temperature were added 211 mg (0.30 mmol) bis(triphenylphosphine)palladium(II) chloride, 10 mg (0.04 mmol) triphenylphosphine, 0.25 ml (2.28 mmol) phenylacetylene and 0.31 ml (2.22 mmol) triethylamine. Stirring was continued for 30 minutes then 3.0 mg (0.02 mmol) copper(I) iodide was added and the reaction mixture stirred for an additional 72 hours at room temperature. The reaction mixture was then concentrated in vacuo. Chromatography (1/4-1/1 ethyl acetate/hexane) afforded 161 mg (35%) 4-furan-2-yl-6-methylsulfanyl-5-phenylethynyl-pyrimidin-2-ylamine as a yellow crystalline solid. EI-MS m/e (%): 307 (M+, 100), 306 ([M—H]+, 52), 230 (38).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[C:5](=[CH:10][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-])=O)=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]>[Pd].C(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[C:4]1[C:5](=[CH:10][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Oc2ccccc2[N+](=O)[O-])cc1C(=O)OC
Agent: [Pd]
Solvent: ClCCl
Product: COC(=O)c1ccc(Oc2ccccc2N)cc1C(=O)OC
Reaction time: 16 h

Procedure:
A mixture of 4-(2-nitrophenoxy)phthalic acid dimethyl ester (2.16 g, 6.53 mmol) and palladium on activated charcoal (10% Pd, 120 mg) in methylene chloride (115 ml) was hydrogenated in a Parr apparatus at 207 kPa (30 psi) for 16 hours. The mixture was filtered and evaporated to dryness in vacuo to give 4-(2-aminophenoxy)phthalic acid dimethyl ester as an yellow oil (yield: 1.88 g (96%)). 1H—NMR (CDCl3) in ppm: δ 3.86 (3H,s); 3.90 (3H, s); 6.7-6.97 (3H,m); 7.0-7.1 ( 2H,m); 7.15 (1H,d); 7.78 (1H,d). 13C—NMR (CDCl3) in ppm: δ 52.9; 53.2; 116.5; 117.4; 118.2; 119.4; 121.6; 124.4; 126.7; 132.1; 136.1; 139.2; 141.6; 160.8; 167.1; 168.8.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Br[CH2:25][C:26]([O:28]C(C)(C)C)=[O:27].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][O:23][CH2:25][C:26]([OH:28])=[O:27])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCO)cc2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCOCC(=O)O)cc2)cc1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-2-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)ethanol (80 mg, 0.259 mmol) and tert-butyl 2-bromoacetate (605 mg, 3.10 mmol) in CHCl3 (3 mL) was added 2M Na2CO3 (1.939 mL, 3.88 mmol). The mixture was stirred overnight at 55° C. The aqueous layer was separated, washed with DCM, and neutralized with 2M HCl. The aqueous mixture was then purified by HPLC. LCMS m/z=368.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Nc1cccc(-c2ccc(Cl)nn2)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1cccc(-c2ccc(Cl)nn2)c1

Procedure:
A solution of 34.0 g of 3-(6-chloro-3-pyridazinyl)benzenamine, 18.8 ml of acetic anhydride, 28.7 ml of diisopropylethylamine and 750 ml of dichloromethane was stirred for 2.5 hrs. The solution was concentrated in vacuo to half of the original volume and 200 ml of hexane was added. The solution was filtered, affording 26.4 g of tan solid. The filtrate was washed with saturated aqueous sodium bicarbonate, dried (Na2SO4) and concentrated in vacuo. The residue and the solid collected previously were combined and recrystallized from dichloromethane-acetone-hexane to give 35 g of tan crystals, mp 203°-205° C.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([C:10](O)=[O:11])=[C:4]2[CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][OH:11])[C:4]=2[CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc2c1CCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccc2c1CCO2

Procedure:
A solution of 2,3-dihydrobenzofuran-4-carboxylic acid (10 g, 61 mmol) in THF (100 mL) was stirred as LAH (4.64 g, 122 mmol) was slowly added. The mixture was heated to reflux for 30 min. The mixture was cooled and quenched cautiously with ethyl acetate and then with 1N HCl (150 mL). The mixture was then made acidic with 12N HCl until all the inorganic precipitate dissolved. The organic layer was separated, and the inorganic layer was extracted twice with ethyl acetate. The organic layers were combined, washed twice with brine, and then concentrated in vacuo. This oil was Kugelrohr distilled to a clear oil that crystallized upon cooling (8.53 g, 87.6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][N:16](C(=O)C(F)(F)F)[CH2:15][CH2:14]1.[F:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([Mg]Br)=[CH:28][CH:27]=1.[Cl-].[NH4+]>C1COCC1>[F:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([N:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[CH:5]=2)(=[O:10])=[O:11])=[CH:28][CH:27]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1N1CCN(C(=O)C(F)(F)F)CC1
Reactant: Fc1ccc([Mg]Br)c2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)c2ccc(F)c3ccccc23)cc1N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-methoxy-3-[4-(2,2,2-trifluoro-acetyl)piperazin-1-yl]bezenesulfonyl chloride (0.19 g; 0.5 mmol), prepared as in Example 1 Step 2, in THF (0.5 mL) at ambient temperature under argon atmosphere was added dropwise a solution of 4-fluoro-1-naphthylmagnesium bromide in THF (0.25 M, 4 mL; 1 mmol). After stirring at this temperature for 1 h a saturated solution of ammonium chloride was added and the mixture was extracted into ethyl acetate (20 mL). The organic phase was dried (Na2SO4) and concentrated in vacuo .The residue was dissolved in dioxane (2 mL) and a solution of 6N NaOH (0.5 mL) was added. After stirring at ambient temperature for 1 h water was added (10 ml) and the mixture was extracted into ethyl acetate (20 ml). The organic phase was extracted into 2N aqueous HCl. The aqueous layer was adjusted with 6N NaOH solution to pH 14 and extracted with ethyl acetate. The organic phase was dried (Na2SO4) and concentrated in vacuo to give the 1-[5-(4-fluoro-naphthalene-1-sulfonyl)2-methoxyphenyl]piperazine (401) as a white solid (0.060 g; 30%). The hydrochloride salt was prepared from ethanol-hydrogen chloride, m. p. 155.0-159.0° C.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([S:9][CH3:10])[C:5]=2[C:11](=[O:26])[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[S:22]([CH3:25])(=[O:24])=[O:23])[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:35])C=1.C(OCC)(=O)C.CCCCCC.C(OC(C)C)(C)C>ClCCl>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([S:9]([CH3:10])=[O:35])[C:5]=2[C:11](=[O:26])[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][C:13]=2[S:22]([CH3:25])(=[O:23])=[O:24])[CH2:3][CH2:2]1
Reactant: CSc1noc(C2CC2)c1C(=O)c1ccc(C(F)(F)F)cc1S(C)(=O)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: CS(=O)c1noc(C2CC2)c1C(=O)c1ccc(C(F)(F)F)cc1S(C)(=O)=O
Reaction time: 18 h
Yield: 75.9 %

Procedure:
1.0 g (2.5 mmol) 5-Cyclopropyl-3-methylsulfanyl-4-(2-methanesulfonyl-4-trifluoromethylbenzoyl)isoxazole is dissolved in 12 ml dichloromethane. The solution is then cooled to a temperature of −5° C., and 0.62 g (70%, 2.5 mmol) m-chloroperbenzoic acid is added in portions. After 18 hours' agitation at a temperature of 0 to 5° C., the reaction mixture is diluted with dichloromethane and the resulting precipitate filtered off. The dichloromethane phase is successively extracted with 5% aqueous NaHCO3 solution, twice with water and 15% aqueous sodium chloride solution. After the organic phase has been separated off, it is dried over magnesium sulfate. The raw product obtained is subjected to flash chromatography on silica gel using ethyl acetate/hexane (first 1:1 then 2:1) as eluent. After stirring in a little diisopropylether, 0,8 g of 5-cyclopropyl-3-methylsulfinyl-4-(2-methanesulfonyl-4-trifluoromethylbenzoyl)isoxazole is obtained in the form of crystals with a melting point of 153-155° C. 1H-NMR (CDCl3, ppm): 0.96-1.16 (m, 2H), 1.2-1.36 (m, 1H), 1.32-1.4 (m, 2H), 3.12 (s, 3H), 3.32 (s, 3H), 7.72 (d, 1H), 8.05 (d, 1H), 8.41 (s, 1H).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[C:9]([O:13][C:14](=[O:35])[C@@H:15]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:21][C@H:22]([OH:26])[CH2:23][CH2:24][NH2:25])([CH3:12])([CH3:11])[CH3:10].C(OC(=O)[C@@H](NC(OC(C)(C)C)=O)CCCCN(C(OCC1C=CC=CC=1)=O)C[C@@H](O)CC#N)(C)(C)C>C(O)(=O)C.[Pd].O=[Pt]=O>[C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[C:9]([O:13][C:14](=[O:35])[C@@H:15]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:21][C@@H:22]([OH:26])[CH2:23][CH2:24][NH2:25])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC[C@H](O)CCN)C(=O)OC(C)(C)C
Agent: O=[Pt]=O
Agent: [Pd]
Agent: CC(C)(C)OC(=O)N[C@@H](CCCCN(C[C@@H](O)CC#N)C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC[C@@H](O)CCN)C(=O)OC(C)(C)C

Procedure:
According to the method described for the preparation of 15a, to a solution of 14b (172 mg, 0.33 mmol) in glacial acetic acid (5 mL) was added 10% Pd—C (17 mg) and PtO2 (35 mg) under an H2 atmosphere to obtain 15b in quantitative yield as a colorless oil: 1H NMR (D2O) δ 1.30-2.00 (m, 8H), 1.45 (s, 9H), 1.48 (s, 9H), 1.92 (s, 6H), 2.99-3.28 (m, 6H), 3.99 (dd, 1H, J=9.0, 5.11), 4.06 (it, 1H, J=9.5, 3.3); HRMS m/z calcd for C19H40N3O5 390.2968, found 390.2967. [α]22D−7.5° (c 1.03, CH3OH).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][OH:21])[O:17][N:16]=1.O[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][C:30]([O:32][CH3:33])=[O:31].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][O:21][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([O:32][CH3:33])=[O:31])[O:17][N:16]=1
Reactant: COC(=O)Cc1ccccc1O
Reactant: Cc1sc(-c2ccccc2)nc1COc1cc(CO)on1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccccc1OCc1cc(OCc2nc(-c3ccccc3)sc2C)no1
Reaction time: 72 h
Yield: 46.1 %

Procedure:
To a mixture of 3-(5-methyl-2-phenyl-4-thiazolylmethoxy)-5-isoxazolylmethanol (0.80 g), methyl 2-(2-hydroxyphenyl)acetate (0.45 g), tributylphosphine (1.05 g) and tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.31 g) at room temperature and the mixture was stirred for 3 days. The precipitated crystals were filtered off. The filtrate was concentrated and the residue was subjected to silica gel column chromatography to give crystals (0.55 g, 47%) of methyl 2-[2-[[3-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-5-isoxazolyl]methoxy]phenyl]acetate from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 108-109° C.
Reaction SMILES: [C:1]([C@H:6]1[C@H:15]([C:16]([O:18]CC)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].[OH-].[Na+].Cl>C(O)C.C(OCC)(=O)C>[C:1]([C@H:6]1[C@H:15]([C:16]([OH:18])=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)[C@@H]1Cc2ccccc2C[C@H]1C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1Cc2ccccc2C[C@H]1C(=O)O
Reaction time: 16 h
Yield: 72.6 %

Procedure:
To a stirred solution of trans 2,3-dicarboethoxy-1,2,3,4-tetrahydronaphthalene (2.1 g, 7.6 mmol) in ethanol (10 mL) at room temperature under nitrogen was added 1.0 M aqueous sodium hydroxide solution (7.6 mL, 7.6 mmol). After 16 h, 1.0 M aqueous hydrochloric acid solution (10 mL) was added to quench the reaction mixture. Upon completion of addition, the reaction mixture was concentrated under vacuum to yield a residue. The residue was diluted with ethyl acetate. The organic layer was washed with 1.0 M aqueous hydrochloric acid solution, saturated aqueous ammonium chloride solution and brine, dried over anhydrous magnesium sulfate, and concentrated under vacuum to yield a residue. The residue was purified by silica gel chromatography (50% ethyl acetate in hexane was used) to yield the title compound (1.37 g, 73%). 13C NMR (400 MHz, (CD3)2CO) δ 175.7, 174.7, 135.0, 134.9, 129.3, 129.2, 127.0, 61.0, 42.8, 42.5, 32.2, 14.4. 1H NMR (400 MHz, (CD3)2CO) δ 7.02 (s, 4H), 4.03 (m, 2H), 2.74-3.09 (m, 6H), 1.13 (t, J=7.0 Hz, 6H). MS [M+Na]+, 271.
Reaction SMILES: C1O[CH:4]([CH:5]2[CH2:14][CH2:13][C:12]3[C:7](=[C:8]([O:17][CH3:18])[CH:9]=[C:10]([O:15][CH3:16])[CH:11]=3)[C:6]2=O)[O:3]C1.COC1C=C2C(=C(OC)C=1)C=C(C=O)C=C2>>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[C:8]([O:17][CH3:18])[CH:9]=1)[CH:6]=[C:5]([CH2:4][OH:3])[CH:14]=[CH:13]2
Reactant: COc1cc2c(c(OC)c1)C(=O)C(C1OCCO1)CC2
Agent: COc1cc(OC)c2cc(C=O)ccc2c1
Product: COc1cc(OC)c2cc(CO)ccc2c1

Procedure:
Following a procedure similar to that described in Example 155 but substituting for 1,2,3,4-tetrahydro-6,8-dimethoxy-1-oxo-2-naphthaldehyde ethylene acetal an equivalent amount of 6,8-dimethoxy-2-naphthaldehyde, there is obtained 6,8-dimethoxy-2-naphthalenemethanol.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][CH:6]=1)=[O:4].CC(C)=O>CO>[OH:4][CH2:3][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(C(=O)O)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: O=C(O)c1ccc(CO)s1
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
Sodium borohydride (218 mg, 5.76 mmol) was added to a solution of commercially available 5-formyl-2-thiophenecarboxylic acid (599 mg, 3.84 mmol) in methanol (19 mL), and the mixture was stiffed under nitrogen atmosphere at room temperature for 4 hours and 30 minutes. Acetone was added to the reaction mixture, and the mixture was concentrated under vacuum. 2 M hydrochloric acid and ethyl acetate were added to the residue for partition, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum and the precipitate was washed with diethyl ether and n-hexane to obtain the title compound (529 mg, 87%).
Reaction SMILES: N12CCCN=C1CCCCC2.[Cl:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([NH:20][CH3:21])=[N:18][OH:19])=[C:15](F)[C:14]=1[I:25]>C1COCC1>[Cl:12][C:13]1[CH:23]=[CH:22][C:16]2[C:17]([NH:20][CH3:21])=[N:18][O:19][C:15]=2[C:14]=1[I:25]
Reactant: CNC(=NO)c1ccc(Cl)c(I)c1F
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CNc1noc2c(I)c(Cl)ccc12
Temperature: 165 °C

Procedure:
1,8-diazabicyclo[5.4.0]undec-7-ene (0.102 g, 0.670 mmol) was added to a solution of 4-chloro-2-fluoro-N′-hydroxy-3-iodo-N-methylbenzamidine (0.200 g, 0.609 mmol) in THF (2 mL) in a sealed microwave tube. The reaction mixture was heated in a microwave at 165° C. for 80 min. The resulting mixture was purified by flash chromatography on silica gel (dichloromethane:hexane 10:90) to give 6-chloro-7-iodo-N-methylbenzo[d]isoxazol-3-amine as an off white solid. MS (ESI, pos.ion) m/z: 308.9 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C@@H:4]([CH3:36])[NH:5][C:6](=[O:35])[C@H:7]([CH2:19][CH2:20]/[CH:21]=[C:22](/[C:31]([O:33][CH3:34])=[O:32])\[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[H][H]>C(O)(=O)C.C1COCC1.Cl([O-])(=O)(=O)=O.[Rh+]>[CH3:1][O:2][C:3](=[O:37])[C@@H:4]([CH3:36])[NH:5][C:6](=[O:35])[C@@H:7]([CH2:19][CH2:20][CH2:21][CH:22]([C:31]([O:33][CH3:34])=[O:32])[NH:23][C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: [H][H]
Reactant: COC(=O)/C(=C/CC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C)C(=O)OC)NC(=O)OC(C)(C)C
Agent: [Rh+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C(CCC[C@@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C)C(=O)OC)NC(=O)OC(C)(C)C
Yield: 92.6 %

Procedure:
A solution of 8.5 g of 47c in 25 mL of acetic acid and 250 mL of THF is hydrogenated at 48 psi of hydrogen over 0.5 g of (bicyclo(2.2.1.)hepta-2,5-diene[2S,3S]bis(diphenylphosphino)butane)rhodium(I) perchlorate for 18 h. The reaction is filtered and evaporated to a residue. The residue is chromatographed using variable gradient hexane-ethyl acetate to give 7.9 g of reduced product as a residue. Multiple crystallization give 2.6 g of diastereomerically pure 40c. NMR (CDCl3) δ 1.40 (d, J=6 Hz, 3 H); 1.43 (s, 9 H); 1.60-1.97 (m, 6 H); 3.73 (s, 3 H); 3.74 (s, 3 H); 4.12-4.37 (m, 2 H); 4.52-4.61 (m, 1 H); 5.12 (bs, 3 H); 5.44-5.55 (b s, 1 H); 6.73 (b s, 1 H); 7.36 (b s, 5 H); 13C-NMR: δ 18.02 (CH--CH3); 21.12 (CH2 --CH2 --CH2); 28.23 (--OC(CH3)3); 31.87 (--CH2 --CH2 --); 32.29 (--CH2CH2 --); 47.99 (--CHCH3); 52.23 (--OCH3); 52.38 (--OCH3); 52.75 (OCCHN); 54.41 (OCCHN); 67.01 (--OCH2Ar); 79.97 (--OC(CH3)3); 127.99 (phenyl ring carbon); 128.09 (phenyl ring carbon); 128.44 (ArCH); 136.13 (ArCC); 155.48 (OCONH): 156.23 (OCONH); 171.10 (--CONH--); 173.03 (--CO2 --2X); IR (KBR) (cm-1): 3340(s); 1760(s); 1740(s); 1680(s); 1660(s); 1660(s); 1520(s); MS (FAB) m/z 546 (M+Na)+ ; 524 (MH)+ ; 424 (MH-C4H8CO2)+ ; Anal. Calcd: C, 57.35; H, 7.12; N, 8.03; Found: C, 57.23; H, 7.27; N, 8.03; rotation [α]D25 -9±1; m.p. 120°-121° C.
Reaction SMILES: [N+:1]([C:4]1[CH:41]=[CH:40][C:7]([CH2:8][O:9][C:10]([C@@H:12]2[N:16]3[C:17](=[O:30])[C@@H:18]([NH:19]C(=O)COC4C=CC=CC=4)[C@H:15]3[S:14][C@:13]2([CH2:32][O:33][C:34](=[O:39])[NH:35][C:36](=[O:38])[CH3:37])[CH3:31])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C)C1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.N>C(Cl)Cl.CO>[N+:1]([C:4]1[CH:41]=[CH:40][C:7]([CH2:8][O:9][C:10]([C@@H:12]2[N:16]3[C:17](=[O:30])[C@@H:18]([NH2:19])[C@H:15]3[S:14][C@:13]2([CH2:32][O:33][C:34](=[O:39])[NH:35][C:36](=[O:38])[CH3:37])[CH3:31])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)NC(=O)OC[C@]1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: N
Solvent: CO
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: CC(=O)NC(=O)OC[C@]1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 45.9 %

Procedure:
A solution of (2R,3S,5R,6R) 2-(N-acetyl)carbamoyloxymethyl-2-methyl-6-phenoxyacetamidopenam-3-carboxylic acid p-nitrobenzyl ester (4.68 gm, 8 mmols) in dry methylene chloride (40 ml) was cooled to -60° under nitrogen. It was charged with dimethylaniline (4.06 gm, 33.5 mmol) and phosphorus pentachloride (3.68 gm, 17.7 mmol) and stirred for 30 minutes at -64° to -56°, during which time the phosphorus pentachloride dissolved. A solution of dry methanol (8.10 ml) in dry methylene chloride (8.10 ml) was then slowly added at -55° to -45°. The reaction mixture was stirred for 20 minutes at -60° to -55° and then poured into 16 ml of ice-water. The pH was adjusted to 1.7 with concentrated ammonia and the layers were separated. The methylene chloride layer was washed with 20 ml of pH 2.0 buffer which was separated and combined with the aqueous layer. Methylene chloride (20 ml) was added to the combined aqueous layers and the mixture was adjusted to pH 6.5 with concentrated ammonia. The phases were separated, the water was washed with 20 ml of methylene chloride, and the combined methylene chloride layers were dried over molecular sieves. After filtration, the solution was concentrated in vacuo to about 20 ml and then added dropwise to 400 ml of stirring heptane. The heptane was decanted from the solid which precipitated and was replaced by 100 ml of fresh heptane. The suspension was thoroughly stirred, filtered, washed, air dried, and finally dried in vacuo. There was obtained 1.66 gm of the title product as a white amorphous solid. The purity was estimated from its nmr spectrum to be about 90%, the remainder being primarily the non-acetylated material.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])O[C:10]=1[C:28]([OH:30])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S(C(N)C2[N:46](C)[C:45](C(O)=O)=C(OCC3C=CC=CC=3)C(=O)C=2)(=O)=O)C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])[N:46]([CH3:45])[C:10]=1[C:28]([OH:30])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C(=O)O)o2)c1
Reactant: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(OCc2ccccc2)c1C(=O)O
Product: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C(=O)O)n2C)c1
Yield: 78.77 %

Procedure:
3-Benzyloxy-1-methyl-4-oxo-6-[(toluene-3-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid (13-04) (1.3 g, 78.77%) was synthesized as a white solid from 3-benzyloxy-4-oxo-6-[(toluene-3-sulfonylamino)-methyl]-4H-pyran-2-carboxylic acid (12-04) (1.6 g, 3.73 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-01).
Reaction SMILES: [CH2:1]([CH2:3]N)[OH:2].C1(C)C(C)=CC=CC=1.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26](=[N:29][O:30][CH3:31])[C:27]#[N:28])=[CH:16][CH:15]=1>O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C.O>[CH3:31][O:30][N:29]=[C:26]([C:27]1[O:2][CH2:1][CH2:3][N:28]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[O:19][CH2:18][C:17]1[CH:16]=[CH:15][C:14]([Cl:13])=[CH:33][CH:32]=1
Reactant: NCCO
Reactant: CON=C(C#N)c1ccccc1OCc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: Cc1ccccc1C
Solvent: O
Product: CON=C(C1=NCCO1)c1ccccc1OCc1ccc(Cl)cc1
Yield: 9.8 %

Procedure:
Zinc acetate dihydrate (400 mg, 1.8 mmol), ethanolamine (975 mg, 15.9 mmol) and xylene (8 ml) were added to 2-(4-chlorobenzyloxy)-α-methoxyiminophenylacetonitrile (4.00 g, 13.3 mmol), and the mixture was stirred under reflux for 63 hours. After completion of the reaction, water (100 ml) was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give isomer A (1.31 g, 28.6%, as crystals) and isomer B (0.45 g, 9.8%, as crystals) of 2-(4-chlorobenzyloxy)phenyl 2-oxazolin-2-yl ketone O-methyloxime.