Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([CH2:12][C:13]([OH:15])=[O:14])[CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(=O)C)(=O)C>C(OCC)C>[C:1]1([CH:7]2[CH2:8][C:9](=[O:11])[O:15][C:13](=[O:14])[CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CC(CC(=O)O)c1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: O=C1CC(c2ccccc2)CC(=O)O1

Procedure:
10 mmol of 3-phenylglutaric acid and 30 mmol of acetic anhydride are heated under reflux until they have dissolved completely. After cooling, 3 ml of diethyl ether are added and the precipitate is filtered off and washed with diethyl ether. This gives 3-phenylglutaric anhydride.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH2:11]([O:13][C:14]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)=[O:15])[CH3:12].C([O-])([O-])=O.[Na+].[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>O1CCOCC1.C(OCC)(=O)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>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:20]2[CH:21]=[C:16]([CH:17]=[CH:18][CH:19]=2)[C:14]([O:13][CH2:11][CH3:12])=[O:15])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc(-c2ccc([N+](=O)[O-])cn2)c1
Temperature: 90 °C
Reaction time: 10 h
Yield: 89.1 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (5.23 g, 32.99 mmol) in dioxane (170 mL) was added 3-(ethoxycarbonyl)phenylboronic acid (6.28 g, 32.99 mmol) and 1N Na2CO3 aqueous solution (82.5 mL, 82.5 mmol). The reaction mixture was degassed using Argon gas for 20 min followed by the addition of dichlorobis(triphenylphospine)palladium(II) (1.38 g, 1.99 mmol) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (1.26 g, 2.97 mmol). The reaction flask was put into the preheated oil-bath at 90° C. The reaction mixture was further stirred at 90° C. for a period of 10 h after which it was filtered and partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography using a 95:5 v/v hexane:ethyl acetate as solvent to afford ethyl 3-(5-nitropyridin-2-yl)benzoate (8.0 g, 89% yield) as a bright yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:13]([O-])=O)[CH:8]=2)[N:3]=1.[H][H]>[Pd]>[NH2:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH3:1])[C:11]([CH3:12])=[N:10]2
Reactant: Cc1nc2ccc([N+](=O)[O-])cc2nc1C
Reactant: [H][H]
Agent: [Pd]
Product: Cc1nc2ccc(N)cc2nc1C

Procedure:
A near solution of 2,3-dimethyl-6-nitroquinoxaline (62.9 g, 0.31 mole) in 1 L of absolute alcohol (Mallinkrodt) was hydrogenated in Parr apparatus using 5% Palladium on carbon 50% wet catalyst (Englehard). Hydrogen uptake (100% of theory) in 2 hours was noted. After the reduction stopped the catalyst was removed by filtration and the filtrate remaining concentrated to dryness in vacuo. The residue remaining was used without further purification as an intermediate in part C. Yield 52 g (96%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([CH:11]=[CH2:12])[N:3]=1.[F:13][C:14]1[CH:35]=[CH:34][C:17]([O:18][C:19]2[CH:24]=[CH:23][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:21][CH:20]=2)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[F:13][C:14]1[CH:35]=[CH:34][C:17]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:2]3[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([CH:11]=[CH2:12])[N:3]=3)=[CH:21][CH:20]=2)=[CH:16][CH:15]=1
Reactant: CC1(C)OB(c2ccc(Oc3ccc(F)cc3)cc2)OC1(C)C
Reactant: C=Cc1cc(C(=O)O)nc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C=Cc1cc(C(=O)O)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Temperature: 90 °C
Yield: 82 %

Procedure:
As shown in Scheme 4, a suspension of 2-chloro-6-vinylpyrimidine-4-carboxylic acid (9) (4.38 g, 0.02 mol), 2-(4-(4-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (22) (7.45 g, 0.02 mol), Na2CO3 (5.3 g, 0.05 mol), and PdCl2(PPh3)2 (Aldrich, 701 mg, 1.0 mmol) in dimethoxy ethane(DME)/EtOH/H2O (500 mL, 2:1:2 ratio) was degassed by repeating with Ar2/vacuum cycles. The mixture was heated at 90° C. for 23 h. Upon cooling to the room temperature, the mixture was poured into DCM. The solids were filtered off and the filtrates were washed with H2O and the aqueous phase was extracted with EtOAc. The combined organic layers were dried with anhydrous MgSO4 and concentrated to give 2-(4-(4-fluorophenoxy)phenyl)-6-vinylpyrimidine-4-carboxylic acid (23) pale yellow oil which was then purified by column chromatography (EtOAc:Hexanes=1:1) to give 6.5 g (82% yield), Rf=0.3 (DCM:MeOH=9:1); LC/MS: m/z=337 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3](=[O:13])[N:4]([CH3:12])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:14]([O:18][C:19](=[O:28])[NH:20][CH2:21][C:22](N(OC)C)=[O:23])([CH3:17])([CH3:16])[CH3:15].C([Mg]Cl)(C)C>C1COCC1.ClCCl>[C:14]([O:18][C:19](=[O:28])[NH:20][CH2:21][C:22]([C:2]1[C:3](=[O:13])[N:4]([CH3:12])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:23])([CH3:17])([CH3:15])[CH3:16]
Reactant: CON(C)C(=O)CNC(=O)OC(C)(C)C
Reactant: Cn1c(=O)c(Br)cc2ccccc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1c(=O)c(C(=O)CNC(=O)OC(C)(C)C)cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 0.3 M solution of 3-bromo-1-methylquinolin-2(1 H)-one (1 equiv; prepared as described in Tetrahedron, 64 (26), 6030-6037; 2008) and tert-butyl(2-(methoxy(methyl)amino)-2-oxoethyl)carbamate (1.2 eq) in dry THF, isopropylmagnesium chloride (3 eq) was added dropwise at room temperature. The mixture was stirred for 30 min at room temperature, diluted with dichloromethane, washed with sat. aq. NH4Cl dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, Pethroleum ether/EtOAc, from 7% to 60% EtOAc). The pooled fractions were concentraded under vacuum to the title compound. MS (ES) C17H20N2O4 requires: 316.35, found: 317. 1H-NMR (400 MHz, DMSO-d6) δ: 8.53 (1 H, s), 7.99 (1 H, d, J=7.2 Hz), 7.78 (1 H, t, J=6.8 Hz), 7.61 (1 H, d, J=8.4 Hz), 7.35 (1 H, t, J=7.2 Hz), 6.97 (1 H, bt, J=5.6 Hz), 4.45 (1 H, d, J=5.6 Hz), 3.70 (3 H, s), 1.39 (9 H, s).
Reaction SMILES: C[C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][C:3]=1C=O.ClC1C(C(OO)=[O:21])=CC=CC=1.[OH-].[Na+].Cl.[Na+].[Cl-]>C(Cl)Cl.C(OCC)(=O)C>[O:10]1[C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][C:7]=2[CH2:8][CH:9]1[OH:21]
Reactant: Cc1c(C=O)ccc2occc12
Reactant: O=C(OO)c1ccccc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: OC1Cc2ccccc2O1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 34 (33.06 g, 206 mmol) in methylene chloride (580 mL) was added 80% m chloroperbenzoic acid (52.0 g, 211 mmol) and the mixture heated at reflux for 17 hours. The reaction mixture was allowed to cool, diluted with ethyl acetate (580 mL) and extracted with 5% NaHCO3 (2×725 mL). The aqueous layers were back extracted with additional portions of ethyl acetate (290 mL) and the combined organic layers dried (MgSO4) and concentrated. The resulting yellow oil (47 ) was taken up in methanol (700 mL) and 2.5N NaOH (185 mL, 462 mmol) was added. The mixture was stirred at room temperature for 20 minutes, cooled with an ice bath, and acidified with 2N HCl (810 mL). The resulting mixture was saturated with NaCl and extracted with ethyl acetate (3×1200 mL). The combined extracts were washed with 20% NaCl (2×900 mL), dried (MgSO 4) and concentrated. The resulting dark oil (51 g) was chromatographed through a large (9 cm diameter) column of flash silica gel. Elution with 12.5% ethyl acetate in hexane afforded 36 as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH2:11][CH2:12][C:13]#[C:14][Si](C)(C)C)[N:10]=2)[CH:5]=[CH:6][CH:7]=1>CCOCC>[CH2:11]([C:9]1[N:10]=[C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]2[CH:8]=1)[CH2:12][C:13]#[CH:14]
Reactant: C[Si](C)(C)C#CCCc1cn2cccc(Cl)c2n1
Solvent: CCOCC
Product: C#CCCc1cn2cccc(Cl)c2n1
Yield: 73.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 108(B), from 8-chloro-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (2.00 g, 7.22 mmol). The crude residue was taken in Et2O, filtered and concentrated to yield 1.09 mg (5.31 mmol, 74%) of 2-(but-3-ynyl)-8-chloro-imidazo[1,2-a]pyridine as a yellow solid.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].CC1C2[O:20]C3C(=CC=CC=3C)C(=O)C=2C=CC=1.[CH:24]1[C:37]2[CH2:36][C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([C:38]([OH:40])=[O:39])[C:30]=3[O:29][C:28]=2[C:27]([C:41]([OH:43])=[O:42])=[CH:26][CH:25]=1.C1(C(O)=O)C(C(O)=O)=CC=C2C=1CC1C(=CC=CC=1)O2>>[O:20]=[C:36]1[C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([C:38]([OH:40])=[O:39])[C:30]=2[O:29][C:28]2[C:27]([C:41]([OH:43])=[O:42])=[CH:26][CH:25]=[CH:24][C:37]1=2
Reactant: O=C(O)c1cccc2c1Oc1c(cccc1C(=O)O)C2
Reactant: Cc1cccc2c(=O)c3cccc(C)c3oc12
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=C(O)c1ccc2c(c1C(=O)O)Cc1ccccc1O2
Agent: [K+]
Product: O=C(O)c1cccc2c(=O)c3cccc(C(=O)O)c3oc12

Procedure:
9-Oxoxanthene-4,5-dicarboxylic acid which is prepared by potassium permanganate oxidation of the corresponding 4,5-dimethylxanthen-9-one [M. Schopff, Ber. 25, 3647 (1892)]49 is reduced to xanthene-4,5-dicarboxylic acid by a Wolff-Kishner reduction (N. Ishikawa, Yuki Gose: Kagaku Kyokai Shi 17, 553-6 (1959); CA 54:450]. The xanthene dicarboxylic acid derivative is converted to xanthene-4,5-dipiperidide by conventional procedures.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:9]([O:10][C:11](=[O:13])[CH3:12])[CH:8]=[CH:7][S:6]1)=[O:4].S(Cl)(Cl)(=O)=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[O:10][C:11](=[O:13])[CH3:12])=[O:4]
Reactant: COC(=O)C1SC=CC1OC(C)=O
Solvent: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1sccc1OC(C)=O
Yield: 79 %

Procedure:
20.2 Parts of 3-acetoxydihydrothiophene-2-carboxylic acid methyl ester are reacted with 6.75 parts by volume of sulfuryl chloride in 150 parts by volume of CCl4 at 0° C. for one hour. The end product is isolated from the reaction mixture by the method described in Example 14c). 15.8 parts (79% of theory) of 3-acetoxythiophene-2-carboxylic acid methyl ester of boiling point 84°-86° C./0.04 mbar are obtained.
Reaction SMILES: C([N:8]1[CH2:23][CH2:22][C:11]2([NH:20][C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[C].[Pd]>[NH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19](=[O:21])[NH:20][C:11]21[CH2:22][CH2:23][NH:8][CH2:9][CH2:10]2
Reactant: O=C1NC2(CCN(Cc3ccccc3)CC2)Nc2ccccc21
Agent: [Pd]
Solvent: CO
Product: O=C1NC2(CCNCC2)Nc2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.2 %

Procedure:
1-Benzyl-1′H-spiro[piperidine-4,2′-quinazolin]-4′ (3′H)-one (5.0 g) and 10% palladium-carbon (500 mg) were suspended in methanol (200 mL), and the suspension was stirred at room temperature for 2 days under a hydrogen atmosphere. The catalyst was removed by filtration through celite. The solvent was evaporated under reduced pressure and the residue was crystallized from ethanol/ether to give the object product (2.34 g, 41%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:12][C@H:13]2[C@H:17]([CH3:18])[CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:26][N:27](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.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>[C:26]([C:2]1[N:3]=[C:4]([O:12][C@H:13]2[C@H:17]([CH3:18])[CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)#[N:27]
Reactant: CN(C)C=O
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Oc1nc(Cl)cc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Oc1nc(C#N)cc2ccccc12
Temperature: 160 °C
Yield: 82 %

Procedure:
A mixture of tert-butyl trans-3-((3-chloroisoquinolin-1-yl)oxy)-4-methylpyrrolidine-1-carboxylate (1 g, 2.76 mmol), zinc cyanide (0.647 g, 5.51 mmol), Pd(PPh3)4 (0.318 g, 0.276 mmol) and DMF (7.83 mL) was heated in a microwave reactor at 160° C. for 20 minutes. The reaction mixture was subsequently taken up in EtOAc (100 mL), washed with brine (50 mL) and water (50 mL), dried over Na2SO4, and concentrated onto silica gel. The crude product was purified by flash column chromatography (SiO2) eluting with a 5-50% gradient of heptane in EtOAc to give title compound as a white solid (0.796 g, 82%). 1H NMR (500 MHz, CDCl3) δ ppm 1.17 (d, 3H), 1.41-1.54 (m, 9H), 2.60 (br s, 1H), 3.26 (br s, 1H), 3.45-3.65 (br s, 1H), 3.74 (br s, 1H), 3.93 (dd, 1H), 5.40 (dt, 1H), 7.67-7.87 (m, 4H), 8.27 (d, 1H); ESI-MS m/z [M+H-tert-butyl]+ 298.6.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]([N:11]2[C:17]3[CH:18]=[CH:19][C:20]([NH2:22])=[CH:21][C:16]=3[O:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH2:3]1.Cl[C:24]1[N:29]=[C:28]([NH:30][C:31]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:32]=2[C:33]([NH:35][CH3:36])=[O:34])[C:27]([Cl:42])=[CH:26][N:25]=1>>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]([N:11]2[C:17]3[CH:18]=[CH:19][C:20]([NH:22][C:24]4[N:29]=[C:28]([NH:30][C:31]5[C:32]([C:33](=[O:34])[NH:35][CH3:36])=[CH:37][CH:38]=[CH:39][C:40]=5[F:41])[C:27]([Cl:42])=[CH:26][N:25]=4)=[CH:21][C:16]=3[O:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH2:3]1
Reactant: CN1CCCC(OC(=O)N2CCCOc3cc(N)ccc32)C1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)OCCCN3C(=O)OC2CCCN(C)C2)ncc1Cl

Procedure:
The title compound was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 1-methyl-piperidin-3-yl ester and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1410. Product isolated as an orange foam (84 mg, 44%). LCMS (m/e) 584 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.98-8.75 (m, 1H), 8.09 (s, 1H), 7.40-7.17 (m, 4H), 7.16-6.97 (m, 2H), 6.95-6.84 (m, 1H), 6.40-6.22 (m, 1H), 4.91-4.70 (m, 1H), 4.15-3.95 (m, 2H), 3.82-3.58 (m, 2H), 2.98-2.77 (m, 4H), 2.64-2.48 (m, 1H), 2.38-2.13 (m, 4H), 2.11-1.75 (m, 5H), 1.65-1.40 (m, 1H), 1.30-1.10 (m, 1H); 19F-NMR (CDCl3, 400 MHz) δ −111.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C@@H:5]1[CH2:9][C@H:8]([OH:10])[CH2:7][C@@H:6]1[C:11]([O:13]CC)=[O:12])[CH3:4]>C([C@@H]1C[C@H](O)C[C@@H]1C(O)=O)C>[CH2:3]([CH:5]1[CH2:9][CH:8]([OH:10])[CH2:7][CH:6]1[C:11]([OH:13])=[O:12])[CH3:4]
Reactant: CCOC(=O)[C@H]1C[C@@H](O)C[C@H]1CC
Agent: CC[C@@H]1C[C@H](O)C[C@@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCC1CC(O)CC1C(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Aqueous NaOH (1 N, 12 mL, 12 mmol) was added to a scalemic mixture enriched in (1S,2R,4S)-ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate (1.11 g, 5.96 mmol). The reaction mixture was stirred at ambient temperature for about 3 days and then extracted with Et2O (3×25 mL). The Et2O extracts were discarded and the aqueous portion was cooled to about 0° C. Aqueous HCl (5 N) was slowly added to bring the pH to about 2. The resulting aqueous suspension was extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (2×80 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give a scalemic mixture enriched in (1S,2R,4S)-2-ethyl-4-hydroxycyclopentanecarboxylic acid (0.943 g, 100%) as clear oil: 1H NMR (CDCl3) δ 4.36 (tdd, J=2.6, 4.9, 7.4, 1H), 2.95 (td, J=2.4, 7.3, 1H), 2.41 (dt, J=7.7, 14.1, 1H), 2.16-1.94 (m, 3H), 1.65-1.49 (m, 1H), 1.49-1.32 (m, 2H), 0.96 (q, J=7.4, 3H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:19](=[O:21])[CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 4 h

Procedure:
One gram of 3-[3-(1-piperidinylmethyl)phenoxy]propylamine was dissolved in 1 ml of pyridine, and 0.5 ml of acetic anhydride was added. The mixture was allowed to stand at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and small amounts of water and potassium carbonate were added. The mixture was extracted with chloroform, washed with water, and dried. Then, the solvent was distilled off. The residue was purified by TLC (developing solvent: chloroform/methanol=9/l) to afford 753 mg of N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl] acetamide as an oil.
Reaction SMILES: C(O)(=O)C.[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([O:14]CC(Cl)(Cl)Cl)=[O:13])[N:9]2[C:20](=[O:33])[CH:21]([NH:22][C:23](=[O:32])[CH2:24][O:25][C:26]3[S:27][C:28]([CH3:31])=[N:29][N:30]=3)[C@H:8]2[S:7]1>CN(C)C=O.[Zn]>[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[N:9]2[C:20](=[O:33])[CH:21]([NH:22][C:23](=[O:32])[CH2:24][O:25][C:26]3[S:27][C:28]([CH3:31])=[N:29][N:30]=3)[C@H:8]2[S:7]1
Reactant: Cc1nnc(OCC(=O)NC2C(=O)N3C(C(=O)OCC(Cl)(Cl)Cl)=CC(C)S[C@H]23)s1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1nnc(OCC(=O)NC2C(=O)N3C(C(=O)O)=CC(C)S[C@H]23)s1
Reaction time: 1.5 h
Yield: 41.1 %

Procedure:
Acetic acid (8 ml) and zinc powder (6 g) were added under ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-[2-(5-methyl-1,3,4-thiadiazol-2-yloxy)acetamido]-3-cephem-4-carboxylate (6.60 g) in anhydrous dimethylformamide (40 ml), and the mixture was stirred for 1.5 hours. After the reaction, zinc powder was filtered and washed with dimethylformamide. The filtrate and the washings were combined, and the combined solution was poured into an ice-cooled mixture of ethyl acetate and 2 to 3% hydrochloric acid, and then extracted. The extract was extracted with a sodium bicarbonate aqueous solution and the aqueous solution was acidified with hydrochloric acid, and then extracted with ethyl acetate. The aqueous layer was saturated with sodium chloride, and then extracted, four times with ethylacetate (80 ml), after which the both ethyl acetate extract was combined. After the combined extracted was dried over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was crystallized by adding ether to give dimethylformamide adduct of 2-methyl-7-[2-(5 -methyl-1,3,4-thiadiazol-2-yloxy)acetamido]-3-cephem-4-carboxylic acid (2.0 g), mp 113° to 116° C.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[N:8][C:9]=1[NH:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1.Br[CH2:24][CH:25]1[CH2:28][CH2:27][CH2:26]1.C(N(CC)C(C)C)(C)C.CCOC(C)=O>CN(C=O)C.O>[Cl:3][C:4]1[CH:5]=[C:6](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[N:8][C:9]=1[NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([CH2:24][CH:25]2[CH2:28][CH2:27][CH2:26]2)[CH2:12]1
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCNC2)c(Cl)c1
Reactant: BrCC1CCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(CC3CCC3)C2)c(Cl)c1
Yield: 36.1 %

Procedure:
A solution of ethyl (2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylate dihydrochloride (1.0 g), bromomethylcyclobutane (456 mg) and N,N-diisopropylethylamine (1.26 g) in DMF (30 ml) was stirred at 80-85° C. for 12 hours under atmospheric pressure of nitrogen. The reaction mixture was poured into a mixture of AcOEt and H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (95:5). The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl (2E)-3-(5-chloro-6-{[(3R)-1-(cyclobutylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (356 mg).
Reaction SMILES: [CH2:1]([OH:34])[C@H:2]1[O:7][C@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@@H:12]([O:17][C@H]3[C@H](O)[C@@H](O)[C@@H](O)O[C@@H]3CO)[O:11][C@@H:10]2[CH2:29][OH:30])[C@H:5]([OH:31])[C@@H:4]([OH:32])[C@@H:3]1[OH:33]>NCC(O)=O.[OH-].[Na+]>[CH2:1]([OH:34])[C@H:2]1[O:7][C@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@H:12]([OH:17])[O:11][C@@H:10]2[CH2:29][OH:30])[C@H:5]([OH:31])[C@@H:4]([OH:32])[C@@H:3]1[OH:33]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@H]3[C@H](O)[C@@H](O)[C@@H](O)O[C@@H]3CO)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 1 h

Procedure:
The activity of α-isomaltosyl glucosaccharide-forming enzyme was measured by the following assay: A substrate solution was prepared by dissolving maltotriose in 100 mM Glycine-NaOH buffer (pH 8.4) to give a concentration of 2% (w/v). A reaction mixture was prepared by mixing 0.5 ml of the substrate solution and 0.5 ml of an enzyme solution, and incubated at 40° C. for 60 minutes. After stopping the reaction by boiling for 10 minutes, the amount of maltose formed in the reaction mixture was determined by high-performance liquid chromatography (HPLC). One unit of α-isomaltosyl glucosaccharide-forming activity was defined as the amount of the enzyme that forms one μmole of maltose per minute under the above conditions. HPLC was carried out using “SHODEX KS-801”, a column commercialized by Showa Denko K.K., Tokyo, Japan, at a column temperature of 60° C. and a flow rate of 0.5 ml/minutes of water, and using “RI-8012”, a differential refractometer commercialized by Tosoh Corporation, Tokyo, Japan.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][C:12]=1[O:18][CH3:19])=[O:10])([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[N:34][CH:35]=1>>[C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:32]2[CH:33]=[N:34][CH:35]=[C:30]([F:29])[CH:31]=2)=[CH:13][C:12]=1[O:18][CH3:19])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cncc(F)c1
Reactant: COc1cc(Br)ccc1C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Product: COc1cc(-c2cncc(F)c2)ccc1C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared rac-[2-(4-bromo-2-methoxy-phenyl)-1-(3,4-dichloro-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and 5-fluoropyridine-3-boronic acid in analogy to Example 1b): MS (ISP): 507.4 (M+H)+ (100%) and 522.7 (M+NH4)+.
Reaction SMILES: C(O[C:5]1[N:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([C@H:16]2[CH2:18][C@@H:17]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])[CH3:12])=[CH:7][CH:6]=1)(C)C.[CH3:25]C1N=CC([C@@H](N)C)=CC=1>>[CH3:25][C:5]1[N:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([C@H:16]2[CH2:18][C@@H:17]2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:15])[CH3:12])=[CH:7][CH:6]=1
Reactant: Cc1ccc([C@H](C)N)cn1
Reactant: CC(C)Oc1ccc([C@H](C)NC(=O)[C@H]2C[C@@H]2c2ccccc2)cn1
Product: Cc1ccc([C@H](C)NC(=O)[C@H]2C[C@@H]2c2ccccc2)cn1

Procedure:
Prepared analogously to Compound 1 using IM46 and commercially available (S)-1-(6-methyl-pyridin-3-yl)-ethylamine (Supplier Netchem Inc., Catalog No 519526). Yield=0.27 g (21%). 1H NMR (600 MHz, DMSO) δ 8.61 (d, 1H), 8.37 (s, 1H), 7.57 (d, 1H), 7.26 (m, 2H), 7.16 (m, 2H), 7.09 (d, 2H), 4.92 (m, 1H), 2.41 (s, 3H), 2.19 (m, 1H), 1.91 (m, 1H), 1.36 (m, 4H), 1.20 (m, 1H). LC-MS (m/z) 251.2 (MH+), tR=0.88 min (method A).