Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[C:20]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH2:32][CH:33]=[CH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])#N.CC[O:42]CC>II>[CH3:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=[CH:13][CH2:12][CH:11]=[CH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:20](=[O:42])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH2:32][CH:33]=[CH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCC=CCC=CCCCCCCCCBr
Reactant: CCCCCC=CCC=CCCCCCCCCC#N
Reactant: CCOCC
Agent: II
Product: CCCCCC=CCC=CCCCCCCCCC(=O)CCCCCCCCC=CCC=CCCCCC
Reaction time: 1 h
Yield: 74 %

Procedure:
To a flame dried 500 mL 2NRB flask, freshly activated Mg turnings (0.144 g, 6 mmol) were added and the flask was equipped with a magnetic stir bar and a reflux condenser. This set-up was degassed, flushed with argon and 10 mL of anhydrous ether was added to the flask via syringe. The bromide 3 (1.65 g, 5 mmol) was dissolved in anhydrous ether (10 mL) and added dropwise via syringe to the flask. An exothermic reaction was noticed (to confirm/accelerate the Grignard reagent formation, 2 mg of iodine was added and immediate decolorization was observed confirming the formation of the Grignard reagent) and the ether started refluxing. After the completion of the addition the reaction mixture was kept at 35° C. for 1 h and then cooled in ice bath. The cyanide 4 (1.38 g, 5 mmol) was dissolved in anhydrous ether (20 mL) and added dropwise to the reaction mixture with stirring. An exothermic reaction was observed and the reaction mixture was stirred overnight at ambient temperature. The reaction was quenched by adding 10 mL of acetone dropwise followed by ice cold water (60 mL). The reaction mixture was treated with aq. H2SO4 (10% by volume, 200 mL) until the solution became homogeneous and the layers were separated. The aq. phase was extracted with ether (2×100 mL). The combined ether layers were dried (Na2SO4) and concentrated to get the crude product which was purified by column (silica gel, 0-10% ether in hexanes) chromatography. The pure product fractions were evaporated to provide the pure ketone 7 as a colorless oil (2 g, 74%). 1H NMR (CDCl3, 400 MHz) δ=5.33-5.21 (m, 8H), 2.69 (t, 4H), 2.30 (t, 4H), 2.05-1.95 (m, 8H), 1.55-1.45 (m, 2H), 1.35-1.15 (m, 18H), 0.82 (t, 3H). 13C NMR (CDCl3) δ=211.90, 130.63, 130.54, 128.47, 128.41, 43.27, 33.04, 32.01, 30.93, 29.89, 29.86, 29.75, 29.74, 27.69, 26.11, 24.35, 23.06, 14.05. MS. Molecular weight calculated for C37H66O, Cal. 526.92. Found 528.02 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:15][CH2:14][CH:10]([C:11]([OH:13])=O)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[NH2:20][C:21]1[CH:37]=[CH:36][CH:35]=[CH:34][C:22]=1[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)=[O:24].N1C=CC=CC=1>ClCCl>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:23](=[O:24])[C:22]2[CH:34]=[CH:35][CH:36]=[CH:37][C:21]=2[NH:20][C:11]([CH:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH2:15][CH2:14]2)=[O:13])=[CH:31][CH:30]=1
Reactant: COc1ccc(NC(=O)c2ccccc2N)cc1
Reactant: O=C(O)C1CCN(c2ccncc2)CC1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2ccccc2NC(=O)C2CCN(c3ccncc3)CC2)cc1
Reaction time: 8 h
Yield: 30.2 %

Procedure:
To a stirred suspension of N-(4-pyridyl)isonipecotic acid (0.2 g, 1 mmol) in dichloromethane (70 mL) was added thionyl chloride (0.11 mL, 1.5 mmol). After stirring overnight, the solvent was removed in vacuo and the residue was dissolved in dichloromethane (10 mL) and added to a stirred solution of 2-amino-N-(4-methoxyphenyl)benzamide (0.186 g, 0.77 mmol) and pyridine (0.19 g, 0.85 mmol) in dichloromethane (25 mL). After stirring for 72 h, the solution was transferred to a separatory funnel and washed with water, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. The organic phase was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was suspended in a mixture of diethyl ether and hexanes, sonicated, and filtered. The resulting solid was washed with diethyl ether and dried in vacuo to give 0.10 g (30%) of the title compound as a pale tan solid.
Reaction SMILES: C([O:5][CH2:6][C:7]1[N:11]=[C:10]([NH2:12])[NH:9][N:8]=1)(=O)CO.[CH3:13][C:14]([CH2:16][C:17]([CH3:19])=O)=O>CCO.CC(O)=O>[CH3:13][C:14]1[CH:16]=[C:17]([CH3:19])[N:9]2[N:8]=[C:7]([CH2:6][OH:5])[N:11]=[C:10]2[N:12]=1
Reactant: CC(=O)CC(C)=O
Reactant: Nc1nc(COC(=O)CO)n[nH]1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(C)n2nc(CO)nc2n1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared by a slight modification of a reported procedure (Lippman, E.; Becker, V., Z. Chem., 1974, 14, 405): A solution of (5-amino-1H-1,2,4-triazol-3-yl)methanol glycolate (30.7 g, 0.161 mol, from Step 1, above) and 2,4-pentadione (32.3 g, 0.323 mol, 2 equiv) in a mixture of EtOH (750 mL) and AcOH (250 mL) was refluxed 20 h. At the beginning the reaction mixture was clear solution, then gradually turned yellow towards the end of the heating period. The solvent was removed under reduced pressure, and the resulting yellow paste triturated with EtOH (100 mL) and stirred for 15 min. The slurry was chilled to 5° C. (ice bath) with stirring for 30 min, filtered, and washed with cold (0–5° C.) EtOH. The product was dried in vacuo at 25–30° C. to give 24 g (83.7%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7][C:8]1[C:9]([CH2:24][CH3:25])=[N:10][N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][C:17]=2[F:23])[C:12]=1[CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].O1CCOCC1.C(N(C(C)C)CC)(C)C.[C:42](=O)([O-:44])[O-:43].[K+].[K+]>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo].O>[C:1]([O:5][C:6]([CH2:7][C:8]1[C:9]([CH2:24][CH3:25])=[N:10][N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:42]([OH:44])=[O:43])=[CH:18][C:17]=2[F:23])[C:12]=1[CH2:13][CH3:14])=[O:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1nn(Cc2ccc(Br)cc2F)c(CC)c1CC(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [Mo]
Agent: [C-]#[O+]
Agent: [K+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCc1nn(Cc2ccc(C(=O)O)cc2F)c(CC)c1CC(=O)OC(C)(C)C
Temperature: 150 °C

Procedure:
To a microwave vial was added [1-(4-bromo-2-fluorobenzyl)-3,5-diethyl-1H-pyrazol-4-yl]acetic acid tert.-butyl ester (6.5 g), dioxane (30 ml), water (15 ml), molybdenum hexacarbonyl (2.1 g), Hermann's catalyst (1.5 g) and diisopropylethylamine (6 ml). After 20 min microwave heating at 150° C., the vial is allowed to cool to room temperature and the content is added to water. The reaction mixture is made alkaline with potassium carbonate and extracted twice with ethyl acetate. The aqueous phase is separated, acidified with glacial acetic acid and extracted several times with dichloromethane. The organic phase is then separated, dried over magnesium sulfate and concentrated in vacuo to yield 4-(4-tert.-butoxycarbonylmethyl-3,5-diethylpyrazol-1-ylmethyl)-3-fluorobenzoic acid (3.4 g; [M+H]=391; HPLC retention time 1.00 min (Method K)).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[OH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[N:28][C:29]([C:32]2[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][CH:33]=2)=[N:30][CH:31]=1.[C:40](O)(=[O:43])[CH:41]=[CH2:42]>CN(C)C1C=CN=CC=1.ClCCl>[C:40]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[N:28][C:29]([C:32]2[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][CH:33]=2)=[N:30][CH:31]=1)(=[O:43])[CH:41]=[CH2:42]
Reactant: C=CC(=O)O
Reactant: O=Cc1ccc(-c2ncc(OCCCCCCCCO)cn2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCCCOc1cnc(-c2ccc(C=O)cc2)nc1
Reaction time: 8 h
Yield: 75.4 %

Procedure:
4.2 g of N,N'-dicyclohexylcarbodiimide were added within 5 minutes while stirring to a solution of 5.5 g of 4-(5-[8-hydroxyoctyloxy]pyrimidin-2-yl)benzaldehyde, 1.2 g of acrylic acid and 0.2 g of 4-(dimethylamino)pyridine in 25 ml of dichloromethane. The reaction mixture was stirred overnight, filtered and the filtrate was concentrated. Chromatography of the residue on silica gel with hexane/ethyl acetate (vol. 8:2) and recrystallization from ethyl alcohol of the fractions which were pure according to thin-layer chromatography gave 4.8 g of 4-(5-[8-acryloyloxyoctyloxy]pyrimidin-2-yl)benzaldehyde.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18](B(O)O)[CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>O.COCCOC.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>[F:14][C:6]1[C:5]([CH3:15])=[C:4]2[C:9]([CH:10]=[C:11]([CH:12]=[O:13])[C:2]([C:18]3[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: OB(O)c1cccnc1
Reactant: Cc1c(F)ccc2cc(C=O)c(Cl)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1c(F)ccc2cc(C=O)c(-c3cccnc3)nc12
Yield: 92.7 %

Procedure:
Prepared according to the procedure described for Intermediate 1, utilising 2-chloro-7-fluoro-8-methylquinoline-3-carbaldehyde (5.0 g, 22.36 mmol), 3-pyridylboronic acid (3.02 g, 24.6 mmol), tetrakis(triphenylphosphine)palladium(0) (127 mg, 0.11 mmol) and Na2CO3 (3.55 g, 33.54 mmol) in water (30 mL) and DME (60 mL). The title compound (5.52 g, 93%) was obtained as a beige solid. δH (DMSO-d6) 10.13 (s, 1H), 9.08 (s, 1H), 8.95 (dd, J 2.3, 0.8 Hz, 1H), 8.75 (dd, J 4.9, 1.7 Hz, 1H), 8.24 (dd, J 9.0, 6.4 Hz, 1H), 8.16-8.21 (m, 1H), 7.68 (t, J 9.2 Hz, 1H), 7.61 (ddd, J 7.9, 4.0, 0.8 Hz, 1H), 2.66 (d, J 2.4 Hz, 3H). LCMS (ES+) 267 (M+H)+, RT 2.16 minutes.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[C:11]([C:23](O)([CH3:25])[CH3:24])[C:12]([O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1>C(O)C.[Pd]>[CH:23]([C:11]1[C:12]([O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[CH:13][CH:14]=[C:15]2[C:10]=1[CH:9]=[N:8][N:7]2[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)([CH3:25])[CH3:24].[CH:23]([C:11]1[C:12]([OH:16])=[CH:13][CH:14]=[C:15]2[C:10]=1[CH:9]=[N:8][N:7]2[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)([CH3:25])[CH3:24]
Reactant: CC(C)(O)c1c(OC2CCCCO2)ccc2c1cnn2C1CCCCO1
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1c(O)ccc2c1cnn2C1CCCCO1
Product: CC(C)c1c(OC2CCCCO2)ccc2c1cnn2C1CCCCO1
Yield: 42 %
Yield: 16 %

Procedure:
In an autoclave, 10%-palladium/carbon (containing 50% water, 1.0 g) was added to a solution of 2-[1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazol-4-yl]propan-2-ol (1.92 g, 5.33 mmol) in ethanol (26 ml), and the resulting mixture was stirred at 60° C. for 5 hours under a hydrogen atmosphere of 30 atmospheric pressure. The reaction mixture was filtered by the use of Celite and washed with methanol, and then the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 4-isopropyl-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole (301 mg, 16%) and 4-isopropyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-ol (586 mg, 42%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[S:10](=[O:19])(=[O:18])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C.[CH3:30][Si:31]([CH3:38])([CH3:37])[CH2:32][CH2:33][O:34][CH2:35]Cl>ClCCl>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[S:10](=[O:19])(=[O:18])[N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:35][O:34][CH2:33][CH2:32][Si:31]([CH3:38])([CH3:37])[CH3:30]
Reactant: COC(=O)c1cccnc1S(=O)(=O)Nc1ccccc1
Reactant: C[Si](C)(C)CCOCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccnc1S(=O)(=O)N(COCC[Si](C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-phenylsulfamoylnicotinic acid methyl ester (1.1 g), N,N-diisopropylethylamine (1.9 mL) and dichloromethane at 0° C. was treated with 2-(trimethylsilyl)ethoxymethyl chloride (0.67 mL), and the resulting mixture was stirred at room temperature overnight. The mixture was cooled to 0° C., treated with additional (trimethylsilyl)ethoxymethyl chloride (0.30 mL), and stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and cyclohexane (0:1 to 1:0 by volume) to afford the title compound (1.6 g).
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH3:14][NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.[C:24]1([P:30](Cl)(Cl)=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CCCCCC.CCOCC.C1CCCCC1>[C:24]1([P:30]2(=[O:31])[C:18]3[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=3[CH2:16][N:15]2[CH3:14])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CNCc1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)c1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCCCC1
Solvent: CCOCC
Product: CN1Cc2ccc(Cl)cc2P1(=O)c1ccccc1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 13.2 %

Procedure:
Under a static nitrogen atmosphere at 0° C., a solution of n-butyllithium (7.87 g, 0.123 mol) in hexane was added to a solution of tetramethylethylenediamine (14.3 g, 0.123 mol) in 60 ml. of anhydrous cyclohexane with constant stirring. The resulting mixture was stirred for an additional 15 minutes and then cooled to -70° C. using a solid carbon dioxide-acetate bath. A solution of N-methyl-4-chloro-benzylamine (9.6 g, 0.06 mol) in 60 ml. of anhydrous cyclohexane was added to the reaction mixture to produce a suspension containing a dilithio compound. This suspension was stirred for 2 hours at 26° C. and then cooled to -70° C. using a solid carbon dioxide-acetone bath. A solution of phenylphosphonic dichloride (12.5 g, 0.064 mol) in 60 ml. of anhydrous cyclohexane was rapidly added to the suspension causing the temperature of the reaction to increase to -20° C. The reaction mixture was allowed to cool to -70° C., after which time the solid carbon dioxide-acetone bath was removed and the reaction mixture was stirred for 2.5 hours. The reaction mixture was cooled to 0° C. and then quenched with the rapid addition of 12 ml. of acetic acid. The cyclohexane was removed on a rotary evaporator, and the resulting residue was partitioned between methylene chloride and water. The layers were separated and the methylene chloride layer was dried over magnesium sulfate and concentrated in vacuo to yield a red oil. Distillation of the red oil at 180° C. and 0.25 mm yielded a yellow solid which was slurried in ether to yield 1-phenyl-2-methyl-6-chloro-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (2.2 g, 13% yield) as a pale yellow solid having a melting point of 159°-162° C. and the following analysis:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.O>C(#N)C>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: C1CNCCN1
Reactant: COc1ccnc(Cl)n1
Solvent: O
Solvent: CC#N
Product: COc1ccnc(N2CCNCC2)n1
Yield: 90 %

Procedure:
A suspension of 2-chloro-4-methoxypyrimidine (21.5 g) and piperazine (64.0 g) in acetonitrile (200 ml) was refluxed for 30 min. The reaction mixture was poured into water (500 ml) and extracted with chloroform (400 ml). The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound (26.0 g) as a pale-yellow oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([CH2:34][CH2:35][OH:36])[CH2:20][C:21]([N:23]([CH3:33])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])=[O:22])[CH:15]=[CH:16][C:17]=1[Cl:18].CCN(CC)CC>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([CH2:34][CH:35]=[O:36])[CH2:20][C:21]([N:23]([CH3:33])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])=[O:22])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: COc1ccccc1CN(C)C(=O)CC(CCO)c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1CN(C)C(=O)CC(CC=O)c1ccc(Cl)c(Cl)c1
Reaction time: 0.25 h
Yield: 73.5 %

Procedure:
Cool a solution of oxalyl chloride (1.43 mL) in CH2Cl2 (30 mL) to -78° C., add DMSO (2.32 mL) dropwise over 15 mins., stir for 15 min., then add a CH2Cl2 (20 mL) solution of the product of Step 5 (1.3 g) over 20 min. Stir the mixture for 30 min, treat with Et3N (9.2 mL) and stir for an additional 30 min. at -78° C., followed by 1.5 h at room temperature. Quench the reaction mixture with water and dilute with CH2Cl2 (100 mL). Separate the organic fraction, wash sequentially with 1N HCl (1×50 mL), sat. NaHCO3 (1×50 mL) and brine (1×50 mL), dry over MgSO4, filter and concentrate under reduced pressure to yield an oil. Chromatograph on silica gel, eluting with 50-100% EtOAc/hexane to give 3,4-dichloro-β-(2-oxoethyl)-N-methyl-N-[(2-methoxyphenyl)methyl] benzenepropanamide (950 mg).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Si:12]([N:19]1[CH:22]([CH2:23][C:24](=[O:29])[Si](C)(C)C)[CH:21]([C@H:30]([OH:32])[CH3:31])[C:20]1=[O:33])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>C(Cl)(Cl)Cl>[Si:12]([N:19]1[C@H:22]([CH2:23][C:24]([OH:9])=[O:29])[C@@H:21]([C@H:30]([OH:32])[CH3:31])[C:20]1=[O:33])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: C[C@@H](O)C1C(=O)N([Si](C)(C)C(C)(C)C)C1CC(=O)[Si](C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: C[C@@H](O)[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1CC(=O)O

Procedure:
m-Chloroperbenzoic acid (1.00 mmol) is added to a solution of (3S,4R)-1-(t-butyldimethylsilyl-3-[(R)-1-hydroxyethyl]-4-(2-oxo-2-trimethylsilylethyl)azetidin-2-one (1.00 mmol) in chloroform (4 ml). The resulting solution is heated at reflux for 4 hr, then cooled, concentrated in vacuo, and the residue chromatographed on silica gel (2% glacial acetic acid in methylene chloride). (3S, 4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-hydroxyethyl]-4-carboxymethyl-azetidin-2-one, 238 mg (83%) is isolated as a colorless solid, Rf =0.25. n.m.r. (CDCl3 and D2O) δ3.6-4.3 (2H, m, H-5, H-8), δ2.98 (1H, dd, J=7, 2.1 H-6), δ 2.7 (2H,d of ABq)-CH2CO2H), δ1.29 (3H, d, J=6, CH3 --)δ 0.95 (9H, S, Si±), δ 0.25 (6 H, S, (CH3)2 --Si).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[O:12])[N:9]([CH2:13][C@H:14]1[CH2:19][C:18](OCC)([O:20]CC)[CH2:17][CH2:16][N:15]1[C@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:27])[CH2:8]2.C(=O)([O-])[O-].[Na+].[Na+]>FC(F)(F)C(O)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[O:12])[N:9]([CH2:13][C@H:14]1[CH2:19][C:18](=[O:20])[CH2:17][CH2:16][N:15]1[C@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:27])[CH2:8]2
Reactant: CCOC1(OCC)CCN([C@@H](C)c2ccccc2)[C@@H](CN2Cc3cccc(OC)c3C2=O)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cccc2c1C(=O)N(C[C@H]1CC(=O)CCN1[C@@H](C)c1ccccc1)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
2-(R)-(7-Methoxy-2,3-dihydro-isoindol-1-one-2-ylmethyl)-4,4-diethoxy-1(1-(S)-phenyl-ethyl)-piperidine (2.0 g, 4.4 mmol) was dissolved in a ice cold mixture of trifluoroacetic acid and water (10 ml, 9:1) and stirred or 0.5 hour on an ice bath. The reaction mixture was poured on aqueous sodium carbonate (100 ml) and extracted with dichloromethane (2×50 ml). The organic phase was dried (MgSO4), filtered and evaporated in vacuo, affording 1.67 g (100%) of 2-(R)-(7-methoxy-2,3-dihydro-isoindol-1-one-2-ylmethyl)-4-oxo-1(1-(S)-phenyl-ethyl)-piperidine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1.O>C1COCC1>[CH:19]1([C:22]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]2)=[O:23])[CH2:21][CH2:20]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C1CCN(C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a solution of ethyl piperidine-4-carboxylate (5 g) and triethylamine (5.3 mL) in THF (100 mL) was added cyclopropylcarbonyl chloride (3.99 g) at 0° C., and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and brine and dried, and the solvent was evaporated under reduced pressure to give ethyl 1-(cyclopropylcarbonyl)piperidine-4-carboxylate (6.32 g, 81%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:30])[CH2:15][NH:16][C:17]([C:19]2[CH:28]=[C:27]([OH:29])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:37]([O:44][C:45](=[O:48])[CH2:46]Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C=O)C.O>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:30])[CH2:15][NH:16][C:17]([C:19]2[CH:28]=[C:27]([O:29][CH2:46][C:45]([O:44][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:48])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[O:18])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(O)c3ccccc3n2)CC1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)OCc3ccccc3)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 10 g 4-{2-[(4-Hydroxy-quinoline-2-carbonyl)-amino]acetyl}-piperazine-1-carboxylic acid butyl ester in 41 ml of DMF, 8.6 g of cesium carbonate and 6.1 g of Bromo-acetic acid benzyl ester were added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 5.2 g.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[C:6](=[CH:12][C:13]([NH2:17])=[C:14]([OH:16])[CH:15]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[CH2:19](C(CC)(CC)C([O-])([O-])[O-])[CH3:20]>>[CH3:19][C:20]1[O:16][C:14]2[CH:15]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:18])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][C:13]=2[N:17]=1
Reactant: CCOC(=O)c1cc(N)c(O)cc1C(=O)OCC
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Product: CCOC(=O)c1cc2nc(C)oc2cc1C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of diethyl-4-amino-5-hydroxyphthalate (4.00 g, 15.8 mmol) and triethylorthoacetate (29.0 mL, 158 mmol) is stirred for 2 hours at reflux temperature, cooled to room temperature and diluted with hexanes. Silica gel chromatography (gradient elution:hexanes to (2:1) hexanes:ethyl acetate) followed by recrystallization from 1% ethyl acetate:-hexanes affords the title product as an off-white crystalline solid, 3.54 g (80.8%), identified by NMR, IR and mass spectral analyses.