Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:6]1)=[O:4].[OH-].[Na+]>C([O-])(=O)C.[Mg+2].C([O-])(=O)C.CC1CCCCC1>[OH:17][C:14]1[CH:13]=[CH:12][C:11]([N:7]2[C:8](=[O:10])[CH2:9][C@H:5]([C:3]([OH:4])=[O:2])[CH2:6]2)=[CH:16][CH:15]=1
Reactant: COC(=O)C1CC(=O)N(c2ccc(O)cc2)C1
Agent: CC(=O)[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CC1CCCCC1
Product: O=C(O)[C@H]1CC(=O)N(c2ccc(O)cc2)C1
Temperature: 28 °C
Yield: 45.9 %

Procedure:
8.00 g Polyethyleneglycol 6000 was dissolved in 150 mL (100 mM) magnesium acetate buffer pH 6.0 under stirring, and the solution added to a stirred suspension of 10.00 g (42.51 mmol) (RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (99.7%) in 40 mL methylcyclohexane. The mixture was heated to 28° C. and the pH readjusted to 6.0 with 2 M NaOH. The reaction was started by adding 33.2 mg Candida cylindraceae cholesterase (16.88 kU/g), and the pH was maintained at 6.0 by the controlled addition of 1.0 M NaOH solution under stirring. After a total consumption of 20.35 mL (20.35 mmol) 1.0 M sodium hydroxide solution (after 17.1 h; 47.9% conversion) the reaction mixture was passed through a sintered glass filter. The filtrate spontaneously separated into an aqueous and an organic phase.The aqueous phase was washed with 2×200 mL ethyl acetate to remove uncleaved ester. The aqueous phase was set to pH 4.0 with 25% sulfuric acid and concentrated in vacuo to a volume of ca. 80 mL (bath 60° C.). The solution was cooled to 1° C. (formation of white precipitate/crystals) and the pH set to 1.5 with 25% sulfuric acid. The precipitate/crystals were stirred overnight at 1° C., filtered off on a sintered glass filter (washed with a minimum amount of water) and dried overnight on high vacuum (RT, 6×10−2 mbar) to give 4.32 g (19.53 mmol; 45.9%) (S)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid. Analysis: HPLC (area A226nm): 99.3%, 0.7% ester. 98.9%ee. The product contains 5.3% water (according to Karl Fischer determination) and 2.1% (w/w) PEG (according to NMR).
Reaction SMILES: C(OC1C=CN([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=2[CH3:26])=[O:17])C(=O)C=1)C1C=CC=CC=1.[CH3:28][O:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][O:37][C:38]2[CH:43]=[CH:42][NH:41][C:40](=[O:44])[CH:39]=2)=[N:34][CH:35]=1>>[OH:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:16](=[O:17])[CH2:15][N:41]2[CH:42]=[CH:43][C:38]([O:37][CH2:36][C:33]3[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:35][N:34]=3)=[CH:39][C:40]2=[O:44])=[C:19]([CH3:26])[CH:20]=1
Reactant: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Reactant: COc1ccc(COc2cc[nH]c(=O)c2)nc1
Product: COc1ccc(COc2ccn(CC(=O)c3ccc(CO)cc3C)c(=O)c2)nc1
Yield: 59 %

Procedure:
1-[2-(4-Hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-methoxy-pyridin-2-ylmethoxy)-1H-pyridin-2-one is prepared following preparation 1c employing 4-(5-methoxy-pyridin-2-ylmethoxy)-1H-pyridin-2-one (preparation 11b) instead of 4-benzyloxy-1H-pyridin-2-one.
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:19]([CH3:29])[CH:18]=2)O1.O.O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:29][C:19]1[CH:18]=[C:17]([C:2]2[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:22]=[CH:21][C:20]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ncccc1Br
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1-c1ccccc1
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: COCCOC
Solvent: O
Product: Cc1cc(-c2cccnc2N)ccc1-c1ccccc1

Procedure:
Pd(dppf)Cl2 (0.089 g) was added to a mixture of 4-bromo-2-methylbiphenyl (1.5 g), potassium acetate (1.787 g) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.312 g) in DME (25 mL) and DMSO (1.25 mL). The mixture was stirred at 80° C. under nitrogen overnight. Activated-carbon powder was added and the mixture was stirred for 5 min. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo to give crude 4,4,5,5-tetramethyl-2-(2-methylbiphenyl-4-yl)-1,3,2-dioxaborolane. Tetrakis(triphenylphosphine)palladium(0) (173 mg) was added to a suspension of 3-bromopyridin-2-amine (865 mg), the prepared 4,4,5,5-tetramethyl-2-(2-methylbiphenyl-4-yl)-1,3,2-dioxaborolane and sodium carbonate decahydrate (2861 mg) in DME (30 mL) and water (6 mL) and the mixture was stirred at 80° C. under nitrogen for 6 hr. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH-silica gel, eluted with EtOAc in hexane) to give the title compound (1.25 g) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH2:11][CH2:10][C:6](=[C:7]([CH3:9])[CH3:8])[C:4](=O)[CH:3]=1.C[C@H]1C[C@@H](O)[C@H](C(C)C)CC1.C1(C)CCC(C(C)C)C(O)C1>O>[CH:2]1([CH3:1])[CH2:11][CH2:10][CH:6]([CH:7]([CH3:9])[CH3:8])[CH2:4][CH2:3]1
Reactant: CC1=CC(=O)C(=C(C)C)CC1
Agent: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Agent: CC1CCC(C(C)C)C(O)C1
Solvent: O
Product: CC1CCC(C(C)C)CC1

Procedure:
The hydrogenation of the crude piperitenone is expediently carried out at temperatures at which as much d,l-menthol as possible is present in the menthol isomer mixture and no splitting off of water to form p-menthane takes place. Temperatures of 100° to 260°C, especially of 160° to 220°C, have proved advantageous.
Reaction SMILES: Br[C:2]1[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:4]([CH3:17])[C:5]([C:15]#[N:16])=[C:6]2[C:10]=1[O:9][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:7]2.[C:24]([O:28][C:29]([NH:31][CH:32]1[CH2:36][CH2:35][C:34]([Sn](CCCC)(CCCC)CCCC)=[CH:33]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)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.O1CCOCC1>[C:11]([C:8]1[O:9][C:10]2[C:2]([C:34]3[CH2:35][CH2:36][CH:32]([NH:31][C:29](=[O:30])[O:28][C:24]([CH3:26])([CH3:25])[CH3:27])[CH:33]=3)=[C:3]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:4]([CH3:17])=[C:5]([C:15]#[N:16])[C:6]=2[N:7]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CC(NC(=O)OC(C)(C)C)CC1
Reactant: Cc1c(-c2ccccc2)c(Br)c2oc(C(C)(C)C)nc2c1C#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2)c(C2=CC(NC(=O)OC(C)(C)C)CC2)c2oc(C(C)(C)C)nc2c1C#N
Yield: 61 %

Procedure:
A 1,4-dioxane (20 ml) solution of 7-bromo-2-tert-butyl-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-9) (414 mg, 1.12 mmol), 1-(N-tert-butoxycarbonylamino)-3-tri-n-butylstannyl-2-cyclopentene (530 mg, 1.12 mmol), bis(triphenylphosphine)palladium(II) chloride (39.3 mg, 56.1 μmol), 2,6-di-tert-butyl-p-cresol (28 mg, 127 μmol) was refluxed overnight. After cooling, the reaction liquid was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1→8:1) to obtain tert-butyl [3-(2-tert-butyl-4-cyano-5-methyl-6-phenyl-1,3-benzoxazol-7-yl)-2-cyclopentenyl]carbamate (322 mg, 61%) as a yellow white solid. A part of it (270 mg) was stirred in hydrochloric acid/1,4-dioxane solution, followed by purifying by silica gel column chromatography to obtain 7-(3-amino-cyclopent-1-enyl)-2-tert-butyl-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (157 mg). This was dissolved in methanol (4 ml), aqueous formalin solution (324 μl, 46-38%, 4.23 mmol), sodium cyanoborohydride (80 mg, 1.27 mmol) and acetic acid (87 μl, 1.52 mmol) were successively added, followed by stirring at room temperature for 2.5 hours. The reaction liquid was concentrated under reduced pressure, aqueous 10% sodium carbonate solution was added to the residue, the organic matter was extracted with chloroform. The organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=40:1) to obtain the entitled compound (84.8 mg, 50%) as a yellow solid.
Reaction SMILES: C1C[NH:6][C:4](=[O:5])[NH:3]C1.C(N(CC)CC)C.[Cl:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>C1(C)C=CC=CC=1>[Cl:15][CH2:16][CH2:17][C:18]([NH:3][C:4]([NH2:6])=[O:5])=[O:19]
Reactant: O=C(Cl)CCCl
Reactant: O=C1NCCCN1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: NC(=O)NC(=O)CCCl
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
20.0 g of N,N'-trimethyleneurea are partially dissolved in 1000 ml of toluene under reflux and admixed with 20.2 g of triethylamine and then dropwise, in the course of 90 minutes, with a solution of 25.4 g of 3-chloropropionyl chloride. Subsequent stirring for 30 minutes, cooling down to 5° C., removal of undissolved matter by filtration and evaporating the filtrate in vacuo gives 24 g of chloropropionylurea of the formula ##STR70## as a beige powder.
Reaction SMILES: C([O:3][C:4](=[O:41])[C:5]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C@@H:14]([CH3:28])[CH2:13][C@H:12]2[N:29]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:30](=[O:33])[CH2:31][CH3:32])([CH3:7])[CH3:6])C.ClC1C=CC(N(C(=O)CC)[C@H]2C3C(=CC=C(OCC(O)=O)C=3)N(C(=O)C3C=CC(F)=CC=3)[C@@H](C)C2)=CC=1>>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([N:29]([C:30](=[O:33])[CH2:31][CH3:32])[C@H:12]2[C:11]3[C:16](=[CH:17][CH:18]=[C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:41])=[O:3])[CH:10]=3)[N:15]([C:19](=[O:27])[C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[C@@H:14]([CH3:28])[CH2:13]2)=[CH:35][CH:36]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc2c(c1)[C@H](N(C(=O)CC)c1ccc(Cl)cc1)C[C@H](C)N2C(=O)c1ccc(F)cc1
Agent: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(OCC(=O)O)cc21
Product: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(OC(C)(C)C(=O)O)cc21

Procedure:
(±)-Cis-2-[4-[(4-chloro-phenyl)-propionyl-amino]-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-6-yloxy]-2-methyl-propionic acid was prepared from (±)-cis-2-[4-[(4-chloro-phenyl)-propionyl-amino]-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-6-yloxy]-2-methyl-propionic acid ethyl ester. The saponification conditions detailed in the procedure for the synthesis of (±)-cis-[4-[(4-chloro-phenyl)-propionyl-amino]-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-6-yloxy]-acetic acid were used.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][C:15]=1[NH2:16])[CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].[C:17](O)(=O)C.C(N)=N>COCCO>[NH:16]1[C:15]2[CH:14]=[CH:13][C:6]([CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12])=[CH:5][C:4]=2[N:3]=[CH:17]1
Reactant: CC(=O)O
Reactant: Nc1ccc(CCOCCO)cc1N
Agent: Cl
Agent: N=CN
Solvent: COCCO
Product: OCCOCCc1ccc2[nH]cnc2c1
Yield: 56.6 %

Procedure:
In 10 mL of ethylene glycol monomethyl ether is dissolved 1.2 g of 2-[(3,4-diaminophenethyl)oxy]-1-ethanol dihydrochloride, to which is added 0.93 g of formamidine acetate. The mixture is heated under reflux for 30 minutes. Then, the solvent is distilled off under reduced pressure, water and methylene chloride are added to the residue, pH is adjusted to 9 with 2 mol/L aqueous solution of sodium hydroxide, and the organic layer is separated. The aqueous layer is salted out and extracted with methylene chloride. The organic layers are collected, washed with saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: chloroform:methanol=10:1) to obtain 0.52 g of 2-[2-(1H-benzo[d]imidazol-5-yl)ethoxy]-1-ethanol as an oily product.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:9])[CH2:7][SH:8])[CH3:4].Cl[C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:12]=1[C:13]#[N:14]>CN(C)C=O>[NH2:14][C:13]1[C:12]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:11]=2[S:8][C:7]=1[C:6]([O:5][CH2:3][CH3:4])=[O:9]
Reactant: CCOC(=O)CS
Reactant: Cc1cccc(Cl)c1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2cccc(C)c2c1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.5 %

Procedure:
At 0° C., sodium hydride, 60% dispersion in mineral oil, (280 mg, 7 mmol) was added to a solution of ethyl-2-mercaptoacetate (750 μL, 6.8 mmol) in N,N-dimethylformamide (20 mL). After 15 minutes, 2-chloro-6-methylbenzonitrile (1 g, 6.60 mmol) was also added to the mixture which was stirred at room temperature for 2 hours more. The mixture was then concentrated and the residue was diluted with ethyl acetate. The organic layer was washed with water (30 mL), brine (30 mL), dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (cyclohexane/dichloromethane 50/50) to afford the desired benzothiophene (23a) as a white solid (800 mg, 3.40 mmol, 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].Cl.[NH2:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N:24]1[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]1>C(#N)C>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([NH:6][C:7](=[O:8])[NH:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N:24]1[CH2:25][CH2:26][CH:27]([C:30]([OH:32])=[O:31])[CH2:28][CH2:29]1)=[O:5]
Reactant: Nc1cc(F)ccc1N1CCC(C(=O)O)CC1
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Agent: Cl
Solvent: CC#N
Product: O=C(NC(=O)c1cc(F)c(F)cc1Cl)Nc1cc(F)ccc1N1CCC(C(=O)O)CC1

Procedure:
The equimolar solution of 2-chloro-4,5-difluorobenzoyl isocyanate in acetonitrile was added dropwise to the solution of 53 mg of 1-(2-amino-4-fluorophenyl)piperidine-4-carboxylic acid hydrochloride in 3 ml of acetonitrile with stirring. The mixture was stirred at RT for 6 h and the precipitate was filtered off with suction and dried at RT under reduced pressure.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH3:11])[C:3]1=[S:12].[Cl:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:13][C:4]1([CH3:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[C:3]1=[S:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1C(=S)N(C)c2ccccc21
Solvent: ClC(Cl)(Cl)Cl
Product: CN1C(=S)C(C)(Cl)c2ccccc21

Procedure:
A solution of 1-methyl-3-methylthiooxindole (1.07 g, 5.56 mmol) and N-chlorosuccinimide (800 mg, 6.0 mmol) in 75 ml of carbon tetrachloride was stirred at room temperature for 1 hour, filtered, and the filtrate was evaporated to give a residue yielding 3-chloro-1-methyl-3-methylthiooxindole. The residue was dissolved in 20 ml of tetrahydrofuran and rapidly added to a vigorously stirred slurry of red mercuric oxide (1.20 g, 5.56 mmol) and boron trifluoride etherate (790 mg, 5.56 mmol) in 75 mol of 20 percent aqueous tetrahydrofuran. After stirring at room temperature for 1 hour, the reaction mixture was filtered through a Celite pad and the filtrate was extracted with ether. Evaporation of the ether layer gave a residue which was purified by chromatography on silica gel. Elution with methylene chloride gave 1-methylisatin (550 mg, 61%), mp 131°-133°; nmr (CDCl3) τ2.23-2.60 (m, 2H, aromatic H), 2.71-2.90 (m, 2H, aromatic H) and 6.70 (s, 3H, N--CH3).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([I:19])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[I:19][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH3:12])[C:9]=2[CH:13]=1
Reactant: COc1cc2c(cc1I)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1I)C(C)CNCC2
Reaction time: 3 h
Yield: 92.4 %

Procedure:
A solution of N-trifluoroacetyl-8-iodo7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.600 g, 1.45 mmol) in methanol (20 mL) was treated with 15% aqueous NaOH (20 mL), and stirred for 3 hours at 50 C. The product mixture was diluted with water (100 mL), extracted twice with EtOAc (100 mL), the combined organic phases were washed with brine (100 mL), dried with Na2SO4 and concentrated to give 0.425 g of a yellow solid. 1H NMR (400 MHz, CDCl3) d 7.52 (s, 1H), 6.57 (s, 1H), 3.86 (s, 3H), 3.12-3.06 (m, 4H), 2.95 (m, 2H), 2.75 (m, 1H), 2.43 (bs, 1H), 1.33 (d, J=8 Hz, 3H). MS calculated for C12H16INO+H: 318, observed: 318.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[Br:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1>N1CCC[C@H]1C(O)=O.CN(C=O)C>[OH:11][CH:10]([C:9]1[CH:12]=[CH:13][C:6]([Br:5])=[CH:7][CH:8]=1)[CH2:1][C:2](=[O:3])[CH3:4]
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(C)=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CN(C)C=O
Product: CC(=O)CC(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 68 h

Procedure:
A stirred solution of catalyst 35 (0.01 g, 0.011 mmol) in dry DMF (0.785 mL) and acetone (0.392 mL, 2.72 mmol) was treated with 4-bromobenzaldehyde (0.0072 g, 0.04 mmol), stirred at room temperature for 68 h and Resin 35 was filtered off. The mixture was treated with Et2O and washed twice with water Et2O phase was dried and concentrated The product was analyzed by the 1H NMR spectroscopy of the crude 1H NMR spectroscopy of the crude showed a 70% conversion by measuring the CHOH peak of the aldol product at 5.12 ppm vs the CHO peak of the p-bromobenzaldehyde at 9.90 ppm 1H NMR (CDCl3, 400 MHz): δ=2.20 (s, 3H), 2.82 (m, 2H), 5.12 (m, 1H), 3.58-3.69 (m, 1H), 4.11-4.17 (m, 1H), 4.29-4.35 (m, 2H), 7.24-47 (m, 4H). Moreover, examination of the aldol product by chiral HPLC using a Chiralpak AS Daicel (i-PrOH/hexane 15/85), UV 280 nm, flow rate 1.0 mL/min, tRminor 8.950 min and tRmajor 10.143 min showed the presence of one single peak at 8.950 min retention time.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:13]([NH:15][C@H:16]([C:22]([O:24][CH3:25])=[O:23])[CH2:17][O:18][CH2:19][CH:20]=O)=[O:14]>C(Cl)Cl.FC(F)(F)C(O)=O>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH:12]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:13]([N:15]1[CH:20]=[CH:19][O:18][CH2:17][CH:16]1[C:22]([O:24][CH3:25])=[O:23])=[O:14]
Reactant: COC(=O)[C@H](COCC=O)NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1COC=CN1C(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 65.3 %

Procedure:
Dissolve N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo3-phenylpropyl]-O-2-oxoethyl-L-serine, methyl ester (13.6 g) in methylene chloride/trifluoroacetic acid (10:1/330 mL). Stir at room temperature for 2.5 hours and evaporate the solvent in vacuo. Purify by silica gel chromatography (35% ethyl acetate/hexane) and recrystallize (ethyl acetate/hexane) to give the title compound (8.52 g, 68%); mp 70°-72° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[CH2:13][OH:14].CCOC(C)=O.CCCCCC>CCOC(C)=O.O=[Mn]=O>[OH:1][C:2]1[C:3]([CH:13]=[O:14])=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[CH:6][C:7]=1[CH:8]=[O:9]
Reactant: O=[N+]([O-])c1cc(CO)c(O)c(CO)c1
Agent: O=[Mn]=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=Cc1cc([N+](=O)[O-])cc(C=O)c1O
Yield: 40 %

Procedure:
A mixture of (2-hydroxy-5-nitro-1,3-phenylene)dimethanol (0.50 mmol) and MnO2 (3.5 mmol) was dissolved in 2 ml EtOAc and the reaction was refluxed for 24 hours while being monitored by TLC (using EtOAc/Hexane 30:70 as eluent). The reaction mixture, once completed, was concentrated by evaporation under reduced pressure. The crude product was purified by column chromatography on silica gel (using EtOAc/Hexane 30:70 as eluent) to give 2-hydroxy-5-nitroisophthalaldehyde (40% yield) as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([CH2:9][N:10]2[CH2:13][CH:12]([C:14]([O:16]C)=[O:15])[CH2:11]2)[CH:6]=[CH:5][C:4]=1[C:18]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([CH3:32])[CH3:31])=[C:25]([CH3:33])[CH:24]=2)[O:20][N:19]=1)[CH3:2].[OH-].[Na+]>>[CH2:1]([C:3]1[N:8]=[C:7]([CH2:9][N:10]2[CH2:13][CH:12]([C:14]([OH:16])=[O:15])[CH2:11]2)[CH:6]=[CH:5][C:4]=1[C:18]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([CH3:32])[CH3:31])=[C:25]([CH3:33])[CH:24]=2)[O:20][N:19]=1)[CH3:2]
Reactant: CCc1nc(CN2CC(C(=O)OC)C2)ccc1-c1noc(-c2ccc(CC(C)C)c(C)c2)n1
Agent: [Na+]
Agent: [OH-]
Product: CCc1nc(CN2CC(C(=O)O)C2)ccc1-c1noc(-c2ccc(CC(C)C)c(C)c2)n1
Yield: 79.4 %

Procedure:
The title compound (0.10 g) was synthesized in a yield of 82% as a white crystalline solid by conducting the reaction similar to that mentioned in Example 3 (3e) using methyl 1-({6-ethyl-5-[5-(4-isobutyl-3-methylphenyl)-1,2,4-oxadiazol-3-yl]pyridin-2-yl}methyl)azetidine-3-carboxylate (0.13 g, 0.29 mmol) that was obtained in Example 29 (29b) and a 1 N aqueous solution of sodium hydroxide (0.87 mL, 0.87 mmol).
Reaction SMILES: [CH:1]([Si:4]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[O:5][CH2:6][C:7]1[CH:11]=[CH:10][O:9][C:8]=1[CH3:12])([CH3:3])[CH3:2].C([Li])CCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46].[Cl-].O1C=CC=C1[Zn+]>O1CCCC1.[Cl-].[Zn+2].[Cl-].C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Ni+2]>[CH2:48]([O:47][C:45](=[O:46])[CH2:44][C:10]1[O:9][C:8]([CH3:12])=[C:7]([CH2:6][O:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:13]([CH3:15])[CH3:14])[CH:16]([CH3:18])[CH3:17])[CH:11]=1)[CH3:49]
Reactant: Cc1occc1CO[Si](C(C)C)(C(C)C)C(C)C
Reactant: CCOC(=O)CBr
Agent: [Ni+2]
Agent: CC(=O)/C=C(/C)[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cc(CO[Si](C(C)C)(C(C)C)C(C)C)c(C)o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of triisopropyl-(2-methyl-furan-3-ylmethoxy)-silane (14) (5.0 g) in tetrahydrofuran (15 mL) was cooled to −78° C. with stirring. This solution was treated drop-wise with n-butyl lithium (2.5 M in hexanes, 8.94 mL). The resulting solution was warmed to 0° C. and allowed to stand for 30 minutes after which a solution of dried zinc chloride (3.04 g) in tetrahydrofuran (10 mL) was added and the resulting solution allowed to stand for a further 1 hour at room temperature. Concurrently, a second reaction vessel was charged with tetrahydrofuran (10 mL), nickel(II) acetylacetonate (120 mg), and triphenylphosphine (122 mg) and cooled (−5° C.). Ethyl bromoacetate (1.03 mL) was added to this mixture, followed by the addition of the previously prepared solution of the furyl-zinc chloride. The resulting reaction mixture was allowed to warm to room temperature then stirred for a further 16 hours at room temperature. The reaction was quenched by the addition of saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (3×150 mL). The combined organic extracts were successively washed with water (200 mL) and brine (250 mL), dried, filtered and concentrated in vacuo. The residue was purified by flash chromatography using a gradient elution (diethyl ether/petroleum ether (40-60°) 1:49 to 1:25 by volume) to give compound 29 as a clear oil (1.44 g). LC/MS System A: Rt=5.16 min.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH:8](OCC)[O:9][CH2:10][CH3:11])[N:5]=[CH:4][C:3]=1[C:15](O)=O.[H-].COCCO[Al+]OCCOC.[Na+].[H-].ClCCl.O>C1(C)C(C)=CC=CC=1.C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:6](/[CH:7]=[CH:8]/[O:9][CH2:10][CH3:11])[N:5]=[CH:4][C:3]=1[CH3:15]
Reactant: CCOC(Cn1ncc(C(=O)O)c1N)OCC
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1C
Product: CCO/C=C/n1ncc(C)c1N
Yield: 21.7 %

Procedure:
To a suspension of 5-amino-4-carboxy-1-(2,2-diethoxyethyl)pyrazole (4 g) in xylene (15.6 ml) was added dropwise 3.4M solution of sodium bis(2-methoxyethoxy)-aluminum hydride in toluene (15.6 ml) at room temperature in an atmosphere of nitrogen. Then the mixture was refluxed for 6 hours, and poured into a mixture of dichloromethane and water. The precipitate was filtered off, and the organic layer was separated and dried over magnesium sulfate. The organic solvent was evaporated in vacuo to give 5-amino-4-methyl-1-[(E)-2-ethoxyvinyl]-pyrazole (598 mg).