Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1)(C)(C)C.C(S)CCCCCCCCCCC.N(C(C)(C)C#N)=NC(C)(C)C#N>O1CCOCC1>[CH:11]#[C:10][C:9]1[CH:12]=[CH:13][C:6]([OH:5])=[CH:7][CH:8]=1
Reactant: C=Cc1ccc(OC(C)(C)C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCCCCCCCCCCS
Solvent: C1COCCO1
Product: C#Cc1ccc(O)cc1

Procedure:
In 100 ml of dioxane were dissolved 176 g (1.0 mole) of p-t-butoxystyrene, 4.0 g (0.02 mole) of dodecylmercaptan and 8.2 g (0.05 mole) of azobisisobutyronitrile, and the resulting solution was subjected to reaction for 10 hours while the internal temperature was kept at 75° C., after which the reaction mixture was subjected to several reprecipitation treatments to remove the unreacted monomer, thereby obtaining poly(p-t-butoxystyrene). Subsequently, this poly(p-t-butoxystyrene) was hydrolyzed with an acid to obtain poly(p-hydroxystyrene) having a Mw of 8,900. This resin is referred to hereinafter as Resin A2.
Reaction SMILES: C([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1)(C)(C)C.N(C(C)(C)C#N)=NC(C)(C)C#N>O1CCOCC1>[CH:11]#[C:10][C:9]1[CH:12]=[CH:13][C:6]([OH:5])=[CH:7][CH:8]=1
Reactant: C=Cc1ccc(OC(C)(C)C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C1COCCO1
Product: C#Cc1ccc(O)cc1

Procedure:
In 100 ml of dioxane were dissolved 176 g (1.0 mole) of p-t-butoxystyrene and 8.2 g (0.05 mole) of azobisisobutyronitrile, and the resulting solution was subjected to reaction for 24 hours while the internal temperature was kept at 70° C., after which the reaction mixture was subjected to several reprecipitation treatments to remove the unreacted monomer, thereby obtaining poly(p-t-butoxystyrene). Subsequently, this poly(p-t-butoxystyrene) was hydrolyzed with an acid to obtain poly(p-hydroxystyrene) having a Mw of 30,000. This resin is referred to hereafter as Resin A1.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:21]4[CH:20]=[CH:19][C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc5ccccc5c4)cc3CC[C@@H]12
Yield: 54.5 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 2-naphthylboronic acid (168 mg, 0.98 mmol) ,0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80° for 16 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 126 mg (55%) of the title compound as a white solid. mp 221°-223°. FDMS: m/e=355. α[D]589 =+73.58 (c=1.06, chloroform).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([CH2:12]Cl)=[O:11].[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([CH2:12][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:11]
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: C1CNCCN1
Solvent: CCO
Product: Cc1cccc(C)c1NC(=O)CN1CCNCC1

Procedure:
The crude [(2,6-dimethylphenyl)aminocarbonylmethyl]chloride, prepared in Preparation B (50 g, 0.25 mole) and piperazine (86 g, 1 mole) are dissolved in 500 ml of ethanol. The mixture is refluxed for two hours, and then cooled and evaporated. The product is harvested by adding aqueous ammonia to the residue, and extracting with methylene chloride. Three portions of methylene chloride are used, which are collected, washed with water, and evaporated to a semi-solid. Upon addition of ether, the product crystallizes and is filtered. The resulting crude mixture is boiled with ether and then evaporated to a residue and triturated with hexane to yield pure material, 1-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine. This material is of sufficient purity for use in Reaction Sequences 1 or 2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)(Cl)=O.[BH4-].[Na+].[NH4+].[Cl-]>O1CCCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:7][OH:8])[CH:10]=1
Reactant: O=C(O)c1cncc(Br)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: OCc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 8.1 %

Procedure:
Under a nitrogen atmosphere, a solution of 5-bromonicotinic acid (5.05 g, 25.0 mmol) and thionyl chloride (10 mL) was stirred and heated. The excess thionyl chloride was removed by distillation, and the residue was dried briefly under high vacuum. To the resulting light-yellow solid in dry tetrahydrofuran (40 mL) was added sodium borohydride (1.90 g, 50.0 mmol) at 0° C. under a nitrogen atmosphere. The mixture was stirred 1 h at 0° C. and allowed to warm to ambient temperature. The mixture was added to a cold, saturated aqueous NH4Cl solution (100 mL) and extracted with diethyl ether (3×50 mL). The combined ether extracts were dried (Na2 SO4), filtered, and concentrated by rotary evaporation to a semisolid (2.77 g). Thin layer chromatography analysis on silica gel indicated mostly 5-bromonicotinic acid; therefore the semisolid was partitioned between ether and saturated aqueous NaHCO3 solution. The ether layer was separated and concentrated by rotary evaporation to a residue (0.75 g). Purification by column chromatography on silica gel, eluting with ethyl acetate-hexane (1:1, v/v) afforded 379 mg (8.1%) of 3-bromo-5-hydroxymethylpyridine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].C1N=CN(C(N2C=NC=C2)=O)C=1.[BH4-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cncc(Br)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1cncc(Br)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
5-Bromonicotinic acid (3.44 g, 17.0 mmol) is placed in THF (40 mL), combined with CDI (3.00 g, 18.5 mmol) and stirred for 2 h at 50° C. Then while cooling with ice the reaction mixture is poured onto an aqueous NaBH4 solution (600 mg, 15.9 mmol in 100 mL H2O), stirred for 3 d at RT and extracted 7× with DCM. The combined organic phases are dried on Na2SO4, filtered and evaporated down using the rotary evaporator. The (5-bromo-pyridin-3-yl)-methanol thus obtained (HPLC-MS: tRet.=0.21 min; MS (M+H)+=188/190) is further used without any further purification steps.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].C(N(CC)CC)C.[C:17]([Cl:20])(Cl)=[O:18]>C(Cl)(Cl)Cl>[C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[Cl:20][C:17]([O-:18])=[O:5]
Reactant: O=C(Cl)Cl
Agent: C=C(C)C(=O)OCCO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C([O-])Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of hydroxyethyl methacrylate (HEMA, 1.3 g, 10 mmol) and triethyl amine (1.1 g, 11 mmol) in 10 mL of chloroform was added dropwise to a stirred solution of phosgene (20% solution in toluene, 15.6 ml, 30 mmol) in 15 mL of chloroform at 0° C. The mixture was stirred for 1 hour at 0° C. and subsequently put under 50 mbar pressure to remove the excess of phosgene. After 30 min, the mixture was further concentrated under reduced pressure using a rotavap. The product was dissolved in 25 mL of THF and filtered to remove solid Et3N.HCl. The THF was evaporated under reduced pressure and the residue was purified by Kugelrohr-distillation (90° C., 0.6 mmHg) affording the HEMA-chloroformate as a colourless oil (1.3 g, 67%).
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[C:12]1([CH:22]([OH:38])[CH2:23][O:24][CH2:25][CH2:26][O:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.[O:39]1[CH:44]=[CH:43][CH2:42][CH2:41][CH2:40]1>C(Cl)Cl>[C:12]1([CH:22]([O:38][CH:40]2[CH2:41][CH2:42][CH2:43][CH2:44][O:39]2)[CH2:23][O:24][CH2:25][CH2:26][O:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)(=[O:29])=[O:30])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOCC(O)c2cccc3ccccc23)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCC(OC2CCCCO2)c2cccc3ccccc23)cc1
Reaction time: 0.17 h

Procedure:
0.82 g of pyridimium p-toluenesulfonate was added to a solution of 6.3 g of 1-(1-naphthyl)-2-[2-(p-toluenesulfonyloxy)ethoxy]ethanol and 2.97 ml of 3,4-dihydro-2H-pyran dissolved in 63 ml of methylene chloride at room temperature. The resulting mixture was stirred at the same temperature for 20 minutes and further at 35°-40° C. for 10 minutes. The reaction mixture was cooled, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: toluene/ethyl acetate=10/1) to obtain 7.53 g of colorless, oily 1(1-naphthyl)-1-(tetrahydropyran-2-yloxy)-2-[2-(p-toluenesulfonyloxy)ethoxy]ethane.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[NH:16][C:15]4[N:23]=[CH:24][CH:25]=[CH:26][C:14]=4[N:13]3[C:27]=2[C:28]2[CH:33]=[CH:32][C:31]([C:34]3([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:37][CH2:36][CH2:35]3)=[CH:30][CH:29]=2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[NH:16][C:15]4[N:23]=[CH:24][CH:25]=[CH:26][C:14]=4[N:13]3[C:27]=2[C:28]2[CH:33]=[CH:32][C:31]([C:34]3([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:43])([CH3:42])[CH3:44])[CH2:35][CH2:36][CH2:37]3)=[CH:30][CH:29]=2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc([N+](=O)[O-])cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(N)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reaction time: 4 h
Yield: 65.5 %

Procedure:
10% Pd/C (51.4 mg) was added to a solution of tert-butyl (1-{4-[2-(4-nitrophenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (51.4 mg, 0.0856 mmol) in MeOH (5 mL), and the mixture was stirred for 4 hours under hydrogen atmosphere. The catalyst was filtered off and washed with MeOH. The combined filtrate and washings were concentrated, and the residue was purified by PTLC (CHCl3/MeOH=9:1) to afford desired product (32.0 mg, 65.5%) as an orange solid. 1HNMR (CDCl3) 400 MHz δ: 8.16 (dd, J=7.8, 1.4 Hz, 1H), 8.02-7.97 (m, 1H), 7.46-7.24 (m, 5H), 7.18-7.09 (m, 3H), 6.97-6.91 (m, 1H), 6.83-6.73 (m, 1H), 6.64-6.55 (m, 3H), 6.45 (s, 1H), 5.21 (br s, 1H), 3.70 (br s, 2H), 2.65-2.25 (m, 4H), 2.19-2.05 (m, 1H), 1.94-1.81 (m, 1H), 1.38 (br s, 9H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][CH3:14])(=[O:12])[CH:10]=[CH2:11]>C(O)C>[CH3:14][O:13][C:9]([CH2:10][CH2:11][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:11][CH2:10][C:9]([O:13][CH3:14])=[O:12])=[O:12]
Reactant: C=CC(=O)OC
Reactant: NCc1ccccc1
Solvent: CCO
Product: COC(=O)CCN(CCC(=O)OC)Cc1ccccc1
Reaction time: 312 h

Procedure:
107 g of benzylamine in 200 ml of ethanol are cooled in an ice bath and 172.2 g of methyl acrylate in 250 ml of ethanol are slowly added. After 13 days at RT, the solvent is evaporated under vacuum and a part of the oily residue is then distilled.
Reaction SMILES: [Cl-].[Ce+3:2].[Cl-].[Cl-].[C:5](=[O:8])([OH:7])[O-:6].[Mg+2].[C:10](=[O:13])([OH:12])[O-:11].[Ce]>>[C:5](=[O:6])([O-:8])[O-:7].[Ce+3:2].[C:10](=[O:11])([O-:13])[O-:12].[C:5](=[O:6])([O-:8])[O-:7].[Ce+3:2]
Reactant: O=C([O-])O
Agent: [Ce+3]
Agent: [Ce]
Agent: [Cl-]
Product: O=C([O-])[O-]

Procedure:
Adding 3 m3 of cerium chloride solution (1.5 mol/L) into a reactor containing 14 m3 of magnesium bicarbonate solution (MgO: 29.2 g/L, Fe: 1.5 ppm, Al: 0.3 ppm) to react for 3 hours at 35° C., and controlling the pH value of mother liquor at 7.5, cerium ions are precipitated. And then cerium carbonate is obtained after filtration, washing and drying.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:11]C(=O)[O:9][C:8](=O)[C:7]=2[CH:14]=1.[OH-].[NH4+:16]>C(OCC)(=O)C>[NH2:11][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][C:7]=1[C:8]([NH2:16])=[O:9]
Reactant: COc1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1ccc(N)c(C(N)=O)c1
Yield: 53 %

Procedure:
6-methoxy-2H-3,1-benzoxazine-2,4(1H)-dione (3.0 g, 16 mmol, Trans World Chemicals) was treated directly with 27% aqueous ammonium hydroxide. After one hour the organic phase was diluted with ethyl acetate, washed twice with aqueous sodium bicarbonate and saturated aqueous sodium chloride, and dried over sodium sulfate. Filtration and removal of the residual solvent gave 2-amino-5-(methyloxy)benzamide as a white solid (1.42 g, 53% Yield);. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.63 (s, 3 H), 6.07 (s, 2 H), 6.60 (d, J=8.97 Hz, 1 H), 6.79 (dd, J=8.79, 2.93 Hz, 1 H), 7.03 (s, 1 H), 7.06 (d, J=2.93 Hz, 1 H), 7.71 (s, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:15][NH:16][O:17][CH3:18]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH3:10])[C:11]([N:16]([O:17][CH3:18])[CH3:15])=[O:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CNOC
Agent: Cl
Product: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Yield: 52.5 %

Procedure:
With 2.00 g of N-(tert-butoxy carbonyl)-L-alanine and 1.55 g of N,O-dimethyl hydroxylamine hydrochloride as starting materials, 1.29 g of the title compound (colorless solid) was obtained by a similar procedure to Step 10-1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:11]/[C:10](=[CH:26]\N(C(C)C)C(C)C)/[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[CH2:11][C:10](=[CH2:26])[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)N(/C=C1\C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O)C(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Crude (R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) (67.5 g) is dissolved in THF (340 ml) and cooled to 0° C. Hydrochloric acid (37%; 13.1 ml) is added followed by water (143.4 ml). Mixture is stirred at room temperature for 2 h. Phases are separated. To the organic phase is added formaldehyde solution (37% in water; 138 ml). Potassium carbonate (31.8 g) is added portionwise over 4 h. 1% Tetra-n-butylammoniumhydroxide solution (14.2 ml) is added followed by sodium hydroxide solution (30% in water) until pH 10.5. The mixture is stirred for 2 h. The phases are separated. The organic phase is washed with water (100 ml) and sodium bisulfite (20 g) added. Toluene (100 ml) and sodium chloride solution (20%; 50 ml). The phases are separated. The organic phase is extracted with a sodium chloride solution (20%; 50 ml), dried (Na2SO4) and concentrated in vacuo to give (R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (4-a, R1=Boc) (63 g). The material can be recrystallised as follows: crude (R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (4-a, R1=Boc) (58.4 g) is dissolved in methanol (525 ml) at 50° C. Water (175 ml) is added and the mixture is cooled to 0° C. The solid is collected by filtration and the cake washed with a mixture of methanol (53 ml) and water (18 ml). The solid is then dried in vacuo, giving (R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (4-a, R1=Boc). Spectroscopic data as Example 23.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([CH2:18][F:19])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[F:19][CH2:18][C:10]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: CCOC(=O)C1(CF)CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C1(CF)CCNC1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
A solution of ethyl 1-benzyl-3-(fluoromethyl)pyrrolidine-3-carboxylate (2.98 g, 11.2 mmol) and ammonium formate (3.54 g, 56.2 mmol) in ethanol (100 mL) was flushed with nitrogen for 15 minutes. 10% Pd/C (1.2 g, 1.12 mmol) was added and the mixture heated at reflux for 30 minutes. The reaction mixture was cooled to ambient temperature, filtered through a pad of Celite, washing with ethanol (50 mL). The filtrate was concentrated under reduced pressure to afford ethyl 3-(fluoromethyl)pyrrolidine-3-carboxylate (1.86 g, 95%).
Reaction SMILES: P(=O)(O)(O)O.[Cl-].[Na+].[O:8]=[CH:9][C@@H:10]([C@H:12]([C@@H:14]([C@@H:16](CO)[OH:17])[OH:15])[OH:13])[OH:11]>O>[O:8]=[CH:9][C@@H:10]([C@H:12]([C@@H:14]([CH2:16][OH:17])[OH:15])[OH:13])[OH:11]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Reaction time: 48 h
Yield: 120 %

Procedure:
To 1 ml of a buffer solution (pH 6.8) containing 20 mM phosphoric acid and 6.7 mM sodium chloride, 10 mg of glucose was dissolved, and then, 10 mg of xylose isomerase prepared by using Bacillus coagulans) was added and dissolved. The spores of Bacillus cereus (equivalent to 103 colony-forming unites) were inoculated to the solution and then allowed to react at30° C. for 2 days. After the reaction was completed, the reaction solution was heated in a boiled water to stop the enzyme reaction. The solution was left at 30° C. for 24 hrs. and then filtered through a 0.45 μm membrane filter. The quantities of fructose and glucose in the filtrate were measured by a high speed liquid chromatographic method (column: Showa denko K.K. product, #SC1011). Both fructose and glucose were not detected.
Reaction SMILES: [C:1]1([CH:7]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:21])[CH2:8][C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)([N:24]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1>[C:1]1([CH:7]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:21])[CH2:8][C:9]([NH2:24])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CC(c1ccccc1)N1Cc2ccccc2C1=O
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)CC(c1ccccc1)N1Cc2ccccc2C1=O
Reaction time: 1.5 h
Yield: 57.5 %

Procedure:
To a stirred solution of 3-phenyl-3-(1-oxoisoindolin-2-yl)propionic acid (0.703 g, 2.50 mmol) in 15 mL of tetrahydrofuran under nitrogen was added carbonyldimidazole (0.438 g, 2.70 mmol), and a few crystals of 4-N,N-dimethylaminopyridine [DMAP]. The reaction mixture was stirred for 1.5 hours and then 0.25 mL of 15 N ammonium hydroxide was added. After 20 minutes, the reaction mixture was concentrated in vacuo and the residue slurried in water. The resulting solid was isolated by filtration and dried in vacuo to afford 0.58 g (80%) of crude product as an off-white powder. The (crude product was recrystallized from ethanol to afford 0.403 g (57%) of 3-phenyl-3-(1-oxoisoindolin-2-yl)-propionamide as white prisms: 1H NMR (DMSO-d6, 250 MHz) 7.8-7.2 (m, 10H), 6.92 (br s, 1H), 5.81 (overlapping dd, 1H) 4.59 (d, J=17.5 Hz, 1H), 4.16 (d, J=17.5 Hz, 1H), 3.1-2.8 (m, 2H); 13C NMR (DMSO-d6) 171.3, 167.0, 140.7, 132.2, 131.4, 128.6, 127.9, 127.5, 126.9, 123.5, 122.8, 51.5, 46.3, 37.9; Anal. Calcd for C17H16N2O2 : Theory C, 72.84; H, 5.75; N, 9.99. Found: C, 72.46; H, 5.68; N, 9.91.
Reaction SMILES: Cl.C1C2C(COC(NCCOCCOCCN)=O)C3C(=CC=CC=3)C=2C=CC=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].Cl.C[O:49][C:50](=[O:57])[C@H:51]([CH2:53][C:54](=[O:56])[NH2:55])[NH2:52].Cl>CS(C)=O>[NH2:52][C@H:51]([C:50]([OH:57])=[O:49])[CH2:53][C:54](=[O:56])[NH2:55]
Reactant: COC(=O)[C@@H](N)CC(N)=O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: NCCOCCOCCNC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CS(C)=O
Product: NC(=O)C[C@H](N)C(=O)O
Reaction time: 6 h

Procedure:
1-(9-fluorenylmethyloxycarbonyl-amino)-3,6-dioxa-8-octanamine hydrochloride (Fmoc-EDOBEA, Iris Biotech GmbH) was added to an anhydrous DMSO solution (5 mg/mL) of HA-TBA synthesized using HA-Na (99 kDa) as a starting material in Example 1-2 in an amount of 0.1 molar equivalents relative to the HA unit. Next, DMT-MM was added in an amount of 0.2 molar equivalents relative to the HA unit, and stirring was performed at room temperature for 6 hours. Then, L-asparagine methyl ester hydrochloride and DMT-MM were added in this order in amounts of 5 and 3-6 molar equivalents, respectively, relative to the HA unit, and stirring was performed at room temperature overnight. The reaction solution was dialyzed for purification against DMSO. Piperidine (Wako Pure Chemical Industries, Ltd.) was added to the resulting dialyzate to g a concentration of 20%, and stirring was performed for 2 hours to remove the Fmoc group. Thereafter, the mixture was dialyzed for purification against DMSO, an aqueous solution of 0.3 M NaCl, and distilled water in this order. 5N NaOH solution was added to the resulting dialyzate to adjust the pH to at least 12.5, and stirring was performed for an hour to perform ester hydrolysis and carboxy deprotection. Thereafter, the mixture was neutralized with 5N HCl solution and further dialyzed for purification against distilled water and ultrapure water in this order, and then the dialyzate was freeze-dried to give HA-Asn/EDOBEA.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)=[CH:3][CH:2]=1.[C:18](OCC)(=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:22]([O:21][C:19](=[O:20])[C:18]([C:9]1[O:8][C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:2][CH:3]=2)=[CH:11][CH:10]=1)=[O:24])[CH3:23]
Reactant: CCOC(=O)C(=O)OCC
Reactant: c1ccc(-c2ccc(-c3ccco3)cc2)cc1
Product: CCOC(=O)C(=O)c1ccc(-c2ccc(-c3ccccc3)cc2)o1
Yield: 74 %

Procedure:
According to the procedure described in Example 13 for the preparation of 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(biphenyl-4-yl-1H-pyrrol-3′-yl)ethane-1,2-dione, 2-biphenyl-4-yl-furan was deprotonated and alkylated with diethyl oxalate to give in 74% yield 2-(2-biphenyl-4-yl-furan-5-yl)-2-oxoacetic acid ethyl ester as a yellow solid, mp 91-94° C. 1H NMR: δ 7.94 (d, 2H, J=8.5 Hz), 7.83 (d, 1H, J=4.1 Hz), 7.69 (d, 2H, J=8.1 Hz), 7.64 (d, 2H, J=7.7 Hz), 7.47 (t, 2H, J=7.4 Hz), 7.39 (t, 1H, J=7.2 Hz), 6.90 (d, 1H, J=4.2 Hz), 4.44 (q, 2H, J=7.0 Hz), 1.45 (t, 3H, J=7.2 Hz). Anal. Calculated for C20H16O4: C, 74.99; H, 5.03. Found: C, 75.1 1; H, 5.07.