Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([O-])=O.[CH:8]1([C:14]2[C:15]3[CH:16]=[CH:17][C:18]([C:36](O)=[O:37])=[CH:19][C:20]=3[N:21]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][C:24]4[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:23]=4[C:22]=23)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.CCN=C=NCCCN(C)C.Cl.[CH3:51][N:52]([CH3:57])[S:53]([NH2:56])(=[O:55])=[O:54]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:8]1([C:14]2[C:15]3[CH:16]=[CH:17][C:18]([C:36]([NH:56][S:53]([N:52]([CH3:57])[CH3:51])(=[O:55])=[O:54])=[O:37])=[CH:19][C:20]=3[N:21]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][C:24]4[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:23]=4[C:22]=23)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CN(C)S(N)(=O)=O
Reactant: COc1ccc2c(c1)CN(C)CCn1c-2c(C2CCCCC2)c2ccc(C(=O)O)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)CN(C)CCn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)C)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
1.5 eq of DMAP was added to the trifluoroacetate salt of 14-cyclohexyl-3-methoxy-6-methyl-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylic acid (from Example 4) in dry DCM (0.1 M). Then 1.5 eq of EDAC.HCl was added and after 5 min of stirring at RT 1.5 eq of N,N-dimethylsulfamide. The reaction mixture was stirred overnight at RT. The solvent was removed in vacuo and the residue directly purified by RP-MS-HPLC (stationary phase: column Waters XTERRA prep. C18, 5 um, 19×100 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound as a white powder (38%).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:8][NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[S:6][CH:7]=1.[CH3:19]OS(OC)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:19][N:9]([S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:11])=[O:12])[CH2:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][Br:1])[CH:4]=1
Reactant: O=S(=O)(NCc1cc(CBr)cs1)c1ccccc1
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(Cc1cc(CBr)cs1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.4 %

Procedure:
A mixture of 4-bromomethylphenylsulphonyl-2-thienylmethylamine (10.0 g, 28.9 mmol), dimethylsulphate (2.75 ml, 28.9 mmol) and potassium carbonate (19.96 g, 144 mmol) in acetone (100 ml) was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue taken up in ethyl acetate, washed with water and brine, dried, filtered and evaporated. Chromatography of the residue (1:2 ethyl acetate/hexane) gave N-methyl 4-bromomethylphenylsulphonyl-2-thienylmethylamine (1.60 g, 15%) as a colourless oil which was used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([CH2:6][NH:7][C:8](=[O:17])[C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])=[CH:4][C:3]=1[CH3:20].[O:21]=[C:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[CH:24][NH:23]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([Cl:15])[C:9]=1[C:8]([NH:7][CH2:6][C:5]1[CH:18]=[CH:19][C:2]([C:26]2[CH:25]=[CH:24][NH:23][C:22](=[O:21])[CH:27]=2)=[C:3]([CH3:20])[CH:4]=1)=[O:17]
Reactant: O=c1cc(B(O)O)cc[nH]1
Reactant: Cc1cc(CNC(=O)c2c(Cl)cccc2Cl)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(CNC(=O)c2c(Cl)cccc2Cl)ccc1-c1cc[nH]c(=O)c1
Temperature: 85 °C

Procedure:
N-(4-Bromo-3-methylbenzyl)-2,6-dichlorobenzamide (0.13 g, 0.35 mmol), 2-oxo-1,2-dihydropyridin-4-ylboronic acid (0.053 g, 0.39 mmol), cesium carbonate (0.34 g, 1.05 mmol), [1,1′ Bis(diphenylphosphino(ferrocene]dichloropalladium(II) (25 mg, 0.035 mmol) were dissolved in degassed DMF (3 mL) and H2O (1.5 mL). The reaction mixture was degassed again by bubbling nitrogen through for 15 min then heated in the microwave at 85° C. for 20 min. The reaction mixture was diluted with EtOAc and extracted three times with water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuum. The resulting solid was purified by reverse phase chromatography to afford 2,6-dichloro-N-(3-methyl-4-(2-oxo-1,2-dihydropyridin-4-yl)benzyl)benzamide.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:45]([O:52][CH2:53]Cl)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN(C=O)C.C1COCC1>[CH2:45]([O:52][CH2:53][CH:3]1[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:4]1=[O:34])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: ClCOCc1ccccc1
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)CN2C(=O)C(COCc3ccccc3)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.08 h
Yield: 39.7 %

Procedure:
To a stirring solution of 1.0 g (2.18 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Intermediate 4, in 10 mL of DMF at -5° C. is added 2.40 mL (2.40 mmol, 1.1 equiv) of a 1.0M solution of NaN(TMS)2 in THF. The resulting solution is stirred 5 min, and then 530 μL (3.05 mmol, 1.4 equiv) of chloromethyl benzyl ether (80%, tech.) is added neat. The resulting solution is stirred for 1 h at RT then quenched with 5 mL of H2O. The reaction mixture is poured into 100 mL of EtOAc and extracted with H2O (2×80 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel flash column chromatography using a gradient elution of hexane/EtOAc 4/1 to hexane/EtOAc 1/2 as eluent afforded 500 mg of the title compound as a white solid, along with 320 mg of recovered starting benzodiazepine: mp. 203°-204° C.; 1H NMR (CDCl3, 400 MHz) δ7.37-7.18 (m, 13H), 7.10 (m, 2H), 6.92 (m, 3H), 4.98 (m, 1H), 4.56 (dd, 2H, J=11.8, 22.7), 4.25 (m, 3H), 4.08 (dd, 1H, J=5.0, 9.8), 3.83 (s, 3H), 3.67 (dd, 1H, J=5.0, 7.5), 1.06 (2×d, 6H, J=6.2); low resolution MS (FAB)m/e 578 (MH+), 443, 413, 277, 223; Anal. (C35H35N3O5) Calcd. C, 72.77; H, 6.11; N, 7.27 Found C, 71.62; H, 6.06; N, 7.10.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:43])[C@:10]3([C@@H:14](C4C=CC=C(Cl)C=4F)[C@H:13]([C:23](=[O:33])[NH:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=4)[NH:12][C@H:11]3CC(C)(C)COC(=O)C)[C:5]2=[CH:4][CH:3]=1.[OH:44]O.[OH-].[Na+]>CS(C)=O>[C:31]([C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:23]([CH:13]2[NH:12][CH2:11][C:10]3([C:5]4[C:6](=[CH:7][CH:2]=[CH:3][CH:4]=4)[NH:8][C:9]3=[O:43])[CH2:14]2)=[O:33])=[CH:26][CH:27]=1)(=[O:44])[NH2:32]
Reactant: OO
Reactant: CC(=O)OCC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C#N)cc2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(NC(=O)C2CC3(CN2)C(=O)Nc2ccccc23)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 160.3 %

Procedure:
To the solution of acetic acid rac-3-[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-5′-(4-cyano-phenylcarbamoyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidin]-2′-yl]-2,2-dimethyl-propyl ester prepared in Example 104 (80 mg, 0.13 mmol) in DMSO (0.5 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.22 g, 1.9 mmol), then aqueous solution (1N) of NaOH (0.64 mL, 0.64 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 5 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (50 to 100% EtOAc in CH2Cl2) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′43-hydroxy-2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-phenyl)-amide as a white solid (Yield 73 mg, 95%)
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:19]3[O:18][CH2:17][CH2:16][NH:15][CH2:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:20](C(OC(C)(C)C)=O)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=O>C(Cl)Cl>[C:1]1([CH2:7][O:8][C:9]2[C:19]3[O:18][CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])[CH2:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: c1ccc(COc2cccc3c2OCCNC3)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2OCc2ccccc2)C1
Reaction time: 1 h

Procedure:
9-[(Phenylmethyl)oxy]-2,3,4,5-tetrahydro-1,4-benzoxazepine (Preparation 60) (7.01 g, 27.5 mmol) and BOC2O (7.01 ml, 30.2 mmol) were dissolved in DCM (100 ml) and left at room temperature for one hour then evaporated and biotage chromatographed in 5% EtOAc in hexane to remove excess BOC2O and changing to 15% EtOAc in iso-hexane to elute the title compound (8.25 g) as a white solid. MS (ES): C21H25NO4 requires 355; found 256 [M+H−100]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12]1([CH3:21])[C:13]([N:18]=[C:19]=[O:20])=[CH:14][CH:15]=[CH:16][CH:17]=1>>[C:12]1([CH3:21])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](=[O:20])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccccc1N=C=O
Reactant: Nc1ccc(CC(=O)O)cc1
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1

Procedure:
4-o-Tolylureidophenylacetic acid was prepared using procedure C with 4-amino-phenylacetic acid and o-tolyl isocyanate: 1H NMR (CD3SOCD3, 300 MHz, ppm) 8.97 (s, 1H), 7.88 (s, 1H), 7.83 (d, 1H), 7.38 (d, 2H), 7.17-7.09 (m, 4H), 6.92 (t, 1H), 3.48 (s, 2H), 2.23 (s, 3H); m/z 285.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][OH:17].Cl.C([O-])(=O)C.[Na+]>C(Cl)Cl.C(Cl)Cl.CC(C)=O.C(O)C.O>[C:1]1([S:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[N:16][OH:17])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=Cc1ccc(Sc2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: ON=Cc1ccc(Sc2ccccc2)cc1
Yield: 85.9 %

Procedure:
To 4.20 g (19.6 mmol) of 4-phenylsulfanyl-benzaldehyde, 1.50 g (21.6 mmol) of H2NOH—HCl and 2.71 g (33.1 mmol) of sodium acetate are added 6.5 mL of H2O and 19.5 mL of ethanol. This reaction mixture is heated to reflux for 2 h. After adding H2O to dissolve the precipitated inorganic salt, ethanol is removed by evaporation in vacuo. The crude product is extracted twice with CH2Cl2. The CH2Cl2 layer is dried over anhydrous MgSO4 and then condensed. The residue is applied to column chromatography on silica gel with CH2Cl2 and CH2Cl2-acetone (10:1) as eluent. 3.86 g of white solid are obtained as the first fraction (86%). This product is assigned to be (E) oxime by 1H-NMR spectrum (CDCl3). δ [ppm]: 7.25 (d, 2H), 7.32-7.35 (m, 3H), 7.42 (d, 2H), 7.47 (d, 2H), 7.77 (s, 1H), 8.09 (s, 1H); 0.29 g of white solid are obtained as the second fraction (6.6%). This product is assigned to be (Z) oxime by 1H-NMR spectrum (CDCl3). δ [ppm]: 7.25 (d, 2H), 7.32-7.38 (m, 4H), 7.45 (d, 2H), 7.84 (d, 2H). 9.55 (broad s, 1H)
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:39][O:40][Si](C(C)(C)C)(C)C)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:30]=[CH:31][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:37][CH:38]=2)(=[O:28])=[O:27])=[C:15]1[CH2:39][OH:40])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)CCc2c(CO[Si](C)(C)C(C)(C)C)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(S(=O)(=O)CCc2c(CO)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
Methyl 4-({2-[1-benzhydryl-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)benzoate (1 eq) was dissolved in THF (0.3M), followed by nBu4NF (1M in THF) (1.2 eq). The resulting mixture was stirred at rt for 3 hrs, then quenched with NH4Cl(aq). Extracted with EtOAc and washed with brine. Purified with prep plate and 1:3 EtOAc/Hexane as eluent to give methyl 4-({2-[1-benzhydryl-5-chloro-2-(hydroxymethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate (light brown gum) in 95% yield.
Reaction SMILES: C=C(OP(O)(O)=O)C(O)=O.[CH2:11]([OH:26])[C@H:12]1[O:17][CH:16]([O:18][P:19]([OH:22])([OH:21])=[O:20])[C@H:15]([OH:23])[C@@H:14]([OH:24])[C@@H:13]1[OH:25].P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.[CH:58]1[C:64](=[O:65])[NH:63][C:61](=[O:62])[N:60]([C@@H:66]2[O:70][C@H:69]([CH2:71][O:72][P:73](OP(O)(O)=O)([OH:75])=[O:74])[C@@H:68]([OH:81])[C@H:67]2[OH:82])[CH:59]=1.C1C(=O)NC(=O)N([C@@H]2O[C@H](COP(OP(OP(O)(O)=O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=1.C([O-])(=O)C(C)=O>>[CH:58]1[C:64](=[O:65])[NH:63][C:61](=[O:62])[N:60]([C@@H:66]2[O:70][C@H:69]([CH2:71][O:72][P:73]([O:20][P:19]([O:18][C@H:16]3[O:17][C@H:12]([CH2:11][OH:26])[C@@H:13]([OH:25])[C@H:14]([OH:24])[C@H:15]3[OH:23])([OH:22])=[O:21])([OH:75])=[O:74])[C@@H:68]([OH:81])[C@H:67]2[OH:82])[CH:59]=1
Reactant: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: O=P(O)(O)OC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: C=C(OP(=O)(O)O)C(=O)O
Agent: CC(=O)C(=O)[O-]
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Product: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@@H](O)[C@H]2O)c(=O)[nH]1

Procedure:
The multi-enzyme system (Scheme 15) started with 1-13C-Gal, [99 Atom Percent, purchased from Isotec Inc., Miamisburg, Ohio), GlcNAcβOallyl (Compound 40), (Lee et al., Carbohydr. Res., 37:193 (1974)] phosphoenolpyruvate (PEP), and catalytic amounts of Glc-1-P, ATP and UDP. UDP was converted into UTP with pyruvate kinase (PK; EC 2.7.1.40) and PEP, and UTP reacted with Glc-1-P catalyzed by UDPGP to produce UDP-Glc. The byproduct inorganic pyrophosphate (PPi) was decomposed by inorganic pyrophosphatase (PPase; EC 3.6.1.1). With Gal-1-P UT, UDP-Glc reacted with 13C-Gal-1-P, generated from 13C-Gal and ATP in the presence of GK, to give UDP-13C-Gal and Glc-1-P. The 13C-Gal of UDP-13C-Gal was transferred onto the acceptor (GlcNAcβOallyl) by GalT to give [Gal-1-13C]-containing LacNAcβOallyl (Compound 41). The produced UDP was again converted to UTP by a reaction of PK and PEP, which reacted with the released Glc-1-P to regenerate UDP-Glc. Using this multienzyme system, [Gal-1-13C]-LacNAcβOallyl was obtained in 54 percent yield. The same procedure was also used in the preparation of unlabelled LacNAc and analogs. Exemplary analogs 41a-c are illustrated in the scheme.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[C:10]([CH2:12][O:13]C2CCCCO2)[CH:9]=[CH:8][C:7]=1[C:20]1[N:24]=[C:23]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:22][N:21]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CO>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][C:7]=1[C:20]1[N:24]=[C:23]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[O:22][N:21]=1
Reactant: c1ccc(CCCCc2nc(-c3ccc(COC4CCCCO4)cc3-c3ccco3)no2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: OCc1ccc(-c2noc(CCCCc3ccccc3)n2)c(-c2ccco2)c1
Temperature: 55 °C
Yield: 75.4 %

Procedure:
To a solution of Intermediate 9 (1.02 g, 2.2 mmol) in methanol (20 mL) was added PPTS (56 mg). After heating to 55° C. for 24 h, the reaction mixture was cooled to RT and concentrated. Purification by MPLC (30% ethyl acetate in hexanes) gave 621 mg of Intermediate 16 as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C@H:9]2[CH2:17][N:12]3[CH2:13][CH2:14][NH:15][CH2:16][C@@H:11]3[CH2:10]2)=[N:6][CH:7]=1.C(N(CC)CC)C.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C@H:9]2[CH2:17][N:12]3[CH2:13][CH2:14][N:15]([CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[C:27]([C:26]([F:25])([F:35])[F:36])[CH:28]=4)[CH2:16][C@@H:11]3[CH2:10]2)=[N:6][CH:7]=1
Reactant: Clc1ccc(O[C@@H]2C[C@H]3CNCCN3C2)nc1
Reactant: FC(F)(F)c1cccc(CCl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: FC(F)(F)c1cccc(CN2CCN3C[C@H](Oc4ccc(Cl)cn4)C[C@H]3C2)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of Example 57 (76.2 mg, 0.3 mmol) and triethylamine (61 mg, 0.6 mmol) in dichloromethane (2 mL) was added 3-(trifluoromethyl)benzyl chloride (93 mg, 0.48 mmol). The mixture was stirred at 50° C. for 8 hours and then concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/methanol=10:1) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.80 (m, 3H), 2.16-2.26 (m, 3H), 2.38 (m, 1H), 2.70 (m, 1H), 2.86 (m, 2H), 3.60 (m, 3H), 5.24 (m, 1H), 6.83 (d, 1H, J=7 Hz), 7.60 (m, 4H), 7.80 (d, 1H, J=7 Hz), 8.18 (s, 1H), 8.40 (s, 1H); MS (ESI) m/z 412 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[N:15]=[C:14]([NH:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH3:18])[C:13]([NH2:26])=[CH:12][CH:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.Cl.[C:28](N)(=N)[CH3:29].C([O-])(O)=O.[Na+].CCOC(C)=O>CCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[N:15]=[C:14]4[N:16]([C@H:17]([C:19]5[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=5)[CH3:18])[C:28]([CH3:29])=[N:26][C:13]4=[CH:12][CH:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)ccc1N)c1ccc(F)cc1
Reactant: CC(=N)N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1nc2ccc(Nc3cc(C4CC4)[nH]n3)nc2n1[C@@H](C)c1ccc(F)cc1
Temperature: 25 °C
Yield: 43 %

Procedure:
A mixture of crude (S)—N6-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,3,6-triamine (Method 9; 0.120 g, 0.34 mmol) and acetamidine hydrochloride (0.052 g, 0.55 mmol) in EtOH (5 ml) was heated at reflux overnight. After cooling to 25° C., saturated NaHCO3 solution (10 ml) and EtOAc (30 ml) were added to the reaction mixture. The organic layer was separated, washed with brine (10 ml), dried over Na2SO4, concentrated, and purified by chromatography (EtOAc:MeOH=100:1) to give the title compound as an off-white solid (0.055 g, 43%). NMR (400 MHz, d6-Acetone) 11.14 (br s, 1H), 8.44 (br s, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.44 (m, 2H), 7.11 (m, 2H), 7.00 (br s, 1H), 6.00 (m, 2H), 2.12 (s, 3H), 2.11 (d, J=7.2 Hz, 3H), 0.89 (m, 2H), 0.65 (m, 2H). MS: Calcd.: 376. Found: [M+H]+ 377.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:22](=[CH:23][CH:24]=1)[C:10]1[NH:11][N:12]=[C:13]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[C:9]=1[CH2:8]2)[CH:2]=[CH2:3].[N-:25]=[N+:26]=[N-:27].[Na+].N(CC)(CC)CC.Cl>CN(C=O)C>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:22](=[CH:23][CH:24]=1)[C:10]1[NH:11][N:12]=[C:13]([C:14]3[CH:15]=[CH:16][C:17]([C:18]4[NH:27][N:26]=[N:25][N:19]=4)=[CH:20][CH:21]=3)[C:9]=1[CH2:8]2)[CH:2]=[CH2:3]
Reactant: [N-]=[N+]=[N-]
Reactant: C=CCOc1ccc2c(c1)Cc1c(-c3ccc(C#N)cc3)n[nH]c1-2
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCOc1ccc2c(c1)Cc1c(-c3ccc(-c4nnn[nH]4)cc3)n[nH]c1-2
Reaction time: 8 h
Yield: 28.6 %

Procedure:
A mixture of Example 62B (61.5 mg, 0.196 mmol), NaN3 (19.1 mg, 0.294 mmol), and Et3N.HCl (40.5 mg, 0.294 mmol) in DMF (2 mL) was heated at 140° C. for 4 hours. To this mixture were added more NaN3 (60.0 mg) and Et3N.HCl (120 mg). The reaction mixture was stirred overnight, cooled, and concentrated. The crude material was purified using the HPLC condition in Example 8 to give 20.0 mg (29%) of the desired product as brown solid. MS (DCI/NH3) m/z: 357.1 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 3.90 (s, 2H), 4.53-4.71 (m, 2H), 5.29 (dd, J=10.51, 1.70 Hz, 1H), 5.44 (dd, J=17.29, 2.03 Hz, 1H), 6.07 (m, 1H), 6.98 (dd, J=8.31, 2.20 Hz, 1H), 7.22 (d, J=2.03 Hz, 1H), 7.57 (d, J=8.14 Hz, 1H), 8.02 (d, J=8.14 Hz, 2H), 8.16 (d, J=8.48 Hz, 2H), 13.22 (s, brd, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7].Cl.Cl[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[C:11]([O:14][CH3:15])[C:12]([O:13][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: ClCCN1CCOCC1
Reactant: COC(=O)c1cc(OC)c(O)c(OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OC)c(OCCN2CCOCC2)c(OC)c1
Yield: 105.2 %

Procedure:
To a solution of methyl 3,5-dimethoxy-4-hydroxybenzoate (3.0 g, 14 mmol) in DMF (10 mL) was added 4-(2-chloroethyl)-morpholine hydrochloride (3.99 g, 21 mmol) and solid K2CO3 (8.4 g, 60 mmol). The mixture was heated at 60 C under N2 for 30 h. Diluted with EtOAc (100 mL) and washed with H20 (2×50 mL), back extracted the aqueous phase, and washed combined organics with brine. Dried over Na2SO4, filtered and evaporated to give the product as a brown solid (4.79 g, quantitative). 1H-NMR (CDCl3, 500 MHz 7.28 (s, 2H), 4.15 (t, 2H), 3.91 (s, 3H), 3.88 (s, 6H), 3.75-3.71 (m, 4H), 2.78 (t, 2H), 2.59 (br s, 4H) ppm; MS (FIA) 326.17 (M+H)
Reaction SMILES: C(O[C:4](=[O:26])[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[N:11]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]3[N:20]=[CH:21][S:22][C:18]=3[CH:17]=2)[C:12]1=[O:25])C.CO.[NH3:29]>C(Cl)(Cl)Cl>[S:22]1[C:18]2[CH:17]=[C:16]([N:13]3[CH2:14][CH2:15][N:11]([C:6]4[CH:7]=[N:8][CH:9]=[CH:10][C:5]=4[C:4]([NH2:29])=[O:26])[C:12]3=[O:25])[CH:24]=[CH:23][C:19]=2[N:20]=[CH:21]1
Reactant: CCOC(=O)c1ccncc1N1CCN(c2ccc3ncsc3c2)C1=O
Reactant: N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: NC(=O)c1ccncc1N1CCN(c2ccc3ncsc3c2)C1=O
Temperature: 40 °C
Yield: 28.57 %

Procedure:
3-(3-Benzothiazol-6-yl-2-oxo-imidazolidin-1-yl)-isonicotinic acid ethyl ester (I-185a: 0.16 g, 0.4 mmol) in methanolic ammonia (20 mL) was taken in a reaction flask and the flask was heated to 40° C. overnight. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was cooled to room temperature and concentrated. The concentrate was partitioned between DCM and water. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (10% MeOH in CHCl3) afforded 40 mg of the product (28.57% yield).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[F:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][NH2:24])[CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[F:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:11][C:5]3[C:4](=[C:9]([I:10])[CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:13])[CH:18]=[CH:19][CH:20]=1
Reactant: NCCCc1cccc(F)c1
Reactant: COC(=O)c1c(I)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=C1c2c(I)cccc2CN1CCCc1cccc(F)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 66.3 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.150 g, 0.42 mmol), 3-(3-fluoro-phenyl)-propylamine (0.091 mL, 0.6 mmol), and K2CO3 (0.138 g, 1 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-[3-(3-fluoro-phenyl)-propyl]-7-iodo-2,3-dihydro-isoindol-1-one (0.110 g, 69%). 1H NMR (300 MHz, CDCl3): δ ppm) 2.01 (m, 2H), 2.72 (t, 2H), 3.66 (t, 2H), 4.25 (s, 2H), 6.82-7.24 (m, 5H), 7.41 (d, 1H), 7.92 (d, 1H).