Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][CH:23]=1>ClCCl.N1C=CC=CC=1>[NH2:28][C:26]([C:25]1[CH:29]=[CH:30][C:22]([NH:21][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][CH:23]=2)=[O:13])=[CH:23][CH:24]=1)=[O:27]
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: NC(=O)c1ccc(N)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: NC(=O)c1ccc(NC(=O)c2ccccc2SSc2ccccc2C(=O)Nc2ccc(C(N)=O)cc2)cc1
Yield: 8.9 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (4.00 g, 11.7 mmol) in 100 mL of dichloromethane and 4-aminobenzamide (3.20 g, 23.5 mmol) in 26 mL of pyridine. The crude product was triturated with a hot mixture of acetonitrile and DMF, filtered, recrystallized from ethanol-water-DMF, triturated with a hot mixture of methanol and DMF, and filtered to yield 0.563 g of the title compound, mp >270° C.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[N:10]N[C:8]=2N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CC#N)C=CC=CC=1.C([O:24]C(OCC)OCC)C>>[O:24]=[CH:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:11]#[N:10]
Reactant: Nc1[nH]ncc1-c1ccccc1
Reactant: CCOC(OCC)OCC
Solvent: N#CCc1ccccc1
Product: N#CC(C=O)c1ccccc1

Procedure:
4-Aryl-3-aminopyrazoles such as 4-phenyl-2H-pyrazol-3-ylamine may be prepared according to the procedures described in patent EP269,859 and illustrated in scheme 8, by reacting benzeneacetonitrile with orthoformic acid triethyl ester to give 3-oxo-2-phenyl-propionitrile which is reacted with hydrazine.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[NH:7][CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:32])=[CH:17][N:16]=1.Cl.O1CCOCC1.O>>[Cl:32][C:18]1[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:20][C:15]([NH:1][C:2]2[CH:13]=[CH:12][C:5]3[C:6](=[O:11])[NH:7][CH2:8][CH2:9][O:10][C:4]=3[CH:3]=2)=[N:16][CH:17]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)OCCNC2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)OCCNC3=O)ncc1Cl
Temperature: 100 °C
Yield: 73.2 %

Procedure:
A mixture of 8-amino-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (0.092 g, 0.0003 mol), 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (0.05 g, 0.00028 mol), 4 N HCl in dioxane/water (0.07 mL, 0.00028 mol) was heated at 100° C. for 4 hrs. The slurry was evaporated and the residue treated with ethyl acetate and a 10% sodium carbonate solution. The insoluble solid was collected, washed, dried to give 2-[5-chloro-2-(5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-8-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (0.09 g, 74%) as a yellow solid. MP: 293-5° C.; 1H-NMR (DMSO-d6) δ 11.62 (s, 1H), 9.74 (s, 1H), 8.72-6 (d, 1H), 8.70 (d, 1H) 8.29 (s, 1H) 8.11 (s, 1H), 7.77 (m, 2H), 7.51-3 (d, 2H), 7.33-5 (d, 1H), 7.15-9 (t, 1H), 4.27 (s, 1H); LC/MS (ESI+): 439 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[C:3]([NH:5][C:6]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([N+:16]([O-])=O)[C:9]([N:19]2[CH2:23][CH2:22][CH2:21][C:20]2=O)=[CH:8][CH:7]=1)=[O:4]>C(O)(=O)C.[Fe]>[CH3:1][C:2]([CH3:26])([CH3:25])[C:3]([NH:5][C:6]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[N:16]=[C:20]3[CH2:21][CH2:22][CH2:23][N:19]3[C:9]2=[CH:8][CH:7]=1)=[O:4]
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)ccc(N2CCCC2=O)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1nc1n2CCC1
Temperature: 115 °C
Yield: 79.7 %

Procedure:
A mixture of methyl 6-(2,2-dimethylpropionylamino)-2-nitro-3-(2-oxopyrrolidin-1-yl)-benzoate (Intermediate 57, 0.89 g), and iron powder (1.37 g) in acetic acid (25 mL) was stirred and heated at 115° C. for 2.5 hours. After cooling, the mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate and 2M sodium hydroxide solution and filtered through celite. The organic phase was dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 50-100%. The product was repurified by chromatography on silica, eluting with a mixture of methanol and ethyl acetate with a gradient of 0-10% to give methyl 6-(2,2-dimethylpropionylamino)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-5-carboxylate (0.616 g) as an off-white solid.
Reaction SMILES: Br[C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13](B(O)O)[CH:12]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C([O-])([O-])=O.[Na+].[Na+]>CCCCO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:10][C:4]1[CH:3]=[C:2]([C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)[C:8]([CH3:9])=[CH:7][C:5]=1[NH2:6]
Reactant: OB(O)c1cccnc1
Reactant: Cc1cc(Br)c(C)cc1N
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCCCO
Product: Cc1cc(-c2cccnc2)c(C)cc1N
Reaction time: 8 h

Procedure:
A suspension of 4-bromo-2,5-dimethylaniline (4.00 g, 20 mmol), pyridin-3-ylboronic acid (2.70 g, 11 mmol), Pd2(dba)3 (0.55 g, 0.6 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.98 g, 1.2 mmol) and Na2CO3 (10.6 g, 100 mmol) in n-BuOH (50 mL) was degassed by a stream of argon gas for 15 min. The reaction flask was sealed and placed in a pre-heated oil bath (115° C.). After stirring overnight, the reaction was cooled and filtered. The filter cake was washed with DCM and the filtrate was concentrated in vacuo. The resulting residue was dissolved in EtOAc (150 mL). EtOAC was sequentially washed with water (20 mL), brine (20 mL), dried over Na2SO4 and evaporated. The crude product was purified by silica chromatography (0-50% EtOAC in hexanes gradient) to give 2,5-dimethyl-4-(pyridin-3-yl)aniline as a yellow solid; ESMS m/z 199.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)[CH:3]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23].O>ClCCl.CN(C1C=CN=CC=1)C>[C:21]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[C:9]1[N:10]=[CH:11][NH:12][CH:13]=1)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: Oc1ccc(Br)cc1-c1c[nH]cn1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)C(=O)Oc1ccc(Br)cc1-c1c[nH]cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.7 %

Procedure:
To a solution of 4-bromo-2-(1H-imidazol-4-yl)phenol (2.9 g, 12.13 mmol) in dichloromethane was added DMAP (296 mg, 2.43 mmol), triethylamine (5.1 mL, 36.4 mmol) and pivaloyl chloride (3.7 mL, 30.33 mmol). The reaction was stirred at room temperature for 16 h. The reaction mixture was poured into water (100 mL) and extracted with dichloromethane (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated. The crude product was dissolved in methanol (70 mL) and refluxed for 2 h. The solution was concentrated and the residue was purified by flash column chromatography (silica gel, 20%-70% EtOAc/hexanes as eluent) to afford the desired product as yellow solid (1.2 g, 3.72 mmol, 31%). 1H NMR: 1.35 (s, 9H), 6.90 (d, 1H, J=8.4 Hz), 7.31 (s, 1H), 7.38 (dd, 1H, J=8.4 Hz, 2.4 Hz), 7.67 (s, 1H), 8.00 (d, 1H, J=2.4 Hz).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH2:26]([O:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33])[CH3:27]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:32]([C:31]4[CH:35]=[CH:36][CH:37]=[C:29]([O:28][CH2:26][CH3:27])[CH:30]=4)=[O:33])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: CCOc1cccc(C(=O)Cl)c1
Agent: Cl
Product: CCOc1cccc(C(=O)N2CCC(N3N=C(c4ccc(OC)c(OC)c4)C(C)(C)C3=O)CC2)c1

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 3-ethoxybenzoyl chloride as starting compounds. The crude product is purified by column chromatography (silica gel and EA) and crystallization of the product containing fractions from EA and diethyl ether to yield the title compound.
Reaction SMILES: C([N:11]1[CH2:25][CH2:24][N:14]2[C:15]3[N:23]=[CH:22][CH:21]=[CH:20][C:16]=3[NH:17][C:18](=[O:19])[CH:13]2[CH2:12]1)(OCC1C=CC=CC=1)=O>[Pd].C(O)C>[N:23]1[C:15]2[N:14]3[CH2:24][CH2:25][NH:11][CH2:12][CH:13]3[C:18](=[O:19])[NH:17][C:16]=2[CH:20]=[CH:21][CH:22]=1
Reactant: O=C1Nc2cccnc2N2CCN(C(=O)OCc3ccccc3)CC12
Agent: [Pd]
Solvent: CCO
Product: O=C1Nc2cccnc2N2CCNCC12

Procedure:
A mixture of 1.5 g. of 8-carbobenzoxy-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one, 1 g. of 10% palladium on carbon, and 150 ml. of ethanol is hydrogenated at 45 psi for 2 hours. The catalyst is filtered and the filtrate is concentrated. The residue is dissolved in a small amount of ethanol and ethanolic hydrogen chloride is added. Filtration of the precipitated salt gives 0.72 g. of the title product, m.p. 270° dec. Recrystallization from ethanol-water gives 0.60 g., m.p. 278°-279°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:12][C:13](=[O:26])[N:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[C:39]([O:47][C:48]([F:51])([F:50])[F:49])[CH:38]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:43]([C:40]1[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][C:39]=1[O:47][C:48]([F:49])([F:50])[F:51])(=[O:45])=[O:44])[C:6](=[O:11])[C:5]2([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:12][C:13](=[O:26])[N:14]1[CH2:15][CH2:16][N:17]([C:20]2[N:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH2:18][CH2:19]1
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Reactant: COc1ccccc1C1(CC(=O)N2CCN(c3cccnn3)CC2)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccc(S(=O)(=O)N2C(=O)C(CC(=O)N3CCN(c4cccnn4)CC3)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 75.3 %

Procedure:
With 170 mg of the compound obtained in Step 49-1 and 114 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 196 mg of the title compound (colorless amorphous) was obtained by a similar method to Example 2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2].[C:40]1(B(O)O)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(COC)OC>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:25]=[C:26]([O:28][CH2:29][CH3:30])[CH:27]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(OCC)c2)c1CCC(=O)OCC
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC)cc(-c3ccccc3)c2)c1CCC(=O)OCC
Temperature: 120 °C
Yield: 84.3 %

Procedure:
To a mixture of 4-[3-[6-(3-bromo-5-ethoxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (305 mg, 0.5 mmol), phenylboronic acid (125 mg, 1.0 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (55 mg, 0.075 mmol), and cesium carbonate (331 mg, 1.0 mmol) in a microwave tube was added dimethoxyethane (5.9 mL) under nitrogen atmosphere at room temperature. The resulting brown reaction mixture was heated to 120° C. in a microwave for 30 minutes. The reaction mixture was diluted with ethyl acetate (50 mL) and the undissolved residue was filtered off and washed with water (50 mL). Then, the two layers of filtrate were separated and the aqueous layer was extracted with ethyl acetate (20 mL). The combined organic extracts were washed with water (50 mL) and brine solution (50 mL). The organic layer was dried over anhydrous magnesium sulfate and filtration of the drying agent and removal of the solvent under vacuum gave the colored residue which was purified by using an ISCO 40 column, eluting with 2-25% ethyl acetate in hexanes to obtain 4-[3-[6-(5-ethoxy-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (255 mg, 84%) as a colorless viscous oil: ES(+)-LRMS m/e calcd for C37H48O7 (M+Na)+ 627.3292. found 627.3292.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[N+:7]([C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1F)([O-:9])=[O:8]>C([O-])(O)=O.[Na+].C(O)C>[N+:7]([C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: NCCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
To a solution of beta-alanine (1.0 g, 11.1 mmole) in 50 ml of 1M NaHCO3 was added 2,4-dinitrofluorobenzene (10.4 g, 56 mmole) in 100 ml of ethanol. The reaction mixture was stirred at room temperature for 2 hours and evaporated to remove the volatile in vacuo. The residue was transferred to a separatory funnel with water and washed twice with ethyl ether. The aqueous layer was acidified with 1N HCl until precipitation was complete. The mixture was filtered and the wet cake washed with ether. This purification process, starting from dissolving the solid in 1M NaHCO3, washing the ether, and precipitating with 1N HCl, was repeated in the same manner to give yellow solid (1.6 g, 77%). e(MeOH)=7900 (260 nm), 15900 (350 nm). NMR spectral analysis was consistent with the structure.
Reaction SMILES: OS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[F:20][C:21]1[CH:22]=[C:23]([C:27]2([C:33]([CH:35]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:36]([O:38]CC)=O)=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]2[C:24]([C:36]([OH:38])=[C:35]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:33](=[O:34])[C:27]32[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:25][CH:26]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2cccc(F)c2)CCOCC1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1=C(O)c2ccc(F)cc2C2(CCOCC2)C1=O
Reaction time: 1 h
Yield: 22.1 %

Procedure:
H2SO4 (25 mL, 296 mmol) was cooled to 0° C. and treated with P2O5 (10 g, 70 mmol). The mixture was brought to room temperature and was then added to diethyl 2-(4-(3-fluorophenyl)-tetrahydro-2H-pyran-4-carbonyl)malonate (4.23 g, 12 mmol). The resulting reaction mixture was then stirred for 1 hour. Ice (H2O) was added, and the aqueous mixture was extracted with EtOAc (2×). The combined organic layers were washed with water (2×) and brine, dried (MgSO4), and concentrated in vacuo to give the crude compound as an orange oil. The crude oil was purified by silica flash chromatography (50-100% DCM/hexane) to give the desired compound as a white solid (850 mg). MS (m/e)=321.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3](COCC[Si](C)(C)C)[C:4]2[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:7][C:5]=2[N:6]=1.Cl.C(=O)([O-])O.[Na+].C(OCC)(=O)C>C(O)C>[CH3:1][C:2]1[NH:3][C:4]2[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:7][C:5]=2[N:6]=1
Reactant: CCOC(=O)c1cc2c(nc(C)n2COCC[Si](C)(C)C)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cc2[nH]c(C)nc2s1
Yield: 80.4 %

Procedure:
Ethyl 2-methyl-1-(2-(trimethylsilyl)ethoxymethyl)-1H-thieno[2,3-d]imidazol-5-carboxlate (745 mg) was dissolved in ethanol (10 ml) and 6N hydrochloric acid (10 ml) was added, which was followed by reflux under heating for 1 hr. A saturated aqueous sodium hydrogencarbonate solution was added under ice-cooling until the solution became weak alkaline, and the mixture was stirred with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the objective compound (370 mg) as white crystals.
Reaction SMILES: CN(C)C([S:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([N+:16]([O-:18])=[O:17])=[C:9]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O.[OH-].[Na+].CO.Cl>O1CCOCC1.O>[SH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([N+:16]([O-:18])=[O:17])=[C:9]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN(C)C(=O)Sc1ccc2ncc([N+](=O)[O-])c(-c3ccccc3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: O=[N+]([O-])c1cnc2ccc(S)cc2c1-c1ccccc1
Reaction time: 7 h

Procedure:
To a solution of 6-(N,N-dimethylcarbamoylthio)-3-nitro-4-phenylquinoline (2.50 g) in dioxane (100 ml) were added 2N-NaOH (50 ml) and methanol (20 ml), and the whole was stirred for 7 hrs. at room temperature. After diluted with water, the mixture was acidified with hydrochloric acid. The precipitating crystals were collected by filtration and recrystallized from acetone to give 6-mercapto-3-nitro-4-phenylquinoline as yellow needles. Yield 1.68 g (84.0%). m.p. 160°-163° C.
Reaction SMILES: BrC1C=CC(O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.[N:37]1(CCC(=O)C)[CH:41]=[CH:40][CH:39]=[N:38]1.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:12]=[C:11]3[C:10](=[CH:15][CH:14]=2)[N:9]=[C:8]([CH2:17][CH2:16][N:37]2[CH:41]=[CH:40][CH:39]=[N:38]2)[CH:6]=[CH:7]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)CCn1cccn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(CCn4cccn4)ccc3c1)n2C1CCCCC1
Yield: 50 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 4-pyrazol-1-yl-butan-2-one (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in Ethanol (506 μL, 0.64 mmol) to produce the title compound (14 mg, 50% yield). MS: 466.27 (M+H+); HPLC Procedure A, retention time=8.41 min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15](=[O:32])[N:16]([CH:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[O:30][CH3:31])[CH2:21]2)[CH2:17][CH2:18][CH3:19])[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O>[CH3:31][O:30][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[CH2:28][CH2:29][CH:20]([N:16]([CH2:17][CH2:18][CH3:19])[C:15](=[O:32])[CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH2:21]2
Reactant: CCCN(C(=O)CN1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2c(cccc2OC)C1
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C(=O)CN1CCNCC1)C1CCc2c(cccc2OC)C1
Yield: 93.9 %

Procedure:
This compound was prepared from 36b (6.6 g, 14.8 mmol), and TFA (40 ml) by following Procedure D to give 37b (4.8 g, 92%). 1H NMR (400 MHz, CDCl3) 0.92-0.964 (t, 3H, J=7.6 Hz), 1.63 (m, 3H), 1.84-1.97 (m, 3H), 2.55 (m, 1H), 2.80-2.87 (m, 5H), 2.97-3.34 (m, 9H), 3.82 (s, 3H), 6.64-6.71 (m, 2H), 7.06-7.15 (m, 1H).
Reaction SMILES: [OH:1][C:2]([C:4]1([O:15][C@@H:14]([C@@H:16]([C@@H:18]([CH2:20][OH:21])[OH:19])[OH:17])[C@H:9]([NH:10]C(C)=O)[C@@H:7]([OH:8])[CH2:6]1)[OH:5])=[O:3].[O:22]([C@@H:34]1[C@@H:40]([CH2:41][OH:42])[O:39][CH:37]([OH:38])[C@H:36]([NH:43][C:44]([CH3:46])=[O:45])[C@H:35]1[OH:47])[C@@H:23]1[O:31][C@H:30]([CH2:32]O)[C@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]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.[Mg+2].[Cl-].[Cl-].[Cl-].[K+].CC(N[C@H]1C([C@H](O)[C@H](O)CO)O[C@](OP(OC[C@H]2O[C@@H](N3C(=O)N=C(N)C=C3)[C@H](O)[C@@H]2O)([O-])=O)(C(O)=O)C[C@@H]1O)=O.[Na+].C1N(CCO)CCN(CCS(O)(=O)=O)C1.C=CC(N)=O>O>[OH:1][C:2]([C@@:4]1([O:15][C@@H:14]([C@@H:16]([C@@H:18]([CH2:20][OH:21])[OH:19])[OH:17])[C@H:9]([NH2:10])[C@@H:7]([OH:8])[CH2:6]1)[O:5][CH2:32][C@H:30]1[O:31][C@@H:23]([O:22][C@@H:34]2[C@@H:40]([CH2:41][OH:42])[O:39][CH:37]([OH:38])[C@H:36]([NH:43][C:44]([CH3:46])=[O:45])[C@H:35]2[OH:47])[C@H:24]([OH:25])[C@@H:26]([OH:27])[C@H:28]1[OH:29])=[O:3]
Reactant: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(O)(C(=O)O)C[C@@H]1O
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@@H]1O
Agent: C=CC(N)=O
Agent: CC(=O)N[C@H]1C([C@H](O)[C@H](O)CO)O[C@](OP(=O)([O-])OC[C@H]2O[C@@H](n3ccc(N)nc3=O)[C@H](O)[C@@H]2O)(C(=O)O)C[C@@H]1O
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Solvent: O
Product: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO[C@]3(C(=O)O)C[C@H](O)[C@@H](N)[C@H]([C@H](O)[C@H](O)CO)O3)[C@H](O)[C@H](O)[C@H]2O)[C@@H]1O
Temperature: 25 °C
Yield: 97 %

Procedure:
NeuAc (0.92 g, 3 mmol), Galβ1,4GlcNAc (1.1 g, 3 mmol), CMP (0.1 g, 30 μmol), ATP (16 mg, 3 μmol), PEP (2.8 g, 6 mmol), MgCl2. 6H2O (0.61 g, 3 mmol), MnCl2.4H2O (0.15 g, 0.8 mmol), KCl (0.22 g, 3 mmol), NMK or MK (450 U), PK (6,000 U), PPase (300 U), CMP-NeuAc synthetase (24 U) , and Siaα2,6Gal sialyl transferase (4 U) were mixed with 150 ml of HEPES buffer (0.2M, pH 7.5) to form a reaction mixture and the reaction mixture maintained under argon at about 25° C. for about 48 hours. After the disappearance of NeuAc (determined by thin-layer chromatography) the reaction mixture was reduced in volume to 20 ml by lyophilization and the lyophilized reaction mixture applied to a Bio Gel P2 (200-400 mesh) column with water as the mobile phase. The trisaccharide-containing fractions were eluted, collected and lyophilized to give pure Neuα2,6Galβ1,4GlcNAc in 97 percent yield.
Reaction SMILES: [CH:1]1([O:6][CH2:7][CH2:8][OH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.O>ClCCl>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:9][CH2:8][CH2:7][O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: OCCOC1CCCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(OCCOC1CCCC1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 572.7 %

Procedure:
To a solution of 2-(cyclopentyloxy)-1-ethanol (prepared as described in J. Org. Chem., 1968, 33, 2271-2284: 127 mg, 0.97 mmol) and triethylamine (101 mg, 0.1 mmol) in dichloromethane (3 mL) at 0° C. was added 4-bromobenzenesulfonyl chloride (255 mg, 0.1 mmol) in dichloromethane (2 mL) dropwise over 5 minutes. The reaction was then warmed to room temperature and stirred for 16 hours. The mixture was then poured into water (3 mL) and the two layers were separated. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a crude residue. This was purified by column chromatography on silica gel (50 g), eluting with a gradient of dichloromethane:hexane (50:50 to 0:100), to give the title compound (200 mg, 59%) as a colourless oil.