Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([OH:13])[C@H:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])(=O)=O>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([O:13][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C@H:10]([O:14][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOS(C)(=O)=O
Reactant: O[C@@H]1CN(Cc2ccccc2)C[C@@H]1O
Product: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CN(Cc2ccccc2)C[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC

Procedure:
Compound VI-3 (398 mg, 40.7%) was obtained in the same manner as that in Reference Example 1, by using (3R,4S)-1-benzylpyrrolidine-3,4-diol (Diverchim S. A.; 274 mg, 1.42 mmol) and (9Z,12Z)-octadec-9,12-dienyl methanesulfonate (Nu-Chek Prep, Inc; 1.22 g, 3.54 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH:19]=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:29][CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].O>CN(C)C=O>[Si:32]([O:31][CH2:30][CH2:29][N:20]1[C:21]2[C:17](=[CH:16][C:15]([C:13]([N:10]3[CH2:11][CH2:12][CH:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:25][CH:24]=4)[CH2:8][CH2:9]3)=[O:14])=[CH:23][CH:22]=2)[CH:18]=[CH:19]1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=C(c1ccc2[nH]ccc2c1)N1CCC(Oc2ccc(Cl)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCn1ccc2cc(C(=O)N3CCC(Oc4ccc(Cl)cc4)CC3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a stirred solution of (4-(4-chlorophenoxy)piperidin-1-yl)(1H-indol-5-yl)methanone (30 mg, 0.085 mmol, Step-1 of Example 353) and sodium hydride (60% in oil, 4 mg, 0.17 mmol) in N,N-dimethylformamide (1.5 mL) was added (2-bromoethoxy)(tert-butyl)dimethylsilane (24 mg, 0.10 mmol) at room temperature. After stirring at room temperature for 2 hours, the mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with water (20 mL), and dried over sodium sulfate. After removal of the solvent, the residue was purified by silica-gel column chromatography (NH-gel, eluting with ethyl acetate) to give 43 mg (>99% yield) of (1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indol-5-yl)(4-(4-chlorophenoxy)piperidin-1-yl)methanone as orange oil. This material was treated with 2M aqueous hydrochloric acid solution (0.4 mL) and tetrahydrofuran (1.5 mL) at room temperature for 1 hour. The mixture was neutralized by saturated sodium hydrogen carbonate aqueous solution and extracted with ethyl acetate (3 mL). The organic layer was dried over sodium sulfate. After removal of the solvent, the residue was purified by silica-gel column chromatography (NH-gel, eluting with ethyl acetate) and then preparative LC-MS to give 7.1 mg (18% yield) of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH2:12]([Mg]Cl)[C:13]([CH3:16])([CH3:15])[CH3:14]>C1COCC1.CCCCCC>[CH3:12][C:13]([CH3:16])([CH3:15])/[CH:14]=[CH:8]/[C:7]1[CH:10]=[CH:11][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)C[Mg]Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)/C=C/c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled (0° C.) and well stirred suspension of 4-carboxy benzaldehyde (2.0 g, 13.32 mmol) in anhydrous THF (90 mL) is added 33.3 mmol of neopentyl magnesium chloride in hexane during 20 minutes and the mixture is stirred at the same temperature for an additional two hours before being quenched with satyrated ammonium chloride solution. Most of the THF is evaporated and the aqueous mixture is treated with conc. HCl (50 mL) and the mixture is heated to reflux for 2 hours. The mixture is then cooled to ambient temperature and extracted with methylene chloride (2×100 mL), the organic layer is dried over sodium sulfate and concentrated to obtain the desired 4-(3,3-dimethyl-but-1-enyl)-benzoic acid.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[O:19][CH2:20][CH3:21])[CH2:10]1)=O)(C)(C)C>C(O)C>[CH2:20]([O:19][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[CH2:17][CH2:18][NH:9][CH2:10]2)[CH3:21]
Reactant: CCOc1cccc2c1CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCO
Product: CCOc1cccc2c1CCNC2
Reaction time: 3 h

Procedure:
Excess of 3 mol L-1 hydrochloric acid in ethanol was added to a solution of 2-t-butoxycarbonyl-5-ethoxy-1,2,3,4-tetrahydroisoquinoline (Example 8) (1.55 g, 5.6 mmol) in ethanol. After 3 hours, the solution was evaporated to dryness, and the hydrochloride salt of 5-ethoxy-1,2,3,4-tetrahydroisoquinoline was dissolved in water. The solution was made strongly alkaline with sodium hydroxide, and the product was extracted in dichloromethane, dried over Na2SO4, and evaporated. The product was purified by recrystallization from absolute ethanol. Yield 0.69 g, 71%. 1H NMR (DMSO-d6, 500 MHz): 7.02 (1H, t, 7.8 Hz). 6.70 (1H, d, 8.0 Hz), 6.57 (1H, d, 7.2 Hz), 3.98 (2H, q, 6.9 Hz), 3.77 (2H, s), 3.24 (2H, s), 2.91 (2H, s), 1.31 (3H, t, 6.9 Hz); 13C NMR (DMSO-d6, 120 MHz): 156.1, 137.5, 125.7, 123.5, 118.1, 108.2, 62.9, 47.7, 43.0, 23.1, 14.7; MS(EI+): 177 (95%, M+), 148 (100%), 132 (25%), 120 (43%), 104 (56%), 91 (33%).
Reaction SMILES: [P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:28]=[C:26]([CH3:27])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[O:29][NH:30]C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)([O:4][P:5]([O:8][P:9]([OH:12])([OH:11])=[O:10])([OH:7])=[O:6])(=[O:3])[OH:2]>N1CCCCC1.CN(C=O)C>[P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:28]=[C:26]([CH3:27])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[O:29][NH2:30])([O:4][P:5]([O:8][P:9]([OH:11])([OH:12])=[O:10])([OH:7])=[O:6])(=[O:2])[OH:3]
Reactant: Cc1cn([C@H]2C[C@H](ONC(=O)OCC3c4ccccc4-c4ccccc43)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]c1=O
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: Cc1cn([C@H]2C[C@H](ON)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3′-O-(Fmoc)amino-thymidine-5′-triphosphate is dissolved in 20% piperidine in DMF (0.5 mL). The mixture is stirred at room temperature for 30 minutes and then concentrated in vacuo. The residue is redissolved in triethylammonium acetate buffer (aqueous, 10 mM; pH 7; 2 mL) and purified by rp-HPLC (C18, gradient 0-21% acetonitrile in 10 mM triethylammonium acetate over 27 minutes) to give 3′-O-amino-thymidine-5′-triphosphate as a colorless foam. The purity of the product is confirmed by analytical ion-exchange chromatography (DEAE, gradient 0-1 M triethylammonium bicarbonate in water over 30 minutes). 1H-NMR (D2O; 300 MHz): δ (ppm)=1.80 (s, 3H); 2.18 (m, 1H); 2.34-2.39 (m, 1H); 4.03-4.09 (m, 2H); 4.25 (m, 1H); 4.45 (m, 1H); 6.17 (dd, J=6.0, 9.1 Hz, 1H); 7.66 (s, 1H). 31P-NMR (D2O; 162 MHz): δ (ppm; H3PO4=0)=−14.1 (br s, IP); −16.3 (br s, IP); −27.7 (br s, 1P). MS-ESI−: [M-H]− calcd. for C10H17O14N3P3, 496.0; found, 496.4.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[N:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1>CO>[N:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:2]3[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=3)[CH2:21][CH2:22]2)=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CO
Product: O=C(O)c1ccc(N2CCN(c3ccncc3)CC2)nc1
Temperature: 220 °C
Reaction time: 0.17 h
Yield: 43.4 %

Procedure:
A mixture of 6-chloronicotinic acid (3.21 g) and 1-(4-pyridyl) piperazine (3.32 g) was heated to 220° C. for 3 minutes. The mixture was cooled and methanol (10 ml)was added. The resulting suspension was boiled for 10 minutes, cooled and filtered to give 6-[4-(4-pyridyl)piperazin-1-yl] nicotinic acid (2.51 g) which was used without further purification.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]2[N:11]3[C:12](=[O:24])[NH:13][C:14]3[C:15]2=[N:21][NH:22][CH:23]=3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1.[Cl-].[Na+]>CN1CCCC1=O>[CH:25]1([NH:28][C:12]([NH:13][C:14]2[C:15]([C:16]3[NH:17][C:18]4[CH:19]=[CH:20][C:8]([CH2:7][N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[CH:9][C:10]=4[N:11]=3)=[N:21][NH:22][CH:23]=2)=[O:24])[CH2:27][CH2:26]1
Reactant: O=c1[nH]c2c[nH]nc2c2nc3ccc(CN4CCOCC4)cc3n12
Reactant: NC1CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)NC1CC1
Temperature: 100 °C

Procedure:
7-Morpholin-4-ylmethyl-2,4-dihydro-1,2,4,5a,10-pentaaza-cyclopenta[a]fluoren-5-one (1.0 wt, prepared as outlined above in Example 66A) and 1-methyl-2-pyrrolidinone (3.0 vol) are charged to a suitably sized flange flask equipped with a mechanical stirrer, condenser and thermometer. Cyclopropylamine (0.351 wt) is added at 15 to 30° C. under nitrogen. The contents are then heated to 95 to 105° C. and stirred at this temperature until the reaction is judged complete by 1H NMR analysis. Once complete, the reaction mixture is cooled to 16 to 25° C. and added slowly (approximately 2 to 3 hours) to stirred ca. 13% w/w sodium chloride solution (11.5 vol) whilst maintaining the mixture at 16 to 25° C. A precipitate is formed. The transfer of the reaction mixture is completed with a 1-methyl-2-pyrrolidinone (0.5 vol) rinse at 16 to 25° C. The precipitated solid is collected by filtration, washed with water (0.5 vol) and pulled dry on the filter until deemed suitable for handling. The solid is suspended in ethyl acetate (5.0 vol) and water (6.0 vol) and stirred at 16 to 25° C. for 60 to 70 minutes. The solid is collected by filtration, sequentially washed with ethyl acetate (1.0 vol) and mixed heptanes (2×2.0 vol) and dried on the filter until deemed suitable for handling. The solid is suspended in ethyl acetate (4.0 vol) and stirred at 15 to 25° C. for at least 60 minutes. The solid is collected by filtration, washed with ethyl acetate (1.0 vol) and pulled dry on the filter to yield crude 1-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea (60 to 80% w/w) as a dark brown/red solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([NH2:13])=[CH:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:16]=[CH:17][C:18](F)=[C:19]([CH:22]=1)[C:20]#[N:21].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH2:1]([N:8]1[C:12]([NH:13][C:18]2[CH:17]=[CH:16][C:15]([Cl:14])=[CH:22][C:19]=2[C:20]#[N:21])=[CH:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc(Cl)ccc1F
Reactant: Nc1cnnn1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1cc(Cl)ccc1Nc1cnnn1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 59.6 %

Procedure:
1-Benzyl-1H-1,2,3-triazol-5-amine 5a (1.00 g, 5.74 mmol) and 5-chloro-2-fluoro-benzonitrile (892.9 mg, 5.74 mmol) were combined in THF (6 mL) and cooled to −78° C. LiHMDS (6.31 mL of 1 M, 6.31 mmol) was added dropwise and the reaction stirred for 5 min and then allowed to warm to room temperature and subsequently heated at 60° C. for 1 h. The mixture was quenched water and then evaporated and the residue partitioned between EtOAc and 1M HCl, the organic layer separated and concentrated. Trituration of the residue in EtOAc and hexanes afforded 2-[(3-benzyltriazol-4-yl)amino]-5-chloro-benzonitrile as a brown solid (1.06 g, 60%). MS m/z: 310.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])[N:7]([C:16](=[O:18])[CH3:17])[CH2:6][C:5]2([CH3:20])[CH3:19].[NH4+].[Cl-]>C1COCC1.[Zn]>[CH2:14]([S:11]([C:10]1[CH:9]=[C:8]2[C:4]([C:5]([CH3:19])([CH3:20])[CH2:6][N:7]2[C:16](=[O:18])[CH3:17])=[CH:3][CH:2]=1)(=[O:12])=[O:13])[CH3:15]
Reactant: CCS(=O)(=O)c1cc2c(cc1Br)C(C)(C)CN2C(C)=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc2c(c1)N(C(C)=O)CC2(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.4 %

Procedure:
To a solution of 1-(5-bromo-6-ethanesulfonyl-3,3-dimethyl-2,3-dihydro-indol-1-yl)-ethanone (180 mg, 0.5 mmol) in THF (5 mL) containing saturated aqueous NH4Cl (1 mL), zinc dust (325 mg, 5 mmol) was added. The suspension was stirred at room temperature for 3 days and then partitioned between water and EtOAc. The aqueous phase was extracted twice with EtOAc. The organic extracts were filtered through a plug of Celite and the filtrate was evaporated in vacuo to give the title compound (130 mg) as a colourless gum which was used in the next step without further purification. MS: [M+H]+=282.
Reaction SMILES: [Na+].[CH:2]1([CH2:8][S:9]([O-:12])(=O)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.O=P(Cl)(Cl)[Cl:15]>>[CH:2]1([CH2:8][S:9]([Cl:15])(=[O:12])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=S(=O)([O-])CC1CCCCC1
Agent: [Na+]
Product: O=S(=O)(Cl)CC1CCCCC1
Temperature: 100 °C

Procedure:
To the compound of Example 12 (4.0 g, 20 mmole) was added POCl3 (15 mL) and the mixture heated at 100° C. for 48 hours. Upon cooling to room temperature the mixture was poured onto crushed ice and then the aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic extracts were then washed with saturated aqueous sodium bicarbonate (2×50 mL), brine and then dried over MgSO4, filtered and the solvent was evaporated under vacuum to provide 3.46 g of the title compound as a light yellow oil. Thin layer chromatography analysis of the title compound showed a single spot with Rf =0.53 (silica, 4:1 hexanes/ethyl acetate).
Reaction SMILES: Br[C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)CB([C:17]2[CH2:18][CH2:19][O:20][CH2:21][CH:22]=2)C1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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]>[Cl:8][C:3]1[C:2]([C:17]2[CH2:22][CH2:21][O:20][CH2:19][CH:18]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CC1(C)CB(C2=CCOCC2)CC1(C)C
Reactant: Clc1ncccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Clc1ncccc1C1=CCOCC1
Temperature: 110 °C
Reaction time: 8 h
Yield: 131.5 %

Procedure:
To a solution of 3-bromo-2-chloropyridine (4 g, 10.8 mmol), 4-(3,3,4,4-tetramethyl-borolan-1-yl)-3,6-dihydro-2H-pyran (5.7 g, 13.1 mmol) and Na2CO3 (2.28 g, 21.6 mmol) in 1,4-dioxane (60 mL) and H2O (6 mL) was added Pd(dppf)Cl2 (410 mg, 0.56 mmol). The reaction mixture was stirred at 110° C. under N2 for overnight. The reaction mixture was filtered through CELITE® and washed CH2Cl2. The organic layers were concentrated to give the crude product which was purified by silica gel column chromatography to give the title compound (3.5 g, 14.2 mmol, 70% yield).
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)C.[Cl:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][CH2:23][C:24]2[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:22][CH2:23][C:24]2[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:4]3[C:5](=[O:16])[C:6](=[O:15])[C:7]=3[NH:8][C:9]3[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=3)=[CH:26][CH:25]=2)=[CH:32][CH:33]=1
Reactant: CCOc1c(Nc2ccncc2)c(=O)c1=O
Reactant: NCc1ccc(COc2ccc(Cl)cc2)cc1
Product: O=c1c(NCc2ccc(COc3ccc(Cl)cc3)cc2)c(Nc2ccncc2)c1=O
Yield: 71 %

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridine-4-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 7A and 4-(4-chlorophenoxy-methyl)-benzylamine.
Reaction SMILES: [CH3:1][C@H:2]1[O:8][C@H:7]([O:9][P:10]([O:13][P:14]([O:17][CH2:18][C@H:19]2[O:23][C@@H:22]([N:24]3[C:28]4[NH:29][C:30]([NH2:34])=[N:31][C:32](=[O:33])[C:27]=4[N:26]=[CH:25]3)[C@H:21]([OH:35])[C@@H:20]2[OH:36])([OH:16])=[O:15])([OH:12])=[O:11])[C@@H:6]([OH:37])[C@@H:5]([OH:38])[C:3]1=[O:4].C1N([C@@H]2O[C@H](COP(OP(O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C2NC(N)=NC(=O)C=2N=1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[Mg+2].[Cl-].[Cl-].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>O>[CH3:1][CH:2]1[O:8][CH:7]([O:9][P:10]([O:13][P:14]([O:17][CH2:18][CH:19]2[O:23][CH:22]([N:24]3[C:28]4[NH:29][C:30]([NH2:34])=[N:31][C:32](=[O:33])[C:27]=4[N:26]=[CH:25]3)[CH:21]([OH:35])[CH:20]2[OH:36])([OH:16])=[O:15])([OH:12])=[O:11])[CH:6]([OH:37])[CH:5]([OH:38])[CH:3]1[OH:4]
Reactant: C[C@H]1O[C@H](OP(=O)(O)OP(=O)(O)OC[C@H]2O[C@@H](n3cnc4c(=O)nc(N)[nH]c43)[C@H](O)[C@@H]2O)[C@@H](O)[C@@H](O)C1=O
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: Nc1nc(=O)c2ncn([C@@H]3O[C@H](COP(=O)(O)OP(=O)(O)O[C@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]4O)[C@@H](O)[C@H]3O)c2[nH]1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Product: CC1OC(OP(=O)(O)OP(=O)(O)OCC2OC(n3cnc4c(=O)nc(N)[nH]c43)C(O)C2O)C(O)C(O)C1O

Procedure:
A coupled assay was employed to assay YEF B activity. This was required since its substrate, GDP-4-keto-6-deoxymannose, is unstable and not commercially available. Twenty mUnit of GDP-mannose dehydratase was allowed to react with 480 nMole of GDP-mannose for 20 minutes under standard assay conditions as previously. At this time greater than 90% of the GDP-mannose has been converted to GDP-4-keto-6-deoxymannose, the substrate for YEF B. The following additions were then made: 500 nmole glucose, MgCl2 to 20 mM, NADPH to 0.15 mM, 10 mUnit glucose dehydrogenase, 100 nmole CTP (to normalize for losses that may occur when sample is injected onto HPLC), YEF B and water to 50 μl. The reaction was allowed to proceed for ten minutes at which point the reaction was stopped by freezing on dry ice. After thawing 10 μl aliquots were analyzed by reverse phase HPLC analysis. The amount of GDP fucose formed was calculated by analyzing a separate assay mix in the absence of GDP-mannose dehydratase to yield a 100% value for the absorption peak of GDP-mannose. This peak area was then divided by the peak area of GDP-fucose formed to yield percentage of GDP-fucose formed. (% GDP-fucose)(nMole GDP-mannose in reaction)=nMole GDP-fucose formed.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C@@H:15]1[CH2:20][C@@H:19]([N:21]([CH2:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=[CH:31][CH:30]=2)C(=O)C(F)(F)F)[CH2:18][CH2:17][N:16]1[C:39](=[O:56])[C@H:40]([CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[NH:41]C(OC(C)(C)C)=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([C@@H:15]1[CH2:20][C@@H:19]([NH:21][CH2:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=[CH:31][CH:30]=2)[CH2:18][CH2:17][N:16]1[C:39](=[O:56])[C@H:40]([CH2:49][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[NH2:41])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccccc1)C(=O)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.1 ml (4.09 mmol) of trifluoroacetic acid are added to 920 mg (1.36 mmol) of (2R*,4S*)-2-benzyl-1-((S)-N-tert.-butyloxycarbonyl-phenylalanyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine, and the reaction mixture is stirred at room temperature for 2 hours. It is then concentrated in a rotary evaporator, the residue is taken up in water, basified with 1N sodium bicarbonate solution at 0° C. and extracted with methylene chloride. The organic phases are washed with brine, dried over magnesium sulfate and evaporated to dryness. The residue is chromatographed on silica gel with methylene chloride/methanol/conc. ammonia (2500:50:1) to separate the diastereomers. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH:8]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:6].C([O-])([O-])=O.[K+].[K+].C(O)(=O)C.[CH3:39][NH:40][CH3:41]>C1COCC1.O>[CH3:39][N:40]([CH3:41])[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH:8]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:6]
Reactant: O=C(O)CCCCCCCC(CCCCCCCC(=O)O)OC(=O)CCCBr
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCCC(=O)OC(CCCCCCCC(=O)O)CCCCCCCC(=O)O
Temperature: 50 °C

Procedure:
The Bromoacid 251 (2 mmol) is dissolved in 2M solution of dimethylamine in THF (20 mL) and to it 1 g of anhydrous K2CO3 was added and the mixture was heated in a pressure bottle at 50° C. overnight. The TLC showed the completion of the reaction. The reaction mixture was acidified with acetic acid and diluted with water (100 mL) and extracted with dichloromethane (2×60 mL). The combined organic layers were concentrated dried and used as such in the next reaction. MW calcd for C23H43NO6 429.59. Found 430.6 (MH)+. 1H NMR (400 MHz, DMSO) δ 11.87-11.82 (m, 7H), 5.75 (d, J=0.7 Hz, 15H), 4.85-4.69 (m, 38H), 3.64-3.55 (m, 12H), 3.35-2.83 (m, 106H), 3.01-2.90 (m, 59H), 2.94 (ddd, J=30.6, 7.7, 4.0 Hz, 63H), 2.90-2.73 (m, 9H), 2.70 (s, 221H), 2.57-2.46 (m, 91H), 2.44-2.30 (m, 76H), 2.17 (t, J=7.3 Hz, 147H), 1.89 (tq, J=15.5, 7.6 Hz, 88H), 1.79-1.69 (m, 13H), 1.65-1.32 (m, 311H), 1.28 (d, J=46.0 Hz, 598H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([CH:15](C#N)[C:16]2[CH:17]=[C:18]([CH:21]=[C:22]([CH3:24])[CH:23]=2)[C:19]#[N:20])[C:12]([CH2:27][CH3:28])=[C:11]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CN(C=[O:43])C>>[CH2:1]([O:8][C:9]1[N:14]=[C:13]([C:15]([C:16]2[CH:17]=[C:18]([CH:21]=[C:22]([CH3:24])[CH:23]=2)[C:19]#[N:20])=[O:43])[C:12]([CH2:27][CH3:28])=[C:11]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1c(OCc2ccccc2)nc(OCc2ccccc2)nc1C(C#N)c1cc(C)cc(C#N)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCc1c(OCc2ccccc2)nc(OCc2ccccc2)nc1C(=O)c1cc(C)cc(C#N)c1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred solution of 3-[(2,6-Bis-benzyloxy-5-ethyl-pyrimidin-4-yl)-cyano-methyl]-5-methyl-benzonitrile (10 g, 21.1 mmol) in anhydrous DMF (80 mL) in a water bath under an atmosphere of nitrogen, was added 60%, in portions, sodium hydride (869 mg, 21.7 mmol). After 30 min, oxygen gas was bubbled into the reaction mixture for 5 hr. The mixture was neutralized with aqueous saturated ammonium chloride solution. The crude product was extracted with ether and recrystallized from dichloromethane-hexane to afford 8 g (80%) of a white solid; m.p. 123-124° C.; 1H NMR (200 MHz, CDCl3) δ: 1.09 (3H, t, J=7.4 Hz), 2.43 (3H, s), 2.50 (2H, q, J=7.4 Hz), 5.35 (2H, s), 5.50 (2H, s), 7.27-7.46 (10H, m), 7.67 (1H, s), 7.87 (1H, s), 7.92 (1H, s); m/z (EI): 463 (M+).