Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([OH:33])([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:18]=3)[NH:13][C:12](=[O:34])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].Cl[C:36]1C=C(C2C3C(=CC=C(C(C4C=C(Cl)N=CC=4)(O)C4N(C)C=NC=4)C=3)NC(=O)C=2)C=CC=1>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([OH:33])([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH:18]=3)[N:13]([CH3:36])[C:12](=[O:34])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc(-c2cc(=O)[nH]c3ccc(C(O)(c4cccnc4)c4cccnc4)cc23)c1
Reactant: Cn1cncc1C(O)(c1ccnc(Cl)c1)c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1
Product: CCOc1cccc(-c2cc(=O)n(C)c3ccc(C(O)(c4cccnc4)c4cccnc4)cc23)c1
Yield: 13 %

Procedure:
The same procedure was used as that in example 2, except that 4-(3-ethoxy-phenyl)-6-(hydroxy-di-pyridin-3-yl-methyl)-1H-quinolin-2-one (91 mg, 0.202 mmol) was used in the place 4-(3-chloro-phenyl)-6-[(6-chloro-pyridin-4-yl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1H-quinolin-2-one to give the title compound of example 37C as a white solid (12 mg, 13% yield).
Reaction SMILES: [F:1][C:2]1([F:35])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[CH:25][C:26](=[O:33])[N:27]([CH2:29][C:30]([OH:32])=O)[CH:28]=5)[C:20]([CH3:34])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[N:36]#[C:37][NH2:38].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[NH:38]([C:30](=[O:32])[CH2:29][N:27]1[C:26](=[O:33])[CH:25]=[CH:24][C:23]([C:21]2[N:22]=[C:17]([NH:16][C:14]([C:11]3([C:9]4[CH:8]=[CH:7][C:5]5[O:6][C:2]([F:35])([F:1])[O:3][C:4]=5[CH:10]=4)[CH2:13][CH2:12]3)=[O:15])[CH:18]=[CH:19][C:20]=2[CH3:34])=[CH:28]1)[C:37]#[N:36]
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(=O)n(CC(=O)O)c1
Reactant: N#CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(=O)n(CC(=O)NC#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
To 2-(5-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-2-oxopyridin-1(2H)-yl)acetic acid (0.13 g, 0.27 mmol), cyanamide (27 μL, 0.32 mmol), and triethylamine (75 μL, 0.54 mmol) in N,N-dimethylformamide (3 mL) was added 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.12 g, 0.33 mmol) and the reaction mixture was stirred at room temperature for 1 hour. At this point the reaction mixture was filtered and purified by reverse-phase HPLC. The resulting trifluoroacetic acid salt was dissolved in dichloromethane and washed with a saturated sodium bicarbonate solution and 1N Hydrochloric acid. The organics were dried over sodium sulfate and evaporated to dryness to give the product (45 mg, 31%). ESI-MS m/z calc. 507.14. found 508.4 (M+1)+ Retention time 1.63 minutes.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[C:13]([CH:29]3[CH2:31][CH2:30]3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(O)C.O.[OH-].[Li+].O>>[NH2:23][C@@:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:7][CH2:6][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]3)[C:13]=2[CH:29]2[CH2:31][CH2:30]2)[CH:18]=1)([CH3:28])[CH2:26][OH:25]
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2C2CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2C2CC2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(R)-4-[6-(4-tert-Butyl-cyclohexyloxy)-5-cyclopropyl-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (0.1093 g, 0.0002593 mol) was dissolved in ethanol (2.00 mL, 0.0342 mol) in a capped 40 mL vial equipped with a magnetic stir bar. 4.2 M lithium hydroxide, monohydrate in water (1.00 mL, 0.00420 mol) was added and the reaction was stirred overnight at 80° C. HPLC analysis showed that the reaction was complete. The solvent was removed under reduced pressure. Methylene chloride and water were added and the layers were separated. The combined organic layer was concentrated to dryness and purified by HPLC to give 41.0 mg of the title compound (40% yield). MS; m/z=379.33 [M−16]+. 1H NMR (MeOD) δ: 8.52 (d, J=9.0 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.77 (d, J=9.0 Hz, 1H), 7.57 (dd, J=9.2, 2.1 Hz, 1H), 7.34 (d, J=9.3 Hz, 1H), 4.26-4.36 (m, 1H), 3.95 (d, J=11.5 Hz, 1H), 3.84 (d, J=11.5 Hz, 1H), 2.18-2.27 (m, 2H), 1.85-1.95 (m, 3H), 1.80 (s, 3H), 1.43-1.57 (m, 2H), 1.08-1.28 (m, 5H), 0.92 (s, 9H), 0.68-0.75 (m, 2H)
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([OH:19])[CH:5]=2.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.O[CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]1>>[Br:1][C:2]1[C:3](=[O:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:12]=[C:13]([F:18])[CH:14]=[C:15]([F:17])[CH:16]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])[CH2:44][CH2:43]1)[CH:5]=2
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Reactant: O=C1C(Br)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Product: CC(C)(C)OC(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Reaction time: 96 h

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-hydroxy-1H-inden-1-one obtained in Step 5 of Example 36 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, t-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate instead of 4-(2-hydroxyethyl)morpholine, being stirred for 4 d, and being purified by silica gel column chromatography (EtOAc/hexanes=1:4) to obtain the title compound.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16](=[O:24])[NH:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][NH:21][CH2:20]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=2)[N:29]=[C:28]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[OH:43])[N:27]=1>C(Cl)Cl>[CH2:8]([O:15][C:16](=[O:24])[NH:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][N:21]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=3)[N:29]=[C:28]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[OH:43])[N:27]=2)[CH2:20]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Oc1ccccc1-c1nc(Cl)c2cc(F)ccc2n1
Reactant: O=C(NC[C@@H]1CCNC1)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC[C@@H]1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)C1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of triethylamine (507 μL, 3.64 mmol) and benzyl((R)-pyrrolidin-3-yl)methylcarbamate (0.47 g, 2 mmol) in CH2Cl2 was added dropwise to a solution of 2-(4-chloro-6-fluoroquinazolin-2-yl)phenol (0.5 g, 1.82 mmol) in CH2Cl2 (20 mL). The reaction was stirred at room temperature for 3 h. After quenching the reaction with water, the aqueous phase was extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 5-10% EtOAc in CH2Cl2 yielded benzyl((S)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate. LC/MS: m/z 473.1 (M+H)+ at 2.91 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@:20]1([C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=[CH:39][CH:38]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH:33]([CH3:35])[CH3:34])[CH:27]=2)[CH2:21]1)(=O)=O.C(#N)C>>[C:37]1([C@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][CH:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:36])[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH:33]([CH3:34])[CH3:35])[CH:27]=3)[CH2:21]2)[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: CC(C)Oc1cccc(C(=O)N2CC[C@](CCOS(C)(=O)=O)(c3cccc4ccccc34)C2)c1
Solvent: CC#N
Product: CC(C)Oc1cccc(C(=O)N2CC[C@@](CCN3CCC(N4CCCCC4)CC3)(c3cccc4ccccc34)C2)c1

Procedure:
In 30 ml of acetonitrile (S)-3-(2-methanesulfonyloxyethyl)-3-(1-naphthyl)-1-(3-isopropoxybenzoyl)pyrrolidine (3.17 g), prepared as described, supra, is mixed with an equimolar amount of 4-(piperidin-1-yl)piperidine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum an the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH:14]([C:16]2[CH:21]=[C:20]([F:22])[C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:18][C:17]=2[F:31])O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:32]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH:14]([C:16]2[CH:21]=[C:20]([F:22])[C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:18][C:17]=2[F:31])[Br:32])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](C(O)c2cc(F)c(OCc3ccccc3)cc2F)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCO[C@H](C(Br)c2cc(F)c(OCc3ccccc3)cc2F)C1
Reaction time: 1 h

Procedure:
To a solution of 7.5 g of ((S)-2-[(4-benzyloxy-2,5-difluoro-phenyl)-hydroxy-methyl]-morpholine-4-carboxylic acid tert-butyl ester in dichloromethane (90 ml) was added with cooling (0-5° C.) tetrabromomethane (12.5 g) and afterwards triphenylphosphine (13.5 g) in small portions. Stirring continued for 1 hour at room temperature before the mixture was added dropwise to diethyl ether (600 mL). Solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was then purified by column chromatography (heptane-ethyl acetate (3:1)/silica gel) to give 5.6 g of the title compound.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:9][CH2:8][N:7]([C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[NH2:16])[CH2:6]1)(=[O:3])[CH3:2].[CH3:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([CH3:27])[CH:26]=1)[C:21](Cl)=[O:22]>>[C:1]([O:4][CH:5]1[CH2:9][CH2:8][N:7]([C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[NH:16][C:21](=[O:22])[C:20]2[CH:24]=[C:25]([CH3:27])[CH:26]=[C:18]([CH3:17])[CH:19]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCN([C@H]2CCCC[C@H]2N)C1
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Product: CC(=O)OC1CCN([C@H]2CCCC[C@H]2NC(=O)c2cc(C)cc(C)c2)C1

Procedure:
Following the procedure of Example 1b, using cis-N-[2-(3-acetyloxy-1-pyrrolidinyl)cyclohexyl]amine and 3.5-dimethylbenzoyl chloride there is obtained as product cis-N-[2-(3-acetyloxy-1-pyrrolidinyl)cyclohexyl]-3,5-dimethylbenzamide.
Reaction SMILES: C=C.[Cl:3][C:4]1[C:13]([CH:14]=[N:15][OH:16])=[C:12]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[C:21]([O-])(=O)[CH3:22].[Na+].Cl[O-].[Na+]>ClCCl>[Cl:3][C:4]1[C:13]([C:14]2[CH2:22][CH2:21][O:16][N:15]=2)=[C:12]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=NO)c1Cl
Reactant: CC(=O)[O-]
Agent: C=C
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C2=NOCC2)c1Cl
Reaction time: 12 h
Yield: 2525.3 %

Procedure:
At 15-20° C., ethylene is introduced into a solution of 158.0 g (0.54 mol) of methyl 2-chloro-3-hydroxyiminomethyl-4-methylsulfonylbenzoate and 1 l of dichloromethane for 30 minutes. After the addition of 1.6 g of sodium acetate, 454 ml of sodium hypochlorite solution were added dropwise at 10° C., while simultaneously introducing ethylene. Subsequently, ethylene was introduced at 10° C. for a further 15 minutes. The mixture was stirred for 12 hours, the phases were separated and the organic phase was washed with water, dried and concentrated. 156.5 g (90% of theory) of methyl 2-chloro-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoate were obtained.
Reaction SMILES: [Br:1][CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]([NH:5][C:6]([CH3:11])([CH3:10])[C:7]([OH:9])=O)=[O:4].Cl.CN(CCCN=C=NCC)C.[Cl:30][C:31]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:32]=1[NH2:33].O>ClCCl>[Cl:30][C:31]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:32]=1[NH:33][C:7](=[O:9])[C:6]([NH:5][C:3](=[O:4])[CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[Br:1])([CH3:11])[CH3:10]
Reactant: Nc1cc(Cl)ccc1Cl
Reactant: CC(C)(NC(=O)C(Br)c1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)(NC(=O)C(Br)c1ccccc1)C(=O)Nc1cc(Cl)ccc1Cl
Reaction time: 0.17 h
Yield: 83.9 %

Procedure:
A solution of 2-(α-bromophenylacetylamino)isobutyric acid (1.9 g) in dichloromethane (30 mL) was cooled to 0° C., to which dimethylaminopropylethylcarbodiimide hydrochloride (1.3 g) was added. The mixture was stirred for 10 minutes at 0° C. to room temperature. 2,5-Dichloroaniline (1.0 g) was added to the mixture, which was stirred overnight at room temperature. The reaction solution was poured into water and the mixture was extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent, 2.3 g of N-(2,5-dichlorophenyl)-2-(α-bromophenylacetylamino)isobutyramide was obtained as viscous liquid.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([NH2:11])[C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:7]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[N:6]=1)(=O)=O.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:31][OH:32]>>[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:31][O:32][C:5]1[N:10]=[C:9]([NH2:11])[C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:7]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[N:6]=1
Reactant: OCc1ccc(F)c(F)c1
Reactant: CS(=O)(=O)c1nc(N)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Product: Nc1nc(OCc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
The title compound obtained by treating 2-(methylsulfonyl)-4-(amino)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (Example 32, Step A,) with 3,4-difluorobenzyl alcohol by the same general procedure described in Reference Examples 6 and 7. Workup and flash column chromatography on silica gel (eluted with 80/20 hexanes/ethyl acetate) afforded 2-(3,4-difluorobenzyloxy)-4-(amino)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine. HPLC/MS: m/e=494 (M++1); Rt=3.91 min. 1H-NMR 500 MHz (CDCl3): δ 5.10 (bs, 2H), 5.38 (s, 2H), 7.0-7.10 (m, 2H), 7.11-7.23 (m, 6H), 7.15-7.19 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:26])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1.C(NC(C)C)(C)C.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:26][C:34](=[O:37])[CH2:35][CH3:36])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1
Reactant: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCC(=O)Nc1ccc(-c2nnc(-c3c(-c4ccccc4)noc3C)o2)c(OC)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 89.4 %

Procedure:
To a solution of 3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine (200 mg, 0.57 mmol) in tetrahydrofuran (4 mL) were added N,N-diisopropylamine (111 mg, 0.86 mmol), 4-dimethylaminopyridine (7.0 mg, 0.06 mmol) and propionyl chloride (69 mg, 0.75 mmol) and the reaction mixture was stirred at ambient temperature for 22 h. After heating at 50° C. for another 26 h the resulting suspension was extracted with ethyl acetate (20 mL) and the combined organic layers were washed with aqueous sodium carbonate (saturated). Drying over sodium sulfate and concentration afforded the title compound (206 mg, 89%) as a yellow solid. MS: m/e=405.3 [M+H]+.
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2]([Cl:4])=O.[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13]([OH:15])=O)([O-:9])=[O:8]>C(Cl)Cl.CN(C=O)C>[Cl:4][C:2]1[CH:19]=[C:18]([CH:17]=[CH:16][C:1]=1[Cl:6])[CH2:10][NH:7][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:18]([CH3:19])=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Oxalyl chloride (4.8 ml) was added to a solution of 3-nitro-4-methylbenzoic acid (9.06 g) in methylene chloride (100 ml) and DMF (a few drops) and the reaction stirred at ambient temperature for 16 hours. The reaction mixture was evaporated and the residue was dissolved in methylene chloride (100 ml). 3,4-Dichlorobenzylamine (7.04 g), 4-dimethylaminopyridine (0.31 g) and triethylamine (13.9 ml) were added and the reaction mixture was stirred at ambient temperature for 16 hours. The mixture was washed with a saturated aqueous sodium bicarbonate solution, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography using a 250:8:1 mixture of methylene chloride, methanol and a saturated aqueous ammonium chloride solution as eluent to give N-(3,4-dichlorobenzyl)4-methyl-3-nitrobenzamide as a solid (9.95 g); NMR Spectrum: (DMSOd6) 2.57 (s, 3H), 4.47 (d, 2H), 7.31 (m, 1H), 7.56 (m, 2H), 7.61 (d, 1H), 8.1 (m, 1H), 8.47 (d, 1H), 9.3 (t, 1H).
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([F:24])=[C:19]([CH:23]=1)[C:20](Cl)=[O:21]>CN(C1C=CN=CC=1)C>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:20]([C:19]1[CH:23]=[C:15]([Cl:14])[CH:16]=[CH:17][C:18]=1[F:24])=[O:21])[CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)c1cc(Cl)ccc1F
Reactant: CCCC[n+]1c(C)sc(C)c1C
Agent: CN(C)c1ccncc1
Agent: [I-]
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1cc(Cl)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 5-chloro-2-fluorobenzoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.93 (t, 3 H) 1.33-1.42 (m, 2 H) 1.61-1.68 (m, 2 H) 2.19 (s, 3 H) 2.23 (s, 3 H) 3.94-4.01 (m, 2 H) 6.36 (s, 1 H) 7.27-7.35 (m, 1 H) 7.47-7.53 (m, 1 H) 7.75-7.81 (m, 1H); MS (ESI) m/z 340 (M+H)+.
Reaction SMILES: C(C1C=CC(S(Cl)(=O)=O)=CC=1)#N.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23](CNC)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CNCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: N#Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 184 %

Procedure:
To a stirred solution of 4-cyanobenzenesulfonyl chloride (411 mg, 2.2 mmol) in CH2Cl2 (10 mL) was added 4-methylaminomethyl-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 2.2 mmol) and triethylamine (0.91 mL, 6.5 mmol) and the reaction stirred at RT for 2 h after which time silica was added and solvent removed. The crude residue was purified by silica gel chromatography eluting with isohexane, and increasing the polarity to 100% EtOAc to afford 4{[4-cyano-benzenesulfonyl)-methyl-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester as a white solid (750 mg, 87%).
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([O:18][P:19]([O-:22])([O-:21])=[O:20])[O:16][C@@H:15]([CH3:17])[C@@H:13]([OH:14])[C@@H:11]([OH:12])[C@@H:9]1[OH:10].C([NH+](CC)CC)C.C([NH+](CC)CC)C.C1CCC(NC(N2CCOCC2)=NC2CCCCC2)CC1.C1N([P:64]([O:67][CH2:68][C@H:69]2[O:73][C@@H:72]([N:74]3[C:78]4[NH:79][C:80]([NH2:84])=[N:81][C:82](=[O:83])[C:77]=4[N:76]=[CH:75]3)[C@H:71]([OH:85])[C@@H:70]2[OH:86])([OH:66])=[O:65])CCOC1.N1C=NN=N1>N1C=CC=CC=1>[CH3:17][CH:15]1[O:16][CH:8]([O:18][P:19]([O:21][P:64]([O:67][CH2:68][CH:69]2[O:73][CH:72]([N:74]3[C:78]4[NH:79][C:80]([NH2:84])=[N:81][C:82](=[O:83])[C:77]=4[N:76]=[CH:75]3)[CH:71]([OH:85])[CH:70]2[OH:86])([OH:66])=[O:65])([OH:22])=[O:20])[CH:9]([OH:10])[CH:11]([OH:12])[CH:13]1[OH:14]
Reactant: Nc1nc(=O)c2ncn([C@@H]3O[C@H](COP(=O)(O)N4CCOCC4)[C@@H](O)[C@H]3O)c2[nH]1
Reactant: C[C@@H]1OC(OP(=O)([O-])[O-])[C@@H](O)[C@H](O)[C@@H]1O
Agent: C1CCC(N=C(NC2CCCCC2)N2CCOCC2)CC1
Agent: CC[NH+](CC)CC
Agent: c1nnn[nH]1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC1OC(OP(=O)(O)OP(=O)(O)OCC2OC(n3cnc4c(=O)nc(N)[nH]c43)C(O)C2O)C(O)C(O)C1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.9 %

Procedure:
Compound 26 (624 mg, 1.41 mmol; wherein R, R'=OH; Sigma) was dissolved in H2O (15 mL), applied to a Bio-Rad AG 50W-X2 cation exchange column (Et3N+, 2.5×8 cm), and eluted with H2O (150 mL). The solution was evaporated, coevaporated with MeOH (2×10 mL) and dried for 3 d under vacuum to give triethylammonium β-L-fucopyranosyl phosphate 29 (512 mg). The content of triethylamine was determined to be 1.16 equiv. (1H NMR) A mixture of 29 (57.5 mg, 159 μmol) and guanosine 5'-monophospho morpholidate 4-morpholine-N,N'-dicyclohexylcarboxamidine salt 27 (201 mg, 255 μmol) was coevaporated with dry pyridine (3×1.5 mL). 1H-Tetrazole (33 mg, 477 μmol) and dry pyridine (0.8 mL) were added, and the solution stirred at rt. After a while, product starts to precipitate. The reaction was monitored by TLC (2:1 i-PrOH/1M NH4OAc). After 2 d, the mixture was diluted with water (1.5 mL) to become a clear solution, evaporated, and coevaporated with water (2×1.5 mL). The residue was purified on a Bio-Gel P-2 column (2.5×70 cm), eluated with 250 mM NH4 HCO3 to give 30 (82.4 mg, 85%) as a white solid after lyophilization (Rf 0.43, 2:1 i-PrOH/1M NH4OAc). The 1H NMR spectral data were in agreement with the published ones (Nunez et al. Can. J. Chem. 1981, 59, 2086-2095; Gokhale et al. Can. J. Chem. 1990, 68, 1063-1071).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[Br-].[Mg+2].[CH2:10]=[CH2:11].[Br-]>O1CCCC1.CO>[C:10]([C:4]1([OH:7])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)#[CH:11]
Reactant: O=C1CCOCC1
Reactant: C=C
Agent: [Br-]
Agent: [Mg+2]
Solvent: CO
Solvent: C1CCOC1
Product: C#CC1(O)CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
A solution of tetrahydro-4H-pyran-4-one (1.25 g, 12.5 mmol) in tetrahydrofuran (10 mL) was cooled to 0° C. and then treated with a 0.5M solution of ethylene magnesium bromide in tetrahydrofuran (40 mL, 20 mmol). The mixture was stirred at 0° C. for 2 h and at 25° C. for 4 h. The resulting mixture was cooled to 0° C. and then diluted with methanol (10 ml). The solvents were concentrated in vacuo, and the residue was extracted with a saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dried in vacuo to afford solid 4-ethynyl-tetrahydro-pyran-4-ol (1.2 g, 95.2%).