Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Li+].Cl[Si](C)(C)C.[CH2:8]([O:15][C:16]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:19]=[C:18]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:17]=1[CH:30]=[CH:31][N+:32]([O-])=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CO>C1COCC1>[CH2:8]([O:15][C:16]1[CH:21]=[C:20]([C:22]([CH3:23])([CH3:25])[CH3:24])[CH:19]=[C:18]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:17]=1[CH2:30][CH2:31][NH2:32])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)c1cc(OCc2ccccc2)c(C=C[N+](=O)[O-])c(C(C)(C)C)c1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(OCc2ccccc2)c(CCN)c(C(C)(C)C)c1
Reaction time: 0.03 h

Procedure:
To a suspension of 0.0 g (4.59 mmol) of lithium borohydride in 3 mL THF was carefully added 1.3 mL (10.2 mmol) of chlorotrimethylsilane. The reaction mixture was stirred for 2 min and then a solution of 0.367 g (1.0 mmol) of 1-(benzyloxy)-3,5-di-tert-butyl-2-[2-nitrovinyl]benzene from Step B of Example 75 dissolved in 1.5 mL of anhydrous THF was slowly added. The resulting reaction mixture was stirred overnight at room temperature then cooled using an external ice water bath and 15 mL of methanol was slowly added. The resulting mixture was evaporated in vacuo, the residue was the treated with 20 mL of 5 N aqueous sodium hydroxide and then the reaction mixture was extracted with 5 times with 20 mL portions of CH2Cl2. The combined extracts were dried Na2SO4), filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted initially with 5% MeCOH in CH2Cl2 followed by a 95/5/0.5 mixture of CH2Cl2-MeOH-conc. NH4OH. Combination of the purified fractions and evaporation in vacuo afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[N:3]=1.I[CH:19]([CH3:21])[CH3:20].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>>[CH3:17][C:14]([C:4]1[N:3]=[C:2]([Cl:1])[C:7]([CH:8]([CH:19]([CH3:21])[CH3:20])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][N:5]=1)([CH3:16])[CH3:15]
Reactant: CCOC(=O)Cc1cnc(C(C)(C)C)nc1Cl
Reactant: CC(C)I
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CCOC(=O)C(c1cnc(C(C)(C)C)nc1Cl)C(C)C

Procedure:
4-chloro-5-ethoxycarbonylmethyl-2-(2-methylprop-2-yl)pyrimidine was reacted with 2-iodo-propane in the presence of lithium bis(trimethylsilyl)amide according to the procedure illustrated in example 6, to give ethyl (RS)-2-[2-(2-methylprop-2-yl)-4-chloropyrimidin-5-yl]-3-methylbutyrate.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]2)OCC1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>CN(C=O)C>[CH2:15]([O:12][CH2:11][CH:8]1[CH2:7][CH2:6][C:5](=[O:1])[CH2:10][CH2:9]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCC1CCC2(CC1)OCCO2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C1CCC(COCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
1,4-dioxaspiro[4.5]decan-8-ylmethanol (1.33 g, 7.72 mmol) was dissolved in DMF (14 mL) and then cooled to 0° C. To the solution was added NaH (0.402 g, 10.04 mmol) in portions and the mixture agitated at 10° C. for 1 h and then benzyl bromide (1.194 mL, 10.04 mmol) was added and the mixture agitated over 72 h. The reaction mixture was quenched with water and extracted with ether and the combined organic extracts dried (MgSO4), filtered and concentrated in vacuo and the crude product 8-((benzyloxy)methyl)-1,4-dioxaspiro[4.5]decane dissolved in acetonitrile (35 mL) and water (25 mL) and treated with 3N HCl (13 mL) and agitated at room temperature for 20 min upon which LCMS indicated desired product. The reaction mixture was quenched with 40 mmol aqueous NaOH and then extracted with EtOAc (200 mL) and the organic layer was washed with water and dried (MgSO4), filtered and concentrated in vacuo and the residue purified by flash chromatography (0-50% EtOAc/heptane) to afford 1.23 g of the desired product as a colorless syrup (73%). LCMS (m/z): 329.2 (MH+), 1.33 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:9]([C:12]2[N:16]([CH3:17])[N:15]=[N:14][N:13]=2)[CH:10]=O)=[CH:4][CH:3]=1.C1(P(=CC=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O:50][CH2:51][CH3:52])(=O)C.[Br-].[Li+]>C1(C)C=CC=CC=1.CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)=[C:9]([C:12]2[N:16]([CH3:17])[N:15]=[N:14][N:13]=2)[CH:10]=[CH:52][CH:51]=[O:50])=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: Cn1nnnc1C(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cn1nnnc1C(C=CC=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 55 °C
Reaction time: 0.33 h
Yield: 86.6 %

Procedure:
A mixture of 448 g (1.37 mol) of 3,3-bis(4-flurophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal and 445 g (1.46 mol) of triphenylphosphoranylidene acetaldehyde in 5.5 L of toluene was heated with stirring to 55° C. After turning off the heat source, the temperature rose to 62° C. After 20 minutes, heat was applied and 60° C. was maintained for 30 minutes. Analytical TLC indicated that the reaction was complete (50% ethyl acetate in hexane). Lithium bromide (128 g, 1.47 mol) was added and the mixture was stirred at 60° C. for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in 900 mL of boiling absolute ethanol. To this solution was slowly added 900 mL of hexane. After 16 hours at ambient temperature and 2 hours at cold freezer temperature, the mixture was filtered to give 418 g (86.6%) of the title compound; m.p.=161°-165° C.
Reaction SMILES: [NH:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH3:8].[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=1)([O-:11])=[O:10]>C1C=CC=CC=1>[CH3:8][N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]1=[N:1][C:19]([NH:18][C:15]1[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:17][CH:16]=1)=[O:20]
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: CN1CCCCC1=N
Solvent: c1ccccc1
Product: CN1CCCCC1=NC(=O)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 6 h

Procedure:
The hydrochloride salt of 2-imino-1-methylpiperidine (7.43 g.; 0.05 mole) is converted to the free base in benzene in the usual manner. After drying over K 2 CO 3 and filtering, a benzene solution of 0.05 mole of p-nitrophenylisocyanate is added dropwise with stirring. After addition is complete, further stirring is continued for about 6 hours at room temperature. The benzene is evaporated in vacuo and the solid residue is recrystallized from methanol to give the product, 1-(1-methyl-2-piperidylidene)-3-(4-nitrophenyl)urea.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C@@H:2]([CH3:4])[OH:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])O.[Na+]>ClCCl>[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[O:3][C@H:2]([CH3:4])[C:1]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)[C@@H](C)O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H](C)OC1CCCCO1
Reaction time: 1 h
Yield: 94.5 %

Procedure:
Methyl (R)-(+)-lactate (25.0 g) was dissolved in dichloromethane (250 ml), to which was added, under ice-cooling, p-toluenesulfonic acid.hydrate (456 mg). To the mixture was then added dropwise 3,4-dihydro-2H-pyran (24.2 g) during 30 minutes, which was stirred for one hour under ice-cooling. To the reaction mixture was added a 5% aqueous solution of sodium hydrogen carbonate (50 ml), and the mixture was stirred vigorously, followed by separating the organic layer. The organic layer was further washed with a 5% aqueous solution of sodium hydrogen carbonate, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure to leave methyl (2R)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionate (42.7 g) as a pale yellow oily product.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[CH:5][C:6]=1[C:7](OCC)=[O:8].[CH:20]([NH2:22])=O>CN(C=O)C.C(O)=O>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([C:4]2[NH:3][C:2]3[N:1]=[CH:20][N:22]=[C:7]([OH:8])[C:6]=3[CH:5]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cc(-c2cccc(OC)c2)[nH]c1N
Reactant: NC=O
Solvent: O=CO
Solvent: CN(C)C=O
Product: COc1cccc(-c2cc3c(O)ncnc3[nH]2)c1

Procedure:
Under a protective gas, 7.19 g (29 mmol) of 2-amino-3-ethoxycarbonyl-5-(3-methoxy-phenyl)-1H-pyrrole in 59 ml of formamide, 29.5 ml of DMF and 14.7 ml of formic acid are heated at 150° C. overnight. Working-up analogously to Step 8.2 yields the title compound; TLC-Rf =0.3 (hexane/ethyl acetate [1:1]).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N(CC)C(C)C)(C)C.[C:20]1([S:26]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])(=[NH:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([N:28]=[S@:26]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:27])=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: CCOC(=O)CS(=N)(=O)c1ccccc1
Reactant: O=C(O)c1cncc(Br)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 33.7 %

Procedure:
To a solution of 5-bromonicotinic acid (343 mg, 1.66 mmol) in anhydrous DMF (5.5 μL) was added N,N-diisopropylethylamine (0.58 mL, 3.32 mmol) and ethyl (S-phenylsulfonimidoyl)acetate (415 mg, 1.83 mmol) followed by the final addition of (benzotriazol-1-yloxy)-tris(dimethylamino)-phosphonium hexafluorophophate (0.81 g, 1.83 mmol). The reaction mixture was stirred at room temperature for 20 min, and then partitioned between saturated aqueous NaHCO3 and EtOAc. The organic layer was separated and washed once with brine and dried over anhydrous Na2SO4. The organic layer was concentrated and the residue purified by chromatography (silica gel, gradient elution (5:1 Hexane/EtOAc to 3:1 Hexane/EtOAc). The product containing fractions were concentrated to give the title compound as a white solid (230 mg, 34%).
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3].[C:25]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH2:1]([C:4]1[C:13]([O:14][CH3:25])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)c(OC)cc2ncnc(Nc3ccc(Cl)cc3)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: C=CCc1c(OC)c(OC)cc2ncnc(Nc3ccc(Cl)cc3)c12
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of 5-allyl-4-(4-chloro-phenylamino)-7-methoxy-quinazolin-6-ol (0.45 g, 1.32 mmol) (from Example 16, Step D, supra) in acetone (30 mL) was added K2CO3 (0.36 g, 2.6 mmol) and methyl iodide (0.75 g, 5.3 mmol) (Aldrich). The reaction mixture was heated with stirring at 90° C. for 4 hours. The mixture was cooled to room temperature, filtered and the filtrate was concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:2:0.01) as eluent to give the desired (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-(4-chloro-phenyl)-amine as a white solid. (Yield 0.3 g, 84%).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:23][NH2:24]>CO>[CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[O:11][C@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([NH:23][NH2:24])=[O:2])[CH2:6][CH2:7]1
Reactant: COC(=O)[C@H]1CC[C@H](Oc2ccc3ccccc3c2)CC1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)[C@H]1CC[C@H](Oc2ccc3ccccc3c2)CC1
Temperature: 80 °C

Procedure:
A mixture of trans-4-(naphthalen-2-yloxy)-cyclohexanecarboxylic acid methyl ester (0.130 g, 0.457 mmol) and hydrazine hydrate (0.02 ml, 0.45 mmol) in methanol (0.5 ml) was heated at 80° C. for 16 h. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (50 ml) and 1 M aqueous sodium hydroxide solution (50 ml). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.112 g, 86%) as yellow solid, which was used in the next step without further purification. MS m/e: 285 (M+H+)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:12][CH2:11][C@H:10]([NH:13][OH:14])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C[Si]([N:19]=[C:20]=[O:21])(C)C.CO>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:12][CH2:11][C@H:10]([N:13]([OH:14])[C:20]([NH2:19])=[O:21])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: ON[C@H]1CC[C@@H](c2cccc(F)c2)C1
Reactant: C[Si](C)(C)N=C=O
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)N(O)[C@H]1CC[C@@H](c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57 %

Procedure:
To a stirred solution of the compound prepared in Step 6, above (2.4 g, 12 mmol), in THF (10 ml) was added trimethylsilylisocyanate (85%, 2.4 ml, 18 mmol) and the reaction mixture was stirred at room temperature for 1.5 hours. Methanol (10 ml) was added and 10 minutes later the solvent was removed under reduced pressure to afford a white solid. Recrystallization from IPE/hexane afforded the title compound (1.6 g, 57% yield) as a colorless solid, m.p. 104.2-105.7° C.
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[N:27]1[S:28][N:29]=[C:30]2[CH:35]=[C:34]([CH2:36][N:37]3[CH2:41][CH2:40][N:39]([C:42]4[S:43][C:44]([C:48]([OH:50])=O)=[C:45]([CH3:47])[N:46]=4)[C:38]3=[O:51])[CH:33]=[CH:32][C:31]=12.[NH2:52][CH2:53][C:54]1[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=1>>[N:27]1[S:28][N:29]=[C:30]2[CH:35]=[C:34]([CH2:36][N:37]3[CH2:41][CH2:40][N:39]([C:42]4[S:43][C:44]([C:48]([NH:52][CH2:53][C:54]5[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=5)=[O:50])=[C:45]([CH3:47])[N:46]=4)[C:38]3=[O:51])[CH:33]=[CH:32][C:31]=12
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCN(Cc3ccc4nsnc4c3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc4nsnc4c3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 44 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(benzo[c][1,2,5]thiadiazol-5-ylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 44% yield: mp 105-107° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.57 (s, 1H), 8.50-8.48 (m, 1H), 7.96-7.93 (m, 1H), 7.71-7.68 (m, 1H), 7.57-7.55 (m, 2H), 7.29-7.24 (m, 1H), 6.18 (br s, 1H), 4.96 (s, 2H), 4.57 (d, J=5.8 Hz, 2H), 4.09-4.04 (m, 2H), 3.68-3.62 (m, 2H), 2.58 (s, 3H); MS (ES+) m/z 466.2 (M+1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=O)[CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:16][C:17]([C:19]1([NH2:28])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:28][C:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)c1cccc2cccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc3cccnc23)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
To a solution of quinoline-8-carboxylic acid (421 mg, 2.43 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (500 mg, 2.43 mmol), HATU (1.39 g, 3.65 mmol) in anhydrous DMF (15 mL) is added DIPEA (603 μL, 3.65 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (50 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (47) as white solid (281 mg, 32%).
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:8][CH2:7][NH:6][CH2:5][C@H:4]1[NH:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH2:18]([N:6]1[CH2:7][CH2:8][C@@H:3]([O:2][CH3:1])[C@H:4]([NH:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[CH2:5]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccccc1
Reactant: CCOP(=O)(N[C@@H]1CNCC[C@H]1OC)OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOP(=O)(N[C@@H]1CN(Cc2ccccc2)CC[C@H]1OC)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
A mixture of diethyl trans-4-methoxypiperidin-3-ylphosphoramidate (1.30 g, 4.88 mmol), benzaldehyde (0.74 mL, 7.32 mmol) and acetic acid (0.56 mL, 9.76 mmol) in methanol (20 mL) was stirred at 0° C. for 30 minutes. NaCNBH3 (0.46 g, 7.32 mmol) was added at 0° C. The resulting solution was warmed to room temperature and stirred at room temperature for 1 hour. The solvent was removed in vacuo and saturated sodium bicarbonate (20 mL) and ethyl acetate (30 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate) and concentrated in vacuo to give diethyl trans-1-benzyl-4-methoxypiperidin-3-ylphosphoramidate (1.70 g, 98%), which was used directly in the next step without purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>C(Cl)Cl.N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:19][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:8][CH2:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.4 %

Procedure:
To a solution of (tetrahydro-2H-pyran-4-yl)methanol (5.0 g, 43.0 mmol) in CH2Cl2 (40 mL) and pyridine (30 mL) was added 4-(dimethylamino)pyridine (0.26 g, 2.2 mmol) followed by p-toluenesulfonyl chloride (8.2 g, 43.0 mmol). The mixture was allowed to stir at ambient temperature for 16 hours then was quenched with 5% aqueous HCl (15 mL) and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 75% hexanes in EtOAc) afforded the title compound (9.1 g, 33.7 mmol, 78% yield). MS (DCI/NH3) m/z 288 (M+NH4)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[Si](CC)(CC)CC.C([Li])(C)(C)C.CCCCC.[C:24]([C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1)#[N:25]>C1COCC1>[OH:31][CH:30]([C:6]1[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=1)[C:29]1[CH:32]=[CH:33][C:26]([C:24]#[N:25])=[CH:27][CH:28]=1
Reactant: CC[Si](CC)(CC)c1nccn1C
Reactant: N#Cc1ccc(C=O)cc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cn1cncc1C(O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
A solution of 1-methyl-2-(triethylsilyl)-1H-imidazole (3.35 g, 17.08 mmol) in THF (50 mL) at −78° C. was treated dropwise with 2.5M tert-butyllithium in pentane (22.4 mL, 17.1 mmol), stirred for 30 minutes, treated dropwise with a solution of 4-cyanobenzaldehyde (2.04 g, 15.56 mmol) in THF (10 mL), and stirred for 1 hour. The mixture was quenched with methanol (4 mL), treated with 1N HCl (40 mL), warmed to room temperature, adjusted to pH 12 with 30% NaOH, and extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was triturated with 4:1 hexanes/ethyl acetate to provide 2.95 g (89%) of the desired product. MS (DCI/NH3) m/z 214 (M+H)+; 1H NMR (CDCl3) δ 7.67 (d, 2H), 7.53 (d, 2H), 7.40 (s, 1H), 6.67 (s, 1H), 5.95 (s, 1H), 3.53 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1.[CH3:33][C:34]([Si:37](Cl)([CH3:39])[CH3:38])([CH3:36])[CH3:35]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Si:37]([O:18][CH2:17][C@H:10]1[O:9][C@:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:30])[F:31])=[CH:24][CH:23]=3)[CH:4]=2)([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@@H:11]1[OH:16])([C:34]([CH3:36])([CH3:35])[CH3:33])([CH3:39])[CH3:38]
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OC(F)(F)F)cc3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OC(F)(F)F)cc3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 16 h
Yield: 97 %

Procedure:
(2S,3R,4S,5S,6R)-2-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 61 (1.33 g, 2.78 mmol) was dissolved in 12 mL pyridine, followed by addition of 4-dimethylamino pyridine (67.93 mg, 0.55 mmol) and TBSCl (0.50 g, 3.34 mmol) in turn. The reaction mixture was stirred for 16 hours. Thereafter, the reaction mixture was concentrated under reduced pressure and partitioned after 75 mL ethyl acetate and 75 mL water were added. The aqueous phase was extracted with ethyl acetate (50 mL×2) and the organic extracts were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3R,4S,5S,6R)-6-[(tert-butyl(dimethyl)silyl)oxymethyl]-2-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 6j (1.60 g, white solid), yield: 97.6%. 1H NMR (400 MHz, CD3OD): δ 7.55 (d, 1H), 7.46 (d, 1H), 7.41 (d, 1H), 7.26 (d, 2H), 7.17 (d, 2H), 4.17 (s, 2H), 4.04 (d, 1H), 3.92-3.88 (m, 1H), 3.77 (t, 1H), 3.61-3.59 (m, 1H), 3.09 (s, 3H).