Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([S:25]([NH:28][C@H:29]([C:33]([OH:35])=[O:34])[CH:30]([CH3:32])[CH3:31])(=[O:27])=[O:26])=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)=[O:11])=[CH:7][C:6]=2[CH:36]=1.C(N(CC)C(C)C)(C)C.[C:46](Cl)(=[O:48])[CH3:47]>C(Cl)Cl>[C:46]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[CH:21][C:22]([S:25]([NH:28][C@H:29]([C:33]([OH:35])=[O:34])[CH:30]([CH3:32])[CH3:31])(=[O:26])=[O:27])=[CH:23][CH:24]=4)=[CH:15][CH:14]=3)=[O:11])=[CH:7][C:6]=2[CH:36]=1)(=[O:48])[CH3:47]
Reactant: CC(=O)Cl
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3cc4cc(N)ccc4o3)cc2)cc1)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc4)cc3)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-[(4′-{[(5-amino-1-benzofuran-2-yl)carbonyl]amino}-1,1′-biphenyl-4-yl)sulfonyl]-L-valine-Wang resin (0.3 g), from Example 7, was suspended in methylene chloride (6 mL). To the suspension was added N,N-diisopropylethylamine (6.0 equiv.) and acetyl chloride (3.0 equiv.). The reaction was allowed to proceed at room temperature for 0. h and the reagent was removed by filtration. The resin was washed with methylene chloride (2×), methanol and methylene chloride (2×) before being treated with a 95% solution of TFA in methylene chloride (5 mL) and agitated at room temperature for 2 h. The solution was collected by filtration and the solvent was removed via vacuum. The crude product was then purified by flash chromatography to give N-{[4′-({[5-(acetylamino)-1-benzofuran-2-yl]carbonyl}amino)-1,1′-biphenyl-4-yl]sulfonyl}-L-valine. LCMS MH+ (m/z) 550. 1H NMR (300 MHz, DMSO-d6): δ 10.50 ppm (s, 1H), 9.92 ppm (s, 1H), 8.00-7.34 ppm (m, 12H), 3.33 ppm (m, 1H), 1.89 ppm (s, 3 H), 1.76 ppm (m, 1H), 0.63 ppm (m, 6H).
Reaction SMILES: [Cl-].[Cl-].[NH3+:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][NH+:10]=[CH:9][CH:8]=1)=[O:6].CO[C:15]1([C:22](OC)=O)[CH2:19][CH2:18][CH:17]([O:20][CH3:21])[O:16]1.C([O-])(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(O)(=O)C.C(Cl)Cl>[O:6]=[C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)[CH2:4][N:3]1[CH:22]=[CH:15][CH:19]=[C:18]1[C:17]([O:20][CH3:21])=[O:16]
Reactant: COC(=O)C1(OC)CCC(OC)O1
Reactant: [NH3+]CC(=O)c1cc[nH+]cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1cccn1CC(=O)c1ccncc1
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 11.1 %

Procedure:
4-(ammonioacetyl)pyridinium dichloride (crude, 100 mg, 0.48 mmol), methyl 2,5-dimethoxytetrahydrofuran-2-carboxylate (99 mg, 0.52 mmol) and sodium acetate (157 mg, 1.9 mmol) were suspended in glacial acetic acid (1.5 mL) and the mixture heated at 100° C. After 4.5 hours the dark mixture was allowed to cool to room temperature and ice (5 g) was added. The mixture was neutralised with solid NaHCO3 and allowed at room temperature. The resulting suspension was diluted with CH2Cl2 (5 mL), filtered and the aqueous layer extracted with CH2Cl2 (3×5 mL). The organic layers were dried (MgSO4), filtered and concentrated in vacuo to yield a brown oil that was purified by flash chromatography (Biotage SP4 (4 g cartridge, gradient hexanes 3 CV, 0-100% EtOAc in hexanes 15 CV, hold for 5 CV) to give methyl 1-[2-oxo-2-(pyridin-4-yl)ethyl]-1H-pyrrole-2-carboxylate (13 mg, yield 11%). ESI-MI m/z [M+H]+ 245.1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]2[C:14]3[CH:20]=[C:19]([S:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)(=[O:23])=[O:22])[CH:18]=[CH:17][C:15]=3[O:16][CH:10]2[CH2:9]1)=O)(C)(C)C.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>C(Cl)Cl>[Cl:30][C:26]1[CH:25]=[C:24]([S:21]([C:19]2[CH:18]=[CH:17][C:15]3[O:16][CH:10]4[CH2:9][NH:8][CH2:13][CH2:12][CH:11]4[C:14]=3[CH:20]=2)(=[O:22])=[O:23])[CH:29]=[CH:28][CH:27]=1.[F:34][C:33]([F:36])([F:35])[C:31]([OH:37])=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCC2c3cc(S(=O)(=O)c4cccc(Cl)c4)ccc3OC2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1cccc(Cl)c1)c1ccc2c(c1)C1CCNCC1O2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-(3-Chloro-benzenesulfonyl)-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester (0.20 mmol, 1.0 eq) was dissolved into 20% TFA in DCM and shaken at room temperature for 3 h. The reaction solution was then concentrated and the crude product purified by preparative LC/MS to afford 6-[(3-chlorophenyl)sulfonyl]-1,2,3,4,4a,9a-hexahydro[1]benzofuro[2,3-c]pyridine as a trifluoroacetic acid salt. MS m/z 350 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[O:28][CH2:29][C:30]#[N:31])[C:22]([Cl:36])=[CH:21][N:20]=1>>[Cl:36][C:22]1[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[O:28][CH2:29][C:30]#[N:31])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Reactant: N#CCOc1ccccc1Nc1nc(Cl)ncc1Cl
Product: CCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(Nc4ccccc4OCC#N)n3)cc21

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and [2-(2,5-Dichloro-pyrimidin-4-ylamino)-phenoxy]-acetonitrile to yield an off-white solid (3.3%). mp 253° C.; LCMS: m/z=491.16 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.41 (d, 1H, J=7.8 Hz), 8.31 (s, 1H), 7.65 (m, 2H), 7.28 (m, 2H), 7.18 (m, 1H), 7.07 (m, 3H), 4.91 (s, 2H), 3.76 (m, 2H), 2.34 (m, 2H), 2.04 (m, 2H), 1.36 (s, 6H), 1.24 (t, 3H).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]2[N:29]=[C:28]([C:30]([O:32]CC)=[O:31])[O:27][N:26]=2)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)C.O>[C:1]([N:20]1[CH:24]=[C:23]([C:25]2[N:29]=[C:28]([C:30]([OH:32])=[O:31])[O:27][N:26]=2)[N:22]=[CH:21]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1nc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)no1
Temperature: 0 °C

Procedure:
Ethyl 3-(1-trityl-1H-imidazol-4-yl)-1,2,4-oxadiazole-5-carboxylate (1.1 g, 2.442 mmol) was dissolved in ethanol (60 ml) and the resulting solution was cooled to 0° C. Cesium carbonate (6.36 g, 19.53 mmol) was dissolved in water (25 ml) and added into the solution. The reaction mixture was refluxed for 1 h. Ethanol was evaporated, diluted with water, filtered and washed with water. The solid was dried in vacuum at 40° C. The product was purified by recrystallization from THF and ethyl acetate, respectively. LC-MS: [M+1]=423.435.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:12][C:13]#[C:14][C:15]3[CH:23]=[CH:22][CH:21]=[C:20]4[C:16]=3[CH2:17][C:18](=[O:24])[NH:19]4)[CH2:8][CH2:9][C:10]=2[N:11]=1.O.CC(C)=O.CCOCC>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(O)C>[NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:12]/[CH:13]=[CH:14]\[C:15]3[CH:23]=[CH:22][CH:21]=[C:20]4[C:16]=3[CH2:17][C:18](=[O:24])[NH:19]4)[CH2:8][CH2:9][C:10]=2[N:11]=1
Reactant: Nc1nc2c(s1)CCN(CC#Cc1cccc3c1CC(=O)N3)CC2
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: Nc1nc2c(s1)CCN(C/C=C\c1cccc3c1CC(=O)N3)CC2
Yield: 51 %

Procedure:
Prepared analogously to Example 12 by catalytic hydrogenation of 2-amino-6-(3-(2-oxo-indolin-4-yl)-2-propyn-1-yl)-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d]azepine. 0.75 H2O using Lindlar catalyst (palladium on calcium carbonate, contaminated with lead) for 3 hours at ambient temperature in ethanol. Yield: 51% of theory, Melting point: 192°-195° C. (acetone/ether).
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][C:4](=[O:7])[NH:3][C:2]1=[O:8].[CH2:9]([O:16][CH2:17]Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>ClCCl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:9]([O:16][CH2:17][N:1]1[CH:6]=[CH:5][C:4](=[O:7])[NH:3][C:2]1=[O:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClCOCc1ccccc1
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: O
Product: O=c1ccn(COCc2ccccc2)c(=O)[nH]1
Reaction time: 2 h
Yield: 86.1 %

Procedure:
After N,O-bis(trimethylsilyl)acetoamide (18.5 ml, 74.8 mmol) was added dropwise to a suspension of pyrimidine-2,4-dione (3.36 g, 30.0 mmol) in dichloromethane (90 ml) at room temperature, the mixture was stirred for 2 hours. Tetra-n-butyl ammonium iodide (1.12 g, 3.0 mmol) was added to the reaction mixture, and benzyloxymethyl chloride (4.4 ml, 31.7 mmol) was further added to it. This mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized with water and a saturated aqueous solution of sodium hydrogencarbonate, and it was extracted with ethyl acetate. The organic layer was washed with a 10% aqueous solution of sodium thiosulfate and with water successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The solid residue was washed with diisopropyl ether and collected by filtration to give the title compound (6.00 g, yield 86%) as a white powder.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[CH:9]1([CH2:15][N:16]2[CH2:24][C:23]3[C:18](=[C:19]([CH3:32])[CH:20]=[C:21]([CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:22]=3)[C:17]2=[O:33])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>O>[CH:9]1([CH2:15][N:16]2[CH2:24][C:23]3[C:18](=[C:19]([CH3:32])[CH:20]=[C:21]([CH2:25][CH:26]4[CH2:27][CH2:28][N:29]([CH2:2][C:3]5[N:8]=[CH:7][CH:6]=[CH:5][N:4]=5)[CH2:30][CH2:31]4)[CH:22]=3)[C:17]2=[O:33])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Cc1cc(CC2CCNCC2)cc2c1C(=O)N(CC1CCCCC1)C2
Reactant: ClCc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(CC2CCN(Cc3ncccn3)CC2)cc2c1C(=O)N(CC1CCCCC1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To a mixture of 2-Chloromethylpyrimidine (32 mg, 0.247 mmol), 2-Cyclohexylmethyl-7-methyl-5-piperidin-4-ylmethyl-2,3-dihydro-isoindol-1-one (56 mg, 0.164 mmol) and cesium carbonate (160 mg, 0.492 mmol) was added acetonitrile (3.0 mL). The mixture was allowed to stir at room temperature overnight. Water (2.0 mL) was added and the product was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated. Column chromatography provided the title compound as a yellow oil (48 mg, 69%). 1H NMR (300 Adz, CDCl3): δ 8.76-8.72 (d, 2H), 7.18 (t, 1H), 6.99 (s, 1H), 6.95 (s, 1H), 4.30 (s, 2H), 3.78 (s, 2H), 3.40-3.37 (d, 2H), 2.97-2.93 (d, 2H), 2.70 (s, 3H), 2.58-2.56 (d, 2H), 2.10-2.05 (t, 2H), 1.71-1.42 (m, 10H), 1.26-1.13 (m, 4H), 1.09-0.98 (m, 2H).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:3]=1.[CH3:15][O:16][C:17]([C:19]1[N:20]([S:33]([C:36]2[C:41]([CH3:42])=[CH:40][C:39]([CH3:43])=[CH:38][C:37]=2[CH3:44])(=[O:35])=[O:34])[CH:21]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:23]=1)=[O:18].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][O:16][C:17]([C:19]1[N:20]([S:33]([C:36]2[C:41]([CH3:42])=[CH:40][C:39]([CH3:43])=[CH:38][C:37]=2[CH3:44])(=[O:34])=[O:35])[CH:21]=[C:22]([C:2]2[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:3]=2)[CH:23]=1)=[O:18]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cn1S(=O)(=O)c1c(C)cc(C)cc1C
Reactant: Cc1cnc(-c2ccccc2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2cc(-c3ccccc3)ncc2C)cn1S(=O)(=O)c1c(C)cc(C)cc1C

Procedure:
13 (29 mg, 0.12 mmol, 1.0 equiv.) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2,4,6-trimethylbenzensulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester (52 mg, 0.12 mmol, 1.0 equiv.) were dissolved in benzene (1.2 mL). After adding aqueous Na2CO3 (0.2 mL), Pd(PPh3)4 (28 mg, 0.024 mol, 0.2 equiv.) was then added and the resulting mixture was refluxed for 16 hours. The reaction mixture was dissolved in ethyl acetate and washed with water. After drying the organic layer over Na2SO4, the solvent was removed under reduced pressure. The crude product 14 was used without further purification (100 mg, HPLC Rt=7.005 minutes, ES+ 475.4, ES− not observed).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:6]2[O:7][CH2:8][CH2:9][O:10][C:5]=2[CH:4]=1.BrCC1CCCCO1.[O:21]=[C:22]1[C:30]2([C:34]3[CH:35]=[CH:36][C:37]([C:39]#[N:40])=[CH:38][C:33]=3[O:32][CH2:31]2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]1CC1C=CC=CN=1.N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[O:7]1[C:6]2[CH:11]=[CH:12][C:3]([CH2:2][N:23]3[C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:30]4([C:34]5[CH:35]=[CH:36][C:37]([C:39]#[N:40])=[CH:38][C:33]=5[O:32][CH2:31]4)[C:22]3=[O:21])=[CH:4][C:5]=2[O:10][CH2:9][CH2:8]1
Reactant: N#Cc1ccc2c(c1)OCC21C(=O)N(Cc2ccccn2)c2ccccc21
Reactant: ClCc1ccc2c(c1)OCCO2
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: N#Cc1ccc2c(c1)OCC21C(=O)N(Cc2ccc3c(c2)OCCO3)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 6-(chloromethyl)-2,3-dihydrobenzo[b][1,4]dioxine (Capilla, A. S. et al., Tetrahedron (2001), 57:8297) to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 1′-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile was obtained (54%) as a colorless solid: mp 181-183° C. (dichloromethane/diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.29-7.16 (m, 1H), 7.15-6.97 (m, 3H), 6.89-6.75 (m, 5H), 5.04 (d, J=9.2 Hz, 1H), 4.94 (d, J=15.3 Hz, 1H), 4.80-4.67 (m, 2H), 4.25-4.19 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 176.2, 160.8, 143.8, 143.3, 142.2, 134.7, 131.3, 129.5, 128.5, 125.8, 124.4, 123.8, 123.7, 120.5, 118.5, 117.8, 116.3, 113.8, 113.3, 109.8, 80.2, 64.3 (2C), 57.8, 43.8.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:20]([C@H:23]2[C@H:28]([O:29]CC3C=CC=CC=3)[C@@H:27]([O:37]CC3C=CC=CC=3)[C@H:26]([O:45]CC3C=CC=CC=3)[C@@H:25]([CH2:53][O:54]CC3C=CC=CC=3)[O:24]2)=[CH:19][C:3]=1[CH2:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][N:10]([CH:14]2[CH2:16][CH2:15]2)[C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1.CO.ClC1C=CC=CC=1Cl>C1COCC1.[Pd]>[Cl:1][C:2]1[CH:22]=[CH:21][C:20]([C@H:23]2[C@H:28]([OH:29])[C@@H:27]([OH:37])[C@H:26]([OH:45])[C@@H:25]([CH2:53][OH:54])[O:24]2)=[CH:19][C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH:14]2[CH2:15][CH2:16]2)[C:11](=[O:13])[CH3:12])=[CH:17][CH:18]=1
Reactant: CC(=O)N(Cc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1)C1CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: Clc1ccccc1Cl
Solvent: CO
Product: CC(=O)N(Cc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1)C1CC1

Procedure:
To a solution of N-(4-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)benzyl)-N-cyclopropylacetamide (intermediate AR) (20 mg) in THF:CH3OH (v/v=1:1) (4 mL) at room temperature was added Pd/C and 1,2-dichlorbenzene (0.05 mL). The mixture was stirred under H2. After LC-MS showed the starting material was consumed, Pd/C was removed by filtration, and the solvent was removed under reduced pressure. The crude product was purified by preparative LC-MS to give compound AS (4 mg). 1H NMR (400 Hz, CD3OD): δ 0.77-0.87 (4H, m), 2.26 (3H, s), 2.62-2.66 (1H, m), 3.26 (1H, d, J=8.8 Hz), 3.36-3.46 (3H, m), 3.66-3.69 (1H, m), 3.86 (1H, d, J=12.8 Hz), 4.02-4.12 (3H, m), 4.56 (2H, s), 7.11-7.16 (4H, m), 7.26-7.29 (1H, m), 7.33-7.35 (2H, m); MS ESI (m/z): 520 (M+HCO2)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][OH:6].[H-].[Na+].Cl[C:15]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=[C:17]([S:26][CH3:27])[N:16]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][O:6][C:19]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][N:16]=[C:17]([S:26][CH3:27])[N:18]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: COc1ccc(CO)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(SC)nc1OCc1ccc(OC)c(Cl)c1
Yield: 11.7 %

Procedure:
3-Chloro-4-methoxybenzyl alcohol (20 g, 116 mmol) was dissolved in 200 mL of DMF, NaH (7.0 g, 174 mmol) was added under ice-water-bath. After 1 h of reaction, ethyl 4-chloro-2-(methylmercapto)pyrimidine-5-carboxylate (27 g, 116 mmol) was added in portions for continuing the reaction for 3 h. 300 mL of water was added, extraction was performed with ethyl acetate, the organic layer was dried, concentrated and separated with silica gel column (petroleum ether: ethyl acetate=10:1) to obtain ethyl 4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)pyrimidine-5-carboxylate as white solid (5.0 g, 12%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([O:17]CC)=O)=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.Cl[C:21](=[O:27])[CH2:22][C:23]([O:25][CH3:26])=[O:24]>>[CH2:8]([C:6]1[CH:7]=[C:2]2[C:3]([C:15]([OH:17])=[C:22]([C:23]([O:25][CH3:26])=[O:24])[C:21](=[O:27])[NH:1]2)=[N:4][CH:5]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1ncc(Cc2ccccc2)cc1N
Reactant: COC(=O)CC(=O)Cl
Product: COC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 3-amino-5-benzylpyridine-2-carboxylate and methyl 3-chloro-3-oxopropionate employing methods similar to those described in Example 1, Steps 10-11. The product was obtained as a tan solid: 1H NMR (d6-DMSO) δ 11.9 (1H, br), 11.59 (1H, s), 8.46 (1H, d, J=1.6 Hz), 7.43 (1H, d, J=1.6 Hz), 7.33-7.20 (5H, m), 4.11 (2H, s), 3.74 (3H, s); HRMS calcd for C17H14N2O4+H+: 311.1032. Found: 311.1025.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C@H:13]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Cl)[CH:27]=1.[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]([CH2:32][C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)[C@H:13]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: ClCc1cccnc1
Reactant: COc1ccc(S(=O)(=O)N[C@H](CC(C)C)C(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@H](CC(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of t-butyl 2(R)-[[4-methoxybenzenesulfonyl]amino]-4-methylpentanoate (10.0 g, 27.92 mmol) in dimethylformamide (250 mL) at room temperature is added 3-picolyl chloride hydrochloride (4.81 g, 29.32 mmol) followed by sodium hydride (2.79 g, 69.80 mmol, 60% in oil). The reaction mixture is stirred at room temperature for 48 hours. The mixture is quenched with water and extracted with ethyl acetate. The combined organic extracts are washed with brine, dried (Na2SO4), and the solvent is evaporated. The crude product is purified by silica gel chromatography (45% ethyl acetate/hexanes) to provide t-butyl 2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)-amino]-4-methylpentanoate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:7]
Reactant: Nc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Nc1cc(C(=O)N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.2 %

Procedure:
In N,N-dimethylformamide (DMF) (108 ml), 3-amino-4-nitrobenzoic acid [the compound of the formula (1a)] (10.8 g) which was prepared in accordance with a known method (HECHENG HUASUE, page 91, 1995) was dissolved. Further, morpholine (10.3 ml), 1-Hydroxybenzotriazole (HOBt) (9.60 g), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSCI.HCl) (13.6 g) were successively added to the solution, and the mixture was stirred at room temperature for 18 hours. The reaction solution was poured into a 1N HCl aqueous solution to precipitate crystals, and the whole was filtrated to obtain the crystals and a filtrate. The filtrate was extracted with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The above crystals and the concentrate were combined to obtain 3-amino-4-nitrobenzoic acid morpholide (12.1 g; yield=81.2%) as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[S:23])=[CH:17][CH:16]=1>CS(C)=O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[S:23])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: Fc1ccc(N=C=S)cc1
Solvent: CS(C)=O
Product: CCOC(=O)C(=O)c1csc(NC(=S)Nc2ccc(F)cc2)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 5 g of ethyl 2-aminothiazol-4-ylglyoxylate, 4.6 g of p-fluorophenyl isothiocyanate and 20 ml of dimethyl sulfoxide. The resulting product was a pale yellow powder having the following physical properties.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C1COCC1.CCCCCCC.[CH2:21]([C:23]1[CH:28]=CC=C[CH:24]=1)C.[CH3:29][O:30][C:31](=[O:55])[CH2:32][C:33]1[CH:38]=[C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:36]=[C:35]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:34]=1.BrCC(C)=C>C1COCC1>[CH3:29][O:30][C:31](=[O:55])[CH:32]([C:33]1[CH:34]=[C:35]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:36]=[C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:38]=1)[CH2:24][C:23]([CH3:28])=[CH2:21]
Reactant: COC(=O)Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: CCc1ccccc1
Agent: C=C(C)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: C=C(C)CC(C(=O)OC)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Temperature: 0 °C
Yield: 94.3 %

Procedure:
A 2M solution of LDA in THF-heptane-ethylbenzene (21.5 mL, 43.0 mmol) was added dropwise over 12 min to a stirred solution of (3,5-bis-benzyloxyphenyl)acetic acid methyl ester (13.0 g, 35.9 mmol) in THF (80 mL) at −78° C. under a nitrogen atmosphere. The temperature was maintained below −70° C. for a further 50 min then 3-bromo-2-methylpropene (4.0 mL, 39.7 mmol) was added in one portion and the reaction mixture was warmed to 0° C. After 2 h the mixture was concentrated in vacuo, diluted with sat. aq. NH4Cl (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine (100 mL), dried (MgSO4), concentrated in vacuo and purified by flash chromatography (silica, 0-10% EtOAc in petroleum ether) to afford the title product as a yellow oil (14.1 g, 94%).