Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH2:9][CH3:10])[CH:3]=1.COC1C=CC(CS[C:19]([S:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=CC=1>O1CCCC1>[CH3:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][S:31]/[C:19](/[CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:8](/[C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=2)\[CH2:9][CH3:10])=[CH:38][CH:37]=1
Reactant: CCCc1cc(Cl)ccn1
Reactant: CCOC(=O)C(C(=O)OCC)=C(SCc1ccc(OC)cc1)SCc1ccc(OC)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)/C(SCc1ccc(OC)cc1)=C(/CC)c1cc(Cl)ccn1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
Lithium diisopropylamide (LDA) is formed by dropwise addition of n-butyllithium (1.6 M in hexanes, 10.1 mL, 16.2 mmol) to a stirred solution of diisopropylamine (2.3 mL, 16.4 mmol) in tetrahydrofuran (25.0 mL) at −78° C. The resulting solution is stirred at −78° C. for 5 min, stirred at 0° C. for 15 min, and then re-cooled to −78° C. A solution of 4-chloro-2-propylpyridine (2, 2.29 g, 14.7 mmol) in tetrahydrofuran (25.0 mL) is added dropwise to this solution over a period of 30 min. The resulting deep red suspension is stirred at −78° C. for 1 h. A solution of diethyl 2-[bis(4-methoxybenzylsulfanyl)methylene]malonate (1, 7.03 g, 14.8 mmol) in tetrahydrofuran (40.0 mL) is then added dropwise over a period of 15 min. The resulting yellow solution is stirred at −78° C. for 1.5 h, −15° C. for 1.5 h, and room temperature for 30 min. to give a dark orange solution. The reaction mixture is quenched with a saturated aqueous solution of ammonium chloride (100 mL) and extracted with diethyl ether (2×100 mL). The combined organic extracts are dried over magnesium sulfate and evaporated under reduced pressure to give an orange oil. The product is purified by flash column chromatography (eluting with 5% ethyl acetate in methylene chloride; Rf0.50) to give 3 as an orange oil. 1H NMR (DMSO-d6): δ0.76 (t, J=7.5 Hz, 3H, CH2CH3), 1.17 (t, J=7.0 Hz, 6H, 2×CO2CH2CH3), 2.81 (q, J=7.5 Hz, 2H, CH2CH3), 3.74 (s, 3H, OCH3), 4.01 (s, 2H, SCH2), 4.10 (q, J=7.0 Hz, 4H, 2×CO2CH2CH3), 4.41 (s, 1H, CH(CO2CH2CH3)2), 6.90 (m, 2H, benzylic H-3/H-5), 7.28 (m, 2H, benzylic H-2/H-6), 7.44 (d, J=2.0 Hz, 1H, pyridyl H-3), 7.52 (dd, J=5.5 Hz, 2.0 Hz, 1H, pyridyl H-5), 8.56 (d, J=5.5 Hz, 1H, pyridyl H-6). 13C{1H} NMR (DMSO-d6): δ12.4 (CH2CH3), 13.9 (CH(CO2CH2CH3)2), 28.3 (CH2CH3), 39.5 (SCH2), 55.0 (OCH3), 58.5 (CH(CO2CH2CH3)2), 61.1 (CH(CO2CH2CH3)2), 113.9 (benzylic C-3/C-5), 122.9 (pyridyl C-5), 123.0 (pyridyl C-3), 125.7 (═C(SAr)(CH(CO2CH2CH3)2)), 129.3 (benzylic C-1), 130.2 (benzylic C-2/C-6), 143.4 (pyridyl C-4, C—Cl), 150.6 (pyridyl C-6), 153.3 (═C(CH2CH3)(pyridyl)), 158.4 (benzylic C-4, C—OCH3), 159.1 (pyridyl C-1), 167.2 (CH(CO2CH2CH3)2). LCMS m/z calcd for C24H28ClNO5S 477 ([M+]); found 478 ([M+H]+).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[NH:6]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:7]([C:18](ON1C(=O)CCC1=O)=[O:19])[C@@H:8]([CH3:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[NH:6]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C@H:7]([C:18]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:19])[C@@H:8]([CH3:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: NCC(=O)O
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Yield: 97.1 %

Procedure:
By using 5.40 g of H-Gly-OH and 22.40 g of Boc-Thr(Bzl)-OSu, and the same procedure as in Reference Example 14 was repeated to obtain 19.60 g (yield: 97.3%) of the above-mentioned objective product.
Reaction SMILES: [O:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=[CH:2]1.Cl.[NH2:10][C@H:11]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[O:32][CH3:33])=[CH:21][CH:20]=1)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[F:31][C:29]1[CH:28]=[CH:27][C:26]([O:32][CH3:33])=[C:25]([C:22]2[CH:21]=[CH:20][C:19]([CH2:18][C@@H:11]([NH:10][C:6]([C:5]3[O:1][CH:2]=[N:3][CH:4]=3)=[O:8])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:24][CH:23]=2)[CH:30]=1
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cc(F)ccc2OC)cc1
Reactant: O=C(O)c1cnco1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(F)ccc2OC)cc1)NC(=O)c1cnco1
Reaction time: 2 h

Procedure:
To a solution of oxazole-5-carboxylic acid (70 mg, 0.61 mmol) in DMF (1.5 mL) and DCM (1.5 mL) is added (R)-ethyl 3-amino-4-(5′-fluoro-2′-methoxybiphenyl-4-yl)butanoate hydrochloride, intermediate 10, (150 mg, 0.41 mmol), HATU (233 mg, 0.61 mmol), and TEA (284 μL, 2.04 mmol). After stirring for 2 hours, the reaction is quenched with H2O, and the crude is diluted with EtOAc, the organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN), and then lyophilized to give (R)-ethyl 4-(5′-fluoro-2′-methoxybiphenyl-4-yl)-3-(oxazole-5-carboxamido)butanoate (157 mg). HPLC retention time=1.50 minutes (condition A); MS (m+1)=427.4; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.19 (t, J=7.2 Hz, 3H) 2.46-2.62 (m, 2H) 2.86 (dd, J=13.6, 8.1 Hz, 1H) 3.02 (dd, J=13.6, 6.1 Hz, 1H) 3.67 (s, 3H) 4.05-4.15 (m, 2H) 4.52-4.69 (m, 1H) 6.76-6.82 (m, 1H) 6.83-6.96 (m, 2H) 7.11-7.21 (m, 3H) 7.37 (d, J=8.1 Hz, 2H) 7.61 (s, 1H) 7.80 (s, 1H)
Reaction SMILES: [CH3:1][N:2]1[CH:9]=[CH:8][C:6](=[O:7])[NH:5][C:3]1=[O:4].[CH2:10]([C:12]1[CH:13]=[CH:14][C:15]2[CH:25](O)[C:20]3[N:21]=[C:22]([CH3:24])[S:23][C:19]=3[CH:18]=[CH:17][C:16]=2[CH:27]=1)[CH3:11].FC(F)(F)C(O)=O>ClCCl>[CH2:10]([C:12]1[CH:13]=[CH:14][C:15]2[CH:25]([C:8]3[C:6](=[O:7])[NH:5][C:3](=[O:4])[N:2]([CH3:1])[CH:9]=3)[C:20]3[N:21]=[C:22]([CH3:24])[S:23][C:19]=3[CH:18]=[CH:17][C:16]=2[CH:27]=1)[CH3:11]
Reactant: Cn1ccc(=O)[nH]c1=O
Reactant: CCc1ccc2c(c1)C=Cc1sc(C)nc1C2O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1ccc2c(c1)C=Cc1sc(C)nc1C2c1cn(C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-Methyluracil (0.064 g) was added to a solution of the product from step (xi) (0.10 g) in dichloromethane (2 ml), followed by trifluoroacetic acid (1 ml). The orange solution was stirred at room temperature for 10 minutes before the solvent was removed under reduced pressure. The residue was azeotroped twice with acetonitrile, and the crude product purified by chromatography, eluting with 0-5% methanol in ethyl acetate.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4](C(OC)=O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]>[OH-].[K+]>[C:19]([OH:21])(=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:26])=[O:2]
Reactant: COC(=O)C(CCCCCCCCCCCCCCC(=O)O)C(=O)OC
Agent: [K+]
Agent: [OH-]
Product: O=C(O)CCCCCCCCCCCCCCCC(=O)O
Temperature: 140 °C
Reaction time: 2 h

Procedure:
2-Methoxycarbonyl-heptadecanedioic acid 1-methyl ester (4.63, 12.4 mmol g) was dissolved in 20% aqueous KOH (15 ml) by heating. The resulting solution was refluxed for 2.5 h. The cold reaction mixture was carefully concentrated. The residue was suspended in water (30 ml) on an ice bath and acidified with 10% aqueous HCl. The resulting slurry was refluxed for 2 h. After cooling the precipitate was isolated by filtration and dried over night in vacuo. The compound was decarboxylated by heating under stirring at 140° C. for 2 h. (the reaction should be followed, heating to 180° might be necessary). The crude product (4.0 g, 100%) was used without further purification. HPLC-MS: 323 (M+Na), Rt 4.61. 1H-NMR (DMSO-d6): δ 1.22 (br s, 22H) 1.47 (m, 4H), 2.18 (t, 4H).
Reaction SMILES: [S:1]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5](=[O:11])[NH:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[CH2:18]([O:20][CH:21]([O:24][CH2:25][CH3:26])[CH2:22]Br)[CH3:19].O>CN(C)C=O>[CH2:18]([O:20][CH:21]([O:24][CH2:25][CH3:26])[CH2:22][N:4]1[C:5](=[O:11])[C:6]2[CH:10]=[CH:9][S:8][C:7]=2[S:1][CH2:2][CH2:3]1)[CH3:19]
Reactant: CCOC(CBr)OCC
Reactant: O=C1NCCSc2sccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(CN1CCSc2sccc2C1=O)OCC

Procedure:
To a solution of 8.0 g of 2,3-dihydrothieno[3,2-f]-1,4-thiazepin-5(4H)-one in 160 ml of N,N-dimethylformamide was added 6.3 g of potassium t-butoxide with stirring under ice-cooling and the mixture was stirred for an hour at room temperature. Then to the mixture was added 8.4 ml of bromoacetaldehyde diethyl acetal under ice-cooling. The mixture was stirred for 5 hours at room temperature and water was added thereto and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and the solvent was distilled off. The residue was chromatographed on a silica gel using and chloroform and methanol (98.8:0.2) as an eluent to give 6,9 g of 4-(2,2-diethoxyethyl)-2,3-dihydrothieno[3,2-f]1,4-thiazepin-5(4H)-one as a pale yellow oil. To the solution of thus obtained 6.7 g of 4-(2,2-diethoxyethyl)-2,3-dihydrothieno[3,2-f]-1,4-thiazepin-5(4H)-one in 150 ml of tetrahydrofuran was added 20 ml of 10% hydrochloric acid and the mixture was allowed to stand for 20 hours at room temperature, and then poured into water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and the solvent was distilled off to give 4.4 g of 2,3,4,5-tetrahydro-5-oxothieno[3,2-f]-1,4-thiazepin-4-acetaldehyde as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[N+:19]([C:22]1[CH:32]=[CH:31][CH:30]=[C:24]2[C:25]([O:27][C:28](=O)[C:23]=12)=[O:26])([O-:21])=[O:20]>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:28](=[O:27])[C:23]3[C:24](=[CH:30][CH:31]=[CH:32][C:22]=3[N+:19]([O-:21])=[O:20])[C:25]2=[O:26])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: CC(=O)O
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Yield: 81 %

Procedure:
A stirred solution 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (640 mg, 2.34 mmol) and 3-nitrophthalic anhydride (460 mg, 2.34 mmol) in acetic acid (10 mL) was heated at reflux for 15 h. The solvent was removed in vacuo to yield an oil. Chromatography of the resulting oil yielded 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-nitroisoindoline-1,3-dione as a yellow solid (850 mg, 81% yield): mp, 110.0-114.0° C.; 1H NMR (CDCl3); δ 1.47 (t, J=7.0 Hz, 3H, CH3), 2.90 (s, 3H, CH3), 3.71 (dd, J=4.3, 14.4 Hz, 1H, CHH), 3.85 (s, 3H, CH3), 4.10 (q, J=7.0 Hz, 2H, CH2), 4.58 (dd, J=10.7, 14.4 Hz, 1H, CHH), 5.93 (dd, J=4.2, 10.7 Hz, 1H, NCH), 6.84 (d, J=8.8 Hz, 1H, Ar), 7.11-7.15 (m, 2H, Ar), 7.89 (t, J=7.8 Hz, 1H, Ar), 8.08-8.13 (m, 2H, Ar); 13C NMR (CDCl3) δ 14.67, 41.56, 49.19, 53.97, 55.96, 64.56, 111.52, 112.51, 120.62, 123.44, 127.35, 128.65, 128.84, 133.73, 135.48, 145.24, 148.68, 149.92, 162.53, 165.33; Anal Calcd for C20H20NO8S: C, 53.57; H, 4.50; N, 6.23. Found: C, 53.54; H, 4.28; N, 6.32
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.F[C:13]1[CH:22]=[C:21]([NH:23][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[O:25])[C:20]([N+:32]([O-:34])=[O:33])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].[CH2:35]([S:37]([C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=1)(=[O:39])=[O:38])[CH3:36]>O>[CH2:35]([S:37]([C:40]1[CH:45]=[CH:44][C:43]([O:46][C:13]2[CH:22]=[C:21]([NH:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[O:25])[C:20]([N+:32]([O-:34])=[O:33])=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[CH:42][CH:41]=1)(=[O:39])=[O:38])[CH3:36]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(NC(=O)c2ccccn2)cc1F
Reactant: CCS(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCS(=O)(=O)c1ccc(Oc2cc(NC(=O)c3ccccn3)c([N+](=O)[O-])cc2C(=O)OC)cc1
Temperature: 80 °C
Yield: 82.2 %

Procedure:
3.5 g of potassium carbonate was added to a dimethylformamide (110 ml) solution of 6 g of methyl 2-fluoro-5-nitro-4-[(2-pyridinylcarbonyl)amino]benzoate and 3.48 g of 4-(ethylsulfonyl)phenol obtained in Reference Example 2, and stirred under heat at 80° C. for 30 minutes. The reaction liquid was restored to room temperature, poured into 300 ml of water, and the formed solid was taken out through filtration. This was dried under reduced pressure to obtain 7.46 g of the entitled compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][CH:9]=[C:8]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[CH:7]=1)=[O:5])[CH3:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(O)(C(F)(F)F)=O>[O:16]=[C:14]1[C:9]2[NH:10][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][C:8]=2[CH2:11][CH2:12][CH2:13]1
Reactant: CCOC(=O)c1cc(CCCC(=O)O)c[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCOC(=O)c1cc2c([nH]1)C(=O)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Into a 1000-mL round-bottom flask was placed a solution of 113h (30 g, 133.19 mmol, 1.00 equiv) in CF3COOH (500 mL) and trifluoroacetyl 2,2,2-trifluoroacetate (42 g, 199.97 mmol, 1.50 equiv). See FIG. 14. The resulting solution was stirred at room temperature for 60 min, concentrated under vacuum, diluted with 500 mL of water and 500 mL of EA, and extracted with 3×500 mL of ethyl acetate. The combined organic layers were washed with 1×500 mL of saturated aqueous potassium carbonate and 1×500 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 24 g (87%) of 113i as a light brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:4]=1[CH2:5][N:6]=[C:7]=[O:8].[N+:15](=[C:17]1[N:21]=[CH:20][N:19]=[C:18]1[C:22]([NH2:24])=[O:23])=[N-:16]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:4]=1[CH2:5][N:6]1[C:7](=[O:8])[N:21]2[CH:20]=[N:19][C:18]([C:22]([NH2:24])=[O:23])=[C:17]2[N:15]=[N:16]1
Reactant: COc1ccc(CN=C=O)c(OC)c1
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Solvent: CS(C)=O
Product: COc1ccc(Cn2nnc3c(C(N)=O)ncn3c2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4-dimethoxybenzyl isocyanate (0.717 g, 4.4 mmol) was added drop wise to a suspension of 5-diazoimidazole-4-carboxamide (0.548 g, 4 mmol) in dry dimethylsulfoxide (5 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of ice and the solid product (purple) removed by filtration, washed with water and ethyl acetate and recrystallised from chloroform/hexane to give the title compound. Yield: 0.613 g, 46%. IR vmax/cm−1 3473, 3121, 1734, 1697, 1605, 1589. 1H NMR δH (DMSO-d6) 3.76 (3H, s, OMe), 3.80 (3H, s, OMe), 5.37 (2H, s, CH2Ar), 6.48 (1H, dd, J=8.4, 2.4, ArH), 6.60 (1H, d, J=2.4, ArH), 7.22 (1H, d, J=8.4, ArH), 7.68 (1H, br s, NH), 7.80 (1H, br s, NH), 8.81 (1H, s, 6-H). δC (DMSO-d6) 47.5, 55.8, 56.1, 98.9, 105.1, 115.9, 129.3, 130.7, 131.2, 134.8, 139.4, 158.5, 161.1, 162.0.
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]([C@@H:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:15])[CH2:12][OH:13])C1C=CC=CC=1.[H][H].O>[Pd].CO>[NH2:10][C@@H:11]([C@@H:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH3:15])[CH2:12][OH:13]
Reactant: C[C@H](OC(C)(C)C)[C@@H](CO)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CO
Product: C[C@H](OC(C)(C)C)[C@H](N)CO
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.1 %

Procedure:
To a round bottom flask containing benzyl((2R,3S)-3-(tert-butoxy)-1-hydroxybutan-2-yl)carbamate (5.27 g, 17.8 mmol) was added MeOH (100 mL). Solution was degassed with nitrogen for 15 min at which time palladium on carbon (0.95 g, 0.89 mmol) in MeOH (5 mL) was added. A hydrogen atmosphere was then inserted. Resulting reaction mixture allowed to stir 40 min at room temperature at atmospheric pressure when water (2 mL) was added and once again a hydrogen atmosphere was inserted at atmospheric pressure and the subsequent reaction mixture allowed to stir 18 hr at room temperature. The reaction mixture was filtered through a pad of celite and concentrated to a brown oil. Oil redissolved in toluene and concentrated to afford (2R,3S)-2-amino-3-(tert-butoxy)butan-1-ol (2.5 g, 15.5 mmol, 87% yield) as a brown oil. LCMS m/z 162.1 (M+H)+, Rt 0.41 min (Mass ion only, no UV peak).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:18])[CH2:15][CH:16]=[CH2:17])=[CH:4][CH:3]=1.I[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14](=[O:18])[CH2:15][CH2:16][CH2:17][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:6][CH:7]=1
Reactant: Ic1ccccc1
Reactant: C=CCC(O)c1c(C)noc1-c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CCCc1ccccc1
Temperature: 85 °C

Procedure:
1-[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-but-3-en-1-ol (1.76 g, 5.69 mmol), iodobenzene (0.638 mL, 5.69 mmol), and triethylamine (1.59 mL, 11.38 mmol) were dissolved in ACN (17 mL) and the solution was purged with bubbling N2 (g). Palladium(II) acetate (0.064 g, 0.28 mmol) was added, the reaction vessel was sealed, and the reaction was heated to 85° C. overnight. After cooling, the reaction was submitted to standard aqueous workup then purified on silica gel (0-30% EtOAc in hexanes) to give a separable mixture of two compounds, one of which was the title compound.
Reaction SMILES: [CH2:1](O)[C@H:2]([C@H:4]([C@@H:6]([C@@H:8]([CH2:10]O)O)O)O)O.C[C:14]1([CH3:21])[O:18][C@@H:17]([CH2:19][OH:20])[CH2:16][O:15]1>>[CH2:14]([O:15][CH2:16][C@H:17]([CH2:19][OH:20])[OH:18])[CH2:21][CH2:1][CH2:2][CH2:4][CH2:6][CH2:8][CH2:10][CH2:1][CH2:2][CH2:4][CH2:6][CH2:8][CH2:10][CH2:1][CH2:2][CH2:4][CH3:6]
Reactant: CC1(C)OC[C@H](CO)O1
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CCCCCCCCCCCCCCCCCCOC[C@@H](O)CO

Procedure:
According to the procedure of the reference [FEBS Letters, Vol. 116, 161 (1980)], D-mannitol was used as a starting material to give 25 g of the desired compound (needles) through 1,2-isopropylidene-sn-glycerol.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=[CH:16][C:4]=2[NH:3]1.ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)Cl>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6](=[O:29])[C:5]2[CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=[CH:16][C:4]=2[NH:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc2c(c1)Sc1ccccc1C(=O)N2
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)S(=O)c1ccccc1C(=O)N2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100.4 %

Procedure:
Suspend 1.14 gm (4 mmole) of the ester of Example 23 in 60 ml of methylene chloride and add 1.035 gm of commercial m-chloroperbenzoic acid. Stir at room temperature for 45 minutes and filter. Concentrate the filtrate and separate the solids. Combine the solids to obtain the title product (yield 1.21 gm).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[N:7][C:2]([N:29]5[CH2:30][CH2:31][N:27]([CH3:26])[C:28]5=[O:32])=[CH:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: CN1CCNC1=O
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)nn2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCN(C)C3=O)nn2)CC1
Yield: 43.7 %

Procedure:
Using (6-chloropyridazin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (179 mg) described in Preparation Example 233 and 1-methylimidazolidin-2-one (50 mg) and by the reaction and treatment in the same manner as in Example 536, the title compound (92 mg) was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.[C:23]([O:26][CH2:27][C:28]1[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=[CH:30][C:29]=1[N:43]1[N:52]=[CH:51][C:50]2[C:45](=[C:46]([F:57])[CH:47]=[C:48]([C:53]([CH3:56])([CH3:55])[CH3:54])[CH:49]=2)[C:44]1=[O:58])(=[O:25])[CH3:24].C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[C:53]([C:48]1[CH:49]=[C:50]2[C:45](=[C:46]([F:57])[CH:47]=1)[C:44](=[O:58])[N:43]([C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([C:2]3[CH:3]=[C:4]([NH:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]([N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)=[O:16])=[CH:13][N:14]=4)[N:5]=[CH:6][N:7]=3)[C:28]=1[CH2:27][O:26][C:23](=[O:25])[CH3:24])[N:52]=[CH:51]2)([CH3:54])([CH3:55])[CH3:56]
Reactant: O=C(c1ccc(Nc2cc(Cl)ncn2)nc1)N1CCOCC1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
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: O
Solvent: C1COCCO1
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)ncn2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 80 °C
Reaction time: 13 h
Yield: 30.7 %

Procedure:
To a stirred solution of (6-(6-chloropyrimidin-4-ylamino)pyridin-3-yl)(morpholino)methanone (0.15 g, 0.45 mmol) in 1,4-dioxane (5 mL) was added 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (0.250 g, 0.5 mmol), Pd(PPh3)4 (30 mg, 0.08 mmol), Na2CO3(212 mg, 2 mmol) and H2O (2 mL). The mixture was stirred at 80° C. for 13 hrs under N2. The mixture was evaporated and ethyl acetate (50 mL) and H2O (20 mL) were added to the resulting residue. The organic phase was washed with H2O (2×20 mL), brine (2×20 mL) and dried over Na2SO4. After filtration and concentration, the final product (90 mg, 30%) was obtained as yellow solid. LC-MS: 652.2 [M+H]+, tR=1.499 min.
Reaction SMILES: [NH2:1][C@@:2]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[CH2:7][O:6][C@@H:5]([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4][C@H:3]1[C@@H:17]([OH:19])[CH3:18].C(OC[C@@H]1OC[C@@](N[C:52]([NH:54][C:55](=[O:62])[C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[S:53])(C2C=CC(F)=CC=2F)[C@H](CO)C1)C1C=CC=CC=1>>[CH2:10]([O:9][CH2:8][C@@H:5]1[O:6][CH2:7][C@@:2]([NH:1][C:52]([NH:54][C:55](=[O:62])[C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)=[S:53])([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[C@H:3]([C@@H:17]([OH:19])[CH3:18])[CH2:4]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C[C@H](O)[C@@H]1C[C@H](COCc2ccccc2)OC[C@@]1(N)c1ccc(F)cc1F
Reactant: O=C(NC(=S)N[C@@]1(c2ccc(F)cc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO)c1ccccc1
Product: C[C@H](O)[C@@H]1C[C@H](COCc2ccccc2)OC[C@@]1(NC(=S)NC(=O)c1ccccc1)c1ccc(F)cc1F

Procedure:
The product was prepared from (1 S)-1-[(2R,4R,5S)-5-amino-2-[(benzyloxy)methyl]-5-(2,4-difluorophenyl)tetrahydro-2H-pyran-4-yl]ethanol (C19) according to the general procedure for the synthesis of N-{[(3S,4R,6R)-6-[(benzyloxy)methyl]-3-(2,4-difluorophenyl)-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide (C7) in Preparation P1. In this case, after concentration of the reaction mixture in vacuo, the residue was chromatographed on silica gel (Gradient: 0% to 50% ethyl acetate in heptane) to afford the product as a yellow foam. Yield: 13.36 g, 24.71 mmol, 67%. LCMS m/z 539.2 [M−H+].