Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][C:45]=3[Cl:48])[C:40]2=[O:49])[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.Cl.[NH2:51][C:52]1[S:53][C:54]([Cl:57])=[CH:55][N:56]=1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>>[Cl:57][C:54]1[S:53][C:52]([NH:51][C:36](=[O:38])[C@@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][C:45]=3[Cl:48])[C:40]2=[O:49])[CH2:34][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[N:56][CH:55]=1
Reactant: Nc1ncc(Cl)s1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2c(Cl)cccc2C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(Nc1ncc(Cl)s1)[C@H](CC1CCCCC1)N1Cc2c(Cl)cccc2C1=O
Yield: 32.5 %

Procedure:
BOP coupling of (S)-3-cyclohexyl-2-(4-Chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (ca. 1:1 mixture of regioisomers, prepared in Example 36, Step C; 151 mg; 0.47 mmol) and 2-amino-5-chlorothiazole hydrochloride(186 mg; 1.05 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide as outlined in Example 9, Step B) provided after chromatography (Biotage 40M column, eluent: 5% to 20% gradient of ethyl acetate/hexanes) 67 mg of (S)-N-(5-Chloro-thiazol-2-yl)-3-cyclohexyl-2-(4-Chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide: EI-HRMS m/e calcd for C20H21Cl2N3O2S (M+) 437.0731, found 437.0727; and 46 mg of regioisomeric S)-N-(5-Chloro-thiazol-2-yl)-3-cyclohexyl-2-(7-Chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide: EI-HRMS m/e calcd for C20H21Cl2N3O2S (M++Na+) 437.0731, found 437.0726.
Reaction SMILES: [OH:1][C@H:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][C:8]1[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=1.[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=O.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:13]([C:11]1[S:12][C:8]([CH2:7][CH2:6][CH2:5][N:4]2[CH2:3][C@@H:2]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:1][CH:24]2[C:23]([O:27][CH3:28])=[O:26])=[CH:9][CH:10]=1)([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1ccc(CCCNC[C@H](O)c2ccccc2)s1
Reactant: COC(=O)C=O
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CCCN2C[C@@H](c3ccccc3)OC2C(=O)OC)s1
Yield: 64.4 %

Procedure:
1.91 g of methyl 5-[3-[[(R)-β-hydroxyphenethyl]amino]propyl]-2-thiophenecarboxylate and 1.05 g of methyl glyoxylate were heated to reflux in 20 ml of toluene for 1 hour on a water separator. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate solutions were dried and evaporated in vacuo. Chromatography of the residue on silica gel gave 1.5 g of methyl(2RS,5R)-3-[3-(5-carbomethoxy-2-thienyl)propyl]-5-phenyl-2-oxazolidinecarboxylate, [α]D =-12° (0.1% in dioxan); ε278 =12300, ε255 =9300.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[C:25]([CH2:27][CH2:28][C:29]4[CH:30]=[C:31]([CH:36]=[CH:37][N:38]=4)[C:32](OC)=[O:33])[C:24]([C:39]([F:42])([F:41])[F:40])=[CH:23][N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O.C[N:47](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl-].[NH4+]>C1COCC1.O.CO.CN(C=O)C>[C:32]([C:31]1[CH:36]=[CH:37][N:38]=[C:29]([CH2:28][CH2:27][C:25]2[C:24]([C:39]([F:41])([F:40])[F:42])=[CH:23][N:22]=[C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([CH:11]4[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9][CH2:10]4)=[CH:15][CH:16]=3)[N:26]=2)[CH:30]=1)(=[O:33])[NH2:47]
Reactant: COC(=O)c1ccnc(CCc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4cc(C(N)=O)ccn4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl 2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)isonicotinate (I129) (70.0 mg, 0.120 mmol), and LiOH.H2O (15 mg, 0.36 mmol) in THF (5 mL), water (1 mL) and MeOH (0.5 mL) was stirred at room temperature for 4 hours. The volatiles were evaporated under reduced pressure to give a yellow solid which was dissolved in dry DMF (4 mL). HATU (133 mg, 0.350 mmol), DIPEA (60 μL, 0.034 mmol) and ammonium chloride (187 mg, 3.50 mmol) were added and the resulting mixture was stirred at room temperature overnight. The volatiles were evaporated under reduced pressure and the residue diluted with ethyl acetate. The resulting solution was washed with 10% aqueous NaHCO3, then the organic layer was dried (MgSO4) and volatiles removed by evaporation under reduced pressure. The residue was adsorbed onto silica gel and purified by chromatography (SiO2, 0-100% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I130) (50 mg, 50%) as a colourless solid; 1H NMR (400 MHz, CDCl3) δ 8.67 (dd, J=5.1, 0.7 Hz, 1H), 8.51 (s, 1H), 7.60 (s, 1H), 7.55 (s, 1H), 7.53 (d, J=8.6 Hz, 2H), 7.44 (dd, J=5.1, 1.6 Hz, 1H), 7.18 (d, J=8.5 Hz, 2H), 6.37-6.20 (m, 1H), 6.18-5.96 (m, 1H), 4.22 (s, 2H), 3.34 (tt, J=10.4, 5.0 Hz, 4H), 2.63 (s, 1H), 1.81 (d, J=12.7 Hz, 2H), 1.73 (s, 2H), 1.60 (dd, J=12.7, 4.1 Hz, 2H), 1.48 (s, 9H). LCMS Method C: rt 6.04 min; m/z 571.2 [M+1C, 569.2 [M−1]−, 515.2 [M−t-Bu+2]+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[N:5][N:4]([CH2:7][C:8]2[O:9][CH:10]=[C:11]([C:13](=[O:15])[CH3:14])[N:12]=2)[N:3]=1.[C:16]1([C:22]2[O:26][CH:25]=[N:24][C:23]=2[C:27](O)=[O:28])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:13]([C:11]1[N:12]=[C:8]([CH2:7][N:4]2[N:3]=[C:2]([NH:1][C:27]([C:23]3[N:24]=[CH:25][O:26][C:22]=3[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:28])[CH:6]=[N:5]2)[O:9][CH:10]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)c1coc(Cn2ncc(N)n2)n1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(=O)c1coc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)n1

Procedure:
Following general procedure A, starting from 1-[2-(4-amino-[1,2,3]triazol-2-ylmethyl)-oxazol-4-yl]-ethanone and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Cl[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)=[CH:18][CH:19]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)cc1
Temperature: 80 °C
Yield: 93.8 %

Procedure:
According to Scheme 2 Step 1: A suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (25.8 mmol, 5.00 g), 1-(chloromethyl)-4-methoxybenzene (25.8 mmol, 3.49 mL) and K2CO3 (25.8 mmol, 3.56 g) in acetonitrile (40 mL) was heated at 80° C. for 5 hours. After filtration over celite, the filtrate was evaporated and the resulting crude product was purified by flash chromatography over silica gel using EtOAc/cyclohexane (90:10 to 70:30) as eluent to afford 1-(4-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (24.2 mmol, 7.61 g, 94%) as a colorless solid.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][C:5]=1[C:16]1[CH:21]=[C:20]([CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH:19]=[CH:18][C:17]=1[O:28]C>N1C=CC=CC=1>[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][C:5]=1[C:16]1[CH:21]=[C:20]([CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH:19]=[CH:18][C:17]=1[OH:28]
Reactant: COc1ccc(CCCC(=O)O)cc1-c1cc(CCCC(=O)O)ccc1OC
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)CCCc1ccc(O)c(-c2cc(CCCC(=O)O)ccc2O)c1
Temperature: 180 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
A mixture of pyridine (30 ml) and conc. hydrochloric acid (30 ml) was heated at about 180° C. for 30 mins. A known compound, 2,2'-dimethoxy-5,5'-bis (3-carboxypropyl) biphenyl (1.2 g) was added thereto and the mixture was heated at about 180° C. with stirring overnight. Upon cooling, the reaction mixture was poured into ice water and the mixture was extracted with ethyl acetate under acidic conditions with hydrochloric acid. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried by adding anhydrous magnesium sulfate, then the solvent was evaporated off under reduced pressure. A residue was re-precipitated by adding ethyl acetate-toluene to obtain 2,2'-dihydroxy-5,5'-bis (3-carboxypropyl) biphenyl (1.01 g, 91%) as a white powder. 1H-NMR (CD3OD) δ (ppm): 1.8-2.1 (4H, m, 2CH2), 2.32 (4H, t, 2CH2), 2.63 (4H, t, 2CH2), 6.84 (2 H, d, arom-H), 6.9-7.2 (4H, m, arom-H) MS (FAB): 357 (M-H)-
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:32]=[CH:31][C:17]([C:18]([NH:20][CH2:21][CH2:22][NH:23]C(=O)OC(C)(C)C)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][N:35]=2)[CH2:6][C@@H:5]1[CH3:42])(=[O:3])[CH3:2].[ClH:43]>O1CCOCC1>[ClH:43].[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:32]=[CH:31][C:17]([C:18]([NH:20][CH2:21][CH2:22][NH2:23])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][N:35]=2)[CH2:6][C@@H:5]1[CH3:42])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCNC(=O)OC(C)(C)C)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCN)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reaction time: 1 h
Yield: 104 %

Procedure:
A suspension of tert-butyl (2-(4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzamido)ethyl)carbamate (for a preparation see Intermediate 39)(65 mg, 0.114 mmol) in 1,4-dioxane (1 mL) at room temperature was treated with hydrogen chloride in 1,4-dioxane (4N, 2 mL, 8.00 mmol) and the resulting suspension was stirred at this temperature for 1 h then concentrated in vacuo. The precipitate formed was triturated with Et2O isolated by filtration and dried under vacuum to give 4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(2-aminoethyl)benzamide, hydrochloride (60 mg, 0.119 mmol, 104% yield) as a white solid. LCMS (HpH, 2 min), Rt=0.75 min, MH+=469.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([NH:21][C:22]([NH:24][C:25]3[N:29]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)[N:28]=[C:27]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:26]=3)=[O:23])=[CH:13][CH:12]=2)[CH:5]=[CH:4][N:3]=1.ClC(Cl)(Cl)[C:43]([N:45]=C=O)=[O:44]>N1C=CC=CC=1>[C:37]([C:27]1[CH:26]=[C:25]([NH:24][C:22](=[O:23])[NH:21][C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([O:10][CH2:9][CH2:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:43](=[O:44])[NH2:45])[CH:7]=3)=[CH:12][CH:13]=2)[N:29]([C:30]2[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=2)[N:28]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCc3ccnc(N)c3)c3ccccc23)cc1
Solvent: c1ccncc1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCc3ccnc(NC(N)=O)c3)c3ccccc23)cc1
Temperature: 25 °C

Procedure:
To a solution of 1-(4-(2-(2-aminopyridin-4-yl)ethoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (7) (Intermediate D) (50 mg, 0.094 mmol) in pyridine (1.0 mL) was added trichloroacetylisocyanate (12 μl, 0.103 mmol). The mixture was stirred at RT until judged to be complete by LC-MS and solvent was evaporated under reduced pressure. The resulting residue was subjected to SCX capture and release and triturated from DCM (10 mL) to give 4-(2-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)ethyl)-3-(pyridin-2-yl)urea (Example 21) as an off white solid (25 mg, 44%): m/z 578 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.26 (9H, s), 2.38 (3H, s), 3.12 (2H, t), 4.35 (2H, t), 6.34 (1H, s), 6.94-6.99 (2H, m), 7.19 (1H, dd), 7.33-7.35 (2H, m), 7.41-7.50 (5H, m), 7.52-7.56 (1H, m), 7.60 (1H, d), 7.87 (1H, d), 8.09-8.13 (2H, m), 8.54 (1H, s), 8.75 (1H, s), 9.08 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[N:4][C:3]=1[CH3:10].C1C(=O)N([Br:18])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:10][C:3]1[C:2]([CH3:1])=[N:7][C:6]([CH3:8])=[C:5]([CH3:9])[N:4]=1
Reactant: Cc1nc(C)c(C)nc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nc(C)c(CBr)nc1C
Yield: 70 %

Procedure:
Dehydrated tetramethylpyrazine 10 g was dissolved into CCl4 60 ml and then NBS 9.17 g was added at a molar ratio of tetramethylpyrazine to NBS=1:0.7 (a minute amount of benzoylperoxide can be added as radical initiator). Reaction was carried out under reflux under the illumination of an incandescent lamp for 10-12 h. The reaction sample was cooled and condensed, and the excess tetramethylpyrazine was sucked away at reduced pressure in 60-70° C. water bath. The residue was kept in a fridge for standing and a pale red half-oily substance 7.75 g was obtained with a yield of 70%.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])=[CH:7][CH:8]=1
Reactant: OCCc1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 80 %

Procedure:
A solution of 2-(4-trifluoromethylphenyl)-ethanol (570 mg, 3.0 mmol) in pyridine (6 mL) was stirred on an ice/acetone bath and treated with p-toluenesulfonyl chloride (630 mg, 3.3 mmol). The cooling bath was replaced with an ice/water bath and the mixture was stirred for 3.5 hours. Ice-cold water (12 mL) was added slowly, and the mixture was extracted three times with chloroform. The combined organic phases were washed with water, then with cold 1.0 N aqueous sulfuric acid until the wash phase was acidic. The organic phase was dried over sodium sulfate and concentrated to provide a white solid (826 mg) which contained about 10% by weight of residual alcohol. This was used without further purification. 1H NMR (300 MHz, CDCl3) for toluenesulfonate: δ7.65 (d, J=8 Hz, 2H), 7.50 (d, J=8 Hz, 2H), 7.26 (d, J=8 Hz, 2H), 7.23 (d, J=8 Hz, 2H), 4.26 (t, J=7 Hz, 2H), 3.02 (t, J=7 Hz, 2H), 2.44 (s, 3H).
Reaction SMILES: [Li+].[Cl-].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[CH2:14]([O:21][C:22](=[O:35])[NH:23][CH:24]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:25]CC=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C.C(OCC)C.[NH4+].[Cl-]>[CH3:3][O:4][C:5](=[O:6])[CH2:7][CH2:25][CH:24]([NH:23][C:22]([O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=CCCC(NC(=O)OCc1ccccc1)c1ccccc1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)CCC(NC(=O)OCc1ccccc1)c1ccccc1
Reaction time: 0.08 h
Yield: 81.6 %

Procedure:
To a stirring room temperature suspension of LiCl (0.84 g, 19.8 mmol) in dry acetonitrile (50 mL) was added trimethyl phosphonoacetate (4 mL, 24.75 mmol). The resulting mixture was stirred for 5 minutes, then TEA (2.76 mL, 19.8 mmol) was added. The reaction mixture was stirred for 10 minutes, and then a solution of (4-oxo-1-phenyl-butyl)-carbamic acid benzyl ester (16.5 mmol) in acetonitrile (15 mL) was added. The reaction mixture was stirred at room temperature for 18 hours, then diluted with diethyl ether and saturated aqueous NH4Cl. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to an oil, which was chromatographed (5%-40% EtOAc in hexanes) to give 4.41 g (79%) of 4-benzyloxycarbonylamino-4-phenyl-butyric acid methyl ester as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH3:26]O>>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16]([O:18][CH3:26])=[O:17])=[CH:5][CH:4]=1
Reactant: O=C(O)CCc1cnoc1-c1ccc(C(F)(F)F)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc(C(F)(F)F)cc1
Yield: 74 %

Procedure:
To a solution of 3-[5-(4-trifluoromethylphenyl)-4-isoxazolyl]propionic acid (2.20 g) in methanol (50 ml) was added conc. sulfuric acid (1 ml) and the mixture was heated under reflux for 1 hr. The reaction mixture was concentrated, and iced water was poured into the residue. The precipitated crystals (1.70 g, yield 74%) of methyl 3-[5-(4-trifluoromethylphenyl)-4-isoxazolyl]propionate were collected by filtration. The crystals were recrystallized from ethyl acetate-hexane to give a colorless prism. melting point: 68–69° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])=[C:5]([CH3:15])[CH:4]=1)=[O:2].CCN(C(C)C)C(C)C>C(O)C.[Pd]>[OH:2][CH2:1][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[C:5]([CH3:15])[CH:4]=1
Reactant: Cc1cc(C=O)cc(C)c1C=CC(=O)O
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1cc(CO)cc(C)c1CCC(=O)O
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a solution of 3-(4-formyl-2,6-dimethyl-phenyl)-acrylic acid (2.2 g, 10.8 mmol) and DIPEA (2.0 mL, 11.9 mmol) in ethanol (80 mL), Pd/C (200 mg, 10% Pd, moistened with 50% water) is added. The suspension is vigorously stirred under 1 bar of H2 for 1 h. The mixture is filtered over Celite and the filtrate is evaporated. The residue is poured onto 1 N aq. HCl/ice and extracted with EA. The organic extract is washed once with 1 N aq. HCl and once with brine, dried over MgSO4, filtered and evaporated to give 3-(4-hydroxymethyl-2,6-dimethyl-phenyl)-propionic acid (2.2 g) as a pale yellow resin; LC-MS: tR=0.71 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=O.[O:31]=[C:32]1[NH:37][C@H:36](C(O)=O)[CH2:35][CH2:34][CH2:33]1>O>[Cl:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([CH:36]2[NH:37][C:32](=[O:31])[CH2:33][CH2:34][CH2:35]2)=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Cl)cc(OC)c1
Reactant: O=C1CCC[C@@H](C(=O)O)N1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: COc1cc(Cl)cc(OC)c1C1CCCC(=O)N1
Temperature: 100 °C

Procedure:
A mixture of commercially available 1-chloro-3,5-dimethoxybenzene (1.243 g; 6.98 mmol), P2O5(991 mg; 6.98 mmol), and methanesulfonic acid (5.659 g; 58.89 mmol) was treated with commercially available (S)-6-oxopiperidine-2-carboxylic acid (1.000 g; 6.98 mmol), and the resulting mixture was heated to 100° C. for 30 min. After cooling to rt, water was added, and the resulting solution was extracted with DCM. The mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by preparative HPLC afforded 6-(4-chloro-2,6-dimethoxyphenyl)piperidin-2-one as a colorless solid. LC-MS (conditions E): tR=0.61 min.; [M+H]+: 270.26 g/mol.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.Cl[CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:17]1>CN(C)C=O>[C:22]1([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][CH2:13][O:3][C:4]3[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=3)[CH2:21][CH2:20]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClCCCN1CCN(c2ccccc2)CC1
Reactant: O=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCCN2CCN(c3ccccc3)CC2)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
Sodium hydride (3.59 g of 60% in oil) is added to 4-hydroxybenzaldehyde (9.95 g) in dimethylformamide (250 mL) and the mixture stirred at 60° C. for 30 minutes. 1-(3-Chloropropyl)-4-phenylpiperazine (Step A) (19.5 g) is added and the mixture stirred for 14 hours at 60° C. The solvent is evaporated and the residue treated with water (300 mL) and extracted with dichloromethane (3×150 mL). The extracts are dried over magnesium sulfate, filtered and evaporated to leave a beige solid. This solid is recrystallized from ethyl acetate/diethyl ether to give 18.4 g of the title compound as a light beige solid.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH2:11][C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][CH:5]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Product: CCOC(=O)C(=O)CC(=O)c1ccc(OC)cc1

Procedure:
The title compound was prepared in the same manner as intermediate 29 using sodium metal (0.168 g, 7.32 mmol), 1-[4-(methyloxy)phenyl]ethanone (1 g, 6.66 mmol), and diethyl ethanedioate (0.903 mL, 6.66 mmol). The crude product was purified using column chromatography (0 to 100% EtOAc/hexanes) to give 0.95 g of product (57%). LCMS E-S (M+H)=250.9. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43 (m, 3H), 3.91 (s, 3H), 4.41 (q, J=6.65 Hz, 2H), 6.94-7.12 (m, 3H), 8.01 (d, J=8.59 Hz, 2H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[F:38][C:39]1[N:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1.[F-].[Cs+].C(=O)([O-])O.[Na+]>COCCOC.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:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:42]3[CH:43]=[N:44][C:39]([F:38])=[CH:40][CH:41]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccc(F)nc1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=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: [Cs+]
Solvent: COCCOC
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4ccc(F)nc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 88.5 %

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene 71 (500 mg) obtained in Example 128-(4) was dissolved in 1,2-dimethoxyethane (15 ml), and added thereto were 6-fluoropyridine-3-boronic acid 58 (228 mg), tetrakis(triphenylphosphine)palladium(0) (94 mg) and cesium fluoride (738 mg). The mixture was heated under reflux for 30 minutes. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=75:25-60:40) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(6-fluoro-3-pyridyl)-2-thienylmethyl)benzene (454 mg) as a colorless solid. APCI-Mass m/Z 634/636 (M+H). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(6-fluoro-3-pyridyl)-2-thienylmethyl)benzene was treated in a manner similar to Example 106-(3) to give the desired 1-(β-D-glucopyranosyl)-4-chloro-3-(5-(6-fluoro-3-pyridyl)-2-thienylmethyl)benzene as colorless powder. APCI-Mass m/Z 483 (M+NH4), 466 (M+H).