Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([NH:10]C(OC(C)(C)C)=O)[CH2:5][O:6][CH2:7][CH:8]=[CH2:9].[ClH:19]>O1CCOCC1>[ClH:19].[CH3:1][O:2][C:3](=[O:18])[C@@H:4]([NH2:10])[CH2:5][O:6][CH2:7][CH:8]=[CH2:9]
Reactant: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: Cl
Solvent: C1COCCO1
Product: C=CCOC[C@H](N)C(=O)OC

Procedure:
Methyl ester 37 (1.00 g, 3.86 mmol) was dissolved in 4M hydrogen chloride in 1,4-dioxane (40 mL). The resultant solution was stirred at rt for 18 h before being concentrated in vacuo to afford a white solid, 0.656 g, 87%. m.p. 87-89° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.[CH2:29]([CH2:33][C:34](=O)[CH3:35])[C:30]([CH3:32])=O.O.[OH-].[Li+]>C1(C)C=CC=CC=1>[CH3:35][C:34]1[N:28]([C:25]2[CH:24]=[CH:23][C:22]([CH2:21][N:7]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]([C:13]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[C:6]3[C:4]([OH:3])=[O:5])=[CH:27][CH:26]=2)[C:30]([CH3:32])=[CH:29][CH:33]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2ccccc2n1Cc1ccc(N)cc1
Reactant: CC(=O)CCC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccc(Cn2c(C(=O)O)c(-c3ccccc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.9 %

Procedure:
A mixture of 1-(4-amino-benzyl)-3-phenyl-1H-indolecarboxylic acid ethyl ester (0.20 g, 0.54 mmol), acetonylacetone (0.16 mL, 1.35 mmol), and toluene (15 mL) was heated at reflux under nitrogen using a Dean-Stark trap for 6 h. The reaction was cooled and concentrated. The residue was re-dissolved in 10 mL of 2:1:1 THF/MeOH/water. Lithium hydroxide monohydrate (0.09 g, 2.1 mmol) was added and the mixture was stirred at room temperature overnight. Most of the organic solvents was removed and the reaction mixture was made acidic (pH 6) with glacial acetic acid, and the solid was collected and purified by HPLC to afford the title compound (0.027 g, 6%) as a brown solid: 1H NMR (DMSO-d6) δ 1.91 (s, 6H), 5.75 (s, 2H), 7.01-7.30 (m, 6H), 7.32-7.38 (m, 2H), 7.40-7.50 (m, 6H), 7.68 (d, J=8.54 Hz, 1H), 12.80 (br s, 1H); MS (ESI) m/z 421 (MH+); MS (ESI) m/z 419 ([M−H]−); HRMS calcd for C28H26N2O2: 421.1905; found (ESI+): 421.1915.
Reaction SMILES: [Cl:1][CH:2]([CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH:19]([F:21])[F:20])[C:15]([CH3:22])=[N:14]2)[C:10]([Cl:23])=[CH:9][C:8]=1[Cl:24])[C:3](O)=[O:4].S(Cl)(Cl)=O.[CH3:29][S:30]([NH2:33])(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([NH:33][C:3](=[O:4])[CH:2]([Cl:1])[CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH:19]([F:21])[F:20])[C:15]([CH3:22])=[N:14]2)[C:10]([Cl:23])=[CH:9][C:8]=1[Cl:24])(=[O:32])=[O:31]
Reactant: Cc1nn(-c2cc(CC(Cl)C(=O)O)c(Cl)cc2Cl)c(=O)n1C(F)F
Reactant: CS(N)(=O)=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1nn(-c2cc(CC(Cl)C(=O)NS(C)(=O)=O)c(Cl)cc2Cl)c(=O)n1C(F)F
Temperature: 120 °C
Yield: 33.8 %

Procedure:
In a manner similar to Example 4, the reaction of 0.50 g (0.0013 mole) of 2-chloro-3-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl]propionic acid (compound 2) with 5 mL of thionyl chloride produced a residue. To this residue was added 0.50 g (0.0052 mole) of methanesulfonamide. The mixture was stirred and heated at 120° C. for two hours. The mixture was cooled, diluted with methylene chloride, and a resultant precipitate was removed by filtration. The filtrate was washed with water. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated under reduced pressure to give 0.21 g of N-methylsulfonyl-2-chloro-3-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl]propionamide as a foam, Compound 25 of Table 1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[NH:7][C:8]1[CH:9]=[C:10]2[CH:16]=[C:15]([C:17]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=3)=[CH:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[N:14](S(C3C=CC=CC=3)(=O)=O)[C:11]2=[N:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:43])[NH:7][C:8]1[CH:9]=[C:10]2[CH:16]=[C:15]([C:17]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=3)=[CH:18][CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[NH:14][C:11]2=[N:12][CH:13]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
A mixture of {1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-carbamic acid tert-butyl ester (0.75 g, 1.21 mmol) and tetrabutylammonium fluoride in tetrahydrofuran (1 M, 24 mL, 24 mmol) was stirred for 3 h at 60° C. After cooling, the mixture was poured into brine (15 mL), extracted with ethyl acetate (2×100 mL), washed with a saturated aqueous ammonium chloride solution (3×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to give {2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-carbamic acid tert-butyl ester (0.58 g, 100%) which was used in the next step without purification: LC/MS m/e calcd for C26H31N3O4S [M+H]+ 482.62, observed 482.2
Reaction SMILES: NCC1C=C(NC([O:17][CH2:18][CH2:19][C:20]2C=C[C:23](C(NC3C=C4C(=CC=3)C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=NC=C4)C(O)=O)=[CH:22][C:21]=2C)=O)C=CC=1S(CC)(=O)=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:90]([OH:96])([C:92](F)(F)F)=[O:91]>>[OH:91][CH:90]1[C:92]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:17])[O:96]1
Reactant: O=C(O)C(F)(F)F
Reactant: CCS(=O)(=O)c1ccc(NC(=O)OCCc2ccc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2C)cc1CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Product: O=C1OC(O)c2ccccc21
Yield: 35 %

Procedure:
Using a procedure analogous to that used to prepare Example 28, 31D (400 mg, 0.51 mmol) was cyclized with PyBOP instead of BOP, deprotected with TFA, and purified by reverse phase HPLC to give Example 31 (100 mg, 35%) as a tan solid. 1H NMR (400 MHz, CD3OD) δ ppm 1.09-1.24 (m, 3 H) 2.27 (s, 2 H) 2.49 (s, 2 H) 2.67-2.88 (m, 1 H) 3.05-3.17 (m, 1 H) 3.22-3.28 (m, 2 H) 4.05 (d, J=9.89 Hz, 0.5 H) 4.13-4.25 (m, 0.5 H) 4.29-4.39 (m, 1 H) 5.01-5.12 (m, 2 H) 5.14-5.18 (m, J=3.30 Hz, 1 H) 6.43 (none, 1 H) 6.68 (d, J=2.75 Hz, 1 H) 6.70-6.78 (m, J=5.50 Hz, 1 H) 6.78-6.86 (m, 1 H) 6.92-7.16 (m, 2.5 H) 7.21 (m, 0.5 H) 7.44 (m, 0.5 H) 7.51 (s, 0.5 H) 7.65-7.74 (m, 1 H) 7.90-8.02 (m, 1 H) 8.76-8.92 (m, J=6.05 Hz, 1 H). MS (ESI) m/z 574.18 (M+H)+.
Reaction SMILES: C(OC(N1C2C(=CC=C([Br:15])C=2)C(O)=N1)=O)C.[CH2:17]([O:19][C:20]([N:22]1[C:30]2[C:25](=[C:26](Br)[CH:27]=[CH:28][CH:29]=2)[C:24]([O:32][CH3:33])=[N:23]1)=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([N:22]1[C:30]2[C:25](=[CH:26][C:27]([Br:15])=[CH:28][CH:29]=2)[C:24]([O:32][CH3:33])=[N:23]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)n1nc(OC)c2c(Br)cccc21
Reactant: CCOC(=O)n1nc(O)c2ccc(Br)cc21
Product: CCOC(=O)n1nc(OC)c2cc(Br)ccc21

Procedure:
5-Bromo-3-methoxy-indazole-1-carboxylic acid ethyl ester CCXXXVI was prepared from 6-bromo-3-hydroxy-indazole-1-carboxylic acid ethyl ester using the procedure described for preparation of 4-Bromo-3-methoxy-indazole-1-carboxylic acid ethyl ester CLXXXV (Example 37).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[CH2:19][CH2:20][NH2:21].C(=O)(O)[O-].[Na+].O>CCO>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([NH:21][CH2:20][CH2:19][C:13]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=2[Cl:11])[CH:7]=1
Reactant: NCCc1ccc(Cl)cc1Cl
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CSc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Temperature: 85 °C
Yield: 72.3 %

Procedure:
A mixture of 4,6-dichloro-2-methylsulfanyl-pyrimidine (2.66 g, 13.6 mmol), 2-(2,4-dichloro-phenyl)-ethylamine (2.26 mL, 15 mmol) and sodium bicarbonate (2.29 g, 27.2 mmol) in EtOH (35 mL) is heated to 85° C. for 1 hour and poured into water (100 mL). The solid precipitate is collected by filtration and dissolved in hot EtOH (75 mL). After cooling overnight the crystals that formed are collected by filtration and dried to afford (6-chloro-2-methylsulfanyl-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine (3.43 g, 72%) as a solid.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([OH:33])[CH:14]([S:23]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])(C(C)(C)C)(C)C.N1C=CC=CC=1.F.CCCCCC.C(OCC)(=O)C.CCCCCC>O1CCCC1.C(OCC)(=O)C>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([S:23]([CH:14]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[CH:13]([OH:33])[CH2:12][CH2:11][CH2:10][CH2:9][OH:8])(=[O:25])=[O:24])=[CH:31][CH:30]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCCC(O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: F
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)C(O)CCCCO
Temperature: 25 °C
Reaction time: 20 h
Yield: 55 %

Procedure:
The 6-(t-butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]-1-(2,5-difluorophenyl)-2-hexanol (Isomer 234-B) (120 mg, 0.231 mmol) obtained in Example 234 was dissolved in tetrahydrofuran (5 ml), followed by the addition of hydrogen fluoride-pyridine (0.5 ml). The resulting mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water, a saturated aqueous solution of sodium bicarbonate, and brine, dried over magnesium sulfate and then, concentrated. The residue thus obtained was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=1:1 eluate was concentrated. The solid thus obtained was recrystallized from ethyl acetate-hexane, whereby the title compound (51.3 mg, 0.127 mmol, 55%) was obtained as a white powder.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:6])[O:4][CH3:5].[CH:7]1[CH2:12][CH2:11][CH:10]=[CH:9][CH:8]=1.I([O-])(=O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.I([O-])(=O)(=O)=O.S(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:5][O:4][C:3]([N:2]1[CH:9]2[CH2:10][CH2:11][CH:12]([CH:7]=[CH:8]2)[O:1]1)=[O:6]
Reactant: COC(=O)NO
Reactant: C1=CCCC=C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)N1OC2C=CC1CC2
Temperature: -10 °C
Reaction time: 3 h

Procedure:
A suspension of methyl N-hydroxycarbamate (17.81 g) in methylene chloride (350 ml) was cooled to about -13° C. (ice/acetone bath), and sequentially treated with 1,3-cyclohexadiene (14.24 g) and a suspension of tetrabutylammonium periodate (84.73 g) in methylene chloride (550 ml). The periodate suspension was added over a one hour period causing the temperature of the reaction to rise to a maximum of -5° C. After the addition of the periodate suspension was complete, the resulting reaction mixture was stirred at about -10° C. for three hours. A 10% sodium bisulfite solution (750 ml) was carefully added to the reaction mixture, while cooling in an ice/acetone bath. After about 45 minutes, the addition of the sodium bisulfite solution was complete. The organic phase was removed, washed with water (2×200 ml) and saturated sodium bicarbonate solution (2×500 ml). The organic phase was dried over sodium chloride, filtered, and concentrated in vacuo to give 180 g of the crude product. A solution of the crude product in methylene chloride was added to silica gel (200 g), and the resulting mixture evaporated to dryness. The title compound was isolated by flash silica-gel filtration, eluting with hexane/ethyl acetate (9:1, 2 L) and hexane/ethyl acetate (7:3, 500 ml). The fractions containing the title compound were combined, dried over sodium chloride and magnesium sulfate, filtered, and concentrated in vacuo to give 27.85 g of an oil. The oil was placed in a freezer to induce crystalization.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][S:10]([C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][NH:19][CH2:20]3)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:23]([O:27][CH2:28][CH3:29])(=[O:26])[CH:24]=[CH2:25]>C1COCC1>[CH2:28]([O:27][C:23](=[O:26])[CH2:24][CH2:25][N:19]1[CH2:18][CH2:17][C:16]2[C:21](=[CH:22][C:13]([S:10](=[O:12])(=[O:11])[NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=3)=[CH:14][CH:15]=2)[CH2:20]1)[CH3:29]
Reactant: O=S(=O)(Nc1cccc(Cl)c1)c1ccc2c(c1)CNCC2
Reactant: C=CC(=O)OCC
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CCN1CCc2ccc(S(=O)(=O)Nc3cccc(Cl)c3)cc2C1
Yield: 107.5 %

Procedure:
A mixture of 7-(3-chlorophenylsulphamoyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (3.25 g, 9 mmol) (EP No. 0038177-A) and ethyl acrylate (0.91 g, 9 mmol) in THF (8 ml) was heated under reflux for 18 hr. Concentration and chromatography (silica gel, ether) gave ethyl-3-[7-(3-chlorophenylsulphamoyl)-1,2,3,4-tetrahydroisoquinolin-2-yl]propionate as a viscous oil (4.09 g, 98.7%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]2[S:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:8][CH:7]=1.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24].Cl>>[CH2:23]([N:25]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]2[S:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:8][CH:7]=1)[CH2:26][CH3:27])[CH3:24]
Reactant: ClCCCOc1ccc(/C=C/c2nc3ccccc3s2)cc1
Reactant: CCNCC
Agent: Cl
Product: CCN(CC)CCCOc1ccc(/C=C/c2nc3ccccc3s2)cc1
Yield: 24 %

Procedure:
The title compound was prepared as described in Example 28 starting with (F) of Example 28 (3.0 g, 9.8 mmol) and using diethylamine in place of dibutylamine to produce 0.81 g (24% yield) of the title compound as the HCl salt, mp 187°-188° C. IR(KBr): 3400, 1600 cm-1. MS: 367(MH+). 1H NMR (CD3OD): δ 8.22-6.99 (m, 10H), 4.21 (t, J=5.1 Hz, 2H), 3.34 (m, 6H), 2.33 (m, 2H), 1.42 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(N(CCCC)CCCC)CCC.[C:24]([NH:32][C:33]1[CH:45]=[C:44]([CH:46]=[CH2:47])[CH:43]=[CH:42][C:34]=1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.CN(C)C(=O)C>[C:24]([NH:32][C:33]1[CH:45]=[C:44](/[CH:46]=[CH:47]/[C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:43]=[CH:42][C:34]=1[C:35]([O:37][C:38]([CH3:40])([CH3:41])[CH3:39])=[O:36])(=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2ccccc2)c1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCCCN(CCCC)CCCC
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(/C=C/c2ccc([N+](=O)[O-])cc2)cc1NC(=O)c1ccccc1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 72.8 %

Procedure:
0.14 g of 1-bromo-4-nitrobenzene, 0.22 mL of tributylamine and 5.2 mg of palladium acetate were added to 2.0 mL of N,N-dimethylacetamide solution containing 0.15 g of tert-butyl 2-(benzamido)-4-vinylbenzoate at room temperature and stirred under nitrogen atmosphere at 110° C. for 1 hour and 20 minutes. After the reaction mixture was cooled to room temperature, 10% citric acid aqueous solution and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution, a saturated sodium thiosulfate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1]to obtain 0.15 g of tert-butyl 2-(benzamido)-4-((E)-2-(4-nitrophenyl)vinyl)benzoate as yellow solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH3:12])=[C:6]([F:13])[CH:5]=1)=[O:3].[C:14](=O)([O:17]C)[O:15][CH3:16].FSI>>[CH3:16][O:15][C:14](=[O:17])[CH2:1][C:2](=[O:3])[C:4]1[CH:5]=[C:6]([F:13])[C:7]([O:11][CH3:12])=[C:8]([F:10])[CH:9]=1
Reactant: COC(=O)OC
Reactant: COc1c(F)cc(C(C)=O)cc1F
Agent: FSI
Product: COC(=O)CC(=O)c1cc(F)c(OC)c(F)c1
Yield: 97 %

Procedure:
This compound was prepared from 3,5-difluoro-4-methoxyacetophenone and dimethyl carbonate according to method A. Yellow solid; Yield: 97%; mp 64-67° C.; 1H-NMR (300 MHz, CDCl3) δ 3.77 (s, 3H), 3.93 (s, 2H), 4.13 (t, J=1.7 Hz, 3H), 7.52 (m, 2H). Minor tautomer: 3.81 (s, 3H), 4.06 (m, 3H), 5.58 (s, 1H), 7.34 (m, 2H), 12.47 (s, 1H); MS (FSI) m/z 243 ([M−H]−), 245 ([M+H]+); Anal. Calcd for C11H10F2O4: C, 54.10; H, 4.13. Found: C, 54.37; H, 4.08.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([I:10])=[CH:5][C:6]([F:9])=[N:7][CH:8]=1.[N+](C)([O-])=[O:12].CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl.F[B-](F)(F)F.[Ag+].CO>[F:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][OH:12])=[C:4]([I:10])[CH:5]=1
Reactant: C[N+](=O)[O-]
Reactant: Fc1cc(I)c(CBr)cn1
Agent: [Ag+]
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CO
Product: OCc1cnc(F)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
Combine 5-bromomethyl-2-fluoro-4-iodo-pyridine (0.9 g, 2.85 mmol), nitromethane (15 mL, 278 mmol), silver tetrafluoroborate (721 mg, 3.7 mmol), and dimethylformamide (5 mL) in a round bottom flask. Stir the mixture overnight at room temperature. Add sodium carbonate (1.81 g, 17.1 mmol) and methanol (10 mL) into the mixture. Stir at room temperature for another 4 hours. Dilute the reaction mixture with chloroform, and wash with water and saturated aqueous sodium chloride. Separate the organic layer from the aqueous layer and dry over MgSO4. After filtration, evaporate the organic solvent in vacuo to give the crude product. Purify the crude with flash column chromatography (eluted with 10% methanol in dichloromethane) to give the desired product (0.6 g, 83%). MS (ES) m/z 254 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=4)[CH:17]=3)=[C:11]([CH3:27])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:26]=[CH:25][C:21]([C:22]([NH:28][CH:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[O:24])=[CH:20][N:19]=4)[CH:17]=3)=[C:11]([CH3:27])[N:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Reactant: NC1CCOCC1
Product: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)NC3CCOCC3)cn2)cn1
Yield: 76 %

Procedure:
As described for example 36b, 6-(4-(1-(4-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (56 mg, 0.154 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (52 mg, 76%) which was obtained as an off white solid. MS: m/e=448.3 [M+H]+.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:23]=[C:21](C)[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[OH:24])(C(C)(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:45]1[C:49](=[O:50])[C:48]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:47]2[C:46]1=[O:55].CCOCC>C1COCC1>[C:49]1(=[O:50])[N:45]([O:8][CH2:9][C@H:10]2[O:14][C@@H:13]([N:15]3[CH:23]=[CH:21][C:19](=[O:20])[NH:18][C:16]3=[O:17])[CH2:12][C@@H:11]2[OH:24])[C:46](=[O:55])[C:47]2=[CH:54][CH:53]=[CH:52][CH:51]=[C:48]12
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O
Temperature: 0 °C
Yield: 62 %

Procedure:
To a solution of 5′-O-t-butyldimethylsilylthymidine (1, 21.36 g, 60 mmol, prepared according to the procedure of Nair, et al., Org. Prep. Procedures Int. 1990, 22, 57 in dry THF (750 ml)), triphenylphosphine (17.28 g, 66 mmol) and N-hydroxyphthalimide (10.74 g, 66 mmol) were added. The solution was cooled to 0° C. and diisoprbpylazodicarboxylate (15.15 g, 75 mmol) was added dropwise over a period of 3 hr while stirring under nitrogen. The reaction mixture was then stirred at room temperature for 12 hr. The solution was evaporated and the residue was dissolved in CH2Cl2 (750 ml), extracted with sat. NaHCO3 (200 ml), and water (200 ml), dried (MgSO4), filtered and concentrated to furnish yellow oily residue. Silica gel column chromatography (100% hexanes, and then hexanes:Et2O gradient to 90% Et2O) of the residue gave compound 2 as a colorless glass (18.68 g, 62%); 1H NMR (CDCl3) δ 0.05 [2s, 6, (CH3)2], 0.91 [s, 9, (CH3)3], 2.0 (s, 3, CH3), 2.5-2.65 (m, 2, 2′CH2), 4.05-4.2 (m, 2, 5′CH2), 4.25-4.35 (m, 1, 4′H), 5.0 (m, 1, 3′H), 6.15 (m, 1, 1′H), 8.6 (br s, 1, NH), and aromatic protons. Anal. Calcd. for C24H31N3O7Si: C, 57.46;H, 6.23; N, 8.37. found : C, 57.20; H, 6.26; N, 8.27.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:15]=1[C:16](Cl)=O.C(NC1C=CC2N=C(C3C(F)=CC=CC=3F)OC(=O)C=2C=1)(=O)C>C(N(CC)CC)C.C1(C)C=CC=CC=1>[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:15]=1[C:16]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([F:12])[C:9]([F:11])=[CH:10][C:2]=2[N:1]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Agent: CC(=O)Nc1ccc2nc(-c3c(F)cccc3F)oc(=O)c2c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1oc(-c2c(F)cccc2F)nc2cc(F)c(F)cc12

Procedure:
2-Amino-4,5-difluorobenzoic acid (0.5 g), 2,6-difluorobenzoyl chloride (0.80 mL) and triethyl amine/toluene (1/1) (18 mL) were reacted as described under (10). Reaction time 1 day. Extraction between ethyl acetate (20 mL) and HCl (2N,20 mL), followed by separation of the organic toluene and precipitated with hexane. The resulting mixture was further purified on a silicagel column using dichloromethane as eluent. The isolated fraction identified as 2-(2,6-difluoro-phenyl)-6,7-difluoro-benzo[d][1,3]oxazin-4-one (0.71 g), mp. 165 C, MS m/e: 295 M+.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH2:20][O:21][CH3:22])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]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.[NH2:50][C:51]1[S:52][CH:53]=[CH:54][N:55]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH2:20][O:21][CH3:22])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([NH:50][C:51]2[S:52][CH:53]=[CH:54][N:55]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nccs1
Reactant: COCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.6 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methoxymethanesulfonyl-phenyl)-propionic acid (31 mg, 0.09 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (67 mg, 0.15 mmol), and 2-aminothiazole (15 mg, 0.15 mmol) in methylene chloride (1 mL) at 25° C. was treated with triethylamine (0.04 mL, 0.29 mmol). The reaction was stirred at 25° C. for 20 h. At this time, the reaction was treated with a saturated aqueous sodium bicarbonate solution. The resulting organic layer was washed with a 1N aqueous hydrochloric acid solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 80/20 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methoxymethanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (23 mg, 59.2%) as a white solid: mp 157–160° C.; EI-HRMS m/e calcd for C19H24N2O4S2 (M+) 408.1178, found 408.1178.