Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]([CH2:37][CH3:38])[C:9]([NH:11][C:12]1[NH:16][C:15]2[C:17]([C@H:32]3[CH2:36][CH2:35][CH2:34][O:33]3)=[C:18]([F:31])[C:19]([C:21]3[CH:22]=[N:23][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[N:25][CH:26]=3)=[CH:20][C:14]=2[N:13]=1)=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=NN=N1.CC(N([P:51]([O:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[O:52]CC1C=CC=CC=1)C(C)C)C.C1C=C(Cl)C=C(C(OO)=[O:76])C=1>C(Cl)Cl>[CH2:61]([O:60][P:51]([OH:52])([O:33][CH2:32][C:17]1[CH:15]=[CH:14][CH:20]=[CH:19][CH:18]=1)=[O:76])[C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1.[C:1]([N:8]([CH2:37][CH3:38])[C:9]([NH:11][C:12]1[NH:16][C:15]2[C:17]([C@H:32]3[CH2:36][CH2:35][CH2:34][O:33]3)=[C:18]([F:31])[C:19]([C:21]3[CH:22]=[N:23][C:24]([C:27]([OH:30])([CH3:28])[CH3:29])=[N:25][CH:26]=3)=[CH:20][C:14]=2[N:13]=1)=[O:10])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: CC(C)N(C(C)C)P(OCc1ccccc1)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CCN(C(=O)Nc1nc2cc(-c3cnc(C(C)(C)O)nc3)c(F)c([C@H]3CCCO3)c2[nH]1)C(=O)OC(C)(C)C
Agent: c1nnn[nH]1
Solvent: ClCCl
Product: O=P(O)(OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To Boc-1-ethyl-3-[6-fluoro-5-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-7-[(2R)-tetrahydrofuran-2-yl]-1H-benzimidazol-2-yl]urea (25) (12.69 g, 23.58 mmol) and tetrazole (3.304 g, 47.16 mmol) under N2 at 23° C. was added DCM (240 mL) followed by N-dibenzyloxyphosphanyl-N-isopropyl-propan-2-amine (9.775 g, 9.509 mL, 28.30 mmol). After 3 hours at 23° C., the reaction was cooled to 0° C. then mCPBA (6.977 g, 28.30 mmol) was added. The resulting solution was stirred for 45 min at 0° C. then for 20 min at 23° C. The reaction mixture was then partitioned between DCM (50 mL) and saturated aqueous sodium bicarbonate (400 mL). The organic layer was separated, then washed successively with aqueous sodium bisulfite (63 g in 350 mL water) and saturated aqueous sodium bicarbonate (400 mL), then dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by MPLC using an ISCO COMBIFLASH brand flash chromatography purification system (330 g silica column) eluting with a 0-100% EtOAc in hexanes linear gradient over 16 column volumes at 200 mL/min. Product containing fractions were evaporated in vacuo to give Boc-1-ethyl-3-[6-fluoro-5-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-7-[(2R)-tetrahydrofuran-2-yl]-1H-benzimidazol-2-yl]urea dibenzyl phosphate (26) (11.92 g, 15.11 mmol, 64.09%). ESMS (M+1)=789.2; 1H NMR (300.0 MHz, CDCl3) δ 9.51 (s, 1H), 9.03 (t, J=5.4 Hz, 1H), 8.91 (d, J=1.6 Hz, 2H), 7.73 (d, J=6.5 Hz, 1H), 7.37-7.28 (m, 10H), 5.58 (t, J=7.8 Hz, 1H), 5.17-5.05 (m, 4H), 4.23 (t, J=7.5 Hz, 1H), 4.05 (td, J=7.8, 4.3 Hz, 1H), 3.53-3.44 (m, 2H), 2.39 (dd, J=7.9, 14.5 Hz, 2H), 2.28-2.15 (m, 2H), 1.98 (s, 6H), 1.72 (m, 9H) and 1.31 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][CH2:21][O:22][CH3:23])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:37][OH:38]>O1CCCC1>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][CH2:21][O:22][CH3:23])[N:16]=2)[CH2:11][C:12]([NH:37][OH:38])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCCc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Reactant: NO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COCCc1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
A solution of ((3R)-6-cyclohexyl-3-[3-(2-methoxyethyl)-1,2,4-oxadiazol-5-yl]hexanoic acid (Preparation 51) (245 mg, 0.76 mmol) in anhydrous tetrahydrofuran (10 ml) was treated with 1,1′-carbonyldiimidazole (123 mg, 0.76 mmol) and the mixture stirred at room temperature under a nitrogen atmosphere for 1 hour. Hydroxylamine hydrochloride (53 mg, 0.76 mmol) was then added and the mixture stirred for 18 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia (95:5:0.5). The residue was dissolved in ethyl acetate, washed with hydrochloric acid (1M), dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound as an oil (100 mg)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].IC.[C:16](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:10][C:8](=[O:9])[CH:7]([CH3:16])[C:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:13])[CH3:12]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CC(=O)c1ccco1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)C(C)C(=O)c1ccco1

Procedure:
In a flask were placed ethyl 3-(2-furyl)-3-oxopropanoate (0.5 g), iodomethane (0.14 ml), finely ground potassium carbonate (0.75 g) and acetone (5 ml). The mixture was stirred at reflux for 2 h. A further portion of iodomethane (0.9 mmol, 0.056 ml) and potassium carbonate (0.9 mmol, 0.12 g) were added and the mixture stirred at reflux for 1 h. The reaction mixture was filtered and concentrated under vacuum. Yield (0.5 g, 93%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]1.C(N(CC)CC)C.[CH3:15][N:16]1[CH:20]=[C:19]([S:21](Cl)(=[O:23])=[O:22])[N:18]=[C:17]1[CH3:25]>C(Cl)Cl>[CH3:15][N:16]1[CH:20]=[C:19]([S:21]([N:1]2[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]2)(=[O:23])=[O:22])[N:18]=[C:17]1[CH3:25]
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Reactant: O=Cc1cn[nH]c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(S(=O)(=O)n2cc(C=O)cn2)cn1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve 1H-pyrazole-4-carboxaldehyde (0.150 g, 1.56 mmol) in DCM (5 mL). Add triethylamine (240 μL, 1.72 mmol) and 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride (0.334 g, 1.72 mmol). Stir at ambient temperature for 18 hr. Concentrate, and purify via silica gel chromatography, eluting with 50:50 to 100:0 ethyl acetate:hexanes to give the title preparation (317 mg, 80%). GC-MS: m/z=254 [M+].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]([NH2:15])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C:13]#[N:15])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NC(=O)CCCc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#CCCCc1ccc([N+](=O)[O-])cc1
Yield: 63.4 %

Procedure:
To a solution of compound 81 (3.2 g, 22.4 mmol) in DCM (60 mL) was added TEA (10 mL, 77 mmol) at room temperature with stirring. Then to the mixture was added dropwise TFAA (4 mL, 30.8 mmol) at 0° C. The reaction mixture was stirred at room temperature for 4 h. Then the mixture was diluted with DCM, washed by water and brine, dried over Na2SO4 and concentrated to dryness to give compound 82 (2.7 g, 93%) as a yellow oil. 1H NMR (400 MHz, CDCl3) 8.12 (d, 2H, J=8.1 Hz), 7.30 (d, 2H, J=8.1 Hz), 2.85 (t, 2H, J=7.5 Hz), 2.31 (t, 2H, J=7.3 Hz), 1.92-2.05 (m, 2H).
Reaction SMILES: C1CCCCC1.C1(C(C)C)C=CC=CC=1.[CH3:16][NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([Li])CCC.[CH:29]12[O:35][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34]2>>[CH3:16][N:17]([C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[OH:35])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CNc1ccccc1
Reactant: C1CCC2OC2C1
Agent: [Li]CCCC
Solvent: CC(C)c1ccccc1
Solvent: C1CCCCC1
Product: CN(c1ccccc1)[C@@H]1CCCC[C@H]1O
Reaction time: 24 h
Yield: 75 %

Procedure:
To a 500 mL round bottom flask was added 100 mL of 1.2 M potassium t-amylate in cyclohexane (0.12 moles) and 41.7 mL of cumene (0.3 moles) under a constant flow of nitrogen gas. Then 10.8 mL of N-methylaniline (0.1 moles) was added to the reaction mixture while the reaction was continuously stirred. n-Butyllithium (46 mL of a 2.2 M solution, 0.1 moles) was added and the resulting amide was left stirring for two days. Cyclohexene oxide (10.1 mL, 0.1 moles) was added. After 24 hours, the reaction was quenched by carefully adding water under the flow of nitrogen. Washing of the product with 100 mL of distilled water yielded two layers of which the organic layer was extracted. Repeated rotovapor distillations removed most of the cumene. Any leftover cumene after rotovapor distillation was removed by vacuum horizontal distillation. This device employs a vacuum (<1 mm Hg) and liquid nitrogen to trap cumene, which distilled at about 85° C., but 16 g of racemic MPAC (0.075 moles, 75% yield) distilled at 120° C. The product, MPAC, was analyzed by NMR spectroscopy and the spectrum confirmed the presence of the compound when it was compared to that of literature (Swamy and Raghavendra, 2002).
Reaction SMILES: [NH:1]([C:5]1[C:13]2[C:8](=[C:9]([CH2:14][S:15][C:16]3[NH:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[N:10]=[CH:11][CH:12]=2)[S:7][CH:6]=1)[C:2]([CH3:4])=[O:3].C1C=C(Cl)C=C(C(OO)=[O:33])C=1.[O-]S([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[NH:1]([C:5]1[C:13]2[C:8](=[C:9]([CH2:14][S:15]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[N:17]=3)=[O:33])[N:10]=[CH:11][CH:12]=2)[S:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Nc1csc2c(CSc3nc4ccccc4[nH]3)nccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(=O)Nc1csc2c(CS(=O)c3nc4ccccc4[nH]3)nccc12
Reaction time: 1.5 h
Yield: 58.6 %

Procedure:
To a solution of 83 mg (0.244 mmol) of 2-[(3-acetaminothieno[2, 3-c]pyridin-7-yl)methylthio]benzimidazole (Ia-12) was dissolved in a mixture of 4 ml of CHCl3 and 2 ml of MeOH. To the solution was added 53 mg (1 equivalent) of 80% m-CPBA at -10° C., and the mixture was stirred for 1.5 hr. at the same temperature. By adding an appropriate quantity each of 10% Na2SO3 and saturated aqueous NaHCO3 to the solution, crystals separated out. The crystals were collected by filtration to give 72 mg of crude crystals. The crystals were recrystallized from a solution of CHCl3 - MeOH, whereby 53 mg (Yield : 60.9%) of 2-[(3-acetaminothieno[2, 3-c]pyridin-7-yl)methylsulfinyl]benzimidazole (Ic-27) was obtained as an objective compound.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[C:14]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][CH2:6]1.Cl.[CH3:23]NC.C=O.C(O)(=O)C>CN(C)C=O>[Cl:1][C:2]1[C:15]([Cl:16])=[C:14]([C:17](=[O:21])[C:18](=[CH2:23])[CH2:19][CH3:20])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][CH2:6]1
Reactant: CCCC(=O)c1ccc(OC2(C(=O)O)CCC2)c(Cl)c1Cl
Reactant: CNC
Agent: C=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C=C(CC)C(=O)c1ccc(OC2(C(=O)O)CCC2)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(2,3-dichloro-4-butyrylphenoxy)cyclobutane-1-carboxylic acid (4 g, 0.012 mole), dimethylamine hydrochloride (5.5 g, 0.067 mole), paraformaldehyde (1.2 g, 0.04 equiv.) and acetic acid (0.3 ml) were stirred and heated on a steam bath for 2.25 hours. N,N-dimethylformamide (30 ml) was added and stirring and heating was continued for another 2 hours. The mixture was poured into ice water and extracted with ether. The ether layer was washed with water and then with brine and finally dried over MgSO4. The solution was treated with p-xylene and the solvents were removed in vacuo. The resulting residue was recrystallized from hexane to give 1-[2,3-dichloro-4-(2-methylenebutyryl)phenoxy]cyclobutane-1-carboxylic acid, m.p. 120° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[C:6]([F:12])[CH:5]=1)([O-:3])=[O:2].[C:13]([CH2:18][CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:15][CH2:16][CH3:17])=[O:14].CCCCCCC>C1(C)C=CC=CC=1>[F:12][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=[CH:10][C:7]=1/[CH:8]=[C:18](\[CH3:19])/[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1F
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(C)=C/c1ccc([N+](=O)[O-])cc1F
Temperature: 120 °C
Yield: 79132.3 %

Procedure:
Compound 14b (14.6 mg) was dissolved in toluene (132 ml), and (carbetoxyethylidene)triphenylphosphorane (46.9 g) was added thereto. The obtained mixture was stirred under heating at 120° C. for 2 hours. After the reaction mixture was allowed to cool, n-heptane was added thereto and stirred. The precipitated solid was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methanol (125 ml), and purified water was added thereto. The precipitated solid was filtered off and then dried under reduced pressure. Thus, Compound 14c (17.3 g, 79%) was obtained as an opalescent solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH:11]2[CH2:13][C:12]2([CH3:17])[C:14]([OH:16])=[O:15])=[O:10])=[N:6][CH:7]=1.[CH3:18]O>S(Cl)(Cl)=O>[CH3:18][O:15][C:14]([C:12]1([CH3:17])[CH2:13][CH:11]1[C:9](=[O:10])[NH:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:16]
Reactant: CC1(C(=O)O)CC1C(=O)Nc1ccc(Cl)cn1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C1(C)CC1C(=O)Nc1ccc(Cl)cn1
Temperature: 0 °C

Procedure:
A suspension of (1SR,2RS)-2-(5-chloro-pyridin-2-ylcarbamoyl)-1-methyl-cyclopropane-carboxylic acid (176 mg) in MeOH (5 ml) was cooled to 0° C. and treated with thionyl chloride (15 drops). After stirring for 2 hrs at 0° C. additional thionyl chloride (10 drops) was added. The clear solution was concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2−>CH2Cl2/MeOH 9:1) to give (1SR,2RS)-2-(5-chloro-pyridin-2-ylcarbamoyl)-1-methyl-cyclopropanecarboxylic acid methyl ester (163 mg) as colorless amorphous solid. MS 269.5 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:8])(F)[S:3]([O-:6])(=[O:5])=[O:4].[CH:9]1([S:15][C:16]2[CH:21]=[CH:20][C:19]([S+:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[F:35][C:36]([F:42])(F)S([O-])(=O)=O.ClCl.[CH3:45]O>>[CH:29]12[CH2:45][CH:32]([CH2:31][CH2:30]1)[CH2:33][CH:34]2[C:36]([F:42])([F:35])[C:2]([F:8])([F:1])[S:3]([O-:6])(=[O:5])=[O:4].[CH:9]1([S:15][C:16]2[CH:21]=[CH:20][C:19]([S+:22]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:18][CH:17]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: CO
Agent: ClCl
Agent: c1ccc([S+](c2ccccc2)c2ccc(SC3CCCCC3)cc2)cc1
Product: O=S(=O)([O-])C(F)(F)C(F)(F)C1CC2CCC1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
19.2 g of the resulting 4-cyclohexylthiophenyl diphenylsulfonium trifluoromethane sulfonate was dissolved in 100 g of methanol in a reaction flask. The mixture was fed into an ion-exchange chromatography (an ion-exchange resin: Shephadex R-QAE A-25, packing amount: 60 g, manufactured by Aldrich Corporation) to replace trifluoromethanesulfonate anions with chlorine ions. After evaporating methanol using an evaporator, the resulting residue was dissolved in 100 g of dichloromethane. 15 g of 30 wt % 2-(bicyclo[2.2.1]heptan-2-yl)-1,1,2,2-tetrafluoroethane sodium sulfonate aqueous solution was added. The mixture was stirred for one hour at room temperature and transferred to a separatory funnel, shaken, and allowed to stand still. The water layer was removed. 100 ml of distilled water was added and the mixture was shaken again and allowed to stand still. The water layer was removed. The resulting dichloromethane solution was dried with anhydrous magnesium sulfate and filtered. After evaporating dichloromethane from the dried solution, the residual liquid was dried under reduced pressure to obtain 20.1 g of 4-cyclohexylthiophenyl diphenylsulfonium 2-(bicyclo[2.2.1]heptan-2-yl)-1,1,2,2-tetrafluoroethanesulfonate.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:20])[NH:4][C:5](=[O:19])[N:6]([C@H:8]2[C@@:12]([F:14])([CH3:13])[C@H:11]([OH:15])[C@@:10]([F:18])([CH2:16][OH:17])[O:9]2)[CH:7]=1.C([Mg]Cl)(C)(C)C.Cl[C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]=1[O:38][P:39](=[N:41][C@@H:42]([CH3:49])[C:43]([O:45][CH:46]([CH3:48])[CH3:47])=[O:44])=[O:40].CO>C1COCC1>[CH:46]([O:45][C:43](=[O:44])[C@@H:42]([N:41]=[P:39]([O:38][C:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:36]=[CH:37][C:28]=1[O:17][CH2:16][C@:10]1([F:18])[C@@H:11]([OH:15])[C@:12]([F:14])([CH3:13])[C@H:8]([N:6]2[CH:7]=[C:2]([Br:1])[C:3](=[O:20])[NH:4][C:5]2=[O:19])[O:9]1)=[O:40])[CH3:49])([CH3:47])[CH3:48]
Reactant: C[C@]1(F)[C@H](n2cc(Br)c(=O)[nH]c2=O)O[C@](F)(CO)[C@H]1O
Reactant: CC(C)OC(=O)[C@H](C)N=[P+]([O-])Oc1c(Cl)ccc2ccccc12
Agent: CC(C)(C)[Mg]Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)OC(=O)[C@H](C)N=[P+]([O-])Oc1c(OC[C@@]2(F)O[C@@H](n3cc(Br)c(=O)[nH]c3=O)[C@](C)(F)[C@@H]2O)ccc2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
To a solution of chiral 5-bromo-1-((2R,3R,4S,5S)-3,5-difluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidine-2,4-dione (50 mg, 0.14 mmol) prepared in Preparation 7 in THF (3 ml) at 0° C. was added a THF solution (Aldrich, 1 M) of tert-butylmagnesium chloride (0.35 mL, 0.35 mmol) dropwise. The mixture was stirred at 0° C. for 15 min, followed by the addition of THF solution (0.5 M) of (2S)-isopropyl 2-(chloro(naphthalen-1-yloxy)phosphorylamino)propanoate prepared in Example 2 Step B (0.7 mL, 0.35 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h. Methanol (2 mL) was added to quench the reaction. The mixture was purified by flash chromatography (5-10% MeOH in DCM) to give (S)-2-[[(2S,3S,4R,5R)-5-(5-bromo-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionic acid isopropyl ester as a white solid (50 mg, 52%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15].[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[S:30]([NH:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])(=[O:32])=[O:31]
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: COC(=O)c1cccc(CSc2ccc(F)cc2N)c1
Solvent: c1ccncc1
Product: COC(=O)c1cccc(CSc2ccc(F)cc2NS(=O)(=O)c2cc3ccccc3o2)c1
Yield: 49.4 %

Procedure:
Following General Procedure B, the title compound (601 mg, 50%) was prepared from methyl 3-(((2-amino-4-fluorophenyl)thio)methyl)benzoate (750 mg, 2.58 mmol) and benzofuran-2-sulfonyl chloride (556 mg, 2.58 mmol) in pyridine (5 ml).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]([NH2:43])[CH:40]=[CH:41][CH:42]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]2[C:6]3[CH2:5][C:4]4[S:3][C:2]([C:37]5[CH:38]=[C:39]([NH2:43])[CH:40]=[CH:41][CH:42]=5)=[CH:9][C:8]=4[C:7]=3[N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:26])[CH3:27])[N:11]=2)=[CH:18][CH:17]=1
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4cccc(N)c4)cc2-3)cc1
Temperature: 100 °C
Yield: 67 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.95 g, 1.9 mmol), 3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (0.34 g, 1.1 mmol), Na2CO3 (2 M, 4.6 mL), and Pd(PPh3)2Cl2 (226 mg, 0.1 mmol) in toluene/ethanol (1:1, 16 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (30% EtOAc in hexane) to give 3-[6-(4-Methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-phenylamine as brown solid in 67% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:15])=[N:10][CH:11]=[C:12](Br)[N:13]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:25]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:15])=[N:10][CH:11]=[C:12]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)[CH:25]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccnc(N3CCOCC3)c2)OC1(C)C
Reactant: Nc1ccc(-c2nc(Br)cnc2N)cc1
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: C1COCCO1
Solvent: O
Product: Nc1ccc(-c2nc(-c3ccnc(N4CCOCC4)c3)cnc2N)cc1
Temperature: 90 °C
Yield: 84.3 %

Procedure:
A suspension of the compound prepared in Example 12 (7.6 g), Pd(PPh3)4 (3.3 g), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (8.3 g), and Na2CO3 (9.1 g, 85 mmol) in a 3 to 1 mixture of dioxane/water (280 mL) was degassed with a stream of nitrogen for 10 minutes. The reaction was heated at 90° C. overnight, at which time LC/MS indicated the reaction was complete. The mixture was concentrated, diluted with aqueous saturated sodium bicarbonate solution (200 mL) and extracted with EtOAc (3×200 mL). The organic layers were combined, dried over Na2SO4, and evaporated under reduced pressure. The crude product was obtained as a brown oil which was precipitated from DCM (50 mL) to give a dark yellow solid. The solid was filtered and triturated with a 1 to 1 solution of DCM/EtOAc (3×50 mL) to give the title compound (8.4 g) having the following physical data as a light yellow solid.
Reaction SMILES: ClN1C(=O)CCC1=O.[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[SH:16].[CH2:17]([O:19][C:20]([C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:31][CH3:32])=[C:26]([O:33][CH3:34])[CH:25]=2)=[O:21])[CH3:18]>ClCCl>[CH2:17]([O:19][C:20]([C:22]1[NH:23][C:24]2[C:29]([C:30]=1[S:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH3:9])=[CH:28][C:27]([O:31][CH3:32])=[C:26]([O:33][CH3:34])[CH:25]=2)=[O:21])[CH3:18]
Reactant: Cc1ccccc1S
Reactant: CCOC(=O)c1cc2cc(OC)c(OC)cc2[nH]1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2cc(OC)c(OC)cc2c1Sc1ccccc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
To a −78° C. solution of dichloromethane (30mL) and N-chlorosuccinimide was added 2-methyl benzenethiol (0.709 mL, 6.01 mmol) dropwise. The reaction was allowed to warm 0° C. and then stirred for 30 minutes. 5,6-dimethoxy-1H-indole-2-carboxylic acid ethyl ester (Lancaster Synthesis Inc., Windham, N.H.) (1.5 g, 6.01 mmol) was added drop wise in dichloromethane (15 mL). The reaction was allowed to warm to room temperature and stirred overnight. The reaction was concentrated under reduced pressure. Methanol (5 mL) was added to the residue and a solid formed. The solid was collected, washed with diethyl ether (20 mL) and air dried to yield a beige solid (1.46 g, 66%). MS: M+−1=370.2 Da.