Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C@:5]1([OH:13])[CH2:11][N:10]2[CH2:12][C@@H:6]1[CH2:7][CH2:8][CH2:9]2.[N:14]([C:17]1[N:18]=[CH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:15]=S.C(=O)([O-])[O-].[Cs+].[Cs+].C(N=C=NC(C)C)(C)C>CN(C=O)C>[CH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[C:17]([NH:14][C:15]2[O:13][C@:5]3([CH2:11][N:10]4[CH2:12][C@@H:6]3[CH2:7][CH2:8][CH2:9]4)[CH2:4][N:3]=2)[N:18]=1
Reactant: NC[C@]1(O)CN2CCC[C@H]1C2
Reactant: S=C=Nc1cc2ccccc2cn1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: c1ccc2cc(NC3=NC[C@@]4(CN5CCC[C@H]4C5)O3)ncc2c1
Temperature: 80 °C
Yield: 20.4 %

Procedure:
To (5S*,6S*)-6-(aminomethyl)-1-azabicyclo[3.2.1]octan-6-ol dihydrochloride (84 mg, 0.54 mmol) in DMF (3 mL) was added 3-isothiocyanatoisoquinoline (100 mg, 0.54 mmol) and cesium carbonate (526 mg, 1.61 mmol). The reaction was heated to 80° C. for 2 hours and then treated with 1,3-diisopropylcarbodiimide (0.168 mL, 1.08 mmol). The reaction was maintained at 80° C. for 18 hours and then cooled to room temperature. The crude reaction was purified by silica gel chromatography, eluting with 5-40% (10% NH4OH/methanol) in chloroform. The desired product was collected and concentrated to give (5S*,5′R*)—N-(isoquinolin-3-yl)-4′H-1-azaspiro[bicyclo[3.2.1]octane-6,5′-oxazol]-2′-amine as a yellow solid (34 mg, 20% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.15 (br. s., 1H) 8.96 (s, 1H) 7.86 (d, J=8.03 Hz, 1H) 7.70 (d, J=8.28 Hz, 1H) 7.55 (t, J=7.28 Hz, 1H) 7.31-7.42 (m, 2H) 4.10 (d, J=9.03 Hz, 1H) 3.96 (d, J=9.03 Hz, 1H) 3.60 (d, J=14.05 Hz, 1H) 3.31 (d, J=11.80 Hz, 1H) 3.09 (dd, J=14.05, 2.01 Hz, 1H) 2.81-3.01 (m, 3H) 2.30 (d, J=3.01 Hz, 1H) 1.74-1.91 (m, 2H) 1.42-1.58 (m, 2H). MS: (LC/MS) RT=0.797 mins [M+H]=309.01.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH2:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([CH2:34][C:35](=[O:40])[C:36]([CH3:38])([CH3:37])[CH3:39])(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: CC(C)(C)C(=O)CS(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: CC(C)(C)C(=O)CS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 1-((2-bromophenyl)sulfonyl)-3,3-dimethylbutan-2-one. MS (ESI): mass calcd. for C22H22FN3O3S, 427.14; m/z found, 428.0 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 8.51 (d, J=1.5, 2H), 8.09 (dd, J=8.0, 1.3, 1H), 7.82-7.76 (m, 1H), 7.75-7.69 (m, 1H), 7.68-7.62 (m, 1H), 7.44 (dd, J=7.6, 1.3, 1H), 7.39-7.34 (dd, J=11.6, 1.8, 1H), 7.29 (dd, J=7.9, 1.7, 1H), 6.96 (s, 2H), 4.44 (s, 2H), 0.94 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.Cl.[CH3:16][N:17]([CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34][CH2:33]1)[C:18]([C:20]1[N:25]=[C:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:22][CH:21]=1)=[O:19].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH3:16][N:17]([CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34][CH2:33]1)[C:18]([C:20]1[N:25]=[C:24]([CH:26]2[CH2:27][CH2:28][N:29]([C:8](=[O:10])[CH2:7][N:6]3[C:2]([CH3:1])=[CH:3][C:4]([C:11]([F:14])([F:13])[F:12])=[N:5]3)[CH2:30][CH2:31]2)[CH:23]=[CH:22][CH:21]=1)=[O:19]
Reactant: CN(C(=O)c1cccc(C2CCNCC2)n1)C1CCCc2ccccc21
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2cccc(C(=O)N(C)C3CCCc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
To a solution of (5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (81 mg, 0.39 mmol), 1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-6-carboxylic acid methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amide hydrochloride salt (150 mg, 0.39 mmol), and diisopropylethylamine (0.41 mL, 0.39 mmol) in DMF (10 mL) was added dropwise BOP (191 mg, 0.39 mmol) at RT. After stirring overnight at RT, the reaction mixture was poured on water (10 mL) and extracted with ethylacetate (20 mL). The aqueous phase was re-extracted with ethylacetate (20 mL). The combined organic layers were washed with aq. sat. sodium bicarbonate solution (30 mL), 1M HCl solution (30 mL) and brine (30 mL), dried over sodium sulfate, filtered, and evaporated under reduce pressure. The crude mixture was purified by column chromatography on silica gel (ethylacetate) to give 1′-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-6-carboxylic acid methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (150 mg, 71%). M.p 62-65° C. 1H-NMR (400 MHz, CDCl3): δ=1.67-2.02 (m, 6H), 2.18-2.22 (m, 1H), 2.30 (s, 3H), 2.71 (s, 3H), 2.72-2.75 (m, 2H), 3.17-3.27 (m, 2H), 3.97-4.05 (m, 2H), 4.58-4.78 (m, 2H), 4.96 (s, 2H), 5.05-5.15 (m, 1H), 6.33 (s, 1H), 7.10-7.24 (m, 4H), 7.28-7.32 (m, 1H), 7.57-7.58 (m, 1H), 7.76-7.78 (m, 1H).
Reaction SMILES: CC1(C)[O:6][CH:5]([C:7]([NH:9][C:10]2[C:11]([I:33])=[C:12]([C:18]([I:32])=[C:19]([NH:22][C:23]([CH:25]3[CH2:29][O:28]C(C)(C)[O:26]3)=[O:24])[C:20]=2[I:21])[CH2:13]CC([O-])=O)=[O:8])[CH2:4][O:3]1.[OH2:35]>CO.Cl>[OH:26][CH:25]([CH2:29][OH:28])[C:23]([NH:22][C:19]1[C:18]([I:32])=[C:12]([C:11]([I:33])=[C:10]([NH:9][C:7](=[O:8])[CH:5]([OH:6])[CH2:4][OH:3])[C:20]=1[I:21])[CH2:13][OH:35])=[O:24]
Reactant: CC1(C)OCC(C(=O)Nc2c(I)c(CCC(=O)[O-])c(I)c(NC(=O)C3COC(C)(C)O3)c2I)O1
Reactant: O
Agent: Cl
Solvent: CO
Product: O=C(Nc1c(I)c(CO)c(I)c(NC(=O)C(O)CO)c1I)C(O)CO
Reaction time: 4 h

Procedure:
N,N′-Bis(2,2-dimethyl-1,3-dioxolane-4-carbonyl)-3,5-diamino-2,4,6-triiodobenzylacetate (1.25 g, 1.55 mol) was dissolved in a mixture of water (50 ml), methanol (25 ml) and concentrated HCl (0.5 ml). After stirring for 4 h, the solution was neutralized with aqueous NaH2PO4 and the solvents were removed by evaporation. The residue was dissolved in water (10 ml) and the pH was adjusted to 12 with aqueous NaOH. After 30 min, the solution was again neutralized and the solvent was evaporated. The product was purified by preparative HPLC. Yield: 483 mg (45%).
Reaction SMILES: [CH3:1][Li].[C:3]([NH:6][CH:7]1[C:29](=[O:30])[N:9]2[C:10]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[O:18])=[C:11]([N:14]=[C:15]=[O:16])[CH2:12][S:13][C@H:8]12)(=[O:5])[CH3:4]>>[C:3]([NH:6][CH:7]1[C:29](=[O:30])[N:9]2[C:10]([C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)=[O:18])=[C:11]([NH:14][C:15](=[O:16])[CH3:1])[CH2:12][S:13][C@H:8]12)(=[O:5])[CH3:4]
Reactant: COc1ccc(COC(=O)C2=C(N=C=O)CS[C@@H]3C(NC(C)=O)C(=O)N23)cc1
Reactant: [Li]C
Product: COc1ccc(COC(=O)C2=C(NC(C)=O)CS[C@@H]3C(NC(C)=O)C(=O)N23)cc1

Procedure:
As in the case of the aforedescribed reaction of amines with the 3-isocyanato-2-cephems, the reaction of such isocyanates with carbanionic reagents is accompanied by the rearrangement of the double bond in the cephem ring. Thus, benzhydryl 7-benzyloxycarbonylamino-3-isocyanato-2-cephem-4-carboxylate reacts with 1.1 equivalents of sodium diethylmalonate in tetrahydrofuran at -20° C. over a 5 minute period, to provide after hydrolysis with about 3 equivalents of 1N.HCl, benzhydryl 7 -benzyloxycarbonylamino-3-di(ethoxycarbonyl)acetamido-3-cephem-4-carboxylate. Likewise tert-butyl 7-(3-chlorophenylacetamido)-3-isocyanato-2-cephem-4carboxylate reacts with about 1.1 equivalents of isopropylmagnesium bromide in tetrahydrofuran at about --70° C. over a 30 minute period to give, upon acid hydrolysis, tert-butyl 7-(2-chlorophenylacetamido)-3-(2-methyl-propionamido)-3-cephem-4-carboxylate. The reaction of methyllithium with 4-methoxybenzyl 7-acetamido-3-isocyanato-3-cephem-4-carboxylate under similar conditions yields 4-methoxybenzyl 7-acetamido-3-acetamido-3-cephem-4-carboxylate.
Reaction SMILES: C(N(CC)CC)C.Br.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[CH:39][CH:38]=2)(=[O:36])=[O:35])[C:18]([C:20]2[C:21]3[C:26]([N:27]=[C:28]4[C:33]=2[CH:32]=[CH:31][CH:30]=[CH:29]4)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])=[CH:13][CH:12]=1.ClC(OCC)=O.O[N:55]1[C:59](=[O:60])[CH2:58][CH2:57][C:56]1=[O:61]>O1CCCC1>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([S:34]([C:37]2[CH:38]=[CH:39][C:40]([CH2:43][CH2:44][C:45]([O:47][N:55]3[C:59](=[O:60])[CH2:58][CH2:57][C:56]3=[O:61])=[O:46])=[CH:41][CH:42]=2)(=[O:36])=[O:35])[C:18]([C:20]2[C:33]3[C:28]([N:27]=[C:26]4[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]4)=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:19])=[CH:13][CH:12]=1
Reactant: O=C1CCC(=O)N1O
Reactant: COc1ccc(N(C(=O)c2c3ccccc3nc3ccccc23)S(=O)(=O)c2ccc(CCC(=O)O)cc2)cc1
Agent: Br
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(N(C(=O)c2c3ccccc3nc3ccccc23)S(=O)(=O)c2ccc(CCC(=O)ON3C(=O)CCC3=O)cc2)cc1
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
1.41 ml of triethylamine are added to 3.1 g of (4) in 50 ml of tetrahydrofuran, the mixture is cooled to -20° C., and 0.474 ml of ethyl chloroformate is added. After stirring for 20 min, 575 mg of N-hydroxysuccinimide are added, and the mixture is stirred at -20° C. for 3 hours and left to reach room temperature overnight while stirring. The precipitate is filtered off with suction, the filtrate is concentrated, the residue is taken up in dichloromethane or ethyl acetate, and the resulting solution is washed with water, NaHCO3 solution and water and dried over MgSO4. The organic phase is concentrated, and the residue is recrystallized from toluene.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:13][CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:7]2=[O:12].CN(C)C=O.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][C:26]=1[C:35]([F:38])([F:37])[F:36].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]([CH2:13][CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:7]3=[O:12])=[O:33])=[CH:27][C:26]=1[C:35]([F:36])([F:37])[F:38]
Reactant: O=C(O)Cc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CS(=O)(=O)CCn1ccc2c(N)cccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)CCn1ccc2c(NC(=O)Cc3ccc(Cl)c(C(F)(F)F)c3)cccc2c1=O
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of 5-amino-2-(2-(methylsulfonyl)ethyl)isoquinolin-1(2H)-one (30 mg, 0.0001 mol) in N,N-dimethylformamide (700 μL, 0.009 mol) was added 2-(4-chloro-3-(trifluoromethyl)phenyl)acetic acid (51 mg, 0.00021 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (102 mg, 0.000268 mol) and N,N-diisopropylethylamine (93 μL, 0.00054 mol). The reaction mixture was stirred for 16 hours at 50° C. LC-MS analysis showed the formation of the desired product. The mixture was taken up in saturated NaHCO3 solution and washed twice with ethyl acetate. The organic layer was dried with sodium sulfate, reduced in vacuo and purified via HPLC to afford the title compound as a white solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=2)=[O:15])=[N:12][O:11][N:10]=1)(=O)=O.CCN(C(C)C)C(C)C.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(#N)C>[Cl:24][C:19]1[CH:18]=[C:17]([NH:16][C:14]([C:13]2[C:9]([CH2:8][CH2:7][CH2:6][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[N:10][O:11][N:12]=2)=[O:15])[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: C1COCCN1
Reactant: CS(=O)(=O)OCCCc1nonc1C(=O)Nc1ccc(F)c(Cl)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)c(Cl)c1)c1nonc1CCCN1CCOCC1
Temperature: 70 °C
Yield: 54.2 %

Procedure:
3-(4-[(3-Chloro-4-fluorophenyl)amino]carbonyl-1,2,5-oxadiazol-3-yl)propyl methanesulfonate (19 mg, 0.051 mmol) was dissolved in anhydrous ACN (100 μL,) followed by the addition of DIPEA (44 μL, 0.26 mmol) and morpholine (6.7 μL, 76.8 μmol). The reaction were stirred and heated at 70° C. for 3 h. The reaction was concentrated and purified by silica gel chromatography (60-100% ethyl acetate/hexanes) to give the desired product (10.2 mg, 54%). LCMS for C16H19ClFN4O3 (M+H)+: m/z=369.1.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[N:14]1([CH2:3][C:4]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: c1c[nH]cn1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2nc(Cn3ccnc3)ccc2c1
Yield: 21.5 %

Procedure:
A mixture consisting of 2-chloromethylquinoline hydrochloride (10.0 g.), imidazole (3.2 g.) and sodium carbonate (14.8 g.) in N,N-dimethylformamide (100 ml.) was heated on a steam bath for a period of seven hours and then evaporated. The residue was taken up in chloroform and the resulting solution was filtered to give a clear filtrate. Evaporation of the latter liquid while under reduced pressure then gave a solid substance, which was subsequently crystallized from chloroform/petroleum ether (b.p. 60°-80° C.) and then recrystallized from diethyl ether to give pure 2-(1-imidazol-1-ylmethyl)quinoline (yield, 2.10 g.), m.p. 106°-107° C.
Reaction SMILES: [OH:1][PH:2]([CH2:4][CH:5]([CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[O:3].[C:22](O)([CH3:25])([CH3:24])[CH3:23].O>ClCCl.CN(C)C1C=CN=CC=1>[C:22]([O:3][PH:2]([CH2:4][CH:5]([CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])=[O:1])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)O
Reactant: CC(C)(C)OC(=O)CCC(C[PH](=O)O)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)CCC(C[PH](=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
To a solution of di-tert-butyl 2-[(hydroxy-phosphinyl)methyl]pentane-1,5-dioate (315 g, 0.977 mol) in dichloromethane (1000 ml) cooled in an ice bath and under nitrogen were added tert-butanol (123.1 g, 1.66 mol), 4-dimethylaminopyridine (1 g, 8.2 mmol), andl-ethyl-3-(3-dimethylaminopropyl) carbodiimide (281 g, 1.47 mol). The reaction was allowed to stir overnight. Water was added to the reaction mixture and the dichloromethane layer was retained and dried, and the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography and the desired product was eluted with 1:1 to 2:3 hexane/ethyl acetate. The fractions containing product were concentrated under reduced pressure leaving a clear oil (260 g, 70%). 1H NMR (CDCl3) : δ 1.4 (m, 27H), 1.8 (m, 1H), 1.9 (m, 2H), 2.1 (m, 1H), 2.3 (m, 2H), 2.7-2.8 (m, 1H), 6.7 & 8.0 (d, 1H, the P-H).
Reaction SMILES: [O:1]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH:31](O)[C:30]3[CH:34]=[C:35]([S:37]([NH2:40])(=[O:39])=[O:38])[S:36][C:29]=3[S:28]2(=[O:42])=[O:41])=[CH:23][CH:22]=1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:43]([N:45](CC)CC)[CH3:44].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N)C>C1COCC1>[CH2:43]([NH:45][CH:31]1[C:30]2[CH:34]=[C:35]([S:37]([NH2:40])(=[O:39])=[O:38])[S:36][C:29]=2[S:28](=[O:41])(=[O:42])[N:27]([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][O:1][Si:2]([C:15]([CH3:16])([CH3:18])[CH3:17])([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:22][CH:23]=2)[CH2:32]1)[CH3:44]
Reactant: CC(C)(C)[Si](OCCc1ccc(N2CC(O)c3cc(S(N)(=O)=O)sc3S2(=O)=O)cc1)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Agent: CCN
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: CCNC1CN(c2ccc(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2)S(=O)(=O)c2sc(S(N)(=O)=O)cc21
Temperature: 5 °C
Reaction time: 4.5 h
Yield: 43.4 %

Procedure:
The product from Step D (1.77 g, 2.75 mmol) was dissolved in dry THF (15 mL) containing triethylamine (1.54 mL, 11 mmol) and cooled to 5° C. p-Toluenesulfonyl chloride (1.05 g, 5.5 mmol) was added and the mixture stirred at 5° C. for 4.5 hr. An excess of ethylamine was condensed into the reaction mixture which was stirred at ambient temperature for 18 hr and then evaporated to dryness. The residue was suspended in water and this mixture was extracted with ethyl acetate (2×50 mL). The combined extracts were dried (NaSO4) and purified by column chromatography (silica, 3.5% ethanol/methylene chloride) to provide 0.8 g (44%) of a solid: mp 66° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]1([CH3:18])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][SH:17].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C.O>[CH3:18][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][S:17][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1CS
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1CSc1ccc(C=O)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
4-fluoro-benzaldehyde (1.16 g, 9.32 mmol) was added dropwise over 2 minutes to a solution of o-tolyl-methanethiol (1.35 g, 9.79 mmol) and Cesium carbonate (3.19 g, 9.79 mmol) in DMF (20 mL). The solution was stirred at 40° C. overnight and then poured into copious water. The pH of the solution was adjusted to 4 with 1N HCl(aq), and the aqueous solution was extracted with ethyl acetate (2×35 mL). The combined organic layers were washed with water, followed by brine. The combined organic layers were then dried (Na2SO4) and the solvent removed under reduced pressure. The resulting residue was purified via radial chromatography (15% ethyl acetate in hexanes) to yield 1.29 g (54%) of 4-(2-Methyl-benzylsulfanyl)-benzaldehyde (28.1). LC/MSD m/e: 243.0 (M+H).
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([OH:30])[CH2:4]1)[CH3:2].[C:31](Cl)(=[O:42])[O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.C(=O)(OC1C=CC([N+]([O-])=O)=CC=1)O[C@@H]1C[C@H](C2N3C4C=CN(S(C5C=CC(C)=CC=5)(=O)=O)C=4N=CC3=NN=2)[C@H](CC)C1>[C:31](=[O:42])([O:32][C:33]1[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=1)[O:30][CH:5]1[CH2:6][CH:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH:3]([CH2:1][CH3:2])[CH2:4]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC[C@@H]1C[C@H](O)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Agent: CC[C@@H]1C[C@H](OC(=O)Oc2ccc([N+](=O)[O-])cc2)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCC1CC(OC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a scalemic mixture enriched in (1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol (6.11 g, 14.4 mmol) in pyridine (100 mL) was added DMAP (1.93 g, 15.8 mmol) and 4-nitrophenyl carbonochloridate (4.34 g, 21.5 mmol). The resulting mixture was stirred at ambient temperature for about 3.5 h and heated at about 33° C. for about 1 h. The solid was filtered off and washed with EtOAc (30 mL). The filtrated was concd under reduced pressure. The residue was purified using silica gel chromatography eluting with 0-30% EtOAc in heptane to give a scalemic mixture enriched in (1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl 4-nitrophenyl carbonate (6.63, 78%). LC/MS (Table 1, Method b) Rt=2.65 min; MS m/z: 591 (M+H)+.
Reaction SMILES: O1CCCC1.[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[O:12][C:13]([CH3:47])=[C:14]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C@@H:27]([O:32][C:33]([O:35]C3C=CC([N+]([O-])=O)=CC=3)=O)[C:28]([O:30][CH3:31])=[O:29])=[CH:20][C:19]=2[O:45][CH3:46])[N:15]=1.[NH3:48]>O>[C:33]([O:32][C@H:27]([CH2:26][CH2:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][C:14]2[N:15]=[C:11]([C:7]3[O:6][CH:10]=[CH:9][CH:8]=3)[O:12][C:13]=2[CH3:47])=[C:19]([O:45][CH3:46])[CH:20]=1)[C:28]([O:30][CH3:31])=[O:29])(=[O:35])[NH2:48]
Reactant: N
Reactant: COC(=O)[C@@H](CCCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@@H](CCCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OC(N)=O
Yield: 89 %

Procedure:
Into a tetrahydrofuran (THF) (80 ml) solution of methyl (R)-(+)-5-[4-[2-(2-furyl)-5-methyl-4-oxazolyl methoxy]-3-methoxyphenyl]-2-(4-nitrophenoxycarbonyloxy)pentanoate (4.25 g) was introduced ammonia (gas) for 10 minutes at temperature ranging from -65 to -70° C. The reaction mixture was poured into water-6N HCl, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate-hexane (1:1), was obtained methyl (R)-(+)-2-carbamoyloxy-5-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]pentanoate (3.0 g, 89%), which was recrystallized from acetone-isopropyl ether to give colorless needles, m.p.110-111° C. [α]D +5.30° (c=1. 0, CH3OH)
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Mg]Br.[CH2:17]=[O:18].Cl>O1CCCC1.C(OCC)C.C(N(CC)CC)C.C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH:17]=[O:18])[C:8]=2[OH:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccccc1-c1ccccc1
Reactant: C=O
Agent: C[Mg]Br
Agent: Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=Cc1cccc(-c2ccccc2)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To 100.6 mmol of 2-phenyl phenol in 40 ml of tetrahydrofuran was added dropwise a 3-molar methylmagnesium bromide solution (36.7 ml; 110 mmol) in diethyl ether. After two hours of stirring at room temperature, gas evolution ceased. About 90% of the solvent were removed in vacuo and toluene (250 ml), triethylamine (20 ml), and paraformaldehyde (7.55 g; 251 mmol) were added. The mixture was heated to 88° C. and held at this temperature for two hours. After cooling down to room temperature, the yellow solution was introduced into cold hydrochloric acid (1M, 250 ml). The organic phase was separated and dried over sodium sulphate. After removal of the solvent in vacuo, 3-phenyl salicylaldehyde was recrystallized from ethanol at −20° C. Yield: 71%.