Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:10]3[NH:15][C:14](=O)[CH2:13][N:11]3[N:12]=2)=[CH:4][CH:3]=1.B#B.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:10]3[NH:15][CH2:14][CH2:13][N:11]3[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C1Cn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2N1
Agent: B#B
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: Fc1ccc(-c2nn3c(c2-c2ccncc2)NCC3)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 29.4 %

Procedure:
A mixture of 2,3-dihydro-6-(4-fluorophenyl)-2-oxo-7-(pyridin-4-yl)-1H-imidazo[1,2-b]pyrazole (50 mg) and diborane (0.34 mmol) in anhydrous tetrahydrofuran (5 ml) was refluxed under nitrogen atmosphere for 5 hours. After cooling of the reaction mixture, to the mixture was added 1N-hydrochloric acid (2 ml). The mixture was stirred at 60° C. for 30 minutes, cooled and neutralized with an aqueous saturated sodium bicarbonate solution. The separated oil was extracted with dichloromethane and the extract was washed with brine, dried and concentrated in vacuo. The residue was purified by thin layer chromatography on silica gel and the obtained crude solid was recrystallized from a mixture of diisopropyl ether and dichloromethane to yield 2,3-dihydro-6-(4-fluorophenyl)-7-(pyridin-4-yl)-1H-imidazo[1,2-b]pyrazole (14 mg).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([I:11])[CH:3]=1.O.O.Cl[Sn]Cl.[OH-].[Na+]>C(O)C>[I:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([I:11])[CH:3]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cc(I)cc(I)c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc(I)cc(I)c1
Temperature: 80 °C
Yield: 75.9 %

Procedure:
To a solution of 1,3-diiodo-5-nitro-benzene (15.80 g, 0.042 mol) in ethanol (200 mL) was added SnCl2.2H2O (28.50 g, 0.13 mol) portion wise at room temperature. The reaction mixture was heated under reflux at 80° C. for 1.5 h. After cooling to room temperature, the solvent was evaporated under reduced pressure and the crude solid thus obtained was basified with 4N NaOH solution to pH 12. The mixture was extracted with ethyl acetate (×3) and the combined organic layer was washed with brine solution and dried over Na2SO4. The solvent was removed under reduced pressure, to give the desired compound as a yellow solid (11.0 g, 75%).
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C@@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@H:10]1[NH:18][C:19]([C:21]1[NH:25][C:24]2[C:26]([Cl:30])=[C:27]([Cl:29])[S:28][C:23]=2[CH:22]=1)=[O:20])=[O:7])(=O)C.CO.C([O-])([O-])=O.[K+].[K+].O>C1COCC1>[Cl:29][C:27]1[S:28][C:23]2[CH:22]=[C:21]([C:19]([NH:18][C@@H:10]3[CH2:11][C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C@H:9]3[NH:8][C:6](=[O:7])[CH2:5][OH:4])=[O:20])[NH:25][C:24]=2[C:26]=1[Cl:30]
Reactant: CC(=O)OCC(=O)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(CO)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.2 %

Procedure:
N-{(1R,2R)-1-[(2-Acetoxyacetyl)amino]-2,3-dihydro-1H-inden-2-yl}-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide (Example 6; 632 mg, 1.36 mmol) was dissolved in THF (10 mL), MeOH (10 mL) and K2CO3 (100 mg) were then added and the suspension stirred at ambient temperature for 16 hours. Water (50 mL) was added and the aqueous phase was extracted with EtOAc (3×30 mL). The combined organic phases were washed with water (2×50 mL), brine (50 mL) and dried (MgSO4). The solvent was removed by evaporation under reduced pressure, the crude product was triturated (EtOAc:isohexane, 1:10), filtered, washed with isohexane (5 mL) and dried to give the title compound (428 mg, 74%) as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:30]=[C:31]([CH2:35][C:36](O)=[O:37])[CH:32]=[CH:33][CH:34]=1.C(Cl)CCl.C([O-])(O)=O.[Na+]>CN(C=O)C.[Cl-].[Na+].O.CCOC(C)=O>[CH3:5][N:4]([O:3][CH3:2])[C:36](=[O:37])[CH2:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)[CH:30]=1
Reactant: CNOC
Reactant: O=C(O)Cc1cccc(-c2ccccn2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CON(C)C(=O)Cc1cccc(-c2ccccn2)c1
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a stirred solution of N-methoxy-N-methylamine hydrochloride (0.980 g, 10.0 mmol) in DMF (25 mL) was added N-methylmorpholine (1.21 mL, 11.0 mmol), HOBt (1.50 g, 11.1 mmol), 3-(2-pyridyl)-phenylacetic acid (2.36 g, 11.1 mmol), and EDC (2.13 g, 11.1 mmol). The reaction was stirred overnight whereupon it was poured into a rapidly-stirred mixture of 150 mL each of EtOAc, 10% NaHCO3, and brine. After stirring for 30 min, the layers were separated and the aqueous layer was washed with fresh EtOAc (150 mL). The combined organic layers were washed with 10% Na2CO3, and brine, then dried (MgSO4), filtered, and concentrated. Column chromatography (silica gel, 3:1 EtOAc:hexane) gave 2.275 g of the title compound: MS (ES+) (MH+) 257.2.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:9]([CH3:10])[S:8][CH2:7][C:6]=1[C:11]([O:13][CH3:14])=[O:12])(=[O:3])[CH3:2].S(Cl)(Cl)(=O)=O>C(Cl)Cl>[C:1]([O:4][C:5]1[C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][S:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: COC(=O)C1=C(OC(C)=O)C(C)SC1
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: COC(=O)c1csc(C)c1OC(C)=O
Temperature: 25 °C

Procedure:
To methyl 4-acetoxy-2,5-dihydro-5-methyl-3-thiophene-carboxylate (68.3 g) in anhydrous methylene chloride (143 ml) was added sulphuryl chloride (30.4 ml) dropwise over 30 minutes. The black solution was stirred at room temperature over night.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.N1CCCC1>CO.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8](=[O:10])[CH2:9][C:16]3([O:11][C:4]=2[CH:3]=1)[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]3
Reactant: CC(=O)c1ccc(F)cc1O
Reactant: CN1CCC(=O)CC1
Solvent: ClCCl
Solvent: CO
Solvent: C1CCNC1
Product: CN1CCC2(CC1)CC(=O)c1ccc(F)cc1O2
Reaction time: 0.5 h

Procedure:
A stirred solution of 4′-fluoro-2′-hydroxyacetophenone (15.97 g), 1-methyl-4-piperidone (12.74 cm3) and pyrrolidine (4.325 cm3) in methyl alcohol (250 cm3) was heated to reflux under nitrogen. After 0.5 h, further pyrrolidine (4.33 cm3) was added and, after another 0.5 h, the solution was allowed to cool. The reaction mixture was then evaporated under reduced pressure to give an oil, which was dissolved in dichloromethane (400 cm3). This solution was washed with water (3×400 cm3), dried (Na2SO4) and evaporated to give an oil (25.7 g). Flash chromatography on silica (eluting with dichloromethane-methyl alcohol-33% aqueous ammonia=380:20:1) gave the purified product as an oil (14.41 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C@H:23]3[CH2:28][CH2:27][C@H:26]([CH2:29][C:30](O)=[O:31])[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)=[O:15])=[N:11][N:10]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:66]1[CH2:75][CH2:74][CH:69]([C:70]([O:72][CH3:73])=[O:71])[CH2:68][CH2:67]1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C@H:23]3[CH2:28][CH2:27][C@H:26]([CH2:29][C:30]([N:66]4[CH2:75][CH2:74][CH:69]([C:70]([O:72][CH3:73])=[O:71])[CH2:68][CH2:67]4)=[O:31])[CH2:25][CH2:24]3)=[CH:21][CH:22]=2)=[O:15])=[N:11][N:10]=1
Reactant: COC(=O)C1CCNCC1
Reactant: O=C(O)C[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4ccccc4F)o3)cc2)CC1
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: COC(=O)C1CCN(C(=O)C[C@H]2CC[C@H](c3ccc(NC(=O)c4nnc(Nc5ccccc5F)o4)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (trans-4-{4-[({5-[(2-fluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]phenyl}cyclohexyl)acetic acid (Example 112, 300 mg, 0.68 mmol) in DMF (3 mL) was added HATU (286 mg, 0.75 mmol), diisopropylethylamine (0.14 mL, 0.75 mmol) followed by methyl isonipecotate (0.15 mL, 0.75 mmol). The reaction mixture was allowed to stir at ambient temperature overnight. The DMF was evaporated and the residue re-dissolved in DMSO/MeCN/H2O (7:2:1); a suspension formed which was filtered, washed with ether (2×10 mL) and dried to leave the title compound (137 mg). The filtrate was purified on an acidic reverse phase HPLC system eluting 5-95% MeCN 0.2% TFA, isolated 112 mg of the title compound (249 mg, 65%) as a solid; 1H NMR δ 1.07-1.16 (m, 2H), 1.36-1.53 (m, 4H), 1.75-1.88 (m, 7H), 2.24 (d, 2H), 2.41-2.47 (m, 1H), 2.59-2.65 (m, 2H), 3.11 (t, 1H), 3.62 (s, 3H), 3.85 (d, 1H), 4.26 (d, 1H), 7.14-7.34 (m, 5H), 7.68 (d, 2H), 8.04 (t, 1H), 10.75 (s, 1H), 10.93 (s, 1H); MS m/e MH+ 564.
Reaction SMILES: Br[CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([N:13]3[C:17](=[O:18])[N:16]([CH:19]([F:21])[F:20])[C:15]([CH3:22])=[N:14]3)=[C:8]([F:12])[CH:9]=2)[NH:4][C:3]1=[O:23].C(N(CC)CC)C>O1CCCC1.O>[F:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N:13]1[C:17](=[O:18])[N:16]([CH:19]([F:20])[F:21])[C:15]([CH3:22])=[N:14]1)[NH:4][C:3](=[O:23])[CH:2]=[CH:11]2
Reactant: Cc1nn(-c2cc3c(cc2F)CC(Br)C(=O)N3)c(=O)n1C(F)F
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nn(-c2cc3[nH]c(=O)ccc3cc2F)c(=O)n1C(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.5 %

Procedure:
A solution of 7.0 g (0.018 mole) of 1-[3-bromo-6-fluoro-3,4-dihydroquinolin-2(1H)-one-7-yl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one in 60 mL of tetrahydrofuran was stirred, and 4.0 g (0.040 mole) of triethylamine was added. Upon completion of addition the reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to give a residual solid. The solid was slurried in water and collected by filtration. The dried solid was slurried in 100 mL of hot ethyl acetate. The mixture was cooled, and the solid was collected by filtration to yield 3.6 g of 1-[6-fluoroquinolin-2(1H)-one-7-yl]-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one; m.p. 215°-217° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[N:11]=[CH:10][NH:9][C:8]=2[C:7](=O)[NH:6][C:5]1=[O:14])[CH2:2][CH3:3].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:16]>N1C=CC=CC=1>[CH2:1]([N:4]1[C:12]2[N:11]=[CH:10][NH:9][C:8]=2[C:7](=[S:16])[NH:6][C:5]1=[O:14])[CH2:2][CH3:3]
Reactant: CCCn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: CCCn1c(=O)[nH]c(=S)c2[nH]cnc21

Procedure:
A suspension of 9.32 g. (48 mM) of 3-propylxanthine in 80 ml. of pyridine, was treated with 17.33 g. (78 mM.) of phosphorus pentasulfide in 80 ml. of pyridine, and worked up analogously to Example I. 8.9 g. of 3-propyl-6-thioxanthine was obtained. Recyrstallization from methanol-acetone gave 7.4 g. (59% yield) of needles with a melting point of 249°-250° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[N:13]=[C:14]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)[O:15][C:16]=2[CH3:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:60]([NH2:67])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>CN(C=O)C.CCOC(C)=O>[CH2:60]([NH:67][C:22](=[O:24])[C:21]1[CH:20]=[CH:19][C:18]([C:14]2[O:15][C:16]([CH3:17])=[C:12]([CH2:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[N:13]=2)=[CH:26][CH:25]=1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccc(Br)cc1
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccc(C(=O)NCc3ccccc3)cc2)nc1CS(=O)(=O)c1ccc(Br)cc1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 65.5 %

Procedure:
Benzoic acid 29 (150 mg, 0.34 mmol) was dissolved in anhydrous DMF (5 mL), DIEA (0.12 mL, 0.69 mmol) and HBTU (171 mg, 0.45 mmol) were successively added and the reaction mixture was stirred at 20° C. for 10 min. Benzylamine (0.16 mL, 1.4 mmol) was added and the reaction mixture was stirred at 20° C. for 1 h. The mixture was diluted with EtOAc (150 mL), washed with H2O (3×50 mL), washed with brine (50 mL) and dried. The solvent evaporated and the residue was purified by column chromatography, eluting with a gradient (50-100%) of EtOAc/pet. ether followed by a gradient (1-4%) MeOH/DCM, to afford amide 57 (117 mg, 66%) as a white solid: mp (DCM/MeOH) 234-237° C.; 1H NMR δ □ (t, J=5.9 Hz, 1H, CONH), 8.01 (br d, J=8.6 Hz, 2H, H-2, H-6), 7.87 (br d, J=8.7 Hz, 2H, H-3, H-5), 7.85 (dt, J=8.8, 2.1 Hz, 2H, H-2′, H-6′), 7.72 (dt, J=8.7, 2.1 Hz, 2H, H-3′, H-5′), 7.34 (s, 2H, H-2″, H-6″), 7.33 (s, 2H, H-3″, H-5″), 7.22-7.28 (m, 1H, H-4″), 4.74 (s, 2H, CH2SO2), 4.49 (d, J=5.9 Hz, 2H, CH2NH), 2.21 (s, 3H, CH3); 13C NMR δ□ 165.3, 158.0, 150.0, 139.4, 137.7, 135.6, 132.2 (2), 130.3 (2), 128.6, 128.2 (2), 128.1, 128.0 (2), 127.2 (2), 126.7, 125.6, 125.3 (2), 52.6, 42.6, 9.7; MS m/z 526.5, 528.5 (MH+, 100%). Anal. calcd for C25H21BrN2O4S: C, 57.15; H, 4.03; N, 5.33. Found: C, 57.34; H, 3.74; N, 5.50%.
Reaction SMILES: Cl.[NH2:2]C1C(C)=C2C(NC3C=CC(OC4C=CC=CC=4OC)=CC=3)=C(C#N)C=NN2C=1.C(NC1C=CC(C(O)=O)=CC=1)(=O)C.[C:44]([NH:47][C:48]1[CH:49]=[C:50]([CH:82]=[CH:83][CH:84]=1)[C:51]([NH:53][C:54]1[C:55]([CH3:81])=[C:56]2[C:61]([NH:62][C:63]3[CH:68]=[CH:67][C:66]([O:69][C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][C:71]=4[O:76][CH3:77])=[CH:65]C=3)=[C:60]([C:78]#[N:79])[CH:59]=[N:58][N:57]2[CH:80]=1)=[O:52])(=[O:46])[CH3:45]>>[C:44]([NH:47][C:48]1[CH:49]=[C:50]([CH:82]=[CH:83][CH:84]=1)[C:51]([NH:53][C:54]1[C:55]([CH3:81])=[C:56]2[C:61]([NH:62][C:63]3[CH:68]=[CH:67][C:66]([O:69][C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][C:71]=4[O:76][CH3:77])=[CH:65][N:2]=3)=[C:60]([C:78]#[N:79])[CH:59]=[N:58][N:57]2[CH:80]=1)=[O:52])(=[O:46])[CH3:45]
Reactant: COc1ccccc1Oc1ccc(Nc2c(C#N)cnn3cc(N)c(C)c23)cc1
Reactant: COc1ccccc1Oc1ccc(Nc2c(C#N)cnn3cc(NC(=O)c4cccc(NC(C)=O)c4)c(C)c23)cc1
Agent: CC(=O)Nc1ccc(C(=O)O)cc1
Agent: Cl
Product: COc1ccccc1Oc1ccc(Nc2c(C#N)cnn3cc(NC(=O)c4cccc(NC(C)=O)c4)c(C)c23)nc1
Yield: 50 %

Procedure:
The title compound (27.3 mg, 50%) was prepared from the hydrochloride salt of 430F (42 mg, 0.10 mmol) and 4-acetylamino-benzoic acid (27 mg, 0.15 mmol) by a route analogous to that used for the preparation of compound 430. It is a slight yellow solid and has a retention time of 6.14 min (standard LC1 method, 8 min run). MS Found: (M+H)+=547.1
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4](OS(C(F)(F)F)(=O)=O)[CH2:3][CH2:2]1.CC1(C)COB([C:22]2[CH:43]=[CH:42][C:25]3[C:26]4[N:30]([CH2:31][CH2:32][O:33][C:24]=3[CH:23]=2)[CH:29]=[C:28]([C:34]2[N:35]([CH:39]([CH3:41])[CH3:40])[N:36]=[CH:37][N:38]=2)[N:27]=4)OC1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>C(Cl)Cl.O>[O:1]1[CH2:6][CH:5]=[C:4]([C:22]2[CH:43]=[CH:42][C:25]3[C:26]4[N:30]([CH2:31][CH2:32][O:33][C:24]=3[CH:23]=2)[CH:29]=[C:28]([C:34]2[N:35]([CH:39]([CH3:41])[CH3:40])[N:36]=[CH:37][N:38]=2)[N:27]=4)[CH2:3][CH2:2]1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(B3OCC(C)(C)CO3)cc1OCC2
Reactant: O=S(=O)(OC1=CCOCC1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3=CCOCC3)cc1OCC2
Yield: 39.4 %

Procedure:
A mixture of trifluoro-methanesulfonic acid 3,6-dihydro-2H-pyran-4-yl ester (125 mg, 0.54 mmol), 8-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (200 mg, 0.491 mmol), PdCl2dppf.DCM (41 mg, 0.05 mmol, 10 mol %), cesium carbonate (400 mg, 1.23 mmol), DME (2 mL) and water (0.2 mL) was heated at 80° C. for 90 min. The cooled reaction mixture was diluted with DCM, filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 100% ethyl acetate in cyclohexane) to give 8-(3,6-Dihydro-2H-pyran-4-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (73 mg, 39%). LCMS RT=4.36, [M+H]+=378.
Reaction SMILES: N1[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=[CH:10][O:9][CH:8]=2)=[CH:3][CH:2]=1.BrC1C=C[C:16]([C:17]#[N:18])=CC=1.O1C=CC(B(O)O)=C1>>[C:17]([C:16]1[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=[CH:10][O:9][CH:8]=2)=[CH:3][CH:2]=1)#[N:18]
Reactant: N#Cc1ccc(Br)cc1
Reactant: c1cc(-c2ccoc2)ccn1
Agent: OB(O)c1ccoc1
Product: N#Cc1ccc(-c2ccoc2)cc1

Procedure:
As described in Example 1(d) for the preparation of 3-(pyridin-4-yl)furan, 4-bromobenzonitrile (4.00 g, 22.0 mmol) was coupled to 3-furanboronic acid to furnish in high yield crude 3-(4-cyanophenyl)-furan as a brown solid, mp 55-7° C., which was used immediately without further purification.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:13][CH2:12][O:11][C:9](=[O:10])[CH2:8][CH2:7]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl.O1CCCC1>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([S:21]([NH:24][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]2[CH2:13][CH2:12][O:11][C:9](=[O:10])[CH2:8][CH2:7]2)(=[O:22])=[O:23])=[CH:19][CH:20]=1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: O=C1CCC(CCCCO)CCO1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1CCC(CCCCNS(=O)(=O)c2ccc(Cl)cc2)CCO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3.53 g of 4-(4-hydroxybutyl)-epsilon-caprolactone in 14 ml methylene chloride and 14 ml tetrahydrofuran is added 4.24 g p-chlorophenylsulfonamide followed by 7.44 g triphenylphosphine. The reaction mixture is stirred at room temperature for 0.5 h and then 6.1 ml diethyl azodicarboxylate is added slowly with cooling. After the addition, the cooling bath is removed and the solution is stirred at room temperature overnight. The reaction mixture is evaporated to dryness to yield 4-[4-(p-chlorophenylsulfonamido)butyl)-epsilon-caprolactone.
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[CH3:27][C:28]1[N:29]=[C:30]([N:36]2[CH2:40][CH2:39][N:38]([CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[C:46]4[C:51]=3[N:50]=[CH:49][CH:48]=[CH:47]4)[C:37]2=[O:52])[S:31][C:32]=1[C:33](O)=[O:34].[NH2:53][CH2:54][C:55]1[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=1>>[CH3:27][C:28]1[N:29]=[C:30]([N:36]2[CH2:40][CH2:39][N:38]([CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[C:46]4[C:51]=3[N:50]=[CH:49][CH:48]=[CH:47]4)[C:37]2=[O:52])[S:31][C:32]=1[C:33]([NH:53][CH2:54][C:55]1[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=1)=[O:34]
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCN(Cc3cccc4cccnc34)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3cccc4cccnc34)C2=O)sc1C(=O)NCc1cccnc1
Yield: 44 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-(quinolin-8-ylmethyl)imidazolidin-1-yl)thiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 44% yield: mp 225-228° C. (methanol); 1H NMR (300 MHz, DMSO-d6) δ 8.98-8.96 (m, 1H), 8.59-8.53 (m, 2H), 8.46-8.39 (m, 2H), 7.96-7.93 (m, 1H), 7.72-7.70 (m, 2H), 7.63-7.58 (m, 2H), 7.38-7.33 (m, 1H), 5.09 (s, 2H), 4.40 (d, J=5.8 Hz, 2H), 4.07-4.01 (m, 2H), 3.63-3.58 (m, 2H), 2.48 (s, 3H); MS (ES+) m/z 459.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[CH:22]=[N:21]2)=[CH:17][CH:16]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:22]=[N:21]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)CCc1cnn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CCC(=O)O)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
A mixture of ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (1.34 g), 1 N aqueous sodium hydroxide solution (6 ml), ethanol (12 ml), and tetrahydrofuran (12 ml) was stirred at room temperature for two hours. After 1 N hydrochloric acid (6 ml) was added to the reaction mixture, the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained crystals were collected by filtration, 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (1.21 g, yield: 97%) was obtained. This was recrystallized from ethanol-hexane. Melting point: 124–125° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][C@H:18]([C:20]([OH:22])=O)[CH3:19])=[O:16])[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[S:23]1[CH2:27][CH2:26][NH:25][CH2:24]1>C(Cl)(Cl)Cl.CO>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][C@H:18]([C:20]([N:25]2[CH2:26][CH2:27][S:23][CH2:24]2)=[O:22])[CH3:19])=[O:16])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: C1CSCN1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H](C)C(=O)N1CCSC1

Procedure:
Following General Procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example D7 above) and thiazolidine (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.25 in 9:1 CHCl3/MeOH).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.[NH2:30][CH:31]1[C:57](=[O:58])[N:33]2[C:34]([C:54]([OH:56])=[O:55])=[C:35]([CH2:38][S:39][C:40]3[S:41][C:42]([CH2:45][NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[N:43][N:44]=3)[CH2:36][S:37][C@H:32]12.C[Si](CC(N)=O)(C)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>C(OCC)(=O)C.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([NH:30][CH:31]2[C:57](=[O:58])[N:33]3[C:34]([C:54]([OH:56])=[O:55])=[C:35]([CH2:38][S:39][C:40]4[S:41][C:42]([CH2:45][NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[N:43][N:44]=4)[CH2:36][S:37][C@H:32]23)=[O:12])[N:8]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)NCc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Reactant: CC(C)(C)OC(=O)NCCON=C(C(=O)O)c1csc(NC=O)n1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: C[Si](C)(C)CC(N)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CNC(=O)OC(C)(C)C)s3)CS[C@H]12)c1csc(NC=O)n1
Yield: 89.6 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetic acid (syn isomer, 2 g.), N,N-dimethylformamide (0.45 g.), phosphoryl chloride (1.03 g.), 7-amino-3-(5-tert-butoxycarbonylaminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (2.6 g.), trimethylsilylacetamide (5.9 g.) and bis(trimethylsilyl)acetamide (3.4 g.) and ethyl acetate (50 ml.) were treated in a similar manner to that of Example 6-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-(5-tert-butoxycarbonylaminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 4.0 g.).