Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].[C:18]1(=[O:24])[CH2:23][CH2:22][CH2:21][CH:20]=[CH:19]1>CO.[NH4+].[Cl-]>[CH3:14][O:13][C:11](=[O:12])[CH:10]([S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:9])=[O:8])[CH:20]1[CH2:21][CH2:22][CH2:23][C:18](=[O:24])[CH2:19]1
Reactant: COC(=O)CS(=O)(=O)c1ccccc1
Reactant: O=C1C=CCCC1
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)C(C1CCCC(=O)C1)S(=O)(=O)c1ccccc1
Reaction time: 0.25 h
Yield: 185.3 %

Procedure:
To a stirred solution of 9 g (0.042 mol) of methyl phenylsulfonylacetate in 90 mL of MeOH at 0° C., 1.56 mL (0.008 mol, 0.2 eq) of a solution of sodium methoxide (5.4 M in MeOH) were added. After 15 min, 4.04 g (0.02 mol) of 2-cyclohexen-1-one were added. The reaction mixture was allowed to reach RT within 4 hours, diluted with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel with heptane/EtOAc 1:1 yielded 11.50 g (88%) of benzenesulfonyl-(3-oxo-cyclohexyl)-acetic acid methyl ester as a racemic mixture of diastereomers, light yellow oil, MS: 311 (MH+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:23])=[C:9](/[CH:11]=[CH:12]/[C:13]2[CH:22]=[CH:21][C:16]([C:17](OC)=[O:18])=[CH:15][CH:14]=2)[N:10]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:23])=[C:9](/[CH:11]=[CH:12]/[C:13]2[CH:14]=[CH:15][C:16]([CH2:17][OH:18])=[CH:21][CH:22]=2)[N:10]=1
Reactant: COC(=O)c1ccc(/C=C/c2nc(-c3ccco3)oc2C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1oc(-c2ccco2)nc1/C=C/c1ccc(CO)cc1

Procedure:
Methyl (E)-4-[2-[2-(2-furyl)-5-methyl-4-oxazolyl]vinyl]benzoate was reduced with lithium aluminum hydride in the same manner as in Reference Example 12 to yield (E)-4-[2-[2-(2-furyl)-5-methyl-4-oxazolyl]vinyl]benzyl alcohol, which was then recrystallized from ethyl acetate-hexane to yield colorless prisms having a melting point of 150°-15° C.
Reaction SMILES: Cl.OC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N.CCN(C(C)C)C(C)C.C1CN([P+]([O:39][N:40]2[N:48]=[N:47][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:39][N:40]1[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[N:47]=[N:48]1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: On1nnc2ccccc21
Reaction time: 0.5 h

Procedure:
Nvan—(N-Fmoc-2-n-decylaminoethyl) vancomycin (100 mg, 48 umol, 1-0 eq) was dissolved in 1 mL DMF and glucosamine hydrochloride was added (31 mg, 144 mmol, 3.0 eq). The mixture was stirred vigorously for 30 minutes (the glucosamine hydrochloride did not fully dissolve), DIPEA (60 uL, 344 umol, 7.2 eq) was added and the mixture stirred vigorously for a further 30 minutes. A solution of benzotriazole-t-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP, 50 mg, 96 umol, 2.0 eq) and 1-hydroxybenzotriazole (14 mg, 104 umol, 2.2 eq) in 500 uL DMF was prepared. The PyBOP solution was added in 5 batches of 60 uL at intervals of 5 minutes to the vigorously stirred suspension of the other reaction components. The reaction was stirred an additional 30 minutes then precipitated into acetonitrile. The solid was collected by centrifugation, taken up in 1 mL N,N-dimethylformamide and treated with 200 uL piperidine for 30 minutes. Precipitation into ether was followed by centrifugation and the solid washed with acetonitrile. Reverse-phase preparative HPLC (10-70% acetonitrile in water containing 0.1% trifluoroacetic acid over 120 minutes) gave a compound of formula III where R15 is —CH2CH2—NH—(CH2)9CH3 and R22 is —N-(D-glucosamine as its trifluoroacetate salt.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:10](=[O:33])[NH:11][CH2:12][C:13]1[N:22]=[C:21]([N:23]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH3:24])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[CH3:9])(C)(C)C.NCC1N=C(N(C2C=CC(OC)=CC=2)C)C2C(=CC=CC=2)N=1.N(C(OC(C)(C)C)=O)[C@@H](C(O)=O)C.CCN=C=NCCCN(C)C.C(N(C(C)C)C(C)C)C>CN(C=O)C>[NH2:7][C@H:8]([CH3:9])[C:10]([NH:11][CH2:12][C:13]1[N:22]=[C:21]([N:23]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH3:24])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)=[O:33]
Reactant: COc1ccc(N(C)c2nc(CNC(=O)[C@@H](C)NC(=O)OC(C)(C)C)nc3ccccc23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: COc1ccc(N(C)c2nc(CN)nc3ccccc23)cc1
Agent: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N(C)c2nc(CNC(=O)[C@@H](C)N)nc3ccccc23)cc1

Procedure:
[(R)-1-({4-[(4-Methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-carbamoyl)-ethyl]-carbamic acid tert-butyl ester: The title compound was prepared from (2-aminomethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (100 mg, 0.37 mmol), Boc-D-Ala-OH (70 mg, 0.37 mmol), EDCI (86 mg, 0.45 mmol), HOBt-hydrate (68 mg, 0.82 mmol) and ethyl-diisopropyl-amine (191 μL, 1.1 mmol) in DMF (1.2 mL) by a procedure similar to the preparation of Example 238a and was isolated as a yellow solid, 114 mg (67%). 1H NMR (MeOH-d4) δ 7.7 (d, 1H), 7.62-7.57 (m, 1H), 7.18 (d, 2H), 7.06-6.98 (m, 4H), 4.55 (m, 2H), 4.2 (q, 1H), 3.82 (s, 3H), 3.62 (s, 3H), 1.49 (s, 9H), 1.48 (d, 3H); LC-MS (ESI+; 466 ([M+H]+)).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=C(CCC=O)N=C2)C=CC=CC=1.[Br-].C1(CCC[P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:58]1[CH:62]=[C:61]([CH2:63][CH2:64][CH:65]=[CH:66][CH2:67][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[N:60]=[CH:59]1>>[NH:58]1[CH:62]=[C:61]([CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)[N:60]=[CH:59]1
Reactant: C(=CCCc1c[nH]cn1)CCc1ccccc1
Agent: O=CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Br-]
Agent: c1ccc(CCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: c1ccc(CCCCCCc2c[nH]cn2)cc1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanal (prepared according to standard methods (Swern oxidation) with 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and oxalyl chloride in DMSO at −45° C.) and 5 mmol of 3-phenylpropyltriphenylphosphonium bromide (prepared from triphenylphosphine and 3-phenylpropyl bromide in toluene under reflux for 12 h) are treated as described in Example 51. The 1-(1H-imidazol-4-yl)-6-phenyl-3-hexene is hydrogenated as described in Example 52. The title compound is crystallized in the form of hydrogen oxalate in ethanol and diethyl ether.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](/[CH:10]=[CH:11]/[C:12]([OH:14])=O)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[NH:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[F:9][C:8]1[CH:7]=[CH:6][C:5](/[CH:10]=[CH:11]/[C:12](=[O:14])[N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: C1CCN(C[C@@H]2CCCN2)CC1
Reactant: N#Cc1cc(/C=C/C(=O)O)ccc1F
Product: N#Cc1cc(/C=C/C(=O)N2CCC[C@H]2CN2CCCCC2)ccc1F

Procedure:
300 mg of the title compound were synthesized as described for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-(3-cyano-4-fluorophenyl)acrylic acid instead of (E)-4-bromocinnamic acid and 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1[N:11]=[N:12][CH:13]=[CH:14][CH:15]=1>[Cl-].[Zn+2].[Cl-]>[C:2]1([CH:1]=[CH:9][C:10]2[N:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1cccnn1
Agent: [Cl-]
Agent: [Zn+2]
Product: C(=Cc1cccnn1)c1ccccc1
Temperature: 150 °C
Yield: 59 %

Procedure:
Zinc chloride (820 mg, 6 mmol) was added to a stirred mixture of benzaldehyde (6.11 ml, 60 mmol) and 3-methylpyridazine (2.83 g, 30 mmol) and the resulting mixture heated for 20 hours at 150° C. The cool reaction mixture was partitioned between dichloromethane (40 ml) and 2M aqueous sodium hydroxide solution (20 ml), then the organic phase separated, combined with a dichloromethane extract (80 ml) of the aqueous phase, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using dichloromethane: methanol (99:1) as eluant, to give the title compound (59%) as a solid. δ (CDCL3): 7.12 (1H,d), 7.34 (3H,m), 7.56 (2H,d), 7.72 (1H,d), 8.37 (1H,s), 8.50 (1H,s), 8.60 (1H,s). LRMS: m/z 183 (M+1)+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH2:9][OH:10])[C:6]([O:11]C)=[C:5]([CH3:13])[C:4]=1[CH3:14].C([O-])(=O)C.[Na+].C(#N)C>O>[CH3:14][C:4]1[C:3](=[O:2])[CH:8]=[C:7]([CH2:9][OH:10])[C:6](=[O:11])[C:5]=1[CH3:13]
Reactant: COc1cc(CO)c(OC)c(C)c1C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC1=C(C)C(=O)C(CO)=CC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of intermediate E (1.8 g, 9 mmole), sodium acetate (7.5 g, 91 mmole), acetonitrile (134 ml) and water (29 ml), silver dipicolinate complex (19.2 g, 44 mmole, prepared by the method described by K. Kloc et al in Chem. Lett., 725. 1980) was added slowly with vigorous stirring over 30 minutes at room temperature. The mixture was stirred over 30 minutes longer, water (150 ml) was added, and the silver salts were filtered off and washed with chloroform. The filtrate was extracted several times with chloroform. The combined extracts were dried, concentrated to a small volume and chromatographed (silica, dichloromethane:ethyl acetate, 95:5). There was obtained 900 mg of ETA I, mp 71°-72° C. Calculated elemental analysis for C9H10O3 is C, 65.1, H, 6.1, and 0, 28.9. Elemental analysis found was C, 64.9, H, 5.9, and 0, 28.7.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH:17]=[C:16](B3OC(C)(C)C(C)(C)O3)[CH:15]=[N:14]2)[CH2:9]1)=O)(C)(C)C.Br[C:28]1[CH:29]=[C:30]([C:35]2[N:36]=[CH:37][C:38]3[C:43]([CH:44]=2)=[C:42]([Cl:45])[CH:41]=[CH:40][C:39]=3[F:46])[C:31]([NH2:34])=[N:32][CH:33]=1.C(=O)([O-])[O-].[K+].[K+].[ClH:53]>C(Cl)Cl.CCOCC.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.COCCOC.O>[ClH:45].[ClH:53].[ClH:45].[Cl:45][C:42]1[CH:41]=[CH:40][C:39]([F:46])=[C:38]2[C:43]=1[CH:44]=[C:35]([C:30]1[C:31]([NH2:34])=[N:32][CH:33]=[C:28]([C:16]3[CH:15]=[N:14][N:13]([C@H:10]4[CH2:11][CH2:12][NH:8][CH2:9]4)[CH:17]=3)[CH:29]=1)[N:36]=[CH:37]2
Reactant: Nc1ncc(Br)cc1-c1cc2c(Cl)ccc(F)c2cn1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Solvent: CCOCC
Product: Nc1ncc(-c2cnn([C@H]3CCNC3)c2)cc1-c1cc2c(Cl)ccc(F)c2cn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A solution of (S)-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.0804 g, 0.221 mmol), 5-bromo-3-(5-chloro-8-fluoroisoquinolin-3-yl)-pyridin-2-ylamine (0.065 g, 0.18 mmol), potassium carbonate (0.0815 g, 0.590 mmol), and Pd(PPh3)4 (0.015 g, 0.013 mmol) in previously degassed DME/Water (4:1) (2.05 mL) was placed in a microwave tube and evacuated and charged with N2 (2×). The reaction mixture was heated in the microwave reactor to 100° C. for 45 min. The reaction mixture was diluted with EtOAc and washed with H2O (2×), brine (2×), dried over Na2SO4, filtered and concentrated in vacuo to give a brown oil. This material was purified by chromatography on silica gel [eluting with 1% MeOH in CHCl3] resulting in (R)-3-{4-[6-Amino-5-(5-chloro-8-fluoroisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester, MS (ES+): m/z=508.9/510.8 (76/24) [MH+]. This compound was dissolved in DCM (2.0 mL) and charged with 1.0 M of HCl in Et2O (1.1 mL) and stirred at 40° C. for 5 then at rt for an additional 16 h. The solid that formed was filtered off and washed with diethyl ether (3×), yielding the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.23-2.36 (m, 1H), 2.39-2.49 (m, 1H), 3.33-3.48 (m, 1H), 3.51-3.62 (m, 2H), 3.62-3.82 (m, 2H), 5.14-5.28 (m, 1H), 7.66 (t, J=9.2 Hz, 1H), 8.11 (dd, J=8.4, 4.8 Hz, 1H), 8.17 (s, 1H), 8.47 (d, J=1.8 Hz, 1H), 8.54 (d, J=11.7 Hz, 2H), 8.67 (br. s., 1H), 9.41 (br. s., 1H), 9.54 (br. s., 1H), 9.68 (s, 1H). MS (ES+): m/z=408.88/410.77 (76/24) [MH+]. HPLC: tR=1.84 min (ZQ2, polar—5 min).
Reaction SMILES: [OH-:1].[Ba+2].[OH-:3].O1CCN([C:10](=S)[CH2:11][C:12]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][CH2:18][NH:19]3)=[CH:14][CH:13]=2)CC1>C(O)C>[NH:19]1[C:20]2[C:15](=[CH:14][CH:13]=[C:12]([CH2:11][C:10]([OH:3])=[O:1])[CH:21]=2)[CH2:16][CH2:17][CH2:18]1
Reactant: S=C(Cc1ccc2c(c1)NCCC2)N1CCOCC1
Reactant: [OH-]
Agent: [Ba+2]
Solvent: CCO
Product: O=C(O)Cc1ccc2c(c1)NCCC2
Temperature: 80 °C

Procedure:
110 ml of a 20% barium hydroxide solution were added dropwise to a solution of 1-morpholino-2-(1,2,3,4-tetrahydroquinolin-7-yl)-ethanethione (11 g; 1 equiv.) in 55 ml of ethanol, and the resulting reaction mixture was heated for 10 hours at reflux. When the conversion was complete, the solvent was removed under reduced pressure and the residue was taken up in 100 ml of water and heated to 80° C. The reaction mixture was then neutralised carefully with dry ice, filtered over Celite and concentrated under reduced pressure. The resulting crude product (14 g) was used in the next stage without further purification.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8](OCC)=[O:9])=[C:4]([N+:15]([O-])=O)[CH:3]=1>CO.[Ni]>[F:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][CH2:7][C:8](=[O:9])[NH:15][C:4]=2[CH:3]=1
Reactant: CCOC(=O)COc1ccc(F)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: O=C1COc2ccc(F)cc2N1
Yield: 88.6 %

Procedure:
A solution of 46 g of ethyl 4-fluoro-2-nitrophenoxyacetate, prepared in Example 18, in 500 ml of methanol is hydrogenated under atmospheric pressure in the presence of Raney nickel. After absorption of the theoretical quantity of hydrogen, the catalyst is filtered off, the solution is concentrated in vacuo and the residue is taken up in either, from which it crystallizes. The crystals formed are filtered off, washed with ether and dried. 28 g of 6-fluoro-2H-1,4-benzoxazin-3(4H)-one are thus obtained in the form of crystals of melting point 206°-207° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([CH:14]([OH:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[N:11]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:8]2=[N:9][CH:10]=1)=[O:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.ClCCl>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14](=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[N:11]([S:20]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)(=[O:21])=[O:22])[C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc2c(c1)cc(C(O)CC(C)C)n2S(=O)(=O)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(=O)c1cnc2c(c1)cc(C(=O)CC(C)C)n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
To a 25 ml, round bottomed flask charged with 1-benzenesulfonyl-2-(1-hydroxy-3-methyl-butyl)-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (938 mg, 2.33 mmol) was added a solution of Dess-Martin periodinane in dichloromethane (0.3M, 15 mL, 4.5 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 1 h and then quenched with a saturated aqueous sodium bicarbonate solution (10 mL). The mixture was extracted with ethyl acetate (150 mL), washed with a saturated aqueous sodium bicarbonate solution (3×20 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to give 1-benzenesulfonyl-2-(3-methyl-butyryl)-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (613 mg, 66%) as a light yellow solid which was used without further purification: LC/MS m/e calcd for C20H21N2O5S [M+H]+ 401.46, observed 401.3; 1H NMR (400 MHz, CDCl3) δ ppm 1.07 (d, J=6.6 Hz, 6H), 2.36 (m, 1H), 2.89 (d, J=7.0 Hz, 2H), 3.97 (s, 3H), 7.00 (s, 1H), 7.57 (brt, 2H), 7.64 (brt, 1H), 8.44 (br. d., 2H), 8.58 (d, J=2.0 Hz, 1H), 9.20 (d, J=2.0 Hz, 1H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:23]=[C:22]([C:24]([OH:26])=O)[O:21][N:20]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[C:28]1([S:34]([NH:37][C@@H:38]([CH2:43][NH2:44])[C:39]([O:41][CH3:42])=[O:40])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)CCl.CN(C=O)C>[CH3:42][O:41][C:39](=[O:40])[C@@H:38]([NH:37][S:34]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:36])=[O:35])[CH2:43][NH:44][C:24]([C:22]1[O:21][N:20]=[C:19]([O:18][CH2:17][CH2:16][CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)[CH:23]=1)=[O:26]
Reactant: COC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCCOc2cc(C(=O)O)on2)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CNC(=O)c1cc(OCCCCC2CCN(C(=O)OC(C)(C)C)CC2)no1)NS(=O)(=O)c1ccccc1
Reaction time: 72 h
Yield: 72.3 %

Procedure:
A stirred mixture of 4-5 (147 mg, 0.4 mmol), 2-9a (149 mg, 0.4 mmol), HOBT (61 mg, 0.4 mmol), DIEA (215 μL, 1.2 mmol), and DMF (6 mL) at -15° C. was treated with EDC (77 mg, 0.4 mL) followed by removal of the cooling bath. After 72 h, the reaction mixture was diluted with EtOAc and then washed with 1M NaHSO4 and brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 10% acetone/CH2Cl2) gave 4-6 (176 mg) as a viscous oil. Rf 0.24 (silica, 10% acetone/CH2Cl2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9](O)[N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.C(N(S(F)(F)[F:27])CC)C>C(Cl)Cl>[F:27][CH:9]1[N:8]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[NH:11][C:10]1=[O:12]
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C1Nc2ccc(Br)cc2C(c2ccccc2)=NC1O
Solvent: ClCCl
Product: O=C1Nc2ccc(Br)cc2C(c2ccccc2)=NC1F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 88 %

Procedure:
A well stirred suspension of 6.0 g (0.018 mole) of 7-bromo-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one in 250 ml methylene chloride was cooled to -70°, and 7.5 ml (0.06 mole) of diethylaminosulfur trifluoride was added dropwise. The reaction mixture was allowed to warm slowly to -10° over a period of 30 min., and held at -10° for 20 min., until most of the solid had dissolved. The reaction mixture was poured into 500 ml of ice water and stirred until the yellow color faded. The organic layer was separated, dried over MgSO4, and evaporated to dryness under reduced pressure. The residue was dissolved in 300 ml of hot benzene and filtered hot. The filtrate was mixed with 400 ml hexane and cooled. The crystals that separated were collected on a filter, washed with hexane, and dried in air to give 5.28 g (88%) of 3-fluoro-7-bromo-1,3-dihydro- 5-phenyl-2H-1,4-benzodiazepin-2-one as colorless crystals: mp 207°-209° (dec.); 19F nmr (acetone-d6) δ -162.6 ppm (d, J=57 Hz); 1H nmr (acetone-d6) δ 5.86 ppm (d, J=57 Hz, 1H), 7.2-8 ppm (m, 8H), 9.90 ppm (NH); ir (KBr) 5.84μ (C=O). A sample was dried in a vacuum oven for analysis.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 70 %

Procedure:
7 g (30.56 mmol) of ethyl 4-bromobenzoate are dissolved in 60 ml of 1,2-dimethoxyethane and, under argon, 6.96 g (36.67 mmol) of 4-trifluoromethylphenylboronic acid, 271 mg of bis(triphenylphosphine)palladium(II) chloride and 40.7 ml of a 2 M aqueous sodium carbonate solution are added. The reaction mixture is then stirred under reflux for 12 hours. The mixture is then cooled, filtered through 1 g of Extrelute, washed with dichloromethane and concentrated. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/dichloromethane 2:1). 6.31 g (21.4 mmol, 70% yield) of a colourless solid are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Br-].[Mg+2].[Br-].[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[O:26])[S:23][CH:24]=1>O1CCCC1.CCCCCC.ClCCl>[Br:19][C:20]1[CH:21]=[C:22]([CH:25]([OH:26])[C:2]2[CH:15]=[CH:14][CH:13]=[C:4]([O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[CH:3]=2)[S:23][CH:24]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Reactant: O=Cc1cc(Br)cs1
Agent: [Br-]
Agent: [Mg+2]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(O)c2cc(Br)cs2)c1
Temperature: -78 °C
Yield: 48.2 %

Procedure:
3-Bromophenoxy-tert-butyldimethylsilane (30.2 g, 0.105 mol), prepared as in Example 1, was dissolved in 300 mL of dry tetrahydrofuran under nitrogen and cooled to -78° C. A solution of 1.6M n-butylithium in hexane (66 mL, 0.105 mol) was added dropwise at a rate to maintain a temperature below -65° C. The reaction was stirred for thirty minutes after the addition was complete and the cold solution was transferred to another vessel containing a room temperature solution of magnesium bromide (20.2 g, 0.11 mol) in 400 mL of dry tetrahydrofuran under nitrogen. The resulting solution was allowed to warm to 15° C. while stirring. After one hour a solution of 4-bromo-2-thiophenecarboxaldehyde (20.0 g, 0.105 mol) in 100 mL of dry tetrahydrofuran was added slowly at a rate to maintain a temperature below 25° C. The resulting solution was stirred for three hours at room temperature, then washed three times with aqueous ammonium chloride, dried over sodium sulfate and evaporated to give a yellow oil. Chromatography on silica gel with dichloromethane:hexane/50:50 gave 20.23 g (48.2%) of α-(4-bromo-2-thienyl)-3-((tert-butyldimethylsilyl)-oxy)benzyl alcohol as a viscous yellow oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10]CC)=[O:9])[N:7]=1.[Li+].[OH-]>CO>[CH3:1][S:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([OH:10])=[O:9])[N:7]=1
Reactant: CCOC(=O)c1csc(SC)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CSc1nc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.4 %

Procedure:
Ethyl 2-(methylthio)-1,3-thiazole-4-carboxylate (5.0 g) (Sinha, Subhash C et al. Tet. Lett. 2000, 41 (43), 8243-8246) was dissolved in MeOH (50 ml) and 2N LiOH (74 ml) was added. After stirring at room temperature for five minutes the reaction mixture was concentrated to remove MeOH and the residue was suspended in water and acidified with conc. HCl to pH 3. The white precipitate was filtered and dried to yield the title compound (3.42 g). NMR: 2.72 (s, 3H), 8.35 (s, 1H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[C:13]([CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:15][CH2:16][CH3:17])=[O:14]>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:18]/[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc2ccccc2n1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc2ccccc2n1
Reaction time: 2 h
Yield: 77.6 %

Procedure:
A solution of quinoline-2-carboxaldehyde (1.51 g, 9.65 mmol) in THF (15 ml) was heated under reflux with (carbethoxymethylene) triphenylphosphorane (3.36 g). After 2 hr, the THF was removed and the residue was chromatographed using toluene/EtOAc (18:1) as eluent to afford 1.70 g of the title compound.