Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:17])C=1>C(Cl)(Cl)Cl.C(OCC)(=O)C.CCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N+:6]([O-:17])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(Br)cn1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(Br)c[n+]1[O-]
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromo-2-methylpyridine (1.0 eq.) in chloroform (0.38 M) was added 77% meta-chloroperbenzoic acid (mCPBA) (4.0 eq.) and heated at 60° C. for 20 hours. After cooling to room temperature, Ca(OH)2 (5.3 eq.) was added, and the resulting precipitate was stirred for 30 minutes. The precipitate was filtered and washed with 3:1 CHCl3/methanol. The filtrate was concentrated en vacuo to give a solid, which was stirred in 30% ethyl acetate in hexane and filtered to give the desired N-oxide. The filtrate was concentrated en vacuo, and the residue was purified by a COMBIFLASH® system (ISCO) using 0-100% ethyl acetate in hexane to give more of the desired N-oxide. The two batches were combined and carried onto the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C:13]([CH2:21][CH:22]3[CH2:24][CH2:23]3)([CH2:16][C:17]3([CH3:20])[CH2:19][O:18]3)[O:12][C:11]2=[O:25])[CH3:9])=[CH:4][CH:3]=1.OO>O1CCCC1.COC(C)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([CH2:21][CH:22]3[CH2:24][CH2:23]3)([CH2:16][C:17]([OH:18])([CH3:20])[CH3:19])[O:12][C:11]2=[O:25])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CCC(CC2CC2)(CC2(C)CO2)OC1=O
Agent: OO
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@@](CC2CC2)(CC(C)(C)O)OC1=O
Temperature: 2.5 °C
Reaction time: 1.5 h

Procedure:
LiBHEt3 solution (1 mol/L, 34 mL) was added dropwise to a solution of 3-[(S)-1-(4-bromophenyl)ethyl]-6-(cyclopropylmethyl)-6-[(2-methyloxiran-2-yl)methyl]-1,3-oxazinan-2-one (1.40 g) in tetrahydrofuran (200 mL) at 0° C. The resulting solution was stirred at 2-3° C. for 1.5 h and then at room temperature for another 3 h. 30% aqueous H2O2 solution (30 mL) was added dropwise at 0° C. and the mixture was diluted with tert-butyl methyl ether (200 mL). The mixture was washed with 3% aqueous Na2SO2O3 solution and saturated aqueous NaHCO3 solution (4×100 mL) and dried (Na2SO4). The solvent was evaporated and the residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate 1:1→3:1) to afford the title compound; besides, the diastereomer, 3-[(S)-1-(4-bromophenyl)ethyl]-(R)-6-(cyclopropylmethyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one was also isolated (0.40 g, 29% yield). Yield: 0.55 g (40% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>C(O)(C)C.Cl>[ClH:1].[OH:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH:26][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Nc1cccc(O)c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCn1ccnc1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3cccc(O)c3)ncnc2cc1OCCn1ccnc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
A mixture of 4-chloro-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline (49 mg, 0.16 mmol) and 3-hydroxyaniline (21 mg, 0.19 mmol) in isopropanol (3 ml) and isopropanolic hydrogen chloride (0.2 ml of a 5M solution) was stirred at 80° C. for 1 hour. The precipitated solid was collected by filtration, washed with isopropanol and ether and dried under vacuum to give 4-(3-hydroxyanilino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline hydrochloride (56 mg, 93%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][CH2:8][C@H:7]([NH:16][C:17]([O:19]C(C)(C)C)=O)[C:6]1=[O:24].[CH2:26]([N:33]=[C:34]=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:34]([NH:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:35])[CH2:8][C@H:7]([NH:16][C:17](=[O:19])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]1=[O:24]
Reactant: O=C=NCc1ccccc1
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)c2ccccc2)CN(C(=O)NCc2ccccc2)c2ccccc21
Temperature: 25 °C
Yield: 164.4 %

Procedure:
A solution of 600a/103 (400 mg, 1.1 mmol) and benzylisocyanate (166 mg, 1.2mmol) in 10 ml of CH2Cl2 and 10 ml of DMF and heated at 80° C. for 3 days. The reaction was cooled to RT poured onto H2O and extracted with EtOAc (2×). The combined organic layers were washed with H2O (4×) and sat. aq. NaCl, dried over MgSO4 and concentrated in vacuo. Chromatography (flash, SiO2, 50% to 80% EtOAc/hexane) gave 440 mg (80%) of 602p as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14](O)=O)=[C:4]([NH:9][CH2:10]C(O)=O)[CH:5]=[CH:6][C:7]=1[F:8].[C:17]([O-:20])(=[O:19])[CH3:18].[Na+].C(O[C:26](=[O:28])[CH3:27])(=O)C>>[C:17]([O:20][C:14]1[C:3]2[C:4](=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[Cl:1])[N:9]([C:26](=[O:28])[CH3:27])[CH:10]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[O-]
Reactant: O=C(O)CNc1ccc(F)c(Cl)c1C(=O)O
Agent: [Na+]
Product: CC(=O)Oc1cn(C(C)=O)c2ccc(F)c(Cl)c12
Yield: 94 %

Procedure:
A suspension of 2.63 g of N-[3-chloro-2-(hydroxycarbonyl)-4-fluoro-phenyl]glycine and 2.63 g of sodium acetate in 25 ml of acetic anhydride was boiled under reflux for 45 minutes. The solvent was removed in a vacuum and the residue was treated with 50 ml of water. The crystals were filtered off, washed with water and dried. There were obtained 2.7 g (94%) of 3-acetoxy-1-acetyl-4-chloro-5-fluoroindole as yellow crystals with m.p. 168°-169°.
Reaction SMILES: C1(N)CCCCC1.C1(N)CCCCC1.[N+:15]([CH2:18][C@:19]1([CH2:26][C:27]([OH:29])=[O:28])[CH2:25][C@@H:24]2[C@H:20]1[CH2:21][CH2:22][CH2:23]2)([O-])=O.Cl>C(OCC)(=O)C>[NH2:15][CH2:18][C@:19]1([CH2:26][C:27]([OH:29])=[O:28])[CH2:25][C@@H:24]2[C@H:20]1[CH2:21][CH2:22][CH2:23]2
Reactant: O=C(O)C[C@@]1(C[N+](=O)[O-])C[C@H]2CCC[C@H]21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: NC1CCCCC1
Product: NC[C@]1(CC(=O)O)C[C@H]2CCC[C@H]21
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
The cyclohexylamine salt of the nitro acid from example 1 (100 g; 320 mmol) was added to a mixture of ethyl acetate (680 ml) and a 2M aqueous solution of hydrochloric acid (340 ml). The mixture was stirred vigorously for 10 minutes and the phases were separated. The organic layer was further washed with demineralised water (340 ml). The organic layer was separated and demineralised water (1360 ml) was added. To this two phase mixture 5% platinum on carbon as a 50% water wet catalyst (13.65 g) was added. The reaction mixture was then hydrogenated at 50° C. and a hydrogen pressure of 150 psi for 24 hours. The hydrogen was purged with nitrogen and the reaction mixture was heated to 70° C. The reaction mixture was filtered through Celite at 70° C. and the filter pad was washed with hot demineralised water (50 ml). The filtrate was allowed to settle, the phases were separated at 70° C. and the lower aqueous phase was removed and concentrated by distillation at atmospheric pressure to a sixth of its original volume. The white slurry was cooled to 50° C. and isopropanol (705 ml) was then added over a period of 1.7 hours. The white slurry was then cooled to between +5° C. and +10° C. over 90 minutes and stirred for 2.5 hours. The solid was collected by filtration and the damp filter cake washed with isopropanol (60 ml). The isolated solid was then dried in vacuo at 45° C. for 18 hours to give the title compound in high purity as a white crystalline solid (36.3 g) in 62% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[CH:5](O)[C:6]([OH:8])=[O:7].C(N(S(F)(F)[F:20])CC)C.[F:23][C:24]1[CH:25]=[C:26]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH:27]([OH:32])[C:28]([O:30][CH3:31])=[O:29].[OH-].[Li+]>C(Cl)Cl>[F:23][C:24]1[CH:25]=[C:26]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH:27]([OH:32])[C:28]([O:30][CH3:31])=[O:29].[F:1][C:2]1[CH:3]=[C:4]([CH:5]([F:20])[C:6]([OH:8])=[O:7])[CH:10]=[C:11]([F:13])[CH:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C(O)C(O)c1cc(F)cc(F)c1
Agent: COC(=O)C(O)c1cc(F)cc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(O)C(F)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl 3,5-difluoromandelate was prepared following General Procedure G below and using commerically available 3,5-difluoromandelic acid. The resultant α-hydroxy methyl ester was fluorinated according to the general procedure described in W. J. Middleton, et al., Org. Synth. CoL Vol. VI, 835. Specifically, a solution of diethylaminosulfur trifluoride (1.1 eq) in CH2Cl2 was cooled to 0° C. and treated with methyl 3,5-difluoromandelate (1.0 eq) as a solution in CH2Cl2. After 10 min. the cooling bath was removed and the reaction was stirred at ambient temperature for 30 min. The reaction was monitored by tlc (Rf=0.65, 1:1 ethyl acetate/hexanes). The mixture was then poured onto ice and the layers separated. The organic phase was washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo, The product was purified by LC2000 chromatograpy (180 mL/min) using 10% EtoAc/hexanes as the eluent. The resulting methyl 3,5-difluorophenyl-α-fluoroacetate was hydrolyzed by dissolving the ester in 70% aqueous dioxane and treating with lithium hydroxide (2.0 eq.). No starting material remained by tlc after 2 h. The dioxane was removed via rotary evaporation. The aqueous mixture was first washed with ethyl acetate and then acidified with 0.01 N HCl. The aqueous layer was extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude solid was recrystallized from ethyl acetate/hexanes affording 3,5-difluorophenyl-α-fluoroacetic acid as a white solid having a melting point of 90-110° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=O.Cl.CO.P(Br)(Br)[Br:16]>ClCCl>[Br:16][CH2:6][C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([S:2][CH3:1])[CH:4]=1
Reactant: CSc1cccc(C(=O)O)c1
Reactant: BrP(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CSc1cccc(CBr)c1
Reaction time: 8 h

Procedure:
A solution of 1.50 g (8.92 mmol) 3-(methylthio)benzoic acid (Aldrich) in 20 mL of dry dichloromethane is cooled to 0° C. and 1.86 mL (19.6 mmol) borane-methylsulfide complex (Aldrich) is added. The solution is allowed to reach room temperature and stirred overnight, then hydrochloric acid (4 M, 50 mL) is added and the resulting mixture is stirred for additional 2 h. The reaction mixture is extracted with ethyl acetate (50 mL, 3 times) and the collected organic phases are washed with 10% NaHCO3 solution and brine and volatiles evaporated under vacuum to yield 3-methylsulfanyl-phenyl)-methanol (1.20 g, content ca. 75%), which is directly used in the next step. Step B: A solution of 3-methylsulfanyl-phenyl)-methanol (1.20 g, content ca 75%) in dichloromethane (25 mL) and phosphorus tribromide (1 M in dichloromethane, 6.42 mL) is stirred for 3 h at room temperature. The reaction mixture is washed with NaHCO3 solution (10%, 10 mL, 2 times) and the remaining organic phase is dried (MgSO4) and volatiles are evaporated under reduced pressure to yield the title compound (1.35 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[C:5]([N+:26]([O-:28])=[O:27])[CH:4]=1.[C:29]1([CH:35]2[CH2:44][C:43]3[C:38](=[CH:39][C:40]([OH:45])=[CH:41][CH:42]=3)[O:37][CH2:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([O:45][C:40]2[CH:39]=[C:38]3[C:43]([CH2:44][CH:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:36][O:37]3)=[CH:42][CH:41]=2)=[C:5]([N+:26]([O-:28])=[O:27])[CH:4]=1
Reactant: Oc1ccc2c(c1)OCC(c1ccccc1)C2
Reactant: COc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)c([N+](=O)[O-])c1
Product: COc1ccc(Oc2ccc3c(c2)OCC(c2ccccc2)C3)c([N+](=O)[O-])c1

Procedure:
7-(4-Methoxy-2-nitrophenoxy)-3-phenylchroman was prepared as described for 6-(4-methoxy-2-nitrophenoxy)-2-phenylchroman in Example 3(a) using 0.5 g of 3-phenylchroman-7-ol. 1H NMR (400 MHz, d6-DMSO) δ: 7.60 (d, 1H, J 3.1 Hz), 7.35 (m, 4H), 7.32 (dd, 1H, J 9.1, 3.1 Hz), 7.27-7.29 (m, 1H), 7.21 (d, 1H, J 9.1 Hz), 7.12 (d, 1H, J 8.3 Hz), 6.48 (dd, 1H, J 8.3, 2.5 Hz), 6.38 (d, 1H, J 2.5 Hz), 4.26 (dd, 1H, J 10.4, 3.5 Hz), 4.08 (t, 1H, J 10.4 Hz), 3.85 (s, 3H), 3.20 (m, 1H), 2.90-3.04 (m, 2H).
Reaction SMILES: [CH:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=2)[CH2:12][N:13]([CH3:25])[C:14](=[O:24])[CH2:15][NH:16]C(=O)OC(C)(C)C)=[CH:5][CH:4]=1)=O.[NH:29]1[CH2:33][CH2:32][CH2:31][C@@H:30]1[CH2:34][OH:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:50]C(Cl)C>C(O)(=O)C>[ClH:50].[ClH:50].[ClH:50].[OH:35][CH2:34][C@@H:30]1[CH2:31][CH2:32][CH2:33][N:29]1[CH2:1][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=2)[CH2:12][N:13]([CH3:25])[C:14](=[O:24])[CH2:15][NH2:16])=[CH:5][CH:4]=1
Reactant: OC[C@H]1CCCN1
Reactant: CC(Cl)Cl
Reactant: CN(Cc1cccc(-c2ccc(C=O)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(Cc1cccc(-c2ccc(CN3CCC[C@H]3CO)nc2)c1)C(=O)CN
Product: Cl
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl (2-{[3-(6-formylpyridin-3-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (150 mg) and (2R)-pyrrolidin-2-ylmethanol (59 mg) was dissolved in dichloroethane (1 ml) and acetic acid (1 ml), followed by stirring at 60° C. for 30 minutes. Sodium triacetoxyborohydride (166 mg) was added thereto, followed by stirring at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and to the obtained residue was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH). The product was dissolved in MeOH (3 ml), and 4 M hydrogen chloride/EtOAc (1 ml) was added thereto, followed by stirring at room temperature overnight and concentrating under reduced pressure. Then, EtOH was added thereto, and then the precipitated solid was collected by filtration to obtain N-[3-(6-{[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}pyridin-3-yl)benzyl]-N-methylglycinamide trihydrochloride (43 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:10]=2[F:19])[C:3]=1[CH3:20].[CH:21]([C:24]1[N:28]=[C:27]([N:29]2[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]2)[O:26][N:25]=1)([CH3:23])[CH3:22].CC(C)([O-])C.[K+].Cl.CCOCC>C1COCC1.C(Cl)Cl>[F:19][C:10]1[CH:11]=[C:12]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:13]=[CH:14][C:9]=1[NH:8][C:4]1[C:3]([CH3:20])=[C:2]([O:35][CH:32]2[CH2:33][CH2:34][N:29]([C:27]3[O:26][N:25]=[C:24]([CH:21]([CH3:23])[CH3:22])[N:28]=3)[CH2:30][CH2:31]2)[N:7]=[CH:6][N:5]=1
Reactant: CC(C)c1noc(N2CCC(O)CC2)n1
Reactant: Cc1c(Cl)ncnc1Nc1ccc(S(C)(=O)=O)cc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1c(Nc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCN(c2nc(C(C)C)no2)CC1
Yield: 30 %

Procedure:
A mixture of (6-chloro-5-methyl-pyrimidin-4-yl)-(2-fluoro-4-methanesulfonyl-phenyl)-amine (HCl salt, 1.76 g, 5.0 mmol) and 1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ol (1.05 g, 5.0 mmol) in anhydrous THF (10 mL) was treated with potassium t-butoxide (20 mL, 20 mmol), placed under inert atmosphere, and refluxed for 4 hours, at which point the reaction had stalled at 60% conversion. The reaction mixture was cooled, quenched with water (30 mL), and extracted with ether (2×50 mL). The combined organic extract was rinsed with water (20 mL), followed by brine (20 mL), and was dried over MgSO4. After solvent removal, the residue was rinsed with boiling ether (2×20 mL), and the combined rinses were set aside to cool. Crystallization yielded a white solid (91% pure by LCMS) which was triturated in hot ether and filtered hot to furnish Compound A93 as a white solid in >95% purity (731 mg, 30% yield). This material was taken up in CH2Cl2 (10 mL), to which was added 1 N HCl/ether (1.5 mL). Upon solvent removal, a light gray foam was obtained (800 mg): 1H NMR (DMSO-d6) δ 10.26 (brs, 1 H), 8.77 (s, 1 H), 8.22 (s, 1 H), 7.83-7.71 (m, 3 H), 5.33 (m, 1 H), 3.75 (m, 2 H), 3.57 (m, 2 H), 3.37 (s, 3 H), 2.83 (m, 1 H), 2.13 (s, 3 H), 2.04 (m, 2 H), 1.78 (m, 2 H), 1.20 (d, 6 H, J=6.9 Hz), MS m/z 491.2 (M+).
Reaction SMILES: CI.[CH3:3][NH:4][C:5]([C:7]1[NH:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:6].[C:23]([O-])([O-])=O.[Cs+].[Cs+]>N1C=CC=CC=1>[CH3:3][NH:4][C:5]([C:7]1[N:15]([CH3:23])[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:6]
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)c1[nH]c2cccnc2c1Sc1ccccc1
Agent: [Cs+]
Solvent: CI
Solvent: c1ccncc1
Product: CNC(=O)c1c(Sc2ccccc2)c2ncccc2n1C
Yield: 20.3 %

Procedure:
Add methyl iodide (20 mg, 0.164 mmol) at r.t. to a mixture of 3-phenylsulfanyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid methylamide (Ia-33, 47 mg, 0.166 mmol), Cs2CO3 (65 mg, 0.2 mmol) and pyridine (1.5 mL). Heat the reaction at 60° C. in a sealed vessel for 3 hrs. Add additional methyl iodide (20 mg) and moniter the progress on the reaction by chromatography. When complete, cool the mixture, concentrate to dryness and extract into ethyl acetate from brine. Separate the organic phase and concentrate. Purify the residue by flash chromatography twice (SiO2, 3 gm, elute with MeOH 0-4% in DCM; and SiO2, 1 gm, elute with heptane:DCM, 1:1) to provide title compound (10 mg) as a white solid, 1H NMR (CDCl3) and LC-MS (m/e=297) were consistent for the title compound structure.
Reaction SMILES: [Li].[C:2]1([C-:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][SiH:18]([N:20](Cl)[C:21]([CH3:24])([CH3:23])[CH3:22])[CH3:19]>C1COCC1>[CH3:17][SiH:18]([N:20]([CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9]1)[C:21]([CH3:24])([CH3:23])[CH3:22])[CH3:19]
Reactant: C[SiH](C)N(Cl)C(C)(C)C
Reactant: c1ccc(-[c-]2ccc3ccccc32)cc1
Agent: [Li]
Solvent: C1CCOC1
Product: C[SiH](C)N(C1C=C(c2ccccc2)c2ccccc21)C(C)(C)C
Reaction time: 16 h
Yield: 96.2 %

Procedure:
Lithium-1-Phenylindenide (5.53 g, 0.0279 moles) in THF (50 mL) was added dropwise to a solution of dimethylsilyl(t-butylamino)chloride (4.62 g, 0.0279 moles) in THF (100 mL). This mixture was allowed to stir 16 hours. After the reaction period the volatiles were removed and the residue extracted and filtered using hexane. Removal of the hexane resulted in theisolation of the desired product as an oil (8.63 g, 96.2 percent).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:19][S:20]([O:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)[CH:5]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Nc1nc(-c2cccc(CCO)c2)cs1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(-c2cccc(CCOS(C)(=O)=O)c2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of N-{4-[3-(2-hydroxyethyl)phenyl]-1,3-thiazol-2-yl}acetamide (300 mg) in CH2Cl2 (10 ml) were added methansulfonyl chloride (106 μl) and triethylamine (207 μl) at 5° C. The mixture was stirred at 25° C. for 2 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. Resulting residue was purified by silica gel column chromatography with n-hexane and ethyl acetate (1:1) as an eluent to give 2-{3-[2-(acetylamino)-1,3-thiazol-4-yl]phenyl}ethyl methanesulfonate (388 mg) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([CH2:17][O:18][CH3:19])[C:3]=1[CH:4]=[O:5].[O:20](S(C(F)(F)F)(=O)=O)[S:21]([C:24]([F:27])([F:26])[F:25])(=O)=[O:22]>ClCCl.O>[CH:4]([C:3]1[C:6]([CH2:17][O:18][CH3:19])=[CH:7][C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:9][C:2]=1[O:1][S:21]([C:24]([F:27])([F:26])[F:25])(=[O:22])=[O:20])=[O:5]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COCc1cc(OC2CCCCO2)cc(O)c1C=O
Solvent: O
Solvent: ClCCl
Product: COCc1cc(OC2CCCCO2)cc(OS(=O)(=O)C(F)(F)F)c1C=O
Yield: 67.3 %

Procedure:
A solution of 2-hydroxy-6-methoxymethyl-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (5.18 g, 19.5 mmol) and TEA (10.9 mL, 78.0 mmol) in dichloromethane (100 mL) was treated with Tf2O (7.20 mL, 42.8 mmol) at −78° C. for 1 h. The mixture was diluted with water (150 mL) and extracted with dichloromethane. The organic phases were separated, dried (Na2SO4), and concentrated to dryness. The residue was purified by the flash column chromatography (silica, hexanes/ethyl acetate=4:1), affording the title compound (5.23 g, 67%). 1H NMR (300 MHz, CDCl3) δ 10.29 (s, 1H), 7.44 (s, 1H), 6.99 (s, 1H), 5.60-5.58 (m, 1H), 4.84 (s, 2H), 3.78-3.74 (m, 1H), 3.68-3.62 (m, 1H), 3.51 (s, 3H), 1.91-1.88 (m, 2H), 1.74-1.68 (m, 4H).
Reaction SMILES: N[C:2]1[NH:3][C:4]2[CH:10]=[C:9](C(=O)C(C)(C)C)[CH:8]=[CH:7][C:5]=2[N:6]=1.O.N#CBr>CC#N.CCO>[N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH:6][CH:2]=1
Reactant: CC(C)(C)C(=O)c1ccc2nc(N)[nH]c2c1
Agent: N#CBr
Solvent: CCO
Solvent: O
Solvent: CC#N
Product: c1ccc2[nH]cnc2c1
Reaction time: 20 h

Procedure:
2-Amino-5-(2′,2′-dimethylpropionyl)benzimidazole: To a flask containing 60 mL H2O was added 11.32 mL of a 5.0 M solution of cyanogen bromide in CH3CN followed by the addition of 10.71 g 4-(2′,2′-dimethylpropionyl)-1,2-aminobenzene (51.5 mmol, prepared above in step (b), 1.0 equiv) in 60 mL EtOH over 30 min via addition funnel. After stirring for 20 h the solution was concentrated under reduced pressure to remove the EtOH. The resulting aqueous solution was washed (2×EtOAc), and the EtOAc fractions were back extracted 2×H2O. The combined aqueous layers were made basic with sat. NaHCO3, and then extracted (3×EtOAc). The organic layer was then washed (1×brine), dried (MgSO4), and concentrated under reduced pressure to give the product benzimidazole as a brown solid (8.59 g, 36.8 mmol): 1H NMR (DMSO-d6, 400 MHz) δ 7.04 (d, J=8.3 Hz, 1 H), 6.79 (d, J=2.2 Hz, 1 H), 6.53 (dd, J=2.2, 8.3 Hz, 1 H), 6.31 (broad s, 2 H), 1.28 (s, 9 H).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([CH3:7])=[N:5][N:6]=1.B(O)(O)O.C(N(CC)CC)C.[NH2:19][CH:20]1[C:35](=[O:36])[N:22]2[C:23]([C:32]([OH:34])=[O:33])=[C:24]([CH2:27]OC(=O)C)[CH2:25][S:26][C@H:21]12>O>[NH2:19][CH:20]1[C:35](=[O:36])[N:22]2[C:23]([C:32]([OH:34])=[O:33])=[C:24]([CH2:27][S:1][C:2]3[S:3][C:4]([CH3:7])=[N:5][N:6]=3)[CH2:25][S:26][C@H:21]12
Reactant: Cc1nnc(S)s1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: OB(O)O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1

Procedure:
A suspension of 40 g (0.30 mole) of 2-mercapto-5-methyl-1,3,4-thiadiazole (TD) in 3.15 liters of water, with 30 g of boric acid and 30.4 ml (≃0.217 mole) of triethylamine was heated to 70/72° C. While the mixture was being vigorously stirred, at the same temperature, one 40 g shot (0.147 mole) of 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (92%) was added.