Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.F[C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[N:13][CH:14]=1.[C@@H:18]12[NH:25][C@@H:22]([CH2:23][CH2:24]1)[CH2:21][N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:19]2>CS(C)=O.C(OCC)(=O)C>[N+:15]([C:12]1[N:13]=[CH:14][C:9]([N:25]2[CH:18]3[CH2:24][CH2:23][CH:22]2[CH2:21][N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:19]3)=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(F)cn1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CC[C@@H](C1)N2
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC2CCC(C1)N2c1ccc([N+](=O)[O-])nc1
Temperature: 80 °C
Yield: 73.4 %

Procedure:
Triethylamine (6.87 mL, 49.3 mmol) was added to a stirred solution of 5-fluoro-2-nitropyridine (700 mg, 4.93 mmol) and (1R,5S)-tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1.05 g, 4.93 mmol) in 8 mL of DMSO at room temperature. The reaction mixture was heated to 80° C. for 2 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with, saturated ammonium chloride, water (3×), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 1.21 g (73.5%) of tert-butyl 8-(6-nitropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate as yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH3:26])[CH:21]=2)[CH:16]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:26][O:25][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([N:10]1[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]1=[O:13])[CH:24]=[CH:23]2
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc2cc(N3CCN(c4cnccc4C)C3=O)ccc2c1
Yield: 30.1 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847 mmol) was reacted with 2-bromo-6-methoxy-naphthalene (200.74 mg, 0.847 mmol), 1,4-dioxane (15 mL), copper iodide (16.13 mg, 0.0847 mmol), trans-1,2-diamino cyclohexane (0.03 mL, 0.254 mmol) and potassium carbonate (233.97 mg, 1.694 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in chloroform) afforded 85 mg of the product (30.08% yield).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C(C=C)=O.[Al+3].[Cl-].[Cl-].[Cl-].C(=O)=O.[CH:17]([OH:20])([CH3:19])[CH3:18]>C(Cl)Cl>[CH:4]12[O:20][CH:17]([CH:19]=[CH:5]1)[CH2:18][CH:3]2[CH:2]=[O:1]
Reactant: c1ccoc1
Reactant: CC(C)O
Agent: C=CC=O
Agent: O=C=O
Agent: [Al+3]
Solvent: ClCCl
Product: O=CC1CC2C=CC1O2
Temperature: -43 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of furan (9) (15 mL, 200 mmol) and acrolein (13) (6.7 mL, 100 mmol) in DCM (25 mL) was slowly added AlCl3 (666 mg, 5 mmol) under argon at −43° C. (dry ice/isopropanol bath). The reaction mixture was stirred at −43° C. under argon for 30 min, and then quenched with sat. aq. K2CO3 (50 mL). After the reaction mixture was gradually warmed to room temperature, it was extracted with ether (200 mL×5). The combined ether extracts were washed with sat. aq. K2CO3 (200 mL×2) and sat. aq. NaCl (200 mL×2), dried over MgSO4, filtered, and concentrated to give an oily crude product 7-oxa-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde which was used in the next step without further purification. See references Laszlo, P.; Lucchetti, J. Tetrahedron Lett. 1984, 25, 4387-4388. Moore, J. A., Partain, E. M. III. J Org Chem. 1983, 48, 1105-1106. Dauben, W. G.; Krabbenhoft, H. O. J. Am. Chem. Soc. 1976, 98, 1992-1993. Nelson, W. L.; Allen, D. R.; Vincenzi, F. F. J. Med. Chem. 1971, 14, 698-702.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][NH:5][C:6]([C:8]1([CH3:22])[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([CH3:21])[C:12]([CH3:20])=[C:13]([OH:19])[C:14]=2[CH3:18])[O:9]1)=[O:7].[O:24]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C([O-])(O)=O.[Na+]>>[CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][NH:5][C:6](=[O:7])[C:8]([OH:24])([CH3:22])[CH2:17][CH2:16][C:15]1[C:10](=[O:9])[C:11]([CH3:21])=[C:12]([CH3:20])[C:13](=[O:19])[C:14]=1[CH3:18]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCN(C)C)O2
Agent: O=C([O-])O
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCCN(C)C)=C(C)C1=O
Yield: 83.2 %

Procedure:
Oxidation as described in protocol B, using 150 mg N-(2-(dimethylamino)-ethyl)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide (0.468 mmol) and 564 mg CAN (1.03 mmol) with exceptions as noted. The aqueous phase was basified with NaHCO3 (s), extracted with EtOAc and the combined organics dried with Na2SO4, concentrated and flashed yielding 131 mg (83%) of N-(2-(dimethylamino)-ethyl)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:15]=[C:16]([C:24]([CH3:30])([S:26]([CH3:29])(=[O:28])=[O:27])[CH3:25])[CH:17]=[C:18]3[C:23]=2[N:22]=[CH:21][CH:20]=[CH:19]3)[CH:9]=1.[C:31]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)([OH:33])=[O:32].C(Cl)Cl>CO>[CH3:30][C:24]([C:16]1[CH:17]=[C:18]2[C:23](=[C:14]([C:10]3[CH:9]=[C:8]([C:3]4[C:2]([C:37]5[CH:38]=[CH:39][C:34]([C:31]([OH:33])=[O:32])=[CH:35][CH:36]=5)=[CH:7][CH:6]=[CH:5][CH:4]=4)[CH:13]=[CH:12][CH:11]=3)[CH:15]=1)[N:22]=[CH:21][CH:20]=[CH:19]2)([S:26]([CH3:29])(=[O:28])=[O:27])[CH3:25]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CC(C)(c1cc(-c2cccc(-c3ccccc3Br)c2)c2ncccc2c1)S(C)(=O)=O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(c1cc(-c2cccc(-c3ccccc3-c3ccc(C(=O)O)cc3)c2)c2ncccc2c1)S(C)(=O)=O

Procedure:
Prepared according to the general procedure Coupling—1 using Arylbromide from step 1 and 4-carboxybenzeneboronic acid as starting materials. Flash chromatography (CH2Cl2:MeOH, 9:1) afforded the title compound.
Reaction SMILES: [C:1]([CH2:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[NH2:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([NH:13][C:5]([CH3:6])=[CH:4][C:1](=[O:3])[CH3:2])[CH:14]=[C:15]([C:17]([F:18])([F:20])[F:19])[CH:16]=1
Reactant: CC(=O)CC(C)=O
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cc(NC(C)=CC(C)=O)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
1.57 g (15.7 mmol) Acetylacetone, 3.00 g (15.7 mmol) 3-methoxy-5-(trifluoromethyl)aniline, and 0.1 g (1.6 mmol) 4-toluenesulfonic acid are dissolved in 150 ml toluene. The reaction mixture is refluxed for 7 h with a Dean-Stark trap to remove water. After cooling down to room temperature, the suspension is filtered. The solid is purified by recrystallisation from ethanol.
Reaction SMILES: C1(OP(Cl)(OC2C=CC=CC=2)=O)C=CC=CC=1.[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[C:27]([OH:29])=O.C(N(CC)CC)C.[NH2:37][C@@H:38]1[CH:43]2[CH2:44][CH2:45][N:40]([CH2:41][CH2:42]2)[C@H:39]1[CH2:46][C:47]1[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=1.C1(C)C=CC(C([C@](C(O)=O)(O)[C@](C(C2C=CC(C)=CC=2)=O)(O)C(O)=O)=O)=CC=1.[OH-].[Na+]>ClCCl>[N:49]1[CH:50]=[CH:51][CH:52]=[C:47]([CH2:46][CH:39]2[CH:38]([NH:37][C:27]([C:19]3[O:18][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[CH:20]=3)=[O:29])[CH:43]3[CH2:42][CH2:41][N:40]2[CH2:45][CH2:44]3)[CH:48]=1
Reactant: N[C@@H]1C2CCN(CC2)[C@H]1Cc1cccnc1
Reactant: O=C(O)c1cc2ccccc2o1
Agent: Cc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1C2CCN(CC2)C1Cc1cccnc1)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
Diphenylchlorophosphate (0.35 mL, 0.46 g, 1.7 mmol) was added drop-wise to a solution of benzofuran-2-carboxylic acid (0.28 g, 1.7 mmol) and triethylamine (0.24 mL, 0.17 g, 1.7 mmol) in dry dichloromethane (5 mL). After stirring at ambient temperature for 30 min, a solution of (2S,3R)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane (0.337 g, 1.55 mmol) (that derived from the di-p-toluoyl-D-tartaric acid salt) and triethylamine (0.24 mL, 0.17 g, 1.7 mmol) in dry dichloromethane (5 mL) was added. The reaction mixture was stirred overnight at ambient temperature, and then treated with 10% sodium hydroxide (1 mL). The biphasic mixture was separated, and the organic layer was concentrated on a Genevac centrifugal evaporator. The residue was dissolved in methanol (6 mL) and purified by HPLC on a C18 silica gel column, using an acetonitrile/water gradient, containing 0.05% trifluoroacetic acid, as eluent. Concentration of selected fractions, partitioning of the resulting residue between chloroform and saturated aqueous sodium bicarbonate, and evaporation of the chloroform gave 0.310 g (42% yield) of white powder (95% pure by GCMS). 1H NMR (300 MHz, CDCl3) δ 8.51 (d, 1H), 8.34 (dd, 1H), 7.66 (d, 1H), 7.58 (dt, 1H), 7.49 (d, 1H), 7.44 (s, 1H), 7.40 (dd, 1H), 7.29 (t, 1H), 7.13 (dd, 1H), 6.63 (d, 1H), 3.95 (t, 1H), 3.08 (m, 1H), 2.95 (m, 4H), 2.78 (m, 2H), 2.03 (m, 1H), 1.72 (m, 3H), 1.52 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Br:26]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([S:11][C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:26])[N:6]2[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: BrBr
Reactant: Cc1ccc(Sc2nc(N)c3ncn(Cc4ccccc4)c3n2)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(Sc2nc(N)c3nc(Br)n(Cc4ccccc4)c3n2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 19 %

Procedure:
6-Amino-9-benzyl-2-(p-tolylthio)purine (86 mg, 0.37 mmol) and bromine (0.4 ml) were dissolved in 120 ml of methylene chloride and the solution was stirred at room temperature for 4 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on magnesium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (0.5% methanol/chloroform) to give the subject compound (20 mg, yield 19%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][NH2:8].[Cl:9][C:10]1[N:15]=[C:14](Cl)[C:13]([O:17][CH3:18])=[CH:12][N:11]=1>CO.O>[Cl:9][C:10]1[N:15]=[C:14]([NH:7][NH2:8])[C:13]([O:17][CH3:18])=[CH:12][N:11]=1
Reactant: COc1cnc(Cl)nc1Cl
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cnc(Cl)nc1NN
Temperature: 43 °C
Reaction time: 4.5 h
Yield: 95.7 %

Procedure:
Anhydrous sodium carbonate (29.15 g, 0.275 mole), methanol (300 mL), and 35% aqueous hydrazine (54.9 g, 0.60 mole) were loaded into a 1 L glass jacketed reactor equipped with a thermocouple temperature probe, overhead stirrer with glass agitator, condenser, and a programmable circulating bath. 2,4-Dichloro-5-methoxypyrimidine (89.50 g, 0.50 mole) was added as a solid in small increments over 70 min. During the addition, the reactor jacket was kept at 20° C., and the reaction temperature rose from 21° C. to 28° C. Upon completion of the addition, the reaction mixture was heated to 43° C. over 60 min, then held at 43° C. for 4.5 h. Water (300 mL) was then added, and a distillation head was attached to the reactor. Vacuum was applied to lower the pressure to 140 mmHg, and methanol was removed by distillation. Distillation continued for 1.5 h, at which point the rate of distillation had slowed greatly. The pressure as further decreased to 85 mmHg until water started to distill over, then vacuum was broken under a nitrogen flow. The reaction mixture was cooled from 43° C. to 25° C. over 60 min. The resulting slurry was stirred overnight at 25° C. The product was recovered by filtration through Whatman #52 filter paper using a Buchner funnel and aspirator vacuum. After washing the filter cake with water (221 g), the product was dried overnight in vacuo at 42° C., to give 83.5 g of white 2-chloro-4-hydrazino-5-methoxypyrimidine (purity 96.8%, yield=92.7%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[F:9].[H-].[Na+].[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:14]=1[C:15](Cl)=[O:16]>CN(C=O)C>[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:14]=1[C:15]([NH:8][C:4]1[C:3]([F:9])=[C:2]([Cl:1])[N:7]=[CH:6][N:5]=1)=[O:16]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1ncnc(Cl)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ncnc(Cl)c1F)c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 50.2 %

Procedure:
To a solution of 6-chloro-5-fluoropyrimidin-4-amine (1.21 g, 8.2 mmol) in DMF (25 mL) at 0° C. was added NaH (60% in mineral oil, 0.46 g, 11.5 mmol). The reaction mixture was stirred at 0° C. for 20 minutes. 2,6-dichlorobenzoyl chloride (2.06 g, 9.8 mmol) was then added dropwise over 5 minutes. The reaction mixture was warmed to room temperature and stirred under nitrogen overnight. The reaction was quenched with saturated NH4Cl solution (100 mL), and extracted with EtOAc (3×100 mL). The combined organics layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 0-25% EtOAc in hexane gradient to give the desired compound as a white solid (1.32 g, 50% yield). 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 8.10 (s, 1H), 7.39-7.35 (m, 3H). LCMS (ESI) m/z: 320.0 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH2:11]([SH:14])[CH2:12][SH:13]>CCCCCC>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]2[S:14][CH2:11][CH2:12][S:13]2)=[CH:5][CH:4]=1
Reactant: SCCS
Reactant: COc1ccc(C=O)cc1
Solvent: CCCCCC
Product: COc1ccc(C2SCCS2)cc1
Yield: 99.5 %

Procedure:
Following the general procedure as in Example 1, 25 gm (0.184 moles) of 4-methoxybenzaldehyde and 17.3 gm (0.184 moles) of 1,2-ethanedithiol gave, after crystallization from hexane, 39.3 gm (0.183 moles) of a white colored solid (96% yield) m.p. 62°-63° C. Elemental analysis for C10H12OS2 :
Reaction SMILES: C(OC(O[C@@H]([O:10][C:11]([C:13]1[N:14]2[CH:17]([CH:18]([CH3:37])[C:19]=1[S:20][C@@H:21]1[CH2:25][N:24](C(OCC=C)=O)[C@H:23]([CH2:32][O:33][CH2:34][CH2:35][F:36])[CH2:22]1)[CH2:16][C:15]2=[O:38])=[O:12])C)=O)C=C.[CH2:39]([OH:41])[CH3:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1(C)CC(=O)CC(=O)C1>CC(C)CC(=O)C.C(OCC)(=O)C.O.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>[F:36][CH2:35][CH2:34][O:33][CH2:32][C@@H:23]1[CH2:22][C@H:21]([S:20][C:19]2[C@H:18]([CH3:37])[C@H:17]3[N:14]([C:15](=[O:38])[C@@H:16]3[C@H:39]([OH:41])[CH3:40])[C:13]=2[C:11]([OH:10])=[O:12])[CH2:25][NH:24]1
Reactant: CCO
Reactant: C=CCOC(=O)O[C@H](C)OC(=O)C1=C(S[C@H]2C[C@@H](COCCF)N(C(=O)OCC=C)C2)C(C)C2CC(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)CC(=O)CC(=O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)CC(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](COCCF)C3)[C@H](C)[C@H]12

Procedure:
To a solution of allyl (4R,5S,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl-3-[(2S,4S)-1-allyloxycarbonyl-2-(2- fluoroethyl)oxymethylpyrrolidin-4-yl]thio-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (350 mg) in a mixture of 4-methyl-2-pentanone (4.2 ml), ethanol (2.1 ml) and water (170 μl) was added triphenylphosphine (16 mg), 5,5-dimethyl-1,3-cyclohexanedione (255 mg) and tetrakis(triphenylphosphine)palladium(0) (68 mg) at room temperature for 3 hours under nitrogen atmosphere. Evaporation of the solvent gave a residue, which was dissolved in a mixture of ethyl acetate (40 ml) and water (20 ml). The aqueous layer was separated and concentrated. The residual solution was chromatographed on "Diaion HP-20" eluting with 10% aqueous acetone. The fractions containing the desired compound were collected, and lyophilized to give (4R,5S,6S)-3-[(2S,4S)-2-(2-fluoroethyl)oxymethylpyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (100 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:25]=[CH:24][C:8]2[N:9]([CH3:23])[C:10]([NH:12][C:13]3[S:14][C:15]4[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-]>>[CH3:23][N:9]1[C:8]2[CH:24]=[CH:25][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=[C:10]1[NH:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:16]=2[N:17]=1
Reactant: COC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C)cc3s1)n2C
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccc2nc(Nc3nc4cc(C(=O)O)ccc4n3C)sc2c1
Yield: 91.7 %

Procedure:
1-Methyl-2-(6-methyl-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (1.55 g) was prepared by following General Procedure E starting from 1-methyl-2-(6-methyl-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid methyl ester (1.76 g), and LiOH (10.0 ml, 2.0 N solution in water). LC/MS: m/z 340.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]1([CH3:29])[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1[PH:19][C:20]1[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=1[CH3:28].[CH2:30]([O:32]C(OCC)CBr)[CH3:31].[PH2-].[K+].[K+].[K+]>C1(C)C=CC=CC=1.C1COCC1>[C:11]1([CH3:29])[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1[P:19]([CH2:31][CH:30]=[O:32])[C:20]1[C:21]([CH3:28])=[CH:22][C:23]([CH3:27])=[CH:24][C:25]=1[CH3:26]
Reactant: Cc1cc(C)c(Pc2c(C)cc(C)cc2C)c(C)c1
Reactant: CCOC(CBr)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Agent: [PH2-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(C)c(P(CC=O)c2c(C)cc(C)cc2C)c(C)c1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
KHMDS (35 mL of a 0.5 M solution in toluene, 17.5 mmol, Aldrich) 35 was added to a solution of dimesitylphosphine (4.1 g, 15.8 mmol) in THF (50 mL) at −78° C. After stirring for 20 min at −78° C. bromoacetaldehyde diethylacetal (2.85 mL, 19 mmol, Aldrich) was added dropwise to the solution of potassium phosphide. The solution was stirred for 5 min at −78° C., warmed to RT and stirred for 30 min at RT. Assay by 31P-NMR (crude reaction mixture) showed the formation of product (−29.5 ppm). The solvent was evaporated, the residue was flushed through a 6×3.3 cm plug of silica gel and toluene was removed (aspirator) to afford the product as a yellow oil. The product was dissolved in a mixture of degassed acetone (60 mL) and 5% aq. HCl (30 mL) and refluxed under Ar for 2.5 h. A saturated, degassed solution of NaHCO3 (100 mL) was added to the reaction mixture followed by extraction with degassed CH2Cl2 (3×50 mL). The solution was evaporated under Ar followed by filtration through a plug of silica gel (9×3.6 cm; Ar atmosphere), CH2Cl2 eluent, collecting 250 mL. Evaporation afforded product as a very air-sensitive white solid, 4.1 g (83.1%). 31P{1H} NMR (CD2Cl2): −35.6 ppm (s).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=C(C)O[N:11]=2)=[CH:6][C:5]=1[NH:16][CH2:17][C:18]([O:20]CC1C=CC=CC=1)=[O:19].[CH2:28]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](O)=[O:34])[CH3:29]>>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][NH:2][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][CH:38]=[C:30]([CH2:28][CH3:29])[CH:31]=2)=[C:5]([NH:16][CH2:17][C:18]([OH:20])=[O:19])[CH:6]=1)(=[NH:11])[NH2:14]
Reactant: Cc1nc(-c2ccc(CN)c(NCC(=O)OCc3ccccc3)c2)no1
Reactant: CCc1cccc(C(=O)O)c1
Agent: Cl
Product: CCc1cccc(C(=O)NCc2ccc(C(=N)N)cc2NCC(=O)O)c1

Procedure:
Compound 58d was reacted with 3-ethylbenzoic acid and subsequently hydrogenated according to the procedure described in Example 58, to give Example 59. ESI-MS m/e 355.5 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[N:11]([C:17]3[CH:26]=[CH:25][C:20]([C:21]([NH:23][CH3:24])=[O:22])=[C:19]([F:27])[CH:18]=3)[C:10]2=S)=[CH:5][C:4]=1[C:29]([F:32])([F:31])[F:30])#[N:2].[OH:33]O>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[N:11]([C:17]3[CH:26]=[CH:25][C:20]([C:21]([NH:23][CH3:24])=[O:22])=[C:19]([F:27])[CH:18]=3)[C:10]2=[O:33])=[CH:5][C:4]=1[C:29]([F:32])([F:31])[F:30])#[N:2]
Reactant: OO
Reactant: CNC(=O)c1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1F
Solvent: CCO
Product: CNC(=O)c1ccc(N2C(=O)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1F

Procedure:
To a solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide (1.52 g, 3.4 mmol) in ethanol (60 mL) was added 30% aqueous H2O2 (30 mL) at room temperature. The solution was heated to reflux for 1 h. After removal of ethanol, brine (100 mL) was added and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product that was purified by silica gel chromatography. MS (m/z), 449 (M+1). HPLC: Column, YMC ODS A, 4.6×150 mm, 5 μm, Mobile Phase A: 10 mM Ammonium acetate, Mobile Phase B: Acetonitrile, Gradient, 10% B up to 2 min, 10% to 90% B in 3 min, hold for 3 min, 90% to 10% B in 5 min, Retention time, 8.976 min, HPLC Purity, 98.46%, Flow Rate, 1 mL/min. 1H NMR (CDCl3, Freebase): δ (ppm) 8.22 (t, 1H), 8.18 (s, 1H), 8.04 (d, 1H), 7.95 (d, 1H), 7.28 (d, 1H), 7.22 (d, 1H), 6.70 (m, 1H), 3.05 (d, 3H), 1.65 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:5][C:6](=[O:8])[CH:7]=1)=[O:4].C([OH:19])CCCCCCC(C)C>C1(C)C=CC=CC=1>[Br:1]/[C:2](=[CH:7]/[C:6]([OH:5])=[O:8])/[C:3]([OH:19])=[O:4]
Reactant: CC(C)CCCCCCCO
Reactant: O=C1C=C(Br)C(=O)O1
Solvent: Cc1ccccc1
Product: O=C(O)/C=C(/Br)C(=O)O
Yield: 260.6 %

Procedure:
Bromomaleic anhydride (19.5 g), isodecanol (69.5 g) p-toluene sulphonic acid (2 g) and toluene (70 ml) were stirred and boiled under reflux below a Dean-Stark trap of volume 15 ml for 2.5 hours. The solution was then cooled with petroleum ether and the petroleum ether solution was washed with water. The solvent and excess isodecanol were distilled under reduced pressure, finally at 100°/0.2 mm of mercury pressure, leaving the bis(isodecyl)ester of bromomaleic acid (56 g) as an oil with an estimated purity by gas chromatography of 96%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[C:17]([CH2:18][OH:19])=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.C(N(CC)CC)C>ClCCl.CS(C)=O>[Cl:7][C:8]1[C:17]([CH:18]=[O:19])=[C:16]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: OCc1c(Cl)nc2ccccc2c1-c1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=Cc1c(Cl)nc2ccccc2c1-c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 90.5 %

Procedure:
To a solution of oxalyl chloride (2.88 ml, 1.3 equivalents), in 25 ml of dichloromethane at -78° C. under nitrogen is added dropwise a solution of dimethylsulfoxide (DMSO) (4.70 ml, 2.6 equivalents) in 25 ml of dichloromethane. After addition, the mixture is stirred for 15 minutes at -78° C. and then a solution of 2-chloro-4-(4-fluorophenyl)-3-quinolinemethanol (7.30 g) in 50 ml dichloromethane and 20 ml dimethyl sulfoxide is added dropwise. The resulting mixture is stirred at -78° C. for one hour and then quenched by adding triethylamine (17.7 ml, 5.0 equivalents), and removing the cooling bath. A saturated aqueous solution of ammonium chloride is added. The organic layer is separated, washed with water, dried (magnesium sulfate), and evaporated to give 6.56 g of 2-chloro-4-(4-fluorophenyl)-3-quinolinecarboxaldehyde as a yellow solid; mp 168°-169.5° C.; 1H NMR (chloroform-d): δ 10.25 (s, 1H), 8.12 (d, 1H), 7.91-7.83 (m, 1H), 7.57-7.53 (m, 2H), 7.36-7.22 (m, 4H) ppm.