Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[C:5]([N:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[CH3:8])=[O:6].B(OC(C)C)(OC(C)C)[O:30]C(C)C.[Li]CCCC.CC(O)=O.OO.C([O-])(O)=O.[Na+]>C1COCC1.O.CCOC(C)=O>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:7]([CH3:8])[C:5](=[O:6])[C:4]1[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=[C:2]([OH:30])[CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CN(C(=O)c1cc(Br)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl
Agent: O=C([O-])O
Agent: OO
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C(=O)c1cc(O)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-bromo-N-[4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-5-trifluoromethyl-benzamide (332 mg, 707 μmol, example 74) in dry THF (5 ml) was added triisopropyl borate (257 mg, 317 μl, 1.36 mmol, CAS RN 5419-55-6). n-BuLi (552 μl, 884 μmol, 1.6 M solution in n-hexane) was added dropwise at −78° C. The reaction mixture was stirred at −78° C. for 1.5 hours. A solution of AcOH (180 mg, 172 μl, 3.0 mmol) in water (0.2 ml) and hydrogen peroxide (103 mg, 92.8 μl, 1.06 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 18 hours and then poured on 30 ml 10% aqueous NaHCO3 solution and 30 ml EtOAc. The layers were separated and the aqueous layer was extracted a second time with 30 ml EtOAc. The combined organic layers were washed with 30 ml brine, dried over MgSO4, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light yellow solid (77 mg, 27%). MS (ESI): m/z=407.077 [M+H]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]3)=[CH:18][N:17]=2)=[CH:10][CH:9]=1)(=O)=O.[N-:31]=[N+:32]=[N-:33].[Na+].O>CN(C)C=O>[C:28]([N:25]1[CH2:24][CH2:23][N:22]([C:19]2[CH:18]=[N:17][C:16]([CH2:15][CH2:14][C:11]3[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][N:31]=[N+:32]=[N-:33])=[CH:13][CH:12]=3)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1)(=[O:30])[CH3:29]
Reactant: CC(=O)N1CCN(c2ccc(CCc3ccc(CCOS(C)(=O)=O)cc3)nc2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1CCN(c2ccc(CCc3ccc(CCN=[N+]=[N-])cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
To a solution of 2-(4-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}phenyl)ethyl methanesulfonate (608.9 mg, 1.411 mmol) in anhydrous N,N-dimethylformamide (5 ml) was added sodium azide (918.0 mg, 14.12 mmol), and the mixture was stirred at room temperature for 24 hrs. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with tert-butyl methyl ether (10 ml) and dried under reduced pressure to give 1-acetyl-4-(6-{2-[4-(2-azidoethyl)phenyl]ethyl}pyridin-3-yl)piperazine (405.9 mg, yield 76.0%) as a white solid.
Reaction SMILES: [CH:1]1([NH:4][S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-])=O)(=[O:7])=[O:6])[CH2:3][CH2:2]1.Cl>CCO.[Pd]>[NH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[S:5]([NH:4][CH:1]1[CH2:3][CH2:2]1)(=[O:7])=[O:6]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccccc1S(=O)(=O)NC1CC1
Reaction time: 48 h
Yield: 98.5 %

Procedure:
A solution of N-cyclopropyl-2-nitro-benzenesulfonamide (7.9 g, 33.0 mmol) in EtOH (50 ml) was treated with HCl (3.0 ml, 4.0 N in dioxane), Pd/C (10%, 100 mg) and shaken in a Parr Hydrogenator at 50 psi for 48 h. The catalyst was removed by filtration and the solvent evaporated to give 6.9 g (84%) of 2-Amino-N-cyclopropyl-benzenesulfonamide as a light grey solid.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:11]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[N:10]=[C:9]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[S:8]1)=[N+]=[N-].CO.Cl>[Pd]>[NH2:1][CH2:4][CH2:5][CH2:6][C:7]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:11]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[N:10]=[C:9]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[S:8]1
Reactant: CC(C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN=[N+]=[N-])c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 109.4 %

Procedure:
1-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methylpropan-1-one (94 mg, 0.21 mmol) was weighed into a 25 mL 1 neck round bottom, and dissolved in 7 mL of MeOH—HCl (0.547 ml, 1.094 mmol) and Pd/C (23 mg, 0.021 mmol) were then added. The reaction was stirred at ambient temperature and under an atmosphere of H2 for 45 minutes. The reaction was then concentrated affording the desired product (92.7 mg, 96%).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][CH2:15][CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:17].C(N(CC)C(C)C)(C)C>CCO>[OH:17][CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:15][NH:14][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: NCC(O)c1ccccc1
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C(O)c1ccc(NCC(O)c2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A flask, containing 4-fluoro-3-nitrobenzoic acid (8.00 g, 43.2 mmol) and 2-amino-1-phenylethanol (8.89 g, 64.8 mmol) dissolved in EtOH (80 mL), was purged with N2. Anh. N,N-diisopropylethylamine (19 mL, 108 mmol) was added and the reaction mixture was heated at reflux for 24 h. Later the reaction was cooled to rt and concentrated under reduced pressure. The solid residue was dissolved in EtOAc, washed (1 M aq HCl (3×), H2O (2×), brine), dried (Na2SO4) and evaporated to dryness to afford the title compound as a bright yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 8.67 (t, J=5.2 Hz, 1H), 8.61 (d, J=2.0 Hz, 1H), 7.92 (ddd, J=0.4 Hz, 2.0 Hz, 9.2 Hz, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.36 (t, 7.2 Hz, 2H), 7.28 (tt, J=1.2 Hz, 6.8 Hz, 1H), 7.18 (d, J=9.2 Hz, 1H), 5.89 (d, J=4.4 Hz, 1H), 4.91 (q, J=3.6 Hz, 1H), 3.72-3.63 (m, 1H), 3.53-3.45 (m, 1H). MS (ES+): m/z 285.1 (100) [MH+-18]; HPLC: tR=2.80 min (OpenLynx, polar—5 min).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:16][C:17]=2[CH3:18])=[N:9][CH:10]=1.[CH2:25]([O:27][C:28](=[O:41])[CH2:29][C:30]1[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:32][NH:33][CH:34]=1)[CH3:26].O>CN(C)C=O>[CH3:18][C:17]1[S:16][C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:14][C:13]=1[CH2:12][O:11][C:8]1[N:9]=[CH:10][C:5]([CH2:4][N:33]2[CH:34]=[C:30]([CH2:29][C:28]([O:27][CH2:25][CH3:26])=[O:41])[C:31]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:32]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1c[nH]nc1-c1ccccc1
Reactant: Cc1sc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cn(Cc2ccc(OCc3nc(-c4ccccc4)sc3C)nc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
Sodium hydride (60%, oily, 70.0 mg) was added to a solution of 5-chloromethyl-2-(5-methyl-2-phenyl-4-thiazolylmethoxy)pyridine (579 mg) and ethyl(3-phenyl-1H-pyrazol-4-yl)acetate (403 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl [1-[6-(5-methyl-2-phenyl-4-thiazolylmethoxy)-3-pyridylmethyl]-3-phenyl-1H-pyrazol-4-yl]acetate (476 mg, yield: 52%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (2:3, volume ratio).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][C@@H:10](O)S([O-])(=O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+].CC1CCCO1.[OH-].[Na+].Cl.[NH2:30][C@H:31]1[C:40]([CH2:43][CH3:44])([CH2:41][CH3:42])[C:39]2[CH:38]=[C:37]([C:45]([NH2:47])=[O:46])[CH:36]=[CH:35][C:34]=2[CH2:33][C@@H:32]1[O:48][CH3:49].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH3:19][O:18][C:16](=[O:17])[C@@H:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:9][CH2:10][NH:30][C@@H:31]1[C@@H:32]([O:48][CH3:49])[CH2:33][C:34]2[C:39](=[CH:38][C:37]([C:45](=[O:46])[NH2:47])=[CH:36][CH:35]=2)[C:40]1([CH2:43][CH3:44])[CH2:41][CH3:42]
Reactant: CCC1(CC)c2cc(C(N)=O)ccc2C[C@H](OC)[C@H]1N
Reactant: COC(=O)C(CC1CCCCC1)C[C@@H](O)S(=O)(=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC1CCCO1
Product: CCC1(CC)c2cc(C(N)=O)ccc2C[C@H](OC)[C@H]1NCC[C@H](CC1CCCCC1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.7 %

Procedure:
To a slurry of sodium (S)-4-cyclohexyl-1-hydroxy-3-methoxycarbonyl-butane-1-sulfonate (25.8 g, 81.5 mmol) and 2-methyl-tetrahydro-furan (300 mL) was added 1.0 M NaOH in water (76.1 mL) and the reaction mixture was stirred for 20 min at RT. To the reaction mixture was added (6S,7S)-7-amino-8,8-diethyl-6-methoxy-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid amide hydrochloride (17.0 g, 54.3 mmol); the reaction mixture was stirred for 40 min at RT, sodium triacetoxyborohydride (46.1 g, 217 mmol) was added in 4 portions. The reaction mixture was stirred at RT overnight after the first two portions. Water (200 mL) and MeTHF (100 mL) were added; the phases were separated and the organic layer was washed with 1 M NaOH (2×200 mL), diluted brine (200 mL) dried with Na2SO4 and solvent was removed to yield crude title intermediate (22 g) as a glassy yellow solid.
Reaction SMILES: S(=O)(=O)(O)O.[N+]([C:9]1[CH:10]=C(S([O-])(=O)=O)C=[CH:13][CH:14]=1)([O-])=O.[Na+].[CH2:20]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)[CH2:21][CH2:22][CH3:23].C(=O)/C=C/C.[OH-].[Na+]>O>[CH2:20]([C:24]1[CH:30]=[C:29]2[C:27](=[CH:26][CH:25]=1)[N:28]=[C:14]([CH3:13])[CH:9]=[CH:10]2)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCc1ccc(N)cc1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: C/C=C/C=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCCCc1ccc2nc(C)ccc2c1
Temperature: 105 °C
Reaction time: 0.33 h

Procedure:
A stirred mixture of 200 ml. of water, 269 g. of concentrated sulfuric acid and 136 g. of sodium 3-nitrobenzenesulfonate at 75° C. is treated dropwise with 149 g. of 4-butylaniline. The mixture is heated to 105° C. and 117 g. of crotonaldehyde is added dropwise, with stirring, at such a rate that the temperature is maintained at 105° C. The mixture is then heated at 114° C. for 30 minutes, cooled to 80° C. and poured onto chipped ice. The mixture is basified with 50% aqueous sodium hydroxide and steam distilled. The distillate is extracted with dichloromethane. The extract is evaporated at reduced pressure leaving a residue of crude 6-butylquinaldine which is distilled at reduced pressure; b.p. 104°-106° C./0.5 mm. This product is further purified by dissolving it in 600 ml. of ether and treating the solution with 23 ml. of acetic anhydride. After standing for 20 minutes, the solution is extracted with 500 ml. of 10% hydrochloric acid. The acid extract is basified with 50% aqueous sodium hydroxide and extracted with ether. The ether extract is washed with water, dried and evaporated to give a residue of purified 6-butylquinaldine.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[F:14][C:15]([F:28])([F:27])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](O)=O)=[CH:18][CH:17]=1>>[F:14][C:15]([F:27])([F:28])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]2[O:11][C:10]([C:8]3[CH:7]=[CH:6][C:5]4[NH:1][CH:2]=[N:3][C:4]=4[CH:9]=3)=[N:12][N:13]=2)=[CH:18][CH:17]=1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Reactant: O=C(O)CCc1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(CCc2nnc(-c3ccc4[nH]cnc4c3)o2)cc1

Procedure:
The compound was synthesized starting from benzimidazol-5-carbohydrazide (176 mg, 1 mmol) and 3-(4-trifluoromethylphenyl)propionic acid (218 mg; 1 mmol) as described in method 2; yield: 0.043 mg (12.0%); MS m/z: 359.2 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 3.21-3.25 (m, 2H); 3.31-3.35 (m, 2H); 7.54-7.56 (m, 2H); 7.64-7.67 (m, 2H); 7.86 (d, 1H, 3J=8.7 Hz); 7.92 (dd, 1H, 4J=1.7 Hz, 3J=8.7 Hz); 8.24 (d, 1H, 4J=1.7 Hz); 8.87 (s, 1H); HPLC (METHOD [A]): rt 13.82 min (95.9%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@@H:31]2[CH2:35][CH2:34][CH2:33][C@H:32]2[C:36]2[CH:40]=[CH:39][N:38](C3CCCCO3)[N:37]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@@H:31]2[CH2:35][CH2:34][CH2:33][C@H:32]2[C:36]2[NH:37][N:38]=[CH:39][CH:40]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@@H]3CCC[C@H]3c3ccn(C4CCCCO4)n3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ccncn1)c1cc(Cl)c(O[C@@H]2CCC[C@H]2c2ccn[nH]2)cc1F
Yield: 98.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)-4-({(1R,2S)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl]cyclopentyl}oxy)benzenesulfonamide (287 mg, 0.427 mmol) prepared in Example 151a, triethylsilane (0.60 mL), trifluoroacetic acid (4.0 mL) and dichloromethane (6.0 mL), to yield the title compound (185 mg, 99%) as a colorless solid.
Reaction SMILES: [I-].[OH:2][C@@H:3]([C@H:5]1[C:11](=[O:12])[N:10]2[C@@H:6]1[C@@H:7]([CH3:52])[C:8]([S:26][C@@H:27]1[CH2:31][N:30](C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C@H:29]([CH2:45][N+:46]3[CH:50]=[CH:49][N:48]([CH3:51])[CH:47]=3)[CH2:28]1)=[C:9]2[C:13]([O:15]CC1C=CC([N+]([O-])=O)=CC=1)=[O:14])[CH3:4].[H][H]>O1CCCC1.P([O-])([O-])([O-])=O.[OH-].[OH-].[Pd+2]>[OH:2][C@@H:3]([C@H:5]1[C:11](=[O:12])[N:10]2[C@@H:6]1[C@@H:7]([CH3:52])[C:8]([S:26][C@@H:27]1[CH2:31][NH:30][C@H:29]([CH2:45][N+:46]3[CH:50]=[CH:49][N:48]([CH3:51])[CH:47]=3)[CH2:28]1)=[C:9]2[C:13]([O-:15])=[O:14])[CH3:4]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C[n+]4ccn(C)c4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reactant: [H][H]
Agent: [Pd+2]
Agent: O=P([O-])([O-])[O-]
Agent: [I-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S[C@@H]3CN[C@H](C[n+]4ccn(C)c4)C3)[C@H](C)[C@H]12
Yield: 66.1 %

Procedure:
A solution of 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[(2S,4S)-2-(3-methyl-1-imidazolio)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]thio-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate iodide (0.79 g) obtained in Example 3-1 in a mixture of tetrahydrofuran (50 ml) and 0.1M phosphate buffer (pH 6.5) (50 ml) was stirred in the presence of 20% palladium hydroxide on carbon (0.3 g) under atmospheric pressure of hydrogen at ambient temperature for 5 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to remove the tetrahydrofuran. The residual solution was washed with ethyl acetate (50 ml×2) and the organic solvent was removed by evaporation. The aqueous solution was subjected to a column chromatography on nonionic adsorption resin, "Diaion HP-20" (50 ml), washed with water, eluted with a mixture of acetone and water (1:99 V/V). The fractions containing the desired compound were collected and lyophilized to give (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[(2S,4S)-2-(3-methyl-1-imidazolio)methylpyrrolidin-4-yl]thio-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.25 g).
Reaction SMILES: Br/[C:2](/[CH:27]=[CH:28]/[C:29]1[C:30]([CH3:47])([CH3:46])[C:31]2[C:32]([N:45]=1)=[N+:33]([CH2:38][CH2:39][CH2:40][S:41]([O-:44])(=[O:43])=[O:42])[CH:34]=[C:35]([Cl:37])[CH:36]=2)=[CH:3]\[CH:4]=[C:5]1\[N:6]([CH2:20][CH2:21][CH2:22][S:23]([O-:26])(=[O:25])=[O:24])[C:7]2[C:12]([C:13]\1([CH3:15])[CH3:14])=[CH:11][C:10]([S:16]([O-:19])(=[O:18])=[O:17])=[CH:9][CH:8]=2.[Na+:48].[Na+].[C:50]([CH2:53][CH2:54][C:55]1[CH:56]=[C:57](B(O)O)[CH:58]=[CH:59][CH:60]=1)([OH:52])=[O:51].C(=O)([O-])[O-].[Cs+].[Cs+]>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.O>[C:50]([CH2:53][CH2:54][C:55]1[CH:56]=[C:57](/[C:2](/[CH:27]=[CH:28]/[C:29]2[C:30]([CH3:47])([CH3:46])[C:31]3[C:32]([N:45]=2)=[N+:33]([CH2:38][CH2:39][CH2:40][S:41]([O-:44])(=[O:43])=[O:42])[CH:34]=[C:35]([Cl:37])[CH:36]=3)=[CH:3]\[CH:4]=[C:5]2\[N:6]([CH2:20][CH2:21][CH2:22][S:23]([O-:26])(=[O:25])=[O:24])[C:7]3[C:12]([C:13]\2([CH3:15])[CH3:14])=[CH:11][C:10]([S:16]([O-:19])(=[O:17])=[O:18])=[CH:9][CH:8]=3)[CH:58]=[CH:59][CH:60]=1)([OH:52])=[O:51].[Na+:48].[Na+:48]
Reactant: CC1(C)C(/C=C/C(Br)=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)=Nc2c1cc(Cl)c[n+]2CCCS(=O)(=O)[O-]
Reactant: O=C(O)CCc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c2cccc(CCC(=O)O)c2)=Nc2c1cc(Cl)c[n+]2CCCS(=O)(=O)[O-]

Procedure:
Compound 9 (80 mg), 3-(2-carboxyethyl)phenylboronic acid (40 mg), and cesium carbonate (20 mg) were stirred into water (20 mL) under nitrogen at room temperature. Tetrakis(triphenylphosphine)palladium (0) (10 mg) were added to the reaction mixture. The mixture was refluxed for 4 h, and the solvent and volatile compounds then were evaporated under vacuum. The crude product was purified by flash chromatography on silica 60, 200-400 mesh, eluting with a 20/80 acetonitrile/water mixture. The purified compound 56 had λMeOH=680 nm, λPBS=672 nm, ε=160,000. The absorption and emission data is shown in Table 2 and FIG. 1.
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:11]=1)[NH:8][N:7]=[CH:6]2.NC1C(C)=CC([O:30][C:31]([F:34])([F:33])[F:32])=CC=1C(OC)=O>>[F:32][C:31]([F:34])([F:33])[O:30][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:11]=1)[NH:8][N:7]=[CH:6]2
Reactant: COC(=O)c1cc(C(F)(F)F)cc2cn[nH]c12
Reactant: COC(=O)c1cc(OC(F)(F)F)cc(C)c1N
Product: COC(=O)c1cc(OC(F)(F)F)cc2cn[nH]c12

Procedure:
The title compound was prepared as in the method of compound 4 from methyl 2-amino-3-methyl-5-(trifluoromethoxy)benzoate to give an off-white solid (0.355 g, 83%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[CH2:13][C:12]([OH:16])(CO)[CH2:11][O:10][C@@H:9]1[C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[F:25])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.O>[C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[CH2:13][C:12](=[O:16])[CH2:11][O:10][C@@H:9]1[C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[F:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC(O)(CO)CO[C@@H]1c1cc(F)c(F)cc1F
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC(=O)CO[C@@H]1c1cc(F)c(F)cc1F
Reaction time: 3 h

Procedure:
To a solution of tert-butyl[(2R,3S)-5-hydroxy-5-(hydroxymethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl]carbamate (223 mg, 0.59 mmol) in tetrahydrofuran (4 mL) was added a solution of sodium periodate (143 mg, 0.67 mmol) in water (1.3 mL) and the mixture stirred for 3 hours. The mixture was concentrated and purified by flash chromatography (silica, gradient 5-20% ethyl acetate in chloroform) to yield tert-butyl[(2R,3S)-5-oxo-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl]carbamate as white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([O:14][CH3:15])=[O:13].[C:16]([Cu])#[N:17].[C-]#N.[Na+]>CN(C=O)C.O>[C:16]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([O:14][CH3:15])=[O:13])#[N:17]
Reactant: N#C[Cu]
Reactant: COC(=O)c1cccc2c(Br)cccc12
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c(C#N)cccc12
Yield: 94.7 %

Procedure:
A mixture of methyl 5-bromo-1-naphthylcarboxylate (5.2 g, 19 mmol) and CuCN (3.4 g, 38 mmol) in 100 mL anhydrous DMF was refluxed overnight. After cooling the reaction to 70° C., a solution of NaCN (2 g) in 50 mL water was added to destroy the copper complex. Ethyl acetate was added and the two layers were separated. The organic layer was washed with brine, dried over MgSO4, and concentrated. Silica gel column chromatography using hexane/ethyl acetate (5/1) gave the product (3.8 g, 95%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][C:11]([CH3:13])=[O:12].[OH-].[Na+].O>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:10][C:11](=[O:12])[CH:13]=[CH:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)=O
Reactant: O=Cc1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(C=Cc1cccc(F)c1)C=Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.8 %

Procedure:
3-Fluorobenzaldehyde (1s, 0.5 ml, 4.7 mmol) and acetone (19, 0.18 ml, 2.3 mmol) were combined in ethanol (20 ml) and stirred for 10 min at room temperature. A solution of sodium hydroxide (0.29 g, 7.3 mmol) and water (15 ml) was added and the mixture stirred for 18 hr at room temperature. The resulting mixture was filtered and chromatographed on silica gel with ethyl acetate/hexane to give a solid. The crude was recrystallized from ethanol to afford 0.26 g (42%) of yellow crystals: mp 96-97° C. [expected mp 96-97° C.]; 1H NMR: δ 7.03 (d, 2H, J=16.1 Hz), 7.09 (m, 2H), 7.35 (m, 6H), 7.67 (d, 2H, J=15.9 Hz); 13C NMR: δ 114.4, 117.5, 124.4, 126.3, 130.4, 136.9, 142.0, 162.9, 188.1; Anal. Calcd for C17H12OF2: C, 75.55; H, 4.48. Found: C, 75.26; H, 4.65.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](OCC)=[O:15])=[N:6]1.[NH3:23]>CO>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]([NH2:23])=[O:15])=[N:6]1
Reactant: CCOC(=O)c1nn(Cc2ccccc2F)c2ncccc12
Reactant: N
Solvent: CO
Product: NC(=O)c1nn(Cc2ccccc2F)c2ncccc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
10.18 g (34 mmol) of the ester from Example 21A are initially charged in 150 ml methanol which has been saturated with ammonia at 0-10° C. The mixture is stirred at room temperature for two days and subsequently concentrated under reduced pressure.