Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9]([C@@H:11]1[CH2:15][C@@H:14]([S:16][C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][N:12]1[S:36]([C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=1)(=[O:38])=[O:37])=O.C(Cl)Cl.CCOC(C)=O>C1COCC1>[CH:40]1[C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:47]=[CH:48][C:39]=1[S:36]([N:12]1[CH2:13][C@H:14]([S:16][C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:15][C@H:11]1[CH2:9][OH:8])(=[O:38])=[O:37]
Reactant: COC(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc2ccccc2c1)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 81 %

Procedure:
Ester reduction, Method A: 57 ml (57 mmol, 1M THF solution) of LAH was added during 15 min to a cold solution (−20° C.) of 28.2 g (47.5 mmol, ca. (2S,4R)/(2R,4R)-isomer ca 4:1) (2S,4R)-1-(naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid methyl ester in 460 ml THF. The reaction was stirred for 20 min, cooled to −78° C. and quenched with a suspension of 15 g silica gel/15 g MgSO4 7H2O in 60 ml aqueous 10% KHSO4. The suspension was stirred for 15 min at room temperature, filtered and washed with THF. After evaporation of the THF, the residue was taken up in CH2Cl2, dried over Na2SO4 and evaporated to give 29.2 g crude product. Flash column chromatography on silica gel with CH2Cl2/EtOAc(2.5%) to CH2Cl2/EtOAc(10%) gave 21.7 g (81%) of (2S,4R)-[1-(naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidin-2-yl]-methanol and 1.0 g (4%) of [(2R,4R)-4-mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-yl]MS: 566 (MH+).
Reaction SMILES: [CH2:1]([CH:3]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:14])[CH3:2].CC1NC2C=CC=CC=2N=1.C(C(CCCC)CBr)C.[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[SH:45].[S]>N1C=CC=CC=1>[CH2:1]([CH:3]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:14]1[S:45][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=1)[CH3:2]
Reactant: Nc1ccccc1S
Reactant: CCCCC(CC)Cn1c(C)nc2ccccc21
Agent: CCCCC(CC)CBr
Agent: Cc1nc2ccccc2[nH]1
Agent: [S]
Solvent: c1ccncc1
Product: CCCCC(CC)Cn1c(-c2nc3ccccc3s2)nc2ccccc21

Procedure:
48.8 g (0.2 mol) of 1-(2-ethylhexyl)-2-methylbenzimidazole (prepared by the alkylation of 2-methylbenzimidazole and 2-ethylhexyl bromide under phase transfer conditions), 25 g (0.2 mol) of o-aminothiophenol and 19.2 g (0.6 mol) of sulphur in 200 ml of pyridine are heated for 18 hours under reflux. Then the pyridine is distilled off and the remaining residue is dissolved by heating in 80 g of ethanol. After cooling, 55.2 g (76% of theory) of the product, which, according to its melting point and HPLC and UV analysis, is identical to the compound obtained in Example 18 by route A, are precipitated.
Reaction SMILES: NC1C=CC([C:8]2[NH:9][C:10]3[CH:16]=[CH:15][C:14](N)=[CH:13][C:11]=3[N:12]=2)=CC=1.C1(C(Cl)=O)CCCCC1>>[N:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[NH:12][CH:8]=1
Reactant: Nc1ccc(-c2nc3cc(N)ccc3[nH]2)cc1
Agent: O=C(Cl)C1CCCCC1
Product: c1ccc2[nH]cnc2c1

Procedure:
2-(N-Cyclohexylcarbonyl-4′-aminophenyl)-6-cyclohexylcarbonylamino)-benzimidazole was prepared by Method A from 2-(4-aminophenyl)-6-aminobenzimidazole (0.195 g, 0.87 mmole) and cyclohexylcarbonyl chloride (0.291 ml, 0.319 g, 2.175 mmole). The resulting solid (76.7 mg) was purified by preparative HPLC.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:67](=[O:68])[N:6]2[C:7]([C:54]([O:56]CC3C=CC([N+]([O-])=O)=CC=3)=[O:55])=[C:8]([S:11][C@@H:12]3[CH2:16][N:15](C(OCC4C=CC([N+]([O-])=O)=CC=4)=O)[C@H:14]([C:30]([N:32]4[CH2:37][CH2:36][N:35]([C:38](=[NH:53])[NH:39]C(OCC5C=CC([N+]([O-])=O)=CC=5)=O)[CH2:34][CH2:33]4)=[O:31])[CH2:13]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[H][H]>O1CCCC1.O.[Pd]>[C:38]([N:35]1[CH2:36][CH2:37][N:32]([C:30]([C@@H:14]2[CH2:13][C@H:12]([S:11][C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:67](=[O:68])[N:6]4[C:7]=3[C:54]([OH:56])=[O:55])[CH2:16][NH:15]2)=[O:31])[CH2:33][CH2:34]1)(=[NH:39])[NH2:53]
Reactant: [H][H]
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(=O)N4CCN(C(=N)NC(=O)OCc5ccc([N+](=O)[O-])cc5)CC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CCN(C(=N)N)CC4)C3)[C@H](C)[C@H]12
Yield: 63.8 %

Procedure:
680 mg of 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[4-(4-nitrobenzyl -oxycarbonylamidino)piperazin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate [prepared as described in step (1) above] were dissolved in 40 ml of a 1:1 by volume mixture of tetrahydrofuran and water, and 950 mg of a 10% w/w palladium-on-carbon catalyst were added to the resulting solution. The mixture was then hydrogenated in an atmosphere of hydrogen at 28° C. for 1 hour. At the end of this time, the catalyst was removed by filtration, and the filtrate was washed with diethyl ether. The aqueous layer was then concentrated by evaporation under reduced pressure, to 10 ml. The resulting solution was subjected to reverse phase silica gel column chromatography (Cosmosil 75C18 -prep, manufactured by Nacalai Tesque, 30 ml), eluted with mixtures of acetonitrile and water in proportions of 0:100, 2:98, 4:96 and 6:94, in that order. The fractions containing the desired compound were collected, concentrated by evaporation under reduced pressure, and freeze-dried to obtain 211 mg of the title compound as a powder.
Reaction SMILES: [C:1]1([S:7]([OH:10])(=[O:9])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Ca+2].[F:14][C:15]1[CH:28]=[CH:27][C:18]([O:19][CH2:20][CH:21]2[CH2:25][CH2:24][CH:23](O)[O:22]2)=[CH:17][CH:16]=1>C(Cl)Cl>[C:1]1([S:7]([CH:23]2[O:22][CH:21]([CH2:20][O:19][C:18]3[CH:17]=[CH:16][C:15]([F:14])=[CH:28][CH:27]=3)[CH2:25][CH2:24]2)(=[O:9])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(O)c1ccccc1
Reactant: OC1CCC(COc2ccc(F)cc2)O1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)C1CCC(COc2ccc(F)cc2)O1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To benzenesulfonic acid sodium salt (10.0 g, 0.061 mol), 25% HCl was added dropwise with stirring until the solid dissolved. The reaction mixture was extracted (100 mL each, 3 times) with EtOAc, dried over Na2SO4 and concentrated to give benzenesulfonic acid (7.8 g, 90%). To a 100 mL round bottom with a magnetic stir bar, benzenesulfonic acid (4.61 g, 0.0324 mol), CaCl2(3.6 g, 0.0324 mol) and dry dichloromethane (30 mL) were added. The reaction mixture was cooled to 0° C. and (2S) (5RS)-2-(4-fluorophenoxymethyl)-5-hydroxy-tetrahydrofuran (4.6 g, 0.0216 mol) in dry CH2Cl2 (20 mL) was added. The reaction mixture was stirred for 3 h and monitored by TLC (EtOAc-light petroleum ether 1:4, Rf=0.25). The reaction mixture was filtered through celite and washed with CH2Cl2 (3 times). The combined organic layer was washed with saturated aqueous Na2CO3, water brine and dried over Na2SO4. Solvent was removed under reduced pressure to afford the crude (2S) (5RS)-5-benzenesulfonyl-2-(4-fluorophenoxymethyl)tetrahydrofuran 14 which was crystallized from chloroform-hexane to give pure white solid, yield 6.8 g (93%), m.p. 102° C.-104° C. 1H NMR (200 MHz, CDCl3): δ 1.90-3.0 (m, 4 H), 3.85-5.0 (m, 4 H), 6.70-7.05 (m, 4 H), 7.45-7.72 (m, 3 H), 7.77-8.0 (m, 2 H).
Reaction SMILES: CN(C)S([N:6]1[CH:10]=[C:9]([CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][CH3:13])[N:8]=[C:7]1[Si](C(C)(C)C)(C)C)(=O)=O.N>Cl>[C:14]1([CH:11]([C:9]2[N:8]=[CH:7][NH:6][CH:10]=2)[CH2:12][CH3:13])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCC(c1ccccc1)c1cn(S(=O)(=O)N(C)C)c([Si](C)(C)C(C)(C)C)n1
Agent: Cl
Agent: N
Product: CCC(c1ccccc1)c1c[nH]cn1
Yield: 100.3 %

Procedure:
To remove protecting groups the amount of 155 mg (0.38 mmol) 2-(tert-butyl-dimethyl-silanyl)-4-(1-phenyl-propyl)-imidazole-1-sulfonic acid dimethylamide was dissolved in 10 ml 1.5N hydrochloric acid and refluxed for 1 h. The cooled solution was adjusted to pH>8 with 25% aqueous ammonia and the solution was extracted with dichloromethane (2 times). The combined organic layers are dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, dichloromethane/methanol/aqueous conc. ammonia=90:10:1) to yield 71 mg (99%) rac-4-(1-phenyl-propyl)-1H-imidazole as off-white solid: MS (ISP): 187.1 ((M+H)+.).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1.II.[CH:12](=O)[CH2:13][CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1(C)C=CC=CC=1.O1CCCC1>[F:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:12][CH2:13][CH3:14])[CH:4]=1
Reactant: Fc1cccc(Br)c1
Reactant: CCC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: II
Agent: [Mg]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCc1cccc(F)c1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
Magnesium chips (13.2 g) were placed into a 1 L flask equipped with mechanical stirrer, nitrogen inlet, 500 ml pressure-equilibrated dropping funnel, thermometer and reflux condenser connected to the inert gas outlet. The flask was flushed with nitrogen and minor flow was held during whole reaction time. 1-Bromo-3-fluorobenzene (95 g, 0.542 mol) and dry tetrahydrofurane (300 ml) was placed in dropping funnel. Magnesium was moistened with few milliliters of the solution from dropping funnel and an iodine crystal was added. When exothermic reaction starts 1-bromo-3-fluorobenzene solution was added dropwise to keep the boiling temperature of the mixture. After dropping all of the solution, the mixture was refluxed for 2 hours. Then the mixture was cooled down to −78° C. in a dry ice/acetone bath and propionaldehyde was added dropwise while mixture temperature was kept below −70° C. After adding all of the aldehyde, the mixture was left overnight at room temperature. Then the tetrahydrofurane was evaporated and the residue was acidified with hydrochloric acid. The organic phase was separated, washed twice with water and dried over magnesium sulfate. The raw 1-(3-fluorophenyl)propanol was distilled under reduced pressure of 20 mbar at 117° C. Alcohol 60 g, 66% of theor. yield was obtained. The alcohol and toluene (250 ml) and p-toluenesulfonic acid (0.2 g) were placed in (500 ml) round-bottom flask equipped with Dean-Stark trap. The mixture was refluxed. After the water stopped appearing, toluene was evaporated at reduced pressure. The obtained 1-(3-fluorophenyl)propene was placed in a three-necked flask and acetic acid (30 ml), ethyl acetate (50 ml) and catalyst—palladium on active carbon (2 g) were added. The flask was filled with hydrogen from gas burette at room temperature and the mixture was stirred. Reaction temperature increased spontaneously to 30° C. When the absorption of hydrogen was stopped, the catalyst was filtered off, the solution was washed off with water, dried over MgSO4 and the solvent was evaporated. The 1-fluoro-3-propylbenzene was distilled under atmospheric pressure, collecting the fraction boiling at 160° C. 32 g of 1-fluoro-3-propylbenzene were obtained, 42% of theor. yield.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]1([S:19][CH2:20][C:21]([OH:23])=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH2:24][C@@H:25]1[C:32](=[O:33])[N:31]2[C@@H:26]1[S:27][CH2:28][C:29](/[CH:37]=[C:38]1/[C:39](=[O:47])[N:40]([CH2:43][CH:44]3[CH2:46][CH2:45]3)[CH2:41][CH2:42]/1)=[C:30]2[C:34]([OH:36])=[O:35]>CN(C)C=O>[CH:44]1([CH2:43][N:40]2[CH2:41][CH2:42]/[C:38](=[CH:37]\[C:29]3[CH2:28][S:27][C@H:26]4[N:31]([C:32](=[O:33])[C@H:25]4[NH:24][C:21](=[O:23])[CH2:20][S:19][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:30]=3[C:34]([OH:36])=[O:35])/[C:39]2=[O:47])[CH2:46][CH2:45]1
Reactant: O=C(O)CSc1ccccc1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(CC4CC4)C3=O)CS[C@H]12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(CSc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(CC4CC4)C3=O)CS[C@H]12

Procedure:
With 167.0 mg (1.03 mmol) 1,1′-carbonyldiimidazole, 173.0 mg (1.03 mmol) 2-(phenylthio)acetic acid and 300.0 mg (0.86 mmol) (E)-(6R,7R)-7-amino-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid in 6 ml N,N-dimethylformamide.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[C:38]6[CH:37]=[CH:36][C:35]([CH:39]=[O:40])=[CH:34][C:33]=6[C:32]6[C:27]5=[CH:28][CH:29]=[CH:30][CH:31]=6)=[CH:22][CH:21]=4)=[CH:16][CH:15]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.O1CCCC1.[BH4-].[Na+]>CO>[CH:1]1[C:13]2[N:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]4[CH:21]=[CH:22][C:23]([N:26]5[C:38]6[CH:37]=[CH:36][C:35]([CH2:39][OH:40])=[CH:34][C:33]=6[C:32]6[C:27]5=[CH:28][CH:29]=[CH:30][CH:31]=6)=[CH:24][CH:25]=4)=[CH:18][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc2c(c1)c1ccccc1n2-c1ccc(-c2ccc(-n3c4ccccc4c4ccccc43)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccc2c(c1)c1ccccc1n2-c1ccc(-c2ccc(-n3c4ccccc4c4ccccc43)cc2)cc1
Reaction time: 1 h
Yield: 98.4 %

Procedure:
A 100-ml Kolben equipped with a stirrer and a condenser was charged under a nitrogen stream with 18 g (15.6 mmol) of 4-(carbazol-9-yl)-4′-(3-formylcarbazol-9-yl)-biphenyl prepared above and 800 ml of tetrahydrofuran. Sodium tetrahydroborate (0.65 g, 17.2 mmol) was introduced at room temperature into the above mixture, and the mixture was stirred for one hr. Thereafter, 160 ml of methanol was introduced into the reaction solution, and the mixture was stirred for 3 hr. The solvent was distilled off, and the residue was dissolved in 500 ml of toluene. The solution was washed with water, and the solvent was then distilled off to give 4-(carbazol-9-yl)-4′-(3-hydroxymethylcarbazol-9-yl)-biphenyl (7.9 g, yield 98.4%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[OH:15][C:16]1[C:21]([CH2:22][CH2:23][CH3:24])=[C:20]([SH:25])[CH:19]=[CH:18][C:17]=1[C:26](=[O:28])[CH3:27]>CC(C)=O>[C:26]([C:17]1[CH:18]=[CH:19][C:20]([S:25][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])=[C:21]([CH2:22][CH2:23][CH3:24])[C:16]=1[OH:15])(=[O:28])[CH3:27]
Reactant: BrCCCCBr
Reactant: CCCc1c(S)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(SCCCCBr)ccc(C(C)=O)c1O
Yield: 52.5 %

Procedure:
To a refluxing mixture of 1.4-dibromobutane (32.9 g), anhydrous potassium carbonate (5.25 g) and potassium iodide (1 g) in acetone (100 ml) was added dropwise a solution of 2'-hydroxy-4'-mercapto-3'-propylacetophenone (8.00 g) in acetone (20 ml) during an hour and refluxed for 2 hours. The mixture was filtered off and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography, eluting with benzene, to give the title compound (6.90 g, 52.6 %) as yellow oil.
Reaction SMILES: [I-].[C:2]([O:10][CH2:11][Zn+])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=1>C1COCC1.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>[C:2]([O:10][CH2:11][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(OC[Zn+])c1ccccc1
Reactant: Clc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Solvent: C1CCOC1
Product: O=C(OCc1ccc(Cl)cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 63 %

Procedure:
Title compound was prepared according to the procedure described in: Hasnik, Z.; Silhar, P.; Hocek, M. Synlett 2008, 4, 543. A solution of (benzoyloxymethyl)zinc(II) iodide Part B (2.17 mL, 1.949 mmol) was added to a solution of 2-bromo-5-chloropyridine (125 mg, 0.650 mmol) and Pd(PPh3)4 (37.5 mg, 0.032 mmol) in THF (1.30 mL). The reaction mixture was stirred at RT for 5 h at which point it was quenched with 1M NaH2PO4 (30 mL) The solid formed was filtered and washed well with water. The filtrate was extracted with DCM (3×25 mL) and the combined organic layers were dried over anhydrous Na2SO4 and concentrated. The crude product was subjected to flash chromatography (silica gel/hexanes-EtOAc 100:0 to 50:50 gradient) to afford (5-chloropyridin-2-yl)methyl benzoate 16C (101 mg, 63% yield) as an off-white solid. LC-MS, [M+H]+=248. HPLC-Method 8; 3.30 min.
Reaction SMILES: Br.[Br-].[CH3:3][N:4]([CH3:30])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:31]([C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=1)=O>O1CCCC1>[CH3:3][N:4]([CH3:30])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:31]\[C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CN(C)CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Br
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(/C=C\CCCCCN(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.8 %

Procedure:
2.47 g of potassium t-butylate were added to a suspension of 5.06 g of 6-(dimethylamino)hexyl-triphenylphosphonium bromide hydrobromide (see Example 1 a) in 50 ml of tetrahydrofuran at 0° under argon. To this suspension was added dropwise within 15 minutes a solution of 1.64 g of methyl p-formylbenzoate in 20 ml of tetrahydrofuran. The reaction mixture was stirred at room temperature for 18 hours and then evaporated. The residue was dissolved in 100 ml of 1N hydrochloric acid and the aqueous phase was washed three times with 100 ml of diethyl ether. The aqueous phase was made basic with solid potassium carbonate and extracted three times with 100 ml of ether. The ethereal phases were dried over magnesium sulphate and evaporated. The residue was chromatographed on 100 g of silica gel with methylene chloride/methanol/ammonium hydroxide 100:10:1. There were obtained 880 mg (32%) of methyl 4-[(Z)-7-(dimethylamino)-1-heptenyl]benzoate as a colourless oil.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1)[CH:8]=[CH:7]2>CO>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]1)[CH:8]=[CH:7]2
Reactant: O=C1CCC(n2ccc3cc(Br)ccc32)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCC(n2ccc3cc(Br)ccc32)CC1
Temperature: 0 °C

Procedure:
Sodium borohydride (62.198 mg, 1.644 mmol) was added to a mixture of intermediate D30 (2.074 g, 7.098 mmol) in MeOH (50 ml) stirred at 0° C. The resulting reaction mixture was warmed to room temperature and further stirred for 1 h. Subsequently, the mixture was concentrated in vacuo and the residue was dissolved in DCM. This solution was washed with NH4Cl (aqueous sat. solution). The organic layer was separated, dried (Na2SO4), and the solvent was evaporated in vacuo. The residue was purified by column chromatography (silica gel; EtOAc/heptane gradient from 0:100 to 30:70 as eluent). The desired fractions were collected and the solvent was evaporated in vacuo to yield trans-D31 (1.809 g, 86.6%) and cis-D31 (0.110 g, 5.27%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[C:12]1([NH:18][C:19](=O)[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:19]([CH3:20])=[N:9][C:3]=2[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Reactant: CC(=O)Nc1ccccc1
Product: Cc1nc2cc(Br)ccc2n1-c1ccccc1
Yield: 60.6 %

Procedure:
The title compound was prepared with the analogous procedure described in example 1 using 2,5-Dibromonitrobenzene (140 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) as starting materials to yield the title compound as a yellow solid (87 mg, 61%). 1H NMR (DMSO) δ 2.52 (s, 3 H), 7.18 (d, J=8.8 Hz, 1 H), 7.43 (d, J=8.8 Hz, 1 H), 7.58-7.68 (m, 5 H), 7.98 (br s, 1 H); 13C NMR δ 13.5, 112.5, 115.5, 119.5, 126.4, 126.9, 129.6, 130.1, 134.0, 139.0, 154.2, 156.8.
Reaction SMILES: C([N:5]1[CH:9]=[C:8]([S:10]([F:15])([F:14])([F:13])([F:12])[F:11])[C:7]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]1[C:24]([O:26][CH3:27])=[O:25])(C)(C)C>C(S(O)(=O)=O)(F)(F)F.C(Cl)Cl>[F:14][S:10]([F:11])([F:12])([F:13])([F:15])[C:8]1[C:7]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]([C:24]([O:26][CH3:27])=[O:25])[NH:5][CH:9]=1
Reactant: COC(=O)c1c(CCc2ccccc2)c(S(F)(F)(F)(F)F)cn1C(C)(C)C
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1[nH]cc(S(F)(F)(F)(F)F)c1CCc1ccccc1
Reaction time: 2 h
Yield: 78 %

Procedure:
Two drops of CF3SO3H was added to a flask containing 80 mg 6a and 2 mL CH2Cl2 at RT, and the mixture was stirred for about 2 h (monitored by TLC). The mixture was purified directly by column chromatograph to obtain 7 as a white solid (78%): mp 165-167° C., 1H NMR, δ 2.78-2.84 (dd, J=8.1 & 4.2 Hz, 2H), 3.16-3.22 (dd, J=8.1 & 4.2 Hz, 2H), 3.92 (s, 3H), 7.19-7.34 (m, 6H), 9.34 (s, 1H); 13C NMR, δ 28.38, 37.49, 52.12, 118.81 (m), 122.02 (m), 126.19, 128.00 (m), 128.58, 128.61, 138.50 (m), 142.07, 161.26; 19F NMR, δ 88.87 (p, J=148 Hz, 1H), 73.56 (d, J=148 Hz, 4H); HRMS, calc for C14H14F5NO2S, 355.0665; found, 355.0648; Anal, calc for C14H14F5NO2S: C, 47.32; H, 3.97; N, 3.94; found: C, 47.04; H, 3.68; N, 3.86.
Reaction SMILES: [F:1][C:2]1[C:3]2[S:21][CH:20]=[CH:19][C:4]=2[N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([O:9][CH3:10])=[O:8].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(N)CN.COC1C=CC(C=O)=CC=1>CN(C=O)C.CCCCCCC.CCOC(C)=O>[F:1][C:2]1[C:3]2[S:21][CH:20]=[CH:19][C:4]=2[NH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1c(F)c2sccc2n1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: COc1ccc(C=O)cc1
Agent: [F-]
Solvent: NCCN
Solvent: CN(C)C=O
Solvent: CCCCCCC
Product: COC(=O)c1[nH]c2ccsc2c1F
Temperature: 80 °C
Yield: 93.2 %

Procedure:
Methyl 6-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-thieno[3,2-b]pyrrole-5-carboxylate (16 mg, 0.0485 mmol) was dissolved in 3 mL anhydrous DMF. TBAF (1.0 M in THF, 0.485 mL, 10 equiv) and ethylenediamine (0.10 mL, 87.45 mg, 1.455 mmol, 30 equiv) were added, and the reaction was heated to 80° C. for 1 h and then allowed to cool to rt overnight. TLC (1/1 EtOAc in heptane, visualized with anisaldehyde and heat) indicated complete reaction. The product was partitioned with LiCl saturated solution and EtOAc, dried (Na2SO4), filtered, evaporated in vacuo the organic layer to give a residue. The residue was passed through a 5 g silica gel cartridge (1/1 EtOAc in heptane) to give methyl 6-fluoro-4H-thieno[3,2-b]pyrrole-5-carboxylate (9 mg, 94% yield) as a white solid. The regiochemistry of fluorine was determined via NMR-NOE experiments. 1H NMR (400 MHz, (CD3)2CO) δ ppm 3.86 (s, 3H) 7.03 (dd, J=5.27, 2.29 Hz, 1H) 7.55 (d, J=5.27 Hz, 1H) 10.81 (br. s., 1H). 19F NMR (376 MHz, (CD3)2CO) δ ppm −155.88 (dd, J=27.47, 2.29 Hz, 1F).
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].I[CH2:12][CH2:13][CH3:14]>>[CH2:12]([S:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[CH2:13][CH3:14]
Reactant: O=C(O)c1cccnc1S
Reactant: CCCI
Product: CCCSc1ncccc1C(=O)O
Yield: 96 %

Procedure:
2-Mercapto-nicotinic acid (1 g, 6.4 mmol) and 1-iodopropane were reacted in the same manner as in Step A of Preparation Example 10 to obtain the title compound (1.22 g, 96%).