Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[CH:2]([C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=1Br)([CH3:4])[CH3:3].BrCCBr.[CH3:22][O:23][C:24]1[CH:25]=[C:26](F)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1.[Li]CCCC.[I:38]I>C1COCC1>[I:38][C:25]1[C:24]([O:23][CH3:22])=[CH:29][C:28]([O:30][CH3:31])=[CH:27][C:26]=1[C:6]1[C:5]([CH:2]([CH3:4])[CH3:3])=[CH:10][C:9]([CH:11]([CH3:13])[CH3:12])=[CH:8][C:7]=1[CH:14]([CH3:16])[CH3:15]
Reactant: II
Reactant: CC(C)c1cc(C(C)C)c(Br)c(C(C)C)c1
Reactant: COc1cc(F)cc(OC)c1
Agent: [Li]CCCC
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COc1cc(OC)c(I)c(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1
Temperature: 25 °C
Yield: 48 %

Procedure:
An oven-dried three-neck 500 mL round bottom flask, which was equipped with a magnetic stir bar and charged with magnesium shavings (2.8 g, 116 mmol), was fitted with a reflux condenser, glass stopper, and rubber septum. The flask was purged with argon and then THF (45 mL) and 2,4,6-triisopropylbromobenzene (11.4 mL, 45 mmol) were added via syringe. The reaction mixture was heated to reflux and 1,2-dibromethane (40 uL) was added via syringe. The reaction was allowed to stir at reflux for 1.5 h and was then cooled to room temperature. A separate oven-dried 2 L round bottom flask, which was equipped with a magnetic stir bar and fitted with a septum, was purged with argon and then THF (200 mL) and 3,5-dimethoxyfluorobenzene (3 mL, 22.5 mmol) were added to the flask via syringe. The reaction mixture was cooled to −78° C. and n-BuLi (2.5 M in Hexane, 9.2 mL, 23 mmol) was added in a dropwise fashion over a 40 min period. The solution was stirred for 1 h and the Grignard reagent, which was prepared in the first reaction vessel, was added via cannula over a 30 min period and allowed to stir at −78° C. for 1 h. The reaction mixture was warmed to room temperature slowly where it was stirred for an additional 12 h. The mixture was then cooled to 0° C. and a solution of Iodine in THF (1 M, 50 mL, 50 mmol) was added via syringe over a 15 min period and then the dark red solution was warmed to room temperature and stirred for 1 h. The solvent was removed via a rotary evaporator, and the remaining dark brown oil was taken up in Et2O, washed with a saturated solution of sodium sulfite, and washed with brine. The organic layer was then dried over MgSO4, filtered, and the solvent was removed via rotary evaporator to give a yellow solid. The crude material was triturated with hexanes and filtered to give the desired product as an off-white solid (5.059 g, 48%).
Reaction SMILES: C(ON=O)(C)(C)C.Br[CH2:9][C:10](=[CH2:14])[C:11]([OH:13])=[O:12].[N+:15]([C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[CH:24]=1)N)([O-:17])=[O:16].NC1C=CC=CC=1>CC#N>[N+:15]([C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[CH:24]=1)[CH2:9][C:10](=[CH2:14])[C:11]([OH:13])=[O:12])([O-:17])=[O:16]
Reactant: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: C=C(CBr)C(=O)O
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: Nc1ccccc1
Product: C=C(Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)C(=O)O
Temperature: 17.5 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
To a solution of t-butylnitrite (535 μl, 4.5 mmol) and 2-(bromomethyl)acrylic acid (7.42 g, 45.0 mmol) in CH3CN (10 ml), 3,5-dinitroaniline (549 mg, 3.0 mmol) was added during 20 minutes, while maintaining the temperature of the reaction mixture at 15-20° C. At the end of the addition of the aniline extra t-butylnitrite (180 μl, 1.5 mmol) was added to the reaction mixture. After heating to 35° C. for 5 minutes, the mixture was stirred at room temperature for one hour. The volatile material in the reaction mixture was then removed at reduced pressure. The remaining crystalline residue was washed with heptane (5×50 ml) to remove unreacted 2-(bromomethyl)acrylic acid. Column chromatography (heptane-ethyl acetate-methanol-acetic acid 5:4:1:0.04) of the remaining crude product followed by crystallization from toluene gave 450 mg (60%) of 2-(3,5-dinitrobenzyl)acrylic acid as yellow needles. 1H NMR (CDCl3, 300 MHz) δ 8.93, (t, 1H, J=2.1 Hz), 8.43, (d, 2H, J=2.1 Hz), 6.56, (s, 1H), 5.93, (m, 1H), 3.85, (s, 2H).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1I)[CH3:2].FC1C=CC(B(O)O)=CC=1.[C:31]([O:35][C:36]([N:38]1[CH:42]=[CH:41][CH:40]=[C:39]1B(O)O)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1[C:39]1[N:38]([C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])[CH:42]=[CH:41][CH:40]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OCc1ccccc1
Agent: OB(O)c1ccc(F)cc1
Product: CCc1c(-c2cccn2C(=O)OC(C)(C)C)[nH]c(C=O)c1C(=O)OCc1ccccc1

Procedure:
Following the procedures described in Example 5, replacing methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate with benzyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate and 4-fluorophenylboronic acid with 1-(tert-butoxycarbonyl)-1H-pyrrol-2-ylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the title compound. HRMS (ES) exact mass calculated for C19H19N2O3 (M+H): 323.1390. Found 323.1384.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1.C([Li])(C)(C)C.[CH3:27][O:28][C:29]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[CH:33][C:30]=1[CH:31]=[O:32]>C1COCC1>[CH:14]1([N:8]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6](=[O:7])[C:5]2[CH:20]=[CH:21][C:2]([CH:31]([OH:32])[C:30]3[CH:33]=[C:34]([O:39][CH3:40])[C:35]([O:37][CH3:38])=[CH:36][C:29]=3[O:28][CH3:27])=[CH:3][CH:4]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(c1ccc(Br)cc1)N(C1CCCCC1)C1CCCC1
Reactant: COc1cc(OC)c(OC)cc1C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1cc(OC)c(C(O)c2ccc(C(=O)N(C3CCCCC3)C3CCCC3)cc2)cc1OC
Reaction time: 0.33 h

Procedure:
To a cold (-70° C.), stirred solution of 4-bromo-N-cyclohexyl-N-cyclopentylbenzamide (1.5 g, 4.3 mmol) in THF (20 ml) was added slowly a solution of tertbutyllithium (5 ml of 1.7 M solution in pentane) under an Argon atmosphere. The reaction was stirred at -70° to -75° for 20 min. and a solution of 2,4,5-trimethoxybenzaldehyde (843 mg, 4.3 mmol) in THF (10 ml) was added dropwise over 30 min. The reaction was stirred at -70° to -75° for 30 min. and at room temperature for 1 hr. The reaction was quenched by the addition of water and the aqueous layer extracted three times with ethyl acetate. The combined organic layers were washed with water and dried (Na2SO4). The drying agent was filtered and the filtrate concentrated in vacuo to give the crude product. Purification was effected by chromatography on silica gel using mixtures of ethyl acetate and hexane. The product was isolated as a glass.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][Cl:8].[C:10]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1C=CC=CC=1>[Cl-:1].[Cl:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3](=[O:9])[CH2:2][P+:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(CCl)CCCCCl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: O=C(CCCCCl)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]
Reaction time: 144 h

Procedure:
To a solution of 41 parts of 1,6-dichloro-2-hexanone in 400 parts by volume of benzene is added 44 parts of triphenylphosphine and the resulting solution is stored, in the absence of light for about 6 days, at the end of which time the crude product has crystallized from the mixture. That material is collected by filtration and is purified by recrystallization from acetone to afford (6-chloro-2-oxohexyl)triphenylphosphonium chloride. This product melts at 158°-161° C. and is characterized by 60-MHz nuclear magnetic resonance peaks in CDCl3 (deuterated chloroform) at 100 cps (multiplet), 140 cps (multiplet), 180 cps (multiplet), 208 cps (multiplet) and 357 cps (doublet, J≃12) in addition to the aromatic protons. The C1 protons at 375 cps exchange with D2O (deuterated water).
Reaction SMILES: C([O:3][C:4](=O)[C:5](Br)=[C:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)Br)C.Cl.[NH2:21][OH:22].[OH-].[Na+]>>[OH:3][C:4]1[CH:5]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[O:22][N:21]=1
Reactant: CCOC(=O)C(Br)=C(Br)c1cccc2ccccc12
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Oc1cc(-c2cccc3ccccc23)on1
Yield: 78.8 %

Procedure:
α,β-Dibromo-1-naphthylacrylic acid ethyl ester (6.0 g), hydroxylamine hydrochloride (1.3 g) and sodium hydroxide (7.2 g) were subjected to reaction and post-treatment in a similar manner to that described in Reference example 10(c) to obtain the title compound (2.6 g, 78%) as colorless crystals.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[NH:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([OH:13])=[O:12])(=[O:3])[CH3:2].[N:20]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[C@@H:22](O)[CH2:21]2.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[N:20]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[C@@H:22]([O:12][C:11](=[O:13])[CH:10]([NH:9][C:8]1[CH:7]=[CH:6][S:5][C:4]=1[C:1](=[O:3])[CH3:2])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:21]2
Reactant: CC(=O)c1sccc1NC(C(=O)O)c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(=O)c1sccc1NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.4 %

Procedure:
A mixture of 2-(2-acetylthiophen-3-ylamino)-2-phenylacetic acid (I4) (188 mg, 0.68 mmol), (R)-quinuclidin-3-ol (104 mg, 0.82 mmol), HOBT (125 mg, 0.82 mmol) and DCC (169 mg, 0.82 mmol) in dry THF (8 ml) was stirred at room temperature overnight. THF was evaporated, and the crude product was taken up with EtOAc and washed twice with 2M K2CO3. The organic phase was dried (Na2SO4), filtered and evaporated to dryness. The crude product was purified by preparative HPLC. The fractions containing the product were combined and evaporated under vacuum. The residue was dissolved in 2M K2CO3 and extracted twice with EtOAc to obtain (2-acetyl-thiophen-3-ylamino)-phenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (48 mg, 18% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])=[CH:8][N:7]=[CH:6]1.[H-].[Na+].BrC[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1.[CH3:30]N(C=O)C>O>[Cl:29][C:26]1[CH:25]=[CH:24][CH:23]=[CH:28][C:27]=1[CH2:30][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]1[N:5]([CH2:4][CH2:3][C:2]([CH3:18])([CH3:17])[CH3:1])[CH:6]=[N:7][CH:8]=1
Reactant: CN(C)C=O
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(C)(C)CCn1cncc1-c1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)CCn1cncc1-c1ccccc1OCc1ccccc1Cl
Reaction time: 0.17 h
Yield: 30 %

Procedure:
To a stirred solution of 2-(1-(3,3-dimethylbutyl)-1H-imidazol-5-yl)phenol (122.0 mg, 0.5 mmol) in DMF (3 mL) at 0° C. was added NaH (36.0 mg, 0.75 mmol) portion wise. The resulting mixture was allowed to stir for 10 min and 1-(bromomethyl)-4-chlorobenzene (123.0 mg, 0.6 mmol) was added. After stirring overnight the reaction mixture was diluted with water and the aqueous phase extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with water, brine, dried (Na2SO4) and concentrated under reduced pressure to afford the crude residue, which was purified by column chromatography on silica gel to afford the desired product in 30% yield. 1H NMR: 0.78 (s, 9H), 1.38-1.47 (m, 2H), 3.75-3.85 (m, 2H), 5.00 (s, 2H), 6.98-7.09 (m, 3H), 7.15 (d, 2H, J=7.6 Hz), 7.24-7.40 (m, 4H), 7.55 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=O)[CH:3]=1.CN(C)[CH:15]=[O:16].N.[O:19]1CCC[CH2:20]1>[Pt]>[CH3:9][C:8]1[CH:7]=[C:5]2[C:4](=[CH:3][C:2]=1[CH3:1])[N:10]([OH:12])[C:20](=[O:19])[C:15](=[O:16])[NH:6]2
Reactant: C1CCOC1
Reactant: Cc1cc(N)c([N+](=O)[O-])cc1C
Reactant: CN(C)C=O
Agent: [Pt]
Agent: N
Product: Cc1cc2[nH]c(=O)c(=O)n(O)c2cc1C
Yield: 17 %

Procedure:
1.0 g (3.8 mmol) 4,5-dimethyl-2-nitroaniline in 30 ml tetrahydrofuran:dimethylformamide: 25% aqueous ammonia (30:10:0.7) was hydrogenated at atm. pressure by using 60 mg 5% Pt-C as a catalyst. The precipitate was filtered off and washed with tetrahydrofuran. The filter cake was washed several times with 1N aqueous potassium hydroxide, and the filtrate was acidified with concentrated hydrochloric acid. The precipitate was filtered off and washed with water, ethanol and ether to give 0.13 g (17%) of 6,7-dimethyl-1-hydroxyquinoxaline-2,3(1H,4H)-dione. M.p. decomp. 1H-NMR (DMSO-d6): 11.9 (1H, broad s), 7.3 (1H, s), 7.0 (1H, s), 2.3 (6H, s). MS (m/e): 206 (M+, 70%), 161 (100%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](OCCCCCCC)=[C:6]([CH:32]=1)[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24](OC(F)(F)F)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].[F:41][C:42]([F:53])([F:52])[C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1>>[C:18]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:15]([CH2:14][C@H:10]([NH:9][C:7]([C:6]2[CH:32]=[CH:2][C:3]([C:46]3[CH:47]=[CH:48][C:43]([C:42]([F:53])([F:52])[F:41])=[CH:44][CH:45]=3)=[CH:4][CH:5]=2)=[O:8])[C:11]([OH:13])=[O:12])=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCCCCCCOc1ccc(Cl)cc1C(=O)N[C@@H](Cc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1)C(=O)O
Product: O=C(N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 87 %

Procedure:
3-Biphenyl-4-yl-(2S)-[(5-bromo-benzoylamino)-propionic acid (100 mg, 0.23 mmol) was reacted with 4-trifluoromethyl phenyl boronic acid (0.133 mg, 0.69 mmol) by following general procedure D yielding the title compound (98 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:29]=[CH:28][C:9]2[NH:10][C:11]([NH:13][CH2:14][CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].Cl.O1CCOCC1.C(O)C>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:29]=[CH:28][C:9]2[NH:10][C:11]([NH:13][CH2:14][CH:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]3)=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2[nH]c(NCC3CCN(C(=O)OC(C)(C)C)CC3)nc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2[nH]c(NCC3CCNCC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving the 2-[(1-tert-butoxycarbonyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-5-carboxylic acid ethyl ester in tetrahydrofuran (2 ml), a 4N hydrogen chloride/1,4-dioxane solution (3 ml) was added. Since a precipitate was produced, ethanol (5 ml) was added to dissolve it and the solution was stirred at room temperature overnight. The reaction mixture was concentrated to obtain 2-[(piperidin-4-ylmethyl)-amino]-1H-benzimidazole-5-carboxylic acid ethyl ester as a red amorphous solid. The compound was identified by LC-MS.
Reaction SMILES: [H-].[Na+].CCCCCC.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:12][CH:11]=1.Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CN(C=O)C>[CH2:20]([O:19][C:17]([CH2:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:15][CH:14]=1)=[O:18])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(Cc1ccc(O)cc1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(CC(=O)OCc2ccccc2)cc1
Temperature: 4 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (50% w/w dispersion in mineral oil, 2.1 g) was treated under argon with repeated washes of hexane. The oil-free residue was suspended in dry DMF (130 ml) and the product from step (i) (10 g) added in three portions to the cooled (4° C.) stirred mixture. Stirring was continued for a further 15 minutes when tertiary butyl bromoacetate (7.0 ml) was added dropwise over 15 minutes. After 1 hour at 4° C., the mixture was stirred for 6 hours at ambient temperature. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate and water. The aqueous phase was re-extracted with further ethyl acetate and the combined organic phases washed with water and brine, then dried (MgSO4) and evaporated. The residue, after purification by flash chromatography on silica eluting with dichloromethane, gave tertiary butyl 4-(benzyloxycarbonylmethyl)phenoxyacetate, 7.5 g, as a colourless oil: NMR (CDCl3) d 7.31(5H, m), 7.20(2H, m), 6.85(2H, m), 5.12(2H, s), 4.49(2H, s), 3.60(2H, s), 1.48(9H, s); m/e 356 (M°)+.
Reaction SMILES: NC1C=NC=CN=1.[CH3:8][S:9]([CH3:11])=O.[F:12][C:13]([F:26])([F:25])[S:14]([O:17]S(C(F)(F)F)(=O)=O)(=[O:16])=[O:15]>C(Cl)Cl>[OH:17][S:14]([C:13]([F:26])([F:25])[F:12])(=[O:16])=[O:15].[OH:17][S:14]([C:13]([F:26])([F:25])[F:12])(=[O:16])=[O:15].[CH3:8][S:9][CH3:11]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CS(C)=O
Agent: Nc1cnccn1
Solvent: ClCCl
Product: CSC
Product: O=S(=O)(O)C(F)(F)F
Temperature: -78 °C

Procedure:
In carrying out the first step of the conversion the selected amino pyrazine of formula III, the reagent is prepared by mixing dimethylsulfoxide in methylene chloride and cooled to -78° C. To the cooled solution is added trifluoromethane sulfonic anhydride in a ratio of approximately 3 moles dimethylsulfoxide to 2 moles of anhydride to produce dimethyl sulfide ditriflate of the formula ##STR8## Then, there is added to the cooled solution of VI the selected amino pyrazine of formula III while maintaining the temperature of the reaction mixture at -78° C. to produce the sulfilimine of formula IV. The resulting suspension is made alkaline with aqueous sodium bicarbonate or sodium hydroxide. Additional methylene chloride is added and the product extracted into the methylene chloride phase which is separated and evaporated to remove the volatile organic solvent leaving the sulfilimine IV as a residue.
Reaction SMILES: [CH:1]([C:3]1[S:7][CH:6]=[C:5]([C:8]([OH:10])=[O:9])[CH:4]=1)=[O:2].I[CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:12]([O:9][C:8]([C:5]1[CH:4]=[C:3]([CH:1]=[O:2])[S:7][CH:6]=1)=[O:10])[CH3:13]
Reactant: CCI
Reactant: O=Cc1cc(C(=O)O)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1csc(C=O)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
5-Bromo-3-thiophenecarboxylic acid (4.14 g) was dissolved in tetrahydrofuran (50 ml), and the mixture was cooled to -78° C. n-Butyllithium (1.6M in hexane, 27.5 ml) was slowly added dropwise. The resulting mixture was stirred at the same temperature for 1 hour, and N,N-dimethylformamide (3.1 ml) was added. The mixture was warmed slowly to room temperature and concentrated under reduced pressure. The concentrate was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of 5-formyl-3-thiophenecarboxylic acid (3.12 g). 5-Formyl-3-thiophenecarboxylic acid (3.12 g) was dissolved in N,N-dimethylformamide (50 ml), and iodoethane (1.58 ml) and potassium carbonate (2.76 g) were added. The mixture was stirred at room temperature for 15 hours, poured into water and extracted with ethyl acetate. The extract was washed with 5 % potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-formyl-3-thiophenecarboxylic acid ethyl ester (0.71 g). 5-Formyl-3-thiophenecarboxylic acid ethyl ester (1.47 g) synthesized in this manner in methylene chloride (10 ml) was slowly added dropwise to diethylaminosulfur trifluoride (DAST) (1.2 ml) in methylene chloride (10 ml) at room temperature. The mixture was stirred at room temperature for 15 hours, and saturated aqueous sodium bicarbonate was added. The organic layer was collected, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-difluoromethyl-3-thiophenecarboxylic acid ethyl ester (0.7 g). 5-Difluoromethyl-3-thiophenecarboxylic acid ethyl ester was dissolved in a mixture of ethanol (5 ml) and tetrahydrofuran (5 ml), and 1N aqueous sodium hydroxide (5 ml) was added. The mixture was stirred at room temperature for 1 hour and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-difluoromethyl-3-thiophenecarboxylic acid (0.58 g) as crystals.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][N:9]=1)=[O:4].[S:10]1[CH:14]=[C:13]([CH:15]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:16]([O:18][C@@H:19]2[CH:24]3[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]3)[CH2:20]2)=[O:17])[C:12]2[CH:34]=[CH:35][CH:36]=[CH:37][C:11]1=2>CCOC(C)=O>[Br-:1].[S:10]1[CH:14]=[C:13]([CH:15]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:16]([O:18][C@@H:19]2[CH:24]3[CH2:25][CH2:26][N+:21]([CH2:2][C:3](=[O:4])[C:5]4[S:6][CH:7]=[CH:8][N:9]=4)([CH2:22][CH2:23]3)[CH2:20]2)=[O:17])[C:12]2[CH:34]=[CH:35][CH:36]=[CH:37][C:11]1=2
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1csc2ccccc12
Reactant: O=C(CBr)c1nccs1
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(Nc1ccccc1)c1csc3ccccc13)C2)c1nccs1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.1 %

Procedure:
2-Bromo-1-(thiazol-2-yl)ethanone (52.5 mg, 0.25 mmol) was added portion-wise to a solution of (R)-quinuclidin-3-yl 2-(benzo[b]thiophen-3-yl)-2-(phenylamino)acetate (C19) (100 mg, 0.25 mmol) in EtOAc (2 ml). The reaction mixture was stirred at room temperature overnight. The precipitate was filtered, washed with EtOAc and purified by preparative HPLC (Eluent: CH3CN, H2O) to obtain (R)-3-(2-(benzo[b]thiophen-3-yl)-2-(phenylamino)acetoxy)-1-(2-oxo-2-(thiazol-2-yl)ethyl)-1-azoniabicyclo[2.2.2]octane bromide (42 mg, 27.5% yield).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[O:6][CH2:5][CH2:4]1.[CH2:15](OC=O)[CH3:16].C(OC(=O)C)(=O)C>>[CH2:15]([NH:1][CH2:2][CH:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[O:6][CH2:5][CH2:4]1)[CH3:16]
Reactant: CCOC=O
Reactant: COc1ccc2c(c1)OCCC2CN
Solvent: CC(=O)OC(C)=O
Product: CCNCC1CCOc2cc(OC)ccc21

Procedure:
The product from Example 2 was reacted as described in Example 3 replacing ethylformate with acetic anhydride, giving the desired product, (M+H)+ 222. 1H NMR(CDCl3): 1.15 (t,3H); 2.05 (m,2H); 2.6-2.0 (m,4H); 3.75 (s,3H); 4.2 (m,1H), 6.3-7.1 (m,3H).