Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:29]=[C:30](OB(O)O)[CH:31]=[CH:32][CH:33]=1.O>O1CCCC1.C(=O)([O-])O.[Na+].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:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([F:27])[CH:33]=3)=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)Oc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(Br)cc2)cs1
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: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(-c3cccc(F)c3)cc2)cs1
Yield: 64.1 %

Procedure:
Under nitrogen atmosphere, 2-({4-[2-(4-bromophenoxy)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester (447 mg) synthesized in Example 67-1 and 3-fluorophenylboric acid (273 mg) were dissolved in tetrahydrofuran (10 mL) and sodium hydrogen carbonate (1 mol/l, 10 mL), tetrakis(triphenylphosphine)palladium (231 mg) was added, and the mixture was refluxed for 6.5 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1) to give the title compound (296 mg) as a pale-yellow oil.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:13][C:14]1[N:22]([CH2:23][CH2:24][OH:25])[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[OH:25][CH2:24][CH2:23][N:22]1[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[N:15]=[C:14]1[CH2:13][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: CCOC(=O)N1CCNCC1
Reactant: OCCn1c(CCl)nc2cccnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)N1CCN(Cc2nc3cccnc3n2CCO)CC1
Reaction time: 32 h
Yield: 62.7 %

Procedure:
To a stirred mixture of 13.5 parts of ethyl 1-piperazinecarboxylate and 160 parts of ethanol were added 18 parts of 2-(chloromethyl)-3H-imidazo[4,5-b]pyridine-3-ethanol. After the addition of 10.6 parts of sodium carbonate, the reaction mixture was stirred for 32 hours at reflux temperature. The whole was evaporated and the residue taken up in water. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 17.5 parts (62.7%) of ethyl 4-[[3-(2-hydroxyethyl)-3H-imidazo-[4,5-b]pyridin-2-yl]methyl]-1-piperazinecarboxylate; mp. 117.4° C. (compound 18).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1I.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CCN(C(C)C)C(C)C>CC#N>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[N:14]1[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]1
Reactant: CN1CCNCC1
Reactant: Fc1cncc(Cl)c1I
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN1CCN(c2c(F)cncc2Cl)CC1

Procedure:
A solution of 3-chloro-5-fluoro-4-iodo-pyridine (2.18 g, 8.468 mmol), 1-methylpiperazine (1.272 g, 1.409 mL, 12.70 mmol) and DIPEA (2.189 g, 2.950 mL, 16.94 mmol) in MeCN (13.08 mL) was heated at 130° C. in the microwave for 300 min. The reaction mixture was concentrated in vacuo and purified by column chromatography on silica eluting with 0-10% MeOH/DCM. Product fractions were combined and concentrated in vacuo to leave 1-(3-chloro-5-fluoropyridin-4-yl)-4-methylpiperazine as a yellow/brown oil. (1.16 g, 59%). MS (ES+) 230.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]2[C:16](Cl)=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][O:27][CH2:28][CH2:29][NH2:30]>CS(C)=O.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]2[C:16]([NH:30][CH2:29][CH2:28][O:27][CH3:26])=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCN
Reactant: FC(F)(F)c1ccc(-c2ccnc(OCc3ccccc3)c2)c(Cl)n1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COCCNc1nc(C(F)(F)F)ccc1-c1ccnc(OCc2ccccc2)c1
Temperature: 40 °C
Reaction time: 72 h

Procedure:
-(2-(Benzyloxy)pyridin-4-yl)-N-(2-methoxyethyl)-6-(trifluoromethyl)-pyridin-2-amine. To a 2.5-mL microwave vial was added 3-(2-(benzyloxy)-pyridin-4-yl)-2-chloro-6-(trifluoromethyl)pyridine (0.50 g, 1.37 mmol) and 2-methoxyethylamine (0.59 g, 6.58 mmol, Fluka) in 2 mL of DMSO. The vial was sealed and left to stir at 40° C. for 3 d and then heated at 120° C. for 5 h. The reaction mixture was allowed to cool to room temperature and was diluted with EtOAc (20 mL). The organic layer was washed with saturated NaCl (2×30 mL), dried over Na2SO4, filtered, and concentrated to afford a yellow oil. The crude material was purified by normal phase column chromatography (gradient: 5%-20% EtOAc/Hexanes) to give 3-(2-(benzyloxy)pyridin-4-yl)-N-(2-methoxyethyl)-6-(trifluoromethyl)pyridin-2-amine as a clear oil [MS (ESI, pos. ion) m/z: 404 (M+1)].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:11][O:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][C:17](F)=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1>C1COCC1>[CH3:11][O:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][C:17]([NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Br:1])[CH:7]=2)=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1ccnc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Nc2ccnc(Br)c2)c([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 85.2 %

Procedure:
2-Bromo-pyridin-4-ylamine 2 (4.3 g; 25 mmol) and NaH 60% (1.5 g; 37 mmol) was at 0° C. stirred for 1 h in dry THF (50 ml) and then a solution of 4-Fluoro-3-nitro-benzoic acid methyl ester 1 (5 g; 25 mmol) in dry THF (50 ml) was addeddrop. The resulting cold solution was allowed to reach RT and stirred overnight for completion of the reaction. LCMS showed complete conversion to product and the reaction was quenched by addition of iPrOH and H2O. A precipitate was formed and this was filtered off, dried under educed pressure to obtain 3 as a yellow solid (7.5 g). Yield 85%. The product identity was confirmed by NMR and LCMS and taken for the next step.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[O:20][C:19]([C@@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[N:18][N:17]=2)=[N:4][C:5]([O:14][CH3:15])=[C:6]([C:10]([F:13])([F:12])[F:11])[C:7]=1[CH:8]=[CH2:9].[CH3:28]C1(C)C(C)(C)OB(C(C)=C)O1>>[NH2:1][C:2]1[C:3]([C:16]2[O:20][C:19]([C@@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[N:18][N:17]=2)=[N:4][C:5]([O:14][CH3:15])=[C:6]([C:10]([F:12])([F:13])[F:11])[C:7]=1[C:8]([CH3:28])=[CH2:9]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: C=Cc1c(N)c(-c2nnc([C@](C)(O)C(F)(F)F)o2)nc(OC)c1C(F)(F)F
Product: C=C(C)c1c(N)c(-c2nnc([C@](C)(O)C(F)(F)F)o2)nc(OC)c1C(F)(F)F

Procedure:
The title compound was prepared analogously to (S)-2-(5-(3-Amino-6-methoxy-5-(trifluoromethyl)-4-vinylpyridin-2-yl)-1,3,4-oxadiazol-2-yl)-1,1,1-trifluoropropan-2-ol (Example 14.0 step 1) by replacing 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane with 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane;
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1[CH:11]=O)=[N+:2]=[N-:3].[NH2:13][C:14]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:13]/[C:14]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1c(F)cncc1C=O
Reactant: N#Cc1cccc(F)c1N
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccc(F)c1/N=C/c1cncc(F)c1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 4-azido-5-fluoropyridine-3-carbaldehyde (3.66 g, 22.1 mmol) and 2-amino-3-fluorobenzonitrile (3.0 g, 22.05 mmol) in DCM (73 mL) was cooled to 0° C. under an atmosphere of nitrogen. Triethylamine (9.1 mL, 66.0 mmol) was added, followed by dropwise addition of titanium (IV) chloride solution (1 N in DCM, 13.15 mL, 13.15 mmol). The reaction mixture was stirred at 0° C. for 2 hours, then at room temperature overnight. The resultant mixture was concentrated under reduced pressure to afford the title compound as a beige residue (5.19 g, 83% yield). This material was used in the next step without purification. LCMS (Method C): RT=3.49 min, m/z: 257 [M−N2].
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([NH2:38])[CH:34]=[CH:35][CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:39])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:40].O1CCOCC1>O1CCOCC1>[ClH:40].[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([NH2:38])[CH:34]=[CH:35][CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:39])[CH2:22][CH2:21]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(N)cccc32)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cccc2c1ccc(=O)n2CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 80 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-amino-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 3 mL of 1,4-dioxane and 1 mL of 4.0 mol/L hydrogen chloride/1,4-dioxane were added, and stirred at room temperature overnight. The solvent was removed under reduced pressure, and the resulting solid was recrystallized in methanol-ethyl acetate to give 45 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-5-aminoquinolin-2(1H)-one hydrochloride as a brown solid.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:40]=[CH:39][CH:38]=[CH:37][C:14]=1[C:15]([NH:17][C:18]1[CH:34]=[CH:33][C:21]([C:22]([N:24]([CH3:32])[C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[O:23])=[CH:20][C:19]=1[O:35][CH3:36])=[O:16])=O)(C)(C)C.[ClH:41]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[ClH:41].[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:40]=[CH:39][CH:38]=[CH:37][C:14]=1[C:15]([NH:17][C:18]1[CH:34]=[CH:33][C:21]([C:22]([N:24]([CH3:32])[C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[O:23])=[CH:20][C:19]=1[O:35][CH3:36])=[O:16]
Reactant: COc1cc(C(=O)N(C)c2ccc(O)cc2)ccc1NC(=O)c1ccccc1OCCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)N(C)c2ccc(O)cc2)ccc1NC(=O)c1ccccc1OCCCN
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[2-[(3-tert-butoxycarbonylaminoprop-1-yl)oxy]benzoyl]amino-3-methoxy-N-methyl-N-(4-hydroxyphenyl)benzamide (50 mg) in chloroform (3.0 ml) was added a solution of 4N hydrogen chloride in ethyl acetate (1.0 ml) and the mixture was stirred at ambient temperature for 2 hours. The resulting mixture was evaporated in vacuo and the residue was solidified with diethyl ether. Diethyl ether was removed in vacuo to give 4-[2-[(3-aminoprop-1-yl)oxy]benzoyl]amino-3-methoxy-N-methyl-N-(4-hydroxyphenyl)benzamide hydrochloride (40 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:27])[C:11]([C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2)([OH:16])[C:12]([F:15])([F:14])[F:13].C([O-])([O-])=O.[Na+].[Na+]>Br>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:27])[C:11]([OH:16])([C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]([F:14])([F:13])[F:15]
Reactant: COc1ccc(C(C)C(O)(c2cnc3ccccc3c2)C(F)(F)F)c(Cl)c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(c1ccc(O)cc1Cl)C(O)(c1cnc2ccccc2c1)C(F)(F)F
Temperature: 120 °C
Reaction time: 6 h
Yield: 73 %

Procedure:
3-(2-Chloro-4-methoxy-phenyl)-1,1,1-trifluoro-2-quinolin-3-yl-butan-2-ol (2.60 g) was suspended in aqueous HBr (48%, 52 ml). The mixture was stirred for 16 h at 80° C., for 20 h at 105° C., for 7 h at 110° C. and for 6 h at 120° C. The reaction mixture was poured into ice water/EtOAc neutralized with aqueous sat. Na2CO3 solution and extracted with EtOAc. The organic phase was washed with water and dried (MgSO4). The product was purified by chromatography (SiO2, cyclohexane=>cyclohexane/EtOAc 1:1=>EtOAc/MeOH 9:1=>1:1) and subsequently precipitated from hot EtOAc to give the title compound (1.83 g) as an off-white solid. MS (m/e)=382.1 [M+H+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH3:9].[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[C:14]([Si:11]([CH3:13])([CH3:12])[O:10][C@H:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:9])([CH3:17])([CH3:16])[CH3:15]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1Br
Reactant: C1CNCCN1
Product: C[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1N1CCNCC1

Procedure:
To a 25 mL flask containing (S)-(−)-2-bromo-alpha-methylbenzyl alcohol (200 mg, 1.0 mmol), tert-butyldimethylsilyl chloride (165 mg, 1.1 mmol), and imidazole (203 mg, 3.0 mmol) flushed with nitrogen was added 5 mL of dimethylformamide. After stirring overnight, the mixture was quenched with saturated sodium bicarbonate, diluted with ethyl acetate, washed with NaH2PO4, saturated aqueous sodium bicarbonate, water, brine, dried (Na2SO4), filtered, and concentrated. Purification by flash chromatography (10 g SiO2, linear gradient 0-10% ethyl acetate/Hexanes, 30 mL/minute, over 30 minutes) gave about 260 mg (0.82 mmol, 82%) of (5)-[1-(2-Bromo-phenyl)-ethoxy]-tert-butyl-dimethyl-silane as a colorless oil. GC/MS (EI): 315 (M). The (5)-[1-(2-Bromo-phenyl)-ethoxy]-tert-butyl-dimethyl-silane was coupled to piperazine in a manner similar to Preparation 1A. LRMS (ESI+): 321.5 (M+1)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C.C(N(CC)CC)C>[C:18]1([C:17]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[C:5]3[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccc2[nH]nc(-c3ccccc3)c2c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2[nH]nc(-c3ccccc3)c2c1)c1ccccc1
Yield: 7 %

Procedure:
To a mixture of 5-amino-3-phenyl-1H-indazole (190 mg, 0.909 mmol) in acetonitrile (6 mL) was added benzoyl chloride (123 mg, 0.909 mmol). The solution was allowed to reflux for three hours. Triethylamine (3 drops) was added over a period of one hour while reflux continued for an additional hour. The solution was condensed and distilled water was added. The reaction mixture was extracted with ethyl acetate. The organics were dried using sodium sulfate, and condensed to give a solid. The solid was purified using chromatography (SiO2, 30–45% ethyl acetate/hexanes) to give the title compound (20 mg, 8% yield). 1H NMR (DMSO-d6) δ 13.40 (br s, 1H), 10.32 (s, 1H), 8.56 (s, 1H), 7.96 (m, 4H), 7.75 (d, 1H), 7.55 (m, 6H), 7.39 (t, 1H); ES-MS (m/z) 314 [M+1]+.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[O:4][CH:5]=[C:6]([CH:8]=[O:9])[CH:7]=1.[CH2:12]([Mg]Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>O1CCCC1>[OH:9][CH:8]([C:6]1[CH:7]=[C:3]([Si:2]([CH3:11])([CH3:10])[CH3:1])[O:4][CH:5]=1)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCC[Mg]Br
Reactant: C[Si](C)(C)c1cc(C=O)co1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Reaction time: 2 h

Procedure:
A solution of 2-trimethylsilyl-4-furaldehyde (0.5 g, 2.97 mmol) in tetrahydrofuran (5 ml) was added to a solution of dodecyl magnesium bromide (5.95 mmol; prepared from 1.48 g dodecyl bromide and 146 mg magnesium turnings in 30 ml tetrahydrofuran) at room temperature. After 2 hours, the mixture was quenched with ammonium chloride solution and extracted thoroughly with ethyl ether. Evaporation of the dried (magnesium sulfate) extracts gave an oil which was flash chromatographed on silica using 10% ethyl ether/hexane. Fractions with Rf about 0.13 gave, after evaporation, the title alcohol as a pale yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[OH-].[Na+].[CH3:16]I>CN(C)C=O>[CH3:16][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(C)c2c1
Yield: 86.9 %

Procedure:
The reaction was carried out in a manner similar to Reference Example 4 except for using 3.00 (17.1 mmol) of methyl 6-indolecarboxylate, 0.68 g (17.1 mmol) of 60% sodium hydroxide, 4.86 g (34.4 mmol) of methyl iodide and 60 ml of dimethylformamide. Thus 2.75 g (86.9%) of methyl 1-methyl-6-indolecarboxylate was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.COC([CH:15]1[CH2:20][NH:19][CH2:18][CH2:17][N:16]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=O.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:24][O:23][C:21]([CH:18]1[N:19]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:20][CH2:15][N:16]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:17]1)=[O:22]
Reactant: COC(=O)C1CNCCN1C(=O)OC(C)(C)C
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-Chloro phenyl boronic acid (2.0 equiv, 3.68 mmol) and piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1.0 equiv, 1.84 mmol) were dissolved in dichloromethane followed by the addition of copper acetate (1.0 equiv), 4 Å molecular sieves and pyridine (2.0 equiv). The reaction mixture was stirred at room temperature for 72 h. The reaction mixture was concentrated in vacuo, dissolved in ethyl acetate, filtered through celite and concentrated. The crude product was purified using gradient elution from hexane/ethyl acetate (5%) to hexane/ethyl acetate (20%).
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([CH:12]=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:12][C:10]3[S:11][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][CH:9]=3)[CH2:27][CH2:26]2)[CH:20]=1)=[O:17]
Reactant: O=Cc1ccc(-c2ccccc2)s1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(-c4ccccc4)s3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 5-phenyl-2-thiophenecarbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 419.1 (M+H)+.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH2:17][CH2:18][CH3:19])[N:14]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:13]=2[CH:28]=1.C(N(CC)CC)C>C(Cl)Cl>[C:5]([NH:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH2:17][CH2:18][CH3:19])[N:14]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:13]=2[CH:28]=1)(=[O:7])[CH3:6]
Reactant: CCCc1nc2ccc(N)cc2n1Cc1ccccc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1nc2ccc(NC(C)=O)cc2n1Cc1ccccc1Cl
Reaction time: 1 h
Yield: 83.6 %

Procedure:
Acetic anhydride (62 mg) was added to a solution of 150 mg of 6-amino-1-(2-chlorobenzyl)-2-n-propylbenzimidazole and 61 mg of triethylamine in 3 ml of methylene chloride at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was washed with water, and was then dried. The solvent was distilled off under reduced pressure. The residue was crystallized with ether to give 143 mg of 6-acetylamino-1-(2-chlorobenzyl)-2-n-propylbenzimidazole (89).
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][I:16])[N:10]=[CH:9]1)=O)(C)(C)C.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][I:16])[N:10]=[CH:9]1
Reactant: CC(C)(C)OC(=O)n1cnc(CCCI)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: ICCCc1c[nH]cn1

Procedure:
A solution of 5 g (14.2 mmol) of 3-(1-t-butyloxycarbonylimidazol-4-yl)-1-iodopropane (prepared as described in Example 6, part C) is stirred in a mixture of 5 ml of trifluoroacetic acid, 5 ml of CH2CH2 and 1 ml of anisole at 0° C. under nitrogen for 6 hours, then concentrated in vacuo and partitioned between CHCl3 and 15% aq Na2CO3. Evaporation of the organic extracts affords the title A compound.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9][C@H:8]1[CH2:17][O:18][CH2:19][CH2:20][OH:21])=[O:6])[CH:2]=[CH2:3].[C:22]([SH:25])(=[O:24])[CH3:23].[OH-].[Ca+2].[OH-]>CC(C)CC(=O)C>[C:22]([S:25][C@@H:10]1[CH2:11][N:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[C@H:8]([CH2:17][O:18][CH2:19][CH2:20][OH:21])[CH2:9]1)(=[O:24])[CH3:23]
Reactant: CC(=O)S
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1COCCO
Agent: [Ca+2]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1COCCO

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-2-(2-hydroxyethyloxymethyl)-4-methanesulfonyloxypyrrolidine (28.0 g) and thioacetic S-acid (12.47 ml) in 4-methyl-2-pentanone (168 ml) was added calcium hydroxide (6.41 g) below 45° C. Under reduced pressure (50-60 mmHg), the solvent (60 ml) was removed at 40°-50° C. The resulting suspension was heated at 80°-85° C. for 15 hours. After cooling, insoluble material was filtered off and washed with ethyl acetate (50 ml). The filtrate and washing were combined, dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (280 g) and eluted with a mixture of methanol and dichloromethane (1:99 V/V) to give (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-(2-hydroxyethyloxymethyl)pyrrolidine (10.74 g).