Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:23](=[O:24])[N:14]2[C:15]([C:20]([O-:22])=[O:21])=[C:16]([CH3:19])[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].S([O-])([O-])(=O)=O.[OH-].[CH2:32]([N+](CCCC)(CCCC)CCCC)[CH2:33][CH2:34]C.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].C(Br)C=C>C(Cl)Cl.O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:23](=[O:24])[N:14]2[C:15]([C:20]([O:22][CH2:34][CH:33]=[CH2:32])=[O:21])=[C:16]([CH3:19])[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1=C(C(=O)[O-])N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C=CCBr
Product: C=CCOC(=O)C1=C(C)CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N12
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
The solution of sodium 7-phenoxyacetylamino-3-methyl-3-cephem-4-carboxylate was added to a solution of 71.3 g (210 mmole) of tetra-n-butylammonium hydroxide sulfate in 700 ml of methylene chloride and 700 ml of water which had been readjusted to pH 7.5 with 2N sodium hydroxide. The mixture was stirred for about 5 minutes and the methylene chloride layer was separated. The aqueous phase was extracted twice with methylene chloride and the extracts were combined with the organic layer. The organic layer was dried over magnesium sulfate and evaporated to a brown oil. The oil was dissolved in 250 ml of chloroform and 34.6 ml (400 mmole) of allyl bromide (previously filtered through activated alumina) were added with stirring. The mixture was stirred for about 19 hours at room temperature and when thin layer chromatography indicated some remaining starting material, 17 ml of allyl bromide were added and the mixture was heated to 50° C. with stirring for about 2 hours. The reaction mixture was evaporated on a rotary evaporator to remove chloroform and the concentrate was dissolved in 3:1, v:v of diethyl ether:methylene chloride and the solution extracted twice with pH 7 buffer, once with brine and was dried over magnesium sulfate. The solution was evaporated under vacuum to provide allyl 7-phenoxyacetylamino-3-methyl-3-cephem-4-carboxylate as a crude yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:16])[CH2:12][N:13]([CH3:15])[CH3:14])([O-])=O.[H][H]>[Pt]=O.C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:16])[CH2:12][N:13]([CH3:14])[CH3:15]
Reactant: [H][H]
Reactant: CN(C)CC(=O)Nc1ccccc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CCO
Product: CN(C)CC(=O)Nc1ccccc1N
Yield: 77.8 %

Procedure:
N-(2-nitrophenyl)-2-dimethylaminoacetamide (13.8 g), platinum oxide (0.2 g) and ethanol (100 ml) were mixed together and shaken in an atmosphere of hydrogen at atmospheric pressure and laboratory temperature until absorption of hydrogen ceased (4.5 litres of hydrogen were absorbed in 2hours). The mixture was then filtered and the ethanol evaporated off under reduced pressure. The solid residue so obtained was recrystallised from cyclohexane to give N-(2-aminophenyl)-2-dimethylaminoacetamide (9.3 g), m.p. 121°-123° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]=[C:10]([CH2:14]O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])OCC.[N+](C1C=C([N+]([O-])=O)C=CC=1O)([O-])=O.[C:35]([O:38][CH2:39][CH3:40])(=[O:37])[CH3:36]>C1(C)C(C)=CC=CC=1>[CH2:39]([O:38][C:35](=[O:37])[CH2:36][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C:10]1=[CH2:14])[CH3:40]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC=C(CO)C1
Agent: CCOC([O-])[O-]
Agent: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Solvent: Cc1ccccc1C
Product: C=C1CN(C(=O)OC(C)(C)C)CCC1CC(=O)OCC
Temperature: 140 °C
Reaction time: 7 h

Procedure:
In 30 ml of xylene, 1.10 g of 1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-3-methanol (which had been prepared by the method described in Tetrahedron, Vol. 54, No. 25, p. 7045, 1998), 914 mg of ethyl orthoformate and 130 mg of 2,4-dinitrophenol were dissolved, and the formed solution was heated to 140° C. and stirred for 7 hours while removing the ethanol as formed. The reaction liquid was cooled, then ethyl acetate was added thereto and the organic layer was successively washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate and removed of the solvent by distillation. The resulting residue was purified on silica gel column chromatography (hexane/ethyl acetate=10/1) to provide 692 mg of 1-tert-butoxycarbonyl-3-methylenepiperidine-4-acetic acid ethyl ester. The product was dissolved in 20 ml of tetrahydrofuran, cooled to 0° C., 111 mg of lithium aluminium hydride was added thereto, and stirred for an hour. Then an excessive amount of sodium sulfate decahydrate was added to the reaction liquid and stirred for 15 minutes. The resulting mixture was filtered, and the filtrate was concentrated to provide 558 mg of crude 1-tert-butoxycarbonyl-3-methylenepiperidine-4-ethanol.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14](=O)[C:15]([OH:17])=[O:16]>O>[OH:3][N:2]=[C:14]([C:10]1[S:9][CH:13]=[CH:12][CH:11]=1)[C:15]([OH:17])=[O:16]
Reactant: NO
Reactant: O=C(O)C(=O)c1cccs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(O)C(=NO)c1cccs1
Yield: 48.2 %

Procedure:
A cooled solution of hydroxylamine hydrochloride (0.884 g) and sodium bicarbonate (1.08 g) in water (20 ml.) was added to a cooled (0°) solution of thien-2-yl-glyoxylic acid (2.0 g) and sodium bicarbonate (1.08 g) in water (20 ml.). After two days at 20° the solution was extracted with ether, cooled and acidified with concentrated hydrochloric acid. The resulting white solid was filtered off (0.564 g) and the filtrate was then thoroughly extracted with ether. The combined extracts were washed with brine, dried and concentrated. The solid residue was triturated with benzene to give the oxime (syn-isomer) (1.05 g; 51%), m.p. 132°, λmax. (ethanol) 284 nm (ε 9,500), λmax. (Nujol) 2590 and 1706 (CO2H) and 1655 cm-1 (C=N), τ (DMSO-d6), -2.5 to -0.5 (broad multiplet; N--OH and COOH), 2.36 (multiplet; thienyl C-5 H) and 2.82 (multiplet; thienyl C-3 H and C-4 H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:10][CH3:11])[C:3]([C:5]1[O:6][CH:7]=[CH:8][N:9]=1)=[O:4].Cl.[N:13]1([C:19](=[O:34])[CH2:20][CH:21]([CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22](O)=[O:23])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[O:6]1[CH:7]=[CH:8][N:9]=[C:5]1[C:3]([C@@H:2]([NH:1][C:22](=[O:23])[CH:21]([CH2:20][C:19]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[O:34])[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:10][CH3:11])=[O:4]
Reactant: CC[C@H](N)C(=O)c1ncco1
Reactant: O=C(O)C(CCCc1ccccc1)CC(=O)N1CCOCC1
Agent: Cl
Product: CC[C@H](NC(=O)C(CCCc1ccccc1)CC(=O)N1CCOCC1)C(=O)c1ncco1

Procedure:
It is similarly prepared according to the general procedure for Example 10 using (S)-2-Amino-1-oxazol-2-yl-butan-1-one; hydrochloride as the amino component and 2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid as the acidic component but without further oxidation.
Reaction SMILES: [PH2](O)=O.C(N1CCCCC1)C.[CH2:12]=[CH:13][S:14]([O:17][C:18]1[C:23]([F:24])=[C:22]([F:25])[C:21]([F:26])=[C:20]([F:27])[C:19]=1[F:28])(=[O:16])=[O:15].I[CH2:30][C@@H:31]1[CH2:35][CH2:34][CH2:33][N:32]1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37].C(B(CC)CC)C>C(Cl)Cl>[F:24][C:23]1[C:22]([F:25])=[C:21]([F:26])[C:20]([F:27])=[C:19]([F:28])[C:18]=1[O:17][S:14]([CH2:13][CH2:12][CH2:30][C@@H:31]1[CH2:35][CH2:34][CH2:33][N:32]1[C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])(=[O:16])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CI
Reactant: C=CS(=O)(=O)Oc1c(F)c(F)c(F)c(F)c1F
Agent: CCB(CC)CC
Agent: CCN1CCCCC1
Agent: O=[PH2]O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CCCS(=O)(=O)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 0 h

Procedure:
1-Ethylpiperidine hypophosphite (30 g, 168 mmol) were weighed into the reaction flask under an inert gas, and methylene chloride (100 ml) was added. The solution was cooled with ice-water and 2,3,4,5,6-pentafluorophenyl 1-ethylenesulfonate (5.06 g, 18.5 mmol) [Org. Lett.; 2002; 4(15); 2549-2551] and (S)-tert-butyl 2-(iodomethyl)pyrrolidine-1-carboxylate (5.22 g, 16.8 mmol) was added at 10° C. Triethylborane solution (1.6 ml, 1 mol/l) was added and compressed air was then passed through the mixture for 5 sec. After stirring for min the addition of triethylborane solution-compressed air was repeated with the same amount. The cooling bath was removed, the mixture was stirred for 10 min and the reaction mixture was then washed with water (20 ml) and saturated sodium chloride solution (20 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with hexane/diethyl ether (2:1). Yield: 2.81 g (36%)
Reaction SMILES: [Br-:1].[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N+:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]1[C:21]([NH2:22])=[N:20][C:19]([NH2:23])=[C:18]([Cl:24])[N:17]=1)=[O:15])([CH3:10])[CH3:9].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.CN1CCOCC1>CN(C=O)C.CO.C(Cl)Cl>[Br-:1].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N+:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]2[C:21]([NH2:22])=[N:20][C:19]([NH2:23])=[C:18]([Cl:24])[N:17]=2)=[O:15])([CH3:9])[CH3:10])(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: C[N+](C)(CCCCCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Agent: [Br-]
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CO
Product: C[N+](C)(CCCCCNS(=O)(=O)c1ccc(Cl)cc1)CCNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (5-amino-pentyl)-{2-[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-dimethyl-ammonium bromide (Intermediate O) (0.25 g, 0.59 mmol), 4-chlorobenzenesulfonyl chloride (0.13 g, 0.59 mmol) and N-methylmorpholine (0.30 mL, 2.73 mmol) in DMF (5 mL) is stirred at RT for 16 h. The reaction mixture is concentrated in vacuo and is purified by column chromatography (basic alumina, 0-10% MeOH in DCM). The solid that is obtained is dissolved in a minimum amount of MeOH and DCM then precipitated by the addition of diethyl ether. The supernatant solvent mixture is decanted and the product is washed again with diethyl ether then dried under vacuum to give the title compound. M+ 578. 1H NMR (400 MHz, DMSO-d6) δ 8.25 (1H, t), 7.78 (2H, d), 7.74 (1H, t), 7.57 (2H, br), 7.67 (2H, d), 7.11 (2H, br), 3.56 (2H, q), 3.36 (2H, t), 3.28-3.22 (2H, m), 3.04 (6H, s), 2.95 (2H, q), 1.65-1.58 (2H, m), 1.37 (2H, quintet), 1.24-1.16 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[NH:23][N:22]=[C:21]([C:24]([OH:26])=O)[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[NH:23][N:22]=[C:21]([C:24]([N:33]4[CH2:34][CH2:35][N:30]([CH2:29][CH2:28][OH:27])[CH2:31][CH2:32]4)=[O:26])[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCN1CCNCC1
Reactant: O=C(O)c1cc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)[nH]n1
Product: O=C(NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1)c1cc(C(=O)N2CCN(CCO)CC2)n[nH]1

Procedure:
The title compound was prepared as in Example 1 starting from 5-{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylcarbamoyl}-1H-pyrazole-3-carboxylic acid and 1-(2-hydroxyethyl)piperazine. The crude product was purified by flash chromatography using CH2Cl2-MeOH as a gradient eluent (100:0-90:10). 1H NMR (400 MHz, DMSO-d6): 2.40-2.44 (6H, m), 2.95 (2H, t), about 3.5-3.7 (6H, m), about 3.82 (2H, m), 4.41 (1H, t), 6.33 (1H, d), 7.01 (1H, d), about 7.05 (1H, broad s), 7.59 (1H, distorted dd), 7.63 (1H, distorted d), 7.84 (1H, d), about 8.59 (1H, broad s), 13.9 (1H, broad s).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[F:29])[CH:10]([OH:21])[CH2:11][C:12]1[N:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].B(F)(F)F.CCOCC.CO[C:41](OC)([CH3:43])[CH3:42]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[C@H:9]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[CH:10]([CH2:11][C:12]2[N:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])[O:21][C:41]1([CH3:43])[CH3:42])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(C)(C)OC
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1F)C(O)Cc1ncccc1C(=O)O
Agent: FB(F)F
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccccc2F)C(Cc2ncccc2C(=O)O)OC1(C)C
Temperature: 40 °C

Procedure:
To a solution of 2-[3-tert-Butoxycarbonylamino-4-(2-fluoro-phenyl)-2-hydroxy-butyl]-nicotinic acid (13 g, 32 mmol) in 500 mL of 2,2-dimethoxypropane and 500 mL of acetone at 0° C. is added boron trifluoride diethyl etherate (3.2 mL, 25 mmol). The reaction is heated at 40° C. overnight after which time the solvent is removed under reduced pressure. The resultant residue is then partitioned between dichloromethane and water and extracted with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel flash column chromatography gives the title compound.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:47]1[CH:46]=[C:45]3[C:48]([C:55]4[CH:60]=[CH:59][C:58]([CH2:61][CH3:62])=[CH:57][CH:56]=4)=[C:49]([Si](C)(C)C)[S:50][C:44]3=[CH:43][C:42]=1[CH2:41][O:40]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:47]1[CH:46]=[C:45]3[C:48]([C:55]4[CH:56]=[CH:57][C:58]([CH2:61][CH3:62])=[CH:59][CH:60]=4)=[CH:49][S:50][C:44]3=[CH:43][C:42]=1[CH2:41][O:40]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1ccc(-c2c([Si](C)(C)C)sc3cc4c(cc23)[C@]2(OC4)O[C@H](COCc3ccccc3)[C@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1ccc(-c2csc3cc4c(cc23)[C@]2(OC4)O[C@H](COCc3ccccc3)[C@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.3 %

Procedure:
(3′R,4′S,5S,5′S,6′R)-3′,4′,5′-tris-benzyloxy-6′-benzyloxymethyl-3-(4-ethylphenyl)-3′,4′,5′,6′-tetrahydro-2-trimethylsilyl-spiro[thieno[2,3,f]isobenzofuran-5(7H),2′-[2H]pyran] (0.094 g, 0.109 mmol) was dissolved in tetrahydrofuran (0.5 mL). A Solution of tetrabutylammonium fluoride/tetrahydrofuran (1.0 M, 0.43 mL) was added thereto, and then the mixture was stirred for 1.5 hours at room temperature. Saturated aqueous ammonium chloride was added thereto, and the resultant mixture was extracted with diethyl ether. The organic layer was concentrated under reduced pressure, to thereby obtain the titled compound (84.5 mg, 98%).
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][N:31]6[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]6)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[C:38]([NH:45][C@H:46]([C:50](O)=[O:51])[CH:47]([CH3:49])[CH3:48])([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].C(N(CC)CC)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][C:27]([CH2:30][N:31]6[CH2:32][CH2:33][N:34]([C:50](=[O:51])[C@@H:46]([NH:45][C:38](=[O:39])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH:47]([CH3:49])[CH3:48])[CH2:35][CH2:36]6)=[CH:28][CH:29]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCNCC5)cn4)sc23)c(F)c1)NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a stirred solution of compound 49 (150 mg, 0.289 mmol, scheme 15), Boc-L-valine (94 mg, 0.43 mmol) and triethylamine (120 μL, 0.87 mmol) in DMF (5 mL) under nitrogen were added HOBT monohydrate (49 mg, 0.32 mmol) and EDC hydrochloride (139 mg, 0.72 mmol) reagents, and the reaction mixture was stirred at RT overnight. The reaction mixture was then partitioned between AcOEt and a saturated aqueous solution of sodium bicarbonate. The organic layer was successively washed with a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of ammonium chloride and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified by Biotage (Snap 25 g; MeOH/DCM: 1/99 to 10/90 over 20 CV), to afford the title compound 75 (171 mg, 0.238 mmol, 82% yield) as a colorless sticky film. MS (m/z): 718.4 (M+H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.C[Sn](C)(C)[Sn](C)(C)C.Br[C:28]1[C:29]([NH:36][C@H:37]2[CH2:42][C@H:41]([CH3:43])[CH2:40][N:39]([C:44]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:45])[CH2:38]2)=[N:30][C:31]([S:34][CH3:35])=[N:32][CH:33]=1>[Pd].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.C1(C)C=CC=CC=1>[CH2:47]([O:46][C:44]([N:39]1[CH2:38][C@@H:37]([NH:36][C:29]2[C:28]([C:2]3[N:3]=[C:4]4[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]4=[N:6][CH:7]=3)=[CH:33][N:32]=[C:31]([S:34][CH3:35])[N:30]=2)[CH2:42][C@H:41]([CH3:43])[CH2:40]1)=[O:45])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CSc1ncc(Br)c(N[C@H]2C[C@H](C)CN(C(=O)OCc3ccccc3)C2)n1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(Br)cnc21
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)(C)[Sn](C)(C)C
Solvent: Cc1ccccc1
Product: CSc1ncc(-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)c(N[C@H]2C[C@H](C)CN(C(=O)OCc3ccccc3)C2)n1
Yield: 35.5 %

Procedure:
A degassed toluene (15 ml) solution of 2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (1.0 g, 3.0 mmol), 1,1,1,2,2,2-hexamethyldistannane (1.0 g, 3.1 mmol), and tetrakis(triphenylphosphine)palladium(0) (176 mg, 0.15 mmol) was treated in a similar manner as Example 76, step 3. To this was added (3S,5S)-benzyl 3-(5-bromo-2-(methylthio)pyrimidin-4-ylamino)-5-methylpiperidine-1-carboxylate (1.37 g, 3.0 mmol) and another 176 mg of palladium catalyst and following Example 76, step 3. (3S,5S)-3-methyl-5-{2-methylsulfany-l-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-ylamino}-piperidine-1-carboxylic acid benzyl ester (660 mg, 35%) could be isolated as an oil and taken to the next step. (0227-160)
Reaction SMILES: Cl.[OH:2][NH3+:3].[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:35])[CH2:12][CH2:13][CH:14]2[C:17](=[O:18])[N:16]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[CH:15]2[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C>C(O)(C)C>[F:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([OH:35])[CH2:12][CH2:13][CH:14]2[C:17](=[O:18])[N:16]([C:19]3[CH:26]=[CH:25][C:22]([C:23]([NH:3][OH:2])=[NH:24])=[CH:21][CH:20]=3)[CH:15]2[C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)=[CH:9][CH:10]=1
Reactant: [NH3+]O
Reactant: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(C#N)cc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(C(=N)NO)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
199 mg of hydroxylammonium hydrochloride were added to a solution of 200 mg of 4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzonitrile (8) and 0.45 ml of triethylamin in 15 ml of isopropanol. The mixture was stirred at room temperature for 12 h. The reaction solution was extracted twice with ethyl acetate/water. The organic phases were dried over magnesium sulfate and concentrated. This gave the product of molecular weight 463.51 (C26H26F1N3O4); MS (ESI): 464.19 (M+H+).
Reaction SMILES: C([S:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[CH2:17][C:16](O)([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH2:15][C@H:11]1[C:12]([OH:14])=[O:13])=[O:9])(=O)C.N>>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]2[CH2:17][N:10]([C:8](=[O:9])[CH2:7][CH2:6][CH2:5][SH:4])[C@H:11]([C:12]([OH:14])=[O:13])[CH:15]=2)=[CH:19][CH:20]=1
Reactant: CC(=O)SCCCC(=O)N1CC(O)(c2ccc(C)cc2)C[C@H]1C(=O)O
Agent: N
Product: Cc1ccc(C2=C[C@@H](C(=O)O)N(C(=O)CCCS)C2)cc1

Procedure:
The product from part (b) is treated with concentrated ammonia according to the procedure of Example 4 to yield (2S)-2,5-dihydro-4-[(4-methyl)phenyl]-1-(4-mercapto-1-oxobutyl)-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.C([Sn](CCCC)(CCCC)[C:43]1[S:44][CH:45]=[CH:46][N:47]=1)CCC>>[C@@H:6]1([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([CH2:31][C:32]3[S:33][C:34]([C:43]4[S:44][CH:45]=[CH:46][N:47]=4)=[CH:35][CH:36]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(F)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Product: OC[C@H]1O[C@@H](c2ccc(F)c(Cc3ccc(-c4nccs4)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-fluorobenzene obtained in Example 189-(3) and tri-n-butyl(2-thiazolyl)tin were used and treated in a manner similar to Example 128 to give the title compound as colorless crystals. APCI-Mass m/z 438 (M+NH4). mp 161.5-162° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[C:10](OC(=O)C)(=[O:12])[CH3:11]>N1C=CC=CC=1>[C:10]([O:9][CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1)(=[O:12])[CH3:11]
Reactant: OC1CN2CCC1CC2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1CN2CCC1CC2
Reaction time: 4 h
Yield: 62 %

Procedure:
A solution of (RS)-3-quinuclidinol (25 g, 0.2 mmol) in pyridine (100 ml) was treated with acetic anhydride (100 ml), kept at 50° C. for 4 hours and left at room temperature for 15 hours. After removal of the pyridine and excess acetic anhydride under vacuum, the clear light brown oil was then dissolved in water (25 ml) and made slightly alkaline with saturated potassium carbonate. The ester was then extracted with chloroform (5×50 ml) and extracts were dried over K2CO3. After evaporation of the solvent in vacuo the residue was distilled yielding 20.6 g (62%) of (RS)-3-acetoxyquinuclidine as a colorless liquid.