Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[C:15]([CH:17]([CH:19]([C:29]([NH2:31])=[O:30])[C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[CH3:18])[CH:16]=1.C(N(CC)CC)C>CN(C)C=O>[C:1]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[C:15]([CH:17]([CH:19]([C:29]([NH2:31])=[O:30])[C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[CH3:18])[CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(c1cc(N)ccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(c1cc(NC(=O)c2ccccc2)ccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)O)cc1
Reaction time: 2 h

Procedure:
An amount of 0.30 ml (2.62 m mol) of benzoyl chloride was added dropwise to a solution of 1 gm (2.62 m mol) of 4-[(1-(5-amino-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid and of 0.37 ml (2.62 m mol) of triethylamine in 10 ml of anhydrous dimethyl formamide. After stirring for two hours at 20° to 30° C., the reaction mixture was evaporated in vacuo and distributed between water and ethyl acetate. The organic phase was dried, filtered, and evaporated in vacuo. The evaporation residue (1.12 gm) was recrystallized from ethanol by addition of activated charcoal.
Reaction SMILES: [CH:1]1([C:4]2[C:9]3[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=3[CH:7]=[C:6]([CH:16]=O)[CH:5]=2)[CH2:3][CH2:2]1.[CH3:18][NH:19][C:20](=[O:33])[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[CH:1]1([C:4]2[C:9]3[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=3[CH:7]=[C:6]([CH2:16][N:30]3[CH2:29][CH2:28][N:27]([C:24]4[CH:23]=[CH:22][C:21]([C:20]([NH:19][CH3:18])=[O:33])=[CH:26][CH:25]=4)[CH2:32][CH2:31]3)[CH:5]=2)[CH2:2][CH2:3]1
Reactant: CC1Oc2c(cc(C=O)cc2C2CC2)NC1=O
Reactant: CNC(=O)c1ccc(N2CCNCC2)cc1
Product: CNC(=O)c1ccc(N2CCN(Cc3cc4c(c(C5CC5)c3)OC(C)C(=O)N4)CC2)cc1

Procedure:
Using 346A and N-methyl-4-(piperazin-1-yl)benzamide 282 in the general procedure for reductive aminations, the title compound was obtained as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.60-0.71 (m, 2H) 0.87-0.95 (m, 2H) 1.43 (d, J=6.82 Hz, 3H) 2.04-2.12 (m, 1H) 2.40-2.48 (m, 4 H) 2.73 (d, J=4.55 Hz, 3H) 3.18-3.26 (m, 4H) 3.36 (s, 2H) 4.61-4.67 (m, 1H) 6.41 (d, J=1.77 Hz, 1H) 6.69 (d, J=1.77 Hz, 1H) 6.93 (m, 2H) 7.69 (m, 2H) 8.14 (q, J=4.21 Hz, 1H) 10.55 (s, 1H). ESI-MS: m/z 435.4 (M+H)+. mp=256.1-258.6° C.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2].[SH:16][C:17]1[S:21][C:20]([S:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.C(C(C)=O)C>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][S:16][C:17]2[S:21][C:20]([S:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:19][N:18]=2)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2]
Reactant: CCCc1c(CCl)ccc(C(C)=O)c1O
Reactant: CCOC(=O)CCCCSc1nnc(S)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(CSc2nnc(SCCCCC(=O)OCC)s2)ccc(C(C)=O)c1O
Temperature: 60 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
To a mixture of 0.30 g of 4-acetyl-3-hydroxy-2-propylbenzyl chloride, 0.39 g of ethyl 5-[(5-mercapto-1,3,4-thiadiazol-2-yl)thio]valerate, 0.20 g of anhydrous potassium carbonate and 4 ml of methyl ethyl ketone were added catalytic amounts of potassium iodide and tetra-n-butylammonium bromide followed by stirring at 60° C. for 3 hours. The reaction mixture was diluted with ethyl acetate and insoluble matters were filtered off. The filtrate was washed with an aqueous sodium hydroxide solution and dried over anhydrous magnesium sulfate. The solvent was then distilled off. The residue was applied to silica gel column chromatography. Elution with a mixture of hexane-ethyl acetate (5:1) gave 0.52 g of oily ethyl 5-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thio]valerate
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)=[O:4]>CC(O)=O.CC([O-])=O.CC([O-])=O.[Cu+2].O>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([C:2](=[O:1])[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=2)=[O:4])[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc(C(=O)C(O)c2cccc(OC)c2)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc(C(=O)C(=O)c2cccc(OC)c2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
A solution of 2-hydroxy-1,2-bis(3-methoxyphenyl)ethanone (3.5 g, 12.87 mmol, 1.00 equiv), NH4NO3 (1.04 g, 13.00 mmol, 1.00 equiv), and Cu(OAc)2.H2O (260 mg, 1.30 mmol, 0.10 equiv) in 80% aqueous HOAc (30 mL) was allowed to react, with stirring, for 2 hrs while the temperature was maintained at reflux in an oil bath. Upon cooling to 0° C., the solid was filtered and washed with H2O (3×30 ml), affording 2.5 g (72%) of 1,2-bis(3-methoxyphenyl)-1,2-ethandione as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:41][CH2:42][CH2:43][N:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:46]([F:54])([CH3:53])[C:45]1=[O:55]>CC(=O)CC>[F:54][C:46]1([CH3:53])[C:47]2[C:52](=[CH:51][CH:50]=[CH:49][CH:48]=2)[N:44]([CH2:43][CH2:42][CH2:41][N:9]2[CH2:8][CH2:7][C:6]3([N:5]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:4][N:3]([CH2:18][C:19]4[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=4[C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[C:2]3=[O:1])[CH2:11][CH2:10]2)[C:45]1=[O:55]
Reactant: CC1(F)C(=O)N(CCCCl)c2ccccc21
Reactant: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccccc2)C2(CCNCC2)C1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccccc2)C2(CCN(CCCN3C(=O)C(C)(F)c4ccccc43)CC2)C1=O
Temperature: 78 °C
Reaction time: 5 h
Yield: 43.9 %

Procedure:
To a solution of tert-butyl 2-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.17 g, 0.4 mmol), sodium iodide (0.018 g, 0.12 mmol) and potassium carbonate (0.083 g, 0.6 mmol) in 2-butanone (4 mL), was added 1-(3-chloropropyl)-3-fluoro-3-methylindolin-2-one (0.097 g, 0.4 mmol). After stirring at 78° C. for 5 hours, the reaction mixture was filtered and isolated by Biotage flash chromatography (1-10% methanol/dichloromethane) to obtain the title compound (0.11 g, 44%); 1H NMR (DMSO-d6): δ 1.57 (s, 9H), 1.65-1.72 (m, 5H), 1.79 (t, 2H, J=6.8 Hz), 2.35 (t, 2H, J=6.4 Hz), 2.56-2.71 (m, 6H), 3.75 (t, 2H, J=6.4 Hz), 4.61 (s, 2H), 4.84 (s, 2H), 6.76 (t, 1H, J=7.6 Hz), 6.84 (d, 2H, J=8 Hz), 7.12 ((t, 1H, J=7.6 Hz), 7.21-7.26 (m, 4H), 7.38-7.42 (m, 2H), 7.57 (t, 2H, J=6.4 Hz), 7.82 (dd, 1H, J=7.6 and 1.2 Hz); MS for C37H43FN4O4 m/z 627.4 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:25]=[CH:24][C:12]2[N:13]=[C:14]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[O:15][C:11]=2[CH:10]=1.[H][H].Cl>[Ni].N>[NH2:21][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([C:14]2[O:15][C:11]3[CH:10]=[C:9]([C:3]4[CH:2]([CH3:1])[CH2:7][C:6](=[O:8])[NH:5][N:4]=4)[CH:25]=[CH:24][C:12]=3[N:13]=2)=[CH:17][CH:18]=1
Reactant: CC1CC(=O)NN=C1c1ccc2nc(-c3ccc(C#N)cc3)oc2c1
Reactant: [H][H]
Agent: [Ni]
Agent: Cl
Agent: N
Product: CC1CC(=O)NN=C1c1ccc2nc(-c3ccc(CN)cc3)oc2c1

Procedure:
100 mg (303 μmol) 4-[6-(4-methyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-benzoxazol-2-yl]-benzonitrile, 10 mg Raney nickel and 20 ml of methanolic ammonia are hydrogenated at RT and 3.45 bar hydrogen pressure for 4 h. Then the mixture is neutralised with conc. hydrochloric acid and the solv. is eliminated from the reaction mixture by rotary evaporation in vacuo. The residue is purified by RP-HPLC.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=2)=[C:8]([CH:21]=1)[C:9]([O:11]CC1C=CC=C(C#N)C=1)=[O:10]>O.C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=2)=[C:8]([CH:21]=1)[C:9]([OH:11])=[O:10]
Reactant: N#Cc1cccc(COC(=O)c2cc(Br)ccc2OCc2cccc(C#N)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cccc(COc2ccc(Br)cc2C(=O)O)c1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of lithium hydroxide (386 mg, 9.19 mmol) in water (20.00 mL) was added dropwise to a stirred solution of (3-cyanophenyl)methyl 5-bromo-2-{[(3-cyanophenyl)methyl]oxy}benzoate (may be prepared as described in Description 25; 411 mg, 0.92 mmol) in THF (20 ml) over 1 min. The reaction mixture was stirred at 20° C. for 16 h. The organic phase was evaporated and the aqueous phase (20 ml) was extracted by ethyl acetate (20 ml). The aqueous phase (20 ml) was adjusted to pH 2 with 2M hydrochloric acid (1 ml). The aqueous phase was then extracted with ethyl acetate (3×20 ml). The organic phase was evaporated in vacuo to yield the title compound as an off-white solid. 200 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([S:9][CH2:10][C:11]3[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=[CH:13][N:12]=3)=[N:8][C:4]=2[CH:3]=1.C([O-])(O)=[O:24].[Na+].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[Na+].C(OC)=O>C(Cl)Cl.O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([S:9]([CH2:10][C:11]3[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=[CH:13][N:12]=3)=[O:24])=[N:8][C:4]=2[CH:3]=1
Reactant: COc1ccnc(CSc2nc3cc(Cl)ccc3[nH]2)c1OC
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: COC=O
Product: COc1ccnc(CS(=O)c2nc3cc(Cl)ccc3[nH]2)c1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
5-chloro-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-1H-benzimidazole (645 mg, 0.0019 mol) was dissolved in 25 ml CH2Cl2 and mixed with NaHCO3 (323 mg, 0.0038 mol) dissolved in 10 ml H2O. The stirred mixture was cooled to 0° C. and treated with MCPBA (84%, 389 mg, 0.0019 mol) dissolved in 6 ml CH2Cl2. After reacting for 10 min the layers were separted and the aqueous layer extracted with 5 ml CH2Cl2. The organic layers wcre combined and extracted with 20 ml water containing NaOH (154 mg, 0.0038 mol). The latter aqueous layer was collected (residual CH2Cl2 distilled off on the rotavapor) and treated with two portions of HCOOCH3 (2×118 μl, 0.0038 mol).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24](C1NC=CN=1)(C1NC=CN=1)=O.CO.C(N(CC)CC)C>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])[C:11]([O:13][CH3:24])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: COc1ccc(Cl)cc1C[C@H](CNC(=O)OC(C)(C)C)C(=O)O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@@H](CNC(=O)OC(C)(C)C)Cc1cc(Cl)ccc1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
To a solution of (2R)-3-[(tert-butoxycarbonyl)amino]-2-(5-chloro-2-methoxybenzyl)propionic acid (1.1 g, 98% ee) in tetrahydrofuran (32 ml), carbonyl diimidazole (600 mg) was added under ice cooling and the mixture was stirred at room temperature for 1 hour 20 minutes. To the reaction solution, methanol (12.5 ml) and triethylamine (4.3 ml) were added and the mixture was stirred at room temperature for 3 hours. To the reaction solution, water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then solvent was distilled off in vacuo. The obtained residue was purified by silica gel column chromatography to obtain the title compound (1.03 g, 98%ee) as an oily substance.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11]C[C:9]2=[O:15])=[O:7])=[CH:2]1.C1(=O)NCCCC1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][C:9]2=[O:15])=[O:7])=[CH:2]1
Reactant: O=C1CCCCCN1C(=O)c1ccoc1
Agent: O=C1CCCCN1
Product: O=C1CCCCN1C(=O)c1ccoc1

Procedure:
Synthesized as for N-(3-furoyl)caprolactam (Example XI) using valerolactam (Aldrich) in place of caprolactam.
Reaction SMILES: CC1(C)OI([C:11]([F:14])([F:13])[F:12])C2C1=CC=CC=2.[C:16]([O:19][C:20]1([CH2:33][CH:34]=[CH2:35])[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)(=[O:18])[CH3:17]>[Cu]I.CO>[C:16]([O:19][C:20]1(/[CH:33]=[CH:34]/[CH2:35][C:11]([F:14])([F:13])[F:12])[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:22][CH2:21]1)(=[O:18])[CH3:17]
Reactant: C=CCC1(OC(C)=O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC1(C)OI(C(F)(F)F)c2ccccc21
Agent: [Cu]I
Solvent: CO
Product: CC(=O)OC1(/C=C/CC(F)(F)F)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h
Yield: 85.4 %

Procedure:
A flame-dried vial equipped with a magnetic stir bar was charged with Togni reagent (2.0 g, 7.0 mmol) and CuI (34 mg, 0.35 mmol), and was sealed with a septum. The vial was evacuated and backfilled with N2 for three times. MeOH (8 mL) and tert-butyl 4-acetoxy-4-allylpiperidine-1-carboxylate (4.5 g, 14 mmol) were then added via syringe. The vial was kept at 80° C. for 2 h. The reaction mixture was concentrated in vacuo and the crude residue was purified by a standard method to afford the product (2.1 g). 1H NMR (400 MHz, CHLOROFORM-d) δ: 1.47 (s, 9 H), 1.66-1.77 (m, 2H), 2.00-2.07 (m, 3 H), 2.22 (d, J=13.43 Hz, 2 H), 2.85 (qdd, J=10.61, 10.61, 10.61, 7.25, 1.21 Hz, 2 H), 3.11 (t, J=11.82 Hz, 2 H), 3.81 (br. s., 2 H), 5.58 (dt, J=15.98, 7.19 Hz, 1 H), 6.05 (d, J=16.12 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:11][CH3:12])[C:5]([F:10])=[C:6]([O:8][CH3:9])[CH:7]=1.C[OH:14]>O>[Cl:1][C:2]1[CH:3]=[C:4]([S:11]([CH3:12])=[O:14])[C:5]([F:10])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: CO
Reactant: COc1cc(Cl)cc(SC)c1F
Solvent: O
Product: COc1cc(Cl)cc(S(C)=O)c1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 5-chloro-2-fluoro-1-methoxy-3-(methylsulfanyl)benzene (576.1 mg), MeOH (20 mL) and water (4.0 mL) was added NaIO4 (894 mg) at 0° C. The mixture was stirred at room temperature for 1 day. The mixture was concentrated. The residue was diluted with water. The precipitate was filtered off, and the filtrate was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (501 mg).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[CH:15]([NH2:16])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:24][C:25]1[NH:29][N:28]=[N:27][N:26]=1)[CH2:19][CH2:20][C:21](=[O:23])[NH2:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:30][C:31]([F:41])([F:40])[CH2:32][S:33]([CH2:36][C:37](O)=[O:38])(=[O:35])=[O:34].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[CH:15]([NH:16][C:37](=[O:38])[CH2:36][S:33]([CH2:32][C:31]([F:40])([F:30])[F:41])(=[O:34])=[O:35])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:24][C:25]1[NH:29][N:28]=[N:27][N:26]=1)[CH2:19][CH2:20][C:21](=[O:23])[NH2:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1=C(C(CCC(N)=O)Sc2nnn[nH]2)CS[C@@H]2C(N)C(=O)N12
Reactant: O=C(O)CS(=O)(=O)CC(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1=C(C(CCC(N)=O)Sc2nnn[nH]2)CS[C@@H]2C(NC(=O)CS(=O)(=O)CC(F)(F)F)C(=O)N12
Reaction time: 12 h

Procedure:
To a solution of 8.4 g. (0.019 mol.) of 7-amino3-[1-(2-carbamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem4-carboxylic acid t-butyl ester and 3.9 g. (0.019 mol.) of 2,2,2-trifluoroethylsulfonylacetic acid in tetrahydrofuran is added dropwise a solution of 3.9 g. (0.019 mol.) of dicyclohexylcarbodiimide in 100 ml. of tetrahydrofuran. The reaction mixture is stirred at 25° for 12 hours, then filtered and concentrated to about 10 ml. The residue is filtered and evaporated to dryness to give 7-(2,2,2-trifluoroethylsulfonylacetamido)-3-[1-(2-carbamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)[CH:6]=[C:7]([O:12]C)[C:8]=1[CH2:9][CH2:10][CH3:11].Cl.N1C=CC=CC=1>>[OH:22][C:19]1[CH:20]=[CH:21][C:16]([CH:15]=[CH:14][C:5]2[CH:6]=[C:7]([OH:12])[C:8]([CH2:9][CH2:10][CH3:11])=[C:3]([OH:2])[CH:4]=2)=[CH:17][CH:18]=1
Reactant: CCCc1c(OC)cc(C=Cc2ccc(OC)cc2)cc1OC
Agent: Cl
Solvent: c1ccncc1
Product: CCCc1c(O)cc(C=Cc2ccc(O)cc2)cc1O
Yield: 30 %

Procedure:
This material was prepared from 1-(3,5-dimethoxy-4-1-propylphenyl)-2-(4-methoxyphenyl)ethene and pyridine hydrochloride in 30% yield in the same way as described in Example 3. 1H NMR (DMSO-d6, ppm): δ 1.22 (d, J=7.0 Hz, 6H), 3.41 (m, 1H), 6.40 (s, 2H), 6.73 (d, J=6.3 Hz, 4H), 7.33 (s, 1H), 7.41 (s, 1H), 8.98 (s, 2H), 9.51 (s, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.Cl.[N:13]1([CH2:19][CH2:20][CH2:21][C:22](O)=[O:23])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>CCOCC>[N:13]1([CH2:19][CH2:20][CH2:21][CH2:22][OH:23])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(O)CCCN1CCCCC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCCCCN1CCCCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85.3 %

Procedure:
11.68 mL of a 1M solution of lithium aluminum hydride in ether are added to 10 mL of tetrahydrofuran, and then 1 g of 4-piperidin-1-ylbutyric acid hydrochloride (synthesized according to a method described in the literature) is added. The medium is brought to boiling for approximately 10 minutes. After a return to ambient temperature and cooling to 0° C., a mixture of 1 mL of distilled water-30 mL of tetrahydrofuran is added dropwise. A large amount of gas is given off and strong exothermia is observed. After a return to ambient temperature, the medium is evaporated to dryness under reduced pressure in a rotary evaporator. The reaction crude is triturated in 150 mL of ethyl acetate and filtered, and the filtrate is washed with 2×20 mL of distilled water. The organic phase is dried over magnesium sulfate, filtered and then concentrated under vacuum in a rotary evaporator. 646 mg of 4-piperidin-1-ylbutan-1-ol are isolated in the form of a colorless oil. 1H NMR (300 MHz, DMSO-d6, δ in ppm): from 1.30 to 1.53 (m, 10H); 2.20 (t, J=6.5 Hz, 2H); 2.28 (m, 4H); 3.37 (broad t, J=6.5 Hz, 2H); 4.57 (broad s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:9]([O:13]C)=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:15])[NH:7]2.Br>>[Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:9]([OH:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:15])[NH:7]2
Reactant: COc1cc(Cl)c(Cl)c2c1NC(=O)CC2
Agent: Br
Product: O=C1CCc2c(Cl)c(Cl)cc(O)c2N1
Yield: 73.2 %

Procedure:
The thus-obtained 42 g of 5,6-dichloro-8-methoxy-3,4-dihydrocarbostyril are dispersed in 500 ml of 47%-hydrobromic acid aqueous solution and heated for 4 hours under refluxing conditions. After cooling the reaction mixture, the insoluble matter is separated by filtration, washed with water and dried. The crude crystals thus obtained are recrystallized from methanol to obtain 29 g of 5,6-dichloro-8-hydroxy-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with a melting point of 233°-235° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][SH:7])=[CH:4][CH:3]=1.C[O:11][C:12](=[O:30])[C@@H:13]1[CH2:17][C@@H:16](OS(C)(=O)=O)[CH2:15][N:14]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].O>CO>[C:23]([N:14]1[CH2:15][C@@H:16]([S:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:17][C@H:13]1[C:12]([OH:30])=[O:11])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: SCc1ccc(Br)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](SCc2ccc(Br)cc2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
To a solution of Na (0.25 g) (0.011 mol) in 3 mL of MeOH was added 4-bromobenzyl mercaptan (2.2 g) (0.011 mol). The reaction mixture was stirred for 1 h. Trans-N-Boc-4-methanesulfonyloxy-L-proline methyl ester (1.2 g) (0.0037 mol) (Preparation 9) was added and the mixture refluxed for 18 hrs. Upon cooling to RT, 40 mL of water was added and the mixture was extracted with EtOAc. The aqueous layer was acidified with 1 N HCl and extracted with DCM. The combined organic extracts were washed with water, dried over MgSO4, and the solvent evaporated in vacuo to afford cis-N-Boc-4-(4-bromobenzyl thio)-L-proline (1.08 g). NMR (CDCl3, 200 MHz): 10.65 (1H, COOH), 7.4 (2H, d), 7.15 (2H, d), 4.15-4.35 (1H, m), 3.65 (2H, s), 2.95-3.35 (2H, m), 2.4-2.6 (1H, m), 1.85-2.2 (1H, m), 1.3-1.5 (9H). To a solution of cis-N-Boc-4-(4-bromobenzyl thio)-L-proline (1.08 g) in 10 mL of MeOH was added dropwise SOCl2 (0.2 mL), and the mixture was stirred for 72 hrs at RT. The solvent was evaporated under reduced pressure and the residue dissolved in DCM. The organic layer was washed with dilute aqueous NaHCO3, water, and dried over MgSO4. The solvent was evaporated in vacuo to afford cis-4-(4-bromo-benzylthio)-L-proline methyl ester (0.6 g).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:15][C:16]([C:18]1[N:19]=[C:20]([N:23]2[CH2:26][CH:25]([S:27][C:28]3[C@H:29]([CH3:52])[C@@H:30]4[C@@H:47]([C@H:48]([OH:50])[CH3:49])[C:46](=[O:51])[N:31]4[C:32]=3[C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=3)=[O:34])[CH2:24]2)[S:21][CH:22]=1)=[O:17])[C@@H:11]([CH3:14])[CH2:12][CH3:13])(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1.O>[OH:8][CH2:9][C@@H:10]([NH:15][C:16]([C:18]1[N:19]=[C:20]([N:23]2[CH2:24][CH:25]([S:27][C:28]3[C@H:29]([CH3:52])[C@@H:30]4[C@@H:47]([C@H:48]([OH:50])[CH3:49])[C:46](=[O:51])[N:31]4[C:32]=3[C:33]([O:35][CH2:36][C:37]3[CH:38]=[CH:39][C:40]([N+:43]([O-:45])=[O:44])=[CH:41][CH:42]=3)=[O:34])[CH2:26]2)[S:21][CH:22]=1)=[O:17])[C@@H:11]([CH3:14])[CH2:12][CH3:13]
Reactant: CC[C@H](C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)C2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC[C@H](C)[C@@H](CO)NC(=O)c1csc(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)C2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 60.2 %

Procedure:
p-Nitrobenzyl (1R,5S,6S)-2-(1-{4-[(1S,2S)-1-(t-butyldimethylsilyloxymethyl)-2-methyl-butylcarbamoyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (760 mg, 0.982 mmol) (obtained as described in Example 43(1)) in tetrahydrofuran (38ml) was added to acetic acid (169 μl, 2.95 mmol) and 1 M tetrabutylammonium fluoride in tetrahydrofuran solution (2.95 ml, 2.95 mmol) and the mixture was stirred at room temperature for 3 days. After checking the completion of the reaction, ethyl acetate and water were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant: ethyl acetate→ethyl acetate: methanol (9:1)) to afford p-nitrobenzyl (1R,5S,6S)-2-{1-[4-((1S,2S)-1-hydroxymethyl-2-methylbutylcarbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (390 mg, yield 60%) as a pale yellow solid.