Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][S:17][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:18]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([Br:18])[S:17][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccsc2CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2cc(Br)sc2CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The product of step f) (10 mg, 0.039 mmol) dissolved in a 50:50 mixture of chloroform/acetic acid (1 ml) was treated with N-bromosuccinimide (7 mg, 0.041 mmol). The reaction mixture was stirred for 30 minutes at ambient temperature. The reaction mixture was poured into water (5 ml) and extracted with CHCl3 (3×5 ml). The combined organic phases were washed with 10% KOH solution (5 ml), brine (5 ml), dried (MgSO4), and concentrated to give the crude product as an oil. Purification by HPLC gave the subtitle compound as an oil. MS: ESI (positive): 332, 334 (M+H).
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH2:12]([OH:16])[C@H:13]([OH:15])[CH3:14].N1C=CN=C1>CN(C=O)C>[CH:1]([Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[O:16][CH2:12][C@H:13]([OH:15])[CH3:14])([CH3:3])[CH3:2]
Reactant: C[C@@H](O)CO
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](OC[C@@H](C)O)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.7 %

Procedure:
Triisopropylsilyl chloride (83.8 mL, 390 mmol) was added slowly over 15 minutes to a solution of (2R)-propane-1,2-diol (29.7 g, 390 mmol) in DMF at 0° C. (100 mL) keeping the internal temperature below 15° C. This was followed by addition of imidazole (66.4 g, 975 mmol) and the reaction mixture was allowed to warm to RT and stirred under argon for 20 hours. The reaction was quenched with 1M hydrochloric acid/diethyl ether (300 mL/800 mL). The organic layer was separated and washed with 1M hydrochloric acid followed by saturated brine solution. The organic layer was dried (MgSO4), filtered and evaporated. Purification by distillation at 10 mmHg, 90-104° C., afforded the title compound as colourless oil (69.5 g). 1H NMR δ (CDCl3): 1.05 (s, 18H), 1.05-1.1 (m, 3H), 1.05 (d, 3H), 2.55 (s, 1H), 3.45 (dd, 1H), 3.7 (dd, 1H), 3.85 (m, 1H).
Reaction SMILES: [BH4-].[Na+].[CH:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][C:8]=1[N+:17]([O-])=O)([CH3:5])[CH3:4].O>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:17][C:8]1[CH:9]=[C:10]([S:13]([NH2:16])(=[O:14])=[O:15])[CH:11]=[CH:12][C:7]=1[O:6][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)Oc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)Oc1ccc(S(N)(=O)=O)cc1N
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (1.88 g, 49.6 mmol) was added slowly to a solution of nickel (II) chloride hexahydrate (3.93 g, 16.5 mmol) in methanol (60 mL) at 0° C. and the resulting black suspension was stirred for 30 min at 23° C. The mixture was cooled to 0° C. and 4-isopropoxy-3-nitro-benzenesulfonamide (8.6 g, 33.0 mmol, example 2, step c) was added followed by sodium borohydride (4.38 g, 115.6 mmol). The resulting black suspension was stirred for 30 min at 23° C. Water was added to the reaction mixture to quench excess NaBH4, followed by addition of saturated aqueous NaHCO3. The product was extracted with dichloromethane and the organic phase was washed with brine, dried with Na2SO4 and evaporated to give the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][C:6]=1[C:7](OC)=[O:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][C:6]=1[CH2:7][OH:8]
Reactant: CCCc1ccc(OCOC)c(C(=O)OC)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1ccc(OCOC)c(CO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
To a mixture of methyl 2-methoxymethoxy-5-propylbenzoate (6.06 g) and tetrahydrofuran (200 mL) was added lithium aluminum hydride (0.96 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To the mixture was added sodium sulfate 10 hydrate (8.18 g) and the mixture was further stirred at room temperature for 30 min. The insoluble materials were removed by filtration, and the filtrate was concentrated to give (2-methoxymethoxy-5-propylphenyl)methanol as an oil (4.98 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[CH3:10][C:11](OC(C)=O)=[O:12]>CC(O)=O>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11](=[O:12])[CH3:10])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-chloro-2-fluoroaniline (50.0 g, 344 mmol) in AcOH (30 mL) is added Ac2O (60 mL) and the reaction is stirred at room temperature for 2 hours. The mixture is poured into ice water (500 mL) to give a solid precipitate. The mixture is stirred for an additional 1 hour at room temperature. The solid is filtered and washed with water and hexanes, then air dried to give N-(4-chloro-2-fluorophenyl)acetamide.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][CH:6]=2.[I-:13].[Na+].N.Cl>O1CCOCC1.[Cu](I)I>[I:13][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][CH:6]=2
Reactant: [I-]
Reactant: Oc1ccc2ncc(Br)cc2c1
Agent: I[Cu]I
Agent: Cl
Agent: N
Solvent: C1COCCO1
Product: Oc1ccc2ncc(I)cc2c1
Temperature: 120 °C
Reaction time: 14 h

Procedure:
To a stirred mixture of 3-bromo-6-hydroxyquinoline (preparation described in Liebigs Ann Chem 1966, 98-106), (3.0 g), sodium iodide (4.0 g) and copper iodide (0.25 g) in dioxane (19.5 ml) is added N,N′-tetramethyl-ethane-1,2-diamine (0.24 g) in a sealed tube under argon. The mixture is stirred at 120° C. for 14 h and upon cooling is treated with aqueous ammonia followed by aqueous hydrochloric acid to reach pH 5. Extraction with ethyl acetate, drying of the organic phase over magnesium sulphate, filtration and evaporation under reduced pressure gives the required product ((M+1)+272) as a light brown coloured powder that is used as such in the next step.
Reaction SMILES: O=C1N(CC(OC(C)(C)C)=O)C2C=CC=CC=2N1.C([O:23][C:24](=[O:47])[CH2:25][N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]([C:35]2[CH:45]=[CH:44][C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:37][CH:36]=2)[C:27]1=[O:46])(C)(C)C>>[CH2:42]([O:41][C:39]([C:38]1[CH:37]=[CH:36][C:35]([N:28]2[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[N:26]([CH2:25][C:24]([OH:47])=[O:23])[C:27]2=[O:46])=[CH:45][CH:44]=1)=[O:40])[CH3:43]
Reactant: CCOC(=O)c1ccc(-n2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)cc1
Agent: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc21
Product: CCOC(=O)c1ccc(-n2c(=O)n(CC(=O)O)c3ccccc32)cc1

Procedure:
Essentially following the procedures described for Intermediate 4, but using ethyl 4-[3-(2-tert-butoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]benzoate in place of tert-butyl (2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetate, the title compound was prepared. MS: m/z=341 (M+1).
Reaction SMILES: [CH3:1][C:2](=[CH2:23])[CH:3]([C:10]1[CH:15]=[CH:14][C:13]([O:16]C2CCCCO2)=[CH:12][CH:11]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CCO>[OH:16][C:13]1[CH:12]=[CH:11][C:10]([CH:3]([C:2]([CH3:23])=[CH2:1])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:15][CH:14]=1
Reactant: C=C(C)C(CC(=O)OCC)c1ccc(OC2CCCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C=C(C)C(CC(=O)OCC)c1ccc(O)cc1
Reaction time: 16 h
Yield: 104.3 %

Procedure:
To a stirred solution of 15.2 (0.30 g, 0.90 mmol) in EtOH (100 mL) at room temperature was added PPTS (0.20 g, 0.90 mmol). The resulting solution was stirred for 16 hours and then concentrated in vacuo. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0%-20% EtOAc in hexanes) to give 15.3 (0.220 g, 100%) as a clear oil. MS ESI (pos.) m/e: 257.1 (M+Na)+, 252.1 (M+H2O)+, 235.1(M+H)+.
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2/[CH:17]=[CH:18]/[CH3:19])[CH:5]=[CH:6][CH:7]=1.[CH2:21](C([Sn])=C(CCCC)CCCC)[CH2:22]CC>O1CCOCC1.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>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([N:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH:21]=[CH2:22])[C:3]2=[O:20])=[C:9](/[CH:17]=[CH:18]/[CH3:19])[CH:10]=1)([O-:16])=[O:15]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: C/C=C/c1cc([N+](=O)[O-])ccc1-n1cccc(Br)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=Cc1cccn(-c2ccc([N+](=O)[O-])cc2/C=C/C)c1=O

Procedure:
929 mg (2.77 mmol) of the compound from Example 44A are dissolved in 14 ml of anhydrous dioxane, and 64 mg (0.06 mmol) of tetrakis(triphenylphosphine)palladium(0) are added. At room temperature, 1.06 g (3.33 mmol) of tributylvinyl tin are added slowly, and, after the addition has ended, the mixture is heated at reflux for 21 h. The reaction solution is allowed to cool and is filtered through kieselguhr. The filter cake is then washed with ethyl acetate, and the combined organic filtrates are concentrated to dryness under reduced pressure. The product is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate=4:1). This gives 568 mg (70% of theory) of the desired product.
Reaction SMILES: S(Cl)(Cl)(=O)=[O:2].[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][N:14]([S:18]([Cl:21])(=[O:20])=[O:19])[CH2:15]2)=[CH:10][CH:9]=1>C(N(CC)CC)C>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[O:2][CH2:12][CH2:13][N:14]([S:18]([Cl:21])(=[O:20])=[O:19])[CH2:15][C:16]=2[CH:17]=1
Reactant: COc1ccc2c(c1)CN(S(=O)(=O)Cl)CC2
Reactant: O=S(=O)(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CN(S(=O)(=O)Cl)CCO2

Procedure:
This compound was prepared from 1.4 g of 7-methoxy-2,3,4,5-tetrahydro-benzo[f[1,4]-oxazepine, 0.91 mL of sulfuryl chloride and 4.7 mL of triethylamine using the procedure described for 63f. Yield: 0.23 g (oil), EI-MS: 277 (M+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:10][C@@H:9]1[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH3:35])=O)(C)(C)C.Cl>O1CCOCC1>[CH:23]1([O:22][C:16]2[CH:15]=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][C@@H:9]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])[CH2:10]3)[CH:19]=[CH:18][C:17]=2[O:20][CH3:21])[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: COc1ccc(N2CCN(C(=O)OC(C)(C)C)[C@@H](Cc3ccccc3C)C2)cc1OC1CCCC1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(N2CCN[C@@H](Cc3ccccc3C)C2)cc1OC1CCCC1
Reaction time: 2 h
Yield: 74.7 %

Procedure:
A solution of intermediate (S)-4-(3-Cyclopentyloxy-4-methoxy-phenyl)-2-(2-methyl-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (215 mg, 0.447 mmol) in 1,4-dioxane (2 mL) was then treated with a 4 N solution of hydrogen chloride (4 mL) and stirred for 2 h. The reaction was then evaporated to a colorless solid, suspended in EtOAc (10 mL), and washed with a saturated aqueous K2CO3 solution (3 mL) followed by brine (3 mL). The organic portion was then dried over MgSO4, filtered, and evaporated to afford the title compound as a burgundy colored oil (127 mg, 75%). 1H NMR (CDCl3) 7.26-7.11 (m, 4H), 6.78 (d, J=8.8, 1H), 6.53 (d, J=2.9, 1H), 6.43 (dd, 8.7, 2.6, 1H), 4.74-4.71 (m, 1H), 3.78 (s, 3H), 3.39-3.35 (m, 2H), 3.16-3.08 (m, 2H), 2.96 (td, J=11.2, 2.9, 1H), 2.87-2.70 (m, 2H), 2.56-2.49 (m, 1H), 2.36 (s, 3H), 1.92-1.72 (m, 6H), 1.61-1.57 (m, 2H). 13C NMR 148.4, 146.5, 144.8, 136.7, 136.4, 130.7 (CH), 130.2 (CH), 126.8 (CH), 126.1 (CH), 113.3 (CH), 108.6 (CH), 106.8 (CH), 80.6, (CH), 56.8 (CH2), 56.8 (CH3), 55.3 (CH), 51.3 (CH2), 46.0 (CH2), 37.9 (CH2), 32.97 (CH2), 24.2 (CH2), 19.8 (CH3). LC/MS (Method A) 5.03 min, [M+1]+ 381.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4]1[CH:11]=[CH:10]C(C#N)=[CH:6][C:5]=1[C:12]([F:15])([F:14])[F:13])[CH3:2].Cl.[C:19]([OH:22])(=[O:21])[CH3:20]>>[CH2:16]([N:3]([CH2:1][CH3:2])[C:4]1[CH:11]=[CH:10][C:20]([C:19]([OH:22])=[O:21])=[CH:6][C:5]=1[C:12]([F:13])([F:14])[F:15])[CH3:17]
Reactant: CC(=O)O
Reactant: CCN(CC)c1ccc(C#N)cc1C(F)(F)F
Agent: Cl
Product: CCN(CC)c1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 95 °C
Reaction time: 20 h

Procedure:
A mixture of 4-diethylamino-3-(trifluoromethyl)-benzonitrile (1.21 g, 5 mmol), 12 mL of acetic acid and 8 mL of fuming hydrochloric acid (37%) is shaken for 20 hours at 95° C. After cooling, the reaction mixture is evaporated to dryness under reduced pressure. The solid residue is dissolved in a warm half-saturated aqueous sodium carbonate solution and the pH is adjusted to ˜5-6 by dropwise addition of 2M hydrochloric acid. The formed precipitate is filtered off, washed with water and dried in vacuo to yield a white solid.
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:2]([C:20](O)=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].CCN(C(C)C)C(C)C.[NH2:39][CH2:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42].Cl.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:2]([C:20]([NH:39][CH2:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: NCC(=O)OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 83.1 %

Procedure:
To a suspension of Boc—(D)—Arg(Tos)—OH (1 g, 2.34 mmol) in CH2Cl2 (10 mL) was added DIEA (1 mL) at 0° C. To the clear solution was added Gly—OBn.HCl (0.52 g, 2.58 mmol) and BOP (1.2 g, 2.8 mmol). The solution was stirred for 4 h at 0° C. Solvents were evaporated and residue was dissolved in a mixture of EtOAc (100 mL) and water (20 mL). The organic layer was washed with sat. NaHCO3 (10 mL), water (10 mL), 1 N HCl (10 mL) and sat. NaCl (3×10 mL), dried with MgSO4, filtered and evaporated. The solid residue was purified by column chromatography on silica gel (EtOAc) to give 1.12 g of the title compound as a powder. ES—MS (M+H)+=576.3
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[C:26]([O:27][CH3:28])=[C:25]([O:29][CH3:30])[CH:24]=[C:23]([CH3:31])[C:11]=1[C:12]([C:14]1[C:19]([Cl:20])=[CH:18][N:17]=[C:16](Cl)[C:15]=1[Cl:22])=[O:13]>[C].[Pd].CO>[CH3:8][O:9][C:10]1[C:26]([O:27][CH3:28])=[C:25]([O:29][CH3:30])[CH:24]=[C:23]([CH3:31])[C:11]=1[C:12]([C:14]1[C:19]([Cl:20])=[CH:18][N:17]=[CH:16][C:15]=1[Cl:22])=[O:13]
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cnc(Cl)c2Cl)c(OC)c1OC
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1cc(C)c(C(=O)c2c(Cl)cncc2Cl)c(OC)c1OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 708 %

Procedure:
4.6 g (6.9 mmol) of triethylamine and 1.8 g of 10% palladium carbon were added to a methanol 280 ml solution of 17.8 g (4.6 mmol) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-2,3,5-trichloropyridine (compound No. 186), followed by stirring under hydrogen atmosphere at room temperature for 7 hours. The mixture was subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography to obtain 11.6 g (yield 72%) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3,5-dichloropyridine (compound No. 191; m.p. 109-111° C.).
Reaction SMILES: [NH2:1][C:2]1[C:6]([N+:7]([O-])=O)=[CH:5][N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.Cl>CO.[C].[Pd]>[NH2:1][C:2]1[C:6]([NH2:7])=[CH:5][N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: Nc1nn(-c2ccccc2)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1cn(-c2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.2 %

Procedure:
To a solution of 3-amino-4-nitro-1-phenyl-1H-pyrazole (200 mg, 0.98 mmol) in methanol (30 mL) were added conc. hydrochloric acid (0.5 mL) and 10% palladium-carbon (20 mg), and the mixture was stirred for 1.5 hours at room temperature under a hydrogen atmosphere. After removal of the catalyst by filtration, the filtrate was concentrated, and aqueous sodium bicarbonate solution was added to the resulting residue. The solution was extracted 5 times with chloroform, and the chloroform layer was dried over anhydrous magnesium sulfate, and then concentrated in vacuo. Diisopropyl ether was added to the resulting residue, and the precipitates were collected by filtration and dried to obtain the title compound (101 mg, 58.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]3[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][C:18]([C:22]([NH2:24])=[O:23])=[CH:17][CH:16]=4)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[OH-].[K+].I[CH:30]([CH3:32])[CH3:31]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][N:10]([C:13]3[N:14]([CH:30]([CH3:32])[CH3:31])[C:15]4[C:20]([CH:21]=3)=[CH:19][C:18]([C:22]([NH2:24])=[O:23])=[CH:17][CH:16]=4)[CH2:11][CH2:12]2)=[CH:25][CH:26]=1
Reactant: NC(=O)c1ccc2[nH]c(N3CCN(Cc4ccc(Cl)cc4)CC3)cc2c1
Reactant: CC(C)I
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(C)n1c(N2CCN(Cc3ccc(Cl)cc3)CC2)cc2cc(C(N)=O)ccc21
Reaction time: 20 h
Yield: 55.3 %

Procedure:
4-(4-Chlorobenzyl)piperazinyl-indole-5-carboxamide (420 mg, 1.32 mMol) was taken in acetone. Solid KOH (280 mg, 5 mMol) was added followed by the addition of 2-iodopropane (1 g, 6 mMol) and the mixture was refluxed with stirring for 20 h. Acetone was removed in vacuo and the residue was extracted from water using methylene chloride. The extract was dried and evaporated and the residue was chromatographed on a column of silica gel using ethylacetate-hexane (ethylacetate 0 to 25%, gradient) and recrystallized from ether-hexane to yield 300 mg of the product. 1HNMR (CDCl3): δ=7.6 (s, 1H); 7.3-7.1 (m, 6H); 6.5 (s, 1H); 4.65-4.55 (m, 1H); 3.8-3.5 (m, 4H); 3.4 (s, 2H); 2.4-2.5 (s, 4H); 1.5 (d, 6H). MS (ESI) m/e 395 (M+).
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH2:28][NH:29]C(OC(C)(C)C)=O)[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:37]>CO>[ClH:37].[ClH:37].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH2:28][NH2:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CC(C)(C)OC(=O)NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.3 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.70 g.), conc. hydrochloric acid (0.48 g.) and methanol (7 ml.) was stirred at room temperature for 4 hours. After concentrating the resultant solution in vacuo, the residue was dissolved in methanol (10 ml.) and crystallized by adding diisopropyl ether (20 ml.). The precipitates were collected by filtration, washed with a mixture of methanol and diisopropyl ether (1:1) and dried to give 7-[2-(2-aminothiazol-4-yl)-2-(2-aminoethoxyimino)acetamido]-3-cephem-4-carboxylic acid dihydrochloride (syn isomer, 0.58 g.).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:4]([O:7][CH3:8])([CH3:6])[CH3:5].C(=O)([O-])[OH:18].[Na+].[Br-].[K+].Cl[O-].[Na+]>CC(C)=O>[C:12]([O:11][C:10]([NH:9][CH:3]([C:4]([O:7][CH3:8])([CH3:5])[CH3:6])[C:2]([OH:18])=[O:1])=[O:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(C)(C)C(CO)NC(=O)OC(C)(C)C
Reactant: O=C([O-])O
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)O
Yield: 82 %

Procedure:
tert-Butyl 1-(hydroxymethyl)-2-methoxy-2-methylpropylcarbamate (0.23 g) obtained in Example 73b) was dissolved in acetone (8 ml) and a 5% aqueous sodium hydrogen carbonate solution (2.7 ml). Potassium bromide (0.01 g), 2,2,6,6-tetramethyl-1-piperidinyloxy (0.17 g) and an aqueous sodium hypochlorite solution (1.7 ml) were added thereto, and mixed at 0° C. for 50 minutes. Acetone was distilled off under reduced pressure, and the residue was diluted with water, washed with diethyl ether, acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as a pale yellow oil (0.20 g, 82%).
Reaction SMILES: [CH2:1]([N:8]([C:15]1[CH:16]=[C:17]([C:33]2[CH:38]=[CH:37][C:36]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:35][CH:34]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1)[C:9](=[O:14])[C:10]([O:12]C)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+].Cl>O1CCCC1>[CH2:1]([N:8]([C:15]1[CH:16]=[C:17]([C:33]2[CH:34]=[CH:35][C:36]([O:39][C:40]([F:41])([F:42])[F:43])=[CH:37][CH:38]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1)[C:9](=[O:14])[C:10]([OH:12])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)N(Cc1ccccc1)c1cc(-c2ccc(OC(F)(F)F)cc2)ccc1OCc1ccc(C(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1ccc(COc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2N(Cc2ccccc2)C(=O)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
A mixture of methyl N-benzyl-N-{4-[4-(tert-butyl)benzyloxy]-4′-(trifluoromethoxy)biphenyl-3-yl}oxamate (115 mg, 0.194 mmol), methanol (11.0 ml), 2N aqueous sodium hydroxide (0.2 ml) and tetrahydrofuran (11.0 ml) was stirred at room temperature for 1 hour. The reaction mixture was adjusted to pH 5-6 by addition of 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (ethyl acetate methanol=4:1) to give the title compound (75 mg, 67%) as a white solid.