Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][O:8][C:9]([C:11]2[N:16]3[C:17](=[O:29])[C@@H:18]([NH:19][C:20](=[O:28])[CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:15]3[S:14][CH2:13][C:12]=2[CH2:30]Cl)=[O:10])=[CH:5][CH:4]=1.[I-].[Na+].[C:36]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:55]([O:58][C:59]1[C:66]([O:67][C:68](=[O:70])[CH3:69])=[CH:65][CH:64]=[CH:63][C:60]=1C=O)(=[O:57])[CH3:56].C(=O)(O)[O-].[Na+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][O:8][C:9]([C:11]2[N:16]3[C:17](=[O:29])[C@@H:18]([NH:19][C:20](=[O:28])[CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:15]3[S:14][CH2:13][C:12]=2[CH:30]=[CH:36][C:63]2[CH:64]=[CH:65][C:66]([O:67][C:68](=[O:70])[CH3:69])=[C:59]([O:58][C:55](=[O:57])[CH3:56])[CH:60]=2)=[O:10])=[CH:5][CH:4]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Reactant: CC(=O)Oc1cccc(C=O)c1OC(C)=O
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C2=C(C=Cc3ccc(OC(C)=O)c(OC(C)=O)c3)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Reaction time: 1 h
Yield: 45.5 %

Procedure:
To a solution (20 ml) in acetone of 2.6004 g of (6R, 7R)-7-phenylacetamido-3-chloromethylceph-3-em-4-carboxylic acid p-methoxybenzyl ester were dissolved 0.787 g of sodium iodide and 1.377 g of triphenylphosphine and the mixture was stirred for 1 hour. The reaction mixture was concentrated under a reduced pressure, and 25 ml of methylene chloride and 25 ml of water were added to the residue to form two layers. To the reaction mixture, 5.555 g of 2,3-diacetoxybenzaldehyde and 1.47 g of sodium bicarbonate were added and the mixture was stirred for 14 hours at room temperature. The resulting dichloromethane layer was separated, concentrated under a reduced pressure, and was then purified by flash column chromatography using Wako Gel C-300 (300 g, Wako Junyaku KK) (eluent, benzene:ethyl acetate=5:1). The product, (6R,7R)-7-phenylacetamido-3-[2-(3,4-diacetoxyphenyl)vinyl]ceph-3-em-4-carboxylic acid p-methoxybenzyl ester (1.570 g, cis isomer) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[O:10][C@@H:11]([CH3:14])[CH2:12][OH:13])[N:5]=[C:4]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:3]=1.[OH-].[Na+].Cl[C:25]([O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[O:26]>CCOC(C)=O.O>[Cl:30][C:29]([Cl:32])([Cl:31])[CH2:28][O:27][C:25](=[O:26])[NH:1][C:2]1[N:6]([C:7]2[CH:17]=[CH:16][CH:15]=[C:9]([O:10][C@@H:11]([CH3:14])[CH2:12][OH:13])[CH:8]=2)[N:5]=[C:4]([C:18]([CH3:20])([CH3:19])[CH3:21])[CH:3]=1
Reactant: C[C@@H](CO)Oc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](CO)Oc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 108.5 %

Procedure:
A solution of Intermediate 152b (69 mg, 0.24 mmol) in EtOAc (1.2 mL) was treated with aqueous 1N NaOH (0.4 mL, 0.43 mmol) then 2,2,2-trichloroethyl chloroformate (0.034 mL, 0.25 mmol) and the mixture was stirred at RT for 2.5 h. The mixture was treated with another portion of 2,2,2-trichloroethyl chloroformate (0.010 mL, 0.07 mmol) and stirred at RT for a further 0.75 h. The mixture was diluted with EtOAc and water and the phases were separated. The aqueous layer was extracted with EtOAc (×2) and the combined organic phase was washed with brine, dried (Na2SO4), and concentrated in vacuo to give a pale red gum (121 mg). The gum was purified by FCC, using 0-40% EtOAc in cyclohexane, to give the title compound as a pale golden gum (62 mg, 56%). LCMS (Method 3): Rt 4.15 min, m/z 464.2, 466.2 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:14]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:12]=[C:11](OS(C(F)(F)F)(=O)=O)[CH:10]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[C:37]([F:39])[CH:38]=1.C([O-])([O-])=O.[K+].[K+].CO[CH2:51][CH2:52]OC>CCOC(C)=O.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>[CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:10]=[C:11]([C:52]2[CH:51]=[C:37]([F:39])[CH:38]=[C:33]([F:32])[CH:34]=2)[CH:12]=[C:13]([C:35]2[CH:34]=[C:33]([F:32])[CH:38]=[C:37]([F:39])[CH:36]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: COCCOC
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(OS(=O)(=O)C(F)(F)F)c1
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: [K+]
Solvent: CCOC(C)=O
Product: COC(=O)C(CC(C)C)c1cc(-c2cc(F)cc(F)c2)cc(-c2cc(F)cc(F)c2)c1
Temperature: 95 °C

Procedure:
A mixture of 2-(3,5-bis-trifluoromethanesulfonyloxy-phenyl)-4-methyl-pentanoic acid methyl ester (104 mg, 0.21 mmol), 3,5-difluorophenylboronic acid (82 mg, 0.52 mmol), K2CO3 solution (2M, 310 μL) and DME (2 mL) was purged with N2 three times before adding Pd(PPh3)4 (10 mg, 0.01 mmol). The mixture was heated at 95° C. overnight (followed by HPLC). The reaction was diluted with EtOAc (5 mL) and then washed successively with NaHCO3 solution and brine. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give the title compound as an oil. The residue was purified by flash chromatography (0-15% EtOAc in Petroleum ether) to give the title compound (75 mg, 84%) as a yellow oil.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].C1COCC1.Cl[C:13]([O:15][CH3:16])=[O:14]>C(=O)([O-])[O-].[Na+].[Na+]>[CH3:16][O:15][C:13]([NH:1][C@@H:2]([CH3:3])[C:4]([OH:6])=[O:5])=[O:14]
Reactant: COC(=O)Cl
Reactant: C[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N[C@@H](C)C(=O)O
Reaction time: 4.5 h

Procedure:
L-Alanine (2.0 g, 22.5 mmol) was dissolved in 10% aqueous sodium carbonate solution (50 mL), and a THF (50 mL) solution of methyl chloroformate (4.0 mL) was added to it. The reaction mixture was stirred under ambient conditions for 4.5 hours and concentrated in vacuo. The resulting white solid was dissolved in water and acidified with 1N HCl to a pH ˜2-3. The resulting solutions was extracted with ethyl acetate (3×100 mL), and the combined organic phase was dried (Na2SO4), filtered, and concentrated in vacuo to provide a colorless oil (2.58 g). 500 mg of this material was purified by a reverse phase HPLC (H2O/methanol/TFA) to provide 150 mg of Cap-12 as a colorless oil. 1H NMR (DMSO-d6, δ=2.5, 500 MHz) 7.44 (d, J=7.3, 0.8H), 7.10 (br s, 0.2H), 3.97 (m, 1H), 3.53 (s, 3H), 1.25 (d, J=7.3, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5](CBr)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:19]=[CH:18][C:14](C(Cl)=O)=[CH:13][CH:12]=1.[CH2:20]([CH2:23][O:24]C)OC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Zn]>[Cl:10][C:11]1[CH:19]=[CH:18][CH:14]=[CH:13][C:12]=1[CH2:20][C:23]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=1)=[O:24]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Clc1ccc(CBr)cc1
Reactant: COCCOC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Zn]
Product: O=C(Cc1ccccc1Cl)c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 91 %

Procedure:
To dimethoxyethane (100 mL) were added 4-chlorobenzyl bromide (4.1 g), 4-chlorobenzoyl chloride (2.56 mL), bis(triphenylphosphine)palladium dichloride (702 mg) and zinc powder (2.6 g), and the mixture was stirred for 2 hours under nitrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated in vacuo and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo, and the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=49/1 to 9/1) to give (2-chlorobenzyl)(4-chlorophenyl)-methanone (4.85 g, yield: 91%) as a powder.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+]>C1COCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCCCCCCCCCBr
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: BrCCCCCCCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution containing 2.00 g (8.96 mmol) of 9-bromo-1-nonanol in 20 mL of anhydrous THF were added 1.55 mL (12.60 mmol) of benzyl bromide followed by 677 mg (16.94 mmol) of a 60% suspension of NaH in mineral oil. The reaction mixture was stirred overnight under argon atmosphere at room temperature. The reaction mixture was carefully quenched with saturated aqueous sodium bicarbonate. The mixture was poured into 100 nit of water and extracted with two portions of 100 mL of ether. The combined organic solution was washed with a portion of 100 mL of brine, dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with hexanes and then with hexanes-ethyl acetate 4:1 gave the expected product as colorless oil: yield 2.54 g (90%). 1H-NMR (CDCl3) δ 7.86 (m, 5H), 4.51 (s, 2H), 3.47 (t, 2H, J=6.4), 3.40 (t, 2H, J=6.8), 1.85 (m, 2H), 1.62 (m, 2H), 1.39 (m, 10H); 13C-NMR (CDCl3) δ 138.70, 128.34, 127.62, 127.47, 72.86, 70.46, 34.02, 32.83, 29.76, 29.38, 29.36, 28.71, 28.15, 28.16
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:27])[CH2:10][N:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[N:13]=[C:12]1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)C.[OH-].[K+]>C(O)C>[OH2:3].[Cl:26][C:22]1[CH:21]=[C:20]([C:12]2[N:11]([CH2:10][C:9]([NH:8][CH2:7][CH2:6][CH2:5][C:4]([OH:28])=[O:3])=[O:27])[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[N:13]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)CCCNC(=O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O
Product: O=C(O)CCCNC(=O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21

Procedure:
A mixture of 4-[[(2-(3-chlorophenyl)-3H-imidazo[4,5-b] pyridine-3-yl]acetyl]amino]butanoic acid ethyl ester (2.4 g, 0.006 mole) and potassium hydroxide (0.5 g) in 100 ml of ethanol was heated at reflux for 2 hrs. The reaction mixture was evaporated to dryness. The residue was dissolved in water, filtered, and the filtrate was acidified with acetic acid. The precipitate, which had formed, was collected by filtration, washed with water, and dried. The solid was recrystallized from ethanol-water, collected by filtration, washed with water, and dried under high vacuum at 78° C. over 2 days to give 0.93 g (42%), mp 207°-8° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[CH3:10][CH:11]([NH2:14])[CH2:12][OH:13].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CC(O)=O>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:14][CH:11]([CH3:10])[CH2:12][OH:13])[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: CC(N)CO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(CO)NCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 56 h

Procedure:
To a stirred solution of the (6-bromo-2-pyridyl)-formaldehyde (0.52 g, 2.8 mmol) in toluene (14 mL) was added DL-2-amino-1-propanol (0.67 mL). The resulting mixture was heated to reflux with a Dean-Stark trap for 3 h under N2 until complete formation of the imine was observed. The mixture was brought to RT followed by the addition of a solution of NaBH(OAc)3 (2.0 g, 9.8 mmol) in AcOH (6 mL). The resulting mixture was stirred at RT and under N2 for 56 h. The mixture was neutralized (pH 7.0) with a saturated solution of NaHCO3 (aq) and extracted with CH2Cl2 (3×50 mL). The aqueous layer was concentrated by rotary evaporation and the residue obtained was extracted with CH2Cl2 (3×50 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated by rotary evaporation to afford the title compound as a pale yellow oil. EI-MS m/z 245 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[N:10]=[C:11]=S.[NH:13]([C:15](=[O:38])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([C@H:25]2[CH2:30][CH2:29][C@H:28]([C:31]([CH3:37])([CH3:36])[C:32]([O:34][CH3:35])=[O:33])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)=[O:17])[NH2:14].CCN=C=NCCCN(C)C>CC(N(C)C)=O.O>[CH3:37][C:31]([C@H:28]1[CH2:27][CH2:26][C@H:25]([C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:16]([C:15]3[O:38][C:11]([NH:10][C:3]4[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=4[F:1])=[N:14][N:13]=3)=[O:17])=[CH:24][CH:23]=2)[CH2:30][CH2:29]1)([CH3:36])[C:32]([O:34][CH3:35])=[O:33]
Reactant: COC(=O)C(C)(C)[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Reactant: Fc1cc(F)c(N=C=S)cc1F
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)C(C)(C)[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4cc(F)c(F)cc4F)o3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,4,5-trifluorophenyl isothiocyanate (183 mg, 0.96 mmol) in DMA (1 mL) was added in one portion to a suspension of methyl 2-[trans-4-(4-{[hydrazino(oxo)acetyl]amino}-phenyl)cyclohexyl]-2-methylpropanoate (Intermediate 105, 290 mg, 0.80 mmol) in DMA (3 mL) and the reaction mixture was stirred at room temperature for 1 h 30 mins. EDCI (230 mg, 1.20 mmol) was added in one portion and the reaction mixture was heated to 90° C. for 10 mins in the microwave. The mixture was then cooled to room temperature, poured into H2O (20 mL) and stirred for 5 mins. The mixture was centrifuged and the aqueous layer decanted off to leave a solid residue. The solid residue was taken up in H2O (5 mL), stirred for 5 mins and then centrifuged and the aqueous layer decanted off to leave a solid residue. H2O (5 mL) was added and the mixture was filtered to give the title compound (398 mg, 96%) as a solid; 1H NMR δ 1.1 (6H, s), 1.12-1.26 (2H, m), 1.36-1.5 (2H, m), 1.57-1.7 (3H, m), 1.78-1.89 (2H, m), 2.39-2.49 (1H, m), 3.6 (3H, s), 7.2 (2H, d), 7.65-7.78 (1H, m), 7.68 (2H, d), 8.12-8.24 (1H, m), 11.0 (1H, s), 11.1 (1H, s); MS m/e MH+ 517.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:19])[NH2:18])=O)C1C=CC=CC=1.[CH2:23]([S:26]([Cl:29])(=[O:28])=[O:27])[CH2:24][CH3:25].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[ClH:29].[NH:19]=[C:17]([NH:18][S:26]([CH2:23][CH2:24][CH3:25])(=[O:28])=[O:27])[NH:16][CH2:15][CH2:14][CH2:13][C@@H:12]([C:20]([N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:22])[NH2:11]
Reactant: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCCS(=O)(=O)Cl
Reactant: C1CCNC1
Product: CCCS(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)N1CCCC1
Product: Cl

Procedure:
Starting from (S)-N2-(benzyloxycarbonyl)-arginine, propanesulphonyl chloride and pyrrolidine, the expected product is obtained according to the procedure described in Example 1.
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:14]3[NH:13][C:12]4[CH:17]([CH2:20][C:21]([O:23]CC)=[O:22])[CH2:18][CH2:19][C:11]=4[C:10]=3[CH:9]=2)=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].[Br-].[CH:33]1([Zn+])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.O.O[Li].O>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CO>[CH:33]1([C:2]2[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]3[CH:16]=[CH:15][C:14]4[NH:13][C:12]5[CH:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:18][CH2:19][C:11]=5[C:10]=4[CH:9]=3)=[CH:4][C:3]=2[C:28]([F:29])([F:31])[F:30])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: [Zn+]C1CCCCC1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(Cl)c(C(F)(F)F)c3)cc21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Agent: [Li]O
Solvent: O
Solvent: CO
Product: O=C(O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C4CCCCC4)c(C(F)(F)F)c3)cc21
Yield: 27.5 %

Procedure:
A mixture of ethyl 2-(7-(4-chloro-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (50 mg, 0.111 mmol), 0.5 M cyclohexylzinc(II) bromide (0.5 M in THF, 3 mL, 1.5 mmol), and bis(tri-t-butylphosphine)palladium (3 mg, 5.87 μmol) were stirred under reflux for 18 h. The mixture was allowed to cool to room temperature before water (1 mL), MeOH (1 mL) and LiOH hydrate (70 mg, 1.668 mmol) were added. The mixture was stirred at room temperature for 2 h. The mixture was purified by HPLC. Fractions containing product were basified with 1 M NaHCO3 and partially concentrated. The residue was extracted with 0.5 M citric acid and CH2Cl2. The organics were dried over MgSO4, filtered and concentrated to give the title compound as a tanned sticky solid (14.4 mg). LCMS m/z=472.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.38-1.50 (m, 4H), 1.76-1.85 (m, 6H), 2.11-2.17 (m, 1H), 2.58-2.65 (m, 1H), 2.75-2.93 (m, 5H), 3.56-3.60 (m, 1H), 5.07 (s, 2H), 6.84 (dd, J=8.8, 2.5 Hz, 1H), 7.00 (d, J=2.4 Hz, 1H), 7.21 (d, J=8.8 Hz, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.59 (d, J=8.1 Hz, 1H), 7.70 (d, J=1.2 Hz, 1H), 8.27 (s, 1H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[CH2:18][O:19][C:20]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=5)=[CH:23][C:21]=4[CH:22]=3)=[O:16])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[I:35].[C:36](OCC)(=O)C>CN(C=O)C>[I-:35].[CH3:33][C:30]1[CH:29]=[CH:28][C:27]([C:24]2[CH:25]=[CH:26][C:20]3[O:19][CH2:18][C:17]([C:15]([NH:14][C:11]4[CH:12]=[CH:13][C:8]([CH2:7][N+:1]5([CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)=[CH:9][CH:10]=4)=[O:16])=[CH:22][C:21]=3[CH:23]=2)=[CH:32][CH:31]=1
Reactant: CCOC(C)=O
Reactant: CI
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCCCC4)cc2)CO3)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C[N+]4(C)CCCCC4)cc2)CO3)cc1
Product: [I-]
Reaction time: 20 h

Procedure:
To a solution of N-[4—(1-piperidinylmethyl)phenyl)-6—(4-methylphenyl)-2H-1-benzopyran-3-carboxamide (200 mg) in DMF (3 ml) was added methyl iodide (0.1 ml) at room temperature, and the mixture was stirred for 20 hours. To the mixture was added ethyl acetate. Precipitated crystal was collected by filtration and recrystallized from chloroform-ethanol to give 1-[4-[N-[6—(4-methylphenyl)-2H-1-benzopyran-3-carbonyl]-amino]benzyl]-1-methylpiperidinium iodide (Compound 198) (188 mg) as yellow crystals.
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1.[Li].C(O[C:12](=[O:18])[CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])C.O>C(OCC)C>[CH3:17][N:15]([CH2:14][CH2:13][C:12]([C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1)([C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1)[OH:18])[CH3:16]
Reactant: ClC1=CCCCC1
Reactant: CCOC(=O)CCN(C)C
Agent: [Li]
Solvent: O
Solvent: CCOCC
Product: CN(C)CCC(O)(C1=CCCCC1)C1=CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-chloro-1-cyclohexene (5.8 g; 0.049 mol) was added to lithium (1.1 g; 0.049 mol) in diethyl ether (50 ml) in a single portion. After stirring overnight at room temperature, stirring was continued for 7 more hours with reflux. After cooling, ethyl-3-(N,N-dimethylamino)propionate (3.0 g; 0.021 mol) was added and as a result of the exothermic reaction refluxing occurred. After cooling to room temperature and stirring for another 30 minutes 100 ml of water was added. The water layer was separated off and extracted with diethyl ether. The combined ether layer was dried (K2CO3), filtered and evaporated. The yield was 4.5 g (83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:27][CH2:28][CH2:29][CH2:30]O)[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.[CH2:32]([N:34]([CH2:37]C)[CH2:35][CH3:36])[CH3:33].CS(Cl)(=O)=O.[Cl-].[NH4+:45]>O.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:27][CH2:28][CH2:29][CH2:30][N:45]5[CH2:36][CH2:35][N:34]([CH3:37])[CH2:32][CH2:33]5)[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: CCN(CC)CC
Reactant: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2cc1OCCCO
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2cc1OCCCN1CCN(C)CC1
Reaction time: 1 h

Procedure:
To a mixture of 0.067 g (0.15 mmole) of 4-(3-chloro-phenyl)-2-[6-(3-hydroxy-propoxy)-5-methoxy-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.42a), 0.036 g (0.36 mmole) of triethylamine and 2 mL of dimethylformamide at 0 degrees was added, 0.020 g (0.18 mmole) of methanesulfonyl chloride. The mixture was stirred for 1 hour and then 1 mL of saturated ammonium chloride solution was added dropwise. The mixture was poured into 25 mL of water and extracted three times with 20 mL of ethyl acetate. The combined organic extracts were washed three times with 25 mL of water, once with 25 mL of saturated sodium bicarbonate solution, once with 25 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was heated at 80 degrees for 1 hour with 2 mL of dimethylformamide and 0.080 mL of N-methylpiperazine. The mixture was cooled, poured into 25 mL of water extracted three times with 20 mL of ethyl acetate. The combined organic extracts were washed three times with 25 mL of water, once with 25 mL of saturated sodium bicarbonate solution, once with 25 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (25:75) to give 0.026 g of 4-(3-chloro-phenyl)-2-{5-methoxy-6-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzoimidazol-1-yl}thiazole-5-carboxylic acid amide (I.42) as a pink solid. MH+/Z=541
Reaction SMILES: [OH-].[Na+].CO.[C:5]([NH:13][C:14]1[CH:23]=[C:22](/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18]C)=[O:17])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O1CCCC1>[C:5]([NH:13][C:14]1[CH:23]=[C:22](/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:15]=1[C:16]([OH:18])=[O:17])(=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(/C=C/c2ccccc2)cc1NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1cc(/C=C/c2ccccc2)ccc1C(=O)O)c1ccccc1
Reaction time: 7 h

Procedure:
0.37 mL of 2.0 mol/L aqueous sodium hydroxide was added dropwise to a mixed solution of 2 mL of methanol and 2 mL of tetrahydrofuran containing 0.18 g of methyl 2-(benzamido)-4-((E)-2-phenylvinyl)benzoate at room temperature, and stirred at the same temperature for 7 hours. The solvent was evaporated under reduced pressure and water was added and pH was adjusted to pH 4.0 with 1.0 mol/L hydrochloric acid. Solid substances were separated by filtration and purified with silica gel column chromatography [eluent; hexane:ethyl acetate=2:1] to obtain 65 mg of 2-(benzamido)-4-((E)-2-phenylvinyl)benzoic acid as white solid.