Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24]OS(C)(=O)=O)=[O:21])([CH3:18])([CH3:17])[CH3:16].O>CN(C=O)C>[C:15]([O:19][C:20](=[O:21])[NH:22][CH2:23][CH2:24][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.2 %

Procedure:
Next, to a solution of 4-fluorophenol (0.47 g, 4.18 mmol) in DMF (10 mL) was added cesium carbonate (2.72 g, 8.36 mmol) at room temperature. The mixture was stirred at ambient temperature for 15 minutes, then methanesulfonic acid 2-(tert-butoxycarbonylamino)ethyl ester (1.00 g, 4.18 mmol) was added. The reaction mixture was stirred at 100° C. for 16 hours. Water was added and the mixture was concentrated in vacuo. Product mixture was dissolved in ethyl acetate and was washed with water, then with brine. The organic layer was dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (ethyl acetate:hexane=7:1 to 4:1), and obtained [2-(4-fluorophenoxy)ethyl]carbamic acid tert-butyl ester as yellow oil (0.61 g, 57.4% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:21])=[C:4]([C:18]([OH:20])=[O:19])[CH:5]=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])=[O:8].S(=O)(=O)(O)O.[OH-].[Na+].[CH2:29](O)[CH2:30][CH3:31]>>[Br:1][C:2]1[C:3]([OH:21])=[C:4]([C:18]([O:20][CH2:29][CH2:30][CH3:31])=[O:19])[CH:5]=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])=[O:8]
Reactant: CCCO
Reactant: O=C(Nc1ccccc1O)c1cc(Br)c(O)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCOC(=O)c1cc(C(=O)Nc2ccccc2O)cc(Br)c1O
Yield: 54.5 %

Procedure:
5-Bromo-3-carboxy-2',4-dihydroxybenzanilide (1.0 g.) described in Example 4 was dissolved in n-propanol (50 ml.), and after adding conc. sulfuric acid (1 ml.) the solution was refluxed for 8 hours. After neutralizing with sodium hydroxide solution, the reaction solution was evaporated to dryness and the residue was washed with 5% sodium bicarbonate solution and recrystallized from aqueous acetone to give 5-bromo-2',4-dihydroxy-3-n-propyloxycarbonylbenzanilide (0.61 g.). Yield: 54.5% Melting point 198°-200° C.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:10][CH:11]=1)[CH3:4].O>CCOCC>[Br:1][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:3][CH3:4])=[CH:7][C:8]=1[C:12]([F:13])([F:14])[F:15]
Reactant: BrBr
Reactant: CCOc1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CCOCC
Product: CCOc1ccc(Br)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
Bromine (18.2 g) was slowly added dropwise to Compound (b) (19.3 g) at room temperature, and then the mixture was stirred at room temperature for 1 hour. Water and ether were added for liquid separation, and the aqueous layer was extracted three times with ether. The organic layers were combined, washed with saturated aqueous sodium bicarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 21.0 g of Compound (c).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C@@H:10]2[CH2:15][CH:14]=[CH:13][CH2:12][C@H:11]2[N+:16]([O-:18])=[O:17])[CH:7]=[CH:6][C:5]=1[O:19][CH3:20])[CH3:2].[OH-].[K+].S(=O)(=O)(O)O>C(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C@@H:10]2[CH2:15][CH:14]=[CH:13][CH2:12][C@@H:11]2[N+:16]([O-:18])=[O:17])[CH:7]=[CH:6][C:5]=1[O:19][CH3:20])[CH3:2]
Reactant: CCOc1cc([C@@H]2CC=CC[C@H]2[N+](=O)[O-])ccc1OC
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cc([C@@H]2CC=CC[C@@H]2[N+](=O)[O-])ccc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
89.25 g of (+/−)-trans-2-ethoxy-1-methoxy-4-(2-nitrocyclohex-4-enyl)benzene (compound D1) and 37 g of potassium hydroxide are dissolved in 500 ml of absolute ethanol. A solution of 23.5 ml of conc. sulfuric acid in 120 ml of absolute ethanol is then added dropwise such that the internal temperature does not exceed −2° C. After stirring for 1 h, the mixture is added to 4 l of ice water, and the precipitate is filtered off with suction, washed with water and dried. M.p. 66-67° C.
Reaction SMILES: [CH:1]([CH:3]1[CH2:5][C:4]1([C:11]#[N:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH2:2].[O:13]([C:20]1[CH:21]=C([CH:25]=[CH:26][CH:27]=1)CO)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH:1]([CH:3]1[CH2:5][C:4]1([C:11]#[N:12])[C:6]([O:8][CH2:9][C:10]1[CH:25]=[CH:26][CH:27]=[C:20]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:21]=1)=[O:7])=[CH2:2]
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: C=CC1CC1(C#N)C(=O)OCC
Product: C=CC1CC1(C#N)C(=O)OCc1cccc(Oc2ccccc2)c1

Procedure:
Utilizing the product prepared in Example I, a transalcoholysis was carried out with 3-phenoxybenzyl alcohol to obtain (3-phenoxy)benzyl 2-vinyl-1-cyanocyclopropane-1-carboxylate. A three-fold molar excess of the ethyl 2-vinyl-1-cyanocyclopropane-1-carboxylate was employed for the reaction. About 0.7 wt. percent calcium acetate, based on the total reactant charge, was used as the catalyst and a small amount of hydroquinone added as an oxidation and polymerization inhibitor. The reaction mixture was heated with agitation to 150° C. and about 4 wt. percent dibutyltin oxide charged. After 5 hours additional heating the reaction was terminated and the resulting product, containing about 35% of the desired (3-phenoxy)benzyl 2-vinyl-1-cyanocyclopropane-1-carboxylate, dissolved in ethyl ether, filtered to remove insoluble catalyst residue, washed with 5% aqueous sodium hydroxide and saturated sodium chloride solutions. After evaporation of the ethyl ether, the product was dissolved in toluene and separated from the unreacted starting materials using a Waters Preparatory Liquid Chromatograph 500A equipped with a gel permeation column and operated at a flow rate of 0.1 l/min. After two passes, 92+% pure (3-phenoxy)benzyl 2-vinyl-1-cyanocyclopropane-1-carboxylate was obtained and the structure of the product confirmed by mass spectroscopy and nuclear magnetic resonance spectroscopy.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:28]=[C:29]([C:33](=[O:38])[C:34]([F:37])([F:36])[F:35])[CH:30]=[CH:31][CH:32]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.ClC1C=C(C(=O)C(F)(F)F)C=CC=1>>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([C:22]2[O:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33](=[O:38])[C:34]([F:37])([F:35])[F:36])[CH:28]=3)=[CH:25][N:26]=2)=[O:8])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(-c2cccc(C(=O)C(F)(F)F)c2)o1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: O=C(c1cccc(Cl)c1)C(F)(F)F
Product: O=C(CCCCCCc1ccccc1)c1ncc(-c2cccc(C(=O)C(F)(F)F)c2)o1
Yield: 87 %

Procedure:
1-(3-(2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)phenyl)-2,2,2-trifluoroethanone. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (37 mg, 0.056 mmol) and 1-(3-chlorophenyl)-2,2,2-trifluoroethanone following General Procedure B. Flash chromatography (5-20% EtOAc/hexanes) yielded the title compound as a clear oil (26 mg, 87%): 1H NMR (CDCl3, 600 MHz) δ 8.31 (s, 1H), 8.01-7.94 (m, 2H), 7.61 (t, 1H, J=7.2 Hz), 7.38 (s, 1H), 7.27-7.24 (m, 2H), 7.16-7.14 (m, 3H), 4.84 (t, 1H, J=6.0 Hz), 2.58 (t, 2H, J=7.5 Hz), 1.95-1.88 (m, 2H), 1.64-1.55 (m, 2H), 1.37-1.34 (m, 6H), 0.90 (s, 9H), 0.10 (s, 3H), 0.00 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 181.0 (d, J=35 Hz), 166.7, 150.2, 143.6, 131.5, 130.7, 130.4, 130.2, 129.2, 129.1, 129.0, 126.4, 126.2, 124.0, 117.7 (d, J=289 Hz), 69.5, 37.2, 36.8, 32.3, 30.0, 26.6, 26.6, 26.0, 19.1, −4.1, −4.2.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[CH:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13].[CH2:22]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31]I)[CH2:27][CH2:26]1)[CH2:23][CH3:24].Cl>CN(C)C=O.CCCCCCC.C1(C)C=CC=CC=1>[F:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:31][C@H:28]3[CH2:29][CH2:30][C@H:25]([CH2:22][CH2:23][CH3:24])[CH2:26][CH2:27]3)=[C:16]([F:21])[CH:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13]
Reactant: CCC[C@H]1CC[C@H](CI)CC1
Reactant: CCCOc1ccc(-c2ccc(O)c(F)c2)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCOc1ccc(-c2ccc(OC[C@H]3CC[C@H](CCC)CC3)c(F)c2)cc1F
Reaction time: 1 h

Procedure:
In a mixture of 0.7 g (60% oiliness, corresponding to 18.2 mmol) of sodium hydride and 5 ml of dimethyl formamide (DMF) was added by drops a solution of 4.0 g (15.1 mmol) of the 3,3′-difluoro-4′-hydroxy-4-propoxybiphenyl obtained in the previous step in 20 ml of DMF at room temperature, and then stirred at the same temperature for 1 hour. Subsequently, a solution of 6.0 g (22.7 mmol) of trans-4-propyl-l-iodomethylcyclohexane in 20 ml of DMF was added by drops to the reaction solution at room temperature, stirred at the same temperature for 1 hour, and then heated to reflux for 3 hours. After finishing of the reaction, the reaction solution was poured into 50 ml of a diluted hydrochloric acid and then extracted with 150 ml of toluene. The organic layer thus obtained was washed with a diluted aqueous sodium hydroxide solution thrice and with water thrice, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure, and the residue thus obtained was subjected to silica gel column chromatography (eluent: heptane/toluene=7/3) to obtain 2.3 g of a crude 3,3′-difluoro-4′-((trans-4-propylcyclohexyl)methoxy)-4-propoxybiphenyl. This product was recrystallized from mixed solvent of ethanol/ethyl acetate (7/3) to obtain 1.8 g of the subject compound. (Yield: 48.2%)
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[C:14]([C:17](=[O:23])[C:18](=[CH2:22])[CH2:19][CH2:20][CH3:21])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][CH2:6]1.O.C(=O)(O)[O-].[Na+:29]>>[Cl:1][C:2]1[C:15]([Cl:16])=[C:14]([C:17](=[O:23])[C:18](=[CH2:22])[CH2:19][CH2:20][CH3:21])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1([C:9]([O-:11])=[O:10])[CH2:8][CH2:7][CH2:6]1.[Na+:29]
Reactant: C=C(CCC)C(=O)c1ccc(OC2(C(=O)O)CCC2)c(Cl)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C=C(CCC)C(=O)c1ccc(OC2(C(=O)[O-])CCC2)c(Cl)c1Cl

Procedure:
200 mg of 1-[2,3-dichloro-4-(2-methylenevaleryl)phenoxy]cyclobutane-1-carboxylic acid is dissolved in 31 ml of 0.1N sodium bicarbonate and sufficient isotonic buffer to make a final volume of 100 ml. The water from all sources was pyrogen free. The solution is sterilized by filtration.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1.[CH:13]([Mg]Br)=[CH2:14]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]2[C:3]=1[CH:13]=[CH:14][NH:10]2
Reactant: COc1ccc(Br)cc1[N+](=O)[O-]
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: COc1ccc(Br)c2cc[nH]c12
Reaction time: 2 h
Yield: 8 %

Procedure:
To a −60° C. solution of 4-bromo-2-nitroanisole (7.89 g, 33.3 mmol) in THF (300 was added vinylmagnesium bromide (1 M in THF, 100 ml, 0.1 mol) while maintaining the reaction temperature below −40° C. The resulting mixture was stirred allowing the temperature to rise to −40° C. in 2 hours. The reaction mixture was then quenched with a saturated solution of NH4Cl (700 ml) and extracted with Et2O (200 ml). The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated, and purified through flash chromatography affording 4-bromo-7-methoxyindole LII (594 mg, 8% yield).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([OH:15])[C:13]#[CH:14]>C(NCC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:15][CH2:12][C:13]#[C:14][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: COC(=O)c1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: COC(=O)c1ccc(C#CCO)cc1
Yield: 83.1 %

Procedure:
Methyl 4-iodobenzoate (9.0 g, 34.4 mmol) was dissolved in 90 ml of diethylamine. The solution was stirred vigorously and, sequentially, 121 milligrams of bis(triphenylphosphine) palladium chloride and 65 milligrams of cuprous iodide were added, each in a single portion, followed by 1.93 grams of propargyl alcohol. The resultant mixture was stirred for about 20 hours at room temperature in an argon atmosphere. At the end of this period, diethylamine was removed by concentration in vacuo. The residue was diluted with 200 ml of water and extracted three times with 100 ml of benzene and 75 ml of ethyl acetate. The organic extracts were combined, dried over Na2SO4, and concentrated in vacuo, yielding a brown solid. This crude residue was purified by flash chromatography. Elution with a 2 to 1 (V:V) mixture of hexane and ethyl acetate yielded 5.44 grams (83% yield) of a pale yellow solid melting at 81° to 82° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:17])=[C:7]([CH2:13][C:14]([OH:16])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[CH3:18]O>OS(O)(=O)=O>[NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:17])=[C:7]([CH2:13][C:14]([O:16][CH3:18])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: CO
Reactant: Cc1c(CC(=O)O)c(=O)oc2cc(N)ccc12
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1c(C)c2ccc(N)cc2oc1=O
Temperature: 120 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
7-Amino-4-methyl-3-coumarinylacetic acid (43.1 mg, 0.18 mmol) was dissolved in MeOH (40 ml). H2SO4 (5 drops) was added, and the reaction mixture was heated to 120° C. and stirred. After 4 hr, the disappearance of the starting materials was confirmed, and the reaction mixture was cooled to room temperature. The reaction mixture was concentrated to ⅓ and the mixture was neutralized with aqueous saturated NaHCO3 solution. The reaction mixture was extracted with BuOH, and the organic layer was concentrated. The residue was purified by silica gel column chromatography (eluate: hexane:EtOAc=1:2) to give the object compound (34.4 mg, 0.14 mmol, 75%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:23][CH2:24][C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[C:30]([C:38]#[N:39])[CH:29]=1)=O)(=[O:22])[CH3:21].C[Si]([N:44]=[N+:45]=[N-:46])(C)C>C1COCC1.CCOC(C)=O>[C:20]([O:23][CH2:24][C:25]1[N:27]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[C:30]([C:38]#[N:39])[CH:29]=2)[N:46]=[N:45][N:44]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OCC(=O)Nc1ccc(C(F)(F)F)c(C#N)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)OCc1nnnn1-c1ccc(C(F)(F)F)c(C#N)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 138.1 %

Procedure:
Triphenylphosphine (2.29 g, 8.73 mmol) and diisopropylazodicorboxylate (1.76 g, 8.70 mmol) were added to a solution of 2-{[3-cyano-4-(trifluoromethyl)phenyl]amino}-2-oxoethyl acetate (Intermediate 38, 1.0 g, 3.49 mmol) in THF (20 mL), at 0° C. The reaction mixture was stirred for 30 min at 0° C. and trimethylsilyl azide (1.01 g, 8.77 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature, and then heated to reflux for 4 h. The reaction mixture was diluted with EtOAc and washed with ice water, followed by saturated brine solution. The organic layer was dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the crude compound. This was purified by column chromatography (100-200 mesh silica gel), eluting with 10%-50% EtOAc/pet.ether, to give the title compound (1.5 g, impure).
Reaction SMILES: C1(C[O:8][CH2:9][CH:10]([O:20][C:21](=[O:77])[CH2:22][CH2:23][C:24]2([CH2:53][CH2:54][C:55]([O:57][CH:58]([CH2:68][O:69]CC3C=CC=CC=3)[CH2:59][O:60]CC3C=CC=CC=3)=[O:56])[CH2:29][C:28](=[O:30])[C:27]3[CH:31]=[CH:32][C:33]([O:38][CH2:39][CH2:40][CH2:41][O:42][C:43]4[C:52]5[CH2:51][CH2:50][CH2:49][CH2:48][C:47]=5[CH:46]=[CH:45][CH:44]=4)=[C:34]([CH2:35][CH2:36][CH3:37])[C:26]=3[O:25]2)[CH2:11][O:12]CC2C=CC=CC=2)C=CC=CC=1.[H][H]>O1CCCC1.[Pd]>[OH:60][CH2:59][CH:58]([O:57][C:55](=[O:56])[CH2:54][CH2:53][C:24]1([CH2:23][CH2:22][C:21]([O:20][CH:10]([CH2:11][OH:12])[CH2:9][OH:8])=[O:77])[CH2:29][C:28](=[O:30])[C:27]2[CH:31]=[CH:32][C:33]([O:38][CH2:39][CH2:40][CH2:41][O:42][C:43]3[C:52]4[CH2:51][CH2:50][CH2:49][CH2:48][C:47]=4[CH:46]=[CH:45][CH:44]=3)=[C:34]([CH2:35][CH2:36][CH3:37])[C:26]=2[O:25]1)[CH2:68][OH:69]
Reactant: [H][H]
Reactant: CCCc1c(OCCCOc2cccc3c2CCCC3)ccc2c1OC(CCC(=O)OC(COCc1ccccc1)COCc1ccccc1)(CCC(=O)OC(COCc1ccccc1)COCc1ccccc1)CC2=O
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCc1c(OCCCOc2cccc3c2CCCC3)ccc2c1OC(CCC(=O)OC(CO)CO)(CCC(=O)OC(CO)CO)CC2=O
Yield: 74 %

Procedure:
The titled product of Example 46 (0.258 g, 0.246 mmol) was dissolved in 25 ml of tetrahydrofuran, and then hydrogenated at room temperature using hydrogen at atmospheric pressure and 10% palladium on carbon (Pd/C) as catalyst. The insolubles were removed by filtration, and the solvent removed under reduced pressure. The residue was chromatographed on silica gel column. Elution with 5% methanol/ethyl acetate afforded 125 mg of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])=[C:12]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C:10]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1>Cl>[CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]([OH:18])=[O:17])=[C:12]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:11]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[C:10]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(OCC(=O)OC(C)(C)C)c(OCc2ccccc2)c(C(=O)OCC)n1-c1ccc(OC)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1c(OCC(=O)O)c(OCc2ccccc2)c(C(=O)OCC)n1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
Diethyl 3-(benzyloxy)-4-(2-(tert-butoxy)-2-oxoethoxy)-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxylate (UL2-028) (250 mg, 0.45 mmol) was dissolved in 4 M HCl in dioxane (2.5 mL, 10.0 mmol), and the reaction mixture was stirred at RT for 2 h, volatiles were removed in vacuo and the product was azeotroped with toluene (2×5 mL) to afford 2-((4-(benzyloxy)-2,5-bis(ethoxycarbonyl)-1-(4-methoxyphenyl)-1H-pyrrol-3-yl)oxy)acetic acid (24) (216 mg, 87%) as a yellow oil: m/z 498 (M+H)+ (ES+); 496 (M−H)− (ES−).
Reaction SMILES: Cl.[Cl-].[NH2:3][C@H:4]1[CH2:9][CH2:8][CH2:7][N+:6]([CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH:29]=2)([CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:14]=2)[CH2:5]1.[NH2:40][C:41]1[C:42]([C:49](O)=[O:50])=[N:43][C:44]([Cl:48])=[C:45]([NH2:47])[N:46]=1.C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl-:48].[NH2:40][C:41]1[C:42]([C:49]([NH:3][C@H:4]2[CH2:9][CH2:8][CH2:7][N+:6]([CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH:29]=3)([CH2:10][CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:14]=3)[CH2:5]2)=[O:50])=[N:43][C:44]([Cl:48])=[C:45]([NH2:47])[N:46]=1
Reactant: COC(=O)COc1cccc(CCC[N+]2(CCCc3cccc(OCC(=O)OC)c3)CCC[C@H](N)C2)c1
Reactant: Nc1nc(N)c(C(=O)O)nc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc(CCC[N+]2(CCCc3cccc(OCC(=O)OC)c3)CCC[C@H](NC(=O)c3nc(Cl)c(N)nc3N)C2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-3-Amino-1,1-bis-[3-(3-methoxycarbonylmethoxy-phenyl)-propyl]-piperidinium chloride hydrochloride (60 mg, 0.1 mmol), 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid (22 mg, 0.115 mmol) and N,N-Diisopropylethylamine (75 μl, 0.43 mmol) are dissolved in N,N-dimethylformamide (2 ml), 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (34 mg, 0.106 mmol) is added. The reaction is stirred at room temperature overnight and purified by preparative HPLC-MS (MeOH/H2O+0.1% TFA). LC (method L): tR=1.15 min; Mass spectrum (ESI+): m/z=683 [M]+. IC50=0.025 μM
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[N+:7]([C:10]1[CH:18]=[CH:17]C(C(O)=O)=[CH:12][CH:11]=1)([O-:9])=[O:8]>C(Cl)(Cl)Cl.CN(C=O)C>[N+:7]([C:10]1[CH:18]=[CH:17][C:1]([C:2]([Cl:4])=[O:3])=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.3 %

Procedure:
Oxalyl chloride (4.78 g, 37.6 mmol) was added drop wise to a stirred solution of 4-nitrobenzoic acid (4.2 g, 25 mmol) in chloroform (50 mL). After 5 mins DMF (2 drops) was added and the resulting mixture was stirred at room temperature for 2 hours. The solvent was removed to afford 4.7 g (98%) of 4-nitro-benzoyl chloride which was used for next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][NH:13][CH2:12][CH:11]([NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10]1.[N:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(N(CC)CC)C.O>ClCCl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][N:13]([C:30]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:31])[CH2:12][CH:11]([NH:15][C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:23])[CH2:10]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Cc1cccc(C2CNCC(NC(=O)c3ccccc3)C2)c1C
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(C2CC(NC(=O)c3ccccc3)CN(C(=O)N3CCOCC3)C2)c1C
Temperature: 25 °C

Procedure:
At 0° C., 80 mg (0.26 mmol) of N-[5-(2,3-dimethylphenyl)piperidin-3-yl]benzamide were initially charged in 1.5 ml of dichloromethane, and 78 mg (0.52 mmol) of morpholine-4-carbonyl chloride and 55 μl (0.39 mmol) of triethylamine were added. The mixture was slowly warmed to RT overnight. Water was added, and the reaction mixture was extracted. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The residue was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 75 mg (69% of theory)
Reaction SMILES: [CH2:1]([CH2:5][C:6](=O)[CH3:7])[C:2]([CH3:4])=O.[CH3:9][O:10][C:11]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=1[NH2:13]>>[CH3:9][O:10][C:11]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=1[N:13]1[C:6]([CH3:7])=[CH:5][CH:1]=[C:2]1[CH3:4]
Reactant: COc1ccc(N)c(OC)c1
Reactant: CC(=O)CCC(C)=O
Product: COc1ccc(-n2c(C)ccc2C)c(OC)c1

Procedure:
Utilizing the general procedure outlined in EXAMPLE 1, acetonyl acetone (5.88 mL, 50 mmol) and 2,4-dimethoxyaniline (7.12 mL, 50 mmol) reacted to give 1-(2,4-dimethoxyphenyl)-2,5-dimethylpyrrole as a tan solid: 1H NMR (CDCl3, 500 MHz) δ 7.08 (dd, 1H), 6.59 (d, 1H), 6.55 (dd, 1H), 5.90 (s, 2H), 3.91 (s, 3H), 3.80 (s, 3H), 1.97 (s, 6H); MS (ESI) 232 (M+H)+.