Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3](=O)[CH3:4].[C:6]([SiH2:10][O:11][C:12]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:13]1[N:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=1)([CH3:9])([CH3:8])[CH3:7].C([O-])(O)=O.[Na+]>COCCOC.S1(CCCC1)(=O)=O>[C:6]([SiH2:10][O:11][C:12]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:13]1[N:14]=[CH:15][C:16]2[N:17]([CH:2]=[C:3]([CH3:4])[N:19]=2)[CH:18]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)c1cnc(N)cn1
Reactant: CC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O=S1(=O)CCCC1
Product: Cc1cn2cc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)ncc2n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
Bromoacetone (4.3 g, 31.4 mmol, 2.9 equiv) is added to a solution of 5-(tert-butyl-diphenyl-silanyloxymethyl)-pyrazin-2-ylamine (4.0 g, 10.7 mmol) in 1,2-dimethoxyethane (20 ml) and sulfolane (20 ml). The reaction mixture is stirred overnight at 50° C. Then a 10% aqueous solution of NaHCO3 (30 ml) is added, and the mixture is heated to reflux for 1 hour. After cooling, the mixture is extracted three times with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (hexane/EtOAc 3:1) affords the title compound (1.7 g, 40%). 1H NMR (400 MHz, d6-DMSO): δ=8.78 (d, J=0.9 Hz, 1H), 8.43 (d, J=1.4 Hz, 1H), 7.92 (s, 1H), 7.63-7.61 (m, 4H); 7.41-7.35 (m, 6H), 4.72 (s, 2H), 2.34 (s, 3H), 1.00 (s, 9H). MS (ES+): 402 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:7]([C:8](O)=[O:9])[CH:6]=1)[CH3:2].[CH3:17][NH:18]CCC.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:7]([C:8]([NH:18][CH3:17])=[O:9])[CH:6]=1)[CH3:2]
Reactant: CCCNC
Reactant: CCOC(=O)c1cc(CO)cc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(CO)cc(C(=O)NC)c1
Yield: 47.7 %

Procedure:
Stir a solution of 5-hydroxymethyl-isophthalic acid monoethyl ester (1.9 g, 8.4 mmol), N-methylpropylamine (947 μl, 9.2 mmol), 1-hydroxybenzotriazole (1.24 g, 9.2 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.77 g, 9.2 mmol) in a mixture of dichloromethane (12 mL) and DMF (12 mL) at room temperature for 1.5 h. Concentrate and purify (silica gel chromatography, eluting with 50:50 ethyl acetate:hexanes) to give the title compound (950 mg, 40% yield).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[NH:27])[NH:25][OH:26])[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[C:28](Cl)(=O)[CH2:29][CH3:30]>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:27]=[C:28]([CH2:29][CH3:30])[O:26][N:25]=3)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: N=C(NO)N1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: CCC(=O)Cl
Product: CCc1nc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)no1

Procedure:
The title compound is prepared from N-cyclopropyl-N-[1-(N-hydroxycarbamimidoyl)-piperidin-4-yl]-4-oxazol-5-yl-benzamide and propionyl chloride following a procedure analogous to that described in Example 47. LC (method 3): tR=1.83 min; Mass spectrum (ESI+): m/z=408 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=2)[CH2:6][CH2:5][N:4]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:3]1.[H-].[Na+].[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32](F)[CH:31]=1.O>CN(C)C=O>[Cl:29][C:30]1[CH:31]=[C:32]([CH:33]=[CH:34][CH:35]=1)[O:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=2)[CH2:6][CH2:5][N:4]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:3]1
Reactant: Fc1cccc(Cl)c1
Reactant: Cc1ccc(O[C@@H]2CCN(C(=O)OCc3ccccc3)C[C@H]2O)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(O[C@@H]2CCN(C(=O)OCc3ccccc3)C[C@H]2Oc2cccc(Cl)c2)cc1C
Reaction time: 2 h

Procedure:
A solution of 15.0 g (0.04 mol) of the trans-3-hydroxy-4-(3,4-dimethyl-phenoxy)-1-carbobenzyloxy-piperidine described in Example 19 in 100 ml of dimethylformamide is introduced in the course of 30 minutes, at 30°-35°, into a suspension of 2.8 g (0.062 mol) of a 55% strength oily dispersion of sodium hydride in 50 ml of dimethylformamide. The mixture is then warmed to 50° and treated dropwise with 7.16 g (0.055 mol) of 1-chloro-3-fluorobenzene. The reaction mixture is subsequently stirred for 41/2 hours at 60°-70° and then for 15 hours at room temperature, cooled in an ice-water bath and treated with 250 ml of water. The mixture is extracted by shaking with 3 times 250 ml of ethyl acetate and the combined organic phases are washed twice with water, dried over magnesium sulphate and evaporated to dryness, first under a water pump vacuum and then under a high vacuum. The oil which remains behind is dissolved in 100 ml of toluene and the solution is filtered through a layer of silica gel. Elution with a toluene/ethyl acetate mixture (4:1) gives trans-3-(3-chlorophenoxy)-4-(3,4-dimethylphenoxy)-1-carbobenzyloxy-piperidine in the form of a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:16](=O)[CH3:17])[C:12]([O:14][CH3:15])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:20][O:21][C:22]1[CH:32]=[CH:31][C:25]([CH2:26][S:27][C:28](=[NH:30])[NH2:29])=[CH:24][CH:23]=1.C([O-])(=O)C.[Na+].C(OCC)(=O)C>CN(C)C=O>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][S:27][C:28]2[NH:30][C:16]([CH3:17])=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[N:29]=2)=[CH:31][CH:32]=1
Reactant: COc1ccc(CSC(=N)N)cc1
Reactant: COC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(C)NC(SCc2ccc(OC)cc2)=NC1c1cccc([N+](=O)[O-])c1
Temperature: 65 °C
Yield: 79.5 %

Procedure:
A solution of 2-[(3-nitrophenyl)methylene]-3-oxobutanoic acid, methyl ester (5.0 g, 0.02 mole) in 20 ml of dimethylformamide under argon at room temperature was treated with S-(4-methoxybenzyl)thiopseudourea, hydrochloride (4.65 g, 0.02 mole) and sodium acetate (1.64 g, 0.02 mole). The mixture was then heated at 65±5° C. for 3 hours. Upon cooling, ethyl acetate was added and a small amount of solids were filtered. The filtrate was washed with water (twice), aqueous sodium bicarbonate and saturated brine. The aqueous washes were extracted with fresh ethyl acetate. The combined filtrate and washings were dried (magnesium sulfate) and concentrated in vacuo to give about 9 g of crude product. Crystallization from acetone-isopropyl ether gave 6.8 g of product, melting point 125°-127.5° C., tlc, silica gel, ethyl acetate/hexane (1:1), Rf =0.48.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4](=[N+:12]=[N-:13])[C:5](=[O:11])[CH2:6][C:7](OC)=[O:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>C(OCC)C>[CH3:1][O:2][C:3]([C:4]1[N:12]=[N:13][C:7]([OH:8])=[CH:6][C:5]=1[OH:11])=[O:14]
Reactant: COC(=O)CC(=O)C(=[N+]=[N-])C(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)c1nnc(O)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.1 %

Procedure:
A mixture of 2-diazo-3-oxo-pentanedioic acid dimethyl ester (50.0 g, 249.8 mmol) and triphenylphosphine (65.5 g, 249.8 mmol) in diethyl ether (500 mL) was stirred at room temperature for 24 h. The organic solvent was removed under vacuum and then acetic acid (500 mL) and water (50 mL) were added to the residue and the mixture was refluxed for 10 h. The reaction mixture was concentrated under reduced pressure to obtain a viscous residue. Trituration with ethyl acetate generated a yellow solid that was purified by chromatography (silica, 100-200 mesh, 1-5% methanol in dichloromethane) to give 4,6-dihydroxy-pyridazine-3-carboxylic acid methyl ester (12.8 g, 30%) as a yellow solid. LC-MS 169.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][CH:24]([CH2:26]OS(C)(=O)=O)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[N-:33]=[N+:34]=[N-:35].[Na+]>CC(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][CH:24]([CH2:26][N:33]=[N+:34]=[N-:35])[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:10][CH2:9]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CC(COS(C)(=O)=O)OC3=O)cc2F)CC1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CC(CN=[N+]=[N-])OC3=O)cc2F)CC1
Yield: 91.6 %

Procedure:
A solution of 440 mg (0.93 mmol) of mesylate 10 in 22 mL acetone was treated with a solution of 604 mg (9.29 mmol) of sodium azide in 6.4 mL water. The mixture was warmed at reflux for 18 hours. The mixture was cooled and a solution of 600 mg of sodium azide in 6 mL water was added followed by warming at reflux for an additional 18 hours. The mixture was cooled and a solution of 1.2 g of sodium azide in 12 mL water was added followed by warming at reflux for 24 hours. The mixture was cooled and diluted with 60 mL water and extracted with ethyl acetate (3×75). The combined organic layers were extracted with 100 mL saturated NaCl solution followed by drying (Na2SO4). Concentration in vacuo afforded 358 mg (92%) of azide 11 as a white solid, mp=130.5° C.-132.5° C., sufficiently pure for use in the next step.
Reaction SMILES: I.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](SC)=[NH:8].[N:11]1([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][S:21][C:20]3[CH:24]=[C:25]([NH2:28])[CH:26]=[CH:27][C:19]2=3)[CH2:15][CH2:14][CH2:13][CH2:12]1>CCO>[N:11]1([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][S:21][C:20]3[CH:24]=[C:25]([NH:28][C:7]([C:3]4[S:2][CH:6]=[CH:5][CH:4]=4)=[NH:8])[CH:26]=[CH:27][C:19]2=3)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CSC(=N)c1cccs1
Reactant: Nc1ccc2c(c1)SCCN2CCN1CCCC1
Agent: I
Solvent: CCO
Product: N=C(Nc1ccc2c(c1)SCCN2CCN1CCCC1)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
Methyl thiophene-2-carbimidothioate hydroiodide (1.239 g, 4.34 mmol) was added to a mixture of 4-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-amine (0.572 g, 2.172 mmol) in EtOH (20 mL). The reaction was stirred overnight at room temperature. The reaction was quenched with saturated sodium bicarbonate solution (30 mL). The mixture was then extracted with CH2Cl2 (50 mL), and the aqueous phase was washed with CH2Cl2 (50 mL). The combined organic fractions were washed with brine (50 mL) and dried (Na2SO4). The crude material was subject to flash chromatography on silica gel (CH2Cl2 then 5% (2M NH3 MeOH)/CH2Cl2). The collected fractions gave compound 11 as light brown viscous liquid (0.71 g, 88%). 1H NMR (DMSO-d6) δ 7.69 (d, J=3.6 Hz, 1H), 7.56 (d, J=5.1 Hz, 1H), 7.08-7.06 (m, 1H), 6.67 (t, J=8.7 Hz, 1H), 6.50 (d, J=8.4 Hz, 1H), 6.46 (s, 1H), 6.32 (brs, 2H), 3.57-3.53 (m, 2H), 3.39-3.34 (m, 2H), 3.03-3.00 (m, 2H), 2.60 (t, J=7.2 Hz, 2H), 2.50 (brs, 4H), 1.68 (brs, 4H); ESI-MS (m/z, %): 375, 373 (MH+, 47), 278, 276 (100), 98 (21).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.[Li]CCCC.[Sn:12](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16]>C1COCC1>[CH3:1][N:2]1[C:6]([Sn:12]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:5][N:4]=[N:3]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1ccnn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.8 %

Procedure:
To a solution of 1-methyl-1H-[1,2,3]triazole (1.33 g, 16 mmol) in THF (20 mL) at −78° C., was added dropwise n-BuLi (11 mL, 1.6M, 18 mmol). The mixture was stirred at −78° C. for 2 h before addition of Bu3SnCl (4.75 mL, 17.6 mmol). The mixture was stirred at this temperature for 1 h and at r.t. for 1 h. The mixture was concentrated in vacuo and hexanes was added. The insoluble material was removed by filtration and the filtrate was concentrated in vacuo to afford 1-methyl-5-tributylstannanyl-1H-[1,2,3]triazole (6.12 g, 82% yield) as a yellow syrup.
Reaction SMILES: [NH2:1][C@H:2]([C:15]([NH:17][CH3:18])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.[CH:19](=O)[CH3:20].ClCCl.[BH4-].[Na+]>O>[NH:1]([CH2:19][CH3:20])[C@H:2]([C:15]([NH:17][CH3:18])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:12])[CH3:13])[CH:5]=1
Reactant: CNC(=O)[C@@H](N)Cc1ccc(O)c(C(C)(C)C)c1
Reactant: CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCN[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(=O)NC
Yield: 89.8 %

Procedure:
A mixture of Tyr(3-tBu)-NHMe (1.7 g, 6.8 mmol), acetaldehyde (0.76 ml, 13.6 mmol) and dichloromethane (10 ml) was stirred under cooling with ice for 30 min. The reaction mixture was concentrated under reduced pressure under cooling with ice; the thus obtained residue was mixed with methanol (20 ml) and then under cooling with ice with sodium borohydride (0.28 g, 7.4 mmol) and stirred at the same temperature for 15 min. The resultant was mixed with water and extracted with dichloromethane. The organic layer was washed with water, dried and concentrated under reduced pressure under cooling with ice; the thus obtained residue was subjected to silica gel column chromatography (CHCl3:MeOH=20:1), giving N-Et-Tyr(3-tBu)-NHMe (T8) (1.7 g, 90%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].[C:15]([NH:22][CH2:23][CH2:24][CH2:25][NH2:26])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:18]([O:17][C:15]([NH:22][CH2:23][CH2:24][CH2:25][NH:26][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc([N+](=O)[O-])c(NCCCNC(=O)OC(C)(C)C)c1
Yield: 99 %

Procedure:
A mixture of methyl 3-fluoro-4-nitrobenzoate (5.8 g, 1 eq), N-Boc-1,3-diaminopropane (5.75 g, 1.1 eq) and potassium carbonate (8.04 g, 2 eq) in acetonitrile (200 ml) is heated under reflux for 2 hours then concentrated under reduced pressure at 40° C. The residue is taken up in dichloromethane (200 ml) and water (100 ml). After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. The solid obtained is washed with petroleum ether and dried (10.2 g; 99% yield).
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:8][CH2:7][C@@H:6]([CH3:9])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4]1.[CH3:17][NH:18][CH3:19].C(O)C>>[CH3:17][N:18]([CH2:2][C@@H:3]1[O:8][CH2:7][C@@H:6]([CH3:9])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4]1)[CH3:19]
Reactant: C[C@@H]1CO[C@H](CCl)CN1Cc1ccccc1
Reactant: CNC
Solvent: CCO
Product: C[C@@H]1CO[C@@H](CN(C)C)CN1Cc1ccccc1
Temperature: 150 °C

Procedure:
A mixture of (2S,5R)-2-(chloromethyl)-5-methyl-4-benzylmorpholine (1 equivalent) and dimethylamine in ethanol (33%, approx. 5.6 M, 5 equivalents) was heated at 150° C. over 2 days in a glass pressure vessel. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 1 N HCl, and the solution was washed with CH2Cl2. The water phase was made basic with 30% NaOH solution (to pH=12) and extracted with CH2Cl2. The organic extracts were collected and dried (Na2SO4). Evaporation of the solvent under reduced pressure afforded (2S,5R)-2-[dimethylamino(methyl)]-5-methyl-4-benzylmorpholine as a brown oil which was used in the next step without purification. GC/MS: 247 (2%, M-H), 204 (55%, M-NMe2), Rt 15.5 minutes; LC/MS m/z 249.2 (MH+), Rt 0.72 minutes.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2>CCO.O=[Pt]=O>[CH3:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: COc1ccc2c(Oc3ccc([N+](=O)[O-])cc3)c(-c3ccccc3)c(C)cc2c1
Agent: O=[Pt]=O
Solvent: CCO
Product: COc1ccc2c(Oc3ccc(N)cc3)c(-c3ccccc3)c(C)cc2c1
Reaction time: 1.5 h
Yield: 100.1 %

Procedure:
PtO2 (10 mg) was added to a solution of 28 (490 mg, 1.27 mmol, 1 equiv) in EtOH (5 mL). The reaction mixture was stirred under an atmosphere of H2 (50 psi) for 1.5 h. The mixture was then filtered thru a pad of celite and concentration down to provide compound 29 (452 mg, 100%) as a clear oil. 1HNMR (400 MHz, DMSO-d6): δ 7.61 (m, 2H), 7.32-7.23 (m, 4H), 7.16 (m, 2H), 7.02 (m, 1H), 6.32-6.26 (m, 4H), 5.74 (br s, 2H), 3.85 (s, 3H), 2.14 (s, 3H). MS m/z 356.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:27])[CH:8]=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:5])[CH3:2].C1C(=O)N([Br:35])C(=O)C1.O>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:27])[C:8]([Br:35])=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(OCc3ccccc3)cc2)c(C#N)cn1C
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2ccc(OCc3ccccc3)cc2)c(C#N)c(Br)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A solution of 3-(4-benzyloxy-phenyl)-4-cyano-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester. (184.73 g, 0.512 mol, prepared in example E-6a or E-6b) in anhydrous THF (2,000 mL) is treated with NBS (109.47 g, 0.615 mol). The resulting reaction mixture is allowed to stir at room temperature overnight. The reaction mixture is poured into water (2,000 mL). The resulting solution is divided into 2 equal parts, and each is extracted with EtOAc (3×800 mL each). The combined organics are dried over anhydrous MgSO4, filtered, then concentrated in vacuo to afford a yellow solid. The yellow solid is purified by column chromatography (silica gel, EtOAc/Hexanes 1/3) to afford the title compound (133.99 g, ˜60% yield) as a white solid: 1H NMR (500 MHz; CDCl3) δ 7.46-7.44 (m, 2H), 7.41-7.38 (m, 2H), 7.36-7.32 (m, 1H), 7.29-7.26 (m, 2H), 7.01-6.99 (m, 2H), 5.10 (s, 2H), 4.11 (q, 2H), 3.98 (s, 3H), 1.02 (t, 31); MS(ES): m/z 438.9.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[C:5]([OH:33])([CH3:32])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:18](=[O:30])[N:17]2[CH3:31])=[CH:9][CH:8]=1)[CH3:2].[H-].[Na+].I[CH2:38][CH2:39][CH2:40][CH3:41].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:34])[C:5]([O:33][CH2:38][CH2:39][CH2:40][CH3:41])([CH3:32])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[C:18](=[O:30])[N:17]2[CH3:31])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(O)Cc1ccc(OCCC2CN(Cc3ccc(OC)cc3)C(=O)N2C)cc1
Reactant: CCCCI
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOC(C)(Cc1ccc(OCCC2CN(Cc3ccc(OC)cc3)C(=O)N2C)cc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 18 h
Yield: 64.4 %

Procedure:
A slurry of 2-hydroxy-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionic acid ethyl ester (7.35 g, 15.62 mmol) and sodium hydride (2.5 g, 62.5 mmol, 60% dispersion on mineral oil) in DMF (50 mL) i stirred for 45 minutes, then cooled to 0° C. Iodobutane (36 mL, 312 mmol, d=1.617) and 18-crown-6 16.5 g, 62.5 mmol) are added, then the reaction mixture is stirred 18 h at ambient temperature and diluted with ethyl acetate. The organic layer is washed, then dried concentrated in vacuo, and diluted with ethanol (400 mL) and 5N NaOH (40 mL). The reaction mixture is refluxed for 1 h, cooled to ambient temperature, and concentrated in vacuo. The residue is washed, dried, concentrated, and re-dissolved in ethanol (300 mL). Concentrated H2SO4 (30 mL) is added to the reaction solution, then the mixture is refluxed 1 h, cooled to ambient temperature, concentrated, and diluted with ethyl acetate. The organic layer is washed, dried, and concentrated to provide the title compound (5.3 g, 65%). 1H NMR (400 MHz, CDCl3): δ 7.17 (d, 2H, J=8.8 Hz), 7.09 (d, 2H, J=8.8 Hz), 6.84 (d, 2H, J=8.8 Hz), 6.70 (d, 2H, J=8.8 Hz), 4.32, 4.28 (ABq, 2H, J=14.7 Hz), 4.17-4.11 (m, 2H), 3.93 (t, 2H, J=5.9 Hz), 3.78 (s, 3H), 3.61-3.53 (m, 3H), 3.40-3.31 (m, 3H), 2.97-2.89 (m, 3H), 2.97-2.89 (m, 3H), 2.81 (s, 3H), 2.25-2.15 (m, 1H), 1.89-1.81 (m, 1H), 1.59-1.49 (m, 2H), 1.42-1.33 (m, 2H), 1.29 (s, 3H), 1.24 (t, 3H, J=7.2 Hz), 0.91 (t, 3H, J=7.2 Hz). Rf=0.43 in 50% acetone in hexanes.