Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][CH:13]([OH:17])[C:12]3[N:18]=[CH:19][CH:20]=[CH:21][C:11]2=3)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)Cl.CS(C)=O.N1C(Cl)=NC(Cl)=NC=1Cl>O.C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[C:12]3[N:18]=[CH:19][CH:20]=[CH:21][C:11]2=3)=[O:9])=[CH:22][CH:23]=1)([O-:3])=[O:2]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCCC(O)c2ncccc21
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2cccnc21
Temperature: -25 °C
Reaction time: 6.5 h
Yield: 125.4 %

Procedure:
A mixture of 0.313 g of 5-(4-nitrobenzoyl)-9-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepine, 4 ml of CH2Cl2 and 0.75 ml of dimethylsulfoxide is chilled to -25° C. and 0.405 g of cyanuric chloride is added. The mixture is allowed to stand at -25° C. for 6.5 hours and 0.41 g of triethylamine is added. The mixture is stirred 10 minutes and poured into water. The mixture is extracted with dichloromethane and the extract washed with water, brine and dried (Na2SO4). The solvent is removed to give 0.39 g of solid. Chromatography on silica gel with ethyl acetate as solvent gives 0.17 g of crystals, m.p. 188°-190° C.
Reaction SMILES: [OH:1]O.[Se](=O)=O.[CH2:6]([O:8][C:9]([C:11]1[N:12]([CH3:28])[C:13]([CH2:26][CH3:27])=[C:14]([C:24]#[N:25])[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][CH:17]=1)=[O:10])[CH3:7].Cl>>[CH2:6]([O:8][C:9]([C:11]1[N:12]([CH3:28])[C:13]([CH2:26][CH3:27])=[C:14]([C:24]#[N:25])[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([OH:1])=[O:23])=[CH:18][CH:17]=1)=[O:10])[CH3:7]
Reactant: CCOC(=O)c1c(-c2ccc(C=O)cc2)c(C#N)c(CC)n1C
Reactant: OO
Agent: Cl
Agent: O=[Se]=O
Product: CCOC(=O)c1c(-c2ccc(C(=O)O)cc2)c(C#N)c(CC)n1C
Reaction time: 18 h

Procedure:
Add 30% hydrogen peroxide (0.66 mL, 5.8 mmol) and selenium dioxide (0.016 g, 0.15 mmol) to 4-cyano-5-ethyl-3-(4-formyl-phenyl)-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (prepared in example E-152), and heat to reflux with stirring. After 18 hours, cool the reaction mixture and pour into 1N HCl. Extract the quenched reaction with methylene chloride. Combine the organic extracts, wash with water and brine, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Recrystallize the residue from ethyl acetate:hexanes to provide the title compound. Mass spectrum (m/e): 325.1 (M−1).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[F:19][C:20]([F:28])([F:27])[C:21]([CH3:26])=[CH:22][C:23](Cl)=[O:24].O>C1COCC1.CCO>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:23](=[O:24])/[CH:22]=[C:21](\[CH3:26])/[C:20]([F:28])([F:27])[F:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CC(=CC(=O)Cl)C(F)(F)F
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: C/C(=C\C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C(F)(F)F
Temperature: -45 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
(4S)-4-Benzyl-1,3-oxazolidin-2-one (828 g, 4.67 moles) was dissolved in 6.8 L THF and cool to −40 to −50° C. To the solution of (4S)-4-benzyl-1,3-oxazolidin-2-one, 2.5 M BuLi in hexanes (1302 g, 1880 mL, 4.70 mole, 1.01 equivalents) was added while keeping the temperature at <−40° C. To the cold solution of the Li salt of (4S)-4-benzyl-1,3-oxazolidin-2-one, 4,4,4-trifluoro-3-methyl-2-butenoic acid chloride (887 g, 5.14 moles, 1.1 equivalents) was added over 10-30 minutes, all-owing the temperature to rise and wash in with 0.4 L THF. The reaction was warmed to 20-25° C. and stirred for 2 h. 0.9 L water was added and stirred for 16 h. The THF was distilled off with a bath temperature of 35° C. and vacuum<40 mm Hg. Toluene (5.8 L) was added and the phases split. 4-L saturated NaHCO3 was used to wash (2×), the mixture was filtered through Celite and the phases split. 2.5-L water (2×) was used as a wash and the toluene layer was filtered through Celite. The remaining water was removed. The toluene was distilled off with a bath temperature of 40° C. and vacuum<40 mm Hg. At the end of the distillation the product started to crystallize with a pot temperature of 30° C. Distillation is continued to a pot temperature of 35° C. giving a solid mobile mass of 1456 g. The solid is dissolved in 2.9 L (2 vol) EtOH (99.5% EtOH:0.5% toluene). While stirring at 20-25° C., water (1.09 L, 0.75 vol) was added over 1 h forming crystals. Stirring is continued for 16 h at 15-25° C., followed by cooling to 0-5° C. and holding for 1 h. The crystals are filtered, washed with filtrate and dried at 50° C. for 16 h giving 1229 g, 84% of (4S)-4-benzyl-3-[(2E)-4,4,4-trifluoro-3-methyl-but-2-enoyl]-1,3-oxazolidin-2-one.
Reaction SMILES: [CH3:1][CH:2](CC)[O-].[CH3:6][CH:7](CC)[O-].[CH3:11][CH:12](CC)[O-].[Al+3:16].C([O:19][C:20](=[O:25])[CH2:21][C:22]([CH3:24])=[O:23])C>CCCCCCC>[CH2:1]([CH2:24][C:22](=[O:23])[CH2:21][C:20]([O-:19])=[O:25])[CH3:2].[CH2:6]([CH2:24][C:22](=[O:23])[CH2:21][C:20]([O-:19])=[O:25])[CH3:7].[CH2:11]([CH2:24][C:22](=[O:23])[CH2:21][C:20]([O-:19])=[O:25])[CH3:12].[Al+3:16]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCC(C)[O-]
Agent: [Al+3]
Solvent: CCCCCCC
Product: CCCC(=O)CC(=O)[O-]
Yield: 99.2 %

Procedure:
To a flask containing 50.02 g of a mixture of heptane isomers was added 31.0 g (0.125 mol) of aluminium tris(sec-butoxide). To this was added with stirring, 48.37 g (0.376 mol) of ethylacetoacetate. After stirring the liquor was transferred to a rotary evaporator flask and the volatile sec-butanol and heptanes (78.66 g) were removed under vacuum leaving aluminium tris(ethylacetoacetate) (51.23 g, 0.124 mol).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH2:9])=[C:4]([Cl:10])[N:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH:12]1[C:17](O)=[O:18].C(N(CC)CC)C>C(O)C.O>[Cl:1][C:2]1[N:3]=[C:4]([Cl:10])[C:5]2[NH:9][C:17](=[O:18])[CH:12]3[CH2:13][O:14][CH2:15][CH2:16][N:11]3[C:6]=2[N:7]=1
Reactant: O=C(O)C1COCCN1
Reactant: Nc1c(Cl)nc(Cl)nc1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1Nc2c(Cl)nc(Cl)nc2N2CCOCC12
Temperature: 75 °C
Yield: 36.7 %

Procedure:
A round-bottom flask was charged with 2,4,6-trichloropyrimidin-5-amine (982 mg, 4.95 mmol), morpholine-3-carboxylic acid (649 mg, 4.95 mmol) and triethylamine (2.78 mL, 19.79 mmol) in ethanol (20 mL). The mixture was heated at 75° C. for 3 days then diluted with water and extracted with EtOAc. The organic layer was dried over magnesium sulfate, filtered and dried in vacuo to give 500 mg of crude 2,4-dichloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one which was used without further purification. MS [M+H] Found 275.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:24][C:25]1([CH3:36])[O:29][CH:28]([CH2:30]OS(C)(=O)=O)[CH2:27][O:26]1>CN(C)C=O.CCOCC>[CH3:24][C:25]1([CH3:36])[O:29][CH:28]([CH2:30][O:23][C:20]2[CH:19]=[CH:18][C:17]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:22][CH:21]=2)[CH2:27][O:26]1
Reactant: CC1(C)OCC(COS(C)(=O)=O)O1
Reactant: CCCCCCCCCCCCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCc1ccc(OCC2COC(C)(C)O2)cc1
Temperature: 25 °C

Procedure:
To a prewashed suspension of about 10.8 g of sodium hydride in about 800 ml of dimethylformamide was added about 43.5 g of 4-tetradecylphenol. The reaction was then refluxed about 2 hours, cooled to room temperature and about 37.8 g of freshly prepared 2,2-dimethyl-4-[[(methylsulfonyl)oxy]methyl]-1,3-dioxolane was added. The reaction was then refluxed for about 24 hours, cooled, diluted with ether, washed with water and dried, giving about 58.7 g of the desired title compound, mp 52°-53° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH:24]([CH3:26])[CH3:25].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH:24]([CH3:26])[CH3:25])=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 10 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
N-Tertiarybutyloxycarbonyl-L-tyrosine (14.1 g 50 mM) in dry dimethylformamide (200 ml) was treated with sodium hydride (3.45 g, 115 mM) with vigorous stirring under an atmosphere of argon at 10° C. for 1 h. 2-Bromopropane (6.15 g, 50 mM) was added and the stirred solution allowed to warm to 20° C. over 16 h. Water (200 ml) was added and the solution extracted with ethyl acetate (2×200 ml). The reaction was adjusted to pH1 with hydrochloric acid (6M) and extracted with dichloromethane 2×300 ml. The combined extracts were columned on silica in ethyl acetate to afford N-tertiarybutyloxycarbonyl-O-isopropyl-L-tyrosine (13.6 g, 42 mM) as a foam. The foam was dissolved in dichloromethane (200 ml) and treated with methylamine hydrochloride (2.5 g, 80 mM), 1-hydroxybenzotriazole (6.75 g, 44 mM), dicyclohexylcarbodiimide (9.1 g, 44 mM) and N-methyl morpholine (2.5 g, 80 mM) at 0° C. with continuous stirring. The solution was allowed to warm to room temperature over 16 h and filtered. The filtrate was washed with water, aqueous saturated sodium hydrogen carbonate solution and aqueous citric acid (1M), dried over sodium sulphate and concentrated in vacuo to afford N-tertiarybutyloxycarbonyl-O-isopropyl-L-tyrosine-N-methyl amide (6.1 g, 18 mM) which crystallised from ethyl acetate/hexane as needles m.p. 110°-114° C. (Found: C,63.5; H,8.4; N,8.7. C18H28N2O4 0.25 H2O requires: C,63.4; H,8.4; N,8.2%) δ(CDCl3) 1.32 (6H,d,J=7 Hz, (CH3)2CH); 1.4 (9H,s,(CH3)3C); 2.72 (3H,d,J=4 Hz NHCH3); 2.98, (2H,d,J=7 Hz CH2C6H5); 4.26 (1H,m,NHCHCO); 4.5 (1H, heptet, J=5 Hz, CH(CH3)2); 5.08 (1H,m,NH); 5.92 (1H,m,NH); 6.78, and 7.04 (each 2H,each d,each J=8 Hz C6H4).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[C:26]([Cl:29])[CH:27]=3)[N:22]([C:30](=[O:32])[CH3:31])[CH2:21]2)[CH2:17][CH2:16]1)=O)(C)(C)C.CO.ClCCl.C(N(CC)CC)C>ClCCl>[C:30]([N:22]1[C:23]2[C:28](=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:18]2([CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)[CH2:21]1)(=[O:32])[CH3:31]
Reactant: CC(=O)N1CC2(CCN(C(=O)OC(C)(C)C)CC2)c2cc(Cl)ccc21
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(=O)N1CC2(CCNCC2)c2cc(Cl)ccc21
Reaction time: 3 h
Yield: 96.5 %

Procedure:
Trifluoroacetic acid (25 ml) was added to a stirred solution of 1-acetyl-5-chlorospiro[indoline-3,4′-piperidine]-1′-carboxylic acid tert-butyl ester (8 g) in anhydrous dichloromethane (250 ml) under an atmosphere of nitrogen. The reaction was left as such for 3 h. The reaction was washed with saturated bicarbonate solution (200 ml) and dried over sodium sulphate and concentrated in vacuo to yield an off white solid. Flash chromatography [SiO2: methanol-dichloromethane-triethylamine (90:5:5)] yielded 5.6 g (61%) of the desired 1-Acetyl-5-chlorospiro[indoline-3,4′-piperidine]. 1H NMR (400 MHz, CDCl3) δ 6:1 mixture of rotamers. Major rotamer 1.70 (m, 2H), 1.80 (m, 2H), 2.27 (s, 3H), 2.75 (t, J=12 Hz, 2H), 3.15 (m, 2H), 3.90 (s, 2H), 7.12 (d, J=1 Hz, 1H), 7.18 (dd, J=7 & 1 Hz, 1H), 8.15 (d, J=7 Hz, 1H). Minor rotamer (partial data) 2.44 (s, 3H), 2.86 (m, 2H), 3.10 (m, 2H), 4.05 (s, 2H). MS (ES+) 265/267 (M+H+).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([C:18]2[C:19]([O:24]C)=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.C([O-])(O)=O.[Na+]>CC(O)=O>[CH2:1]([C:8]1[CH:9]=[C:10]([C:18]2[C:19](=[O:24])[NH:20][CH:21]=[CH:22][CH:23]=2)[CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ncccc1-c1cc(Cc2ccccc2)cc(C(C)(C)C)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(Cc2ccccc2)cc(-c2ccc[nH]c2=O)c1
Temperature: 25 °C

Procedure:
step 2—A solution of 126 (156 mg, 0.471 mmol), 48% HBr (150 □L, 1.30 mmol) and HOAc (4 mL) in sealed tube was heated overnight at 70° C. The reaction mixture was cooled to RT, carefully poured into a cold saturated aqueous NaHCO3 and then extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified on a preparative SiO2 TLC plate developed with 66% EtOAc/hexanes to afford 124 mg (83%) of I-46 as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH3:18])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][C:27]#[N:28].N1CCOCC1.Cl>CN(C=O)C.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>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:26][C:27]#[N:28])[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH3:18])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCC
Reactant: N#CCBr
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: CCCn1c(=O)n(CC#N)c(=O)c2[nH]c(Cl)nc21
Temperature: 80 °C
Yield: 32.9 %

Procedure:
A solution of 8-chloro-7-(2-propen-1-yl)-3-propyl-3,7-dihydro-1H-purine-2,6-dione (0.067 g, 0.25 mmol) in DMF (2 ml) was treated with caesium carbonate (0.082 g, 0.25 mmol) and bromoacetonitrile (0.044 g, 0.37 mmol). The mixture was heated at 80° C. for 4 hours then cooled to ambient temperature. The DMF was removed in vacuo and the residue treated with THF (2 ml). The solvent was degassed by the successive application of vacuum and nitrogen pressure to the reaction mixture. The mixture was then treated with morpholine (0.035 ml, 0.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.026 mmol). After 2 hours the mixture was treated with 2M aqueous hydrochloric acid (2 ml) and the product extracted with chloroform (3×5 ml). The organic fractions were combined and evaporated. The residue was subjected to purification by mass-directed HPLC to afford the title compound as a white solid (0.022 g, 33%). NMR; δH (400 MHz, d6-DMSO), 0.88 (t, 3H, J=7.5 Hz), 1.63-1.74 (m, 2H), 3.91 (t, 2H, J=7.5 Hz), 4.87 (s, 2H), NH not observed to δH 14; m/z 268 [MH+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH2:10][C:11]1[C:15]([C:16](OC)=[O:17])=[C:14]([CH:20]([CH3:22])[CH3:21])[O:13][N:12]=1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH2:10][C:11]1[C:15]([CH2:16][OH:17])=[C:14]([CH:20]([CH3:22])[CH3:21])[O:13][N:12]=1
Reactant: COC(=O)c1c(COc2c(C)cccc2C)noc1C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1OCc1noc(C(C)C)c1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a solution of methyl 3-{[(2,6-dimethylphenyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolecarboxylate (183 mg, 0.603 mmol) in tetrahydrofuran (2 mL) at 0° C. was added a 1.5 M solution of diisobutylaluminum hydride in toluene (1.33 mL, 1.99 mmol) dropwise. The solution was allowed to warm slowly to ambient temperature and after approximately 5 hours was re-cooled to 0° C. Then 10 mL of Rochelle's salt was slowly added followed by ethyl acetate. The mixture was allowed to stir overnight. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated to afford [3-{[(2,6-dimethylphenyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolyl]methanol (158 mg, 95%). 1H-NMR (400 MHz, DMSO-d6) δ 7.03-6.91 (m, 3H), 4.98 (t, J=5 Hz, 1H), 4.83 (s, 2H), 4.39 (d, J=5 Hz, 2H), 3.29 (septet, J=7 Hz, 1H), 2.19 (s, 6H), 1.24 (d, J=7 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5]([NH2:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:13](C1NC=CN=1)(C1NC=CN=1)=[O:14]>C1COCC1>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]2[NH:11][C:13](=[O:14])[NH:12][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1N
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2[nH]1
Temperature: 23 °C
Reaction time: 20 h
Yield: 76.6 %

Procedure:
To a solution of 4-chloro-5-nitro-benzene-1,2-diamine (8.34 g, 44.4 mmol) and THF (625 mL) was added carbonyl diimidazole (8.65 g, 53.3 mmol) at 0° C. The reaction mixture was allowed to warm to 23° C. and was stirred for 20 h at this temperature. The reaction mixture was concentrated to a volume of 300 mL and 500 mL aqueous 1M HCl was added, followed by water (total volume 2 L). The resulting suspension was cooled at 0° C. for 2 h, and the precipitate was collected and dried on the filter. It was then triturated with cold EtOAc (20 mL) and rinsed EtOAc (2×5 mL) to yield the titled compound (7.26 g, 76% yield). MS (ESI/CI): mass calcd. for C7H4ClN3O3, 213.0; m/z found, 214.0 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:24])[NH:10][CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:12]([OH:14])=O)[N:3]=[CH:2]1.FC(F)(F)C(O)=O.[CH2:32]([O:36][C:37]1([CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[CH2:33][CH2:34][CH3:35].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH2:32]([O:36][C:37]1([CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH2:38][CH2:39][N:40]([C:12](=[O:14])[CH:11]([NH:10][C:9]([NH:8][CH2:7][CH2:6][C:4]2[N:3]=[CH:2][NH:1][CH:5]=2)=[O:24])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:41][CH2:42]1)[CH2:33][CH2:34][CH3:35]
Reactant: COc1ccc(CC(NC(=O)NCCc2c[nH]cn2)C(=O)O)cc1
Reactant: CCCCOC1(C2CCCCC2)CCNCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCOC1(C2CCCCC2)CCN(C(=O)C(Cc2ccc(OC)cc2)NC(=O)NCCc2c[nH]cn2)CC1
Reaction time: 0.5 h
Yield: 22.6 %

Procedure:
To 69 mg (0.21 mmol) of 2-{3-[2-(1H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)-propanoic acid (cf. preparation 2-3) dissolved in 2 mL of DMF is added a solution of 71 mg (0.20 mmol) of 4-butoxy-4-cyclohexylpiperidine trifluoroacetate in 1.5 mL of DMF, 44 mg (0.23 mmol) of EDC and 33 mg (0.24 mmol) of HOBt. After 2 hours 30 minutes, the reaction medium is hydrolysed with aqueous 2% citric acid solution and then extracted with dichloromethane. The organic phase is then washed with aqueous 1N sodium hydroxide solution. The organic phase is dried over MgSO4, filtered and concentrated. This oil is chromatographed on silica gel (eluent: 8/2 DCM/MeOH). 25 mg of 1-[2-(4-butoxy-4-cyclohexylpiperidin-1-yl)-1-(4-methoxy-benzyl)-2-oxoethyl]-3-[2-(1H-imidazol-4-yl)ethyl]urea are obtained in a yield of 22%.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:33]([OH:35])=[O:34])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18]S(C1C(C)=C(C)C(OC)=CC=1C)(=O)=O)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:36][C:37]([NH:48][CH2:49][CH:50]([OH:66])[CH2:51][O:52][C:53]1[C:58]2[C:59]3[C:64]([NH:65][C:57]=2[CH:56]=[CH:55][CH:54]=1)=[CH:63][CH:62]=[CH:61][CH:60]=3)([C:39]1[CH:44]=[CH:43][C:42]([N:45]=[N+:46]=[N-:47])=[CH:41][CH:40]=1)[CH3:38].C1(OC)C=CC=CC=1.ClCC(O)=O.C(OCC)(=O)C>C(Cl)Cl>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:33]([OH:35])=[O:34])[CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:38][C:37]([NH:48][CH2:49][CH:50]([OH:66])[CH2:51][O:52][C:53]1[C:58]2[C:59]3[C:64]([NH:65][C:57]=2[CH:56]=[CH:55][CH:54]=1)=[CH:63][CH:62]=[CH:61][CH:60]=3)([C:39]1[CH:44]=[CH:43][C:42]([N:45]=[N+:46]=[N-:47])=[CH:41][CH:40]=1)[CH3:36]
Reactant: COc1cc(C)c(S(=O)(=O)NCCCC[C@H](NC(=O)[C@@H](N)Cc2ccccc2)C(=O)O)c(C)c1C
Agent: CC(C)(NCC(O)COc1cccc2[nH]c3ccccc3c12)c1ccc(N=[N+]=[N-])cc1
Agent: O=C(O)CCl
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NCCCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O

Procedure:
A solution of MEt-IDA-(Phe-Lys(Mtr)-PABC-MMC)2 30 (134.6 mg, 0.0590 mmol) in methylene chloride (3 mL) at rt was treated with anisole (1.28 mL, 200 equiv) and 1 M chloroacetic acid in methylene chloride (1.18 mL, 20 equiv). After 3.5 h ethyl acetate (30 mL) was added. The resulting purple solid was collected by filtration, washed with ethyl acetate and air-dried (97.8 mg, 82%). The product appeared to decompose in solution to one product by HPLC. 1H-NMR (CDCl3/CH3OD) δ 1.33 (m, 4H), 1.63 (s and M, 12H), 1.77 (m, 2H), 2.52 (m, 2H), 2.82 (m, 6H), 3.03 (m, 2H), 3.10 (s and brs, 10H), 3.27 (m, 2H), 3.53 (ABq, 2H), 3.96 (brs, 4H), 4.11 (m, 2H), 4.35 (d and m, 3H), 4.53 (m, 2H), 4.78 (ABq, 2H), 4.94 (m, 4H), 6.62 (s, 2H), 7.10 (m, 10H), 7.19 (d, 4H), 7.41 (d, 4H). MS (FAB) 1738.3 (M+Na)+, 1776.4 (M+K)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.B(OC)(OC)OC.Cl.B(O)(O)O.[CH2:25]([C@H:30]1[CH2:35][CH2:34][C@H:33]([C:36]2[CH:41]=[C:40]([F:42])[C:39](I)=[C:38]([F:44])[CH:37]=2)[CH2:32][CH2:31]1)[CH2:26][CH2:27][CH2:28][CH3:29].C(C1CCC(=O)CC1)CCCC.FC1C=C([Mg]Br)C=C(F)C=1.[Li]CCCC.II.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C1COCC1.CN(CCN(C)C)C.C1(C)C=CC=CC=1.O>[CH2:25]([C@H:30]1[CH2:35][CH2:34][C@H:33]([C:36]2[CH:37]=[C:38]([F:44])[C:39]([C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=3)=[C:40]([F:42])[CH:41]=2)[CH2:32][CH2:31]1)[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCC[C@H]1CC[C@H](c2cc(F)c(I)c(F)c2)CC1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: CCCCCC1CCC(=O)CC1
Agent: CN(C)CCN(C)C
Agent: COB(OC)OC
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](c2cc(F)c(-c3ccc(OC(F)(F)F)cc3)c(F)c2)CC1
Reaction time: 1 h

Procedure:
A solution of 0.1 mol of p-bromotrifluoromethoxybenzene in 100 ml of THF is added dropwise to a suspension of 0.1 mol of Mg turnings in 50 ml of THF at such a rate that the reaction mixture boils gently. After the mixture has been stirred for one hour, 0.1 mol of trimethyl borate is added dropwise at room temperature, and the mixture is stirred for a further hour and hydrolyzed using dilute hydrochloric acid. After extractive work-up, the resultant boric acid (0.05 mol) is refluxed for two hours together with 0.05 mol of 4-(trans-4-n-pentyl-cyclohexyl)-2,6-difluoroiodobenzene [obtainable by reacting 4-pentylcyclohexanone with 3,5-difluorophenylmagnesium bromide, eliminating water, and hydrogenating the cyclohexylbenzenes on Pd/C. The resultant 3,5-difluoropenyl [sic] compound is metallated at −70° in THF/TMEDA using n-BuLi and subsequently reacted with iodine in THF at −70 °], 38 ml of 2 molar aqueous Na2CO3 solution, 0.6 g of tetrakis(triphenylphosphine)palladium-(0) and 75 ml of toluene. Customary aqueous work-up and chromatographic purification give 4-(trans-4-n-pentylcyclohexyl)-2,6-difluoro-4′-trifluoromethoxybiphenyl.