Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:11])([C:8]([O-:10])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:12]([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O.C(N(CC)CC)C>[CH2:12]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:8](=[O:10])[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])([CH3:1])[CH3:11])[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CCOC(=O)C(C)(C)C(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 78 %

Procedure:
To a solution of the obtained mono-ethyl dimethylmalonate (1 g) in N,N-dimethylformamide (20 mL) were added 1-(benzyloxycarbonyl)piperazine (1.38 g), 1-hydroxybenzotriazole (0.93 g), triethylamine (1.31 mL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.4 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1-2/1) to give 1-benzyloxycarbonyl-4-[2-ethoxycarbonyl-2-(methyl)propionyl]piperazine (1.77 g). This material was dissolved in ethanol (5 mL). To the solution was added 2 mol/L aqueous sodium hydroxide solution (2.93 mL), and the mixture was stirred at 55° C. overnight. The reaction mixture was poured into water, and the resulting mixture was washed with diethyl ether. The aqueous layer was acidified by addition of 2 mol/L hydrochloric acid, and the mixture was extracted with diethyl ether. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (0.28 g).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:19]=[C:18]3[C:13]([C:14](=[O:25])[C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][NH:17]3)=[CH:12][C:11]=2[F:26])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O[CH2:43][CH2:44][F:45])(=O)=O)=CC=1>CN(C)C=O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:19]=[C:18]3[C:13]([C:14](=[O:25])[C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][N:17]3[CH2:43][CH2:44][F:45])=[CH:12][C:11]=2[F:26])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2nc(N3CCN(C(C)=O)CC3)c(F)cc2c1=O
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCF)c2nc(N3CCN(C(C)=O)CC3)c(F)cc2c1=O
Temperature: 50 °C
Yield: 77.6 %

Procedure:
Ethyl 7-(4-acetyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (7.2 g) and anhydrous potassium carbonate (4.1 g) are added to dimethylformamide (60 ml). The mixture is heated at 50° C. for 30 minutes with stirring. 2-Fluoroethyl p-toluenesulfonate (6.5 g) is added to the mixture, and the mixture is heated at 70°-80° C. with stirring. After the reaction is completed, the insoluble substance is removed by filtration. The filtrate is concentrated to dryness under reduced pressure, and the precipitate is collected by filtration. The precipitate is recrystallized from acetone to give 6.3 g of ethyl 7-(4-acetyl-1-piperazinyl)-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (m.p. 183°-185° C.).
Reaction SMILES: [CH:1]([N:4]1[CH2:7][CH:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5]1)([CH3:3])[CH3:2].[C:16]1([OH:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>CCOCC>[C:16]1([O:26][CH2:5][CH:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][NH:4][CH:1]([CH3:2])[CH3:3])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)N1CC(OCc2ccccc2)C1
Reactant: Oc1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)NCC(COc1cccc2ccccc12)OCc1ccccc1
Temperature: 200 °C
Yield: 79 %

Procedure:
To a mixture of 6.2 parts of 1-(iso-propyl)-3-benzyloxyazetidine and 43 parts of α-naphthol 1.5 parts of sodium hydroxide was added, and the mixture was heated at 200° C. for 16 hours. The reaction mixture was cooled, and 100 parts of ether were added thereto. Excessive α-naphthol was removed by extraction with 2 N-sodium hydroxide aqueous solution. The remaining ether layer was washed in water and dried over anhydrous sodium sulfate. After distillation of ether, the residue was subjected to distillation to yield 8.3 parts of 1-(α-naphthoxy)-2-benzyloxy-3-(iso-propylamino)-propane boiling at 192°-195° C. The yield was 79%.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[OH2:11]>C(O)C>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]([NH2:8])=[O:11])=[CH:4][CH:3]=1
Reactant: O
Reactant: N#CCc1ccc(O)cc1
Solvent: CCO
Product: NC(=O)Cc1ccc(O)cc1
Yield: 98.4 %

Procedure:
(0.0032 g, 0.007 mmol) of the platinum complex, prepared as in Example 1, was stirred with 4-hydroxybenzyl cyanide (1.0 g, 7.5 mmol) and 5 ml (0.28 mol) of water and 5 ml ethanol and the mixture heated under reflux for 18 hours. After cooling the liquids were removed using a rotary evaporator to give 4-hydroxy phenylacetamide (1.116 g) corresponding to 98% yield.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.C(C1(N[C:34]([CH:36](NC(N2CCOCC2)=O)CC(C)(C)C)=[O:35])CC(C2C=CC=CC=2)NC(C2C=CC=CC=2)C1)#N.C(C1(NC(C(NC(N2CCOCC2)=O)CC2CCCCC2)=O)CCN(C)CC1C)#N>C(O)(=O)C>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:34](=[O:35])[CH3:36])=[CH:12][CH:11]=1
Reactant: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CC(c2ccccc2)NC(c2ccccc2)C1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: CC1CN(C)CCC1(C#N)NC(=O)C(CC1CCCCC1)NC(=O)N1CCOCC1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CNC(C)=O)cc1

Procedure:
Methyl-4-(acetylamino-methyl)-benzoate was prepared from acetic acid and methyl 4-(aminomethyl)benzoate using a method analogous to that of Example 1-part (d). The crude N-acyl ester was saponified using a method analogous to that of Example 1-part (c). The crude product was used without further purification.
Reaction SMILES: [CH:1]([C:18]1[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:21]=[C:20]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:19]=1[OH:32])([C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[C:5]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:4]=1[OH:17])[CH3:2].CN1CCCC1=O.[P:40](Cl)(Cl)[Cl:41]>C1(C)C=CC=CC=1>[Cl:41][P:40]1[O:17][C:4]2[C:5]([C:13]([CH3:16])([CH3:14])[CH3:15])=[CH:6][C:7]([C:9]([CH3:12])([CH3:10])[CH3:11])=[CH:8][C:3]=2[CH:1]([CH3:2])[C:18]2[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:21]=[C:20]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:19]=2[O:32]1
Reactant: CC(c1cc(C(C)(C)C)cc(C(C)(C)C)c1O)c1cc(C(C)(C)C)cc(C(C)(C)C)c1O
Reactant: ClP(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: CC1c2cc(C(C)(C)C)cc(C(C)(C)C)c2OP(Cl)Oc2c1cc(C(C)(C)C)cc2C(C)(C)C
Temperature: 25 °C
Yield: 34.8 %

Procedure:
To a solution of 50.9 g. (0.12 mol) of 2,2'-ethylidenebis(4,6-di-tert-butylphenol) and 1.73 mL (0.018 mol) of 1-methyl-2-pyrrolidinone in 275 mL of toluene at ambient temperature is added dropwise 15.7 mL (0.18 mol) of phosphorus trichloride. After the addition is complete, the reaction mixture is heated at reflux for 18 hours. After cooling to room temperature, the toluene is removed in vacuo and the residue is then recrystallized twice from 250 mL of acetonitrile. The acetonitrile is decanted from the product which is dried under vacuum to give 21.0 g (34.8% yield) of the title compound as an off-white solid melting at 194°-198° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:12]=1[OH:20])=[O:10].CCCCCC.CCOC(C)=O>CC(O)=O>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]([C:3]2[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=2[OH:1])=[O:10])=[C:12]([OH:20])[CH:13]=1
Reactant: O=C(c1ccc(O)cc1O)c1ccc([N+](=O)[O-])cc1O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: Nc1ccc(C(=O)c2ccc(O)cc2O)c(O)c1
Yield: 29.4 %

Procedure:
(2,4-Dihydroxy-phenyl)-(2-hydroxy-4-nitro-phenyl)-methanone (395) (0.255 g, 0.927 mmol) was dissolved in warm AcOH (10 mL) and TiCl3 (2.0 M solution in aqueous 1M HCl, 5 mL) was added portion wise over a period of 2 hours until the color of the solution remained purple. TLC (Rf: 0.5 compared to Rf: 0.35 for compound 395 in 1:1 hexane/EtOAc, single spot) indicated complete reaction at this point. The mixture was concentrated to remove nearly all the AcOH. The mixture was diluted with EtOAc (100 mL), washed with NaHCO3 (aqueous sat., 500 mL) and brine (500 mL) via extraction, dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of hexane and EtOAc (eluding with 15–100% EtOAc/hexane in 30 minutes) gave the desired product (396) as a yellow/orange oil (0.067 g, 0.273 mmol, 29.4% yield). LC-MS (ESI): (exact mass: 245.07) m/e=246.2 [M+1]+.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[C:12]=1[NH2:13].[CH2:22]([C:34]1[N:35]=[CH:36][N:37]([CH:39]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:40](O)=[O:41])[CH:38]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1.ClCCl>[CH2:22]([C:34]1[N:35]=[CH:36][N:37]([CH:39]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:40]([NH:13][C:12]2[C:14]([O:20][CH3:21])=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:11]=2[O:10][CH3:9])=[O:41])[CH:38]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCc1cn(C(C(=O)O)c2ccccc2)cn1
Reactant: COc1cc(OC)c(N)c(OC)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCc1cn(C(C(=O)Nc2c(OC)cc(OC)cc2OC)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
Excess triethylamine (2 mL) was added to a suspension of 2,4,6-trimethoxyaniline hydrochloride (1.6 g, 7.3 mmol) in 500 mL THF and stirred for 1 hour before filtering to remove triethylamine hydrochloride. The filtrate was concentrated and redissolved in 500 mL dichloromethane along with (±)-4-dodecyl-α-phenyl-1H-imidazole-1-acetic acid (2.45 g, 6.6 mmol) at 0° C. Dicyclohexylcarbodiimide (1.43 g, 6.9 mmol) was added in one portion and the resulting suspension was warmed to room temperature and stirred for 16 hours. Filtered to remove a white solid and partitioned the filtrate between dichloromethane and 1N HCl. The organic layer was washed with 1N NaOH, dried over MgSO4, filtered, and concentrated. The resulting residue was chromatographed (20% EtOAc/hexanes on silica) to give the title compound as a white solid (1.25 g, 35%); mp 95°-102° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([Cl:9])=[C:6](Br)[CH:7]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH:32]([C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)=[CH2:33].C(N(CC)CC)C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[Cl:9][C:5]1[N:4]=[CH:3][C:2]([NH2:1])=[CH:7][C:6]=1/[CH:33]=[CH:32]/[C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1
Reactant: C=Cc1ccncc1
Reactant: Nc1cnc(Cl)c(Br)c1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Nc1cnc(Cl)c(/C=C/c2ccncc2)c1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
A solution of 3-amino-5-bromo-6-chloropyridine (2.0 g, 9.64 mmol), Pd2(dba)3 (440 mg, 0.48 mmol), tri-o-tolylphosphine (438 mg, 1.44 mmol), 4-vinylpyridine (2.08 mL, 19.28 mmol), and triethylamine (4.03 mL, 29 mmol) in DMF (30 mL) was stirred at 100° C. for 15 hours, cooled to room temperature, treated with ethyl acetate (200 mL), washed twice with brine, dried (MgSO4), filtered and concentrated. The residual solid recrystallized from hexanes/dichloromethane to provide desired product (1.86 g, 84%). MS (APCI) m/e 232 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[C:8]([C:10]1[CH:14]=[CH:13][NH:12][CH:11]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:23](Br)[CH3:24]>>[CH2:23]([N:12]1[CH:13]=[CH:14][C:10]([C:8](=[O:9])[C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:17]([OH:18])=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)=[CH:11]1)[CH3:24]
Reactant: CC(C)(C)c1cc(C(=O)c2cc[nH]c2)cc(C(C)(C)C)c1O
Reactant: CCBr
Product: CCn1ccc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c1

Procedure:
For example, using 3-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole as compound "E" in this general reaction together with ethyl bromide as "R-X" yields N-ethyl-3-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole (a compound according to Formula X wherein: m is 0; n is 1; R is ethyl; and X, Y and Z are each H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[N:16]3)[O:11][C:10]2=[O:21])[CH:5]=[CH:6][C:7]=1I.C[Sn](C)(C)[C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH2:34][CH:33]([CH2:35][OH:36])[O:32][N:31]=2)=[N:28][CH:29]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[N:16]3)[O:11][C:10]2=[O:21])[CH:5]=[CH:6][C:7]=1[C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH2:34][CH:33]([CH2:35][OH:36])[O:32][N:31]=2)=[N:28][CH:29]=1
Reactant: Cc1cn(C[C@H]2CN(c3ccc(I)c(F)c3)C(=O)O2)nn1
Reactant: C[Sn](C)(C)c1ccc(C2=NOC(CO)C2)nc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: ClC(Cl)Cl
Product: Cc1cn(C[C@H]2CN(c3ccc(-c4ccc(C5=NOC(CO)C5)nc4)c(F)c3)C(=O)O2)nn1
Temperature: 90 °C
Yield: 26.4 %

Procedure:
(5R)-3-(3-Fluoro-4-iodophenyl)-5-[(4-methyl-1H-1,2,3-triazol-1-yl)methyl]-1,3-oxazolidin-2-one (236 mg, 0.58 mM), {3-[5-(trimethylstannyl)pyridin-2-yl)-4,5-dihydroisoxazol-5-yl}methanol (200 mg, 0.58 mM), tris(dibenzylideneacetone) dipalladium (0)-chloroform adduct (60 mg, 0.058 mM) and tri-2-furylphosphine (27 mg, 0.116 mM) were placed in a flask. The solids were degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the suspension was heated at 90° C. for 5 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was chromatographed on silica gel eluting with 5% methanol in dichloromethane to give the title compound (70 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=O.ClC1C=C(Cl)C=CC=1C1[C:25]([C:26]2[NH:27][CH:28]=[CH:29][N:30]=2)=[CH:24][N:23]=[C:22]([NH:31][CH2:32][CH2:33][NH:34][C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][N:36]=2)[N:21]=1>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]1[C:25]([C:26]2[NH:30][CH:29]=[CH:28][N:27]=2)=[CH:24][N:23]=[C:22]([NH:31][CH2:32][CH2:33][NH:34][C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][N:36]=2)[N:21]=1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Product: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(F)cc3Cl)n2)nc1

Procedure:
[4-(2-chloro-4-fluorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine was prepared from 2-chloro-4-fluorobenzoyl chloride using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:23])=[C:5]([C:19]([O:21][CH3:22])=[O:20])[CH:6]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[CH:24]1([N:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38][NH2:39])[CH2:32][CH2:31]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH3:23][C:4]1[NH:3][C:2]([CH3:1])=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:6]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:39][CH2:38][CH2:37][CH2:36][N:33]2[CH2:32][CH2:31][N:30]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:35][CH2:34]2)=[O:18])[C:5]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: NCCCN1CCN(C2CCCCC2)CC1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1CCCCC(=O)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1CCCCC(=O)NCCCN1CCN(C2CCCCC2)CC1

Procedure:
The compound of Example 4 and 4-(cyclohexyl)-1-piperazinepropanamine were reacted according to the General Procedure of Example 13 to yield 1,4-dihydro-2,6-dimethyl-4-[5-[[3-(4-cyclohexyl-1-piperazinyl) propyl]amino]-5-oxopentyl]-3,5-pyridine dicarboxylic acid, dimethyl ester. 1H NMR (DMSO-d6) δ 8.71 (s, 1 H), 8 7.70 (br. t, 1 H), 3.75 (t, 1 H, J=5.4 Hz), 3.59 (s, 6 H), 3.15 (m, 1 H), 2.99 (m, 2 H), 2.45 (m,4 H),2.15 (s,6 H), 1.94 (t, 2 H, J=7.3 Hz), 1.7 (m, 4 H), 1.4-1.2 (m, 9 H), 1.2-1.0 (m, 11 H); 13C NMR (DMSO-d6) δ 171.8, 167.6, 146.3, 100.5, 62.5, 55.6, 53.4, 50.5, 48.4, 44.8, 36.9, 36.5, 35.6, 34.0, 32.0, 28.4, 26.4, 25.9, 25.6, 18.1. Analysis calculated for C29H48N4O5. 2.0 H2O: C, 61.24; H, 9.22; N, 9.85. Found: C, 61.44; H, 9.30; N, 10.53.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:7].[C:8](Cl)(=[O:10])[CH3:9].N1C=CC=CC=1.O1CCCC1>C(Cl)(Cl)Cl>[C:8]([N:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:7])(=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: O=C1NCCCN1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)N1CCCNC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The mixture of 10 parts by weight of 1,3-diaza-cyclohexan-2-one, 11.8 parts by weight of acetylchloride, 8.7 parts by weight of pyridine, 50 parts by volume of tetrahydrofurane and 50 parts by volume of chloroform was stirred for 24 hours at room temperature, filtered and washed out with tetrahydrofurane chloroform (1:1). The combined solutions were evaporated to dryness, recrystallized from acetone/ethanol; 50 parts by volume of NaHCO3 -solution were added, and the mixture was extracted 3 times with 50 parts by volume of ethylacetate at a time. The combined organic solutions were dried over MgSO4, evaporated to dryness, and the residue was recrystallized from acetone/petrol-ether.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:3]=1[NH:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9]>C(O)(=O)C.[Fe]>[NH2:15][C:13]1[CH:12]=[CH:11][C:3]([NH:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])=[C:2]([Cl:1])[CH:14]=1
Reactant: CCCCC(=O)Nc1ccc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Solvent: CC(=O)O
Product: CCCCC(=O)Nc1ccc(N)cc1Cl

Procedure:
2'-Chloro-4'-nitrovaleranilide (13.0 g.) is dissolved in warm glacial acetic acid (100 ml.) and iron powder (14 g.) is added portionwise to maintain gentle boiling. The resulting reaction mixture is refluxed for one-half hour and filtered. The filtrate is evaporated under reduced pressure and the residue is triturated with water. The solid that forms is collected (11.5 g.) and recrystallized from cyclohexane to yield 7.5 g., m.p. 96.5°-99° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([S:15]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])[C:9]=1[NH:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=O.[CH3:23]/[C:24](/[NH2:28])=[CH:25]\[C:26]#[N:27].[CH2:29]([CH:32]1[CH2:37][C:36](=[O:38])[CH2:35][C:34](=O)[CH2:33]1)[CH2:30][CH3:31]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:35]3[C:36](=[O:38])[CH2:37][CH:32]([CH2:29][CH2:30][CH3:31])[CH2:33][C:34]=3[NH:28][C:24]([CH3:23])=[C:25]2[C:26]#[N:27])[CH:7]=[C:8]([S:15]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])[C:9]=1[NH:10][CH2:11][CH2:12][O:13][CH3:14]
Reactant: CCCC1CC(=O)CC(=O)C1
Reactant: COCCNc1c(Br)cc(C=O)cc1S(=O)(=O)N1CCCC1
Reactant: C/C(N)=C\C#N
Solvent: CCO
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(NCCOC)c(S(=O)(=O)N2CCCC2)c1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A mixture of the product of step c (59 mg), 3-aminocrotonitrile (12.3 mg) and 5-propylcyclohexane-1,3-dione (23.1 mg) in ethanol (5 ml) was stirred at 80° C. for 17 h. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC (Method B). Yield: 57 mg. MS-ESI: [M+H]+=591.3/593.3; HPLC: Rt=18.43 min. Diast. ratio: 9:1
Reaction SMILES: [NH2:1][C:2](=[N:26][N+:27]([O-:29])=[O:28])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:23]([OH:25])=O)[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)=[O:10].[NH2:30][C:31]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][NH2:42])=[CH:37][CH:36]=1)=[O:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CO>[NH2:30][C:31]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][NH:42][C:23](=[O:25])[C@@H:7]([CH2:6][CH2:5][CH2:4][NH:3][C:2]([NH2:1])=[N:26][N+:27]([O-:29])=[O:28])[NH:8][C:9]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[O:10])=[CH:37][CH:36]=1)=[O:32]
Reactant: NC(=N[N+](=O)[O-])NCCC[C@@H](NC(=O)OCc1ccc2ccccc2c1)C(=O)O
Reactant: NCc1ccc(CNC(N)=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CO
Product: NC(=O)NCc1ccc(CNC(=O)[C@@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)OCc2ccc3ccccc3c2)cc1
Yield: 32 %

Procedure:
Prepared analogously to Example 69a) from (R)-N5 -[amino(nitroimino)methyl]-N2 -[(2-naphthyl)methoxycarbonyl]-ornithine, 4-(aminocarbonylaminomethyl)benzenemethanamine and TBTU in a yield of 32% of theory. Colourless crystals, Mp. 155-160° C. (Methanol/glacial acetic acid 20/1, v/v).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:9])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].N1CC[CH2:13][CH2:12][CH2:11]1.C(C=C)=O>C(O)(C)C>[CH3:9][C:2]1[N:1]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C1CCNCC1
Reactant: CCOC(=O)/C=C(/C)N
Agent: C=CC=O
Solvent: CC(C)O
Product: CCOC(=O)c1cccnc1C
Temperature: 100 °C

Procedure:
To a mixture of 800 ml. of ethyl 3-aminocrotonate, 30 ml. of piperidine and 1.4 l. of isopropanol, stirred at 25°-30° C., 540 ml. of acrolein were added slowly over a 2 hour period with stirring. Upon completion of the addition of the acrolein, the reaction mixture was heated to reflux and refluxed for 31/2 hours. Then the reaction mixture was evaporated at reduced pressure to dryness. The residue was heated to 100° C. and 610 g. of sulfur were added thereto portionwise. The reaction mixture was then heated at 100° C. for 2 hours and at 125° C. for 11/2 hours. The reaction mixture was allowed to cool to about room temperature and 1 l. of chloroform was added thereto. The reaction mixture was filtered through Celite and the filter cake was washed with additional chloroform. The combined chloroform filtrate and washings were extracted three times with 1 l. portions of 2 N. hydrochloric acid. The aqueous acidic layers were combined and, with cooling, were made basic with 2 N. sodium hydroxide solution. The obtained aqueous basic solution was extracted three times with 1 l. portions of chloroform. The chloroform extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate and evaporated at reduced pressure to obtain an oily residue which was distilled under high vacuum to obtain the pure product (350 g.), b.p. 73°-77° C./0.5 mm. Hg.