Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:24][CH2:25][CH3:26])=[C:4]([CH:12]=[CH:13][C:14]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22])[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[N:11].[C:27](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(=O)CC>[OH:1][C:2]1[C:3]([CH2:24][CH2:25][CH3:26])=[C:4]([CH:12]=[CH:13][C:14]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:27])[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[N:11]
Reactant: O=C([O-])[O-]
Reactant: CCCc1c(OCCCCC#N)ccc(C(=O)c2ccccc2O)c1O
Agent: [K+]
Solvent: CCC(C)=O
Solvent: COS(=O)(=O)OC
Product: CCCc1c(OCCCCC#N)ccc(C(=O)c2ccccc2OC)c1O
Temperature: 25 °C
Yield: 84.3 %

Procedure:
Five grams of 5-[3-hydroxy-4-(2-hydroxybenzoyl)-2-propylphenoxy]pentanenitrile, 11.7 g of potassium carbonate, and 1.42 ml of dimethyl sulfate in 50 ml of 2-butanone were stirred at reflux for approximately 18 hours. After cooling to 25° C., the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with one volume of water and one volume of a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and evaporated to dryness leaving a yellow oil which crystallized on standing. Recrystallization from ethyl acetate/hexane provided 4.38 g of the desired title product, m.p. 85°-86.5° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[NH2:33][CH2:34][CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[C:6]([C:24]4[CH:29]=[CH:28][C:27]([C:30](=[O:31])[NH:33][CH2:34][CH2:35][C:36]5[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=5)=[CH:26][CH:25]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Reactant: NCCc1cccnc1
Product: O=C(NCCc1cccnc1)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 106.9 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 3-(2-aminoethyl)pyridine (available from Aldrich Chemical Company, Inc.; 76 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(2-pyridin-3-yl-ethylcarbamoyl)-biphenyl-2-carboxylic acid (129 mg, 109%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.14 (br s, 1H), 8.63 (t, J=5.5 Hz, 1H), 8.57 (s, 1H), 8.51 (d, J=4.3 Hz, 1H), 8.47 (s, 1H), 8.39 (d, J=1.8 Hz, 1H), 8.33 (d, J=2.0 Hz, 1H), 8.24 (dd, J=8.0, 2.0 Hz, 1H), 8.09 (dd, J=8.4, 1.9 Hz, 1H), 7.83-7.90 (m, 3H), 7.76 (d, J=8.3 Hz, 1H), 7.58 (d, J=8.3 Hz, 1H), 7.45-7.52 (m, 3H), 3.58 (q, J=6.6 Hz, 2H), 2.95 (t, J=6.9 Hz, 7H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][N:9]=[C:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]([F:19])([F:18])[F:17].[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:8]1[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[C:15]2[C:10]([C:11]([C:16]([F:19])([F:17])[F:18])=[CH:12][CH:13]=[CH:14]2)=[N:9]1
Reactant: Cc1ccccc1B(O)O
Reactant: FC(F)(F)c1cccc2c(-c3ccccn3)[nH]nc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccccc1-n1nc2c(C(F)(F)F)cccc2c1-c1ccccn1

Procedure:
A solution of 3-pyridin-2-yl-7-(trifluoromethyl)-2H-indazole (0.2633 g, 1 mmol), 2-methylphenylboronic acid (0.271 g, 2 mmol, copper(II)acetate (0.181 g, 1 mmol) and pyridine (0.161 mL, 2 mmol) in 20 mL of methylene chloride was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica gel 60, methylene chloride-ethyl acetate, 3:1) to give the title compound (0.08 g).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([O:13]C)[C:8](OC)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].Br.C(O)(=[O:18])C>>[CH2:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:13])[C:6]=1[OH:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(OC)c(OC)c1
Reactant: CC(=O)O
Agent: Br
Product: CCCCc1cccc(O)c1O
Temperature: 25 °C
Yield: 80.6 %

Procedure:
A mixture of 5.64 g (29 mM) of 4-n-butylveratrole, 18.54 g (309 mM) of acetic acid and 55.62 g (323 mM) of 47% hydrobromic acid was heated under reflux for 4 hours with stirring. The reaction mixture was cooled to the room temperature and added with 50 ml of eater. The separated oil was extracted with ether. The ether solution was successively washed with 50 ml of water, 75 g of 5% aqueous sodium thiosulfate solution, and further twice with each 50 ml of water. The resulting solution was dried with anhydrous sodium sulfate, distilled off ether, and vacuum distilled to obtain 3.89 g (23 mM) of n-butylcatechol as light yellow liquid having a boiling point of 125° C./3 mmHg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][CH:6]=2.ClC1C=CC=C(C(OO)=[O:20])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N+:9]2[O-:20])=[N:4][CH:3]=1
Reactant: Fc1cnc2cccnc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cccc2ncc(F)cc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 71.3 %

Procedure:
To a solution of 76 mg of 3-fluoro-1,5-naphthyridine in 3 mL of chloroform, 136 mg of m-chloroperbenzoic acid was added, and the mixture was stirred at room temperature for 2.5 hours. Thereto was added 27 mg of m-chloroperbenzoic acid, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, a 5% aqueous sodium thiosulfate solution and chloroform were added, the organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using silica gel; Silica Gel 60N made by KANTO CHEMICAL CO., INC., and an eluent of chloroform:methanol=50:1 to obtain 60 mg of 7-fluoro-1,5-naphthyridine 1-oxide as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19](O)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:28][CH2:27][C@H:26]([N:29]([CH3:33])[C:30](=[O:32])[CH3:31])[CH2:25][CH2:24]2)[CH:3]=1.[CH3:34][N:35]([CH3:40])[CH2:36][CH2:37][CH2:38][NH2:39]>>[CH3:34][N:35]([CH3:40])[CH2:36][CH2:37][CH2:38][NH:39][C:19]([C:16]1[S:15][C:11]2[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[O:22][C@H:23]3[CH2:28][CH2:27][C@H:26]([N:29]([CH3:33])[C:30](=[O:32])[CH3:31])[CH2:25][CH2:24]3)[C:10]=2[C:17]=1[CH3:18])=[O:20]
Reactant: CN(C)CCCN
Reactant: CC(=O)N(C)[C@H]1CC[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)O)c(C)c23)CC1
Product: CC(=O)N(C)[C@H]1CC[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)NCCCN(C)C)c(C)c23)CC1

Procedure:
Prepared analogously to 1.4 from 0.094 g 4-(4-Fluoro-2-(trans-4-(N-methylacetamido)cyclohexyloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylic acid (cpd.7.2) and 3-(dimethylamino)propylamine (126 μl).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2O.[Br-:14].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[Br:14][C:5]1[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[CH:7][CH:6]=1
Reactant: [Br-]
Reactant: Cc1cc(Cl)cc2c(O)ccnc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Cc1cc(Cl)cc2c(Br)ccnc12
Temperature: 25 °C

Procedure:
A mixture of 6-chloro-4-hydroxy-8-methylquinoline (1.9 g, 9.8 mmol) and triphenylphosphine dibromide (6.2 g, 14.7 mmol) in acetonitrile (50 mL) was refluxed for 2 hours. The mixture was allowed to cool to room temperature then concentrated. The residue was purified by silica gel chromatography eluting with 0-10% EtOAc/hexanes to afford the title compound as a white solid: 1H NMR (500 MHz, CDCl3): δ 8.67 (d, J=4.7 Hz, 1H); 8.06 (d, J=2.2 Hz, 1H); 7.71 (d, J=4.6 Hz, 1H); 7.58 (s, 1H); 2.79 (s, 3H); LC1: 1.88 min. (M+H) 256.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C>O1CCCC1>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[S:3][C:4]=2[CH:10]=1
Reactant: COc1ccc2nc(Cl)sc2c1
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc2nc(N3CCNCC3)sc2c1
Temperature: 160 °C

Procedure:
A mixture of 1.50 mmol 2-chloro-6-methoxybenzothiazole (CA=[2605-14-3]), 4.51 mmol of piperazine and 4.51 mmol of triethylamine in 5 ml of tetrahydrofuran in a sealed tube was heated at 160° C. for 5 min under microwave irradiation. The reaction mixture was concentrated, and the residue was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:18](Br)([CH3:20])[CH3:19].O>CN(C=O)C>[F:1][C:2]1[C:10]2[N:9]([CH:18]([CH3:20])[CH3:19])[C:8]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Br
Reactant: O=C1NCCc2[nH]c3c(F)cccc3c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1c2c(c3cccc(F)c31)C(=O)NCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
A stirred solution of 6-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one (1.006 g) in dry DMF (50 ml) was treated with sodium hydride (73.2% dispersion in oil; 333 mg) and stirred under nitrogen for 1 h. Isopropyl bromide (663 mg) was then added, and the solution was stirred at room temperature for 30 min and then at 50° for 12 h. A further portion of isopropyl bromide (150 mg) was then added, and the reaction was then stirred under nitrogen at 50° for ca. 60 h. The mixture was then cooled to room temperature and added to water (300 ml). The mixture was then extracted with dichloromethane (3×200 ml), adsorbed onto silica, and purified by FCC eluting with System A (150:8:1) to give a solid (240 mg) which was triturated with ether to give the title compound (130 mg), m.p. 183°-184°.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[F:14][C:15]1[CH:16]=[C:17]([CH:23]2[NH:28][C:27]([O:29][CH3:30])=[N:26][C:25]([CH3:31])=[C:24]2[C:32](=[O:34])[CH3:33])[CH:18]=[C:19]([F:22])[C:20]=1[F:21].N1C=CC=CC=1>C(Cl)Cl>[F:14][C:15]1[CH:16]=[C:17]([CH:23]2[N:28]([C:2]([O:4][C:5]3[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=3)=[O:3])[C:27]([O:29][CH3:30])=[N:26][C:25]([CH3:31])=[C:24]2[C:32](=[O:34])[CH3:33])[CH:18]=[C:19]([F:22])[C:20]=1[F:21]
Reactant: COC1=NC(C)=C(C(C)=O)C(c2cc(F)c(F)c(F)c2)N1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC1=NC(C)=C(C(C)=O)C(c2cc(F)c(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
4-Nitrophenyl chloroformate (1.89 g, 9.38 mmol) was added to a solution of 6-(3,4,5-trifluorophenyl)-1,6-dihydro-2-methoxy-5-acetyl-4-meth-ylpyrimidine (2.80 g, 9.38 mmol) and pyridine (10 mL) in CH2Cl2 (200 mL) at 0-5° C., and the resulting mixture was allowed to warm to room temperature. After 12 h, the solvent was evaporated and the residue was purified by flash chromatography (dichloro-methane/EtOAc, 1/9 to 3/20), giving the desired product as a white powder (4.00 g, 92%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:20])[CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]([OH:19])=O)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:22][C:23]1[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:24]=1[OH:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:30][C:24]1[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:23]=1[NH:22][C:17]([C:15]1[O:14][N:13]=[C:12]([O:11][CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:20])[CH:16]=1)=[O:19]
Reactant: C[C@@H](COc1cc(C(=O)O)on1)NC(=O)OC(C)(C)C
Reactant: Nc1cc(O)ccc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](COc1cc(C(=O)Nc2cc(O)ccc2O)on1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.9 %

Procedure:
To a solution of 3-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)isoxazole-5-carboxylic acid (1.5 g), 2-aminobenzene-1,4-diol hydrochloride (0.847 g) and HATU (1.99 g) in DMF (20 mL) was added N,N-diisopropylethylamine (1.80 mL), and the mixture was stirred at room temperature for 5 hr. The solvent was evaporated under reduced pressure, 0.1M hydrochloric acid was added thereto, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (1.11 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.Cl[CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C(=O)C>[CH2:26]([N:27]([CH2:30][CH3:31])[CH2:28][CH2:29][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:21])([CH3:22])[C:6]=2[CH:23]=1)[CH3:25]
Reactant: CCN(CC)CCCl
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCN(CC)CCOc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 33 %

Procedure:
8-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A6, 25 mg, 0.083 mmol) was dissolved in N,N-dimethylacetamide (1 mL), added with 2-chloroethyldiethylamine (16 mg, 1.1 eq.) and cesium carbonate (54 mg, 2 eq.) in order and stirred at 100° C. for 4 hr. The reaction solution was poured over water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by amino silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (11 mg, 32%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[F:22][C:23]([F:37])([F:36])[C:24]1[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:26][CH:27]=[CH:28][CH:29]=1.[K+].[Br-]>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:33]3[CH2:34][CH2:35][N:30]([C:25]4[C:24]([C:23]([F:37])([F:22])[F:36])=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:31][CH2:32]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [Br-]
Agent: [K+]
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCN(c2ncccc2C(F)(F)F)CC1
Yield: 25 %

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(3-trifluoromethyl-pyridin-2-yl)-piperazine, yield 25%. White crystals, m.p. 131–132° C.; HPLC-MS: m/z: 513 (M+1) at Rt=5.0 min.; IR (KBr): ν 1722 (C═O) cm−1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:14][CH2:13]1)[CH:7]=O)([O-:3])=[O:2].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26]C1>>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][N:24]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:14][CH2:13]1)([O-:3])=[O:2]
Reactant: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)c([N+](=O)[O-])c1
Reactant: C1CCNCC1
Product: O=[N+]([O-])c1cc(CN2CCCC2)ccc1N1CCC(CN2CCCC2)CC1

Procedure:
Prepared from the product of Example 64 and piperidine.
Reaction SMILES: [OH:1][CH:2]([CH2:6][O:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]#[N:5].[C:27](OC(=O)C)(=[O:29])[CH3:28].N1C=CC=CC=1.Cl>C(OCC)(=O)C>[C:27]([O:1][CH:2]([CH2:6][O:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:3][C:4]#[N:5])(=[O:29])[CH3:28]
Reactant: N#CCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OC(CC#N)COC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To (±)-3-hydroxy-4-trityloxybutane-nitrile (1.03 g, 3.00 mmol) under N2 was added acetic anhydride (1.53 g, 15.00 mmol) and pyridine (0.26 g, 3.30 mmol) and the resultant mixture was stirred overnight at room temperature. After completion of the reaction (TLC) the reaction mixture was diluted with ethyl acetate (25 mL) and treated with 1N HCl (20 mL). The organic layer was separated, washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated and the residue was purified by column chromatography employing EtOAc-hexane (15:85) as eluent to afford the required 3-acetyloxy-4-trityloxybutanenitrile in nearly quantitative yield. IR (KBr) 3466, 3066, 3019, 2925, 2863, 2235, 1741, 1223, 1004 cm−1; 1HNMR (300 MHz, CDCl3) δ 2.09 (s, 3H), 2.76 (d, 2H, J=5.69, 5.79 Hz), 3.92-4.02 (m, 1H), 7.23-7.41 (m, 15H); Mass (EI) 259, 243, 165, 105, 77.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:6]([OH:7])[C:5]=1[OH:14])([O-:3])=[O:2].[CH3:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:17]=1[C:18](Cl)=[O:19]>>[CH3:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:17]=1[C:18]([O:7][C:6]1[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[OH:14])=[O:19]
Reactant: O=[N+]([O-])c1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: Cc1cccc(C)c1C(=O)Cl
Product: Cc1cccc(C)c1C(=O)Oc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1O
Temperature: 100 °C

Procedure:
A mixture containing 2.0 g of 3,5-dinitrocatechol in 5 ml of 2,6-dimethylbenzoylchloride was heated for 20 hours in 100° C. The excess 2,6-dimethylbenzoylchloride was removed in high vacuum. The residue was purified in silicagel column. Yield 1.5 g (45%), yellow viscous oil, which was crystallized from petroleum ether, m.p. 163°-165° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([O:13][Si](C(C)(C)C)(C)C)[C:5]=1[CH2:21]Br.[CH3:24][NH2:25].CO.Cl>C1COCC1>[OH:13][C:6]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]2[C:5]=1[CH2:21][N:25]([CH3:24])[C:3]2=[O:2]
Reactant: COC(=O)c1c([N+](=O)[O-])ccc(O[Si](C)(C)C(C)(C)C)c1CBr
Reactant: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CN1Cc2c(O)ccc([N+](=O)[O-])c2C1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
At room temperature, a solution of 2-bromomethyl-3-(tert-butyl-dimethyl-silanyloxy)-6-nitro-benzoic acid methyl ester (12.6 g, 25.1 mmol) in 60 mL of THF is added 2M solution of methylamine in THF (37.7 mL, 75.3 mmol) at 0° C. and then the reaction mixture is stirred for 6 hours at the room temperature. Methanol and 1M Hydrochloric acid solution are added to the reaction mixture. The mixture is evaporated in vacuo and the precipitate is collected to give 4-hydroxy-2-methyl-7-nitro-2,3-dihydro-isoindol-1-one (2.1 g) as yellow solid in 40% yields for 3 steps.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:23]=[CH:22][C:21](=[O:24])[N:20]([C:25]3[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.CN(C=O)C.C(Cl)(=O)C([Cl:42])=O>C(Cl)Cl>[CH3:1][C:2]1[C:3]2[CH:23]=[CH:22][C:21](=[O:24])[N:20]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([Cl:42])=[O:30])=[CH:27][CH:26]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1
Reactant: Cc1nc(N2CCN(c3ccccc3)CC2)nc2c1ccc(=O)n2-c1ccc(C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(N2CCN(c3ccccc3)CC2)nc2c1ccc(=O)n2-c1ccc(C(=O)Cl)cc1
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a solution of compound 10 (0.215 g; 0.487 mmol) and anhydrous DMF (120 uL) in 8 mL of methylene chloride, oxalyl chloride (0.18 g; 5 mmol) was added dropwise at room temperature and the reaction mixture was stirred for 2 h. Then it was concentrated and the oxalyl chloride carefully removed by distillation to yield compound L (0.217 g; 97%). The compound was used in the next step without further purification.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]#[N:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.Cl.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1.C(Cl)(Cl)Cl>C(O)C>[NH2:12][C:11]1[N:21]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)[N:22]=[CH:4][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccc(Cl)cc2)c1N
Temperature: 25 °C
Yield: 47.8 %

Procedure:
A solution of ethyl ethoxymethylenecyanoacetate (3 g, 17.7 mmol) and 4-chlorophenylhydrazine hydrochloride (3.33 g, 18.6 mmol) in ethanol (60 mL) was refluxed for 2 days, following the procedure described in Schmidt, P. et al. Helv.Chim.Acta, 1959, 349. The reaction mixture was then allowed to cool to room temperature, whereupon a precipitate was formed. Cold CHCl3 was added, the precipitate was filtered and washed with more CHCl3. The filtrate and the washings were evaporated to dryness, precipitated with ether, filtered and dried to give ethyl 5-amino-1-(4-chlorophenyl)-1H-pyrazole-4-carboxylate (2.25 g, 48%) as a white solid: mp 150°-156° C.; 1H NMR (80 MHz, CDCl3) δ (TMS) 7.77 (s, 1H, pyrazole), 7.48 (s, 4H, arom), 4.30 (q, J=7, 2H, OCH2), 1.36 (t, J=7, 3H, OCH2CH3). Analysis calculated for C12H12ClN3O2 : C 54.25; H 4.55; N 15.81. Found: C 54.77; H 4.49; N 15.65.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[S:7][CH3:8].Cl.[OH:10][C:11]1[C:18]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:17][C:14]([CH:15]=O)=[CH:13][C:12]=1[C:23]([CH3:26])([CH3:25])[CH3:24]>CO>[OH:10][C:11]1[C:18]([C:19]([CH3:21])([CH3:20])[CH3:22])=[CH:17][C:14]([CH:15]=[N:1][N:2]2[CH:6]=[CH:5][N:4]=[C:3]2[S:7][CH3:8])=[CH:13][C:12]=1[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CSc1nccn1N
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CO
Product: CSc1nccn1N=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.65 g of 1-amino-2-methylmercaptoimidazole are dissolved in 50 ml of methanol and treated with 3 ml of 2N hydrochloric acid. After the addition of 1.05 g of 4-hydroxy-3,5-di-tert.-butylbenzaldehyde, the reaction mixture is stirred at room temperature overnight. Subsequently, the solvent is removed by evaporation in a vacuum. The residue is suspended in 30 ml of water and treated with saturated sodium carbonate solution up to an alkaline reaction. The mixture is extracted three times with 20 ml of methylene chloride each time, the combined organic phases are dried over sodium sulfate, filtered and evaporated. The crystalline residue is recrystallized from water/methanol, and there is obtained 1-(4-hydroxy-3,5-di-tert.-butylbenzylideneamino)-2-methylmercaptoimidazole of m.p. 181°-183°.