Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[N:19]([CH3:20])[NH:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:22]([N:26]=[C:27]=[O:28])[CH2:23][CH2:24][CH3:25].[ClH:29]>C(Cl)(Cl)Cl.N#N.CCOCC>[ClH:29].[CH2:22]([NH:26][C:27]([N:18]1[C:17](=[O:21])[CH2:16][CH:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:8]=2)[N:19]1[CH3:20])=[O:28])[CH2:23][CH2:24][CH3:25]
Reactant: CCCCN=C=O
Reactant: COc1ccc(C2CC(=O)NN2C)cc1OC1CCCC1
Agent: Cl
Agent: N#N
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CCCCNC(=O)N1C(=O)CC(c2ccc(OC)c(OC3CCCC3)c2)N1C
Reaction time: 0.25 h
Yield: 56 %

Procedure:
5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinone (2.06 mmol, 0.600 g) is dissolved in dry chloroform (10 mL) in a N2 atmosphere. To this is added dropwise at room temperature butyl isocyanate (5.15 mmol; 0.583 mL) neat. The sample is heated to reflux for 4 hours at which time TLC shows no starting material. The sample is evaporated to yield a clear oil which is dissolved in ether. To this solution is added ethanolic HCl and the sample is stirred for 15 minutes and evaporated in vacuo to afford a solid which is recrystallized from chloroform and hexane to give the title compound as a white solid (0.495 mg; 56%) m.p.: 115°-122° C. (dec) 1H NMR (DMSO-d6, 400 MHz) δ8.3 (s, 1H); 7.91 (t, 3H, J=5.7 Hz); 6.95 (d, 1H, J=1.3 Hz); 6.89 (d, 1H, J=8.3 Hz); 6.81 (dd, 1H, J=8.3, 1.6 Hz); 4.68 (m, 1H); 4.35 (d, 1H, J=5.6 Hz); 3.69 (s, 3H); 3.15 (m, 2H); 2.73 (s, 3H); 1.84 (m, 2H); 1.68 (m, 3H); 1.54 (m, 2H); 1.40 (m, 2H); 1.23 (m, 3H); 0.85 (t, 2H, J=7.3 Hz). IR (KBr, cm-1) 1760
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=[O:2].[C:13]12(O)[CH2:21][CH:17]([C:18]1([CH3:20])[CH3:19])[CH2:16][CH2:15][C:14]2([OH:23])[CH3:22].C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O.C1COCC1>[OH:23][C:14]1([CH3:22])[C:15](=[O:2])[CH2:16][CH:17]2[CH2:21][CH:13]1[C:18]2([CH3:20])[CH3:19]
Reactant: CC1(O)CCC2CC1(O)C2(C)C
Reactant: O=C(O)c1ccccc1I(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC1(O)C(=O)CC2CC1C2(C)C
Yield: 86 %

Procedure:
o-Iodoxybenzoic acid I (420 mg; 1.5 mmol) was added under stirring in one portion to a solution of pinanediol (170 mg; 1 mmol) in DMSO (3.4 ml) and THF (2.9 ml) at 0° C. After 3 h the reaction was poured in 20 ml of a solution of Na2CO3 (10%) and extracted with diethyl ether (3×10 ml). The combined organic layers were dried over sodium sulfate. The organic solvent was distilled under vacuum. The residue was purified by chromatography (SiO2, dichloromethane) to give after trituration with n-hexane, 145 mg (86%) of 2-hydroxy-pinanone, mp 30°-32° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:33])([F:32])[C:20]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:21]=1[CH2:22]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][CH2:22][C:21]1[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[CH:27][C:20]=1[C:19]([F:18])([F:32])[F:33])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1=NC(=O)CN1C(=O)OCc1ccccc1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CN(C(=O)OCc2ccccc2)C(NCc2ccc(C(F)(F)F)cc2C(F)(F)F)=N1
Temperature: 25 °C
Yield: 52.2 %

Procedure:
A suspension of 2-amino-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (93.2 mg, 0.40 mmol), 2,4-bis-trifluoromethyl-benzylbromide (126.6 mg, 0.40 mmol) and K2CO3 (83.01 mg, 0.60 mmol) in acetonitrile (10 mL) was heated to reflux under argon for 1 hr. Cooled to r.t. and the reaction mixture was partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated to give a residue which was triturated with EtOAc and filtered to give 2-(2,4-bis-trifluoromethyl-benzylamino)-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester as a white solid (96.0 mg, 52.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][C:14]=1[CH3:20].C(=O)([O-])[O-].[K+].[K+]>C(OCC)C.[Cu]>[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([O:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:15][C:14]=1[CH3:20]
Reactant: COc1ccc(O)cc1
Reactant: COC(=O)c1ccc(Br)cc1C
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: COC(=O)c1ccc(Oc2ccc(OC)cc2)cc1C
Temperature: 200 °C
Reaction time: 12 h
Yield: 28.2 %

Procedure:
A mixture of 4-methoxyphenol (12 grams, 52.4 mmol), 4-bromo-2-methylbenzoic acid methyl ester (12 grams, 52 mmol), potassium carbonate (14.5 grams, 105 mmol) and copper powder (3.3 grams, 52 mmol) was stirred at 200° C. for 12 hours. The mixture was cooled to 25° C., diluted with diethylether, and the organic phase was washed twice with water, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography (5% ether in hexanes) afforded 4.0 grams of 4-(4-Methoxy-phenoxy)-2-methyl-benzoic acid methyl ester. MS: 273.2 [M+H]+
Reaction SMILES: [CH2:1]1[O:10][C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[O:3][CH2:2]1.[Cl:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([C:20]2[CH:25]=[C:24]([CH2:26]Cl)[CH:23]=[CH:22][N:21]=2)=[CH:14][C:13]=1[O:28][CH3:29]>>[CH2:1]1[O:10][C:4]2([CH2:9][CH2:8][N:7]([CH2:26][C:24]3[CH:23]=[CH:22][N:21]=[C:20]([C:15]4[CH:16]=[C:17]([O:18][CH3:19])[C:12]([Cl:11])=[C:13]([O:28][CH3:29])[CH:14]=4)[CH:25]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1Cl
Reactant: C1CC2(CCN1)OCCO2
Product: COc1cc(-c2cc(CN3CCC4(CC3)OCCO4)ccn2)cc(OC)c1Cl

Procedure:
4-Piperidone ethylene ketal (573 mg) and 2-(4-chloro-3,5-dimetoxyphenyl)-4-chloromethylpyridine (1.19 g) were condensed in the same manner as described in Example 2 to give the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([CH3:22])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[OH:15])[C@@H:9]1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)C1C=CC=CC=1.Cl.[H][H]>CN(C)C=O.[Pd]>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][C@H:9]2[C@@H:10]([C:14]([CH3:22])([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[OH:15])[CH2:11][CH2:12][CH2:13][NH:8]2)=[CH:29][CH:28]=1
Reactant: [H][H]
Reactant: COc1ccc(C[C@H]2[C@@H](C(C)(O)c3ccccc3)CCCN2Cc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc(C[C@@H]2NCCC[C@@H]2C(C)(O)c2ccccc2)cc1

Procedure:
A solution 41.5 g. of cis-1-benzyl-2-(p-methoxybenzyl)-α-methyl-α-phenyl-3-piperidinemethanol in 8.3 ml. of concentrated hydrochloric acid is diluted with dimethylformamide to a volume of 400 ml. and catalytically hydrogenated under 10 atmospheres of hydrogen in the presence of palladium-on-carbon catalyst. The catalyst is removed by filtration and the solvent is evaporated from the filtrate under reduced pressure. The resulting residue is taken up in ethanol and diluted with diethyl ether to yield cis-2-(p-methoxybenzyl)-α-methyl-α-phenyl-3-piperidinemethanol.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].Cl[CH2:7][C:8](=O)[CH2:9][C:10]([O:12]CC)=[O:11].Cl>>[NH:5]=[C:3]1[N:2]([NH2:1])[C:8]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][S:4]1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: NNC(N)=S
Agent: Cl
Product: N=c1scc(CC(=O)O)n1N

Procedure:
Reaction of thiosemicarbazide and ethyl 4-chloroacetoacetate in warm concentrated hydrochloric acid yielded 2-imino-3-aminothiazoline-4-acetic acid (Compound IIIA), which is also obtained by heating the hydrochloride of Compound IA in hydrochloric acid. Refluxing Compound IIIA in ethanolic hydrochloric acid produces the hydrochloride of the corresponding acetate, Compound IIIB (ethyl 2-imino-3-aminothiazoline 4-acetate.)
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:34][CH3:35])=[CH:31][CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[C:30]([O:34][CH3:35])=[CH:31][CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cccc(OC)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2cccc(OC)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-7-methoxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][CH:33]([OH:36])[CH:34]=[CH2:35].O[C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH:41]=[O:42]>C1COCC1>[CH3:32][CH:33]([O:36][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH:41]=[O:42])[CH:34]=[CH2:35]
Reactant: O=Cc1cccc(O)c1
Reactant: C=CC(C)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC(C)Oc1cccc(C=O)c1
Reaction time: 0.17 h

Procedure:
Added DEAD (0.964 mL, 6.142 mmole) dropwise to a solution of triphenylphosphine (0.1.611 g, 6.142 mmole), 3-buten-2-ol (Fluka, 0.423 mL, 4.91 mmole), and 3-hydroxy benzaldehyde (0.5 g, 4.09 mmole) in 10 mL dry THF, at rt, under Argon. After 10 min, the reaction was concentrated in vacuo and was purified on a 35 g Redisep column eluting with a gradient of 5%-30% EtOAc in hexanes.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])([O-])=O.[Na+].[Na+].[C:10]([O:14][C:15](=[O:25])[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=1)([CH3:13])([CH3:12])[CH3:11]>O.CO>[C:10]([O:14][C:15](=[O:25])[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=[NH:24])[NH:2][OH:3])[CH:18]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: NO
Reactant: CC(C)(C)OC(=O)Nc1cccc(C#N)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(C(=N)NO)c1

Procedure:
Hydroxylamine hydrochloride (179 mg, 2.60 mmol) and Na2CO3 (138 mg, 1.30 mmol) was dissolved in 1 mL water. A solution of (3-cyano-phenyl)-carbamic acid tert-butyl ester (560 mg, 2.60 mmol) in 10 mL of methanol was added and the combined solution was stirred at reflux overnight. The solvent was removed and the resulting precipitate was extracted with water and ethyl acetate to yield [3-(N-hydroxycarbamimidoyl)-phenyl]-carbamic acid tert-butyl ester which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:21])(=[O:20])[NH:18][CH3:19])=[CH:13][CH:12]=2)=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:23]>O1CCOCC1>[NH2:23][C:6]1[C:7]([C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:21])(=[O:20])[NH:18][CH3:19])=[CH:13][CH:12]=2)=[O:9])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: CNS(=O)(=O)c1ccc(OC(=O)c2c(Cl)ncnc2Cl)cc1
Reactant: N
Solvent: C1COCCO1
Product: CNS(=O)(=O)c1ccc(OC(=O)c2c(N)ncnc2Cl)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 69 %

Procedure:
4-(N-methylsulfamoyl)phenyl 4,6-dichloropyrimidine-5-carboxylate (1.4 g, 3.18 mmol) was dissolved in dioxane (16 ml) and cooled in an ice bath. Ammonia (2.27 ml, 7N in MeOH) was dropwise added and the mixture was stirred at 0° C. for 6 h. The solvent was removed and ethyl acetate added. The solid precipitate was filtered and washed with ethyl acetate to give 750 mg (69% yield) of the title compound. Purity 100%
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][C:10]([O:13][CH:14]([C:16]([OH:18])=O)[CH3:15])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)([N:21]1C=CN=C1)=O.[OH-].[NH4+]>>[NH2:21][C:16]([CH:14]([O:13][C:10]1[N:11]=[CH:12][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[N:9]=1)[CH3:15])=[O:18]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(Oc1ncn(-c2cccc(Br)c2)n1)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: CC(Oc1ncn(-c2cccc(Br)c2)n1)C(N)=O
Yield: 53.5 %

Procedure:
The process was carried out as was Example 45, starting with 3 g of the compound of Example 38, 2.3 g of carbonyldiimidazole and 0.7 g of ammonium hydroxide. A yield of 1.6 g of the desired product, in unrecrystallized form, m.p. 141°-144°, was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC.Cl.[CH3:31][NH:32][O:33][CH3:34]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([N:32]([O:33][CH3:34])[CH3:31])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)nn1
Reactant: CNOC
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
To a stirred solution of 6-chloropyridazine-3-carboxylic acid (12.5 g, 0.078 mol) in CH2Cl2 (80 mL) at 0° C. were added triphosgene (11.6 g, 0.039 mol), Et3N (55 mL, 0.4 mol), and N,O-dimethylhydroxylamine hydrochloride (7.6 g, 0.078 mol). The reaction mixture was stirred at room temperature for 2 h. The salt was filtered, after removal of the solvent in vacuo, the residue was purified by column chromatography to afford 6-chloro-N-methoxy-N-methylpyridazine-3-carboxamide (13.5 g, 86%). 1H NMR (DMSO-d6, 400 MHz): δ 8.08 (d, J=9.2 Hz, 1H), 8.06 (d, J=9.2 Hz, 1H), 3.33 (s, 3H), 8.06 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH:11][C:12](=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])(=[O:10])[CH3:9]>C(O)C>[C:8]([NH:11][C@@H:12]([C:13]([OH:15])=[O:14])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)NC(=Cc1ccccc1)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)N[C@H](Cc1ccccc1)C(=O)O
Temperature: 50 °C
Reaction time: 20 h

Procedure:
0.0025 m-mol of rhodium-1,5-cyclooctadienechloride complex, 0.0065 m-mol of one of the asymmetric ligand compounds indicated in Table 1 and 0.25 m-mol of triethylamine were dissolved in 20 ml of ethanol, and 5 m-mol of α-acetamidocinnamic acid was added to the solution. The mixture was stirred for 20 hours at 50° C. and under a hydrogen atmosphere of 20 atm. The reaction mixture was concentrated under reduced pressure and then dissolved in 0.5N aqueous solution of caustic soda. Insolubles were filtered off and the filtrate was made acid with diluted hydrochloric acid and extracted with ether. The organic layer was washed with water and dried. The solvent was distilled off to obtain optically active (R)-N-acetylphenylalanine. The results of Synthesis Nos. 1-5 are shown in Table 1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[CH2:9][CH:10]([CH2:16][CH2:17][CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)([O-:22])=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O1CCOCC1>[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:19])[CH2:9][CH:10]([CH2:16][CH2:17][CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=2)=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: CCCC(CC(=O)c1ccc(Br)cc1)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCCC(CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)C(=O)OCC
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 46.9 %

Procedure:
To a 150 mL 3-neck flask fitted with a reflux condenser was added ethyl 2-[2-(4-bromophenyl)-2-oxoethyl]pentanoate (1.33 g, 4.10 mmol) and 4-nitro phenyl boronic acid (0.81 g, 4.9 mmol), dissolved in toluene (37 mL) and dioxane (10 mL), followed by addition of saturated aqueous sodium carbonate (11 mL). A thin-gauge needle was inserted into the bi-phasic mixture and the mixture was degassed with argon over 30 minutes, at which point 1,2-bis[(diphenylphosphino) ferrocene]dichloropalladium(II) (0.17 g, 0.20 mmol) was added, followed by 15 minutes of degassing. The mixture was heated to 85° C. for 16 h. The very darkly colored reaction mixture was allowed to cool, and diluted with ethyl acetate (100 mL) and saturated aqueous sodium chloride solution (100 mL). The layers were separated, the aqueous layer extracted twice with ethyl acetate (50 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (75 mL), dried over anhydrous magnesium sulfate, and filtered in vacuo through 2 cm Celite®/2 cm silica. The filtrate was concentrated under reduced pressure, leaving a dark red-brown oil, that was purified by flash chromatography (10:1 hexane:ethyl acetate, then 7:1 hexane:ethyl acetate, then 4:1 hexane:ethyl acetate) to afford ethyl 2-[2-(4′-nitro-1,1′-biphenyl-4-yl)-2-oxoethyl]pentanoate (0.71 g, 48%). LC-MS ret. time 3.88 min, m/z 369.8 (MH+); 1H NMR (300 MHz, CDCl3) δ 0.95 (t, 3H), 1.30 (t, 3H), 1.35-1.50 (m, 2H), 1.60-1.83 (m, 2H), 3.0-3.18 (m, 2H), 3.5 (dd, 1H), 4.20 (q, 2H), 7.65-7.88 (overlapping d, 4H), 8.10 (d, 2H), 8.35 (d, 2H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:14]([O:15][CH3:16])=[CH:13][C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[CH:5]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:27])[CH:25]=[CH2:26]>ClCCl>[C:24]([N:10]1[CH2:11][CH2:12][C:6]2[CH:5]=[C:4]([O:3][CH3:2])[C:14]([O:15][CH3:16])=[CH:13][C:7]=2[CH2:8][CH2:9]1)(=[O:27])[CH:25]=[CH2:26]
Reactant: COc1cc2c(cc1OC)CCNCC2
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCc2cc(OC)c(OC)cc2CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At ambient temperature, 70 g (287.2 mmol) of the product obtained in Step 2 are dissolved in 1200 mL of dichloromethane, and then 100 mL (718 mmol/2.5 eq.) of triethylamine are added all at once. The mixture is brought to 0° C. and a solution of 25.8 mL (315.9 mmol/1.1 eq.) of acryloyl chloride in 270 mL of dichloromethane is poured in dropwise, maintaining the temperature at about 0° C. After 2 hours at 0° C., the mixture is stirred at ambient temperature overnight. Washing with 750 mL of water, 750 mL of 1N hydrochloric acid and 750 mL of water and then drying over magnesium sulphate are then carried out. After filtration and evaporation, the residue is chromatographed over 3.2 kg of silica (eluant: dichloromethane/ethanol: 95/5), followed by recrystallisation from isopropanol. After filtration over a frit and drying in vacuo at 50° C., the desired product is obtained.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=O.[C:14]([O:18][CH3:19])(=[O:17])[CH2:15][SH:16].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:11][C:10]([F:13])([F:12])[C:7]1[CH:8]=[CH:9][C:2]2[S:16][C:15]([C:14]([O:18][CH3:19])=[O:17])=[CH:4][C:3]=2[CH:6]=1
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(C(F)(F)F)ccc2s1
Temperature: 60 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A mixture of 5.0 g of 2-fluoro-5-(trifluoromethyl)benzaldehyde, 3.3 g of methyl thioglycolate, 4.0 g of potassium carbonate and 50 ml of DMF was stirred at 60° C. for 2 hours. The reaction mixture was cooled down to room temperature. To the reaction mixture was added water, and the mixture was extracted with tert-butyl methyl ether three times. The combined organic layers were washed with water and saturated saline, and dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was recrystallized from methanol, to obtain 6.3 g of methyl 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylate (present condensed ring compound 1).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:18]#[C:19][C:20]2[C:21]([NH2:29])=[N:22][CH:23]=[C:24]([N+:26]([O-:28])=[O:27])[CH:25]=2)[CH:15]=[CH:16][CH:17]=1.O1CCCC1>CN(C)C=O>[CH3:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:18]2[NH:29][C:21]3=[N:22][CH:23]=[C:24]([N+:26]([O-:28])=[O:27])[CH:25]=[C:20]3[CH:19]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: COCCOc1cccc(C#Cc2cc([N+](=O)[O-])cnc2N)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCOc1cccc(-c2cc3cc([N+](=O)[O-])cnc3[nH]2)c1
Temperature: 70 °C
Yield: 83 %

Procedure:
Potassium tert-butoxide (1.18 g, 10.5 mmol) was added to a solution of 3-[3-(2-methoxy-ethoxy)-phenylethynyl]-5-nitro-pyridin-2-ylamine (1.57 g, 5 mmol) in a 2:1 mixture of tetrahydrofuran and dimethylformamide (75 mL). The mixture was heated at 70° C. for 16 hours then the tetrahydrofuran was removed in vacuo. The mixture was poured onto a pad of silica and eluted with ethyl acetate then 10% methanol in ethyl acetate. The organics were concentrated in vacuo to 5% of their original volume and water (30 mL) was added. The resultant orange solid was filtered and dried to afford 2-[3-(2-methoxy-ethoxy)-phenyl]-5-nitro-1H-pyrrolo[2,3-b]pyridine (1.3 g, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][O:8][C:9]2[C:18](=[O:19])[C:17]3[C:12](=[C:13]([C:20]#[N:21])[CH:14]=[CH:15][CH:16]=3)[N:11]([CH3:22])[CH:10]=2)=[CH:5][CH:4]=1.[OH-:25].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[C:18](=[O:19])[C:17]3[C:12](=[C:13]([C:20]([NH2:21])=[O:25])[CH:14]=[CH:15][CH:16]=3)[N:11]([CH3:22])[CH:10]=2)=[CH:23][CH:24]=1
Reactant: COc1ccc(COc2cn(C)c3c(C#N)cccc3c2=O)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(COc2cn(C)c3c(C(N)=O)cccc3c2=O)cc1
Yield: 65.5 %

Procedure:
A solution of 3-((4-methoxybenzyl)oxy)-1-methyl-4-oxo-1,4-dihydroquinoline-8-carbonitrile (1.75 g, 5.46 mmol) and 25% aqueous sodium hydroxide (20 mL) in methanol (100 mL) was stirred at reflux for 3 h. After complete consumption of the nitrile, the mixture was concentrated to remove ˜75% of the methanol. The mixture was acidified to pH 3 with 1 M HCl (aq), and partitioned between EtOAc and brine. The organic phase was separated, dried over sodium sulfate and concentrated in vacuo. The crude product was absorbed onto silica gel and purified by automatic silica gel column chromatography (Combiflash RF), eluting with methanol/dichloromethane (0-30%) to afford 3-((4-methoxybenzyl)oxy)-1-methyl-4-oxo-1,4-dihydroquinoline-8-carboxamide (1.21 g, 3.58 mmol, 65.5% yield) as light brown solid. LCMS (M+H)+: 339.3.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]([C:16]([F:19])([F:18])[F:17])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:20]([O-])([OH:22])=[O:21].OS(O)(=O)=O>C(O)(=O)C>[N+:20]([C:4]1[CH:3]=[CH:2][C:1]([N:7]2[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]([C:16]([F:18])([F:19])[F:17])=[N:8]2)=[CH:6][CH:5]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1cc(C(F)(F)F)nn1-c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)c1cc(C(F)(F)F)nn1-c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
Intermediate 8 (2 g, 7.4 mmol) was dissolved in acetic acid (15 ml), cooled to 0° C. and added nitration mixture (6 ml HNO3 and 6 ml H2SO4) drop-wise. Reaction mixture was heated to 60° C. for overnight. Work up (AcOEt:H2O) and purification on silicagel (60-120 mesh silicagel) using EA and pet ether (3:97) as eluent afforded the title compound (850 mg) as a white solid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.37 (d, J 9, 2H), 7.68 (d, J 9, 2H), 7.31 (s, 1H), 3.87 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][CH:6]([CH2:8][OH:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.[CH2:13]1[O:15][CH2:14]1>CO>[OH:15][CH2:14][CH2:13][N:3]1[C:4]([CH3:11])([CH3:10])[CH2:5][CH:6]([CH2:8][OH:9])[CH2:7][C:2]1([CH3:12])[CH3:1]
Reactant: CC1(C)CC(CO)CC(C)(C)N1
Reactant: C1CO1
Solvent: CO
Product: CC1(C)CC(CO)CC(C)(C)N1CCO
Temperature: 120 °C
Reaction time: 6 h

Procedure:
25 g of 2,2,6,6-tetramethyl-4-hydroxymethyl-piperidine of Example 1 (0.146 moles) were dissolved in 50 cc of methanol and added with 8 g (0.18 moles) of ethylene oxide. The solution was introduced into a steel autoclave and heated under stirring during 6 hours at 120° C. Then the solvent was evaporated and the residue was crystallized from acetonitrile. 30 g of product having a M.P. of 81°-83° C. were obtained, the product being characterized by N.M.R. and I.R. analyses and recognized as the product intended to be obtained.