Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:3]=1[CH3:20].[O:21]1[CH2:26][CH:25]=[C:24]([C:27]2[CH:28]=[C:29]([NH2:33])[CH:30]=[N:31][CH:32]=2)[CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[O:21]1[CH2:22][CH:23]=[C:24]([C:27]2[CH:28]=[C:29]([NH:33][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[C:3]=3[CH3:20])[CH:30]=[N:31][CH:32]=2)[CH2:25][CH2:26]1
Reactant: Nc1cncc(C2=CCOCC2)c1
Reactant: Cc1c(N2CCOCC2)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(N2CCOCC2)nc2cc(F)cc(F)c2c1Nc1cncc(C2=CCOCC2)c1

Procedure:
Essentially prepared according to Procedure H using 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)morpholine (40.0 mg, 0.130 mmol) and 5-(3,6-dihydro-2H-pyran-4-yl)pyridin-3-amine in toluene to give N-(5-(3,6-dihydro-2H-pyran-4-yl)-pyridin-3-yl)-5,7-difluoro-3-methyl-2-morpholinoquinolin-4-amine. 1H NMR (CDCl3) δ ppm 8.28 (1H, d, J=2.0 Hz), 8.07 (1H, d, J=2.5 Hz), 7.32 (1H, ddd, J=10.0, 2.5, 1.4 Hz), 7.03 (1H, t, J=2.2 Hz), 6.94 (1H, d, J=12.7 Hz), 6.81 (1H, ddd, J=13.9, 8.6, 2.5 Hz), 6.11-6.19 (1H, m), 4.32 (2H, q, J=2.7 Hz), 3.93 (2H, t, J=5.5 Hz), 3.83-3.90 (4H, m), 3.34-3.43 (4H, m), 2.42-2.51 (2H, m), 2.06 (3H, s). Mass Spectrum (ESI) m/e=439.1 (M+1).
Reaction SMILES: C(O[CH:4](OCC)[CH:5]1[C:14]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[O:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=O)C.[NH2:31][NH2:32].Cl>CCO>[N:17]1([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:16][CH2:15][C:14]2([C:5]3[CH:4]=[N:32][NH:31][C:6]=3[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[O:13]2)[CH2:19][CH2:18]1
Reactant: NN
Reactant: CCOC(OCC)C1C(=O)c2ccccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccccc1-c1[nH]ncc12
Temperature: 60 °C
Yield: 71.5 %

Procedure:
To tert-butyl 3-(diethoxymethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (15.1 g, 35.9 mmol) and hydrazine (1.35 mL, 43.1 mmol) in EtOH (120 mL) was added hydrochloric acid (900 μL of 4.0 M in dioxanes, 3.6 mmol). The mixture was heated at 60° C. for 2 h before it was cooled and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in hexanes to give tert-butyl spiro[1H-chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (8.76 g, 71%). ESI-MS m/z calc. 341.2. found 342.3 (M+1)+; Retention time: 1.69 minutes (3 min run).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([NH2:16])[CH:10]=2)=[O:5])[CH3:2].N1C=CC=CC=1.[F:23][C:24]([F:41])([F:40])[C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:32]([C:37](Cl)=[O:38])=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([NH:16][C:37]([C:32]1[C:31]([C:28]3[CH:29]=[CH:30][C:25]([C:24]([F:23])([F:40])[F:41])=[CH:26][CH:27]=3)=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:38])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2cc(N)ccc2c1
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Yield: 159.1 %

Procedure:
7-Amino-quinoline-3-carboxylic acid ethyl ester (8.6 g, 39.8 mmol) was combined with pyridine (12.9 ml, 159 mmol) and 4-N,N-dimethylamino-pyridine (0.5 g, 4 mmol) in 100 ml of chloroform. The mixture was stirred as 4′-trifluoromethyl-biphenyl-2-carbonyl chloride (22.64 g, 79.5 mmol) was added as a solution in 100 ml of chloroform. After heating at reflux for 2 h, the mixture was concentrated under vacuum, the residue taken up in ethyl acetate (600 ml) and washed sequentially with a 1 N aqueous hydrochloric acid solution (2×200 ml), water, and brine. The organic phase was then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to yield 29.4 g of a red oil. This oil was purified by chromatography on silica, eluting sequentially with a 70:30 dichloromethane/hexanes solution, followed by dichloromethane, then a 10:90 ethyl acetate/dichloromethane solution. Concentration under vacuum of the product containing fractions afforded 13.15 g of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][NH:27][CH2:28][CH:29]([C:31]1[CH:32]=[N+:33]([O-:37])[CH:34]=[CH:35][CH:36]=1)[OH:30].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:27]([CH2:28][CH:29]([OH:30])[C:31]4[CH:32]=[N+:33]([O-:37])[CH:34]=[CH:35][CH:36]=4)[CH3:26])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: CNCC(O)c1ccc[n+]([O-])c1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN(C)CC(O)c2ccc[n+]([O-])c2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.4 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (135 mg, 0.342 mmol), 2-(methylamino)-1-(1-oxidopyridin-3-yl)ethanol (Preparation 86, 69 mg, 0.50 mmol) and diisopropylethylamine (89 μL, 0.51 mmol) in dry DMF (5.0 mL) was stirred for 20 hours at room temperature. The solution was then diluted with water (20 mL). The resulting precipitate was collected by filtration and the collected solid was dried in vacuo, providing 107 mg of the titled compound as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](Cl)=[O:5].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:9]1([NH:8][C:4](=[O:5])[CH:3]=[C:2]([CH3:7])[CH3:1])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccccc1
Reactant: CC(C)=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)=CC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 3,3-dimethylacryloyl chloride (4.8 mL, 43.2 mmol) in dry DCM (100 mL), was added aniline (4.02 g, 43.2 mmol) followed by diisopropylethylamine (14.28 mL, 86.4 mmol). The mixture was stirred at ambient temperature for 2 hrs. Saturated sodium bicarbonate was added to quench the reaction. The organic layer was separated and washed with sat NaHCO3 (50 mL) and water (50 mL×2). The resulting solution was dried over MgSO4 and the filtrate evaporated to afford 3-methyl-but-2-enoic acid phenylamide as a brown solid in quantitative yield (7.6 g). MS: 176.0 (M+H)+; tR=2.40 min (method 1).
Reaction SMILES: C(O)C.[NH:4](C(OCC1C=CC=CC=1)=O)[C@H:5]([C:25]([O:27]CC1C=CC=CC=1)=[O:26])[CH2:6][CH2:7][C:8]([NH:10][C@H:11]([C:15]([O:17]CC1C=CC=CC=1)=[O:16])[CH2:12][CH2:13][CH3:14])=[O:9].[H][H]>[Pd].O>[NH2:4][C@H:5]([C:25]([OH:27])=[O:26])[CH2:6][CH2:7][C:8]([NH:10][C@H:11]([C:15]([OH:17])=[O:16])[CH2:12][CH2:13][CH3:14])=[O:9]
Reactant: [H][H]
Reactant: CCC[C@H](NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CCC[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)O
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To a mixed solution of ethanol (150 mL) and water (30 mL), Z-Glu(Nva-OBzl)-OBzl (4.05 g) and 5% palladium on carbon (5% palladium/carbon, 0.70 g) was added, and a catalytic reducing reaction was carried out at 50° C. overnight (14 hours) in a hydrogen gas atmosphere. Water (50 mL) was added to the reaction system in small portions during the reaction. The palladium/carbon was removed from the reaction system through filtration and the resulting filtrate was concentrated under reduced pressure. The residue was recrystallized from a small amount of water and ethanol to thus give γ-Glu-Nva (1.50 g) as white crystals. Furthermore, the crystals were dissolved in water (100 mL) followed by the lyophilization of the solution to give γ-Glu-Nva (1.27 g, 5.16 mM) as white powder. The characteristic values thereof are given below:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([NH2:12])=[N:8][NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH2:12])=[N:8][N:9]([CH2:20][C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:27][CH2:28]2)=[O:22])[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N)n[nH]c1C
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(N)nn(CC(=O)N2CCN(c3ccc(F)cc3)CC2)c1C

Procedure:
Protocol T was followed using 3-Amino-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/4) afforded the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3): 6.94–7.1 (m, 2H), 6.84–6.88 (m, 2H), 5.52 (s, 2H), 4.78 (s, 2H), 4.24–4.32 (q, 2H), 3.74–3.82 (m, 4H), 3.0–3.1 (m, 4H), 2.3 (s, 3H), 1.31–1.38 (t, 3H). MS (ES) M+H expected 389.43, found 390.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:12][C:5]2[S:6][C:7]([C:9]([OH:11])=O)=[CH:8][C:4]=2[CH2:3]1.[CH3:14][C:15]([NH2:18])([CH3:17])[CH3:16].C(N(CC)CC)C>O=S(Cl)Cl.ClCCl>[C:15]([NH:18][C:9]([C:7]1[S:6][C:5]2[CH2:12][C:2]([CH3:1])([CH3:13])[CH2:3][C:4]=2[CH:8]=1)=[O:11])([CH3:17])([CH3:16])[CH3:14]
Reactant: CC(C)(C)N
Reactant: CC1(C)Cc2cc(C(=O)O)sc2C1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)Cc2cc(C(=O)NC(C)(C)C)sc2C1
Temperature: 65 °C
Reaction time: 16 h
Yield: 97.8 %

Procedure:
A suspension of 282d (12.0 g, 61.0 mmol) in SOCl2 (80 mL) was heated at 65° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane (20 mL), which was added to the solution of 2-methylpropan-2-amine (4.45 g, 61.0 mmol) and triethylamine (18.0 g, 180 mmol) in dichloromethane (180 mL). The resulting mixture was stirred for 16 h and diluted with dichloromethane (200 mL). It was washed with water (3×50 mL), dried over anhydrous Mg2SO4, filtered, and evaporated under reduced pressure to afford 282e (15.0 g, 97%) as yellow solid. MS-ESI: [M+H]+ 252.0
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:17]([NH:19][C:20]3[S:21][C:22]([C:25]([O:27]C)=O)=[CH:23][N:24]=3)=[O:18])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[CH3:29][NH2:30]>CO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:12][CH2:13][N:14]([C:17]([NH:19][C:20]3[S:21][C:22]([C:25]([NH:30][CH3:29])=[O:27])=[CH:23][N:24]=3)=[O:18])[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cnc(NC(=O)N2CCC(N3CCc4ccc(F)cc43)CC2)s1
Reactant: CN
Solvent: CO
Product: CNC(=O)c1cnc(NC(=O)N2CCC(N3CCc4ccc(F)cc43)CC2)s1
Temperature: 39 °C

Procedure:
In a flask was placed methyl 2-(4-(6-fluoroindolin-1-yl)piperidine-1-carboxamido)thiazole-5-carboxylate (80.8 mg, 0.2 mmol) and MeOH (4 mL) was added. Then, 40 wt % CH3NH2(aq) (6 mL) was added and the resulting mixture was heated to 38-40° C. for 4 h. The resulting mixture was concentrated to remove MeOH and then partitioned in CH2Cl2/H2O (30 mL/30 mL). The aqueous layer was extracted with CH2Cl2 (30 mL). The combined organic layer was dried (Na2SO4) and filtered. The solvent was removed by roto-evaporator and the resulting residue re-solidified from CH2Cl2/hexane to yield 2-(4-(6-fluoroindolin-1-yl)piperidine-1-carboxamido)-N-methylthiazole-5-carboxamide as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH:15]=[CH:16][N:17]=1>ClCCl.N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: Nc1nccs1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1nccs1)c1ccc(Br)cc1
Yield: 85 %

Procedure:
A solution of 4-bromo-benzenesulfonyl chloride (100 mmol) and 2-aminothiazole (100 mmol) in dichloromethane and pyridine (300 mL, 8:2) was stirred for one day. After concentrated in vacuo, the residue was diluted with ethyl acetate (500 mL) and the solution was washed with 1N HCl solution, sat NaHCO3, dried over MgSO4, and concentrated in vacuo. The residue was recrystallized in ethyl acetate to give 4-bromo-N-thiazol-2-yl-benzenesulfonamide (85 mmol) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[N:7]2[C:10]([CH3:14])=[CH:11][CH:12]=[CH:13][C:6]2=[N:5][C:4]=1[CH3:15])[CH3:2].[C:16]([OH:25])(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19]>CC(C)=O>[C:16]([O-:25])(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19].[CH2:1]([C:3]1[C:8](=[O:9])[N:7]2[C:10]([CH3:14])=[CH:11][CH:12]=[CH:13][C:6]2=[NH+:5][C:4]=1[CH3:15])[CH3:2]
Reactant: O=C(O)c1ccccc1O
Reactant: CCc1c(C)nc2cccc(C)n2c1=O
Solvent: CC(C)=O
Product: CCc1c(C)[nH+]c2cccc(C)n2c1=O
Product: O=C([O-])c1ccccc1O
Yield: 67.6 %

Procedure:
10 g. of 3-ethyl-2,6-dimethyl-4-oxo-4H-pyrido(1,2-a)pyrimidine are dissolved in 100 ml. of acetone with heating and a solution of 7 g. of salicylic acid in 100 ml. of acetone is added. The reaction mixture is brought to a boil, then cooled. The precipitated crystals are filtered off, washed with acetone and dried. 11.5 g. (67.6%) of 3-ethyl-2,6-dimethyl-4-oxo-4H-pyrido(1,2-a)pyrimidinium salicylate are obtained, melting at 126° to 128° C. after recrystallization from ethanol.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].O=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1>[Pd].C(O)C.C(O)(=O)C>[OH:2][CH2:1][CH2:3][NH:4][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1
Reactant: NCCO
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(NCCO)CC1

Procedure:
A slurry of 10% palladium on charcoal (catalytic) in dry ethanol (3 mL) and acetic acid (5 drops) was added to a solution of ethanolamine (0.24 mL) and tert-butyl 4-oxopiperidine-1-carboxylate (0.80 g) in dry ethanol (10 mL) and hydrogenated at 2 bar for 26 hours. The solution was filtered through a glass fibre filter and the filtrate concentrated in vacuo to give the sub-titled compound (0.98 g) as a pale yellow oil.
Reaction SMILES: CO.[Cl:3][CH2:4][CH2:5][CH2:6][Si:7]([O:12][CH3:13])([O:10][CH3:11])[O:8][CH3:9].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCCCCC>C(O)(C)C>[Cl-:3].[CH3:9][O:8][Si:7]([CH2:6][CH2:5][CH2:4][N+:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:12][CH3:13])[O:10][CH3:11]
Reactant: CO[Si](CCCCl)(OC)OC
Reactant: c1ccncc1
Solvent: CCCCCC
Solvent: CO
Solvent: CC(C)O
Product: CO[Si](CCC[n+]1ccccc1)(OC)OC
Product: [Cl-]
Reaction time: 1 h

Procedure:
A mixture of 60.0 grams of methanol, 60.0 grams of chloropropyltrimethoxysilane and 15.26 grams of pyridine was prepared. The mixture was heated and allowed to reflux for 72 hours. The mixture was vacuum stripped at 80° C. and 29 inches of Hg, for one hour. Following hexane and isopropanol washes, a white salt formed. The salt was dissolved in 15 grams of isopropanol.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:40])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[S:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH2:27][N:28]2[CH2:33][CH2:32][CH:31]([C:34]([F:37])([F:36])[F:35])[CH2:30][CH2:29]2)=[CH:6][C:5]=1[O:38][CH3:39].N1C=CC=CC=1.[C:47]1([O:53]C(Cl)=O)C=CC=CC=1.O>ClCCl>[CH3:39][O:38][C:5]1[CH:6]=[C:7]([O:10][CH2:11][C:12]2[S:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH2:27][N:28]2[CH2:33][CH2:32][CH:31]([C:34]([F:37])([F:36])[F:35])[CH2:30][CH2:29]2)[CH:8]=[CH:9][C:4]=1[C:3]1[NH:40][C:47](=[O:53])[O:1][N:2]=1
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CN2CCC(C(F)(F)F)CC2)ccc1C(=N)NO
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CN2CCC(C(F)(F)F)CC2)ccc1-c1noc(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 150 mg of N-hydroxy-2-methoxy-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-benzamidine in 5 mL of anhydrous dichloromethane at 0° C. were dropwise added 50 μL of pyridine followed by 40 μL of phenylchloroformate. The resulting mixture was stirred at room temperature for 1 h then water and dichloromethane were added. The aqueous layer was separated and extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. To a solution of the resulting residue in 2.7 mL of acetonitrile was added 60 μL of 1,8-diazabicyclo[5.4.0]undec-7-ene. The mixture was stirred at room temperature overnight. The solvent was removed under vacuo. The resulting residue was taken into tetrahydrofuran/ethyl acetate 50/50, washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient from dichloromethane 100 to dichloromethane 90/methanol 10) to give 105 mg of 3-{2-methoxy-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-phenyl}-4H-[1,2,4]oxadiazol-5-one.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13]C([O-])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]1([C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:4](=[CH:13]/[C:12]([O:18][CH2:19][CH3:20])=[O:17])/[O:6]1)=[O:11]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C1OC(=O)c2ccccc21
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C1\OC(=O)c2ccccc21
Yield: 75 %

Procedure:
59.2 g (0.4 mol) of phthalic anhydride, 26.4 g (0.2 mol) of monoethyl malonate, and 15.8 g (0.2 mol) of pyridine are added to 200 ml of toluene, and the reaction mixture is heated under reflux for 4 hours. After terminating the reaction, 100 ml of water is added to the reaction mixture, and an organic layer is separated out. The organic layer is washed with 100 ml of 5%-aqueous acetic acid solution, and toluene is distilled off under a reduced pressure. The residue thus obtained is recrystallized from ethanol, to give 32.7 g (0.15 mol) of ethyl (Z)-3-phthalidylideneacetate. The yield is 75.0%.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:17]3[CH:18]=[CH:19][S:20][C:16]=3[C:15]3[CH:14]=[CH:13][C:12]([C:21]#[N:22])=[CH:11][C:10]=3[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:23]O.[OH-].[Na+].O>CN1C(=O)CCC1>[C:1]1([NH:7][C:8]2[C:17]3[CH:18]=[CH:19][S:20][C:16]=3[C:15]3[CH:14]=[CH:13][C:12]([C:21]([NH2:22])=[O:23])=[CH:11][C:10]=3[N:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OO
Reactant: N#Cc1ccc2c(c1)nc(Nc1ccccc1)c1ccsc12
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: NC(=O)c1ccc2c(c1)nc(Nc1ccccc1)c1ccsc12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
4-(phenylamino)thieno[3,2-c]quinoline-7-carbonitrile (34 mg, 0.113 mmol) was dissolved in NMP (0.3 ml). 30% aqueous H2O2 (0.2 ml) was added followed by addition of 6N NaOH (50 ul). The mixture was stirred at 50° C. for 2 hours. An extra amount of 30% aqueous H2O2 (0.3 ml) and 6N NaOH (100 ul) were added and a 70% conversion was achieved after 30 min. Water was added and the solid filtered and dried. The material was further reacted under the same conditions in order to achieve a complete transformation. 4-(phenylamino)thieno[3,2-c]quinoline-7-carboxamide was isolated as solid (30 mg, 83% yield). LCMS (ES): 95% pure, m/z 320 [M+1]+.
Reaction SMILES: [CH2:1]([C:8](O)=O)[C:2]([CH2:4][C:5](O)=[O:6])=O.O.[NH3:12].[CH:13](=O)[CH2:14][CH2:15]CC=O>>[CH:2]12[NH:12][CH:14]([CH2:15][CH2:8][CH2:1]1)[CH2:13][C:5](=[O:6])[CH2:4]2
Reactant: O=CCCCC=O
Reactant: O=C(O)CC(=O)CC(=O)O
Reactant: N
Solvent: O
Product: O=C1CC2CCCC(C1)N2

Procedure:
In the first step of the present invention, to an aqueous solution of acetonedicarboxylic acid (3) as a basic material, ammonia water and an aqueous solution of glutaraldehyde (4) are sequentially added slowly under cooling with ice to form a bicyclo-form (5) by condensation reaction. By condensation by Mannich reaction and subsequent decarboxylation, formation of 9-azabicyclo[3.3.1]nonane ring occurs to form 9-azabicyclo[3.3.1]nonan-3-one (5), which can be obtained as a powder only by removing excessive water and ammonia by a freeze-dryer after completion of the reaction.
Reaction SMILES: CC1C(N=C=O)=CC(N=C=O)=CC=1.[C:14]([O:18]CCO)(=[O:17])[CH:15]=[CH2:16].CCCC[CH:26]([C:29]([O-])=[O:30])CC.CCCCC(C([O-])=O)CC.[Sn+2].[N-:43]=[C:44]=[O:45].C(O)CSCCO>>[C:14]([OH:18])(=[O:17])[CH:15]=[CH2:16].[NH2:43][C:44]([O:30][CH2:29][CH3:26])=[O:45]
Reactant: C=CC(=O)OCCO
Reactant: CCCCC(CC)C(=O)[O-]
Reactant: [N-]=C=O
Agent: Cc1ccc(N=C=O)cc1N=C=O
Agent: OCCSCCO
Agent: [Sn+2]
Product: C=CC(=O)O
Product: CCOC(N)=O

Procedure:
354 g of tolylene diisocyanate are reacted with 220 g of hydroxyethyl acrylate and 0.2 ml of tin octoate. When the isocyanate value reaches 15.8%, the mixture is reacted with 36 g of thiodiglycol, 400 g of an ethoxylated trimethylolpropane (OH number 250) and 400 g of the compound according to Example 11. A self-cross-linking urethane acrylate resin is obtained which has a viscosity of 200 Pas after it has been mixed with 200 g of hexanediol-1,6-diacrylate, and when tested as a 20 μm film on paper under the condition described above, it attains a reactivity of 30 m/min.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=3)[CH2:14][CH2:13]2)[N:3]=1.[Cl-].[NH4+]>CO.O.[Fe]>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=3)[NH2:26])[CH2:16][CH2:17]2)[N:3]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc([N+](=O)[O-])c4)CC3)cccc2n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Yield: 84 %

Procedure:
A solution of 2-methyl-5-{4-[2-(3-nitrophenyl)ethyl]-1-piperazinyl}quinoline (D5) (0.14 g; 1 eq) in methanol (3 mL) was added dropwise to a suspension of iron powder (0.07 g; 3.2 eq) and ammonium chloride (0.1 g; 5.3 eq) in water (3 mL). The reactants were heated at reflux for 8 hours, adding additional amounts of iron powder (total 0.07 g; 3.2 eq) and ammonium chloride (total 0.1 g; 5.03 eq) in 3 portions during the reaction. The reaction mixture was filtered using a Millipore filter. The filtrate was concentrated under reduced pressure, diluted with water (5 mL) and a saturated aqueous solution of sodium hydrogen carbonate (2 mL), extracted into ethyl acetate (3×5 mL), dried over Na2SO4 and concentrated under reduced pressure obtaining the title compound in 84% yield (0.11 g).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH2:20]([N:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[ClH:19].[CH2:20]([N:27]1[CH2:32][CH2:31][CH:30]([NH:33][S:16]([C:14]2[O:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:29][CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)o2)c(C)[nH]c1=O
Reactant: NC1CCN(Cc2ccccc2)CC1
Product: CCc1cc(-c2ccc(S(=O)(=O)NC3CCN(Cc4ccccc4)CC3)o2)c(C)[nH]c1=O
Product: Cl
Yield: 38 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)furan-2-sulfonyl chloride is reacted with (1-benzylpiperidin-4-yl)amine as described in step 5, Example 24 to give the title compound as a solid (38% yield). LC/MS: RT 2.20 min; m/e 456 (M+H).