Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[NH:7][C:6](=[O:8])[CH:5](C(OC)=O)[C:4](=[O:13])[CH2:3]1.O>Cl.C(#N)C>[CH3:1][C:2]1([CH3:14])[NH:7][C:6](=[O:8])[CH2:5][C:4](=[O:13])[CH2:3]1
Reactant: COC(=O)C1C(=O)CC(C)(C)NC1=O
Agent: Cl
Solvent: O
Solvent: CC#N
Product: CC1(C)CC(=O)CC(=O)N1
Yield: 39.2 %

Procedure:
A mixture of methyl 6,6-dimethylpiperidine-2,4-dione-3-carboxylate (26.3 g), water (30 ml) and concentrated hydrochloric acid (3 drops) in acetonitrile (300 ml) was heated at reflux for 4 hours. The cooled solution was evaporated under reduced pressure and the residue recrystallised from water (50 ml) to give 6,6-dimethylpiperidine-2,4-dione (7.3 g), mp 183°-184° C., as a cream crystalline solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=2)[C:4](O)=[CH:3][CH:2]=1.CN(C)C1C=CC=CC=1.P(Br)(Br)(Br)(Br)[Br:26]>C(#N)C>[Br:26][C:4]1[C:5]2[C:10](=[CH:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[CH:6]=2)[N:1]=[CH:2][CH:3]=1
Reactant: BrP(Br)(Br)(Br)Br
Reactant: Oc1ccnc2cc3ccccc3cc12
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Product: Brc1ccnc2cc3ccccc3cc12
Temperature: 0 °C
Yield: 56.2 %

Procedure:
Crude benzo[g]quinolin-4-ol (6) (5.07 mmol) was dissolved in 50 mL of acetonitrile (0.1 M) and cooled to 0° C. under a nitrogen atmosphere. N,N-dimethylaniline (3.2 mL, 5 equivalents) was added followed by 3.3 g of phosphorus pentabromide (1.5 equivalents). After removal of the bath, the mixture was heated to reflux and followed by TLC until complete. Upon cooling to rt, the mixture was slowly poured onto ice water and extracted with methylene chloride three times. The organic layers were combined, washed with brine, dried with magnesium sulfate, and concentrated in vacuo. Flash chromatography (gradient: 9:1 to 8:2 to 7:3 hexanes:EtOAc) afforded 736 mg of clean 4-bromobenzo[g]quinoline (7a) in 55% yield for the 2 steps.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13](=[N:15][OH:16])[CH3:14])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[CH3:17][O:18][C:19](=[O:31])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28]Br)=[CH:22][C:21]=1[OH:30]>O1CCCC1>[CH3:17][O:18][C:19](=[O:31])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:16][N:15]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([C:3]([CH3:6])([CH3:4])[CH3:5])=[CH:8][CH:9]=2)[CH3:14])=[CH:22][C:21]=1[OH:30]
Reactant: CC(=NO)c1ccc(C(C)(C)C)cc1
Reactant: COC(=O)c1ccc(OCCBr)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCON=C(C)c2ccc(C(C)(C)C)cc2)cc1O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 38.9 %

Procedure:
To a slurry of sodium hydride (95%) (0.487 g, 20.3 mmol) in tetrahydrofuran (6 mL) was added 1-(4-tert-butyl-phenyl)-ethanone oxime (0.7021 g, 3.67 mmol) as a solution in tetrahydrofuran (18 mL) and the solution was allowed to stir at room temperature for 40 minutes. 4-(2-Bromo-ethoxy)-2-hydroxy-benzoic acid methyl ester (0.908 g, 3.64 mmol) was added as a solution in tetrahydrofuran (10 mL). The reaction was stirred at room temperature 1 hour and then heated at reflux 3 days. The reaction was cooled, quenched with brine and extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/hexanes (5/95 to 10/90) afford 4-{2-[1-(4-tert-butyl-phenyl)-ethylideneaminooxy]-ethoxy}-2-hydroxy-benzoic acid methyl ester (0.546 g, 39%) as a yellow oil which solidified on standing. mp=65.4-66.8° C.; mass spectrum (+ESI, M+H) m/z 386. 1H NMR (400 MHz, DMSO-d6); δ 10.63 (s, 1H), 7.69 (d, 1H), 7.57 (d, 2H), 7.40 (d, 2H), 6.55 (m, 2H), 4.42 (t, 2H), 4.31 (t, 2H), 3.75 (s, 3H), 2.14 (s, 3H), 1.28 (s, 9H). Elemental analysis: Calcd. for C22H27NO5: C, 68.55; H, 7.06; N, 3.63, Found: C, 68.91; H, 7.10; N, 3.60.
Reaction SMILES: [OH-].[Na+:2].[Cl:3][C:4]1[N:9]=[N:8][C:7]([O:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH:18]2[CH2:20][CH2:19]2)=[C:6]([OH:21])[CH:5]=1>C(O)C>[Cl:3][C:4]1[N:9]=[N:8][C:7]([O:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH:18]2[CH2:20][CH2:19]2)=[C:6]([O-:21])[CH:5]=1.[Na+:2]
Reactant: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1[O-]
Temperature: 50 °C
Reaction time: 4 h
Yield: 100.3 %

Procedure:
0.18 mL (0.36 mmol) of 2 mol/L aqueous sodium hydroxide solution was added to an ethanol (2 mL) solution containing 100 mg (0.361 mmol) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol, and the resulting mixture was stirred at 50° C. for 4 hours. The reaction mixture was concentrated to obtain 108 mg (0.361 mmol, Yield: 100%) of sodium 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinolate (Compound No. 3805).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1.N1C=CC=CC=1.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH:22][S:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[F:30])(=[O:39])=[O:38])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C(F)(F)F)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3ccccc3F)c2)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
To a stirred solution of 3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (100 mg, 0.31 mmol) in pyridine (49 mg, 0.62 mmol) and dichloromethane (1.5 mL) at 0° C. was added dropwise a solution of 2-fluoro-benzenesulfonyl chloride (73 mg, 0.37 mmol) in dichloromethane (0.5 mL). The mixture was stirred at room temperature overnight. The mixture was quenched with water (5 mL) and extracted with dichloromethane (5 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel to afford N-[3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-2-fluoro-benzenesulfonamide (97 mg, 65.1%) as a white solid. MS (ESI+APCI) M+1=479.1.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH2:12]([CH:15]([C:21]([CH3:23])=O)[C:16](OCC)=[O:17])[CH2:13][CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]2[N:3]([CH:4]=1)[C:16](=[O:17])[C:15]([CH2:12][CH2:13][CH3:14])=[C:21]([CH3:23])[N:1]=2)=[O:7]
Reactant: COC(=O)c1ccc(N)nc1
Reactant: CCCC(C(C)=O)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCc1c(C)nc2ccc(C(=O)OC)cn2c1=O
Temperature: 150 °C
Reaction time: 42 h

Procedure:
Methyl 6-amino-nicotinate (4g) was reacted with ethyl 2-propylacetoacetate (17.3 g) in the presence of p-toluensulphonic acid (0.16 g) under stirring at 150° C. for 42 hours. After cooling and dilution with hexane the precipitate was filtered and crystallized from methanol, thus giving 2.9 g of 2-methyl-3-propyl-4-oxo-4H-pyrido[1.2-a]pyrimidine-7-carboxylic acid methyl ester m.p. 98°-99° C., which were reacted with benzaldehyde (7 g) in methanol (100 ml), in the presence of sodium methoxide (1.78 g), under stirring at reflux temperature for 144 hours. After cooling the reaction mixture was concentrated in vacuo and diluted with ethyl ether: the precipitate was filtered, washed with ether and then dissolved in water. After acidification with acetic acid the precipitate was filtered and washed with water until neutral: crystallization with methanol gave 1.1 g of 2-trans-(2-phenyl-ethenyl)-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid, m.p. 250°-252° C., NMR (DMSO d6): vinylic protons δHβ =7.60(d), δHα =8.05(d) p.p.m., JHαHβ =16 Hz.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([N:7]=[C:8]=[S:9])[CH:4]([CH3:6])[CH3:5]>>[CH2:3]([NH:7][C:8]([NH:2][CH3:1])=[S:9])[CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)CN=C=S
Reactant: CN
Product: CNC(=S)NCC(C)C
Yield: 98.2 %

Procedure:
Methylamine (2M in methanol, 20.0 mL, 40.2 mmol) was added dropwise to isobutylisothiocyanate (2.00 mL, 16.5 mmol) during 15 minutes at room temperature. The reaction mixture was heated to reflux for 3.5 h and the solvent was evaporated off to give the title compound (2.37 g, 98%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([S:22](C)=O)[N:14]=[C:13]2[CH2:25][CH2:26][CH3:27])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([SH:22])[N:14]=[C:13]2[CH2:25][CH2:26][CH3:27])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: CCCc1nc(S(C)=O)c(C(=O)OCC)n1Cc1cc2c(cc1Cl)OCO2
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCCc1nc(S)c(C(=O)OCC)n1Cc1cc2c(cc1Cl)OCO2
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
800 mg of the product obtained in Stage 5 above is introduced into 16 ml of methylene chloride and 0.54 ml of trifluoroacetic anhydride is added. Agitation is carried out for 30 minutes, followed by evaporating to dryness and the residue is taken up in 10 ml of methanol and 4 ml of triethylamine. Agitation is carried out for 30 minutes, followed by extraction with chloroform, washing with a saturated solution of ammonium chloride, drying and evaporating to dryness. In this way 720 mg of expected product is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25][CH2:26][C:27]3[N:31]([CH2:32][CH2:33][CH3:34])[CH:30]=[N:29][N:28]=3)=[CH:21][CH:20]=2)=[O:17])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:43])C=1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH2:26][C:27]3[N:31]([CH2:32][CH2:33][CH3:34])[CH:30]=[N:29][N:28]=3)=[O:43])=[CH:21][CH:20]=2)=[O:17])=[CH:6][CH:7]=1
Reactant: CCCn1cnnc1CSc1ccc(NC(=O)/C=C/c2cnn(C)c2-c2ccc(F)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: CCCn1cnnc1CS(=O)c1ccc(NC(=O)/C=C/c2cnn(C)c2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.3 %

Procedure:
A mixture of (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-N-(4-{[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]thio}phenyl)acrylamide (96 mg), m-chloroperbenzoic acid (40 mg) and tetrahydrofuran (3 ml) was stirred at room temperature for 3 hrs. The reaction mixture was concentrated and purified by HPLC to give (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-N-(4-{[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]sulfinyl}phenyl)acrylamide (36 mg, 37%) as pale-yellow crystals.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[Cl:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[O:9][CH2:10][CH2:11][OH:12].C(N(CC)CC)C>C(#N)C>[Cl:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[O:9][CH2:10][CH2:11][O:12][S:1](=[O:4])(=[O:3])[NH2:2]
Reactant: OCCOc1ccccc1Cl
Reactant: NS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NS(=O)(=O)OCCOc1ccccc1Cl
Yield: 58 %

Procedure:
The title compound was obtained using the following procedure: The sulfamoyl chloride solution prepared in (a) was reacted as in Example 4 with 17.3 g (0.100 mole) of 2-(2-chlorophenoxy)ethanol and 40.4 g (0.400 mole) of triethylamine in 100 ml of acetonitrile followed by extraction, washing and concentration procedures of Example 4 through the first evaporation. The viscous, oily residue was partitioned between 500 ml of water and 500 ml of ethyl ether. The organic layer was washed with four 300 ml portions of water (pH of wash finally neutral to pH paper), dried over magnesium sulfate and the solvent evaporated under reduced pressure to give a white solid. The solid was recrystallized from ethyl ether-petroleum ether (bp 30°-60° C.) to give 14.5 g (58%) of title compound as white solid, mp 84.5°-86° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][N:8]3[C:9]=2[C:5]([C:6]2[CH2:19][CH2:18][CH2:17][C:7]=23)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:10]2[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][N:8]3[C:9]=2[C:5]([CH:6]2[CH2:19][CH2:18][CH2:17][CH:7]23)=[CH:4][CH:3]=1
Reactant: CN1CCc2c(Cl)ccc3c4c(n(c23)CC1)CCC4
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CCc2c(Cl)ccc3c2N(CC1)C1CCCC31
Temperature: 25 °C
Reaction time: 5 h
Yield: 32.7 %

Procedure:
To a solution of 6-chloro-3-methyl-2,3,4,5,10,11-hexahydro-1H,9H-cyclopenta[b][1,4]diazocino[7,8,1-hi]indole (0.20 g, 0.73 mmole) in acetic acid (50 mL) was added excess sodium cyanoborohydride (0.23 g, 3.65 mmole) and the reaction mixture was stirred at room temperature for 5 hours. The solvent was removed in vacuo and the residue was diluted with ethyl acetate (200 mL) and washed with saturated sodium bicarbonate (150 mL), saturated sodium chloride (150 mL), dried (sodium sulfate) and concentrated. Purification by flash column chromatography (silica gel, ethyl acetate:hexanes 3:2) provided 66 mg of the title compound. This was further treated with one equivalent of fumaric acid in ethanol to form a fumarate salt, mp 196-9° C. MS (ESI) m/z 277 ([M+H]+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[CH:27]=[CH:26][N:25]=[C:24]([O:28]C)[CH:23]=5)[CH:19]=[C:18]([CH3:30])[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Si](I)(C)(C)C.CO>CC#N>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([CH3:30])[CH:19]=[C:20]([C:22]5[CH:27]=[CH:26][NH:25][C:24](=[O:28])[CH:23]=5)[N:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: COc1cc(-c2cc(C)cc(NC(=O)C3(c4ccc5c(c4)CCO5)CC3)n2)ccn1
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: CO
Product: Cc1cc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc(-c2cc[nH]c(=O)c2)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-4-methyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide (78 mg, 0.19 mmol) in CH3CN (3 mL) was added TMSI (55 uL, 0.39 mmol) dropwise at 20° C. The reaction was stirred at 50° C. for 30 min. MeOH (1.0 mL) was added and the solution was evaporated to dryness. The residue was re-dissolved in DCM-EtOAc (1:3) before it was washed with NaHSO3 (2×) and brine. The organics were dried over MgSO4 and evaporated to dryness. The crude material was purified by column chromatography (0-10% MeOH-EtOAc) to yield 1-(2,3-dihydrobenzofuran-5-yl)-N-(4-methyl-6-(2-oxo-1,2-dihydropyridin-4-yl)pyridin-2-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 387.2. found 388.3 (M+1)+. Retention time 1.36 minutes.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11][C:12]#N)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[OH-].[K+].[CH2:16](I)C.O>C(O)C>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([S:11][CH2:12][CH3:16])=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Reactant: CCI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCSc1ccc(N)c([N+](=O)[O-])c1
Reaction time: 0.08 h
Yield: 95.4 %

Procedure:
2-Nitro-4-thiocyanatoaniline (17.55 g.; prepared as hereinbefore described in Example 6) was added portionwise to a stirred solution of potassium hydroxide (13.4 g.) in ethanol (210 ml.), keeping the temperature below 20° C. After 5 minutes, ethyl iodide (14.4 g.) was added during five minutes. The stirring was continued for a further hour and the mixture was allowed to stand overnight. The mixture was then poured into water (1100 ml.) and extracted with chloroform (3× 300 ml.). The chloroform layers were combined, washed with water (500 ml.), dried over magnesium sulphate, and evaporated to give 1-amino-4-ethylthio-2-nitrobenzene (17.0 g.), in the form of a red oil.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH3:29])[C:27]=4[Cl:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].C1COCC1.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:43]2[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=2)[CH2:39][CH2:38]1>CCOC(C)=O>[CH3:36][N:37]1[CH2:38][CH2:39][N:40]([C:43]2[CH:48]=[CH:47][C:46]([NH:49][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[CH:24]=[N:25][N:26]([CH3:29])[C:27]=6[Cl:28])=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:30])=[CH:45][CH:44]=2)[CH2:41][CH2:42]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: Cn1ncc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)c1Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(NC=C3C(=O)Nc4cc(C(=O)c5cccc(NC(=O)c6cnn(C)c6Cl)c5)ccc43)cc2)CC1
Temperature: 65 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
A small screw cap test tube was charged with 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 100 mg, 0.237 mmol) and THF (2.5 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (59.2 mg, 0.309 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and diluted with EtOAc (5 mL) and Hexanes (40 mL). The precipitate that formed was then filtered and washed with acetone (5 mL) to afford the title compound in 71% yield (0.100 g, 0.168 mmol).
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]1([CH3:27])[CH2:26][O:25]1>CO.O1CCCC1>[CH2:16]([N:8]([CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:23][C:24]([CH3:27])([OH:25])[CH3:26])[CH2:14][CH2:15]1)[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(CN(Cc2ccccc2)CC2CCNCC2)cc1
Reactant: CC1(C)CO1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(O)CN1CCC(CN(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 40 °C
Reaction time: 17 h
Yield: 73 %

Procedure:
A mixture of N,N-dibenzyl-N-(piperidin-4-ylmethyl)amine (EXAMPLE 4, Step 3, 3.3 g, 11.21 mmol) and 2,2-dimethyloxirane (12.1 mL, 134.5 mmol) in methanol (40 mL) and tetrahydrofuran (5 mL) was heated at 40° C. with stirring for 17 h. The volatile components were removed and the residue was purified by flash column chromatography on amine gel eluting with hexane/ethyl acetate (50:1) to afford 3.0 g (73%) of the title compound as a colorless amorphous.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][NH2:14])[CH:6]=1)=[O:4].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][CH3:26])=[C:20]([CH:24]=1)[C:21](Cl)=[O:22]>ClCCl.N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][NH:14][C:21](=[O:22])[C:20]2[CH:24]=[C:16]([Cl:15])[CH:17]=[CH:18][C:19]=2[O:25][CH3:26])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(=O)n(CCN)c1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(=O)n(CCNC(=O)c2cc(Cl)ccc2OC)c1

Procedure:
1-(2-aminoethyl)-1,6-dihydro-6-oxo-3-pyridinecarboxylic acid methyl ester (0.985 g, 5.0 mmol) was reacted with 5-chloro-2-methoxybenzoyl chloride (1.04 g, 5.1 mmol) in dichloromethane (25 ml) and pyridine (10 ml). After an aqueous work-up, purification via flash column chromotography (silica gel, 8% methanol/dichloromethane) gave the product, MP: 149°-150° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O.[NH2:20][C:21]1[CH:25]=[CH:24][NH:23][N:22]=1>C(O)(=O)C>[F:14][C:13]([F:16])([F:15])[C:9]1[CH:8]=[C:7]([C:5]2[CH:4]=[C:3]([C:2]([F:19])([F:18])[F:1])[N:22]3[N:23]=[CH:24][CH:25]=[C:21]3[N:20]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cc[nH]n1
Reactant: O=C(CC(=O)C(F)(F)F)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)n3nccc3n2)c1
Yield: 95.3 %

Procedure:
A mixture of 4,4,4-trifluoro-1-(3-trifluoromethyl-phenyl)-butane-1,3-dione (10.3 g, 36.1 mmol) and commercially available 3-aminopyrazole (3.0 g, 36.1 mmol) in acetic acid (100 mL) was refluxed for 4 h and evaporated. The crude product was further purified by crystallization (ethyl acetate/hexane) to yield 5-(3-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (11.4 g, 95%) as a light yellow solid. MS (ISP) 323.3[(M+H)+]; mp 96° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][O:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=O.[NH2:18][OH:19]>CCO.O>[O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][O:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[N:18][OH:19]
Reactant: O=Cc1ccccc1OCCN1CCNC1=O
Reactant: NO
Solvent: O
Solvent: CCO
Product: O=C1NCCN1CCOc1ccccc1C=NO
Temperature: 5 °C
Reaction time: 6 h

Procedure:
A solution of 2-[2-(2-oxoimidazolidin-1-yl)ethoxy]benzaldehyde (10.0 g, 0.043 mol) in EtOH (100 mL) is heated to 50° C. At this temperature, a hydroxylamine solution (4.5 g, 0.068 mol, 50% in water, Aldrich) in EtOH (10 mL) is added. The reaction medium is then stirred for 6 hours at a temperature between 50° C. and 70° C. The reaction medium is evaporated under reduced pressure (Tbath 45° C., 65-70 mbar) until a suspension is obtained. The crude reaction product is then taken up in water (5 mL). The solution obtained is cooled to 5° C. and maintained at this temperature for 15 hours. The precipitate obtained is filtered and washed on the filter with an EtOH/water mixture (2 mL/2 mL) and then with an EtOH/petroleum ether mixture (1 mL/4 mL) and then with petroleum ether (2*10 mL). The solid is then dried under atmospheric pressure at room temperature.
Reaction SMILES: [NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1.[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[Cl:37])[CH:32]=O>>[NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:32][C:31]3[CH:34]=[CH:35][C:36]([Cl:37])=[C:29]([Cl:28])[CH:30]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCN)CC1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCNCc2ccc(Cl)c(Cl)c2)CC1
Yield: 50.7 %

Procedure:
4-Amino-N-(1-(6-aminohexyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (2.0 g) as starting compound and 3,4-dichlorobenzaldehyde (0.97 g) were reacted and treated in the same manner as in Example 121 to give 1.42 g of 4-amino-5-chloro-N-((1-(6-(3,4-dichlorobenzylamino)hexyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)(C)(C)C.Br[CH2:29][CH2:30][O:31][CH3:32]>>[CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[C:18]([C:9]2[O:10][C:11]3[C:16]([C:7](=[N:6][OH:5])[CH:8]=2)=[CH:15][C:14]([O:17][CH2:29][CH2:30][O:31][CH3:32])=[CH:13][CH:12]=3)[N:19]=1
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2ccc(O)cc12
Reactant: COCCBr
Product: COCCOc1ccc2oc(-c3cc4ccccc4cn3)cc(=NO)c2c1

Procedure:
2-isoquinolin-3-yl-6-(2-methoxy-ethoxy)-chromen-4-one oxime was prepared in 67% overall yield using the method described in example 42 and 42A, starting from 6-hydroxy-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (example 41A) and bromoethylmethylether instead of iodomethane. The title compound was isolated as a yellow solid after purification by flash chromatography over silica gel (cyclohexane/ethyl acetate: 0-80%), and as a 85/15 mixture of Z/E oxime isomers.