Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:12])([F:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].Cl[C:14]1[C:18]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[N:17][S:16][N:15]=1>O1CCCC1>[F:3][C:4]([F:12])([F:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:14]1[C:18]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[N:17][S:16][N:15]=1
Reactant: OCCCCCC(F)(F)F
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)CCCCCOc1nsnc1-c1cccnc1
Yield: 31 %

Procedure:
To a mixture of sodium hydride (12.8 mmol) and 6,6,6-trifluoro-1-hexanol (3.0 g, 19.2 mmol) in tetrahydrofuran (40 ml) was added 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (1.3 g, 6.4 mmol). The mixture was refluxed for 36 h. and evaporated. After evaporation the residue was dissolved in water then extracted with diethyl ether. The dried organic phases were evaporated and the residue purified by column chromatography (silica gel, eluent: ethyl acetate/hexanes) to yield 630 mg (31%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][Cl:9])=[CH:6][CH:5]=[C:4]([Cl:10])[N:3]=1.[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([CH2:8][Cl:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[C:4]([Cl:10])[N:3]=1
Reactant: ClCc1ccc(Cl)nc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(CCl)c(Cl)nc1Cl
Temperature: 110 °C

Procedure:
117.5 g (0.6 mol) of 2,6-dichloro-3-chloromethylpyridine are dissoled in a mixture of 540 ml of concentrated sulphuric acid and 600 ml of 100% strength fuming nitric acid. The reaction mixture is then heated at 110°C in an oil bath for 5 hours. After cooling to approx. 20°C, the reaction mixture is poured onto ice. The resulting crystals are filtered off and are purified by being well ground with water in a mortar and then filtered off with suction and rinsed with water on the filter. After drying the crude product in vacuo at 25°C over diphosphorus pentoxide. crude 2,6-dichloro-3-chloromethyl-5-nitropyridine is obtained in the form of pale yellow crystals, which can be recrystallised from methanol.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[C:25]1[C:33](O)=[O:34].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[C:25]1[C:33]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=1)=[O:34]
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)c1cc2ccccc2o1
Yield: 94.6 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.5 g), triethylamine (1.7 mL), benzofuran-2-carboxylic acid (2.0 g), WSC.HCl (2.3 g), and methylene chloride (70 mL), to give the captioned compound (3.4 g, 96%) as an oily product.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:4](=[O:22])[C:3]=1[C:23](=O)[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1.O.[NH2:38][NH2:39].C(=O)([O-])O.[Na+]>CN(C=O)C>[F:33][C:32]([F:35])([F:34])[O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C:23]2[C:3]3[C:4](=[O:22])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:39][N:38]=2)=[CH:26][CH:27]=1
Reactant: NN
Reactant: O=C(Cc1ccc(OC(F)(F)F)cc1)c1c(O)c2cccnc2n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3ccc(OC(F)(F)F)cc3)n[nH]c2c2cccnc2n1-c1cccc(C(F)(F)F)c1
Temperature: 105 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a suspension of 4-hydroxy-3-(4-trifluoromethoxyphenylacetyl)-1-(3-trifluoromethylphenyl)-1,8-naphthyridin-2(1H)-one (307 mg, 0.60 mmol) produced in Synthesis Example 19 in DMF (5 mL) was added hydrazine monohydrate (purity of 80%, 120 μL), and the mixture was stirred at 100 to 110° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, recrystallized from ethanol, and dried to give 3-(4-trifluoromethoxybenzyl)-5-(3-trifluoromethylphenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one (190 mg, yield 63%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[C:3]=1[CH2:11][CH3:12].[NH2:13][C@@H:14]([C:18]([OH:20])=[O:19])[C@H:15]([CH3:17])[OH:16].C(=O)([O-])[O-].[K+].[K+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.CS(C)=O>[Cl:10][C:4]1[C:3]([CH2:11][CH3:12])=[C:2]([NH:13][C@H:14]([C@@H:15]([OH:16])[CH3:17])[C:18]([OH:20])=[O:19])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: CCc1c(F)ccc(C#N)c1Cl
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Reaction time: 0.17 h
Yield: 467.3 %

Procedure:
4-Fluoro-2-chloro-3-ethyl benzonitrile (1.0 g, 5.45 mmol), D-threonine (779 mg, 6.54 mmol), potassium carbonate (1.51 g, 10.9 mmol) and DMSO (6 mL) were heated at 85° C. for 17.5 h. The reaction mixture was allowed to cool to room temperature whereupon water (20 mL) was added followed by citric acid monohydrate (2 g). After stirring for 10 min the mixture was partitioned between EtOAc (40 mL) and water. The organic phase was then washed with water (15 mL), brine (15 mL), dried (Na2SO4) and concentrated to furnish a pale yellow solid (7.2 g). This crude product was then passed through a silica-plug [hexanes-EtOAc (95:5) as eluent] to furnish a white solid (928 mg), which was used directly in the next step.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[F:19][C:20]([F:29])([F:28])[C:21]1([CH2:26][OH:27])[CH2:25][CH2:24][NH:23][CH2:22]1>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([N:23]3[CH2:24][CH2:25][C:21]([CH2:26][OH:27])([C:20]([F:28])([F:29])[F:19])[CH2:22]3)=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: OCC1(C(F)(F)F)CCNC1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: O=C(c1ccc(C2CC2)c(OCC2CC2)n1)N1CCC(CO)(C(F)(F)F)C1
Yield: 36.4 %

Procedure:
In analogy to the procedure described in Example 127 e), 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3 c, 20 mg, 85.7 μmol) was reacted with (3-(trifluoromethyl)pyrrolidin-3-yl)methanol hydrochloride (CAN 1260812-78-9, 21.2 mg, 103 μmol) to obtain the title compound (12 mg, 36%) as colorless liquid, MS (EI): m/e=385.3 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[OH:6].[H-].[Na+].[F:15][C:16]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]([O:25][CH3:26])[C:17]=1[CH2:18]Br.Cl>CN(C)C=O.O>[Cl:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([O:6][CH2:18][C:17]2[C:20]([O:25][CH3:26])=[CH:21][CH:22]=[C:23]([F:24])[C:16]=2[F:15])=[C:4]([OH:12])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(O)c(O)cc1Cl
Reactant: COc1ccc(F)c(F)c1CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(F)c(F)c1COc1cc([N+](=O)[O-])c(Cl)cc1O
Reaction time: 0.17 h
Yield: 97.5 %

Procedure:
To a solution of 4-chloro-5-nitrocatechol (10.4 g) in N,N-dimethylformamide (55 mL) was added sodium hydride (55%, 5.04 g) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. To the reaction mixture was added N,N-dimethylformamide (11 mL), followed by adding a solution of 2,3-difluoro-6-methoxy-benzyl bromide (14.3 g) in N,N-dimethylformamide (22 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes, and then stirred at room temperature for 1.5 hours. The reaction mixture was diluted with water. The mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=7/3−1/1) to give the title compound (18.5 g).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH3:13][CH:14](O)[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([O:9][CH:14]([CH3:15])[CH3:13])=[CH:6][C:7]=1[CH3:8]
Reactant: CC(C)O
Reactant: Cc1cc(O)c([N+](=O)[O-])cc1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OC(C)C)c([N+](=O)[O-])cc1Br

Procedure:
To a mixture of 4-Bromo-5-methyl-2-nitro-phenol from the previous step (0.66 g, 2.84 mmol), 2-propanol (0.262 mL), and triphenylphosphine (894 mg) in 10 mL THF is added diisopropyl asodicarboxylate (0.671 mL) at 22° C. The reaction mixture is concentrated in vacuo. The residue is purified using a SiO2 column (ISCO), affording 1-Bromo-4-isopropoxy-2-methyl-5-nitro-benzene as a bright yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([CH3:13])=[CH:11][C:10]([N:14]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:15]2[C:24]3[C:19](=[CH:20][C:21]([C:25](C)(C)[O:26][SiH2]C(C)(C)C)=[CH:22][CH:23]=3)[C:18](=[O:34])[N:17]([CH:35]([CH3:37])[CH3:36])[N:16]=2)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:12]([CH3:13])=[CH:11][C:10]([N:14]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[C:15]2[C:24]3[C:19](=[CH:20][C:21]([CH2:25][OH:26])=[CH:22][CH:23]=3)[C:18](=[O:34])[N:17]([CH:35]([CH3:36])[CH3:37])[N:16]=2)=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(N(C(=O)OC(C)(C)C)c2nn(C(C)C)c(=O)c3cc(C(C)(C)O[SiH2]C(C)(C)C)ccc23)nn1C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc(N(C(=O)OC(C)(C)C)c2nn(C(C)C)c(=O)c3cc(CO)ccc23)nn1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.7 %

Procedure:
3-{tert-Butoxycarbonyl-[6-(tert-butyl-dimethyl-silanyloxymethyl)-3-isopropyl-4-oxo-3,4-dihydro-phthalazin-1-yl]-amino}-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester (0.78, 1.25 mmol) was dissolved in THF (3 ml), to this was added a 1M solution of tetrabutylammonium fluoride (TBAF) in THF (1.87 ml, 1.87 mmol) and the mixture was stirred at RT for 24 hours. After this time the reaction mixture was concentrated under vacuum and the residue was purified by flash column chromatography (elution: 50% heptane, 50% EtOAc) to give the title compound (0.39 g, 45% yield) as a brown solid MS (ESI+)=(M+H)+ 514.43.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH2:24][CH3:25])[CH2:20][CH2:19]4)[S:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)#[CH:2].C(O)=[O:27]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH2:24][CH3:25])[CH2:20][CH2:19]4)[S:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)(=[O:27])[CH3:2]
Reactant: O=CO
Reactant: C#Cc1ccc(-c2cc3sc(N4CCN(CC)CC4)cc3cn2)cc1
Product: CCN1CCN(c2cc3cnc(-c4ccc(C(C)=O)cc4)cc3s2)CC1

Procedure:
6-(4-Ethynylphenyl)-(4-ethylpiperazin-1-yl)thieno[3,2-c]pyridine (0.59 g) was reacted in formic acid (15 ml) at 100° C. for 12 hr. The reaction solution was evaporated, basified with an aqueous solution of potassium carbonate, and then extracted with ethyl acetate. The organic layer was washed with water and brine, dried and concentrated. The resulting residue was purified by NH-silica gel column chromatography (ethyl acetate/hexane system), to give 0.37 g of the title compound as a pale yellow oil.
Reaction SMILES: [O-]CC.[Na+].[Na].[CH3:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>C(O)C>[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][C:7]([CH3:6])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:21][CH:20]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)(Cc1ccc(Br)cc1)C(=O)OCC
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
Sodium ethoxide was generated by the addition of sodium (9.45 g) to ethanol (370 ml). The resulting solution was cooled to 5° C. and diethyl 2-methylmalonate (68.8 ml) added over 2 minutes. The reaction mixture was stirred at 5° C. for 20 minutes and then 4-bromobenzyl bromide (97.0 g) was added over 20 minutes. The reaction mixture was then heated under reflux for 16 hours. The reaction mixture was cooled to ambient temperature, filtered through diatomaceous earth and evaporated. The residue was partitioned between water (500 ml) and diethyl ether (1000 ml). The diethyl ether was separated and the aqueous layer was extracted with diethyl ether (2×500ml). The combined organic layers were dried (MgSO4) and evaporated to give an amber oil. This was purified by vacuum distillation, affording diethyl 2-(4-bromobenzyl)-2-methylmalonate (84.4 g), b.p.122°-125° C./0.1-0.2 mm Hg; mass spectrum (+ve CI): 343 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([OH:15])=O)[N:10]=[C:9]([C:16]3[N:17]=[N:18][N:19]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH:20]=3)[CH:8]=2)=[CH:4][CH:3]=1.[CH3:32][C:33]([NH2:42])([CH3:41])[CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[CH3:41][C:33]([NH:42][C:13](=[O:15])[CH2:12][N:11]1[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:31][CH:30]=2)=[CH:8][C:9]([C:16]2[N:17]=[N:18][N:19]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[CH:20]=2)=[N:10]1)([CH3:32])[CH2:34][N:35]1[CH2:36][CH2:37][O:38][CH2:39][CH2:40]1
Reactant: COc1ccc(Cn2cc(-c3cc(Cc4ccc(F)cc4)n(CC(=O)O)n3)nn2)cc1
Reactant: CC(C)(N)CN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(-c3cc(Cc4ccc(F)cc4)n(CC(=O)NC(C)(C)CN4CCOCC4)n3)nn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
A mixture of {5-(4-fluorobenzyl)-3-[1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl]-1H-pyrazol-1-yl}acetic acid (1.0 g, 2.37 mmol), 1,1-dimethyl-2-morpholin-4-yl-ethylamine (0.375 g, 2.37 mmol), HATU (0.71 g, 2.85 mmol) and Et3N (0.71 g, 7.1 mol) in DMF (20 mL) was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue was treated with water (50 mL) and CH2Cl2 (50 mL). The aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organics were dried over Na2SO4 and evaporated to afford crude title compound (1.3 g, 92%) as yellow oil that was used without further purification in next step.
Reaction SMILES: [NH2:1][C:2]1[C:34]([Cl:35])=[CH:33][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][NH:21][CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:36][CH3:37])[CH:3]=1.[CH:38](=O)[CH3:39].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:34]([Cl:35])=[CH:33][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][N:21]([CH2:38][CH3:39])[CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:36][CH3:37])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2cccc3ccccc23)CC1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1cccc2ccccc12

Procedure:
4-Amino-5-chloro-2-methoxy-N-((1-(5-(1-naphthylmethylamino)pentyl)-piperidin-4-yl)methyl)benzamide (1.43 g) as starting compound, acetaldehyde (0.16 ml) and sodium cyanoborohydride (0.38 g) were reacted and treated in the same manner as in Example 136 to give 0.75 g of 4-amino-5-chloro-N-((1-(5-(N-ethyl-N-(1-naphthylmethyl)amino)pentyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [C:1]1([CH:7]2[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][CH:11]([CH3:24])[CH2:12][O:13][C:14]1[CH:15]=[C:16]([OH:23])[C:17](=[CH:21][CH:22]=1)[C:18]([NH2:20])=[O:19]>CC(O)C>[C:18]([C:17]1[CH:21]=[CH:22][C:14]([O:13][CH2:12][CH:11]([NH:10][CH2:8][CH:7]([OH:9])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH3:24])=[CH:15][C:16]=1[OH:23])(=[O:19])[NH2:20]
Reactant: CC(N)COc1ccc(C(N)=O)c(O)c1
Reactant: c1ccc(C2CO2)cc1
Solvent: CC(C)O
Product: CC(COc1ccc(C(N)=O)c(O)c1)NCC(O)c1ccccc1

Procedure:
A mixture of 0,96 g of phenyl-ethylene oxide and 2.1 g of 4-(2-amino-propoxy)-salicylamide in 25 ml of 2-propanol is refluxed for 15 hours. The reaction mixture is then evaporated, the residue is partitioned between 10 ml of water and 100 ml of ethyl acetate and the organic phase is washed three times with water. On drying over magnesium sulfate and evaporating the organic phase, crude α-[N-[2-(4-carbamoyl-3-hydroxy-phenoxy)-1-methyl-ethyl]-aminomethyl]-benzyl alcohol is obtained and this is recrystallised analogously to Example 2 and in this way gives the two enantiomer pairs with a melting point of 171°-173° and 149°-151° respectively.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([OH:8])=O.[CH2:18]1COCC1.C[Li].O>C(OCC)C>[F:16][C:2]([F:1])([F:17])[C:3]1[CH:4]=[C:5]([C:6](=[O:8])[CH3:18])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C1CCOC1
Agent: [Li]C
Solvent: CCOCC
Solvent: O
Product: CC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5.16 g (20 mmol) of 3,5-bis(trifluoromethyl)benzoic acid were dissolved in 100 ml of abs. THF and admixed at 0° C. with 31.25 ml of a 1.6 M solution of methyllithium in diethyl ether. After the mixture had been stirred at room temperature for 5 hours, excess methyllithium was hydrolyzed by adding H2O and the solvent was removed in vacuo. The residue was taken up in dichloromethane and washed with saturated NaHCO3 solution. The organic phase was removed, dried over MgSO4 and concentrated. Chromatography on silica gel afforded 3.97 g of the title compound.
Reaction SMILES: C([N:4]1[CH:8]([C:9](=[O:11])[CH3:10])[CH2:7][CH2:6][C:5]1=[O:12])(=O)C.C([O-])([O-])=O.[K+].[K+].Cl>C(OCC)(=O)C.CO>[C:9]([CH:8]1[NH:4][C:5](=[O:12])[CH2:6][CH2:7]1)(=[O:11])[CH3:10]
Reactant: CC(=O)C1CCC(=O)N1C(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)C1CCC(=O)N1
Temperature: 25 °C
Yield: 48 %

Procedure:
In a round bottom flask, Compound 5 (2.2 g, 13×10−3 mol) is treated with a solution of K2CO3 (5.6 g, 40×10−3 mol, in 20 mL of water), with magnetic stirring at room temperature. The progress of the reaction is followed by TLC (eluent: ethyl acetate/methanol, 98/2). After stirring for 3.5 hrs, the reaction is complete. The reaction mixture is neutralized (pH=7) by adding 1N hydrochloric acid and then freeze-dried for 16 hrs. The organic residue is then extracted with CH2Cl2 (40 mL), filtered and then concentrated under reduced pressure to provide a brown viscous liquid. Purification was carried out on a silica gel column (eluent: ethyl acetate/methanol, 98/2). Compound 6 is obtained after such purification as a white powder.
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[C:16]([CH:23]=[CH:24][C:25]=3[CH3:26])[C:17]([NH:19][CH:20]3[CH2:22][CH2:21]3)=[O:18])=[CH:11][CH:12]=2)[CH:7]([CH3:27])[NH:6][N:5]=1)(=[O:3])[CH3:2].[Mn]([O-])(=O)(=O)=O.[K+]>CCO.O>[C:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[C:16]([CH:23]=[CH:24][C:25]=3[CH3:26])[C:17]([NH:19][CH:20]3[CH2:22][CH2:21]3)=[O:18])=[CH:11][CH:12]=2)[C:7]([CH3:27])=[N:6][N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)C1=NNC(C)c2cc(-c3cc(C(=O)NC4CC4)ccc3C)ccc21
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(=O)c1nnc(C)c2cc(-c3cc(C(=O)NC4CC4)ccc3C)ccc12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
3-(1-Acetyl-4-methyl-3,4-dihydrophthalazin-6-yl)-N-cyclopropyl-4-methylbenzamide (24 mg, 66 μmol) was dissolved in EtOH/water (2:1) (664 μl) and potassium permanganate (10 mg, 66 μmol) was added. The mixture was stirred at RT for 40 min, quenched with saturated, aqueous sodium thiosulfate and diluted with 50 mL of chloroform. In a separatory funnel, the mixture was washed 2×20 mL with sodium thiosulfate and the organics were separated, dried over sodium sulfate, concentrated in vacuo, and purified by HPLC to give the title compound. MS (ES+): 360 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[C:38](C1C=CC=CC=1B(O)O)#[N:39]>>[NH2:37][C:9]1[C:8]([C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=2[C:38]#[N:39])=[C:13]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)[N:12]=[CH:11][N:10]=1
Reactant: N#Cc1ccccc1B(O)O
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccccc2C#N)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 2-cyanophenylboronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=522, obsd.=522).
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([CH3:8])[C@@H:6]([CH3:9])[CH2:5][N:4]([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=O)=[CH:12][CH:11]=2)[CH2:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:31][O:32][C:33]2[CH:34]=[C:35]([NH2:38])[NH:36][N:37]=2)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1.C[Al](C)C.C1(C)C=CC=CC=1>>[CH3:30][O:29][C:27]1[CH:26]=[C:25]([CH2:31][O:32][C:33]2[CH:34]=[C:35]([NH:38][C:14](=[O:16])[C:13]3[CH:12]=[CH:11][C:10]([N:4]4[CH2:5][C@H:6]([CH3:9])[N:7]([CH3:8])[C@H:2]([CH3:1])[CH2:3]4)=[CH:20][CH:19]=3)[NH:36][N:37]=2)[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=1
Reactant: CCOC(=O)c1ccc(N2C[C@@H](C)N(C)[C@@H](C)C2)cc1
Reactant: COc1cc(COc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(COc2cc(NC(=O)c3ccc(N4C[C@@H](C)N(C)[C@@H](C)C4)cc3)[nH]n2)cc(OC)c1
Yield: 5.6 %

Procedure:
N-[5-[(3,5-Dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-4-[(3R,5 S)-3,4,5-trimethylpiperazin-1-yl]benzamide was prepared following the procedure for Example 100, but starting from ethyl 4-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)benzoate (0.276 g, 1.00 mmol) and 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (0.249 g, 1 mmol) and a 2M solution of trimethylaluminium in toluene (1.25 mL, 2.5 mmol). The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (0.027 g, 5.63%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15]O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:22][NH2:23].C(O)(=O)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15][NH:23][CH2:22][C:21]1[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:19]([O:18][CH3:17])[CH:20]=1
Reactant: COc1cc2c(cc1OC)C(=CO)C(=O)N2
Reactant: COc1ccc(CN)cc1OC
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(CNC=C2C(=O)Nc3cc(OC)c(OC)cc32)cc1OC

Procedure:
5.00 g. of 5,6-Dimethoxy-3-hydroxymethylene oxindole, 6.00 g. of 3,4-dimethoxy benzylamine and 2.20 g. of acetic acid in 40 ml. benzene were reacted as described in Example 5 to give 5.44 g. of product, m.p. 198°-200° C.