Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH2:18][CH2:19][CH3:20])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[C:21]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1)(=[O:23])[CH3:22]>C(O)C>[O:17]=[C:16]1[NH:15][N:14]=[C:13]([CH2:18][CH2:19][CH3:20])/[C:12]/1=[C:4]1/[NH:5][C:6]2[C:11]([C:2]([S:31][C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:21](=[O:23])[CH3:22])=[CH:30][CH:29]=3)=[CH:3]/1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Reactant: CC(=O)Nc1ccc(S)cc1
Solvent: CCO
Product: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NC(C)=O)cc2)c2ccccc2N1
Temperature: 180 °C

Procedure:
(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one (0.045 g, 0.013 mmol) was dissolved in ethanol (1.5 mL) and 4-acetamidothiophenol (0.023 g, 0.013 mmol) was added. The reaction mixture was heated to 180° C. using a microwave reactor for 5-10 minutes. The mixture was then concentrated and the resulting solid filtered and washed with ether. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.70 (t, J=7.33 Hz, 3H) 1.32 (qd, J=7.45, 7.20 Hz, 2H) 2.11 (s, 3H) 2.25 (t, J=7.07 Hz, 2H) 6.76 (s, 1H) 7.63-7.71 (m, 3H) 7.89 (t, J=8.84 Hz, 3H) 7.93-7.99 (m, 1H) 8.17 (d, J=8.34 Hz, 1H) 10.36 (s, 1H); ESI-MS: m/z calc'd for C23H22N4O2S 418.51. found 419.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[C:14](=[O:15])[C:13]([NH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][C:11]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[N:10]2)=[CH:4][CH:3]=1.[C:32]1([CH2:38][CH2:39][CH2:40]Br)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[C:14](=[O:15])[C:13]([N:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:40][CH2:39][CH2:38][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:12][C:11]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)=[N:10]2)=[CH:30][CH:31]=1
Reactant: CCOC(=O)Nc1cc(-c2ccc(OC)cc2)nn(CC=Cc2ccc(Cl)cc2)c1=O
Reactant: BrCCCc1ccccc1
Product: CCOC(=O)N(CCCc1ccccc1)c1cc(-c2ccc(OC)cc2)nn(CC=Cc2ccc(Cl)cc2)c1=O
Yield: 68.7 %

Procedure:
Using 2-(4-chlorocinnamyl)-4-ethoxycarbonylamino-6-(4-methoxyphenyl)-2H-pyridazin-3-one (70 mg) and 3-phenylpropyl bromide as starting materials, the procedures of Example 116 were repeated likewise, whereby the title compound (61 mg, 68.7%) was obtained.
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:9]([O:11]/[C:12](=[CH:18]\[C:19]1[CH:20]=[N:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N:31]([CH3:44])[C:32]([O:34]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH:26]=2)=[CH:23][CH:24]=1)/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:10].O.C(OCC)(=O)C>CN(C)C=O>[CH2:9]([O:11]/[C:12](=[CH:18]\[C:19]1[CH:20]=[N:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N:31]([CH3:44])[C:32]([NH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:34])[CH:26]=2)=[CH:23][CH:24]=1)/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:10]
Reactant: CCOC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)c2)nc1)OCC
Reactant: CCCCCCCN
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OCC)C(=O)OCC)cn2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
0.16 mL (1.1 mmol) of n-heptylamine is added to a solution of 0.32 g (0.55 mmol) of ethyl (Z)-2-ethoxy-3-(6-{3-[methyl-(4-nitrophenoxycarbonyl)amino]phenyl}pyrid-3-yl)acrylate in 10 mL of dimethylformamide. The tube is sealed and rapidly placed in an oil bath preheated to 80° C. The reaction mixture is stirred at 80° C. for 1 hour 30 minutes. After cooling, the reaction is worked up by addition of 10 mL of water and extraction with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and then dried over magnesium sulfate. The solvents are evaporated off. The crude product obtained is purified by chromatography on a column of silica eluted with a 70/30 heptane/ethyl acetate mixture to give 0.14 g (54%) of ethyl (Z)-2-ethoxy-3-{6-[3-(3-heptyl-1-methylureido)phenyl]pyrid-3-yl}acrylate in the form of a colorless oil.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[NH2:9][C:10]1[C:15]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:14][CH:13]=[CH:12][N:11]=1.[Br:23][C:24]1[CH:29]=[CH:28][C:27](F)=[CH:26][C:25]=1[C:31]([F:34])([F:33])[F:32].O>CS(C)=O.CCOC(C)=O>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([O:22][C:19]2[CH:20]=[CH:21][C:16]([C:15]3[C:10]([NH2:9])=[N:11][CH:12]=[CH:13][CH:14]=3)=[CH:17][CH:18]=2)=[CH:26][C:25]=1[C:31]([F:32])([F:33])[F:34]
Reactant: Nc1ncccc1-c1ccc(O)cc1
Reactant: Fc1ccc(Br)c(C(F)(F)F)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Nc1ncccc1-c1ccc(Oc2ccc(Br)c(C(F)(F)F)c2)cc1
Temperature: 140 °C
Reaction time: 7 h
Yield: 69.2 %

Procedure:
Tripotassium phosphate (3.42 g) was added to a mixture of 4-(2-aminopyridin-3-yl)phenol (1.00 g) and 1-bromo-4-fluoro-2-(trifluoromethyl)benzene (1.57 g) in DMSO (15 mL). The mixture was stirred at 140° C. under nitrogen for 7 hr. Water and EtOAc were added and the extracted organic layer was washed with brine. Silica-gel was added to the organic layer and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH-silica gel, eluted with EtOAc in hexane) and concentrated to give 3-{4-[4-bromo-3-(trifluoromethyl)phenoxy]phenyl}pyridin-2-amine (1.52 g) as orange oil.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[C:11]([O:19][CH3:20])[N:10]=1)C1C=CC=CC=1>CO.CC(O)=O.[OH-].[Pd+2].[OH-]>[CH3:20][O:19][C:11]1[N:10]=[C:9]([NH2:8])[CH:14]=[CH:13][C:12]=1[C:15]([F:18])([F:16])[F:17]
Reactant: COc1nc(N(Cc2ccccc2)Cc2ccccc2)ccc1C(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: COc1nc(N)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of N,N-dibenzyl-6-methoxy-5-(trifluoromethyl)pyridin-2-amine (3.0 g, 8.056 mmol) in a mixture of methanol (30 mL) and AcOH (3 mL) was added palladium hydroxide (0.3 g, 0.43 mmol) under a nitrogen atmosphere. The mixture was stirred under hydrogen atmosphere (55 psi, 25° C.) overnight. The catalyst was removed by filtration through a pad of celite and the filtrate was neutralized by saturated Na2CO3. The aqueous layer was extracted with CH2Cl2 (30 mL×3) and the combined organic layers were concentrated under vacuum to give 6-methoxy-5-(trifluoromethyl)pyridin-2-amine (1.4 g, 90%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J=8.4 Hz, 1H), 6.03 (d, J=8.0 Hz, 1H), 4.64 (brs, 2H), 3.93 (s, 3H). MS (ESI) m/e (M+H+) 193. 13C NMR (100 MHz, CDCl3) 159.4, 138.0 (d, J=5.9 Hz), 125.9, 122.3, 101.9 (d, J=44.4 Hz), 98.3, 53.6. 19F NMR (282.4 MHz, CDCl3) −62.6.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([C:16]#[N:17])=[C:4]([C:18]2[O:19][CH2:20][CH2:21][CH:22]=2)[N:3]=1.[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[CH3:32])[CH2:27][NH2:28]>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:18]2[O:19][CH2:20][CH2:21][CH:22]=2)[C:5]([C:16]#[N:17])=[C:6]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][C:31]([CH3:32])=[C:24]([CH3:23])[CH:25]=2)[N:7]=1
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)nc(N)nc1C1=CCCO1
Reactant: Cc1ccc(CN)cc1C
Solvent: COCCOC
Product: Cc1ccc(CNc2nc(N)nc(C3=CCCO3)c2C#N)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.7 %

Procedure:
To a stirred suspension of 250 mg (0.74 mmol) trifluoromethanesulfonic acid 2-amino-5-cyano-6-(4,5-dihydro-furan-2-yl)-pyrimidin-4-yl ester in 10 ml DME was added 0.20 g (1.49 mmol) 3,4-dimethylbenzylamine and the mixture stirred at room temperature for 1 hour. The reaction mixture was then partitioned between water and ethyl acetate and the organic phase was dried over sodium sulfate and concentrated in vacuo. Chromatography (ethyl acetate) followed by trituration in ether/hexane afforded 35 mg (15%) 2-amino-4-(4,5-dihydro-furan-2-yl)-6-(3,4-dimethyl-benzylamino)-pyrimidine-5-carbonitrile as a white crystalline solid. ES-MS m/e (%): 322 (M+H+, 100).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:23]O>>[C:1]1([S:7]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]3)=[O:23])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCc2cc(OCCCSc3ccccc3)ccc2N1
Reactant: OO
Product: O=C1CCc2cc(OCCCS(=O)c3ccccc3)ccc2N1

Procedure:
Prepared analogous to Example 2 from 6-[3-(phenylmercapto)-propoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([CH3:18])[C:16](I)=[C:12]3[N:11]=[C:10]([N:19]3[CH2:23][CH2:22][CH2:21][C@H:20]3[CH2:24][OH:25])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:16]2[C:15]([CH3:18])=[N:14][N:13]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:9][C:10]([N:19]4[CH2:23][CH2:22][CH2:21][C@H:20]4[CH2:24][OH:25])=[N:11][C:12]=23)=[CH:30][CH:29]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1nn2c(-c3ccc(F)cc3)cc(N3CCC[C@H]3CO)nc2c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(C)nn3c(-c4ccc(F)cc4)cc(N4CCC[C@H]4CO)nc23)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
(S)-(1-(7-(4-Fluorophenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)methanol (56 mg), 4-methoxyphenylboronic acid (30 mg) and tetrakis(triphenylphosphine)palladium (10 mg) are added to toluene (10 mL), ethanol (5 mL) and 1 N NaHCO3 aqueous solution (1.5 mL) and stirred overnight at 90° C. under argon atmosphere. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is concentrated by distillation under reduced pressure and purified by column chromatography to yield the target compound (27 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][Cl:10].[NH2:11][C:12]1[NH:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1>S1(CCCC1)(=O)=O.CC(O)C>[Cl-:10].[NH2:11][C:12]1[N:16]([CH2:9][O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[N+:13]=1[CH2:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: ClCOc1ccccc1Br
Solvent: CC(C)O
Solvent: O=S1(=O)CCCC1
Product: Nc1n(COc2ccccc2Br)c2ccccc2[n+]1COc1ccccc1Br
Product: [Cl-]
Reaction time: 162 h
Yield: 42.1 %

Procedure:
o-Bromo-α-chloroanisole 15.0 g (0.0679 mol) in 20 ml of sulfolane is added to a solution of 4.50 g (0.0339 mol) of 2-aminobenzimidazole in 40 ml of sulfolane. The mixture turns into a semi-solid mass upon standing for several hours. After standing for 6.75 days at room temperature, the reaction mixture is diluted with 40 ml of 2-propanol, filtered, and the product is washed with 2-propanol. Trituration with ether gives 7.7 g (43%) of a white solid; mp 229°-230°. Recrystallization of 3.5 g of this material from 340 ml of 90% ethanol gives 2.5 g of the named product as a white fluffy solid after drying for 6 hours at 78° (1 mm): mp 236°-237°dec.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][O:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].CCN(CC)CC.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl.O>[CH3:23][S:24]([O:1][C@@H:2]1[CH2:7][CH2:6][O:5][CH2:4][C@H:3]1[NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:15])(=[O:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N[C@@H]1COCC[C@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1COCC[C@H]1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 101.2 %

Procedure:
Tert-butyl ((3R,4R)-4-hydroxytetrahydro-2H-pyran-3-yl)carbamate (1.6 g, 7.36 mmol) was taken up in CH2Cl2 (20 ml) and cooled to 0° C. followed by addition of Et3N (1.232 ml, 8.84 mmol). After 5 minutes methanesulfonyl chloride (0.631 ml, 8.10 mmol) in DCM (5 ml) was added dropwise. The reaction mixture was stirred at 0° C. for 30 minutes and allowed to warm to ambient temperature while stirring for 2 hours. The reaction mixture was diluted with water and DCM and the layers were separated. The organic layers were combined and washed with water twice, dried over Na2SO4, and the solvent removed in vacuo. The residue was dried under high vacuum overnight to afford recovered (3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl methanesulfonate (2.2 g, 7.45 mmol, 100% yield) as a white solid.
Reaction SMILES: P(OC1C=CC=CC=1)(OC1C=CC=CC=1)(O[C:4]1[N:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)[C:6](=[O:10])[CH2:7][CH2:8][CH:9]=1)=O.[CH2:37]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1B(O)O)[CH3:38].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:37]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:4]1[N:5]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=2)[C:6](=[O:10])[CH2:7][CH2:8][CH:9]=1)[CH3:38]
Reactant: CCOc1ccccc1B(O)O
Reactant: O=C1CCC=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)N1Cc1ccc(OC(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccccc1C1=CCCC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 40 °C

Procedure:
A mixture of 6-oxo-1-(4-(trifluoromethoxy)benzyl)-1,4,5,6-tetrahydropyridin-2-yl diphenyl phosphate (140 mg; 0.13 mmol; 1.0 equiv.), (2-ethoxyphenyl)boronic acid (34 mg; 0.20 mmol; 1.5 equiv.), PdCl2(PPh3)2 (5 mg; 0.007 mmol; 0.05 equiv.), Na2CO3 (188 mg; 1.78 mmol; 13.2 equiv.) in THF (2 ml) and water (0.9 ml) was heated to 40° C., under nitrogen, for 1.5 h. After cooling to rt, water was added, and the mixture was extracted with Et2O (3×). The mixed organic layers were dried over anh. K2CO3, filtered, and concentrated to dryness under reduced pressure. Purification by preparative HPLC afforded 6-(2-ethoxyphenyl)-1-(4-(trifluoromethoxy)benzyl)-3,4-dihydropyridin-2(1H)-one. LC-MS (conditions E): tR=0.83 min.; [M+H]+: 392.2 g/mol.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C[Al](C)C.C[O:18][C:19]([C:21]1[C:25]2[CH:26]=[CH:27][C:28]([O:30][C:31]3[CH:36]=[CH:35][N:34]=[C:33]([NH2:37])[N:32]=3)=[CH:29][C:24]=2[O:23][CH:22]=1)=O.[NH4+].[Cl-]>C1(C)C=CC=CC=1.C1COCC1>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:19]([C:21]2[C:25]3[CH:26]=[CH:27][C:28]([O:30][C:31]4[CH:36]=[CH:35][N:34]=[C:33]([NH2:37])[N:32]=4)=[CH:29][C:24]=3[O:23][CH:22]=2)=[O:18])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: COC(=O)c1coc2cc(Oc3ccnc(N)n3)ccc12
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Nc1nccc(Oc2ccc3c(C(=O)Nc4ccc(F)c(C(F)(F)F)c4)coc3c2)n1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
In a dried vessel, 108 mg (0.60 mMol) 4-fluoro-3-trifluoromethyl-aniline are dissolved in 10 ml toluene and cooled to 10° C. Then 900 μl Me3Al (2 M in toluene; 1.8 mMol) are added via syringe. After 1 h at rt, a suspension of 171 mg (0.599 mMol) 6-(2-amino-pyrimidin-4-yloxy)-benzofuran-3-carboxylic acid methyl ester (Step 9.6) in 5 ml THF is added and the reaction mixture is stirred for 40 min in an oil bath of 110° C. The solution is cooled in ice and hydrolyzed with 20 ml of a sat. NH4Cl. After 10 min stirring, the mixture is filtered through Celite, the solid washed extensively with EtOAc and water, the aq. phase separated from the filtrate and extracted with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; EtOAc) and crystallization from EtOAc/hexane 1:1 gives the title compound: MS: [M+1]+=433; TLC(hexane/EtOAc 1:9): Rf=0.22.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH2:9])=[N:6][CH:7]=1.[CH3:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[CH3:18])[NH2:14].C([O:22][C:23](=O)[C@H:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:25])(=O)C>>[CH3:10][C:11]1[CH:12]=[C:13]([N:14]([CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)[C:23](=[O:22])[C@@H:24]([OH:25])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:15]=[CH:16][C:17]=1[CH3:18]
Reactant: CC(=O)OC(=O)[C@@H](O)c1ccccc1
Reactant: C=Cc1ccc(F)cn1
Reactant: Cc1ccc(N)cc1C
Product: Cc1ccc(N(CCc2ccc(F)cn2)C(=O)[C@@H](O)c2ccccc2)cc1C

Procedure:
In analogy to example 25 step 1 and 26 step 1-2, (3,4-dimethyl-phenyl)-[2-(5-fluoro-pyridin-2-yl)-ethyl]-amine obtained by reacting 5-Fluoro-2-vinyl-pyridine (CAS: 869108-71-4) with 3,4-dimethylaniline was coupled with (S)-(+)-O-acetyl-L-mandelic acid then hydrolysed to provide the title compound. MS(m/e): 379.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15](O)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[N:31]1([O:40][P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.NO.C(N(CC)CC)C>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]([NH:31][OH:40])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)C(c1ccccc1)c1ccc(-c2ccc(F)cc2)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(NO)C(c1ccccc1)c1ccc(-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
To a solution of 13 (40 mg, 0.14 mmol), BOP (58 mg, 0.13 mmol), and hydroxylamine hydrochloride (9 mg, 0.13 mmol) in pyridine (5 mL) was added triethylamine (0.055 mL, 0.39 mmol) and the reaction mixture was stirred at room temperature for 2 h. The solvents were removed under vacuum and the crude was dissolved in ethyl acetate. The organic layer was washed with water, dried over Na2SO4, filtered and concentrated. The residue was purified via HPLC (Gilson) reverse-phase column with a gradient of methanol (20-75%) in water to afford compound 14 as a white solid (20 mg, 48%). 1H NMR (CD3OD-d4) δ (ppm): 7.62-7.57 (m, 2H), 7.53 (d, J=8.2 Hz, 2H), 7.40-7.22 (m, 7H), 7.14 (t, J=8.8 Hz, 2H), 4.82 (s, 1H). LRMS (ESI): (calc.) 321.1 (found) 320.4 (MH)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH2:13][NH:14][CH3:15].CNCC1C=CC2C(=CC=CC=2)C=1CCC.Cl.[O:33]=[C:34]1[NH:43][C:42]2[N:41]=[CH:40][C:39](/[CH:44]=[CH:45]/[C:46]([OH:48])=O)=[CH:38][C:37]=2[CH2:36][CH2:35]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH2:13][N:14]([CH3:15])[C:46](=[O:48])/[CH:45]=[CH:44]/[C:39]1[CH:40]=[N:41][C:42]2[NH:43][C:34](=[O:33])[CH2:35][CH2:36][C:37]=2[CH:38]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CNCc1c(OC)ccc2ccccc12
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: COc1ccc2ccccc2c1CN(C)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Yield: 71 %

Procedure:
According to the procedure of Example 1 (a), except substituting (2-methoxy-naphthalen-1-ylmethyl)methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.403 g, 71%) was prepared as an orange-brown solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.37 (s, 1H), 8.08-7.81 (m, 4H), 7.70-7.11 (m, 5H), 5.22-5.09 (m, 2H), 3.98-3.90 (m, 3H), 2.91-2.87 (m, 5H), 2.63-2.49 (m, 2H); MS (ESI) m/e 402 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:45])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[C:31]([OH:38])[C:30]=2[CH2:39][CH2:40][CH3:41])[C:10]=1[CH2:42][CH2:43][CH3:44])C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[OH-].[Na+].CO>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:45])=[O:3])=[C:10]([CH2:42][CH2:43][CH3:44])[C:11]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[C:31]([OH:38])[C:30]=1[CH2:39][CH2:40][CH3:41])(=[O:17])[CH3:16]
Reactant: CCCc1c(OCCCCOCCCCOc2c(C(C)=O)ccc(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCCOCCCCOc2c(C(C)=O)ccc(OCCCC(=O)O)c2CCC)ccc(C(C)=O)c1O
Yield: 89.6 %

Procedure:
A solution of 2.71 g of 4-[4-acetyl-3-[4-[4-(4acetyl-3-hydroxy-2-propylphenoxy)butoxy]butoxy]-2-propylphenoxy]butanoic acid ethyl ester in 20 ml of 1.0N sodium hydroxide and 90 ml of methanol was stirred at reflux for 6.5 hours. The methanol was removed in vacuo and the residue was acidified. The product was extracted with ether and the dried (magnesium sulfate) extract was concentrated in vacuo to an oil. Chromatography on 150 g of silica gel and elution with a solvent mixture of 5% acetic acid: 70% toluene: 25% ethyl acetate gave 2.32 g (90% yield) of 4-[4-acetyl-3-[4-[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butoxy]butoxy]-2-propylphenoxy]butanoic acid as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=[O:10])=[C:4]([N+:12]([O-])=O)[CH:3]=1.[H][H]>C(O)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:8][C:9](=[O:10])[NH:12]2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C1Cc2ccc(F)cc2N1

Procedure:
119 g 4-fluoro-2-nitrophenylacetic acid (educt III) are hydrogenated in 600 ml acetic acid with the addition of 20 g palladium on activated charcoal (10%) under 50 psi of hydrogen pressure. The catalyst is suction filtered and the solvent is distilled off. The crude product is extracted with 500 ml petroleum ether, suction filtered, washed with water and dried.
Reaction SMILES: [CH3:1][C:2](=[O:7])[C:3]([CH3:6])([CH3:5])[CH3:4].[C-:8]#[N:9].[K+].C#N>C(OC)(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[OH:7][C@@:2]([CH3:1])([C:3]([CH3:6])([CH3:5])[CH3:4])[C:8]#[N:9]
Reactant: [C-]#N
Reactant: CC(=O)C(C)(C)C
Agent: C#N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: COC(C)(C)C
Product: CC(C)(C)[C@](C)(O)C#N
Temperature: 2.5 °C
Yield: 74.7 %

Procedure:
10 mmol of pinacolone (1.25 g) were dissolved in 30 ml of methyl t-butyl ether, treated with 5 ml of enzyme solution (1000 IU/ml) and cooled to 0-5° C. with stirring. Parallel to this, 20 mmol of potassium cyanide were dissolved in 250 ml of 0.1 M aqueous citric acid with ice-cooling. The hydrocyanic acid solution prepared in this way was added to the reaction mixture and the reaction vessel was sealed pressure-tight. After a reaction time of 2.5 h, the mixture was diluted with 50 ml of methyl t-butyl ether and the reaction solution was extracted. The aqueous phase was separated off, extracted by shaking again with 80 ml of methyl t-butyl ether and then discarded. The combined organic phases were dried using anhydrous sodium sulfate and the solvent was removed under reduced pressure. After column chromatography, 0.95 g of (S)-2-hydroxy-2,3,3-trimethylbutanenitrile (75%) was obtained as a white solid (m.p. 98-99° C.).