Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[OH:8].[NH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](O)=O>>[O:8]1[C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[N:1]=[C:12]1[C:11]1[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=1[NH2:9]
Reactant: Nc1ccccc1C(=O)O
Reactant: Nc1cnccc1O
Product: Nc1ccccc1-c1nc2cnccc2o1
Yield: 39.3 %

Procedure:
3-Amino-4-hydroxypyridine (2.225 g, 20.0 mmol) and 2-aminobenzoic acid (2.740 g, 20.0 mmol) were stirred in polyphosphoric acid (40 mL) at 140° C. for 6 hrs. The reaction mixture was poured into distilled water and sodium hydroxide was added until pH=8. The precipitate was collected by filtration and the crude product was purified by chromatography on silica gel eluting with petroleum ether:ethyl acetate:Et3N (160:40:1) to give 2-(oxazolo[4,5-c]pyridin-2-yl)benzenamine (1.659 g, Yield: 39%). 1H NMR (400MHz, DMSO-d6) δ: 6.68 (1H, t, J=7.6 Hz), 6.93 (1H, d, J=8.0 Hz), 7.17 (2H, s), 7.30 (1H, t, J=7.6 Hz), 7.83 (1H, d, J=5.6 Hz), 7.90 (1H, d, J=8.0 Hz), 8.55 (1H, d, J=5.6 Hz), 9.05 (1H, s); MS(ESI) calcd. for C12H9N3O (m/z): 211, found: 212 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([Si](CC)(CC)CC)[NH:8][C:5]2=[N:6][CH:7]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC[Si](CC)(CC)c1cc2cc(Cl)cnc2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Clc1cnc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
Compound 41 (4.37 g, 0.0164 mol) was dissolved in THF. Molecular sieve (10 g of 3A) was added followed by TBAF (32.75 mL, 0.0328). The reaction mixture was stirred for 5 h at rt. Diluted with ethyl acetate and washed several times with water, brine and the organic layer was dried and concentrated in vacuo to an oil that was subjected to flash chromatography (30% EtOAc-70% hexanes) to give 02.3 g (90%) of the desired material 42. 1H NMR DMSO d6 11.8 (bs, 1H), 8.2 (s, 1H), 8.1 (s, 1H), 7.5 (s, 1H), 6.5 (s, 1H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])=[CH:6][CH:5]=1.[CH2:15]1COCC1>IC>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([CH3:14])([CH3:13])[CH2:11][O:12][CH3:15])=[CH:8][CH:9]=1
Reactant: CC(C)(CO)c1ccc(F)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COCC(C)(C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
Sodium hydride (1.664 g, 41.6 mmol, 60% dispersion in mineral oil) was suspended in dry THF (18 ml) under N2 and 2-(4-fluorophenyl)-2-methylpropan-1-ol (3.500 g, 20.8 mmol) in dry THF (18 ml) was slowly added to the suspension at 0° C. After complete addition the reaction was warmed to r.t. and left for 1 h. Iodomethane (6.5 ml, 0.104 mmol) was slowly added at r.t. and the reaction left for 3 h. The reaction was quenched by slow addition of H2O (35 ml). The layers were separated and the aqueous layer was extracted with EtOAc (3×35 ml). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give the crude product. The product was purified by silica flash column chromatography using between 100% heptane to 10% EtOAc:90% heptane as eluent to give the product as a colourless oil (2.991 g, 79%): LC purity 98% (ret. time, 2.16 min); 1H NMR (500 MHz, CDCl3) δH 7.40-7.32 (m, 2H), 7.11-6.96 (m, 2H), 3.39 (s, 2H), 3.33 (s, 3H), 1.33 (s, 6H).
Reaction SMILES: CS(C)=O.[OH:5][C:6]1[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][NH:10][C:11]2=[O:17].Cl[C:19]1[C:24]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH3:32])[N:26]=2)=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.CC(O)=O>[CH3:16][C:15]1[C:6]([O:5][C:19]2[C:24]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH3:32])[N:26]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:17])[NH:10][CH:9]=[CH:8]2
Reactant: Cc1ccc2c(=O)[nH]ccc2c1O
Reactant: CNc1nccc(-c2cccnc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CNc1nccc(-c2cccnc2Oc2c(C)ccc3c(=O)[nH]ccc23)n1
Temperature: 130 °C

Procedure:
DMSO (65 mL) was added to a vial containing 5-hydroxy-6-methylisoquinolin-1(2H)-one (5.50 g, 31.4 mmol) and 4-(2-chloropyridin-3-yl)-N-methylpyrimidin-2-amine (6.93 g, 31.4 mmol). Cesium carbonate (30.7 g, 94.2 mmol) was added to the vial, and the vial was sealed and heated to 130° C. for 16 hours. The vial was allowed to cool to ambient temperature and the mixture was diluted with water (˜1 L) and neutralized with AcOH. The precipitate was filtered to afford 6-methyl-5-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)isoquinolin-1(2H)-one. MS (M+H)+ 360.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15](O)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:60][C:61]1[CH:66]=[CH:65][C:64]([CH2:67][NH2:68])=[CH:63][CH:62]=1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:68][CH2:67][C:64]3[CH:65]=[CH:66][C:61]([F:60])=[CH:62][CH:63]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CC[C@H](C(=O)NCc2ccc(F)cc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 87.3 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the mixture was stirred at room temperature for 5 minutes. Then 1-(4-fluorophenyl)methanamine (60 mg, 0.48 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and the formed solid was filtered, washed by water, and dried to give the yellow title compound (193 mg) as a yellow solid. LC-MS (ES) m/z=463 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:18]1[CH2:23][CH2:22][CH:21](O)[CH2:20][CH2:19]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([CH:21]2[CH2:22][CH2:23][O:18][CH2:19][CH2:20]2)[C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cc1ccncc1)c1ccc(Cl)cc1
Reactant: OC1CCOCC1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1ccncc1)C1CCOCC1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
A toluene (5 ml) solution of the 4-(4-chlorophenylsulfonylmethyl)pyridine (70 mg, 0.261 mmol) obtained in Example 119, tetrahydropyran-4-ol (51 μl, 0.538 mmol) and cyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol) was heated under reflux for 3 days under an argon atmosphere. After cooling to room temperature, the reaction mixture was added with tetrahydropyran-4-ol (51 μl, 0.538 mmol) and cyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol), followed by heating under reflux for 22 hours under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate (=1:2) eluate was concentrated under reduced pressure to give the title compound (65 mg, 71%) as a white solid. The resulting solid was washed with hexane-ether and collected by filtration, whereby the title compound was obtained as a white powder.
Reaction SMILES: Br[CH2:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:18][SH:19].[Na]>CO>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]([C:6]2[CH:16]=[CH:17][C:3]([CH2:2][S:19][CH3:18])=[CH:4][CH:5]=2)=[O:8])=[CH:10][CH:11]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: CS
Agent: [Na]
Solvent: CO
Product: CSCc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
4-bromomethyl-4'-chlorobenzophenone (3.1 g) and 15% methylmercaptan-sodium aqueous solution (5.6 g) were added to methanol (150 ml), and the mixture was stirred for 30 minutes under reflux. The reaction mixture was concentrated and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure. The residual solid was washed with n-hexane to obtain the desired product (2.3 g, melting point: 59° to 61° C., yield: 83%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]#[N:13]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH2:11][CH2:12][NH2:13]
Reactant: COc1ccc(Br)c(CCC#N)c1
Solvent: C1CCOC1
Product: COc1ccc(Br)c(CCCN)c1
Temperature: 0 °C

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of 3-(2-bromo-5-methoxyphenyl)propanenitrile (2.39 g, 10.00 mmol, 1.00 equiv) in tetrahydrofuran (40 mL). This was followed by the addition of BH3 solution in tetrahydrofuran (30 mL, 3.00 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 6 hs at 20° C. in an oil bath. The reaction was then quenched by the addition of water. The resulting solution was concentrated under vacuum. The residue was diluted in water. The pH value of the aqueous solution was adjusted to 8-9 with 1N sodium hydroxide. The resulting aqueous solution was extracted with 10×50 mL of dichloromethane. The organic layers was combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 2.23 g (crude) of 3-(2-bromo-5-methoxyphenyl)propan-1-amine as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1.[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:17]([CH3:18])[S:19][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1)=[O:16]
Reactant: CC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)c(F)c1
Product: COC(=O)c1nc(C)sc1-c1ccc(F)c(F)c1

Procedure:
prepared by reaction of 3-Chloro-3-(3,4-difluoro-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.92 min; [M+H]+=270.3.
Reaction SMILES: C(NC(C)C)(C)C.CS(O[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)(=O)=O.[NH2:33][C@@H:34]([CH3:44])[C@@H:35]([C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1)[OH:36]>CN(C)C=O>[OH:36][C@H:35]([C:37]1[CH:38]=[CH:39][C:40]([OH:43])=[CH:41][CH:42]=1)[C@@H:34]([NH:33][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:27]=2)=[CH:20][CH:21]=1)[CH3:44]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCOS(C)(=O)=O)cc2)cc1
Reactant: C[C@H](N)[C@H](O)c1ccc(O)cc1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccc(OCCN[C@@H](C)[C@H](O)c3ccc(O)cc3)cc2)cc1
Temperature: 80 °C
Reaction time: 14 h
Yield: 57.5 %

Procedure:
Diisopropylamine (0.40 mL) was added to a mixture of ethyl 4′-(2-methanesulfonyloxyethoxy)biphenyl-4-carboxylate (0.32 g) and 4-((1R,2S)-2-amino-1-hydroxypropyl)phenol (0.32 g) in N,N-dimethylformamide (6 mL), and the mixture was stirred for 14 hrs at 80° C. After being cooled to room temperature, the reaction mixture was partitioned between methylene chloride and water. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:methylene chloride/methanol=15/1) to afford ethyl 4′-{2-[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl-amino]ethoxy}biphenyl-4-carboxylate (0.22 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14](=[N:27][O:28][CH3:29])[CH2:15][N:16]2C(=O)C3=CC=CC=C3C2=O)=[N:4][CH:5]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:7]=1.O.NN.O>C(O)C>[CH3:29][O:28][N:27]=[C:14]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])=[CH:5][N:4]=1)[CH2:15][NH2:16]
Reactant: CON=C(CN1C(=O)c2ccccc2C1=O)c1ncc(OCC(F)(F)F)cc1Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: CON=C(CN)c1ncc(OCC(F)(F)F)cc1Cl
Temperature: 25 °C
Yield: 81.1 %

Procedure:
To 790 mg of N-[2-[3-chloro-5-(2,2,2-trifluoroethoxy)pyridin-2-yl]-2-(methoxyimino)ethyl]phthalimide in 10 ml of ethanol, 187 mg of hydrazine monohydrate was added and refluxed with heating for 1 hour with stirring. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, mixed with 30 ml of water and extracted with ethyl acetate (25 ml×2). The resulting organic layers were combined, washed with water (20 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 446 mg of the desired crude product as a brown oil. The oil was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10]1.Cl.[NH2:17][OH:18].C(N(CC)CC)C>CN(C=O)C>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][CH2:12][C:11](=[N:17][OH:18])[CH2:10]1
Reactant: O=C1CCCC(c2ccc(O)cc2O)C1
Reactant: NO
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: ON=C1CCCC(c2ccc(O)cc2O)C1
Reaction time: 3 h
Yield: 86 %

Procedure:
(±)-3-(2,4-Dihydroxyphenyl)cyclohexanone (13 mg), hydroxylamine hydrochloride (0.0065 g), and triethylamine (16 μl) were heated at 80° C. in DMF (3 ml). After 3 hr, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, petroleum ether/ethyl acetate 3:2 v/v) to furnish the title compound as a white solid (12 mg, 86%). δH (CD3OD) 1.4-2.0 (6H, overlapping m), 2.10 (0.5H, m), 2.20 (0.5H, m), 2.35 (0.5H, m), 2.46 (0.5H, m), 2.94 (1H, m), 6.22-6.26 (2H, overlapping m), 6.92-6.95 (1H, overlapping m); m/z (ES+) 222 (M+H)−.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.C([Li])CCC.[CH2:12]([N:19]1[CH2:23][C@H:22]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:21][C@H:20]1[CH:32]=[O:33])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1.CCCCCC>[CH2:12]([N:19]1[CH2:23][C@H:22]([O:24][Si:25]([C:28]([CH3:29])([CH3:30])[CH3:31])([CH3:27])[CH3:26])[CH2:21][C@H:20]1[CH:32]([C:6]1[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=1)[OH:33])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](C=O)N(Cc2ccccc2)C1
Reactant: Cn1cccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1nccc1C(O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1Cc1ccccc1
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
To a solution of 1-methylpyrazole (30.5 g) in tetrahydrofuran (460 ml) was added dropwise n-butyllithium (1.6N) in hexane (250 ml) keeping the temperature below -60° C. The mixture was warmed to 0°-5° C. over 30 minutes, and stirred for 30 minutes, then cooled to -70°~60° C. To the mixture was added a solution of (2S,4R)-1-benzyl-4-(t-butyldimethylsilyloxy)-2-formylpyrrolidine (91.4 g) in tetrahydrofuran (90 ml) keeping the temperature below -60° C. The reaction mixture was warmed to 0°-5° C. over 40 minutes, and stirred for 2 hours. The mixture was quenched with ice water (300 ml) and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (×2), and the combined organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was column chromatographed on silica gel (3 kg, eluting with ethyl acetate-n-hexane (1:1 to 5:1)) to give 1-{(2S,4R)-1-benzyl-4-(t-butyldimethylsilyloxy)-pyrrolidin-2-yl }-1-(1-methylpyrazol-5-yl)methanol (101 g) (as a 2:1 mixture of diastereomer).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([CH3:17])[CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[OH:19][NH3+:20].C(=O)(O)[O-].[Na+].C(O)C>[Cl-].[Na+].O.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[N:20]/[OH:19])[CH:14]=[C:15]([CH3:17])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH3+]O
Reactant: Cc1cc(C=O)cc(OCc2ccccc2)c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(/C=N/O)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
A mixture of 3-(benzyloxy)-5-methylbenzaldehyde (948 mg), hydroxyl ammonium chloride (320 mg), sodium bicarbonate (837 mg), and ethanol (10 mL) was stirred overnight at room temperature. To the reaction mixture, water and brine were added, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (804 mg).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.[F:33][C:34]([Si](C)(C)C)([F:36])[F:35].Cl>C1COCC1>[F:33][C:34]([F:36])([F:35])[CH:29]([C:28]1[CH:31]=[CH:32][C:25]([C:22]2[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=2)=[CH:26][CH:27]=1)[OH:30]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccc(-c2ccncc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccc(-c2ccncc2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.1 %

Procedure:
Tetrabutylammonium fluoride (0.027 ml; 1.0 M solution in tetrahydrofuran) was added to a solution of 4-pyridin-4-yl-benzaldehyde (500 mg, 2.73 mmol) and trifluoromethyltrimethylsilane (TMSCF3) (485 μl, 3.28 mmol) in 5 ml THF at 0° C. The resulting mixture was warmed up to room temperature and stirred at room temperature for 4 hours. The reaction mixture was then treated with 5 ml of 1N HCl and stirred at room temperature overnight. The solvent was evaporated to dryness, 9 ml of 1M sodium carbonate aqueous solution was added, the aqueous phase was extracted with chloroform (3×10 ml), and the combined chloroform layer was washed with water, dried over MgSO4. The organic solvent was removed in vacuo to give 360 mg of 2,2,2-trifluoro-1-(4-pyridin-4-yl-phenyl)ethanol, yield: 51%.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-])=O)[CH:4]=1.[CH:15](=O)[CH2:16][CH3:17]>>[CH2:16]([CH:15]1[NH:10][C:5]2[C:6](=[CH:8][CH:9]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=2)[N:7]2[CH:2]=[CH:3][CH:4]=[C:5]12)[CH3:17]
Reactant: Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CCC=O
Product: CCC1Nc2cc(C(F)(F)F)ccc2-n2cccc21

Procedure:
4-Ethyl-7-trifluoromethyl -4,5-dihydropyrrolo[1,2-a]quinoxaline was prepared from 4-trifluoromethyl-2-nitro aniline according to the sequence of Example 1 and 2, and the resulting oil treated with proprionaldehyde according tot he procedure of Example 3 to yield a light orange oil, which was used in the next step without further characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]3[N:25]([CH3:26])[C:24](=[O:27])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[CH3:28])[N:17]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1>C1COCC1.C(OCC)(=O)C.CO.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]3[N:25]([CH3:26])[C:24](=[O:27])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[CH3:28])[N:17]=3)=[CH:12][CH:13]=2)=[O:7])=[CH:29][CH:30]=1
Reactant: Cc1cccc2nc(C=Cc3ccc(C(=O)c4ccc(Cl)cc4)cc3)n(C)c(=O)c12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccc2nc(CCc3ccc(C(=O)c4ccc(Cl)cc4)cc3)n(C)c(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.7 %

Procedure:
To a solution of 2-[2-[4-(4-chlorobenzoyl)phenyl]-vinyl]-3,5-dimethyl-4(3H)-quinazolinone (104 mg) in THF-ethyl acetate-methanol (2:1:1) (20 ml) was added 10% Pd/C (50% hydrous) (10 mg) and the mixture was stirred under hydrogen at room temperature for 2 hours. The catalyst was then filtered off and the filtrate was concentrated. The residue was washed with ethyl acetate-methanol and dried to provide 53 mg of white powder.
Reaction SMILES: [C:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.P(OCCCC)(OCCCC)OCCCC.[CH2:28]([NH2:30])[CH3:29].[OH-].[Na+]>>[CH2:28]([NH:30][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH3:29]
Reactant: CCN
Reactant: Oc1cccc2ccccc12
Agent: CCCCOP(OCCCC)OCCCC
Agent: [Na+]
Agent: [OH-]
Product: CCNc1cccc2ccccc12
Yield: 85 %

Procedure:
288 parts of α-naphthol, 10 parts of tributyl phosphite and 110 parts of ethylamine gas are heated for 20 hours at 240° C, whilst stirring. After cooling and letting down the autoclave, the mixture is stirred for 20 minutes with 1,000 parts of 2.5 percent strength by weight aqueous sodium hydroxide solution at 70° C. The organic phase is separated off, washed with 2,000 parts of water at 30° C, separated off and distilled. 290 parts of N-ethyl-α-naphthylamine boiling at 119° - 120° C/0.1 mm Hg are obtained, corresponding to a yield of 85% of theory.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C:8](=[O:20])[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[N:13]=1)([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].Cl[C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=1[N+]([O-])=O>>[C:1]([O:5][C:6]([C:7]1[C:23]2[CH:24]=[CH:25][C:26]([C:27]#[N:28])=[CH:29][C:30]=2[O:20][C:8]=1[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[N:13]=1)([CH3:11])[CH3:10])=[O:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COc1cccc(C(C)(C)C(=O)CC(=O)OC(C)(C)C)n1
Product: COc1cccc(C(C)(C)c2oc3cc(C#N)ccc3c2C(=O)OC(C)(C)C)n1

Procedure:
According to the method that is used for the preparation of Compound FR1, the title compound was synthesized from 4-(6-methoxy-pyridin-2-yl)-4-methyl-3-oxo-pentanoic acid tert-butyl ester and 4-chloro-3-nitrobenzonitrile.
Reaction SMILES: C[O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[N:6][CH:5]=1.CCN(C(C)C)C(C)C.[CH3:21][C:22]([CH3:26])([CH3:25])[C:23]#[CH:24]>O1CCOCC1.[Cu](I)I>[CH3:21][C:22]([CH3:26])([CH3:25])[C:23]#[C:24][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:11])=[CH:5][N:6]=1
Reactant: C#CC(C)(C)C
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: I[Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)C#Cc1ccc(C(=O)O)cn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
6-Chloronicotinic acid methyl ester (500 mg; 2.93 mmol) was suspended in 1,4-dioxane (3 ml) in a 5 ml reaction vial. To the vessel was added dichlorobis(triphenylphosphine) palladium(ii) (70 mg; 3 mol %), copper iodide (12 mg), n,n-diisopropylethylamine (0.63 ml; 3.5 mmol) and 3,3-dimethylbut-1-yne (0.44 ml; 3.5 mmol). The vessel was sealed and the mixture was heated at 80° C. for 24 hrs. The solvents were evaporated to dryness and 20 ml of tetrahydrofuran and 20 ml of 10N NaOH was added. The mixture was stirred at room temperature for 30 minutes and the solvent was evaporated. The basic layer was acidified with concentrated HCl and extracted three times with EtOAc. The organic layers were washed with brine and dried over Na2SO4, filtered and evaporated to give the desired product as a brown powder (590 mg; 99%).