Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[NH:21][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)=[CH:15][CH:14]=3)[N:10]=[C:9]([NH:29][CH:30]3[CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:32]1[CH2:31][CH:30]([NH:29][C:9]2[N:8]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([NH:21][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)=[O:28])=[CH:17][CH:18]=3)[N:10]=2)[CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CC(Nc2nc(-c3ccc(NC(=O)Nc4cccnc4)cc3)nc(N3CCOCC3)n2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(-c2nc(NC3CNC3)nc(N3CCOCC3)n2)cc1)Nc1cccnc1
Reaction time: 24 h

Procedure:
To a stirred solution of tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(pyridin-3-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate 30 mg (0.055 mmoles) in DCM, (20 ml) TFA (1.5 ml) was added at room temperature and stirred for 24 hours. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. Yield: 21 (83%); (M+H) 448.5.
Reaction SMILES: [CH:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1.C([O-])(=O)C.[K+].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27](OS(C(F)(F)F)(=O)=O)[CH:28]=3)[N:23]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[CH:40]=3)[C:22]=2[C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:11]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([CH:1]4[CH2:5][CH2:4][CH:3]=[CH:2]4)[CH:28]=3)[N:23]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[CH:40]=3)[C:22]=2[C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:19][CH:20]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: C1=CCCC1
Reactant: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2n1Cc1cccc(OC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cc(C3C=CCC3)ccc2n1Cc1cccc(OC)c1
Reaction time: 48 h
Yield: 45 %

Procedure:
Cyclopentene (0.44 mL, 341 mg, 5.0 mmol), palladium acetate (22 mg, 0.10 mmol), tetrabutylammonium bromide (322 mg, 1.0 mmol) and potassium acetate (295 mg, 1.0 mmol) were added to a stirred solution of ethyl 3-(4-tert-butylphenyl)-1-(3-methoxybenzyl)-5-{[(trifluoromethyl)sulfonyl]oxy}-1H-indole-2-carboxylate (Example 125, 570 mg, 1.0 mmol) in N,N-dimethylformamide (5 mL). The reaction was stirred for 48 h and then diluted with ethyl acetate (100 mL). The solution was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Flash chromatography of the residue over silica gel using 6:1 ethyl acetate/hexane gave 230 mg, (45%) of the desired product. The product had: 1H NMR (300 MHz, acetone-D6) δ 7.49-7.56 (m, 3 H), 7.37-7.43 (m, 3 H), 7.17-7.23 (m, 2 H), 6.68-6.92 (m, 3 H), 4.09 (q, 3 H), 3.92-4.01 (m, 1 H), 3.75 (s, 3 H), 2.31-2.50 (m, 3 H), 1.62-1.77 (m, 1 H), 1.39 (s, 9 H), 0.98 (t, 3 H).
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=3[CH:8](O)[C:6]=2[N:7]=1)[CH3:2].[NH:19]1[CH:26]=[CH:25][C:23](=[O:24])[NH:22][C:20]1=[O:21]>C(O)(=O)C>[CH2:1]([C:3]1[S:4][C:5]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=3[CH:8]([C:25]3[C:23](=[O:24])[NH:22][C:20](=[O:21])[NH:19][CH:26]=3)[C:6]=2[N:7]=1)[CH3:2]
Reactant: CCc1nc2c(s1)C=Cc1cc(C)ccc1C2O
Reactant: O=c1cc[nH]c(=O)[nH]1
Solvent: CC(=O)O
Product: CCc1nc2c(s1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)[nH]c1=O

Procedure:
A solution of the product from step (iii) (785 mg) in acetic acid (5 ml) was added to a suspension of uracil (0.673 g) in acetic acid (25 ml) at 90° C. over 3 min. After 1.5 h the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with ethyl acetate.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:29]=4[CH3:35])[CH2:24][CH2:23]3)[CH:17]=1)[C:10]([CH3:37])([CH3:36])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH3:35][C:29]1[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:28]=1[N:25]1[CH2:26][CH2:27][N:22]([C:18]2[CH:17]=[C:16]([CH:11]3[C:10]([CH3:37])([CH3:36])[CH2:9][C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[NH:12]3)[CH:21]=[CH:20][CH:19]=2)[CH2:23][CH2:24]1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N3CCN(c4ccc(C)cc4C)CC3)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(N2CCN(c3cccc(C4Nc5ccc(C(=O)O)cc5CC4(C)C)c3)CC2)c(C)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 79.9 %

Procedure:
A mixture of 2-{3-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.20 g, 0.40 mmol), lithium hydroxide hydrate (167 mg, 4.0 mmol), water (0.5 mL) in methanol (1 mL) and tetrahydrofuran (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-{3-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (150 mg, 80%) as a white solid: LC/MS m/e calcd for C30H35N3O2 (M+H)+: 470.6, observed: 470.4.
Reaction SMILES: [C:1]([CH:3]=[C:4]([P:6]([CH2:9][CH2:10][CH2:11][CH3:12])(=[O:8])[OH:7])[F:5])#[N:2].N>C(O)C.[Rh]>[NH2:2][CH2:1][CH2:3][CH:4]([P:6]([CH2:9][CH2:10][CH2:11][CH3:12])(=[O:7])[OH:8])[F:5]
Reactant: CCCCP(=O)(O)C(F)=CC#N
Agent: [Rh]
Agent: N
Solvent: CCO
Product: CCCCP(=O)(O)C(F)CCN
Temperature: 20 °C

Procedure:
A solution of 5.0 g of 2-cyano-1-fluoro-ethenyl(n-butyl)phosphinic acid and 10 ml of liquid ammonia in 150 ml of absolute ethanol is treated with 0.75 g of 5% rhodium on charcoal. The suspension is shaken under hydrogen (20 bars) at 20° C. until thin-layer chromatography indicates complete reaction. The catalyst is removed by filtration and the filtrate is evaporated in vacuo to give a solid. Crystallisation from ethanol/acetone affords 3-amino-1-fluoro-propyl(n-butyl)phosphinic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16]>C(O)C.C(O)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:9]=[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]1[OH:16]
Reactant: Nc1ccccc1O
Reactant: O=Cc1ccccn1
Solvent: CC(=O)O
Solvent: CCO
Product: OC1C=CC=CC1=NCc1ccccn1
Reaction time: 12 h
Yield: 100 %

Procedure:
200 μl (2 mmol) of 2-pyridinecarboxaldehyde (reagent 1) and 220 mg (2 mmol) of 2-aminophenol (reagent 2) were dissolved in 10 mL of dry ethanol. One drop of glacial acetic acid was added and the reaction mixture was stirred during 12 h. The solution was filtered on paper and the filtrate was evaporated to dryness. After a chromatography on silica gel (CH2Cl2, 100 ml then AcOEt 200 ml), 394 mg of ligand L1 were obtained as orange solid with a yield of 100%.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([CH2:15][CH2:16][NH:17][CH2:18][C:19]1[O:20][CH:21]=[CH:22][CH:23]=1)(=[O:14])=[O:13].Cl[C:25]1C2C(=CC=CC=2)C=CC=1SCCNCC1OC(C)=CC=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([CH2:15][CH2:16][NH:17][CH2:18][C:19]1[O:20][C:21]([CH3:25])=[CH:22][CH:23]=1)(=[O:14])=[O:13]
Reactant: O=S(=O)(CCNCc1ccco1)c1ccc2ccccc2c1Cl
Reactant: Cc1ccc(CNCCSc2ccc3ccccc3c2Cl)o1
Product: Cc1ccc(CNCCS(=O)(=O)c2ccc3ccccc3c2Cl)o1
Yield: 59 %

Procedure:
Prepared as described for compound 25, from 2-[(1-chloronaphthalen-2-yl)sulfanyl]-N-[(5-methylfuran-2-yl)methyl]ethanamine in 59% yield as white solid.
Reaction SMILES: [ClH:1].[CH2:2]([CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([N+:14]([O-])=O)=[CH:10][CH:11]=2)[CH2:6][N:5]1[CH3:17])[CH3:3].Cl.C(O)(C)C>CO>[ClH:1].[ClH:1].[NH2:14][C:9]1[CH:8]=[C:7]2[C:12]([CH2:13][CH:4]([CH2:2][CH3:3])[N:5]([CH3:17])[CH2:6]2)=[CH:11][CH:10]=1
Reactant: CCC1Cc2ccc([N+](=O)[O-])cc2CN1C
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: CCC1Cc2ccc(N)cc2CN1C
Reaction time: 1 h
Yield: 192.2 %

Procedure:
To a pressure bottle charged with 3-ethyl-2-methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (3.6 g, 17 mmols) dissolved in methanol (100 ml) and saturated isopropanol-HCl (20 ml) was added 10% Pd--C (250 mg), and the reaction was hydrogenated for 1 h. The catalyst was removed by filtration and the solvent evaporated to give the title compound (4.3 g).
Reaction SMILES: [CH2:1]([C:9](O)([OH:14])[C:10]([F:13])([F:12])[F:11])[C:2](O)([OH:7])[C:3]([F:6])([F:5])[F:4].S(=O)(=O)(O)O>>[CH2:1]([C:2]([C:3]([F:4])([F:5])[F:6])=[O:7])[C:9]([C:10]([F:11])([F:13])[F:12])=[O:14]
Reactant: OC(O)(CC(O)(O)C(F)(F)F)C(F)(F)F
Agent: O=S(=O)(O)O
Product: O=C(CC(=O)C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the obtained crude 1,1,1,5,5,5-hexafluoroacetylacetone dihydrate 70 ml of toluene were added, followed by stirring for 1 hr at room temperature with a magnetic mixer, then filtration and then drying, thereby obtaining 27.3 g of 1,1,1,,5,5,5-hexafluoroacetylacetone dihydrate (see Table). A 100-ml glass reaction vessel, equipped with a thermometer, a stirrer and a reflux condenser filled with glass spheres, was charged with 27.3 g of the obtained 1,1,1,5,5,5-hexafluoroacetylacetone dihydrate and 55 g of 98% sulfuric acid, while nitrogen gas was allowed to flow through the reaction vessel. Then, the mixture was gradually heated to 80° C. with stirring by a magnetic mixer. During this heating, 21.0 g of a distillate of about 70° C. was collected. This distillate was found by the same gas chromatography as that of Example 1 to be 1,1,1,5,5,5-hexafluoroacetylacetone having a purity of 99.9%.
Reaction SMILES: C[C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH2:6][C:7]([CH3:9])=[CH2:8])[C:3]([OH:5])=[O:4].[OH-].[Na+]>O>[C:10]1([CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=C(C)CC(C)(C(=O)O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)CC(C(=O)O)c1ccccc1
Reaction time: 2 h

Procedure:
A solution of methyl 2-phenyl-4-methyl-4-pentenoic acid (850 mg, 4.15 mmole) in 10 mL of MeOHwas treated with 5 mL of 2.5N NaOH and heated to 50° for 30 minutes. The reaction was cooled, diluted with H2O and washed with Et2O. The aqueous phase was acified, and extracted with CH2Cl2. The extracts were washed with H2O, dried and the solvent removed. The residue was dissolved in 25 mL of EtOAc, and hydrogenated over a 10% Pd/C catalyst, at 1 atmosphere H2 pressure, for 2 hours. The catalyst was filtered and the solvent removed and gave the titled compound, 647 mg (81%). MS (ESI) 193 (MH+)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH:6]1[CH2:9][CH:8]([CH2:10][O:11][C:12]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:13]=2[C:14](/[N:16]=[C:17]2/[N:18]([CH2:27][C@H:28]3[CH2:32][CH2:31][CH2:30][O:29]3)[N:19]([CH3:26])[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:21]/2)=[O:15])[CH2:7]1.C(N(CC)CC)C>C1COCC1>[C:22]([C:20]1[N:19]([CH3:26])[N:18]([CH2:27][C@H:28]2[CH2:32][CH2:31][CH2:30][O:29]2)/[C:17](=[N:16]/[C:14](=[O:15])[C:13]2[CH:33]=[C:34]([C:37]([F:40])([F:39])[F:38])[CH:35]=[CH:36][C:12]=2[O:11][CH2:10][CH:8]2[CH2:9][N:6]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:7]2)/[CH:21]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2OCC2CNC2)n1C[C@H]1CCCO1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2OCC2CN(S(C)(=O)=O)C2)n1C[C@H]1CCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
Methanesulfonyl chloride (0.05 g, 0.4 mmol) was added to a solution of Example 54B (0.21 g, 0.4 mmol) in THF (5.0 mL) followed by triethylamine (0.17 mL, 1.2 mmol). The mixture was stirred for 1 hour at ambient temperature, then partitioned between EtOAc (15 mL) and saturated NaHCO3 (1 mL). The organic extract was washed with water and brine, dried with MgSO4, filtered and concentrated. The residue was purified by chromatography (SiO2, solvent A—hexane:EtOAc:Et3N (1:3:0.2), solvent B—hexane:EtOAc:MeOH:Et3N (1:3:1:0.2) 100% solvent A to 100% solvent B over 450 mL then isocratic for 180 mL) to afford the title compound (0.12 g, 0.21 mmol, 49% yield). 1H NMR (500 MHz, pyridine-d5) δ ppm 1.21 (s, 9H), 1.54-1.62 (m, 2H), 1.64-1.71 (m, 1H), 1.75-1.85 (m, 1H), 3.01-3.09 (m, 1H), 3.31 (s, 3H), 3.54-3.63 (m, 1H), 3.69-3.76 (m, 1H), 3.85 (s, 3H), 4.05 (t, J=8.1 Hz, 2H), 4.09 (d, J=4.3 Hz, 2H), 4.22-4.28 (m, 1H), 4.36-4.46 (m, 3H), 4.62 (dd, J=15.1, 3.2 Hz, 1H), 7.12 (d, J=8.8 Hz, 1H), 7.46 (s, 1H), 7.65 (dd, J=8.7, 2.3 Hz, 1H), 8.48 (d, J=2.4 Hz, 1H); MS (ESI+) m/z 573.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[C@@H:7]([CH3:18])[CH2:6][NH:5]2.N1C=CC=CC=1.[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:17])[C:13]([F:14])([F:16])[F:15])[C@@H:7]([CH3:18])[CH2:6][N:5]2[C:28](=[O:29])[C:27]1[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=1[F:25]
Reactant: C[C@H]1CNc2cc(Br)ccc2N1C(=O)C(F)(F)F
Reactant: O=C(Cl)c1ccccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H]1CN(C(=O)c2ccccc2F)c2cc(Br)ccc2N1C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A 50-mL round bottomed flask equipped with a magnetic stir bar was charged with (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (0.500 g, 1.547 mmol), dichloromethane (10 mL), and pyridine (0.188 mL, 2.321 mmol). The resulting solution was cooled to 0° C. and slowly treated with 2-fluorobenzoyl chloride (0.194 mL, 1.625 mmol). The solution was stirred at 0° C. for 1 h and then allowed to warm to rt. After stirring overnight at rt, the reaction mixture was diluted with dichloromethane and washed with 1 M aqueous HCl solution (10 mL) followed by 5% aqueous sodium chloride solution (10 mL). The dichloromethane extract was concentrated to afford crude (S)-1-(6-bromo-4-(2-fluorobenzoyl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (0.686 g, 100%). MS (ESI, pos. ion) m/z 445, 447 [M+1].
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@H:32]([CH2:37][CH3:38])[C:33]([CH3:36])([OH:35])[CH3:34]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][C@H:32]([CH2:37][CH3:38])[C:33]([CH3:36])([OH:35])[CH3:34])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)([CH3:13])[CH3:12]
Reactant: CC[C@@H](N)C(C)(C)O
Reactant: CC(C)n1cnc2c(NCc3cccnc3)nc(F)nc21
Solvent: CS(C)=O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H](Nc1nc(NCc2cccnc2)c2ncn(C(C)C)c2n1)C(C)(C)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-3-ylmethyl-amine (20 mg, 1 eq, 0.07 mmol) in n-BuOH/DMSO (1.25 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.25 mL, 20.5 eq, 1.44 mmol) followed by (3R)-3-amino-2-methyl-pentan-2-ol (22 mg, 2.7 eq, 0.19 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid. Yield: 3.7 mg (14%). 1H-NMR (d-CDCl3, 250 MHz): δ 1.00 (t, 3H, J=7.27 Hz, —NHCH(CH2CH3)C(CH3)2OH), 1.21 & 1.31 (2×s, 6H, —NHCH(CH2CH3)C(CH3)2OH), 1.57 (d, 6H, J=6.63 Hz, —CH(CH3)2), 1.69-1.89 (m, 2H, —NHCH(CH2CH3)C(CH3)2OH), 3.66-3.83 (m, 1H, —NHCH(CH2CH3)C(CH3)2OH), 4.59-4.73 (m, 1H, —CH(CH3)2), 4.77-5.00 (m, 2H, —HNCH2-Pyr), 7.26-7.46 (m, 3H, 2×Pyr-H & —N═CH—N—), 7.49-7.69 (m, 1H, Pyr-H), 7.78 (d, 1H, J=7.10 Hz, Pyr-H). FABMS m/z (relative intensity): 384 ([M+H]+, 65), 366 (23), 324 (100), 217 (35), 192 (55). Accurate Mass (M+H): Actual: 384.2512, Measured: 384.2494.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]([F:37])([F:36])[C:24]([F:35])([F:34])[C:25]([F:33])([F:32])[O:26][C:27]([F:31])=[C:28]([F:30])[F:29]>C1COCC1>[F:30][C:28]([F:29])([O:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])[CH:27]([F:31])[O:26][C:25]([F:32])([F:33])[C:24]([F:34])([F:35])[C:23]([F:22])([F:36])[F:37]
Reactant: FC(F)=C(F)OC(F)(F)C(F)(F)C(F)(F)F
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F)cc(C(=O)OC)c1

Procedure:
Anhydrous THF (12 liters) and dimethyl 5-hydroxy-isophthalate (2100 g) were combined under nitrogen in an oil jacketed 22 liter RB flask equipped with a condenser, mechanical stirrer, pressure equalizing addition funnel. To this stirred solution was added anhydrous potassium carbonate (1035 g), followed by 1,1,1,2,2,3,3-heptafluoro-3-(1,2,2-trifluorovinyloxy)propane (3192 g). Ca. 2 liters of additional THF was used to wash all the reagents into the reaction vessel. The resulting mixture was refluxed for 10.5 hours.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:30]=[CH:29][C:28]([NH:31][C:32](=[NH:34])[CH3:33])=[CH:27][C:15]=4[C:16](=[O:26])[C:17]=3[O:18]CC3C=CC=CC=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:35]>CO.[Pd]>[ClH:35].[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:30]=[CH:29][C:28]([NH:31][C:32](=[NH:34])[CH3:33])=[CH:27][C:15]=4[C:16](=[O:26])[C:17]=3[OH:18])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(=N)Nc1ccc2oc(-c3ccc(-n4ccnc4)cc3)c(OCc3ccccc3)c(=O)c2c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(=N)Nc1ccc2oc(-c3ccc(-n4ccnc4)cc3)c(O)c(=O)c2c1
Reaction time: 4 h
Yield: 75 %

Procedure:
2-[(4-(imidazol-1-yl)-phenyl]-3-benzyloxy-6-[(1-iminoethyl)amino]-4H-1-benzopyran-4-one (1.6 g; 3.34 mmol) was suspended in methanol (100 mL), 3 mL of MeOH saturated with HCl were added to the reaction mixture then 10% Pd/C (160 mg.) was added. The reaction mixture was left under hydrogen bubbling for 4 hours, then the catalyst was filtered off. The solvent was removed and the remaining solid suspended in diethyl ether, then filtered. The titled compound was obtained as a yellow solid, yield: 75%; m.p.: 311.7-312.1° C.; Elem. anal.: C20H16N4O3.HCl, Theory: C, 55.44; H, 4.19; N, 12.93. Found: C, 56.09; H, 4.34; N, 13.22. TLC (8/2 Chloroform/Methanol) Rf: 0.11; IR (KBr): 2996, 2871, 1568, 1592 cm−1; 1H-NMR (d6-DMSO): 11.89 (s, 1H); 10.27 (s, 1H); 9.81 (s, 1H) 9.71 (s, 1H); 8.81 (s, 1H); 8.50 (d, 2H); 8.4 (d, 1H); 8.01 (m, 4H); 7.93 (d, 1H); 7.77 (dd, 1H); 2.58 (d, 2H); 1.28 (m, 1H); MS (EI) 401 (M+1).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7]Br)=[CH:3][CH:2]=1.[CH:9]1[C:14]([C:15]2[CH:16]=[CH:17][C:18]([F:22])=[CH:19][C:20]=2[F:21])=[CH:13][C:12]([C:23]([OH:25])=[O:24])=[C:11]([OH:26])[CH:10]=1.O>CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[F:21][C:20]1[CH:19]=[C:18]([F:22])[CH:17]=[CH:16][C:15]=1[C:14]1[CH:9]=[CH:10][C:11]([OH:26])=[C:12]([C:23]([O:25][CH2:7][C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)=[O:24])[CH:13]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: O=C(OCc1ccccc1)c1cc(-c2ccc(F)cc2F)ccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.9 %

Procedure:
BnBr (1.35 mL, 11.286 mmol) was added to a solution of diflunisal (2.0 g, 7.99 mmol) in TBAF (10 mL, 1 M solution in THF) and the reaction mixture was stirred at r.t. overnight (18 h). The organic layer was poured into H2O (15 mL) and extracted with EtOAc (40 mL). It was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (hexanes) to furnish 2.09 g of benzyl 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylate (white solid, yield: 77%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:14]([OH:16])=[O:15])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.[C:17](=O)([O-])O.[Na+].S(OC)(OC)(=O)=O>CN(C)C=O>[OH:1][C:2]1[C:3]([C:14]([O:16][CH3:17])=[O:15])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2
Reactant: O=C([O-])O
Reactant: COc1ccc2cc(O)c(C(=O)O)cc2c1
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(OC)ccc2cc1O
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
6.55 g of 3-hydroxy-7-methoxy-naphthalene-2-carboxylic acid were dissolved in 20 ml of dimethylformamide, treated with 5.5 g of sodium hydrogen carbonate and 4.0 ml of dimethyl sulfate and stirred at 90° C. under argon for 10 minutes. Subsequently, the reaction mixture was poured on to ice-water and extracted with ether. The combined ether phases were washed with water, dried over magnesium sulfate and concentrated. The thus-obtained residue was recrystallized from ethyl acetate/hexane. Methyl 3-hydroxy-7-methoxy-naphthalene-2-carboxylate with m.p. 138° C. was thus obtained.
Reaction SMILES: Br[CH2:2]Br.[CH3:4][C:5]1([C:12]([O:14][CH3:15])=[O:13])[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1.[Cl-].[Na+]>C1COCC1.[Ti](Cl)(Cl)(Cl)Cl.[Zn]>[CH3:4][C:5]1([C:12]([O:14][CH3:15])=[O:13])[CH2:10][CH2:9][C:8](=[CH2:2])[CH2:7][CH2:6]1
Reactant: BrCBr
Reactant: COC(=O)C1(C)CCC(=O)CC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C1CCC(C)(C(=O)OC)CC1

Procedure:
Under an argon stream, 5.3 ml of dibromomethane and 28 ml of titanium tetrachloride (methylene chloride 2M solution) were added to a solution of 15 g of zinc suspended in 250 ml of THF, under ice cooling. The resultant solution was stirred for one hour. Then, a solution of 8.5 g of methyl 1-methyl-4-oxo-1-cyclohexanecarboxylate in 50 ml of THF was added to the solution. The solution was reacted for 15 hours. After reaction, 500 ml of an aqueous sodium chloride solution was added to the reaction solution. The solution was extracted three times with 100 ml of ethyl acetate. The organic layer obtained was washed three times with an aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed in vacuo. The oily substance formed was subjected to column chromatography using 100 g of silica gel. From the fraction eluted with hexane and ethyl acetate=50:1, the solvent was removed in vacuo, yielding 7 g of methyl 1-methyl-4-methylene-1-cyclohexanecarboxylate as a colorless oil, which had the following physiochemical properties:
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.C1C(=O)N([I:16])C(=O)C1>>[F:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[C:6]([I:16])[CH:7]=1
Reactant: Nc1ncccc1F
Reactant: O=C1CCC(=O)N1I
Product: Nc1ncc(I)cc1F

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 200 mg (1.78 mmol) 3-fluoro-pyridin-2ylamine and 401 mg (1.78 mmol) NIS. Yield after precipitation from the reaction mixture: 380 mg (90%).