Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)CCC.[CH2:20]([O:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30](Br)[CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:20]([O:27][C:28]1[CH:29]=[C:30]([C:6]2[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=2)[CH:31]=[C:32]([F:34])[CH:33]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: Fc1cc(Br)cc(OCc2ccccc2)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Fc1cc(OCc2ccccc2)cc(-c2ccncc2)c1
Temperature: 100 °C

Procedure:
A mixture of 4-tributylstannylpyridine (250 mg), O-benzyl-3-bromo-5-fluorophenol (200 mg; EP 385,662) and tetrakis (triphenylphosphine) palladium (8 mg) in dioxane (3 mL) was heated at 100° C. for 15 h. The solvent was evaporated and the residue chromatographed (silica gel; hexane/EtOAc acetate (4:1-3:2)) to provide the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([NH2:27])([CH:21]2[NH:26][CH2:25][CH:24]=[CH:23][NH:22]2)[C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[N:28]#[C:29]Br>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2([C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[C:21]3=[N:26][CH2:25][CH2:24][CH2:23][N:22]3[C:29]([NH2:28])=[N:27]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NC(c1ccc(OC(F)(F)F)cc1)(c1ccc(F)c(Br)c1)C1NC=CCN1
Reactant: N#CBr
Solvent: CC#N
Product: NC1=NC(c2ccc(OC(F)(F)F)cc2)(c2ccc(F)c(Br)c2)C2=NCCCN12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 36 %

Procedure:
A mixture of 1-(3-bromo-4-fluorophenyl)-1-(tetrahydropyrimidin-2-yl)-1-[4-(trifluoromethoxy)phenyl]methylamine (0.85 g, ˜80% purity, ˜1.52 mmol) and cyanogen bromide (0.81 g, 7.62 mmol) in acetonitrile is stirred at room temperature for 45 min, heated at 100° C. in a sealed tube overnight, cooled to room temperature and concentrated. The resultant residue is purified by flash chromatography (silica, 95:5:0.25 methylene chloride/methanol/concentrated ammonium hydroxide as eluent) to afford the title compound as a tan solid, 0.26 g (36% yield), identified by NMR and mass spectral analyses. 1H NMR (300 MHz, CDCl3) δ 7.74 (dd, J=6.7, 2.3 Hz, 1H), 7.49 (dd, J=6.7, 2.1 Hz, 2H), 7.38 (m, 1H), 7.13 (d, J=8.1 Hz, 2H), 7.03 (t, J=8.5 Hz, 1H), 3.58 (m, 4H), 1.86 (m, 2H); ESI MS m/z 471 [C19H15BrF4N4O+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]1[CH:23]=[CH:22][C:13](/[CH:14]=[C:15]2/[C:16](=[O:21])[NH:17][C:18](=[O:20])[CH2:19]/2)=[CH:12][CH:11]=1)[CH3:8].Br[CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C>CN(C=O)C>[NH2:27][CH2:26][CH2:25][N:17]1[C:18](=[O:20])[CH2:19]/[C:15](=[CH:14]\[C:13]2[CH:22]=[CH:23][C:10]([O:9][CH2:7][CH3:8])=[CH:11][CH:12]=2)/[C:16]1=[O:21]
Reactant: CCOc1ccc(/C=C2\CC(=O)NC2=O)cc1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(/C=C2\CC(=O)N(CCN)C2=O)cc1
Reaction time: 0.33 h

Procedure:
Potassium carbonate (180 mg, 1.30 mmol) was added to a solution of compound 12 (100 mg, 0.43 mmol) in 3 mL of anhydrous DMF at 0° C. After stirring the reaction mixture for 20 min, a solution of tert-butyl (2-bromoethyl)carbamate (96 mg, 0.43 mmol) in anhydrous DMF (1 mL) was added and then the reaction mixture was stirred at room temperature for 3 h. The reaction was quenched by adding water and extracted with ethyl acetate. The ethyl acetate layer was washed with 10% NH4Cl aqueous solution followed by water and dried over anhydrous Na2SO4, filtered, concentrated and purified by silica column chromatography (20% ethyl acetate in hexanes) to afford 70 mg (43.2%) of Boc-protected 13 as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]1([CH:10]=[CH:11][CH:12]([CH3:16])[CH2:13][CH2:14][OH:15])[CH2:9][CH2:8][CH2:7][CH2:6]1.N1C=CC=CC=1.Cl>CN(C1C=CN=CC=1)C.C1CCCCC1.CC(OC)(C)C>[C:1]([O:15][CH2:14][CH2:13][CH:12]([CH3:16])[CH:11]=[CH:10][CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(C=CC1CCCC1)CCO
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCCCC1
Solvent: COC(C)(C)C
Product: CC(=O)OCCC(C)C=CC1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.7 %

Procedure:
Acetyl chloride (1.7 g; 22 mmol) was added to a cooled solution of 5-cyclopentyl-3-methylpent-4-en-1-ol (obtained in example 1; 2.6 g; 15 mmol), pyridine (2.4 g; 30 mmol), and DMAP (0.13 g; 0.1 mmol) in cyclohexane (65 ml). After 3 hours stirring at room temperature, the reaction mixture was poured into 1N HCl (130 ml) and MTBE (65 ml). The organic layer was separated, washed successively with 1N HCl (130 ml), sodium bicarbonate solution (100 ml) and brine (2×100 ml) and treated as in example 1 (distillation at 120° C./0.8 torr) to give 3.05 g (94% yield) of 5-cyclopentyl-3-methylpent-4-en-1-yl acetate.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][N:11]=[C:10]3[O:17][CH2:18][CH2:19][C:9]=23)[CH2:5][C@@H:4]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:3]1>CO.[Pd]>[NH2:14][C:13]1[C:8]([N:6]2[CH2:7][C@H:2]([CH3:1])[CH2:3][C@H:4]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:5]2)=[C:9]2[CH2:19][CH2:18][O:17][C:10]2=[N:11][CH:12]=1
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2c([N+](=O)[O-])cnc3c2CCO3)C1
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2c(N)cnc3c2CCO3)C1
Reaction time: 4 h
Yield: 99.7 %

Procedure:
To a solution of tert-butyl [(3S,5R)-5-methyl-1-(5-nitro-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate (44.5 mg, 0.118 mmol) in MeOH (2.00 mL), 10 wt % Pd on carbon (9.3 mg, 0.0087 mmol) was added under a nitrogen atmosphere. The mixture was then hydrogenated (1 atm.) for 4 h. The reaction mixture was then filtered through a pad of diatomaceous earth (eluted with MeOH). The filtrate was concentrated under reduced pressure to give the crude product as a red semi-solid (41.0 mg). The crude product was used directly in the next step without further purification. LCMS calc. for C18H29N4O3 (M+H)+: m/z=349.2. found 349.2.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:9]([C:10]([OH:12])=[O:11])[C:8]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]O)=[CH:24][C:23]=1[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C=O)C.C1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH:9]([C:10]([O:12][CH2:26][C:25]3[CH:28]=[CH:29][C:22]([F:21])=[C:23]([O:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:24]=3)=[O:11])[C:8]2([CH3:13])[CH3:14])=[CH:15][CH:16]=1
Reactant: CC1(C)C(Oc2ccc(Cl)cc2)C1C(=O)O
Reactant: OCc1ccc(F)c(Oc2ccccc2)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC1(C)C(Oc2ccc(Cl)cc2)C1C(=O)OCc1ccc(F)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3-(4-chlorophenoxy)-2,2-dimethylcyclopropanecarboxylic acid (0.95 g, 3.95 mmol), thionyl chloride (0.342 ml, 4.74 mmol) and DMF (several drops) in 50 ml benzene is stirred at RT for 2 days. The solvent and excess thionyl chloride are evaporated under reduced pressure. The resulting acid chloride is dissolved in 50 ml benzene, and 0.86 g 4-fluoro-3-phenoxybenzyl alcohol (3.95 mmol) and 0.482 g 4-dimethylaminopyridine (3.95 mmol) are added. The mixture is left at 25° for 18 hours and then heated under reflux for 2 hours. The mixture is then poured into water and extracted with ether. The organic phase is washed with dilute HCl, sat. NaHCO3, water and brine, dried and concentrated under vacuum. The crude product is purified by preparative TLC developing with 20% ethyl acetate/hexane to yield 4-fluoro-3-phenoxybenzyl 3-(4-chlorophenoxy)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[CH2:12]([O:14][C:15](=[O:19])[CH2:16][C:17]#[N:18])[CH3:13].CC([O-])(C)C.[K+].CC(O)=O>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH2:12]([O:14][C:15](=[O:19])[CH:16]([C:17]#[N:18])[C:2]1[CH:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1)[CH3:13]
Reactant: CCOC(=O)CC#N
Reactant: FC(F)(F)c1ncc(Br)cn1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCOC(=O)C(C#N)c1cnc(C(F)(F)F)nc1
Temperature: 70 °C
Yield: 12.2 %

Procedure:
A mixture of 5-bromo-2-trifluoromethyl-pyrimidine (1.0 g, 4.41 mmol) and cyano-acetic acid ethyl ester (1.0 g, 4.41 mmol) was added into a suspension of t-BuOK (17.64 mL, 17.64 mmol, 1M in THF) in 1,4-dioxane (10 mL) under Ar atmosphere. To the resulting mixture was added a solution of Pd(OAc)2 (10 mg, 44.1 μmol) and dppf (48.9 mg, 88.2 μmol) in 1,4-dioxane (1 mL). The resulting mixture was heated to 70° C. for 1 h. The reaction mixture was adjusted pH to 7˜8 with 1N AcOH and extracted with EtOAc (3×20 ml). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (EtOAc:petroleum ether=1:10) to give cyano-(2-trifluoromethyl-pyrimidin-5-yl)-acetic acid ethyl ester (140 mg, yield: 12.3%). 1H NMR (CDCl3 400 Hz): δ9.03 (s, 2H), 4.88 (s, 1H), 4.34 (q, J=7.2 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(OC1C(N)=C([C:15]2[N:19]=[C:18]([C:20]3[S:24][C:23]([NH:25][C:26]4[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=4)=[N:22][C:21]=3[NH2:38])[O:17][N:16]=2)C=CC=1C(O)=O)(C)(C)C.[OH-].[Na+]>FC(F)(F)C(O)=O.ClCCl>[NH2:25][C:26]1[CH:27]=[C:28]([C:15]2[N:19]=[C:18]([C:20]3[S:24][C:23]([NH:25][C:26]4[CH:27]=[C:28]([O:36][CH3:37])[C:29]([O:34][CH3:35])=[C:30]([O:32][CH3:33])[CH:31]=4)=[N:22][C:21]=3[NH2:38])[O:17][N:16]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: COc1cc(Nc2nc(N)c(-c3nc(-c4ccc(C(=O)O)c(OC(C)(C)C)c4N)no3)s2)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(Nc2nc(N)c(-c3nc(-c4cccc(N)c4)no3)s2)cc(OC)c1OC
Yield: 189 %

Procedure:
A solution of 267 mg (0.49 mmol) of 3-(3-t-butyloxycarboxy-aminophenyl)-5-[2-[(3,4,5-trimethoxyphenyl)amino]-4-amino-5-thiazolyl]-1,2,4-oxadiazole (prepared according to Example B(2)) in 3 mL of 50% trifluoroacetic acid in dichloromethane was stirred for 60 minutes at ambient temperature and then poured onto ice. 3N NaOH was added dropwise until the solution was basic, and the mixture was extracted with EtOAc. The organic layer was washed with NaHCO3 and brine, and dried over Na2SO4. The solvent was removed to yield 204 mg (95% yield) of the title compound as a light yellow solid.
Reaction SMILES: C(N(CC)CC)C.Cl[CH2:9][C:10]1[O:14][N:13]=[C:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[O:16])[N:11]=1.[C:24]1([SH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CCOCC.CC(C)=O>[C:24]1([S:30][CH2:9][C:10]2[O:14][N:13]=[C:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[O:16])[N:11]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1ccc(C(=O)c2noc(CCl)n2)cc1
Reactant: Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)c2noc(CSc3ccccc3)n2)cc1
Reaction time: 1 h

Procedure:
A solution of 13.4 ml of triethylamine in 35 ml Et2O was added dropwise to a solution of 11.4 g of 5-chloromethyl-3-(4-toluoyl)-1,2,4-oxadiazole and 4.9 ml of thiophenol in 25 ml acetone and 100 ml Et2O at room temperature. The resulting mixture was stirred for one hour. The reaction mixture was diluted with Et2O, washed with 5% HCl (2×), water (2×), and brine, and dried over MgSO4. Concentration gave 13.2 g of an oil. Purification by high pressure liquid chromatography with 70% CH2Cl2 /hexane as an eluent yielded 11.0 g (79%) of an oil.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[OH-].[Na+].[H][H]>[Ni]>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
A 160 ml. electromagnetically stirred autoclave was charged with 2.53 g (0.01 mole) of 1-nitroanthraquinone (roughly purified product with no impurity detected by thin-layer chromatography), 52 g (0.05 mole) of a 4% aqueous solution of sodium hydroxide and 0.07 g of Raney nickel. The 1-nitroanthraquinone was hydrogenated with stirring at room temperature and a pressure of 6 to 3 Kg/cm2. G. The reaction proceeded smoothly, and stopped in 6 hours with the absorption of 0.04 mole of hydrogen. The inside of the autoclave was purged with nitrogen, and the reaction mixture was filtered in an atmosphere of nitrogen to separate the catalyst. The filtrate was oxidized with air at 20° to 30°C. for 1 hour with stirring to afford 2.1 g of 1-aminoanthraquinone having a purity of 97% by weight in a yield of 94% of theory. By a thin layer chromatographic analysis, no impurity was detected in the resulting product.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:20]=[CH:19][C:17]([O-:18])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Na+].Br[CH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1>CC(C)=O>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:18][CH2:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=3)=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([O-])cc2)CC1
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(COc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Temperature: 60 °C

Procedure:
Sodium 4-(1-BOC-piperazin-4-yl)phenoxide (1 equivalent) and methyl 4-bromomethylbenzoate (1 equivalent) were combined in dry acetone and heated to reflux at 60° C. for 18 hours. The slurry was filtered and the filtrate was then concentrated to provide the crude methyl 4-[4-(1-BOC-piperazin-4-yl)phenoxymethyl]benzoate, which was used without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:48])[C@@H:13]([NH:22][C:23]([C:25]2[CH:29]=[C:28]([O:30][CH2:31][C:32]([O:34]CC3C=CC=CC=3)=[O:33])[N:27]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:48])[C@@H:13]([NH:22][C:23]([C:25]2[CH:29]=[C:28]([O:30][CH2:31][C:32]([OH:34])=[O:33])[N:27]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)n(-c3ccccc3)n2)CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)O)n(-c3ccccc3)n2)CC1
Reaction time: 16 h

Procedure:
To a solution of 11.6 g 4-{(S)-2-[(5-Benzyloxycarbonylmethoxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-3-tert-butoxycarbonyl-propionyl}-piperazine-1-carboxylic acid ethyl ester in 60 ml ethyl acetate were added under argon 1.5 g Pd/C (10%) and the suspension was stirred under an atmosphere of hydrogen (3 bar) for 16 h. The suspension was filtered over a plug of Celite® and washed with ethyl acetate. The crude product obtained after evaporation of the solvent was dried under vacuo.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]2)=[N:3][CH:2]=1.[N:17]1[CH:22]=[C:21]([C:23](O)=[O:24])[CH:20]=[N:19][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]1[C:6]2=[N:7][CH:8]=[CH:9][C:5]2=[C:4]([N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:23]([C:21]3[CH:22]=[N:17][CH:18]=[N:19][CH:20]=3)=[O:24])[CH2:14][CH2:15]2)[N:3]=[CH:2]1
Reactant: O=C(O)c1cncnc1
Reactant: NC1CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCN(c2nc[nH]c3nccc2-3)CC1)c1cncnc1
Temperature: 25 °C

Procedure:
To a mixture of 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine D2 (65.2 mg), 5-pyrimidinecarboxylic acid (37.2 mg, 0.300 mmol), HATU (137 mg, 0.360 mmol) and HOAt (24.50 mg, 0.180 mmol) in DMF (1.5 mL) was added DIPEA (252 μL, 1.440 mmol). The reaction mixture was stirred at room temperature until reaction was complete then solvent was removed in vacuo. The crude mixture was purified by MDAP using a high pH method to afford E14 (21 mg), 1H NMR (d6-DMSO) δ 11.70 (1H, brs), 9.30 (1H, s), 9.15 (2H, s), 8.65 (1H, d), 8.17 (1H, s), 7.17 (1H, d), 6.60 (1H, d), 4.65 (2H, dt), 4.15 (1H, m), 3.25 (2H, dt), 1.90 (2H, m), 1.55 (2H, m), MS(ES+) 324 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:14]1(=O)[C:26]2[C:18]([C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][CH:16]=[CH:15]1>CCOCC>[CH:7]1[C:2]2[C:25]3([C:26]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19]4[C:24]3=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: Brc1ccccc1-c1ccccc1
Reactant: O=C1C=CC=C2C1=Cc1ccccc12
Solvent: CCOCC
Product: c1ccc2c(c1)-c1ccccc1C21c2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 80 %

Procedure:
As shown in the following reaction 1, 6.1 g of 2-bromobiphenyl and 0.585 g of dried Mg were dissolved with ether, and 4.2 g of fluorenone dissolved in ether was added thereto, and refluxed while stirring overnight. The produced yellow precipitate was filtered, and stirred in cold ammonium chloride, and then the obtained crystal was filtered again and dried. Thereafter, acetic acid was added to the solid product, and the solution was refluxed while stirring. A small amount of hydrochloric acid was added thereto to obtain the solid target compound. The solid target compound was filtered and washed to obtain pure target compound with the yield of 80%.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([O:15][CH3:16])=[C:11]([CH:14]=2)[C:12]#[N:13])[N:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]=1.C([O-])([O-])=[O:25].[K+].[K+].OO.C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O.O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([O:15][CH3:16])=[C:11]([CH:14]=2)[C:12]([NH2:13])=[O:25])[N:5]=[C:4]([NH:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(-n2nc(Nc3ccccc3)nc2N)cc1C#N
Agent: OO
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(-n2nc(Nc3ccccc3)nc2N)cc1C(N)=O
Reaction time: 1 h
Yield: 380.1 %

Procedure:
To a stirred solution of 5-(5-amino-3-phenylamino-[1,2,4]triazol-1-yl)-2-methoxy-benzonitrile (20 mg, 0.065 mMol) and K2CO3 (2 mg) in DMSO (0.3 mL), at r.t., add a solution of 30% aq. H2O2, (0.3 mL). After 1 h, add additional 30% aq. H2O2 (0.15 mL). After 40 min, water is added along with 5% aq. Na2CO3 and the mixture is stirred for several minutes. The solid was collected and rinsed with several portions of water and dried in vacuo to provide a white solid (18 mg, 0.055 mMol, 85% yield). 1H NMR 500 MHz (dmso) 8.82 (s, 1H), 7.93 (d, 1H), 7.71 (br s, 1H), 7.63 (dd, 1H), 7.60 (br s, 1H), 7.52 (d, 2H), 7.25 (d, 1H), 7.19 (t, 2H), 6.75 (t, 1H), 6.28 (br s, 2H), 3.93 (s, 3H) ppm. LC/MS: Rt=2.27 min, (M+H)=325.2
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH:34]=[O:35])[CH2:24][CH:23]2[OH:36])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(=O)([O-])[O-].C1(C)C=CC(S([CH2:50][N:51]=[C:52]=O)(=O)=O)=CC=1.O>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[O:35][CH:52]=[N:51][CH:50]=3)[CH2:24][CH:23]2[OH:36])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: O=Cc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Reactant: Cc1ccc(S(=O)(=O)CN=C=O)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Product: O=C(NC1(C(=O)NC2CCN(c3ccccc3-c3cnco3)CC2O)CCCCC1)c1cc2ccccc2o1
Yield: 100.9 %

Procedure:
The mixture of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(2-formylphenyl)piperidin-3-ol (3 g, 6 mmol) obtained in Step 1 of Example 61, photassium carbonate (2 g, 20 mmol) and p-toluenesulfonylmethyl isocyanate (TosMIC; 1.8 g, 9 mmol) was refluxed in 500 ml of methanol for about 2 hours. 150 ml of water was added to the concentrated reaction mixture, which was then extracted with dichloromethane. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 3.2 g of the titled compound.
Reaction SMILES: [N:1]1([C:7](=[O:22])[CH2:8][CH:9]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]([OH:12])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:23][CH:24]([CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:25]([C:27]1[O:28][CH:29]=[CH:30][N:31]=1)[OH:26]>>[O:28]1[CH:29]=[CH:30][N:31]=[C:27]1[C:25]([C@@H:24]([NH:23][C:10](=[O:12])[CH:9]([CH2:8][C:7]([N:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1)=[O:22])[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:26]
Reactant: NC(CCc1ccccc1)[C@H](O)c1ncco1
Reactant: O=C(O)C(CCCc1ccccc1)CC(=O)N1CCOCC1
Product: O=C(N[C@@H](CCc1ccccc1)C(=O)c1ncco1)C(CCCc1ccccc1)CC(=O)N1CCOCC1

Procedure:
It is similarly prepared according to general procedure for Example 10 above but using 2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid and (S)-2-Amino-1-oxazol-2-yl-4-phenyl-butan-1-ol.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1.ClC1SC2C=CC=C(Cl)C=2N=1.[CH3:23][OH:24]>O>[CH3:23][O:24][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1
Reactant: Clc1cccc2sc(Br)nc12
Reactant: CO
Agent: Clc1nc2c(Cl)cccc2s1
Solvent: O
Product: COc1nc2c(Cl)cccc2s1
Yield: 92.5 %

Procedure:
A mixture (5 g, 0.023 mole) of 2-bromo-4-chlorobenzothiazole and 2,4-dichlorobenzothiazole and 1,5-diazabicyclo[5.4.0]undecene-5 (DBU) (3.8 g, 0.025 mole) were added to methanol (80 c.c.), and the mixture was heated under reflux for 4 hours. After cooling, water (150 c.c.) was added to the reaction solution, followed by ice-cooling. The deposited crystals were filtered and washed twice with water to obtain 4.23 g of 2-methoxy-4-chlorobenzothiazole. Yield 92.5%, purity 98.5%, m.p. 55°-57° C.