Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:9])=O)[CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:24][CH2:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[C:28](=[O:45])[N:29]([CH:37]1[CH2:42][CH2:41][C:40](=[O:43])[NH:39][C:38]1=[O:44])[C:30]([CH3:36])=[N:31]2>CN(C=O)C>[O:44]=[C:38]1[CH:37]([N:29]2[C:28](=[O:45])[C:27]3[C:32](=[CH:33][CH:34]=[CH:35][C:26]=3[CH2:25][NH:24][C:7](=[O:9])[C:3]3[CH:4]=[CH:5][CH:6]=[C:1]([CH3:10])[CH:2]=3)[N:31]=[C:30]2[CH3:36])[CH2:42][CH2:41][C:40](=[O:43])[NH:39]1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: Cc1cccc(C(=O)O)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)NCc2cccc3nc(C)n(C4CCC(=O)NC4=O)c(=O)c23)c1
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a stirred solution of m-toluic acid (0.24 g, 1.8 mmol) in DMF (8 mL) in a 40° C. oil bath, was added 1,1′carbonyldiimidazole (0.31 g, 1.9 mmol) and stirred for one hour. To the mixture, 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.59 g, 1.8 mmol) was added, and the mixture was stirred for 45 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-3-methyl-benzamide as a light green solid (560 mg, 76% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.00 min (99.2%); mp, 263-265° C.; 1HNMR (DMSO-d6)2.18-2.21 (m, 1H, CHH), 2.38 (s, 3H, CH3Ar), 2.59-2.88 (m, 6H, CHCH2, CH3), 4.95-5.12 (m, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.33-7.76 (m, 7H, Ar), 8.89 (t, J=5 Hz, 1H, CH2NH), 11.05 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.83, 20.92, 23.29, 30.60, 42.12, 56.52, 117.65, 123.98, 124.32, 125.40, 127.76, 128.26, 131.85, 133.93, 134.23, 137.65, 141.04, 148.50, 154.80, 161.11, 166.39, 169.53, 172.61. LCMS MH=419; Anal Calcd For C23H22N4O4+0.6H2O: C, 64.36; H, 5.45; N, 13.05. Found: C, 64.36; H, 5.24; N, 13.22.
Reaction SMILES: C([O:5][C:6](=[O:24])[CH2:7][N:8]([C:15](=[O:23])[CH:16]([CH3:22])[CH2:17][S:18][C:19](=[O:21])[CH3:20])[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(C)(C)C.C[Si](I)(C)C.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:19]([S:18][CH2:17][CH:16]([CH3:22])[C:15]([N:8]([CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)[CH2:7][C:6]([OH:24])=[O:5])=[O:23])(=[O:21])[CH3:20]
Reactant: CC(=O)SCC(C)C(=O)N(CC(=O)OC(C)(C)C)C1CCCCC1
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)SCC(C)C(=O)N(CC(=O)O)C1CCCCC1
Yield: 84.1 %

Procedure:
To a solution of N-(3-acetylthio-2-methylpropanoyl)-N-cyclohexylglycine t-butyl ester (36.4 g, 0.101 mol) in 300 ml of methylene chloride was added trimethylsilyl iodide (20.4 g, 0.102 mol). After stirring at room temperature for 1.75 hours 50 ml of water was added, followed in 10 min. by 500 ml of saturated sodium bicarbonate solution. An emulsion formed which was separated by centrifuging. The aqueous solution was separated, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The extracts were dried, filtered, and concentrated to yield 25.6 g (83.4%) of N-(3-acetylthio-2-methylpropanoyl)-N-cyclohexylglycine as a pale yellow oil. The compound was characterized as its DCHA salt, prepared by dissolving the acid in ether and adding DCHA to pH 8-9. The salt was isolated as a white crystalline solid, m.p. 142°-144°.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[CH:20]=2)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=O)=[CH:5][CH:4]=1.Cl.[NH2:29][OH:30].C([O-])(O)=O.[Na+]>>[CH3:1][N:2]([CH3:27])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[CH:20]=2)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:29][OH:30])=[CH:5][CH:4]=1
Reactant: Cc1cc(C)cc(C(CC(=O)c2ccncc2)c2ccc(N(C)C)cc2)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C)cc(C(CC(=NO)c2ccncc2)c2ccc(N(C)C)cc2)c1

Procedure:
In analogy to example 1, step 2, from 3-(4-dimethylamino-phenyl)-3-(3,5-dimethyl-phenyl)-1-pyridin-4-yl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (2.9:1) as a light yellow foam, MS (ESI+): m/z=374.3 ([M+H]+).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:21])([CH3:20])[C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[OH:21][C:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1)([CH3:20])[C:16]([F:18])([F:19])[F:17]
Reactant: CC(O)(c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(O)(c1ccc(O)cc1)C(F)(F)F

Procedure:
31.3 g (0.106 mol) of 4-(2-hydroxy-1,1,1-trifluoro-2-propyl)phenol benzyl ether were hydrogenated in 380 ml of glacial acetic acid in the presence of 6.3 g of palladium (5% on charcoal) at 50° C. After filtration to remove the catalyst and concentration, 18.9 g (87% of theory) remained of a colorless product.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:13]=[C:14](\[CH2:20][CH3:21])/[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][C:11]=1I)[CH2:2][CH2:3][CH3:4].[CH3:22][N:23]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)[C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:25].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.[Cl-].[NH4+].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>[CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:13]=[C:14](\[CH2:20][CH3:21])/[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][C:11]=1[C:34]1[CH:35]=[CH:36][CH:37]=[C:32]([N:23]([CH3:22])[C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:25])[CH:33]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(/C=C(\CC)C(=O)OCC)ccc1I
Reactant: CCCCCNC(=O)N(C)c1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\CC)C(=O)OCC)cc2OCCCC)c1
Temperature: 92.5 °C
Yield: 76 %

Procedure:
3 mg (0.013 mmol) of palladium acetate and then 9 mg (0.026 mmol) of 2-(dicyclohexylphosphino)biphenyl are added to a mixture of 523 mg (1.3 mmol) of ethyl 2-[1-(3-butoxy-4-iodophenyl)meth-(E)-ylidene]butyrate (prepared according to Example 22a), 446 mg (1.7 mmol) of 3-(1-methyl-3-pentylureido)phenylboronic acid (prepared according to Example 24h) and 1.3 mL of aqueous 2 M potassium phosphate solution in 6.5 mL of dimethylformamide. The reaction mixture is heated at 90-95° C. for 2 hours. The reaction medium is hydrolyzed in saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and dried over magnesium sulfate. After filtration, the solvent is evaporated off and the brown oil obtained (1.2 g) is purified by chromatography on a column of silica eluted with a 70/30 heptane/ethyl acetate mixture. 489 mg (76%) of ethyl 2-[1-[2-butoxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]meth-(E)-ylidene]butyrate are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[C:4]([CH3:11])[C:3]=1[CH3:12].[S-:13][C:14]#[N:15].[K+].BrBr.[OH-].[Na+]>C(O)(=O)C.O>[NH2:15][C:14]1[S:13][C:7]2[C:6]([CH3:8])=[C:5]([O:9][CH3:10])[C:4]([CH3:11])=[C:3]([CH3:12])[C:2]=2[N:1]=1
Reactant: N#C[S-]
Reactant: COc1c(C)cc(N)c(C)c1C
Agent: BrBr
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1c(C)c(C)c2nc(N)sc2c1C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
100 g of 1-amino-4-methoxy-2,3,5-trimethylbenzene was dissolved in 1,000 ml of acetic acid and 50 ml of water. Then 212 g of potassium thiocyanate was added to the solution at room temperature. The reaction mixture was cooled with ice and 37.5 ml of bromine was added dropwise thereto, followed by stirring for 30 minutes. The reaction mixture was neutralized with a 1N aqueous solution of sodium hydroxide. The insoluble matters thus formed were separated by filtering and washed with water. After recrystallizing from methanol/tetrahydrofuran, 123 g of the title compound was obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[Br:15][C:16]1[CH:21]=[C:20](Br)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1.CCN(CC)CC.[OH-].[Na+]>CCO.CCOC(C)=O>[Br:15][C:16]1[CH:21]=[C:20]([NH:1][CH:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: O=[N+]([O-])c1cnc(Br)cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC(Nc2cc(Br)ncc2[N+](=O)[O-])C1
Yield: 43.3 %

Procedure:
The tert-butyl 3-aminopiperidine-1-carboxylate (1.43 g, 7.14 mmol, 1.0 eq) was added dropwise to a solution of 2,4-dibromo-5-nitropyridine (2 g, 7.14 mmol, 1.0 eq) and Et3N (0.73 g, 7.14 mmol, 1.0 eq) in EtOH (20 mL) at reflux temperature. The reaction mixture was heated at refluxing for 16 h and then the solvent was concentrated in vacuo to afford a residue. The residue was treated with 1 N NaOH solution and extraction with EtOAc. The organic phase was separated, dried (Na2SO4) and concentration in vacuo to afford an residue which was purified by silica gel column chromatography with EtOAc in PE (⅕ v/v) to give the title compound (1.24 g, 42%) as yellow solid. 1H NMR (400 MHz, CDCl3) δ: 8.99 (s, 1H), 8.25 (s, 1H), 6.98 (s, 1H), 3.81-3.79 (m, 1H), 3.61-3.60 (m, 2H), 3.37-3.35 (m, 2H), 2.02 (m, 1H), 1.86-1.77 (m, 3H), 1.47 (s, 9H). ESI-MS (M+H+): 401.0.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:12][O:13][C:14](=[O:16])[N:15]=2)[CH:6]=1.[C:19]([O:25][CH2:26]Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21].[Cl-].[NH4+]>CN(C)C=O>[CH3:21][C:20]([CH3:23])([CH3:22])[C:19](=[O:24])[O:25][CH2:26][N:15]1[C:14](=[O:16])[O:13][N:12]=[C:11]1[C:7]1[CH:6]=[C:5]([C:4]([F:3])([F:17])[F:18])[CH:10]=[CH:9][N:8]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCn1c(-c2cc(C(F)(F)F)ccn2)noc1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.2 %

Procedure:
Into 2 ml of N,N-dimethylformamide was suspended 0.05 g of sodium hydride (60% oily), and 0.2 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one was added at room temperature. After stirring for 10 minutes, 0.2 g of chloromethyl pivalate was added, the mixture was stirred at 60° C. for 7 hours, and the reaction solution was allowed to cool to room temperature, and poured into an aqueous saturated ammonium chloride solution, followed by extraction with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.18 g of 4-[(2,2-dimethyl-1-oxopropoxy)methyl]-3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one (present compound (10)).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[N:18]=[C:17]([N:19]4[CH2:24][CH2:23][CH:22]([C:25](O)=[O:26])[CH2:21][CH2:20]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=N1.N1CCCC1>C(N(CC)CC)C>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[N:18]=[C:17]([N:19]4[CH2:24][CH2:23][CH:22]([C:25]([N:35]5[CH2:36][CH2:41][CH2:40][CH2:39]5)=[O:26])[CH2:21][CH2:20]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Nc2ncnc3cnc(N4CCC(C(=O)O)CC4)nc23)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCNC1
Solvent: CCN(CC)CC
Product: Cc1cccc(Nc2ncnc3cnc(N4CCC(C(=O)N5CCCC5)CC4)nc23)c1

Procedure:
Prepared from compound 46 of Example 1 by reaction with O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, triethylamine and pyrrolidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][OH:10])=[CH:7][CH:8]=1.[F:11][CH:12]([CH2:14][C:15](Cl)=[S:16])[F:13]>ClCCl>[F:11][CH:12]([CH2:14][C:15]([O:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[S:16])[F:13]
Reactant: COc1ccc(CO)cc1
Reactant: FC(F)CC(=S)Cl
Solvent: ClCCl
Product: COc1ccc(COC(=S)CC(F)F)cc1
Yield: 80.4 %

Procedure:
To a stirred and ice cooled solution of p-methoxybenzyl alcohol (1.2 equivalents) in dichloromethane (5 parts by weight) is added dropwise difluoromethylthioacetyl chloride, and the mixture is stirred for 4 hours. The mixture is washed with water, dried and concentrated. The residual liquid is distilled to give oily p-methoxybenzyl difluoromethylthioacetate. Yield: 80.4%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[Cl:30])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[ClH:30].[Cl:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[C:22]([NH:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:16]=1)=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1cccc(OC2CCNCC2)c1)c1ccc(F)cc1Cl
Reaction time: 2 h
Yield: 199.2 %

Procedure:
Combine 4-[3-(2-chloro-4-fluoro-benzoylamino)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (preparation 77, 2.99 g, 6.67 mmol), dioxane (30 mL) and a solution of hydrogen chloride in dioxane (4M, 15 mL) and stir at room temperature. After 2 hr., concentrate at reduced pressure to remove the solvent, dry under vacuum to give the title compound as a white solid (2.56 g, 100%): Mass spectrum (ion spray): m/z=349.0 (M+1); Analysis calculated for C18H19Cl2FN2O2.0.25H2O: C, 55.47; H, 5.04; N, 7.19. Found C, 55.26; H, 5.09; N, 6.80.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.IC.[C:14](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A stirred mixture of 4-bromo-2-methylbenzoic acid (6 g, 27.9 mmol), iodomethane (5.21 mL, 84 mmol) and potassium carbonate (11.57 g, 84 mmol) in DMF (60 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between water (250 mL) and 4:1 hexanes:ethyl acetate (650 mL). The organic layer was washed with water and dried over Na2SO4. The solvent was removed under vacuum to give 6.39 g of desired product as an oil in 100% yield. 1H NMR (400 MHz, CD3OD) δ ppm 7.86-7.65 (m, 7H) 7.50 (br. s., 2H) 3.88 (s, 3H) 2.56 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[N:3]=1.[C:19]([NH:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)(=[O:21])[CH3:20].FC1C=CC(C2C=C3C(=CC=2)N=CN=C3O)=CC=1>>[NH2:1][C:2]1[N:11]=[C:10]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:26]3[CH:27]=[CH:28][C:23]([NH:22][C:19](=[O:21])[CH3:20])=[CH:24][CH:25]=3)[CH:8]=2)[N:3]=1
Reactant: Nc1nc(OCC(F)(F)F)c2cc(Br)ccc2n1
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Agent: Oc1ncnc2ccc(-c3ccc(F)cc3)cc12
Product: CC(=O)Nc1ccc(-c2ccc3nc(N)nc(OCC(F)(F)F)c3c2)cc1
Yield: 82 %

Procedure:
This compound, synthesized from 2-amino-6-bromo-4-(2,2,2-trifluoro-ethoxy)-quinazoline and 4-acetamido-phenylboronic acid in 82% yield using the procedure described for the synthesis of 6-(4-fluorophenyl)-4-hydroxy-quinazoline, was characterized by its mass spectrum as follows: MS (m/z): 377 ([M+H]+, 100)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(N(C)C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:33]2[CH2:32][CH2:31][N:30]([C:28]([O:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:29])[CH2:35][CH2:34]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
3.76 ml (35.082 mmol) of 4-fluoronitrobenzene are dissolved in 40 mL DMA and combined with 9.25 mL (52.62 mmol) of N-ethyldiisopropylamine and 7.6 ml (38.59 mmol) of 1-(benzyloxycarbonyl)-piperazine. The reaction mixture is stirred for 18 h at 80° C. Then the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier material used is silica gel and the eluant used is a mixture consisting of cyclohexane:ethyl acetate (50:50).
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6](Br)[N:7]=1.[CH2:21]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C.C1CC=CCC=1>[Pd].O1CCCC1>[CH3:32][N:31]([CH3:33])[CH2:30][CH2:29][N:28]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]1[C:3](=[O:20])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][N:7]=1
Reactant: COC(=O)c1ccc(C)c(-n2cc(Br)nc(Br)c2=O)c1
Reactant: CN(C)CCNCc1ccccc1
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1=CCC=CC1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)c(-n2ccnc(N(CCN(C)C)Cc3ccccc3)c2=O)c1
Temperature: 100 °C

Procedure:
A mixture of 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester (Example 1b, 129 mg), N′-benzyl-N,N-dimethylethylenediamine (0.1 mL), N,N-diisopropylethylamine (0.1 mL) and tetrahydrofuran (1 mL) was heated within a microwave for 15 minutes at 100° C. before being cooled to room temperature. The mixture was transferred to a mixture of palladium on carbon (10%, 50 mg) and tetrahydrofuran (1 mL) and 1,4-cyclohexadiene (1 mL) was added. The mixture was heated within a microwave for 60 minutes at 120° C. before being cooled to room temperature. The mixture was filtered and the filtrated concentrated in vacuo. Purification by preparative HPLC (Gemini column, 0.1% ammonia: acetonitrile eluent) afforded the title compound as a solid (50 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:49][CH:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)[C:40](NC2C=CN(C)N=2)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[C:55]([O:59][C:60]([N:62]1[CH:66]=[CH:65][C:64]([NH2:67])=[N:63]1)=[O:61])([CH3:58])([CH3:57])[CH3:56].CN1CCOCC1>C(Cl)Cl.C(OCC)(=O)C>[C:55]([O:59][C:60]([N:62]1[CH:66]=[CH:65][C:64]([NH:67][C:40](=[O:41])[C@@H:39]([C:31]2[CH:32]=[CH:33][C:34]([S:35]([CH3:38])(=[O:36])=[O:37])=[C:29]([Cl:28])[CH:30]=2)[CH2:49][CH:50]2[CH2:51][CH2:52][CH2:53][CH2:54]2)=[N:63]1)=[O:61])([CH3:58])([CH3:56])[CH3:57]
Reactant: CC(C)(C)OC(=O)n1ccc(N)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Yield: 99.3 %

Procedure:
Triphenylphosphine (1.61 g, 6.15 mmol) was dissolved in methylene chloride (60 mL) and cooled to 0° C. To this solution was added N-bromosuccinimide (1.24 g, 6.97 mmol) and was stirred at 0° C. until it was completely dissolved and became light purple in color. The 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 1.36 g, 4.1 mmol) was then added and it was stirred at 0° C. for 15 min and then warmed to 25° C. and stirred for another 30 min. The mixture was cooled to 0° C. and 3-amino-pyrazole-1-carboxylic acid tert-butyl ester (0.75 g, 4.1 mmol) was added followed by N-methyl-morpholine (540 μL, 4.92 mmol). The mixture was continued to stir at 0-4° C. for 4 h. The reaction was diluted with ethyl acetate (150 mL), washed with water (50 mL), aqueous 0.1 M hydrochloric acid (2×50 mL) and saturated aqueous brine solution (2×50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Flash column chromatography (Merck silica gel 60, 40-63 μm; 5% ethyl acetate/hexanes to 25% ethyl acetate/hexanes) afforded 3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazole-1-carboxylic acid tert-butyl ester (2.02 g, 99%) as a light yellow oil: ESI-LRMS m/e calcd for C23H30ClN3O5S [M+] 495.2, found 496.4 [M+H+], 395.5 [M−CO2tBu+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[N:12]([CH3:13])[N:11]=[C:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[N:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:24][Mg]Br.S(=O)(=O)(O)O.O>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH3:13])[N:11]=[C:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[N:9]=2)([OH:7])[CH3:24])=[CH:22][CH:23]=1
Reactant: C[Mg]Br
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1C(=O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1C(C)(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an atmosphere of nitrogen, to a solution of 1.5 of 5-(4-chlorobenzoyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H 1,2,4-triazole in diethl ether at -70° C. was added dropwise 12 ml of methylmagnesium bromide. After 1 hour, the reaction mixture was warmed to room temperature stirred overnight, Then 36 ml of a 2N aqueous solution of sulfuric acid was added to the solution under iced-cooling, the mixture was poured into iced water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gelchromatography to afford 1.3 g of 5-(4-chloro-α-hydroxy-α-methylbenzyl)-3-(2-chloro-6-fluorophenyl)-1-methyl 1H-1,2,4-triazole. mp.198°-200° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([OH:34])[CH2:33][CH2:32][C:27]4(OCC[O:28]4)[CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[OH:34][C:24]1([C:22]2[S:23][C:19]([C:4]3[CH:5]=[C:6]([NH:8][C:9]4[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][N:10]=4)[CH:7]=[C:2]([CH3:1])[CH:3]=3)=[CH:20][N:21]=2)[CH2:33][CH2:32][C:27](=[O:28])[CH2:26][CH2:25]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCC4(CC3)OCCO4)s2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCC(=O)CC3)s2)c1
Reaction time: 6 h
Yield: 87.4 %

Procedure:
To a stirred solution of 8-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-dioxaspiro[4.5]decan-8-ol (Example 4B-15, 785 mg, 1.59 mmol) in THF (6 mL) was added HCl (6 M, 5.3 mL, 32 mmol) and the reaction was left to stir for 6 h. The mixture was brought to pH 8 with saturated aqueous sodium bicarbonate, extracted with ethyl acetate (×3), and the combined organic portion was washed with saturated aqueous sodium bicarbonate. The solution was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography to afford 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanone (625 mg, 1.39 mmol) as a white foam. APCI: [M+H]+ m/z 449.1. 1H NMR (600 MHz, CDCl3) δ 8.64 (d, J=4.9, 1H), 7.90 (s, 1H), 7.86 (s, 1H), 7.46 (s, 1H), 7.26 (s, 1H), 7.06 (s, 1H), 7.04 (d, J=4.9, 1H), 2.92-2.82 (m, 2H), 2.49-2.29 (m, 6H), 2.38 (s, 3H). rhSYK activity=+++