Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[Cl:2][C:3]([Cl:8])([Cl:7])[C:4]([NH2:6])=[NH:5].[C:9]([CH2:11][C:12](OCC)=[O:13])#[N:10].O>CO.C(O)(=O)C>[NH2:10][C:9]1[N:6]=[C:4]([C:3]([Cl:8])([Cl:7])[Cl:2])[N:5]=[C:12]([OH:13])[CH:11]=1
Reactant: N=C(N)C(Cl)(Cl)Cl
Reactant: CCOC(=O)CC#N
Agent: [Na]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Nc1cc(O)nc(C(Cl)(Cl)Cl)n1
Yield: 71 %

Procedure:
To a solution of 5.8 g (0.025 g atom) sodium in 150 ml methanol at 15° C. was added 11.5 g (0.1 mole) trichloroacetamidine. To this was added 11.5 g (0.1 mole) ethyl cyanoacetate in 100 ml methanol. The solution was refluxed 1 hour and then the solvent was removed under rotary evaporation to give a red paste. This was dissolved in 20 ml warm water and 100 ml of 50% aqueous acetic acid was added, causing product to precipitate. Filtration, washing, and drying of the product gave 16.1 g (71% yield; mp 225°-230° C. (decomposed). The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][C:21]([C:30]#[N:31])=[C:20]([OH:32])[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].OO.C(O)(=[O:40])C>C(O)C.O>[C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][C:21]([C:30](=[O:40])[NH2:31])=[C:20]([OH:32])[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(O)c(C#N)cc3-c3ccccc3)cc2)CCC1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(O)c(C(N)=O)cc3-c3ccccc3)cc2)CCC1
Temperature: 50 °C
Yield: 72 %

Procedure:
To a suspension of tert-butyl(1-(4-(5-cyano-6-hydroxy-3-phenylpyridin-2-yl)phenyl)cyclobutyl)carbamate (14.6 g, 3.58 g, 0.033 mol) in ethanol (112 ml) and water (112 ml) at room temperature was added sodium hydroxide solution (6M, 54.4 ml) and hydrogenperoxide (30%, 21.9 ml). The resulting mixture was heated at 50° C. for 16 h. After cooled down to 0° C., the mixture was added acetic acid to adjust pH=4. The resulting precipitate was filtered and the filter cake was dried to give the title compound as white solid (10.8 g, 72%). LCMS (Method A): RT=5.88 min, M+1=460. 1H NMR (500 MHz, DMSO-d6): 9.65 (1H, br), 8.10 (1H, s), 7.25-7.05 (7H, m), 6.98 (2H, m), 2.45-2.25 (4H, m), 2.0-1.95 (1H, m), 1.79-1.75 (1H, m), 1.3-1.0 (91-1, br).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:6][C:7]=1Cl.[OH-:16].[K+]>C(O)C.O>[Cl:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:6][C:7]=1[OH:16]
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccccc1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=c1c(Cl)c(O)cnn1-c1ccccc1

Procedure:
4,5-Dichloro-2-phenylpyridazin-3-one (2.4 g, 0.01 moles) was suspended in ethanol (50 ml) and potassium hydroxide (2.0 g, 0.03 moles) was added in water (20 ml). Refluxed for 4 hours. Evaporated to dryness and added water. Acidified to pH2 with c. hydrochloric acid. Filtered off the product as a buff solid and dried in a desiccator. (2.1 g) Took 0.5 g and dissolved in methanol, filtered and evaporated. Triturated with ether to give the product as a cream solid. (0.4 g, 76%)
Reaction SMILES: Br[C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1.FC1(F)OC2C=C(C)C(C3N=C[C:25]([NH:28][C:29](=O)[C:30]4[CH:35]=[CH:34]C=CC=4F)=[N:26]C=3)=CC=2O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.O1CCOCC1.O>[CH3:11][C:10]1[C:2]([C:30]2[CH:35]=[CH:34][C:25]([NH2:26])=[N:28][CH:29]=2)=[CH:3][C:4]2[CH2:8][CH2:7][O:6][C:5]=2[CH:9]=1
Reactant: Cc1cc2c(cc1-c1cnc(NC(=O)c3ccccc3F)cn1)OC(F)(F)O2
Reactant: Cc1cc2c(cc1Br)CCO2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: C1COCCO1
Product: Cc1cc2c(cc1-c1ccc(N)nc1)CCO2
Temperature: 85 °C
Yield: 62.9 %

Procedure:
A mixture of 5-bromo-6-methyl-2,3-dihydrobenzo[b]furan (160) (350 mg, purity ca 40%, 0.66 mmol), 2-aminopyridine-5-boronic acid pinacol ester (11) (360 mg, 1.6 mmol), bis(ditertbutyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (113 mg, 5% mol), and K3PO4 (348 mg, 1.6 mmol) in 2 ml ACN, 2 ml dioxane, 1 ml H2O was bubbled with argon before heated at 85° C. for 4 h. After cooling down to r.t., the reaction mixture was taken up in EA, washed with aq. NaHCO3 and brine. Org. phase was dried over Na2SO4, concentrated and then subjected to prep HPLC purification to give 94 mg 5-(6-methyl-2,3-dihydrobenzo[3,4-b]furan-5-yl)-2-pyridylamine (161) (yield: 63%, purity>95%) as light yellow solid.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.CC1(C)C(C)(C)OB([C:19]2[CH:20]=[N:21][CH:22]=[C:23]([CH:26]=2)[CH:24]=[O:25])O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:10][C:4]1[CH:3]=[C:2]([C:19]2[CH:20]=[N:21][CH:22]=[C:23]([CH:24]=[O:25])[CH:26]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(Br)cc1Cl
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cncc(C=O)c2)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-2-chlorobenzonitrile (1.082 g, 5 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinaldehyde (1.165 g, 5.00 mmol), Pd(PPh3)4 (0.144 g, 0.125 mmol), sodium carbonate (2.5 mL, 5.00 mmol) in 1,4-dioxane (20 mL) was heated to reflux for 6 h. After cooling to room temperature, the solid was filtered and washed by ethyl acetate and water. After drying under vacuum, yellow powder was collected (1 g). 1H NMR (400 MHz, CDCl3): δ 7.63 (dd, J=1.68, 8 Hz, 1H), 7.79 (d, J=1.68 Hz, 1H), 7.83 (d, J=8 Hz, 1H), 8.35 (dd, J=2.24 Hz, 2.04 Hz, 1H), 9.07 (d, J=2.36 Hz, 1H), 9.15 (d, J=1.88 Hz, 1H), 10.22 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH:19]([CH3:20])[CH2:18][CH2:17][CH2:16][CH:15]2[CH3:21])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.N12[CH2:44][CH2:43][CH2:42]N=C1CCCCC2.[CH:45]1([S:48]([NH2:51])(=[O:50])=[O:49])[CH2:47][CH2:46]1.Cl>O1CCCC1>[CH:43]1([C:2]2[C:3]([O:12][CH2:13][CH:14]3[CH:19]([CH3:20])[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:21])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=2)[C:7]([NH:51][S:48]([CH:45]2[CH2:47][CH2:46]2)(=[O:50])=[O:49])=[O:9])[CH2:44][CH2:42]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC1CCCC(C)C1COc1cc(F)c(C(=O)O)cc1Cl
Reactant: NS(=O)(=O)C1CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC1CCCC(C)C1COc1cc(F)c(C(=O)NS(=O)(=O)C2CC2)cc1C1CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 27.9 %

Procedure:
To a stirred solution of 5-chloro-4-((2,6-dimethylcyclohexyl)methoxy)-2-fluorobenzoic acid (0.07 g, 0.22 mmol) in tetrahydrofuran (2 mL) under an atmosphere of nitrogen was added carbonyldiimidazole (0.053 g, 0.33 mmol). The reaction mixture was stirred at 70° C. for 1 hour. The mixture was cooled to room temperature and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.07 mL, 0.45 mmol) was added followed by cyclopropanesulfonamide (0.045 mg, 0.374 mmol). Stirring continued at room temperature for 18 hours. 5% aqueous hydrochloric acid solution (0.15 mL) was added and the mixture was concentrated and directly purified by column chromatography (0 to 30% ethyl acetate in hexanes) to afford the title compound (0.026 g, 28%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 12.09-11.90 (m, 1H), 7.71 (d, J=7.07 Hz, 1H), 7.35 (d, J=12.32 Hz, 1H), 4.12-4.06 (m, 2H), 3.11-2.96 (m, 1H), 1.98-0.80 (m, 19H); MS (ES−) m/z 416.2, 418.2 (M−1).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([O:20][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:18][CH:19]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 95.2 %

Procedure:
A mixture of 4-fluorobenzaldehyde (2.0 g, 0.0161 mol), 4-tert-butylphenol (2.42 g, 0.161 mol), and K2CO3 (9.0 g, 0.065 mol) in DMF (50 mL) was heated at 80° C. After 6 h, the reaction mixture was filtered into ice/water and the product was extracted with ethyl acetate. The organic layer was washed with water, dried (MgSO4), concentrated and chromatographed with 1:1 hexane/ethyl acetate to give 3.9 g (95%) of 4-(4-tert-butylphenoxy)benzaldehyde.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[CH:13][CH:12]=2)[CH:7]=1)=[O:5])C.[OH-].[K+].Cl>C1COCC1>[F:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[O:10][N:9]=2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1cc(-c2ccc(OCc3cccc(F)c3)cc2)no1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2ccc(OCc3cccc(F)c3)cc2)no1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
3-[4-(3-Fluoro-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid ethyl ester (which may be prepared as described in Preparation of Intermediate 4; 500 mg, 1.47 mmol) was dissolved in THF (5 mL), and 0.5 M aqueous KOH (12 mL, 1 mmol) was added. The reaction mixture was heated at reflux, cooled to room temperature, and then to 0° C. The mixture was acidified by the addition of 4 M aqueous HCl (10 mL). The resulting solid was filtered off and washed with cold H2O to give 3-[4-(3-fluoro-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid (431 mg, 94%). HRMS Calcd. for C17H13FNO4 (M+H)+, 314.0823. Found: 314.0823.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([Cl:11])[C:4]=1[Cl:12].O.CO.[C-:16]#[N:17].[Na+]>CS(C)=O>[Cl:12][C:4]1[C:5]([Cl:11])=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=1[CH2:2][C:16]#[N:17]
Reactant: [C-]#N
Reactant: COc1ccc(CBr)c(Cl)c1Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Solvent: O
Product: COc1ccc(CC#N)c(Cl)c1Cl
Temperature: 40 °C
Reaction time: 5 h
Yield: 97 %

Procedure:
To a mixture of 1-(bromomethyl)-2,3-dichloro-4-methoxybenzene (1.00 g), water (3.00 mL), methanol (6.00 mL), and dimethyl sulfoxide (2.00 mL) was added sodium cyanide (246 mg) at room temperature, followed by stirring at 40° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, and then water was added thereto. The resulting solid was collected by filtration to obtain (2,3-dichloro-4-methoxyphenyl)acetonitrile (776 mg).
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:5]([F:19])=[C:6]([CH:15]=[CH:16][C:17]=1[F:18])[O:7][CH2:8][CH:9]=[CH:10][C:11]([O:13]C)=[O:12])=[O:3].[OH-].[Na+].Cl>C(O)(C)C.O>[NH2:1][C:2]([C:4]1[C:5]([F:19])=[C:6]([CH:15]=[CH:16][C:17]=1[F:18])[O:7][CH2:8][CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[O:3]
Reactant: COC(=O)C=CCOc1ccc(F)c(C(N)=O)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: NC(=O)c1c(F)ccc(OCC=CC(=O)O)c1F
Temperature: 25 °C
Yield: 48 %

Procedure:
A solution of methyl 4-[3-(aminocarbonyl)-2,4-difluorophenoxy]-2-butenoate (1.25 g, 4.61 mmol, 1 equiv.) and NaOH (0.75 g, 18.44 mmol, 4 equiv.) in isopropanol (10 ml) and H2O (20 ml) was heated under reflux for 1 h. After cooling to r.t., the mixture was acidified with conc. HCl to pH 1. The white precipitant solid was filtered and washed with Et2O (50 ml), to give 568 mg, 48% yield, mp 187-188° C., HPLC-MS (method 1): m/z 258 [M+H]+, Rt=0.98 min. By 1H-NMR analysis it was determined to be a mixture of isomers in a ratio (3:2) E:Z.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[OH:25].O>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[O:25][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2Cl)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 2,4-dichlorophenol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into H2O (100ml), extracted with EtOAc (2×50 mL), washed with H2O (2×50 ml) and brine (50 ml), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(2,4-dichloro-phenoxy)-1-nitrobenzene. The crude product was used for further transformation.
Reaction SMILES: Cl.Cl[CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[N:5]1.[F:9][C:10]([F:19])([F:18])[CH2:11][CH2:12][CH:13]([C:16]#[N:17])[C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:4]1([CH2:3][C:13]([CH2:12][CH2:11][C:10]([F:9])([F:18])[F:19])([C:14]#[N:15])[C:16]#[N:17])[CH:8]=[CH:7][CH:6]=[N:5]1
Reactant: ClCn1cccn1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cccn1
Yield: 29.9 %

Procedure:
0.76 g of 1-(chloromethyl)-1H-pyrazole hydrochloride and 0.81 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 10 ml of N,N-dimethylformamide. 1.38 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for 5 hours. Water was added to the reaction mixture, and then extracted with methyl-t-butyl ether (may be referred as MTBE, hereinafter) . The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain 0.36 g of (1H-pyrazole-1-yl methyl) (3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (1), hereinafter) shown by below formula.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:15]1([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.O>CN(C=O)C>[Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:12])([CH3:14])[CH2:13][N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][C:32]([F:34])([F:35])[F:33])=[CH:29][CH:30]=3)=[O:22])[CH2:20][CH2:19]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: O=C(OCc1ccc(OC(F)(F)F)cc1)N1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@](O)(CN1CCN(C(=O)OCc2ccc(OC(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 67.5 °C
Reaction time: 20 h
Yield: 83.3 %

Procedure:
A mixture of (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (15 g, 68.93 mmol) and 4-trifluoromethoxybenzyl piperazine-1-carboxylate (25.17 g, 82.72 mmol) in DMF (75 ml) was stirred at 65-70° C. for 20 hours. The reaction mixture was allowed to return to room temperature and poured into water (475 ml), and extracted with ethyl acetate (150 ml). The aqueous layer was extracted with ethyl acetate (150 ml) again. The organic phases were combined, washed with water (400 ml) 3 times and a saturated saline solution (100 ml), dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/2) to afford 4-trifluoromethoxybenzyl (S)-4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]-piperazine-1-carboxylate (29.98 g, yield 83%) as a yellow oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:17])[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])C.CO.O.[OH-].[Li+].Cl>O1CCCC1.O>[CH3:17][N:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8]1
Reactant: CCOC(=O)c1cc(-c2ccccc2)nn1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cn1nc(-c2ccccc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Methyl-5-phenyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.32 g, 1.39 mmol) was dissolved in 4.5 mL of tetrahydrofuran, 1.5 mL of methanol and 1.5 mL of water, and treated with lithium hydroxide hydrate (0.12 g, 2.78 mmol). After stirring at room temperature overnight, the mixture was acidified (pH =1) with hydrochloric acid, and extracted with ethyl acetate (3×10 mL) and the combined organic phases washed with 10 mL of brine. The organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford a quantitative yield of the title compound.
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH3:13][S:14][CH2:15][S:16](=[O:18])[CH3:17].CC(C)([O-])C.[K+].O>C(O)(C)(C)C.C(Cl)Cl>[CH3:17][S:16]([C:15]([S:14][CH3:13])=[CH:9][C:8]1[CH:11]=[CH:12][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=1)=[O:18]
Reactant: CSCS(C)=O
Reactant: CC(C)Cc1ccc(C=O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CC(C)(C)O
Product: CSC(=Cc1ccc(CC(C)C)cc1)S(C)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.2 %

Procedure:
p-Isobutylbenzaldehyde (486 mg) and 450 mg of formaldehyde dimethyl mercaptal S-oxide were dissolved in 1 ml of t-butanol, and 2.0 ml of a 0.608N t-butanol solution of potassium t-butoxide was added. The mixture was stirred at room temperature for 12 hours. Water (0.5 ml) and 50 ml of methylene chloride were added to the reaction mixture. The resulting mixture was dried over anhydrous sodium sulfate. The drying agent and the insoluble matter were removed by filtration, and the filtrate was concentrated under reduced pressure. The oily residue was chromatographed on a silica gel column using methylene chloride as an eluant to afford 701 mg of 1-methylsulfinyl-1-methylthio-2-(p-isobutylphenyl)ethylene in a yield of 87%. Samples for analysis were obtained by simple distillation of this product (at a bath temperature of 160° to 170° C./0.02 mmHg).
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](NCC)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)C[CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[NH2:45][C:46]1[CH:47]=[CH:48][C:49]([O:52][CH2:53][CH2:54][OH:55])=[N:50][CH:51]=1.[N+](C1C=CC(OCCO)=NC=1)([O-])=O.[H][H].NC1C=CC=CC=1>C(OCC)(=O)C.CO.[Pd]>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:45][C:46]4[CH:51]=[N:50][C:49]([O:52][CH2:53][CH2:54][OH:55])=[CH:48][CH:47]=4)=[O:27])=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH2:34][CH3:35])[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: Nc1ccc(OCCO)nc1
Reactant: [H][H]
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: [Pd]
Agent: NC(N)=O
Agent: O=[N+]([O-])c1ccc(OCCO)nc1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: Nc1ccccc1
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(OCCO)nc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 2-(5-aminopyridin-2-yloxy)ethanol (prepared by the reduction of 2-(5-nitropyridin-2-yloxy)ethanol in ethyl acetate and methanol with palladium on carbon and hydrogen gas) as the aniline component. (5%, MS=531.2 (M+H))
Reaction SMILES: [C:1]([O:5][P:6]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:26][C:27]4[N:28]=[C:29]([C:32]5[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([C:39]([F:42])([F:41])[F:40])[CH:33]=5)[O:30][CH:31]=4)=[CH:20][CH:21]=3)[O:16][CH:15]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([O:52]O)(C)(C)C.S(=O)(O)[O-].[Na+]>O1CCCC1.C(#N)C.CCCCCCCCCC>[P:6]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:26][C:27]4[N:28]=[C:29]([C:32]5[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([C:39]([F:42])([F:40])[F:41])[CH:33]=5)[O:30][CH:31]=4)=[CH:20][CH:21]=3)[O:16][CH:15]=2)=[CH:10][CH:9]=1)([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:52]
Reactant: CC(C)(C)OP(Oc1ccc(-c2coc3cc(OCc4coc(-c5cc(F)cc(C(F)(F)F)c5)n4)ccc3c2=O)cc1)OC(C)(C)C
Reactant: CC(C)(C)OO
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCCCCCCCCC
Product: CC(C)(C)OP(=O)(Oc1ccc(-c2coc3cc(OCc4coc(-c5cc(F)cc(C(F)(F)F)c5)n4)ccc3c2=O)cc1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of step 1, 3-{4-[bis(tert-butoxy)phosphinooxy]phenyl}-7-({2-[5-fluoro-3-(trifluoromethyl)phenyl](1,3-oxazol-4-yl)}methoxy)chromen-4-one, in a mixture of tetrahydrofuran (20 mL) and acetonitrile (10 mL) was added 6 mL of tert-butyl hydroperoxide in decane (5M-6M). The reaction mixture was stirred at room temperature for 1 hour, chilled in an ice bath, and 50 mL of 5% sodium bisulfite was added. The resulting mixture was stirred for 15 minutes, after which the ice bath was removed. The mixture was extracted with methylene chloride, the organic extract dried over sodium sulfate, and solvent removed under reduced pressure. The residue was purified by biotage column chromatography, eluting with 1:1 ethyl Acetate/hexanes mixture, to afford ditert-butyl 4-[7-({2-[5-fluoro-3-(trifluoromethyl)phenyl](1,3-oxazol-4-yl)}methoxy)-4-oxochromen-3-yl]phenyl phosphate.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([NH:14][CH3:15])=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])C.C([CH:18]([C:22](Cl)=[O:23])[C:19](Cl)=[O:20])C.[CH2:25]([O:27]CC)[CH3:26]>>[CH2:25]([O:27][C:22]([C:18]1[C:19](=[O:20])[N:14]([CH3:15])[C:7]2[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=2[C:4]=1[OH:5])=[O:23])[CH3:26]
Reactant: CCOCC
Reactant: CCOC(=O)c1cnc(SC)nc1NC
Reactant: CCC(C(=O)Cl)C(=O)Cl
Product: CCOC(=O)c1c(O)c2cnc(SC)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4.54 g. (0.02 mole) of 4-methylamino-2-methylthio-5-pyrimidine carboxylic acid ethyl ester in 100 ml. of anhydrous diethyl ether was added 1.5 g. (0.01 mole) of ethyl malonyl chloride. The mixture was stirred at room temperature for 1 hour. The mixture was filtered and the filtrate was evaporated in a rotary evaporator. The residue was triturated with a few ml. of diethyl ether and was filtered. The filtrate was evaporated and the residue was dissolved in 10 ml. of ethanol. This solution was added to a solution of 0.37 g. (0.015 g atom) of sodium in 20 ml. of ethanol. The mixture was stirred at room temperature for 10 minutes. The mixture was diluted with water and was acidified with glacial acetic acid. The precipitate which formed was collected, air dried and was recrystallized from ethanol to afford 0.4 g. of title product--m.p. 166°-168° C.