Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16]CC)=[O:15].[OH-].[Li+]>C(O)C.O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)c1cnn(-c2ccc(F)cc2)c1N
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1c(C(=O)O)cnn1-c1ccc(F)cc1
Yield: 95.7 %

Procedure:
To a suspension of ethyl 5-amino-1-(4-fluorophenyl)-1H-pyrazole-4-carboxylate (12.1 g, 48.5 mmol) in ethanol (250 ml) was added a solution of lithium hydroxide (5.8 g, 242 mmol) in water (100 ml). The mixture was stirred at reflux for 2.5 hours. It was allowed to cool and concentrated to 50% of its volume before 5M hydrochloric acid (47 ml) was added. After stirring for 15 minutes, the resulting white solid was filtered off and further 5M hydrochloric acid (3 ml) was added to the filtrate and the resulting solid was filtered and the combined solids were washed with water and diethyl ether and then dried under vacuum to give the title compound (10.27 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]2[CH:6]=[N:7][NH:8][C:9]=2[CH:10]=1.[H-].[Na+].[C:14]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])([CH3:16])[CH3:15]>O1CCCC1>[Si:18]([O:11][C:4]1[CH:3]=[C:2]([F:1])[CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:20])[CH3:19]
Reactant: Oc1cc(F)cc2[nH]ncc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cc(F)cc2[nH]ncc12
Reaction time: 0.17 h

Procedure:
6-Fluoro-1H-indazol-4-ol (0.91 g) in tetrahydrofuran (20 mL) was treated with 60% sodium hydride (0.251 g). After 10 minutes, tert-butylchlorodimethylsilane (0.992 g) was added. The solution was stirred for 16 hours. The solvent was removed, and the residue was purified by flash column chromatography on silica gel to give the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].Br.[CH3:7][N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][N:10]=[C:9]1[NH2:19].C(=O)(O)[O-].[Na+]>CC(C)=O>[CH3:7][N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][N:10]=[C:9]1[NH:19][C:2]([O:4][CH3:5])=[O:3]
Reactant: CN1C(N)=NCC1c1ccccc1
Reactant: COC(=O)Cl
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)NC1=NCC(c2ccccc2)N1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
This example illustrates another process embodiment of the invention wherein an alkyl chloroformate is used as one of the reagents. In the example, 0.8 g. of methyl chloroformate is added over a five minute period to a stirring mixture of 2 g. 1-methyl-2-amino-5-phenyl-2-imidazoline hydrobromide, 1.4 g. sodium bicarbonate, and 20 ml. acetone held at 0° C. After addition is complete, the mixture is allowed to warm to room temperature and then stirred for 16 hours at room temperature. The mixture is distilled to a low volume and 50 ml. of water is then added. The mixture is filtered and the precipitate collected and washed with water and then dried affording 1-methyl-4,5-dihydro-5-phenyl-2-methoxycarbonylaminoimidazole which is then further purified by recrystallization from chloroform.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][C:7](=[O:18])[NH:8][C:9]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:10]=3[C:11]=2[N:12]=1.Br[C:20]1[CH:21]=[C:22]([CH2:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[C:23]([O:26][CH3:27])=[N:24][CH:25]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>>[Cl:17][C:15]1[CH:14]=[CH:13][C:10]2[C:11]3[N:12]=[C:2]([NH:1][C:20]4[CH:25]=[N:24][C:23]([O:26][CH3:27])=[C:22]([CH2:28][CH2:29][CH2:30][N:31]([CH3:32])[CH3:33])[CH:21]=4)[N:3]=[CH:4][C:5]=3[CH2:6][C:7](=[O:18])[NH:8][C:9]=2[CH:16]=1
Reactant: COc1ncc(Br)cc1CCCN(C)C
Reactant: Nc1ncc2c(n1)-c1ccc(Cl)cc1NC(=O)C2
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Product: COc1ncc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)cc1CCCN(C)C
Temperature: 150 °C
Yield: 20 %

Procedure:
A mixture of 2-amino-9-chloro-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (0.36 g, 1.38 mmol), 3-(5-bromo-2-methoxypyridin-3-yl)-N,N-dimethylpropan-1-amine (0.38 g, 1.38 mmol), xphos (0.047 g, 0.099 mmol), and tris(dibenzyllideneacetone)dipalladium(0) (0.023 g, 0.026 mmol) in a sealed microwave tube was evacuated and purged with nitrogen three times. To the solids were added tert-butyl alcohol (3.6 mL) and t-BuOK (1M in t-BuOH, 2.63 mL) via syringe. The mixture was stirred well and then subjected to microwave irradiation (150 watts) while heating at 150° C. for 45 min. The reaction mixture was then poured into water (25 mL) with vigorous stirring. The precipitate that formed was filtered, washed with water, and air dried. The residue was purified by column chromatography to give 9-chloro-2-({5-[3-(dimethylamino)propyl]-6-methoxypyridin-3-yl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (0.125 g, 18%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[C:13]3[NH:25][C@H:26]2[CH2:31][CH2:30][C@H:29]([NH:32]C(=O)OC(C)(C)C)[CH2:28][CH2:27]2)[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].C(O)(C(F)(F)F)=O>>[NH2:32][C@H:29]1[CH2:30][CH2:31][C@H:26]([NH:25][C:13]2[C:12]3[C:17](=[CH:18][CH:19]=[C:10]([C:4]4[CH:5]=[C:6]([F:9])[C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=4)[CH:11]=3)[N:16]=[CH:15][C:14]=2[C:20](=[O:24])[CH:21]([CH3:22])[CH3:23])[CH2:27][CH2:28]1
Reactant: CC(C)C(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](N)CC1

Procedure:
Following general procedure A-2, tert-butyl trans-4-[6-(3-chloro-5-fluoro-4-hydroxyphenyl)-3-isobutyrylquinolin-4-ylamino]cyclohexylcarbamate (56 mg, 0.100 mmol) was reacted with TFA (2 mL) to afford the desired product (28 mg, 61%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.96 (s, 1H), 8.31 (d, J=1.8 Hz, 1H), 7.99 (dd, J=8.7, 1.9 Hz, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.51-7.47 (m, 1H), 7.39 (dd, J=11.8, 2.3 Hz, 1H), 4.23-4.15 (m, 1H), 3.82-3.69 (m, 1H), 3.28-3.18 (m, 1H), 2.39 (d, J=12.7 Hz, 2H), 2.19 (d, J=12.0 Hz, 2H), 1.71 (q, J=10.5 Hz, 2H), 1.62-1.53 (m, 2H), 1.24 (d, J=6.8 Hz, 6H), ESI MS m/z 456[C25H27ClFN3O2+H]+; HPLC 98.1% (AUC), tR=10.69 min.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[Cl:27].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[Cl:27])[C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2[nH]1
Reactant: Clc1cccc(CBr)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2c(Br)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1Cl
Temperature: 90 °C
Reaction time: 4 h
Yield: 82.2 %

Procedure:
To the mixture of 4-(4-bromo-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine (0.8 g, 2.70 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 1-(bromomethyl)-2,3-dichlorobenzene (0.778 g, 3.24 mmol) and potassium carbonate (1.120 g, 8.10 mmol). The resulting reaction mixture was stirred at 90° C. for 4 h. It was cooled to room temperature and poured into water (100 mL). The aqueous mixture was extracted with DCM (100 mL×2). The combined organic phases were washed with Brine (100 mL) and concentrated. The crude material was purified on silica column (20˜90% EtOAc in Hexane) to give the product as solid (1.01 g, 82%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.55 (s, 3H) 3.03-3.18 (m, 4H) 3.79-3.89 (m, 4H) 5.35 (s, 2H) 6.31 (dd, J=7.83, 1.26 Hz, 1H) 6.54 (d, J=2.02 Hz, 1H) 7.08 (t, J=7.96 Hz, 1H) 7.17 (d, J=2.02 Hz, 1H) 7.45 (dd, J=8.06, 1.55 Hz, 1H); MS (ES+) m/e 453.8 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[F:18][C:19]([F:23])([F:22])[CH2:20][NH2:21].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O>[CH3:8][C:6]1[NH:5][C:4]2[C:3]([N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=2)=[C:2]([NH:21][CH2:20][C:19]([F:23])([F:22])[F:18])[N:7]=1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: NCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Cc1nc(NCC(F)(F)F)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 140 °C
Reaction time: 2.5 h
Yield: 29.8 %

Procedure:
To a mixture of 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (55.9 mg, 0.23 mmol) and 2,2,2-trifluoroethylamine (Aldrich Chemical Company) (95 μL, 1.15 mmol) was added a solution of K2CO3 (0.13 g, 0.92 mmol) in H2O (1.5 mL). This mixture was stirred at 140° C. in a closed-capped Wheaton vial for 2.5 h. After cooling, CH2Cl2 (10 mL) and H2O (10 mL) were added. The organic solution was removed and the aqueous solution was washed with CH2Cl2 (10 mL). The combined organic solutions were washed with saturated aqueous NaCl (15 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was washed with CH2Cl2 until all the color was removed. The remaining solid was recrystallized from hot MeOH to provide 21 mg (29%) of the title compound as a white solid. Mp: >310° C. MS m/z 307 (M+1), 294, 281, 226. 1H NMR (DMSO-d6; 400 MHz): δ 2.31 (s, 3), 2.52 (s, 2), 6.74 (s, 1), 7.33 (t, 1, J=7.3), 7.43 (t, 2, J=7.8), 7.92 (d, 2, J=7.3), 11.74 (s, 1), 12.22 (s, 1). HRMS: Calcd for M+H, C15H13F3N4: 307.1168. Found: 307.1160.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]2[N:7]([C:18]([O:21][CH3:22])=[N:19][N:20]=2)[C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)([CH3:3])[CH3:2].Cl.[CH3:24][NH:25][O:26][CH3:27].ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[CH3:27][O:26][N:25]([CH3:24])[C:15]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]1[C:18]([O:21][CH3:22])=[N:19][N:20]=[C:6]1[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[N:14]2)=[O:17]
Reactant: CNOC
Reactant: COc1nnc2c(NC(C)C)nc3cc(C(=O)O)ccc3n12
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1nnc2c(NC(C)C)nc3cc(C(=O)N(C)OC)ccc3n12
Temperature: 23 °C
Reaction time: 12 h

Procedure:
A mixture of 4-isopropylamino-1-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylic acid (127 mg), N,O-dimethylhydroxylamine hydrochloride (41 mg), 1-hydroxy-7-azabenzotriazole (57 mg), and EDC (81 mg) in DMF (2.0 mL) was stirred at 23° C. for 12 hrs. The solution was then diluted with EtOAc and washed sequentially with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride (2×) solutions. The organic layer was dried over sodium sulfate. The residue was purified by flash chromatography to afford 4-isopropylamino-1-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylic acid-methoxy-methyl-amide. MS (M+H)+=345.7.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][O:15][CH3:16])[N:11]([CH2:17][C:18]([N:20]2[C:28]3[CH:27]=[C:26]([C:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=4)[N:25]=[CH:24][C:23]=3[C:22]([CH3:36])([CH3:35])[CH2:21]2)=[O:19])[CH2:10][C@H:9]1[CH3:37])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][O:15][CH3:16])[N:11]([CH2:17][C:18]([N:20]2[C:28]3[CH:27]=[C:26]([CH:29]4[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]4)[N:25]=[CH:24][C:23]=3[C:22]([CH3:36])([CH3:35])[CH2:21]2)=[O:19])[CH2:10][C@H:9]1[CH3:37])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)N1CC(C)(C)c2cnc(C3=CCCCC3)cc21
Agent: [Pd]
Solvent: CCO
Product: COC[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)N1CC(C)(C)c2cnc(C3CCCCC3)cc21
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a solution of (2R,5R)-4-[2-(6-cyclohex-1-enyl-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl)-2-oxo-ethyl]-5-methoxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (see Table 1) (65 mg, 0.13 mmol) in EtOH (5 mL)was added palladium on carbon (10%, 20 mg) and the mixture was hydrogenated for 2 h. The catalyst was filtered and the filtrate evaporated to afford the title compound (60 mg, 92%) as a white solid. MS: [M+H]+=515.
Reaction SMILES: Br[CH2:2]/[C:3](/[C:11]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH2:12]1)=[C:4](/[F:10])\[C:5]([O:7]CC)=O.C(=O)([O-])O.[Na+].[C:24]1([C@@H:30]([NH2:32])[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)C>[CH2:17]([O:16][C:14]([C:11]1([C:3]2[CH2:2][N:32]([C@H:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:31])[C:5](=[O:7])[C:4]=2[F:10])[CH2:12][CH2:13]1)=[O:15])[CH3:18]
Reactant: CCOC(=O)/C(F)=C(\CBr)C1(C(=O)OCC)CC1
Reactant: C[C@H](N)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1(C2=C(F)C(=O)N([C@@H](C)c3ccccc3)C2)CC1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
To a solution of (E)-ethyl 4-bromo-3-(1-ethoxycarbonylcyclopropyl)-2-fluoro-2-butenoate (143 mmol) in ethanol (1000 ml) was added sodium hydrogencarbonate (30.08 g, 358 mmol). After adding dropwise 1-(S)-phenylethylamine (20.31 ml, 158 mmol) thereinto at room temperature, the mixture was heated under reflux for 3 hours. Then the liquid reaction mixture was cooled and filtered through celite. The filtrate was concentrated under reduced pressure and the residue was subjected to flash silica gel column chromatography (eluent:n-hexane:ethyl acetate=2:1) to obtain 36.95 g (81.2%) of the-title compound as an oily substance.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([N:22]2[CH:26]=[CH:25][CH:24]=[CH:23]2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([N:22]2[CH:26]=[CH:25][CH:24]=[CH:23]2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)n1cccc1
Agent: [Pd]
Product: CCOC(=O)C(Cc1ccc(O)cc1)n1cccc1
Yield: 95.7 %

Procedure:
In a similar manner to that described in Reference example 55(b), a reaction was carried out using ethyl 3-(4-benzyloxyphenyl)-2-(pyrrole-1-yl)propionate (1.00 g) obtained in Reference example 57(a) and palladium on carbon (5%, 0.12 g) and the reaction mixture was treated to afford the title compound (0.71 g) as a syrup.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:11][C:12]1[O:16][N:15]=[C:14]([NH2:17])[CH:13]=1.[O-]C1C=CC=CC=1.[Na+]>O1CCOCC1.C(OC(=O)C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Br:8][C:6]1[CH:7]=[C:2]([NH:17][C:14]2[CH:13]=[C:12]([CH3:11])[O:16][N:15]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: Cc1cc(N)no1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(Br)cn(C)c2=O)no1
Yield: 46.9 %

Procedure:
A solution of 3,5-dibromo-1-methyl-1H-pyridin-2-one (200 mg, 0.75 mmol) in 4 ml dioxane was placed in a microwave tube filled with argon. To this solution was added Xantphos (13 mg, 0.022 mmol), Pd2dba3 (16.8 mg, 18.3 mmol), 5-methyl-isoxazole-3-ylamine (73.6 mg, 0.75 mmol) and sodium phenoxide (127.6 mg, 1.1 mmol).The tube was sealed and heated at 150° ° C. using microwave irradiation. After cooling the reaction mixture was diluted with ethylacetate, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was triturated with ethylacetate. The resulting mixture was filtered affording 100 mg (47% yield) of 5-Bromo-1-methyl-3-(5-methyl-isoxazol-3-ylamino)-1H-pyridin-2-one which was used in the next step without additional purification.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([OH:8])[CH:7]=1.Br[CH:11]([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>>[I:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([O:9][CH:11]([CH3:13])[CH3:12])[CH:3]=1
Reactant: Oc1cc(O)cc(I)c1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(O)cc(I)c1
Temperature: 65 °C
Reaction time: 18 h
Yield: 37.8 %

Procedure:
A mixture of 5-Iodo-benzene-1,3-diol (2 g, 8 mmol), 2-bromopropane (0.88 mL, 9.3 mmol) and potassium carbonate (1.3 g, 9.3 mmol) in DMF (15 mL, 190 mmol) was stirred at 65° C. After 18 h, the mixture was cooled to RT and the solvent was evaporated. The residue was dissolved in DCM, washed with water and brine. The solvent was evaporated and the residue was purified on silica gel using an ISCO instrument and eluting with hexanes:EtOAc (4:1) to afford the title product (841 mg). MS m/z: 279 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([OH:18])=[C:16]([S:19][C:20]([F:23])([F:22])[F:21])[C:15]([C:24]([O:26][CH3:27])=[O:25])=[N:14]1.[H-].[Na+].S(OC)(O[CH3:34])(=O)=O>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([O:18][CH3:34])=[C:16]([S:19][C:20]([F:21])([F:22])[F:23])[C:15]([C:24]([O:26][CH3:27])=[O:25])=[N:14]1
Reactant: COC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(O)c1SC(F)(F)F
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(OC)c1SC(F)(F)F
Yield: 62.3 %

Procedure:
A suspension of 5.8 g (0.013 mole) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methoxycarbonyl-4-trifluoromethylsulfenyl-5-hydroxypyrazole and 0.37 g (0.015 mole) sodium hydride in 150 ml of dioxane was heated to reflux for 0.5 hr. during which time the color changed from brown to orange with evolution of gas. To the cooled mixture was added 1.94 g (0.015 mole) of dimethyl sulfate diluted in 10 ml of dioxane. The mixture was heated again to reflux for 1 hr. It was then cooled, the solids were filtered off and the filtrate was concentrated. The brown oil was taken up in dichloromethane and washed with water. The organic layer was dried and concentrated to afford 3.8 g (62.4 percent yield) of a brown oil. Purification by column chromatography using silica gel gave a solid, m.p. 97°-98° C.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]1(C)C=CC=CC=1.[CH3:18][O:19][C:20](=[O:49])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])[C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=2)=[CH:23][CH:22]=1.IC>C1COCC1.C(OCC)(=O)C>[CH3:18][O:19][C:20](=[O:49])[C:21]1[CH:22]=[CH:23][C:24]([CH2:27][C:28]([C:39]([O:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[O:40])([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=2)[CH3:11])=[CH:25][CH:26]=1
Reactant: Cc1ccccc1
Reactant: COC(=O)c1ccc(CC(C(=O)OCc2ccccc2)c2ccc(C(C)(C)C)cc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC(C)(C(=O)OCc2ccccc2)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
A solution of LiHMDS in toluene (1.0M, 1.6 mL, 1.6 mmol) was cooled in a dry-ice acetone bath (−78° C.) and diluted with 3 mL of THF. A solution of 4-[2-Benzyloxycarbonyl-2-(4-tert-butyl-phenyl)-ethyl]-benzoic acid methyl ester (675 mg, prepared as described in Bioorg. Med. Chem Lett. 2004, 14, 2047-2050) in 5 mL of THF was added via cannula. The mixture was stirred at the same temperature 30 min. It was then transferred to an acetone/ice bath, where it was warmed to ˜10° C. over a 1.5 h period. The mixture was cooled back to −78° C. and iodomethane (0.11 mL) was added via syringe. The mixture was then stirred for a 2 h period while allowing it to warm up to room temperature (approximately 2 h). The mixture was poured over a mixture of ethyl acetate and ice cold aqueous ammonium chloride. The organic phase was washed with water and saturated aqueous sodium chloride and dried over magnesium sulfate. The residue obtained after removal of the solven was treated with hexanes/ethyl acetate to cause the formation to precipitate the title compound (307 mg, 44%) HNMR (500 MHz, DMSO-d6, selected signals): 5.12 (2H, ABquartet), 3.82 (3H, s), 3.47 (1H, d, J=13.0 Hz), 3.22 (1H, d, J=13.2 Hz), 1.37 (3H, s), 1.28 (9H, s)
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])[CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[O:28][C:29]=3[CH3:30])[CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(COc2nn(Cc3ccccc3)cc2CO)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(COc2nn(Cc3ccccc3)cc2C=O)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.3 %

Procedure:
A mixture of {1-benzyl-3-({3-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1H-pyrazol-4-yl}methanol (0.70 g), activated manganese dioxide (2.0 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 15 hrs. Manganese dioxide was removed by filtration, and the filtrate was concentrated. The obtained crystals were collected by filtration to give 1-benzyl-3-({3-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1H-pyrazole-4-carbaldehyde (0.56 g, yield 78%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 131-132° C.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[CH3:4])#[N:2].CN(C)C=O.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:28][CH3:29])=[C:25]([OH:27])[CH:26]=1.C(N(C(C)C)C(C)C)C>C(Cl)(=O)C(Cl)=O.O>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([O:28][CH3:29])=[C:25]([OH:27])[CH:26]=1)=[O:11])([CH3:4])[CH3:5])#[N:2]
Reactant: COc1ccc(N)cc1O
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
To a solution (20 mL) of 3-(1-cyano-1-methylethyl)benzoic acid (4.92 g, 26.0 mmol) in oxalyl chloride was added N,N-dimethylformamide (0.1 mL), and the mixture was stirred at room temperature for 30 min. Excess reagents were evaporated under reduced pressure, and the obtained residue was dissolved in tetrahydrofuran (20 mL), and 5-amino-2-methoxyphenol (4.17 g, 30.0 mmol) and N-ethyl-N-isopropylpropane-2-amine (6.46 g, 50.0 mmol) were successively added dropwise under ice-cooling. The reaction mixture was stirred at room temperature for 18 hr, poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (5 mL)/tetrahydrofuran (5 mL), 8N aqueous sodium hydroxide solution (1 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=5:1), and triturated with diethyl ether to give the title compound (4.70 g, 58%) as a pale-yellow solid.