Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][O:7][C:8]2[CH:13]=[N:12][NH:11][C:10](=[O:14])[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:17][O:18][C:19](=[O:28])[CH:20](Br)[CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>O1CCCC1>[CH3:17][O:18][C:19](=[O:28])[CH:20]([N:11]1[C:10](=[O:14])[CH:9]=[C:8]([O:7][CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:13]=[N:12]1)[CH2:21][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: O=c1cc(OCC2CCCC2)cn[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)n1ncc(OCC2CCCC2)cc1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 80.7 %

Procedure:
A solution of 5-cyclopentylmethoxy-2H-pyridazin-3-one (494.8 mg, 2.54 mmol) in tetrahydrofuran (12 mL, 0.21 M) cooled to 0° C. was treated with a 60% suspension of sodium hydride in mineral oil (0.12 g, 3.0 mmol). The reaction stirred at 0° C. for 5 min and then at 25° C. for an additional 30 min. After this time, the reaction was treated with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10, 0.67 g, 2.84 mmol). The reaction was then warmed to 50° C., where it stirred overnight. The reaction sat at 25° C. for 2 d. After this time, the reaction was partitioned between water (75 mL) and methylene chloride (3×75 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×75 mL), dried over magnesium sulfate, filtered, rinsed and concentrated in vacuo. Silica gel column chromatography (AnaLogix 40 g, 10-30% ethyl acetate/hexanes) afforded 3-cyclopentyl-2-(4-cyclopentylmethoxy-6-oxo-6H-pyridazin-1-yl)-propionic acid methyl ester (713.9 mg, 80%) as a clear light yellow oil; ES+-HRMS m/e calcd for C19H28N2O4 [M+H+] 349.2122, found 349.2120. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18 (m, 2H), 1.23-1.82 (m, 15H), 1.87-1.98 (m, 1H), 2.05-2.23 (m, 1H), 2.23-2.37 (m, 1H), 3.61 (s, 3H), 3.91 (d, J=7.0 Hz, 2H), 5.39 (dd, J=10.9, 4.3 Hz, 1H), 6.31 (d, J=2.8 Hz, 1H), 7.83 (d, J=2.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.[C:21]1(=[O:26])[CH2:25][CH2:24][CH:23]=[CH:22]1>CO.O>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:22]2[C:21](=[O:26])[CH2:25][CH2:24][CH:23]=2)=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][N:9]=1
Reactant: O=C1C=CCC1
Reactant: O=Cc1cc(-c2ccccc2)cnc1Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CO
Product: O=C1CCC=C1C(O)c1cc(-c2ccccc2)cnc1Cl
Yield: 95 %

Procedure:
The clear solution of 2-Chloro-5-phenylnicotinaldehyde (10 mmol, 2.17 g) and imidazole (10 mmol) in 50 ml. of MeOH was slowly charged with 50 ml. of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclopenten-1-one (10.2 mmol., 0.88 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 95% yield (2.84 g).
Reaction SMILES: [N:1]1([C:7]2[S:8][CH:9]=[C:10]([Sn](C)(C)C)[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:16]C1SC=C(Br)N=1.O>N1CCCCC1>[N:1]1([C:7]2[S:8][CH:9]=[C:10]([Br:16])[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Sn](C)(C)c1csc(N2CCCCC2)n1
Reactant: Brc1csc(Br)n1
Solvent: O
Solvent: C1CCNCC1
Product: Brc1csc(N2CCCCC2)n1
Temperature: 50 °C
Yield: 100 %

Procedure:
Synthesis of 2-Piperidinyl-4-(trimethylstannyl)thiazole 373 as illustrated in FIG. 53. 2,4-Dibromothiazole (358; 1.0 equiv) was dissolved in piperidine (0.5 M) and the reaction was warmed to 50° C. for 8 h, upon which completion of the reaction was indicated by TLC. The mixture was poured into water and extracted with ether (2×). Drying (MgSO4) and evaporation of the solvents gave 2-piperidinyl-4-bromothiazole 372, which was isolated after flash column chromatography (silica gel, 5% EtOAc in hexanes) in 100% yield.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][CH:4]=1)=[O:2].[Cl-].[C:16]1([CH2:22][CH2:23][CH2:24][CH2:25][O:26][NH3+:27])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:6](=[N:27][O:26][CH2:25][CH2:24][CH2:23][CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][CH:4]=1)=[O:2]
Reactant: [NH3+]OCCCCc1ccccc1
Reactant: O=Cc1cccc(-c2ccccn2)n1
Agent: [Cl-]
Product: O=CC1=CCC(=NOCCCCc2ccccc2)C(c2ccccn2)=N1

Procedure:
If 6-formyl-2,2'-bipyridine is used instead of 4-formyl-2-(2-pyridyl)-pyrimidine and O-phenylbutylhydroxylammonium chloride instead of hydroxylammonium chloride, 6-formyl-O-4-phenylbutyloximino-2,2'-bipyridine (compound 105c) is obtained in a corresponding manner.
Reaction SMILES: C(O)(=O)CO.[Br:6][CH2:7][C:8]([OH:10])=[O:9].[O:11]1[CH:15]=[CH:14][CH2:13][CH2:12]1>>[O:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[O:9][C:8](=[O:10])[CH2:7][Br:6]
Reactant: C1=COCC1
Reactant: O=C(O)CBr
Agent: O=C(O)CO
Product: O=C(CBr)OC1CCCO1

Procedure:
The glycolic acid derivative is obtained by reacting 6.95 g (0.05 mol) of bromoacetic acid and 2.80 g (0.4 mol) of 2,3-dihydrofuran at room temperature in the absence of moisture, and stirring the mixture after 5 hours (bromoacetic acid is converted quantitatively). This reaction solution was employed in the following synthesis step, without isolation. The glycolic acid derivative has the formula: ##STR6##
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[C:21]4[C:16](=[N:17][CH:18]=[C:19]([C:22]5[CH:27]=[CH:26][C:25]([CH:28]6[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]6)=[CH:24][CH:23]=5)[CH:20]=4)[NH:15][CH:14]=3)[CH:10]=[N:9]2)=[CH:3][CH:2]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:31]1[CH2:32][CH2:33][CH:28]([C:25]2[CH:24]=[CH:23][C:22]([C:19]3[CH:20]=[C:21]4[C:13]([C:11]5[CH:10]=[N:9][N:8]([CH2:7][C:4]6[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=6)[CH:12]=5)=[CH:14][NH:15][C:16]4=[N:17][CH:18]=3)=[CH:27][CH:26]=2)[CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6ccncc6)c5)c4c3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc(Cn2cc(-c3c[nH]c4ncc(-c5ccc(C6CCNCC6)cc5)cc34)cn2)ccn1
Yield: 14.4 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (120 mg, 0.224 mmol) was deprotected in TFA/DCM (5/5 ml) to afford 14 mg (14.3% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.78-8.76 (d, 2H), 8.53-8.51 (t, 2H), 8.35 (s, 1H), 8.07 (s, 1H), 7.75-7.70 (m, 5H), 7.43-7.41 (d, 2H), 5.78 (s, 2H), 3.55-3.51 (d, 2H), 3.21-3.13 (td, 2H), 3.03-2.95 (m, 1H), 2.03-1.90 (m, 2H). MS: m/z=435.6 (M+1), HPLC: 99.16% in method A.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH2:28][CH2:29][OH:30])[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][N:20]3[C:23](=[O:26])[CH2:24][CH2:25][CH:19]3[CH2:18]1)[N:13]=[C:12]([CH3:27])[N:11]=2.[CH3:31]I.[H-].[Na+].Cl>C(OCC)(=O)C.O.CN(C=O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH2:28][CH2:29][O:30][CH3:31])[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][N:20]3[C:23](=[O:26])[CH2:24][CH2:25][CH:19]3[CH2:18]1)[N:13]=[C:12]([CH3:27])[N:11]=2
Reactant: Cc1nc(N2CCN3C(=O)CCC3C2)c2nc(-c3ccccc3Cl)n(CCO)c2n1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCn1c(-c2ccccc2Cl)nc2c(N3CCN4C(=O)CCC4C3)nc(C)nc21
Reaction time: 2 h

Procedure:
Charge a 100 mL flask with 2-[8-(2-chlorophenyl)-9-(2-hydroxyethyl)-2-methyl-purin-6-yl]-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-6-one, Isomer-2 [C09111070-E] (3.3 g, 7.73 mmol) and DMF (35 mL) followed by methyl iodide (1.24 g, 8.50 mmol). Add 60% NaH (0.59 g, 13.9 mmol) in portions at 10-25° C. and stir for 2 h. Pour the mixture into water (100 mL) while stirring and extract the solution with ethyl acetate (3×50 mL). Combine the organic layers, wash with water (2×50 mL), and concentrate under vacuum to give an oil. Purify the crude by silica gel (100 g) column chromatography eluting with dichloromethane/methanol (50:1) to give a yellow solid. Redissolve the solid in ethyl acetate (40 mL) and add a solution of 1 N HCl in ethyl acetate slowly until a solid precipitates. Stir at room temperature for 2 h, filter the cake, and wash with ethyl acetate (10 mL). Dry the cake under vacuum to give 2.8 g of the title compound as an off-white solid (98.0% ee); ES/MS m/z 441.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][O:21][C:22]3[NH:23][CH:24]=[C:25]([CH2:29][CH3:30])[C:26](=[O:28])[N:27]=3)=[CH:15][CH:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:31]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][O:21][C:22]3[N:23]([CH3:31])[CH:24]=[C:25]([CH2:29][CH3:30])[C:26](=[O:28])[N:27]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCc1c[nH]c(OCCc2ccc(Oc3cc(Cl)cc(C(F)(F)F)c3)cc2)nc1=O
Solvent: CI
Solvent: ClCCl
Product: CCc1cn(C)c(OCCc2ccc(Oc3cc(Cl)cc(C(F)(F)F)c3)cc2)nc1=O
Yield: 14 %

Procedure:
The same procedure as E141 from 2-{[2-(4-{[3-chloro-5-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-5-ethyl-4(1H)-pyrimidinone (100 mg, 0.228 mmol), DIPEA (0.099 mL, 0.570 mmol) and MeI (0.028 mL, 0.456 mmol) in DCM (2 mL), except that the reaction time was 3 h, to afford the title compound (18 mg, 0.032 mmol, 13.93% yield). LCMS: rt=3.68 min, [M+H]=453
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH2:21][CH:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].FC(F)(F)C(O)=O.[Cl-].CO.CO>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH2:21][CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Fc1ccc(Nc2ncnc3cnc(NCC4CCNCC4)nc23)cc1Cl

Procedure:
Prepared from 4-[(3-chloro-4-fluorophenyl)amino]-6-[(1-tert-butyloxycarbonyl-4-piperidinyl)methylamino]pyrimido[5,4-d]pyrimidine by reaction with trifluoroacetic acid. Melting point: 204°-206° C.; Rf : 0.42 (alumina; methanol chloride/methanol=10:1)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:23](Br)[CH:24]=[CH2:25]>CN(C=O)C>[CH2:25]([O:20][CH:17]1[CH2:16][CH2:15][CH:14]([CH2:13][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:10]([OH:12])=[O:11])[CH2:19][CH2:18]1)[CH:24]=[CH2:23]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCC(O)CC1)C(=O)O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC1CCC(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5.42 g (18.86 mmol) of (S)-2-tert-butoxycarbonylamino-3-(4-hydroxy-cyclohexyl)propionic acid in 20 ml of DMF was added dropwise over the course of 30 min to a suspension of 1.89 g (47.14 mmol) of 60% sodium hydride in 20 ml of DMF at 0° C. Then 2.28 g (18.86 mmol) of allyl bromide were added, and the mixture was warmed to RT and then stirred for 3 h. It was cautiously quenched with water and concentrated. The residue was dissolved in water and washed with ethyl acetate. The aqueous phase was adjusted to pH 2 with 6M HCl and extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered and concentrated. The title compound obtained in this way was reacted further without further purification.
Reaction SMILES: [N:1]([C:4](=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-]>C1(C)C=CC=CC=1>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH:1]2
Reactant: CCOC(=O)C(=Cc1ccccc1OC)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2c(OC)cccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-azido-3-(2-methoxyphenyl)propenoate (3.566 g, 144 mmol) was suspended in toluene (800 ml) and the mixture was refluxed for three hours, then cooled and stirred at room temperature overnight. The ethyl 4-methoxyindole-2-carboxylate formed as a yellow solid and was collected.
Reaction SMILES: [S:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11]C(=O)C)=[CH:7][N:6]=1)(=[O:4])(=[O:3])[NH2:2]>[OH-].[Na+]>[S:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: CC(=O)Nc1ccc(S(N)(=O)=O)nc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(S(N)(=O)=O)nc1
Temperature: 25 °C
Yield: 70 %

Procedure:
N-(6-Mercapto-pyridin-3-yl)-acetamide (30 g, 17.3 mmol) was dissolved in cold concentrated hydrochloric acid solution (225 ml), followed by the addition of ice water (50 ml). Chlorine was bubbled into solution, and the temperature was kept below 10° C. The solution became dark brown first, and the chlorination was complete after 3 hours when the temperature no longer rose and the color of the solution lightened. The reaction was diluted with ice and water (1.2 kg) while keeping the temperature below 10° C. The product, 5-acetylamino-pyridine-2-sulfo chloride, was collected by filtration and air-dried. This was then suspended in chloroform (CHCl3) (200 mL), followed by the addition of 30% ammonia solution (100 ml), and the resulting reaction mixture was stirred for 2 hours. The solvent was removed in vacuo to give a black solid, 2-sulfamyl-5-acetylamino-pyridine. 2-Sulfamyl-5-acetylamino-pyridine was dissolved in 0.85 N NaOH solution (500 ml), and the resulting solution was stirred at refluxing temperature for 3.5 hours. After cooled down to room temperature, the reaction mixture was extracted with 3:1 of CHCl3/MeOH solution (3×200 ml). The aqueous layer was neutralized to pH 7, and water was removed in vacuo to give the crude product, which was recrystallized from water to afford the title compound (21.6 g, 70%).
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[CH:29][C:30]#[N:31])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:29]=[C:30]([NH2:31])[N:12]3[N:13]=[C:14]([C:16]4[O:17][CH:18]=[CH:19][CH:20]=4)[N:15]=[C:11]3[CH:10]=2)=[CH:26][CH:27]=1
Reactant: N#CC=Cc1ccc(F)cc1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccco2)n1)c1ccccc1
Product: Nc1cc(-c2ccc(F)cc2)cc2nc(-c3ccco3)nn12

Procedure:
The title compound, MS m/e (%): 295 (M+H+, 100), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-furan-2-yl-1H-[1,2,4]triazole and 3-(4-fluoro-phenyl)-acrylonitrile.
Reaction SMILES: Cl.O[CH2:3][C:4]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][N:6](C)[N:5]=1.NC(N)=S.C(=O)([O-])[O-].[K+].[K+].[CH3:24][S:25]([C:28]1[CH2:32][C:31]([CH3:34])([CH3:33])[O:30][N:29]=1)(=O)=O>O1CCOCC1.O>[CH3:33][C:31]1([CH3:34])[O:30][N:29]=[C:28]([SH:25]([CH2:3][C:4]2[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][NH:6][N:5]=2)[CH3:24])[CH2:32]1
Reactant: CC1(C)CC(S(C)(=O)=O)=NO1
Reactant: Cn1cc(C(F)(F)F)c(CO)n1
Agent: Cl
Agent: NC(N)=S
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: C[SH](Cc1n[nH]cc1C(F)(F)F)C1=NOC(C)(C)C1
Temperature: 130 °C
Yield: 10.1 %

Procedure:
Concentrated hydrochloric acid (36% by weight) (3.0 ml, 36 mmol) was added to a solution of 3-hydroxymethyl-1-methyl-4-trifluoromethyl-1H-pyrazole (1.34 g, 7.4 mmol) and thiourea (836 mg, 11 mmol) in 1,4-dioxane (5 ml) and water (2 ml). The mixture was heated in a sealed vessel in the microwave at 130° C. for 10 minutes, cooled to room temperature and potassium carbonate (4.14 g, 30 mmol) dissolved in water (5 ml) was added. 3-Methanesulfonyl-5,5-dimethyl-4,5-dihydroisoxazole (2.12 g, 12 mmol) and 1,4-dioxane (5 ml) were added and the mixture was heated in a sealed vessel in the microwave at 150° C. for 30 minutes. More potassium carbonate (1.38 g, 10 mmol) was added and the mixture was heated in a sealed vessel in the microwave at 150° C. for 20 minutes. The mixture was cooled to room temperature, extracted with ethyl acetate (3×50 ml), the extract dried over magnesium sulfate and concentrated. The residue was purified using preparative HPLC on silica gel (eluent: dichloromethane/ethyl acetate) to give the product as a white solid (220 mg, 10% yield). 1H-NMR (400 MHz, CDCl3): 1.42 (6H, s, Me), 2.84 (2H, s, CH2), 3.89 (3H, s, Me), 4.36 (2H, s, CH2), 7.60 (1H, s, CH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[C:11]([O:13]CC)=[O:12])=[CH:5][C:4]=1[NH:17][C:18](=[O:24])[C:19]([O:21]CC)=[O:20].Cl>[OH-].[Na+].O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[C:11]([OH:13])=[O:12])=[CH:5][C:4]=1[NH:17][C:18](=[O:24])[C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)C(=O)Nc1ccc(OC)c(NC(=O)C(=O)OCC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(NC(=O)C(=O)O)cc1NC(=O)C(=O)O

Procedure:
Diethyl 4-methoxy-N,N'-(m-phenylene)dioxamate (1.0 gm., 0.0029 mole) is stirred in 1.0 N NaOH (10 ml.) at room temperature for one hour, then heated at reflux for thirty minutes. The reaction mixture is diluted with water (25 ml.) and the pH adjusted to 3 with hydrochloric acid. The resulting solid is collected and washed with acetone (0.72 gm., 86%, m.p. >320° ).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].CCN(C(C)C)C(C)C.C(=O)([O-])[O-].[K+].[K+].[Br:41][CH:42]([CH2:45][CH3:46])[CH2:43][CH3:44]>C(#N)C.CN(C=O)C.CO.CS(C)=O>[Br:41][CH:42]([CH2:45][CH3:46])[CH2:43][CH3:44].[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH:42]([CH2:45][CH3:46])[CH2:43][CH3:44])[CH2:18]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCNC3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(Br)CC
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCCN(C(CC)CC)C3)c2n1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A solution of 3-bromopentane was prepared by dissolving 1 mmole in acetonitrile (1 ml). A portion of this solution (0.12 ml, equivalent to 0.12 mmol) was added to a test tube. 2-(Butyloxy)-8-(methyloxy)-9-[2-(3-piperidinyl)ethyl]-9H-purin-6-amine (435 mg, 1.2 mmol) was dissolved in DMF (6.0 ml) and an aliquot (0.5 ml, 0.1 mmol) dispensed to the tube. DIPEA (40 μL, 0.23 mmol) and potassium carbonate (46 mg, 0.3 mmol) added, and heated to 50° C. for 18 hr. An additional aliquot of 3-bromopentane in acetonitrile (80 uL, 0.08 mmol) (total added 0.2 mmol) and DIPEA (40 uL, 0.23 mmol) was added and continued stirring with heat at 50° C. for a further 18 hours. DMSO:MeOH (200 uL) was added, the mixture filtered and purified by Mass Directed AutoPrep (Method A). The solvent was evaporated in vacuo using the Genevac. The residue was redissolved in a solution of 4M HCl/dioxane (0.2 ml) and allowed to stand at room temperature for 4 hours. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus. The material was redissolved in methanol (0.5 ml) and applied to an aminopropyl SPE (0.1 g, 3 ml, preconditioned in methanol (1.5 ml)). The product was eluted with additional methanol (1.5 ml). The solvent was removed to give the title compound (6 mg).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[CH2:8][CH2:7]1)=[O:4].CN(C=O)C.C(N(CC)CC)C.C(O)=O>CCOC(C)=O>[F:1][C:2]([F:17])([F:18])[C:3]([NH:5][C@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]([OH:16])[CH2:8][CH2:7]1)=[O:4]
Reactant: O=C1CC[C@@H](NC(=O)C(F)(F)F)c2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O=CO
Product: O=C(N[C@@H]1CC[C@@H](O)c2ccccc21)C(F)(F)F
Temperature: 25 °C
Reaction time: 7 h
Yield: 82.5 %

Procedure:
Purge a 100 ml round bottom flask containing 0.50 g (1.95 mmol) of (R)-2,2,2-trifluoro-N-(4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide and 0.062 g (0.098 mmol) RuCl[(R,R)-Tsdpen(p-cymene)] with argon (catalyst prepared using procedure from Org Syn, Vol 82, pg 10-17, note 5). Add 25 ml of dry DMF by syringe and stir. To this solution was added a mixture of 0.43 ml (3.11 mmol) of triethylamine and 0.12 ml (3.11 mmol) of HCOOH. The reaction mixture was stirred at 50° C. overnight. To complete the reaction, additional RuCl[(R,R)-Tsdpen(p-cymene)] (0.062 g), triethylamine (0.43 ml) and HCOOH (0.12 ml) were added and stirring continued at 50° C. for an additional 6-8 hr. The reaction mixture was cooled to room temp, then diluted with 150 ml EtOAc, and washed with 20 ml distilled water. The organic phase was dried over MgSO4 and concentrated in vacuo, and purified by column chromatography (eluting with 1% MeOH in DCM), to give 0.417 g (83%) of the titled compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[Cl:23])[C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].Cl>C(O)C.O>[C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:21])([F:22])[F:20])=[CH:14][C:13]=2[Cl:23])[C:10]=1[CH3:11])([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(C(=O)O)cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 93.8 %

Procedure:
By the method of Example 5, Step B, 137.4 g (0.374 mole) of 4-ethoxycarbonyl-5-methyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole dissolved in 767 mL of ethanol was reacted with 23.6 g (0.59 mole) of sodium hydroxide dissolved in 413 mL of water. After being neutralized with 180 mL of 10% hydrochloric acid, this reaction yielded 119 g of 4-carboxy-5-methyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole. The nmr spectrum of this solid was consistent with the proposed structure.
Reaction SMILES: C(O)(=O)C1C=CC=CC=1.C(O[C:15]([NH:17][C:18]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[CH:25][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=O)(C)(C)C.[H-].[Na+].[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42]1[CH:49]=[CH:48][C:45](CBr)=[CH:44][CH:43]=1)#[N:35]>O1CCCC1.FC(F)(F)C(O)=O.C(Cl)Cl.[I-].[K+]>[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42]1[CH:49]=[CH:48][C:45]([CH2:15][NH:17][C:18]2[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[CH:25][C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:44][CH:43]=1)#[N:35]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCOC(=O)c1cccc([N+](=O)[O-])c1NC(=O)OC(C)(C)C
Agent: O=C(O)c1ccccc1
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cccc([N+](=O)[O-])c1NCc1ccc(-c2ccccc2C#N)cc1
Yield: 119 %

Procedure:
To a solution of ethyl 2-t-butoxycarbonylamino-3-nitrobenzoate benzoate (20 g) in tetrahydrofuran (50 ml) was added, while stirring under ice-cooling, sodium hydride (60% dispersion in mineral oil, 2.8 g). The mixture was stirred at room temperature for 20 minutes and to the mixture were then added 4-(2-cyanophenyl)benzyl bromide (18 g) and potassium iodide (360 mg), followed by heating for 10 hours under reflux. The solvent was evaporated to dryness and the residue was partitioned between water (250 ml) and ether (200 ml). The organic layer was washed with water, dried and concentrated to give a yellow syrup. The syrup was dissolved in a mixture of trifluoroacetic acid (60 ml) and methylene chloride (40 ml) and the solution was stirred for one hour at room temperature. The reaction mixture was concentrated to dryness and to the residue was added ethyl ether (200 ml) to give crystals. The crystals were collected by filtration, washed with ether to give pale yellow crystals (22.1 g, 85%), m.p. 118°-119° C.