Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[C:11]([CH2:15][CH:16]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C@H:28]4[CH2:32][CH2:31][NH:30][CH2:29]4)=[CH:23][CH:22]=3)[C:17]([O:19]C)=[O:18])[NH:12]2)=[CH:8][CH:7]=1)(=[NH:5])[NH2:4].O.C(#N)C>Cl>[ClH:1].[ClH:1].[C:3]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[C:11]([CH2:15][CH:16]([C:21]3[CH:22]=[CH:23][C:24]([O:27][C@H:28]4[CH2:32][CH2:31][NH:30][CH2:29]4)=[CH:25][CH:26]=3)[C:17]([OH:19])=[O:18])[NH:12]2)=[CH:8][CH:7]=1)(=[NH:4])[NH2:5]
Reactant: COC(=O)C(Cc1cc2ccc(C(=N)N)cc2[nH]1)c1ccc(O[C@H]2CCNC2)cc1
Agent: Cl
Solvent: CC#N
Solvent: O
Product: N=C(N)c1ccc2cc(CC(C(=O)O)c3ccc(O[C@H]4CCNC4)cc3)[nH]c2c1
Temperature: 5 °C
Reaction time: 168 h
Yield: 148.8 %

Procedure:
1.8 g of methyl (+)-3-(6-amidino-2-indolyl)-2-[4-[((3S)-3-pyrrolidinyl)oxy]phenyl]propionate dihydrochloride was dissolved in 60 ml of concentrated hydrochloric acid, and the solution was stirred at 5° C. for 7 days. After concentrating the resulting reaction solution to dryness under a reduced pressure at a temperature of 50° C. or below, the thus obtained residue was subjected to reversed phase high performance liquid chromatography using a column packed with octadecyl-bonded silica gel and using a water/acetonitrile mixture as an elution solvent. Thereafter, thus eluted fractions of interest were pooled, mixed with dilute hydrochloric acid, and then concentrated to dryness. In this way, 1.3 g of the title compound was obtained in a solid form.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH2:12][C:13]([OH:16])([CH3:15])[CH3:14])N=N1>C(OCC)(=O)C>[CH3:1][C:2]1([CH3:17])[CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]1[CH2:12][C:13]([OH:16])([CH3:15])[CH3:14]
Reactant: CCOC(=O)C1=C(CC(C)(C)O)N=NC1(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)C1C(CC(C)(C)O)C1(C)C
Reaction time: 0.25 h
Yield: 92.9 %

Procedure:
350 mg of the product of Step D were dissolved in 100 ml of ethyl acetate and an inert gas was bubbled therethrough for 15 minutes and the solution was then irridated with a mercury vapor lamp. After 10 minutes, 33 ml of nitrogen were disengaged and the solution was evaporated to dryness to obtain 290 mg of ethyl 3,3-dimethyl-2-(2-hydroxy-2-methyl-propyl)-cyclopropane-1-carboxylate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH2:12][OH:13])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH3:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:19]([CH3:18])[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH2:12][OH:13])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(CO)(C(=O)O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CNCc1ccccc1
Product: CN(Cc1ccccc1)c1ccc(C(C)(CO)C(=O)O)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to Example 1e from 2-(4-chloro-3-nitro-phenyl)-3-hydroxy-2-methyl-propionic acid and N-methyl-benzylamine.
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)(=O)[CH3:2].[CH3:14][N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH:24][NH2:25]>CO.C(O)(=O)C>[CH3:14][N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH:24][N:25]=[C:1]([C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2]
Reactant: CC(=O)c1cc2ccccc2cn1
Reactant: Cn1c(NN)nc2ccccc21
Solvent: CC(=O)O
Solvent: CO
Product: CC(=NNc1nc2ccccc2n1C)c1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A mixture of 3-acetylisoquinoline (1.01 g, 5.9 mmol) and 1-methyl-2-hydrazinobenzimidazole (0.96 g, 5.55 mmol) in 15 ml of methanol is stirred for approximately 7 days at room temperature after the addition of 5 drops of glacial acetic acid. The reaction is monitored by means of thin layer chromatography (Polygram Sil G/UV254 prefabricated foils; eluting agent: petroleum ether:ethyl acetate (3:7)). The reaction mixture is stored over night in the freezer at approximately −20° C. The precipitate is filtered, washed with ether and dried. The product is recrystallized from a mixture of ethylacetate and petroleum ether. Yield: 1.66 g (95% of theory).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:12]([O:14][C:15](=[O:31])[CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N+]([O-])=O)[CH:23]=2)[C:18]1=[O:30])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH2:12]([O:14][C:15](=[O:31])[CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([CH3:1])[S:3][C:4]=4[CH:10]=3)[CH:23]=2)[C:18]1=[O:30])[CH3:13]
Reactant: CCOC(=O)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Reactant: Cc1nc2ccc(O)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CN1C(=O)c2ccc(Oc3ccc4nc(C)sc4c3)cc2C1=O
Temperature: 105 °C
Yield: 42.6 %

Procedure:
A mixture of 2-methyl-benzothiazol-6-ol (2.30 g, 13.92 mmol), 5-nitro-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetic acid ethyl ester (4.26 g, 15.31 mmol), potassium carbonate (2.3 g, 16.64 mmol) and dimethylacetamide (30 mL) was stirred at 105° C. for twenty hours before it was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo and the residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a yellow solid (2.35 g): MS: (+) m/z 397.19 (M+1).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][N:14]=[C:13]([NH:21][CH2:22][C:23]2[CH:24]=[N+:25]([O-:33])[CH:26]=[CH:27][C:28]=2[C:29]([F:32])([F:31])[F:30])[N:12]=1.[NH2:34][CH:35]1[C:38]([CH3:40])([CH3:39])[CH:37]([OH:41])[C:36]1([CH3:43])[CH3:42]>C(O)C>[OH:41][CH:37]1[C:38]([CH3:40])([CH3:39])[CH:35]([NH:34][C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][N:14]=[C:13]([NH:21][CH2:22][C:23]3[CH:24]=[N+:25]([O-:33])[CH:26]=[CH:27][C:28]=3[C:29]([F:32])([F:31])[F:30])[N:12]=2)[C:36]1([CH3:43])[CH3:42]
Reactant: [O-][n+]1ccc(C(F)(F)F)c(CNc2ncc(C(F)(F)F)c(Cl)n2)c1
Reactant: CC1(C)C(N)C(C)(C)C1O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C(O)C(C)(C)C1Nc1nc(NCc2c[n+]([O-])ccc2C(F)(F)F)ncc1C(F)(F)F
Temperature: 80 °C

Procedure:
DIEA (3.0 equiv.) was placed in a sealable flask with 3-(((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)-4-(trifluoromethyl)pyridine 1-oxide (1.0 equiv.), 3-amino-2,2,4,4-tetramethylcyclobutanol (2.0 equiv.)(See J. Med. Chem. 2011, 54, 7693-7704 for preparation), and ethanol. The flask was purged with nitrogen and sealed. The reaction mixture was heated to 80° C. for 9 h. Standard work-up afforded the following compounds. Stereochemistry was assigned based on similar activity as other compounds provided herein in the biochemical assays described herein.
Reaction SMILES: C(OC([N:8]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:9][CH2:10][C:11]1[NH:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O>CN(C=O)C>[C:16]1([C:13]2[N:12]=[C:11]([CH2:10][CH2:9][NH:8][C:22](=[O:23])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[N:15]([CH2:41][C:42]([F:45])([F:44])[F:43])[N:14]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N(CCc1nc(-c2ccccc2)n[nH]1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1nc(-c2ccccc2)nn1CC(F)(F)F
Reaction time: 0.33 h

Procedure:
5-[2-Bis(tert-butoxycarbonyl)aminoethyl]-3-phenyl-[1,2,4]triazole (200 mg, 515 μmol; example 22, step 1) was dissolved in DMF (3.57 mL) and potassium carbonate (157 mg, 1.14 mmol) was added at RT. The mixture was stirred for 20 min, 2,2,2-trifluoroethyl trifluoromethanesulfonate (165 mg, 710 μmol) was added and stirring was continued at RT overnight. The reaction mixture was extracted with ethyl acetate (40 mL) and washed with water (3×20 mL) and brine (1×20 mL). The aqueous layers were back-extracted with ethyl acetate (40 mL) and the combined organic layer was dried over MgSO4 and concentrated in vacuo. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as white solid (140 mg, 378 μmol, 73.4%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:18]2[CH2:26][C:25]3[C:20](=[C:21]([N+:27]([O-])=O)[CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:30])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]>C(OCC)(=O)C.[Pd]>[NH2:27][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:20]=1[C:19](=[O:30])[N:18]([C@@H:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH2:26]2
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc(N)c3C2=O)ccc1OC

Procedure:
A mixture of ethyl 2-(bromomethyl)-6-nitrobenzoate and H—CH2-CH3-Compound D, triethyl amine in DMF is heated to reflux. The solvent is removed in vacuo. The crude mixture is purified by column chromatography to give (S)-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-7-nitroisoindolin-1-one. A mixture of (S)-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-7-nitroisoindolin-1-one and Pd/C in ethyl acetate is shaken under hydrogen. The suspension is filtered thru a pad of Celite. The solvent is removed in vacuo. The crude mixture is purified by column chromatography to give (S)-7-amino-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)isoindolin-1-one.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH:5]1([CH2:11][CH2:12][CH:13]=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:5]1([CH2:11][CH2:12][CH2:13][NH:4][CH2:3][CH2:1][OH:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=CCCC1CCCCC1
Reactant: NCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: OCCNCCCC1CCCCC1
Temperature: 25 °C

Procedure:
To a solution of ethanolamine (0.44 g, 7.1 mmol) in DCM (15 mL) at 0° C. was added a solution of 3-cyclohexylpropionaldehyde (1.0 g, 7.1 mmol) in DCM (10 mL) followed by sodium triacetoxyborohydride (1.67 g, 7.86 mmol). The resulting mixture was warmed to room temperature. After 2.5 hours the desired product was observed by mass spectrometric analysis. The reaction mixture was stirred overnight, then diluted with DCM (50 mL), washed with saturated sodium bicarbonate (2×50 mL), and brine (50 mL), dried over sodium sulfate, filtered, and concentrated to give a clear oil (1.0 g) which was used in the next step without further purification. ((m/z): [M+H]+ calcd for C11H23NO, 186.20. found, 186.0).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:22][N:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1.[CH3:45][C@H:46]1[CH2:48][O:47]1.CCN(C(C)C)C(C)C>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[N:21]=[CH:22][C:23]([N:26]5[CH2:27][CH2:28][N:29]([CH2:45][C@@H:46]([OH:47])[CH3:48])[CH2:30][CH2:31]5)=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1
Reactant: C[C@H]1CO1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)cn4)cnc32)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)cn4)cnc32)cc1
Yield: 91.6 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(5-(piperazin-1-yl)pyridin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (100 mg. 0.164 mmol) was alkylated using (S)-2-methyloxirane (18 mg, 0.329 mmol), DIPEA (58 μL, 0.329 mmol) and ethanol (10 mL) to get 100 mg (91.7%) of the titled compound.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]1[O:10][C:9]2[C:11]([NH:15][C:16](=[O:30])[CH:17]=[CH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:21][CH:20]=3)=[CH:12][CH:13]=[CH:14][C:8]=2[O:7][CH2:6]1.[NH3:32]>C(O)C>[CH2:25]([C:22]1[CH:23]=[CH:24][C:19]([CH:18]=[CH:17][C:16]([NH:15][C:11]2[C:9]3[O:10][CH:5]([CH2:4][C:3]([NH2:32])=[O:2])[CH2:6][O:7][C:8]=3[CH:14]=[CH:13][CH:12]=2)=[O:30])=[CH:20][CH:21]=1)[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCc1ccc(C=CC(=O)Nc2cccc3c2OC(CC(=O)OC)CO3)cc1
Reactant: N
Solvent: CCO
Product: CCCCCc1ccc(C=CC(=O)Nc2cccc3c2OC(CC(N)=O)CO3)cc1
Reaction time: 72 h

Procedure:
8-(p-pentylcinnamoyl)amino-1,4-benzodioxane-2-acetic acid methyl ester (341 mg; synthesized in reference example 3) was dissolved into ethanol which was saturated with ammonia (20 ml). The solution was allowed to stand for 3 days at 100° C. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) to give the title compound (191 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].S(C1C=CC(C)=CC=1)(O[CH3:32])(=O)=O.C(=O)(O)[O-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:32][N:11]([CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)OCc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCc1ccccc1
Temperature: 6 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
A solution of 4-(benzyloxycarbonylaminomethyl)-1-Boc-piperidine (0.360 g, 1.03 mmol) in DMF (10 mL) was treated with sodium hydride (60%, 0.050 g, 1.25 mmol). After 0.5 h, methyl tosylate (0.18 mL, 1.20 mmol) was added and the mixture heated to 6° C. After 12 h, the mixture was poured into EtOAc and saturated aqueous sodium bicarbonate. The combined extracts were washed with water, brine and concentrated to afford 0.300 g (79%) the title compound which was used without further purification.
Reaction SMILES: N1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:11]([C:15]1[C:16](=[O:26])[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][C:19](=O)[CH:20]=1)([CH3:14])([CH3:13])[CH3:12].[NH2:27][C:28]1[CH:33]=[N:32][CH:31]=[CH:30][N:29]=1>ClC(Cl)C>[C:11]([C:15]1[C:16](=[O:26])[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][C:19](=[N:27][C:28]2[CH:33]=[N:32][CH:31]=[CH:30][N:29]=2)[CH:20]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Reactant: Nc1cnccn1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CC(C)(C)C1=CC(=Nc2cnccn2)C=C(C(C)(C)C)C1=O
Temperature: 25 °C
Yield: 58.3 %

Procedure:
A 1.62 ml quantity of pyridine was dissolved in 60 ml of dichloroethane. To the solution was added 0.89 g of aluminum chloride powder, and the mixture was refluxed with heating for 15 minutes. Then to the mixture were added 2.20 g of 2,6-di-tert-butyl-1,4-benzoquinone and 0.95 g of aminopyrazine, and the mixture was refluxed under heating for 17.5 hours. The reaction mixture was cooled to room temperature and filtered through a Celite pad and the insoluble materials were washed there with dicloromethane. The filtrate was concentrated, and the resulting crude product was purified by silica gel column chromatography (eluent: diethyl ether-hexane=3:7), giving 1.73 g of Compound 1a.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[C:12]([F:15])([F:14])[F:13].[Br:17]NC(=O)CCC(N)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[C:4]1[C:5]([C:12]([F:14])([F:13])[F:15])=[CH:6][C:7]([Cl:11])=[CH:8][C:9]=1[CH2:10][Br:17]
Reactant: NC(=O)CCC(=O)NBr
Reactant: COC(=O)c1c(C)cc(Cl)cc1C(F)(F)F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(CBr)cc(Cl)cc1C(F)(F)F

Procedure:
A mixture of 4-chloro-2-trifluoromethyl-6-methyl-benzoic acid methyl ester (1.6 g, 6.3 mmol), N-bromosuccinamide (1.23 g, 6.93 mmol), and benzoyl peroxide (0.050 g, 0.20 mmol) in carbon tetrachloride (50 mL) was heated at reflux until majority of ester was consumed (as analyzed by GC/MS). The resulting mixture was filtered and the filtrate concentrated to afforded 2-bromomethyl-4-chloro-6-trifluoromethyl-benzoic acid methyl ester. The material was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:21])[N:9](C(C)(C3C=CC=CC=3)C)[CH:10](O)[C:6]=2[CH:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>[N+](C)([O-])=O>[Br:1][C:2]1[C:7]2[C:8](=[O:21])[NH:9][CH2:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(c1ccccc1)N1C(=O)c2c(ccnc2Br)C1O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C[N+](=O)[O-]
Product: O=C1NCc2ccnc(Br)c21
Yield: 33.5 %

Procedure:
In a similar manner to Step 4 of Example 16, 4-bromo-1-hydroxy-2-(1-methyl-1-phenylethyl)-1,2-dihydropyrrolo[3,4-c]pyridine-3-one (239 mg, 0.688 mmol) was dissolved in nitromethane (12 mL), and the solution was treated with trifluoroacetic acid (1.17 mL, 15.1 mmol) and triethylsilane (0.440 mL, 2.75 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=15/1) to obtain 4-bromo-1,2-dihydropyrrolo[3,4-c]pyridine-3-one (49.1 mg, yield 34%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[C:14]1[NH:15][C:16](=[O:24])[C:17]([CH2:22][CH3:23])=[C:18]([CH2:20][CH3:21])[N:19]=1)[CH2:2][CH3:3].[CH3:25][N:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH2:31][CH2:32][NH2:33]>>[CH2:20]([C:18]1[N:19]=[C:14]([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:5]=2[O:4][CH2:1][CH2:2][CH3:3])[C:9]([NH:33][CH2:32][CH2:31][C:27]2[N:26]([CH3:25])[CH:30]=[CH:29][CH:28]=2)=[O:11])[NH:15][C:16](=[O:24])[C:17]=1[CH2:22][CH3:23])[CH3:21]
Reactant: Cn1cccc1CCN
Reactant: CCCOc1ccc(C(=O)O)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Product: CCCOc1ccc(C(=O)NCCc2cccn2C)cc1-c1nc(CC)c(CC)c(=O)[nH]1

Procedure:
According to the same manner as that of example 89, the compound of example 58 was reacted with 2-(1-methylpyrrol-2-yl)ethylamine to give the compound of example 117. 1H NMR (DMSO-d6) δ: 12.01 (1H, br), 8.50 (1H, t), 8.12 (1H, d), 7.96 (1H, dd), 7.22 (1H, d), 4.08 (2H, t), 3.28 (2H, m), 2.98 (1H, m), 2.58 (2H, q), 2.47 (2H, q), 2.25 (3H, s), 2.13 (2H, m), 1.90 (2H, m), 1.75 (2H, m), 1.64 (2H, m), 1.45 (2H, m), 1.19 (3H, t), 1.04 (3H, t), 0.96 (3H, t).
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].C(Cl)(=O)C.[CH3:17][C:18]([CH3:20])=O>>[CH3:17][C:18]1([CH3:20])[O:10][CH:9]([CH:7]2[O:8][C:2](=[O:1])[C:3]([OH:4])=[C:5]2[OH:6])[CH2:11][O:12]1
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: CC(C)=O
Solvent: CC(=O)Cl
Product: CC1(C)OCC(C2OC(=O)C(O)=C2O)O1
Reaction time: 2 h
Yield: 79 %

Procedure:
Initially, 5,6-O-isopropylidene-L-ascorbic acid (IAA) was prepared by adding L-ascorbic acid (100 gm, 0.57 mole) into a three-necked 1-liter flask equipped with a mechanical stirrer and a thermometer. The L-ascorbic acid was followed by acetone (450 ml) and acetyl chloride (12.5 ml), and the whole mixture was stirred vigorously at 30°-40° C. for 2 hours.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:20]=[CH:19][C:11]3[NH:12][C:13](=[O:18])[O:14][C:15]([CH3:17])([CH3:16])[C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>C(N(CC)CC)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][C:15]1([CH3:17])[O:14][C:13](=[O:18])[NH:12][C:11]2[CH:19]=[CH:20][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH:3]=3)=[CH:9][C:10]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cccc(Br)c3)cc21
Reactant: C#C[Si](C)(C)C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc(C#C[Si](C)(C)C)c3)cc21
Temperature: 80 °C
Yield: 91.8 %

Procedure:
A mixture of 6-(3-bromo-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.8 g, 2.4 mmol), trimethylsilylacetylene (1 g, 10 mmol), tetrakis(triphenylphosphine) palladium (0) (0.17 g, 0.24 mmol), and cuprous (I) iodide (0.05 g, 0.28 mmol) in triethyl amine (20 mL) was heated under nitrogen at 80° C. for 3 hours. The reaction mixture was cooled to rt and the solvent was removed. The residue was taken up in ethyl acetate (50 mL) and washed with 1N aqueous HCl (3×20 mL) and brine ( 20 mL). The organic layer was separated and dried (MgSO4). After removal of solvent, the residue was purified by a silica gel chromatography (hexane:ethyl acetate/3:1) to afford the title compound as a white solid (0.77 g, 92%): mp 240-242° C.; 1H-NMR (DMSO-d6) δ10.3 (s, 1H), 7.74-7.69 (m, 2H), 7.61-7.58 (m, 2H), 7.48-7.40 (m, 2H), 6.96 (d, 1H, J=7.98 Hz), 1.67 (s, 6H), 0.25 (s, 9H); MS (EI) m/z 349([M+], 50%); Anal. Calc. For C21H23NO2Si0.2 EtOAc: C, 71.32, H, 6.75, N, 3.82. Found: C, 71.08, H, 6.64, N, 3.82.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH2:13][CH3:14])[C:3]=1[C:15]([NH2:17])=[O:16].N[C:19](N)=[O:20].CC(O)=O>[OH-].[Na+]>[CH2:13]([C:4]1[C:3]2[C:15](=[O:16])[NH:17][C:19](=[O:20])[NH:1][C:2]=2[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=1)[CH3:14]
Reactant: NC(N)=O
Reactant: CCc1nn(-c2ccccc2)c(N)c1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCc1nn(-c2ccccc2)c2[nH]c(=O)[nH]c(=O)c12
Temperature: 200 °C
Reaction time: 1 h

Procedure:
Into a 100-mL 3-necked round-bottom flask, was placed 5-amino-3-ethyl-1-phenyl-1H-pyrazole-4-carboxamide (1 g, 4.35 mmol, 1.00 equiv) at room temperature. To the resulting mixture was then added urea (1.75 g, 29.17 mmol, 6.70 equiv), in portions at room temperature. The resulting solution was stirred for 1 h at 200° C. The resulting mixture was then cooled to room temperature. The residue was dissolved in sodium hydroxide (250 mL). The pH value of the solution was adjusted to about 5 with AcOH (conc.). The solids were collected by filtration to yield 3-ethyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione as a white solid. MS (m/z): 257 [MH+].
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10]Br)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:12][C:13]1[CH:14]=[C:15]([OH:34])[CH:16]=[CH:17][C:18]=1[CH:19]([CH3:33])[C:20]([OH:32])([C:25]1[CH:30]=[N:29][C:28]([CH3:31])=[CH:27][N:26]=1)[C:21]([F:24])([F:23])[F:22]>>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][CH2:10][O:34][C:15]1[CH:16]=[CH:17][C:18]([CH:19]([CH3:33])[C:20]([OH:32])([C:25]2[CH:30]=[N:29][C:28]([CH3:31])=[CH:27][N:26]=2)[C:21]([F:22])([F:23])[F:24])=[C:13]([Cl:12])[CH:14]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: Cc1cnc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn1
Reactant: CC(C)(C)OC(=O)NCCBr
Product: Cc1cnc(C(O)(C(C)c2ccc(OCCNC(=O)OC(C)(C)C)cc2Cl)C(F)(F)F)cn1

Procedure:
The title compound was prepared in analogy to Example 74 from 2-(BOC-amino)ethyl bromide and 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenol (Example 72). MS (m/e)=489.9 (MH+).