Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([S:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])[N:8](COC(=O)[C@H](C3C=CC=CC=3)O)[C:7]=2[CH:36]=1.[OH-].[Na+].C(OC)=O>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:10][C:9]([S:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])=[N:8][C:7]=2[CH:36]=1
Reactant: COc1ccc2nc(S(=O)Cc3ncc(C)c(OC)c3C)n(COC(=O)[C@@H](O)c3ccccc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: COC=O
Solvent: O
Product: COc1ccc2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Yield: 81 %

Procedure:
0.76 g (1.5 mmol) of the more hydrophilic diastereomer of 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1-[(S)-mandeloyloxymethyl]-1H-benzimidazole was dissolved in 50 ml methanol. A solution of 0.12 mg (3.0 mmol) sodium hydroxide in 1.5 ml water was added, and after 10 minutes the mixture was evaporated on a rotavapor. The residue was partitioned between 25 ml water and 25 ml dichloromethane. The organic solution was extracted with 25 ml water and to the combined aqueous solutions was added 200 μl (3.2 mmol) methyl formate. After 15 minutes the mixture was extracted with 3×25 ml dichloromethane. The organic solution was dried over Na2SO4 and then evaporated. There was obtained 0.42 g (81%) of the title compound as a colorless syrup. The optical purity (e.e.) which was analyzed by chiral column chromatography was 98%. [α]D20 =+157° (c=0.5%, chloroform).
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[CH3:21][C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[C:26](B1OC(C)(C)C(C)(C)O1)[CH:25]=2.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.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>[CH3:16][N:12]([CH:13]([CH3:15])[CH3:14])[C:11]1[C:2]([C:27]2[CH:28]=[C:29]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22]([CH3:21])=[CH:30]3)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: Cc1cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2[nH]1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]c(C)cc4c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To a solution of methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (200 mg, 0.68 mmol) in DME (5.0 mL) and water (2 drops) was added 2-methyl-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (352 mg, 1.37 mmol), Pd(PPh3)4 (39 mg, 0.03 mmol), and K2CO3 (189 mg, 1.37 mmol) with stirring for 1 hour at 90° C. under atmosphere of nitrogen. The resulting mixture was concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (1% ethyl acetate in petroleum ether) to give methyl 3-[methyl(propan-2-yl)amino]-2-(2-methyl-1H-indol-5-yl)quinoxaline-6-carboxylate as a light yellow solid (180 mg, 68%).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:21])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:3][CH2:4][OH:5].[Cr](O)(O)(=O)=[O:23].S(OS([O-])=O)([O-])=O.[Na+].[Na+]>CC(C)=O.C(O)(=O)C.O>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:21])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:3][C:4]([OH:23])=[O:5]
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCO
Reactant: O=[Cr](=O)(O)O
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
3,7,11,15-Tetramethyl-hexadecan-1-ol (8.96 g, 30.0 mmol) was dissolved in a mixed solvent of acetone (360 ml) and acetic acid (180 ml), a solution of anhydrous chromic acid (7.27 g, 72.7 mmol) in water (9.0 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hr. A solution of sodium disulfite (100 g, 526 mmol) in water (450 ml) was added to the reaction mixture after completion of the reaction, the mixture was stirred at room temperature overnight and extracted 6 times with diethyl ether (135 ml). The solvent of the obtained organic layer was evaporated under reduced pressure. Diethylether (450 ml) and water (150 ml) were added to the oil after concentration to allow partitioning, and the aqueous layer was extracted 3 times with ethyl acetate (150 ml). The combined organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The oil (10.1 g) after concentration was purified by chromatography (silica gel; 250 g, eluate; 50:1→3:1 hexane-ethyl acetate) to give the title compound (6.78 g, 72.3%) as a pale-blue oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N+:5]([C:8]1[C:13]2[NH:14][C:15]([CH2:24][NH2:25])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:16][O:17][C:12]=2[CH:11]=[CH:10][CH:9]=1)([O-:7])=[O:6]>C(Cl)Cl.C(N(CC)C(C)C)(C)C>[N+:5]([C:8]1[C:13]2[NH:14][C:15]([CH2:24][NH:25][C:1](=[O:3])[CH3:2])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:16][O:17][C:12]=2[CH:11]=[CH:10][CH:9]=1)([O-:7])=[O:6]
Reactant: CC(=O)Cl
Reactant: NCC1(c2ccccn2)COc2cccc([N+](=O)[O-])c2N1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCC1(c2ccccn2)COc2cccc([N+](=O)[O-])c2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
Acetyl chloride (15 μL, 0.21 mmol) was added to a mixture of 1-(5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-3-yl)methanamine (50 mg, 0.2 mmol) in methylene chloride (3 mL), N,N-diisopropylethylamine (60 μL) and was stirred at room temperature for 1 h. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude N-[(5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-3-yl)methyl]acetamide (0.040 g. 70%). LCMS calculated for C16H17N4O4 (M+H)+: m/z=329.1. found: 329.0.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1)#[N:13].S(Cl)(Cl)(=O)=O>>[C:12]([C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:13][CH:12]([C:11]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[CH:9][CH:10]=2)[CH:14]([CH2:19][CH3:18])[CH2:15][CH3:16])(=[O:22])=[O:21])=[CH:16][CH:15]=1)#[N:13]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccc(-n2cccn2)cc1
Solvent: O=S(=O)(Cl)Cl
Product: CCC(CC)C(NS(=O)(=O)c1ccc(C#N)cc1)c1ccnn1-c1ccccc1

Procedure:
This compound was prepared using the method described in example 10, but 1-phenyl-1H-pyrazole was used as the starting material in step 10B and 4-cyanobenzenesulfonyl chloride was used as the sulfonyl chloride in step IOE. mp 134.6-136.6° C.; Mass Spectrum (−ES): 407.1 (M−H)−.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C@H:17]1[C@H:22]([OH:23])[CH2:21][CH2:20][CH2:19][O:18]1.[Cr](Cl)(O)(=O)=O.N1C=CC=CC=1.C([O-])(=O)C.[Na+].C(OCC)C>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH:17]1[C:22](=[O:23])[CH2:21][CH2:20][CH2:19][O:18]1
Reactant: O[C@@H]1CCCO[C@H]1COCCCCCCCOC1CCCCO1
Agent: O=[Cr](=O)(O)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C1CCCOC1COCCCCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2.387 g of dl-trans-2-[7-(tetrahydropyran-2-yloxy)heptyloxymethyl]tetrahydropyran-3-ol (prepared as described in Preparation 54) in 10 ml of methylene chloride was added all at once to a mixture of 2.33 g of pyridine chlorochromate, 1.78 g of sodium acetate and 10 ml of methylene chloride. The mixture was then stirred at room temperature for 3 hours, after which it was mixed with 30 ml of diethyl ether, and the solution was passed through a chromatography column containing 50 g of silica gel. The column was then washed with diethyl ether and the eluate was combined with the washings and then concentrated by evaporation under reduced pressure. The oily residue (2.24 g) was subjected to column chromatography through 60 g of silica gel. 1.786 g of the title compound was obtained, as an oil, from those fractions eluted with mixtures of hexane and ethyl acetate ranging from 3:1 to 2:1 by volume.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:24]=[C:11]3[N:12]=[C:13]([CH3:23])[C:14]([C@H:17]([OH:22])[C:18]([O:20][CH3:21])=[O:19])=[C:15]([Cl:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25](OC(=O)C)([CH3:28])([CH3:27])[CH3:26].Cl(O)(=O)(=O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:24]=[C:11]3[N:12]=[C:13]([CH3:23])[C:14]([C@H:17]([O:22][C:25]([CH3:28])([CH3:27])[CH3:26])[C:18]([O:20][CH3:21])=[O:19])=[C:15]([Cl:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](O)c1c(C)nc2cc(-c3cccc(Br)c3)nn2c1Cl
Reactant: CC(=O)OC(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Br)c3)nn2c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.3 %

Procedure:
A mixture of (S)-methyl 2-(2-(3-bromophenyl)-7-chloro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (7.81 g, 19.02 mmol), t-butylacetate (160 mL) in DCM (330 mL) was added perchloric acid (3.43 mL, 57.1 mmol) and the mixture was stirred at rt for 3 h. It was then quenched with sat.aq.NaHCO3 (adjusted to pH=7-8 by the addition of solid NaHCO3). This mixture was diluted with EtOAc and the organic phase was washed with water. The organic phase was dried (MgSO4), filtered, and concentrated in vacuo to obtain ˜7 g of crude product as an oil. Filtration through 70 g of silica gel eluting with CH2Cl2 gave (S)-methyl 2-(2-(3-bromophenyl)-7-chloro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (5.71 g, 12.23 mmol, 64.3% yield). 1H NMR (400 MHz, CDCl3) δ 8.20 (t, J=1.6 Hz, 1H), 7.95 (dt, J=7.8, 1.1 Hz, 1H), 7.63-7.53 (m, 1H), 7.37 (t, J=7.9 Hz, 1H), 6.94 (s, 1H), 5.69 (s, 1H), 3.76 (s, 3H), 2.70 (s, 3H), 1.30 (s, 9H). LCMS (M+H)=466 and 468.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[C:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H].CCCCC>CO.[Pd]>[C:1]1([CH:7]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)[CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: FC(F)(F)c1ccc(C(=C2CCCNC2)c2ccccc2)cc1
Agent: [Pd]
Solvent: CCCCC
Solvent: CO
Product: FC(F)(F)c1ccc(C(c2ccccc2)C2CCCNC2)cc1
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To a solution of 3-(phenyl(4-(trifluoromethyl)phenyl)methylene)piperidine (1.0 g, 3.15 mmol) in methanol (25 mL) was charged with Pd/C under nitrogen atmosphere and fitted with hydrogen balloon using stopcock and covered with Teflon. The reaction mixture was stirred under hydrogen atmosphere for 8 h. It was filtered through celite, the celite was washed with methanol, and the solvent was removed under reduced pressure to afford the crude product which was then crashed out of pentane to give pure 3-(phenyl(4-(trifluoromethyl)phenyl)-methyl)piperidine (1.0 g, 98% yield) as a grey oil. MS (ESI, pos. ion) m/z: 320 (M+1).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:21](=[O:28])[CH:22]=[C:23]([CH2:26][OH:27])[O:24][CH:25]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:38][S:39]([O:27][CH2:26][C:23]1[O:24][CH:25]=[C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:8]2[C:7]3[C:12](=[C:3]([C:2]([F:1])([F:29])[F:30])[CH:4]=[CH:5][CH:6]=3)[N:11]=[CH:10][CH:9]=2)[C:21](=[O:28])[CH:22]=1)(=[O:41])=[O:40]
Reactant: O=c1cc(CO)occ1OCCCCCOc1ccnc2c(C(F)(F)F)cccc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cc(=O)c(OCCCCCOc2ccnc3c(C(F)(F)F)cccc23)co1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a solution of 5-(5-(8-(trifluoromethyl)quinolin-4-yloxy)pentyloxy)-2-(hydroxymethyl)-4H-pyran-4-one 14 (430 mg, 1.02 mmol) in CH2Cl2 (15 mL) was added at 0° C. triethylamine (173 μL, 1.21 mmol), methanesulfonyl chloride (95 μL, 1.21 mmol). The solution was stirred at RT for 1 h. Dichloromethane (50 mL) was added and the solution was washed with water (2×100 mL), dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent (CH2Cl2:MeOH)=95:05. (5-(5-(8-(Trifluoromethyl)quinolin-4-yloxy)pentyloxy-4-oxo-4H-pyran-2-yl)methyl methanesulfonate 19 was obtained (188 mg, 37% yield) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[C:5]([C:7]1[NH:12][C:11](=[O:13])[NH:10][C:9](=[O:14])[C:8]=1[CH:15]([CH3:17])[CH3:16])=[O:6].C(=O)([O-])[O-].[K+].[K+].[I-].[Li+].Cl[CH2:31][C:32]1[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([N:39]2[C:47](=[O:48])[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:49])[CH:33]=1>CN(C=O)C>[CH3:21][C:19]1[CH:18]=[C:4]([CH:3]=[C:2]([CH3:1])[CH:20]=1)[C:5]([C:7]1[N:12]([CH2:31][C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([N:39]3[C:47](=[O:48])[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:40]3=[O:49])[CH:33]=2)[C:11](=[O:13])[NH:10][C:9](=[O:14])[C:8]=1[CH:15]([CH3:17])[CH3:16])=[O:6]
Reactant: Cc1cc(CCl)cc(N2C(=O)c3ccccc3C2=O)n1
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(C)nc(N3C(=O)c4ccccc4C3=O)c2)c1
Reaction time: 8 h
Yield: 50.9 %

Procedure:
To a stirred solution of (20) (286 mg, 1 mmol), anhydrous powdered potassium carbonate (134 mg, 1 mmol), and lithium iodide (134 mg, 1 mmol) in DMF (5 ml) at room temperature, was added 2-(4-Chloromethyl-6-methyl-pyridin-2-yl)-isoindole-1,3-dione (286 mg, 1 mmol). After stirring for overnight, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:1)) to afford 273 mg (51%) of a white solid. m.p. 310-311° C.; 1H NMR (200 MHz, CDCl3) δ 1.14 (3H, d, J=6.9 Hz), 1.22 (3H, d, J=6.9 Hz), 2.27 (6H, s), 2.36 (1H, m), 2.43 (3H, s), 4.54 (1H, d, J=16.2 Hz), 5.04 (1H, d, J=16.2 Hz), 6.82 (1H, s), 6.94 (1H, s), 7.21 (1H, s), 7.39 (2H, s), 7.77-7.82 (2H, m), 7.91-7.95 (2H, m), 8.96 (1H, s).
Reaction SMILES: [BrH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[S:12][C:11](N)=[N:10][N:9]=2)[CH:3]=1.BrBr.N([O-])=O.[Na+].[OH-].[Na+]>O>[BrH:1].[Br:1][C:11]1[S:12][C:8]([C:4]2[CH:3]=[NH+:2][CH:7]=[CH:6][CH:5]=2)=[N:9][N:10]=1
Reactant: Nc1nnc(-c2cccnc2)s1
Agent: Br
Agent: BrBr
Agent: O=N[O-]
Solvent: O
Product: Brc1nnc(-c2ccc[nH+]c2)s1
Temperature: 5 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of aqueous hydrobromic acid (48%, 17 mL) at 5° C. in an ice bath was added 5-pyridin-3-yl-[1,3,4]thiadiazol-2-ylamine (6 g, 33 mmol) followed by bromine (12.8 mL, 0.24 mol) at a rate such that the reaction mixture was kept at a temperature below 11° C. A solution of sodium nitrite (6 g, 85 mmol) in water (8.5 mL) was added at a rate such that the reaction mixture maintained a temperature of around 5° C. The reaction mixture was kept at 2° C. for 2 hours, and then made basic to pH 8.9 using dilute NaOH at a rate needed to maintain the temperature between 5° C. and 15° C. The resulting solids were collected by filtration, washed with ice-cold water (200 mL) until filtrate was acidic (pH 4), and dried in vacuo at 35° C. to afford the title compound as an orange powder (8.68 g, 80%): mp 124-129° C.; IR (KBr thin film) 1374, 1026 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 9.17 (d, J=1.8 Hz, 1H), 8.80 (dd, J=4.5, 0.9 Hz, 1H), 8.42 (dt, J=8.4, 1.8 Hz, 1H), 7.67 (ddd, J=7.2, 4.8, 0.9 Hz, 1H); ESIMS m/z 244 (M+2).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([CH2:11][C:12]3[N:17]=[CH:16][C:15]([C:18]4[CH:25]=[CH:24][C:21]([C:22]#N)=[CH:20][CH:19]=4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C.C1C[O:38]CC1>C(Cl)Cl>[CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([CH2:11][C:12]3[N:17]=[CH:16][C:15]([C:18]4[CH:25]=[CH:24][C:21]([CH:22]=[O:38])=[CH:20][CH:19]=4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(-c2ccc(CN3CCN(C4CCC4)CC3)nc2)cc1
Reactant: C1CCOC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: O=Cc1ccc(-c2ccc(CN3CCN(C4CCC4)CC3)nc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-[6-(4-Cyclobutylpiperazin-1-ylmethyl)pyridin-3-yl]benzonitrile (0.066 g, 0.2 mmol) was dissolved in DCM (1 mL) DIBAL 1M in THF (0.2 mL) was added. The reaction mixture was stirred at RT for 1 hour. LC-MS showed no product. Another 1.5 eq. of DIBAL (0.2 mL) was added and stirring continued 1 hour. LC-MS showed full conversion. The reaction mixture was stored at −20° C. for 3 days. The reaction mixture was added DCM (5 mL) and cold NH4Claq (5 mL). The DCM phase was washed with water (5 mL) and brine (5 mL), dried with MgSO4, filtered and evaporation afforded the title compound as the free base. 34.5 mg (51%).
Reaction SMILES: [CH3:1][C:2]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[C:6]([NH2:10])=[N:7][NH:8][CH:9]=1.O=[C:17]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)[CH2:18][C:19](OCC)=[O:20]>C(O)(=O)C>[CH3:1][C:2]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[CH:9]=[N:8][N:7]2[C:19]([OH:20])=[CH:18][C:17]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[N:10][C:6]=12
Reactant: Cc1cccc(Cc2c[nH]nc2N)c1C
Reactant: CCOC(=O)CC(=O)c1ccncc1
Solvent: CC(=O)O
Product: Cc1cccc(Cc2cnn3c(O)cc(-c4ccncc4)nc23)c1C
Reaction time: 2 h

Procedure:
To a solution of 4-(2,3-dimethylbenzyl)-1H-pyrazol-3-amine (189 mg, 0.93 mmol) in acetic acid (2.0 mL) was added ethyl 3-oxo-3-(4-pyridinyl)propanoate (185 mg, 0.96 mmol) in a microwave reaction vessel. It was sealed and irradiated (microwave) at 140° C. for 60 minutes. The reaction mixture was cooled and stood for 2 hours. Precipitate was observed, filtered. Solid was washed with acetic acid (1 mL), then ethanol (1 mL×2). Solid was dried. The titled compound was obtained. (107 mg, 34%); LC/MS: MS (ES+) m/e 331 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.20 (s, 3H) 2.26 (s, 3H) 4.02 (s, 2H) 6.12 (s, 1H) 6.98-7.06 (m, 3H) 7.56 (s, 1H) 7.82 (br. s., 1H) 7.81 (d, J=5.31 Hz, 1H) 8.80 (dd, J=4.55, 1.52 Hz, 2H) 12.37 (br. s., 1H).
Reaction SMILES: [C:1]([C:4]1[C:8]2[C:9]([Cl:27])=[CH:10][C:11]([F:26])=[C:12]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])[C:7]=2[O:6][C:5]=1[CH3:28])(=O)[CH3:2].C([O-])(=O)C.[K+].Cl.[CH3:35][O:36][NH2:37]>CO>[Cl:27][C:9]1[C:8]2[C:4]([C:1](=[N:37][O:36][CH3:35])[CH3:2])=[C:5]([CH3:28])[O:6][C:7]=2[C:12]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[N:15]([CH3:24])[C:14]2=[O:25])=[C:11]([F:26])[CH:10]=1
Reactant: CON
Reactant: CC(=O)c1c(C)oc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CON=C(C)c1c(C)oc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
50 ml of methanol was added to 0.4 g (1 mmol) of 3-(3-acetyl-4-chloro-6-fluoro-2-methylbenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil, 0.5 g (5 mmol) of potassium acetate and 0.5 g (6 mmol) of methoxyamine hydrochloride, followed by stirring at room temperature for 12 hours and further for 8 hours under heating and refluxing. After completion of the reaction, methanol was distilled off under reduced pressure, ethyl acetate was added to the obtained residue, and the mixture was washed sequentially with water and a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 0.4 g (yield: 100%) of the desired product as pale yellow crystals. Melting point: 65-67° C., 1H-NMR (solvent: CDCl3): 1.54 (1H,s), 2.21(3H,s), 2.35(3H,s), 3.59(3H,s), 3.91(3H,s), 6.41(1H,s), 7.16(1H,d)ppm
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][N:17]4[C:20]([C:23]5[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=5)=[CH:21][N:22]=[C:16]4[CH:15]=3)=[CH:10][N:9]=2)[CH2:4][CH2:3]1.ClC(Cl)(Cl)C[O:33][C:34](=O)[NH:35][C:36]1[CH:40]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[O:38][N:37]=1.C(N(CC)CC)C>CS(C)=O>[C:41]([C:39]1[O:38][N:37]=[C:36]([NH:35][C:34]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([C:20]3[N:17]4[CH:18]=[CH:19][C:14]([C:11]5[CH:12]=[N:13][C:8]([N:5]6[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]6)=[N:9][CH:10]=5)=[CH:15][C:16]4=[N:22][CH:21]=3)=[CH:24][CH:25]=2)=[O:33])[CH:40]=1)([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)no1
Reactant: CN1CCN(c2ncc(-c3ccn4c(-c5ccc(N)cc5)cnc4c3)cn2)CC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1CCN(c2ncc(-c3ccn4c(-c5ccc(NC(=O)Nc6cc(C(C)(C)C)on6)cc5)cnc4c3)cn2)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Combine the amine (0.323 g, 0.838 mmol), (5-tert-butyl-isoxazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (0.291 g, 0.922 mmol) and triethylamine (0.128 mL, 0.922 mmol) in DMSO (10 mL). Heat the mixture to 70° C., stir overnight, and cool to room temperature. Extract the mixture with ethyl acetate versus water. Wash the organic layer with saturated aqueous saturated sodium chloride. Dry the resulting organics over magnesium sulfate, filter, and concentrate. Purify by column chromatography (ethyl acetate→10% methanol in dichloromethane→10% 2 M NH3 in MeOH in dichloromethane) to afford product (0.057 g, 11%, two steps). MS(ES), m/z 552 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[N+:14]([C:17]1[CH:27]=[CH:26][C:20]([CH:21]=[CH:22][C:23](Cl)=[O:24])=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[OH:13][C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[C:4]=1[C:23](=[O:24])[CH:22]=[CH:21][C:20]1[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:27][CH:26]=1
Reactant: O=C(Cl)C=Cc1ccc([N+](=O)[O-])cc1
Reactant: COc1cc(O)cc(OC)c1OC
Product: COc1cc(O)c(C(=O)C=Cc2ccc([N+](=O)[O-])cc2)c(OC)c1OC
Temperature: 80 °C
Yield: 22 %

Procedure:
A mixture of 3,4,5-trimethoxyphenol (1.85 g, 10 mmol) and 4-nitrocinnamoyl chloride (2.11 g, 10 mmol) was dissolved in BF3-Et2O complex (10 ml) and heated to 80° C. for 10 min, and then quenched with excess of water. The aqueous layer was extracted with dichloromethane. The combined organic layer was concentrated and the residue was purified by column chromatography on silica gel (CH2Cl2:EtOAc:Hexane=1:1:3) gave 7a (0.79 g, 22%) and 7b (1.54 g, 43%). 1H NMR (400 MHz, CDCl3) μ 3.81 (s, 3H), 3.90 (s, 3H), 3.91 (s, 3H), 6.29 (s, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.76 (d, J=16.0 Hz, 1H), 8.01 (d, J=16.0 Hz, 1H), 8.26 (d, J=8.8 Hz, 2H), 13.44 (s, 1H).