Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:23])[O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:14]=1)[C:9]([OH:11])=O.[NH2:24][C:25]1[S:26][CH:27]=[C:28]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:29]=1>>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][C:28]1[N:29]=[C:25]([NH:24][C:9](=[O:11])[C:8]2[CH:7]=[C:6]([O:5][C@@H:4]([CH3:23])[CH2:3][O:2][CH3:1])[CH:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:12]=2)[S:26][CH:27]=1)[CH3:35]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(F)cc2)cc(C(=O)O)c1
Product: CCOC(=O)Cc1csc(NC(=O)c2cc(Oc3ccc(F)cc3)cc(O[C@@H](C)COC)c2)n1

Procedure:
{2-[3-(4-Fluoro-phenoxy)-5-((S)-2-methoxy-1-methyl-ethoxy)-benzoylamino]-thiazol-4-yl}-acetic acid ethyl ester was prepared from 3-{(1S)-2-methoxy-(methylethyl)oxy}-5-{[4-fluoro phenyl]oxy}benzoic acid (prepared as described in general synthetic descriptions F) and ethyl 2-aminothiazol-4-ylacetate following general procedure A.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[C:12]1([CH3:20])[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=O)[CH:13]=1>C(O)(=O)C.CCO>[CH3:20][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[CH:18]=[N:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: Cc1cccc(C=O)c1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cccc(C=NNC(=O)c2ccc(O)cc2)c1
Temperature: 25 °C
Yield: 75.6 %

Procedure:
To a solution of 4-hydroxy-benzoic acid hydrazide (0.2 g, 0.0013 mol) in abs. EtOH (10 mL) and m-tolualdehyde (0.32 g, 0.0026 mol) was added 1 drop of acetic acid. The reaction mixture was refluxed for 4 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give white solid 0.25 g, in 76% yield, mp: 241.9° C. 1H NMR (CD3OD) δ 8.27 (s, 1H), 7.83 (d, 2H), 7.67 (s, 1H), 7.59 (d, 1H), 7.31 (t, 1H), 7.24 (d, 1H), 6.88 (d, 2H), 2.37 (s, 3H). 13C NMR (CDCl3) δ 166.9, 162.8, 150.0, 139.7, 135.7, 132.2, 130.8, 129.7, 129.1, 126.1, 124.7, 116.3, 114.9, 21.3. Anal. Calcd for C15H14N2O2.¼H2O: C, 69.61; H, 5.45; N, 10.82. Found: C, 69.38; H, 5.51; N, 10.52.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:8][CH2:9][NH2:10])[CH2:5][CH2:6][NH2:7].C(=O)(O)[O-].[Na+].Cl[C:17]([CH3:23])([CH3:22])[CH:18]([N:20]=[O:21])[CH3:19]>C(#N)C>[CH3:22][C:17]([CH3:23])([NH:1][CH2:2][CH2:3][N:4]([CH2:8][CH2:9][NH2:10])[CH2:5][CH2:6][NH:7][C:17]([CH3:23])([CH3:22])[C:18](=[N:20][OH:21])[CH3:19])[C:18](=[N:20][OH:21])[CH3:19]
Reactant: CC(N=O)C(C)(C)Cl
Reactant: NCCN(CCN)CCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(=NO)C(C)(C)NCCN(CCN)CCNC(C)(C)C(C)=NO
Temperature: 25 °C
Reaction time: 72 h
Yield: 9.5 %

Procedure:
To a solution of tris-(2-aminoethyl)amine (1 ml, 6.68 mmol) in acetonitrile (10 ml) was added sodium bicarbonate (1.12 g, 13.36 mmol, 2 eq). A solution of 3-chloro-3-methyl-2-nitrosobutane (1.359 g, 10.02 mmol, 1.5 eq) in dry acetonitrile (5 ml) was added slowly. The reaction mixture was left to stir at room temperature for 3 days, and then filtered. The residue was washed well with acetonitrile, and the filtrate evaporated. The crude product was then purified by RP-HPLC (System L) to afford Compound 15 (164 mg, 7%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[C@@H:15]([OH:16])[CH2:14][CH2:13][CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[OH-].[K+].C1(C)C=CC=CC=1>O>[CH2:1]([O:8][CH2:9][C@H:10]1[C@@H:15]([O:16][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])[CH2:14][CH2:13][CH2:12][O:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@H]1CCCO[C@H]1COCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCO[C@H]1CCCO[C@H]1COCc1ccccc1
Temperature: 120 °C
Reaction time: 10 h

Procedure:
A mixture of 1.037 g of dl-cis-2-benzyloxymethyl-3-hydroxytetrahydropyran (prepared as described in Preparation 9), 1.709 g of hexadecyl bromide, 0.77 g of potassium hydroxide and 15 ml of toluene was heated, with stirring, at 120° C. for 10 hours. The reaction mixture was cooled and then poured into water. The water layer was extracted twice with diethyl ether. The organic layer and the extracts were combined, washed with water, dried and condensed by evaporation under reduced pressure. The resulting oily residue, 3.3 g, was subjected to column chromatography through 50 g of silica gel. The fraction eluted with a 1:10 by volume mixture of diethyl ether and hexane gave 1.455 g of the title compound as a colorless oily substance.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11](=[O:24])/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:8]=2)[CH:3]=[N:2]1.C1COCC1.[N:30]([CH3:33])=[C:31]=[O:32]>CCOC(C)=O>[C:20]([C:17]1[CH:16]=[CH:15][C:14](/[CH:13]=[CH:12]/[C:11]([NH:10][C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[N:2][N:1]3[C:31](=[O:32])[NH:30][CH3:33])=[CH:5][CH:6]=2)=[O:24])=[CH:19][CH:18]=1)([CH3:21])([CH3:23])[CH3:22]
Reactant: CN=C=O
Reactant: CC(C)(C)c1ccc(/C=C/C(=O)Nc2ccc3cn[nH]c3c2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)n1ncc2ccc(NC(=O)/C=C/c3ccc(C(C)(C)C)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round-bottomed flask, equipped with a magnetic stir bar, was added (2E)-N-(1H-indazol-6-yl)-3-[4-(tert-butyl)phenyl]prop-2-enamide, Example 155, (61 mg, 0.19 mmol), THF (8 mL) and isocyanatomethane (54 mg, 0.96 mmol, Carbolabs). The reaction mixture was stirred at room temperature for 8 h. The reaction mixture was diluted with EtOAc (10 mL), washed with water (8 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (40:20:1 hexane:EtOAc:MeOH) provided the title product as an off-white solid. MP 208-209° C. MS (ESI, pos. ion) m/z: 377 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)[N:22]=1)[CH2:6][C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:20]=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1)=[O:8].[C:33](OC(=O)C)(=[O:35])[CH3:34]>N1C=CC=CC=1>[C:33]([NH:1][CH2:2][CH2:3][CH2:4][N:5]([C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)[N:22]=1)[CH2:6][C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:20]=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1)=[O:8])(=[O:35])[CH3:34]
Reactant: Cc1cc(N(CCCN)CC(=O)NCCc2ccc3c(c2)OCO3)nc(-n2ccnc2)n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NCCCN(CC(=O)NCCc1ccc2c(c1)OCO2)c1cc(C)nc(-n2ccnc2)n1
Reaction time: 16 h
Yield: 41.7 %

Procedure:
To 2-[(3-aminopropyl)[2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide (0.3 g, 0.7 mmol) (a compound of formula (Yc6)) dissolved in pyridine (5 mL) was added acetic anhydride (0.10 mL, 1.0 mmol). After stirring for 16 hours, the reaction was partitioned with ethyl acetate and water. The organic layer was separated, washed with water and brine, dried (Na2SO4), and the solvent was removed in vacuo. Chromatography on silica with CH2Cl2 gave 0.14 g of 2-[[3-(acetylamino)propyl][2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide, a compound of formula (Yc7); NMR (DMSO-d6) 8.4 (s, 1), 8.05 (t, 2), 7.85 (t, 1), 7.8 (s, 1), 7.05 (s, 1), 6.7 (m, 2), 6.6 (m, 1), 6.2 (s, 1), 5.9 (s, 2), 4.1 (m, 2), 3-3.6 (m, 6), 2.6 (m, 2), 2.3 (m, 3), 1.8 (s, 3), 1.65 (m, 2) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([CH3:12])[CH:3]=1.[C:13](O)([CH3:16])([CH3:15])[CH3:14].S(=O)(=O)(O)O>O>[C:13]([C:7]1[C:2]([OH:1])=[CH:3][C:4]([CH3:12])=[C:5]([CH2:8][C:9]([OH:11])=[O:10])[CH:6]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1cc(O)ccc1CC(=O)O
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(O)c(C(C)(C)C)cc1CC(=O)O
Temperature: 25 °C

Procedure:
A solution of 8.5 g (51 mmol) of (4-hydroxy-2-methyl-phenyl)-acetic acid (Indian J. Chem. Sect B. 26, 1987:679-682), tert-butanol (60 g), and conc. sulfuric acid (2 mL) was stirred at 70° C. for 5 days. The solution was cooled to room temperature, poured into water, and extracted with EtOAc. The organic extract was washed with brine, dried (MgSO4), and concentrated to give (5-tert-butyl-4-hydroxy-2-methyl-phenyl)-acetic acid.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:13])C(=O)[NH:6]2.[OH-:14].[Na+].OO>>[NH2:6][C:7]1[C:3]([C:4]([OH:13])=[O:14])=[C:2]([CH3:1])[C:10]([CH3:11])=[CH:9][CH:8]=1
Reactant: [OH-]
Reactant: Cc1ccc2c(c1C)C(=O)C(=O)N2
Agent: OO
Agent: [Na+]
Product: Cc1ccc(N)c(C(=O)O)c1C
Temperature: 85 °C
Reaction time: 2 h

Procedure:
An aqueous solution (80 ml) containing 4,5-dimethyl-1H-indole-2,3-dione (9.8 g, 0.056 mmol) and sodium hydroxide (8.1 g, 0.2 mol) was heated to 85° C., and then 10% aqueous hydrogen peroxide (43 ml) was slowly added. The obtained solution was stirred at 85° C. for 2 hours, cooled to room temperature, and filtered. The filtrate was adjusted to pH 1 using sulfuric acid, to obtain 6-amino-2,3-dimethylbenzoic acid as crystals.
Reaction SMILES: [CH2:1]([C@@H:4]([OH:11])[C@H:5]([OH:10])[C@H:6]([OH:9])[CH2:7][OH:8])[CH:2]=[O:3].CC1(CN2C(=O)S/C(=C\C3C=CC(O)=C(C(F)(F)F)C=3)/C2=[O:22])CCCCC1>>[O:3]=[CH:2][C@@H:1]([C@H:4]([C@@H:5]([C@@H:6]([CH2:7][OH:8])[OH:9])[OH:10])[OH:11])[OH:22]
Reactant: CC1(CN2C(=O)S/C(=C\c3ccc(O)c(C(F)(F)F)c3)C2=O)CCCCC1
Reactant: O=CC[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Glycolytic rate was determined by measuring the conversion of [5-3H]glucose (GE Healthcare, Piscataway, N.J.) to 3H2O according to a published procedure (Ashcroft et al., Biochem J. 126, p. 525-532 (1972)). Briefly, LNCaP cells were seeded in six-well plates (4×105 cells/well) and then treated 24 h later with 10 mM 2-DG or 10 μM OSU-CG12 for various intervals. After washing with PBS, cells were trypsinized and resuspended in 500 μL of Krebs buffer [25 mM NaHCO3, 115 mM NaCl, 2 mM KCl, 2 mM CaCl2, 1 mM MgCl2 and 0.25% BSA (pH, 7.4)] containing 1 mM nonradioactive glucose and 5 μCi/mL [5-3H]glucose for 1 h at 37° C. Aliquots from each treatment group were added to 0.2 N HCl in open tubes that were placed upright in scintillation vials containing 1 mL of H2O. The vials were sealed and H2O produced by glucose consumption was equilibrated with H2O outside the tube for a minimum of 24 h at room temperature. The amount of 3H retained in the tube and the amount that had diffused into the surrounding H2O by evaporation and condensation were determined separately by using a scintillation counter LS6500 (Beckman). [5-3H]glucose-only and 3H2O-only standards were included in each experiment for calculation of the rate of conversion of [5-3H]glucose to H2O using the following equation: glucose utilized (pmol)=[3H] water formed (d.p.m)/[5-3H]glucose (d.p.m/pmol)].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([C:18]2[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:25])[C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([NH2:43])[CH:31]=[CH:32][C:33]=1[O:34][CH2:35][CH:36]1[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]1.[OH-].[Na+]>CC(O)=O>[NH:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[N:8]([C:18]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:25])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:30]2[CH:31]=[CH:32][C:33]([O:34][CH2:35][CH:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)=[C:28]([O:27][CH3:26])[CH:29]=2)[N:7]=1
Reactant: Cc1cccc(C)c1N(c1ccnc(Cl)n1)c1nc2ccccc2[nH]1
Reactant: COc1cc(N)ccc1OCC1CCN(C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1cc(Nc2nccc(N(c3nc4ccccc4[nH]3)c3c(C)cccc3C)n2)ccc1OCC1CCN(C)CC1
Temperature: 80 °C

Procedure:
A pressure tube was charged with a solution of 2-(N-(2-chloropyrimid-4-yl)-2,6-dimethylphenylamino)-1H-benzimidazole (50 mg, 0.14 mmol), from Example 155 Step F, 3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)-phenylamine (36 mg, 0.14 mmol) in glacial AcOH (2 mL). The reaction, a dark brown solution, was heated to 80° C. for 18 h. The reaction was cooled to RT then basified by careful addition of 5M NaOH (15 mL). The aqueous solution was extracted with CH2Cl2. The combined organic extracts were dried (Na2SO4) and the solvent removed in vacuo. The residue was purified by column chromatography (silica; CH2Cl2:MeOH; 9:1, containing TEA [1%]) to afford a brown solid, which was further purified by column chromatography (silica; CH2Cl2:MeOH; 9:1; containing TEA [0.5%]) to afford a light brown solid. MS m/z=564 (M+H). Calc'd for C33H37N7O2=563.
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([O:20][CH3:21])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=O)C>O1CCOCC1.Cl>[NH2:4][C:5]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([O:20][CH3:21])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COc1cc(C(=O)O)c(NC(C)=O)cc1-c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(C(=O)O)c(N)cc1-c1ccccc1
Temperature: 25 °C

Procedure:
A solution mixture of 2-(acetamido)-5-methoxy-4-phenylbenzoic acid (0.41 g) in dioxane (1.2 mL) and concentrated hydrochloric acid (1.2 mL) was heated to reflux for 3 hours and 40 minutes. After cooling the reaction mixture to room temperature, the solvent was evaporated under reduced pressure, and water was added to the residue. After adjusting the pH to 7 with a 1 mol/L aqueous solution of sodium hydroxide, chloroform was added thereto. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 2-amino-5-methoxy-4-phenylbenzoic acid as a brown solid.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Cl:8][C:9]1[C:14]([Cl:15])=[C:13]([CH2:16][CH3:17])[N:12]=[CH:11][N:10]=1.O>O1CCCC1>[Cl:8][C:9]1[C:14]([Cl:15])=[C:13]([CH:16]([CH3:1])[CH3:17])[N:12]=[CH:11][N:10]=1
Reactant: CC(C)NC(C)C
Reactant: CCc1ncnc(Cl)c1Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1ncnc(Cl)c1Cl
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
N-butyl lithium (1.6 mol solution in hexane, 19.4 ml) is added dropwise at 0° C., under a nitrogen atmosphere, to a solution of diisopropylamine (4.4 ml) in tetrahydrofuran (100 ml), and the mixture is stirred for 20 minutes. The solution is cooled to -78° C. and then 5 g of 4,5-dichloro-6-ethylpyrimidine in solution in 10 ml of tetrahydrofuran are added dropwise. The mixture is stirred at -78° C. for one hour and then brought to room temperature over a period of 2 hours. After the addition of water (200 ml), the mixture is extracted with ethyl acetate and the organic phase is dried over sodium sulfate and concentrated. Chromatography on silica gel (eluant: ethyl acetate/hexane 1:10) yields 3.8 g (71% of the theoretical yield) of 4,5-dichloro-6-isopropylpyrimidine in the form of a yellow oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[C:12]([NH2:17])[C:13]([NH2:16])=[CH:14][CH:15]=1.[C:18]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)(=[O:20])[CH3:19].CCOC(C)=O>C(#N)C.N1C=CC=CC=1>[C:18]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:17][C:12]2[CH:11]=[C:10]([C:2]3[O:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)[CH:15]=[CH:14][C:13]=2[NH2:16])=[O:27])=[CH:24][CH:23]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccc(-c2nc3ccccc3o2)cc1N
Solvent: CC#N
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(C(=O)Nc2cc(-c3nc4ccccc4o3)ccc2N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 0.8 %

Procedure:
To a stirred suspension of 227 (350 mg, 1.55 mmol) in acetonitrile (20 mL) and pyridine (2 ml) was added 4-acetamidobenzoyl chloride (307 mg, 1.55 mmol) in acetonitrile (5 ml) at 0° C. The solution was warmed up to room temperature and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel, eluents hexane-EtOAc (1:3), then EtOAc (100%), to afford 228 as a beige solid (5 mg, 1% yield). 1H NMR: (DMSO) δ (ppm): 10.22 (s, 1H), 9.62 (s, 1H), 8.05 (d, J=2.4 Hz, 1H), 7.89 (d, J=8.4 Hz, 2H), 7.80 (1H, dd, J=2.0, 8.4 Hz, 1H), 7.68-7.73 (m, 4H), 7.33-7.35 (m, 2H), 6.91 (d, J=8.4 Hz, 1H), 5.86 (bs, 2H), 2.12 (s, 3H). MS: (calc.) 386.41; (obt.) 387.1 (MH)+.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11]C)=[C:5]([CH3:13])[C:4]=1[C:14]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1)(O)[CH:15]([CH3:17])[CH3:16].Br>C(=O)([O-])O.[Na+]>[CH3:17][C:15]1([CH3:16])[CH:14]([C:19]2[CH:20]=[CH:21][C:22]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[CH:23][CH:24]=2)[C:4]2[C:5]([CH3:13])=[C:6]([OH:11])[C:7]([CH3:10])=[C:8]([CH3:9])[C:3]=2[O:2]1
Reactant: COc1c(C)c(C)c(OC)c(C(O)(c2ccc(N3CCOCC3)cc2)C(C)C)c1C
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1c(C)c2c(c(C)c1O)C(c1ccc(N3CCOCC3)cc1)C(C)(C)O2
Yield: 90.2 %

Procedure:
A mixture of 1-(2,5-dimethoxy-3,4,6-trimethylphenyl)-2-methyl-1-[4-(4-morpholinyl)phenyl]propan-1-ol (8.00 g, 19.3 mmol) and 48% hydrobromic acid (100 mL) was heated under reflux for 3 hours in an argon atmosphere. After cooling, an aqueous saturated sodium hydrogencarbonate (30 mL) was added to the reaction mixture, which was then extracted twice with ethyl acetate. The organic layers were combined, washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from isopropyl ether-hexane to obtain the title compound (6.40 g, yield 90. %).
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[OH:7][N:8]=[C:9]([C:13]1[CH:14]=[N:15][S:16][CH:17]=1)[C:10]([OH:12])=[O:11]>C(Cl)Cl>[Cl:1][CH:2]([Cl:6])[C:3]([O:7][N:8]=[C:9]([C:13]1[CH:14]=[N:15][S:16][CH:17]=1)[C:10]([OH:12])=[O:11])=[O:4]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: O=C(O)C(=NO)c1cnsc1
Solvent: ClCCl
Product: O=C(O)C(=NOC(=O)C(Cl)Cl)c1cnsc1
Yield: 48.7 %

Procedure:
Dichloroacetyl chloride (3.58 g.) was added with stirring and ice-cooling to a suspension of 2-hydroxyimino-2-(isothiazol-4-yl)acetic acid (syn isomer) (1.50 g.) in dry methylene chloride (40 ml.), and the mixture was stirred for 2 hours at the same temperature. The reaction mixture was concentrated to the volume of 10 ml. Petroleum ether (50 ml.) was added to the residue and the mixture was cooled in dry ice-acetone bath. Precipitates were collected by filtration and washed with petroleum ether to give 2-dichloroacetoxyimino-2-(isothiazol-4-yl)acetic acid (syn isomer) (1.20 g.).
Reaction SMILES: [CH2:1]([O:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH:24]=O)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][CH2:34][NH2:35]>>[CH2:1]([O:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][NH:35][CH2:34][CH2:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[F:26])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOc1ccc(C=O)c2ccccc12
Reactant: NCCc1ccccc1F
Product: CCCCCCCCCCCCOc1ccc(CNCCc2ccccc2F)c2ccccc12

Procedure:
The same procedure as employed in the preparation of Example 394 (step b) but using 4-(dodecyloxy)-1-naphthaldehyde and 2-(2-fluorophenyl)ethylamine gave the title compound as an oil. HPLC (Condition A), Rt: 5.48 min (HPLC purity: 86.4%).
Reaction SMILES: CN(C)[CH:3]=[C:4]1[C:9](=O)[CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[F:30][C:31]1[CH:32]=[C:33]([NH:43][C:44]([NH2:46])=[NH:45])[CH:34]=[CH:35][C:36]=1[N:37]1[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]1>>[F:30][C:31]1[CH:32]=[C:33]([NH:43][C:44]2[N:46]=[CH:3][C:4]3[CH2:5][CH2:6][CH2:7][CH:8]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:20])[F:19])[CH:12]=4)[C:9]=3[N:45]=2)[CH:34]=[CH:35][C:36]=1[N:37]1[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]1
Reactant: Cc1cn(-c2ccc(NC(=N)N)cc2F)cn1
Reactant: CN(C)C=C1CCCC(c2cccc(C(F)(F)F)c2)C1=O
Solvent: O=[N+]([O-])O
Product: Cc1cn(-c2ccc(Nc3ncc4c(n3)C(c3cccc(C(F)(F)F)c3)CCC4)cc2F)cn1

Procedure:
The title compound was prepared from crude 6-[1-dimethylamino-methylidene]-2-(3-trifluoromethyl-phenyl)-cyclohexanone (172 mg, 0.5 mmol) and N-[3-fluoro-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (134 mg, 0.37 mmol) using in analogous manner the procedure described in example 45b). Obtained as a pale-yellow solid (106 mg, 61%). MS ISP (m/e): 468.3 [(M+H)+]. mp 207-209° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=2[F:16])[NH:5][C:4](=[O:17])[CH:3]=1.[N+:18]([O-])([OH:20])=[O:19]>C(O)(=O)C>[N+:18]([C:3]1[C:4](=[O:17])[NH:5][C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=2[F:16])=[CH:7][C:2]=1[OH:1])([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(F)c(-c2cc(O)cc(=O)[nH]2)c1
Solvent: CC(=O)O
Product: COc1ccc(F)c(-c2cc(O)c([N+](=O)[O-])c(=O)[nH]2)c1
Temperature: 25 °C

Procedure:
A suspension of 4-hydroxy-6-(2-fluoro-5-methoxyphenyl) pyridone (345 mg, 1.47 mmol) in acetic acid (5 mL) was treated dropwise with 90% nitric acid (0.8 mL) at room temperature. The resulting homogeneous solution was heated to 55°-60° C. for 5 h during which time a precipitate formed. After cooling to room temperature the yellow solid was collected by filtration, washed thoroughly with water, and dried under vacuum to give pure 3-nitro4-hydroxy-6-(2-fluoro-5-methoxyphenyl) pyridone.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH3:25][N:26]([CH3:32])[C@H:27]1[CH2:31][CH2:30][NH:29][CH2:28]1>>[CH3:25][N:26]([CH3:32])[C@H:27]1[CH2:31][CH2:30][N:29]([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:28]1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Reactant: CN(C)[C@H]1CCNC1
Product: CN(C)[C@H]1CCN(CCc2cc3cc(-c4ccc(C#N)cc4)ccc3o2)C1

Procedure:
The product from Example 1C and 3-(S)-(dimethylamino)pyrrolidine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.88 (m, 1H), 7.80 (m, 4H), 7.58 (m, 2H), 6.80 (s, 1H), 4.43 (m, 1H), 3.6-3.9 (m, 4H), 3.35-3.45 (m, 4H), 2.95 (s, 6H), 2.6 (m, 1H), 2.35 (m, 1H); MS (DCI) m/z 360 (M+H)+;
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[N:3]=1.[F-:21].[K+].O>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>[F:21][C:5]1[CH:6]=[C:7]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=3)[N:4]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[N:3]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)n1nc(Br)c2cc([N+](=O)[O-])ccc21
Reactant: [F-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc([N+](=O)[O-])ccc21
Temperature: 50 °C
Yield: 93.6 %

Procedure:
To a solution of 4.5 g of tert-butyl 3-bromo-5-nitro-1H-1-indazolecarboxylate in 20 ml N,N-dimethylformamide were added 2.8 g of 3-fluorophenylboronic aid, 0.16 g of 2-(di-tert-butylphosphino)biphenyl, 60 mg of palladium acetate and 2.31 g of potassium fluoride, and the mixture was heated at 50° C. for two days. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:15), and then recrystallized from diisopropyl ether-hexane, to give 2.2 g of the title compound as a colorless powder.