Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[Cl-].[NH4+]>C(O)C.O.[Zn]>[Cl:1][C:2]1[CH:15]=[C:14]([CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[NH2:16]
Reactant: O=[N+]([O-])c1ccc(OCc2ccccn2)c(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: Nc1ccc(OCc2ccccn2)c(Cl)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
To a solution of 2-[(2-chloro-4-nitrophenoxy)methyl]pyridine from Example 5A (6.65 g, 25.1 mmol) in ethanol (120 mL) was added zinc powder (8.22 g, 126 mmol), and the mixture was heated to 60° C. A solution of ammonium chloride (2.67 g, 50.3 mmol) in water (24 mL) was added dropwise, and the reaction was stirred for additional 2 h at this temperature. The mixture was filtered through Celite®, and the solvent was removed in vacuo. The residue was triturated with water, and the precipitate was collected by suction filtration, washed with water and dried to yield 4.97 g (84%) of the aniline.
Reaction SMILES: [Cl:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:10].Cl[C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[Cl:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH:6][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:4][C:3]=1[F:10]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1cc(F)c(Cl)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1Nc1cc(F)c(Cl)c(F)c1
Temperature: 80 °C
Reaction time: 36 h

Procedure:
A mixture of 4-chloro-3,5-difluoroaniline (1.64 g, 10.0 mmol), 2-chloro-3-nitropyridine (1.56 g, 9.84 mmol) and cesium carbonate (6.56 g, 20.1 mmol) in N,N-dimethylformamide (30 mL) was stirred at 80° C. for 36 hours. The reaction mixture was cooled to room temperature, diluted with water (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (5×50 mL), dried over sodium sulfate, filtered, concentrated in vacuo and purified by chromatography on silica gel (Gradient: 0% to 5% ethyl acetate in petroleum ether) to provide the product as a yellow solid. Yield: 200 mg, 0.70 mmol, 7%. 1H NMR (400 MHz, CDCl3) δ 10.23 (br s, 1H), 8.55-8.61 (m, 2H), 7.52 (br d, J=9 Hz, 2H), 6.96-7.01 (m, 1H).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:46]=[CH:45][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:32]2[CH:37]=[CH:36][C:35]([O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:34][CH:33]=2)\[CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[CH:19][CH:18]=1.CO.Cl>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:46]=[CH:45][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:32]2[CH:33]=[CH:34][C:35]([O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:36][CH:37]=2)\[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:19][CH:18]=1
Reactant: CCOC(=O)CC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCC(=O)O)c2ccc(Oc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (10 ml) was added to a solution of ethyl E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-(4-phenoxyphenyl)butyrate(1.60 g) in tetrahydrofuran (20 ml)-methanol (10 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (10.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-(4-phenoxyphenyl)butyric acid (1.50 g, yield 99%) as colorless crystals. m.p. 131-132° C.
Reaction SMILES: [OH:1][C:2]1([CH2:9][N:10]2[CH2:15][CH2:14][C:13]3[NH:16][C:17]([CH:20]=O)=[C:18]([CH3:19])[C:12]=3[C:11]2=[O:22])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[F:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1[CH2:33][C:34](=[O:40])[NH:35]2>>[F:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1[C:33](=[CH:20][C:17]1[NH:16][C:13]3[CH2:14][CH2:15][N:10]([CH2:9][C:2]4([OH:1])[CH2:3][CH2:4][N:5]([CH3:8])[CH2:6][CH2:7]4)[C:11](=[O:22])[C:12]=3[C:18]=1[CH3:19])[C:34](=[O:40])[NH:35]2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CC1(O)CCN(C)CC1)CC2
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Product: Cc1c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4F)c32)[nH]c2c1C(=O)N(CC1(O)CCN(C)CC1)CC2
Yield: 74.98 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(4-hydroxy-1-methyl-piperidin-4-ylmethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as Starting materials to give 2-[4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-(4-hydroxy-1-methyl-piperidin-4-ylmethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (67 mg, 74.98%) as an orange solid.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13]O)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34]C(Br)(Br)Br>ClCCl>[Br:34][CH2:13][CH2:12][C@H:9]1[CH2:10][CH2:11][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]1
Reactant: BrC(Br)(Br)Br
Reactant: CCCCC[C@H]1CC[C@H](CCO)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](CCBr)CC1
Temperature: -20 °C
Reaction time: 5 h

Procedure:
A mixture of 20 g of 2-(trans-4-pentylcyclohexyl)ethanol, 27.5 g of triphenylphosphine and 350 ml of dichloromethane was treated portionwise while stirring at -30° C. over a period of 45 minutes under an inert gas atmosphere with 36.5 g of tetrabromomethane. The resulting mixture was then stirred at -20° C. for another 30 minutes and at room temperature for 5 hours. The mixture was subsequently concentrated and the residue was triturated with 500 ml of hexane. After cooling to 0° C., the precipitated triphenylphosphine oxide was filtered off and the filtrate was chromatographed on silica gel with hexane. The crude 1-bromo-2-(trans-4-pentylcyclohexyl)ethane obtained (29.0 g) was distilled at 92°-98° C./1.5 Torr. Yield: 21.9 g as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:27]1([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([CH2:41]Br)=[C:37]([CH3:43])[CH:36]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:41][C:38]2[CH:39]=[CH:40][C:35]([O:34][CH2:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:36][C:37]=2[CH3:43])[N:8]=1)=[O:5]
Reactant: Cc1cc(OCc2ccccc2)ccc1CBr
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccccc2)ccc1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Reaction time: 0.33 h

Procedure:
To a solution of 2,6-difluoro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 9)(1.31 g, 5.87 mmol) in anhydrous THF (30 ml) was added 1.0 M lithium bis(trimethylsilyl)amide in THF (6 ml, 6 mmol) at ambient temperature under nitrogen. The yellow solution was stirred for 20 min. To the solution was added a solution of 4-(bromomethyl)-3-methylphenyl phenylmethyl ether (1.72 g, 5.91 mmol) in THF (13 ml). The mixture was stirred overnight. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (120 ml) and saturated aqueous sodium hydrogen carbonate (100 ml). The phases were separated and the aqueous phase washed with ethyl acetate (30 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo to leave a yellow oil (3.10 g). The residue was loaded in DCM and purified on silica (100 g) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and the solvent evaporated in vacuo to give the title compound as a yellow gum (1.9 g); LCMS: (System 4) MH+=434, tRET=3.14 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)=[O:19])=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:28]([O:32][C:33](=[O:50])[NH:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][N:36]=1)([CH3:31])([CH3:30])[CH3:29].C(=O)([O-])[O-].[Na+].[Na+]>O>[C:28]([O:32][C:33](=[O:50])[NH:34][C:35]1[CH:40]=[CH:39][C:38]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]3[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18](=[O:19])[NH:20][O:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][O:23]4)=[CH:12]3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:37][N:36]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(/C=C/c1ccn(S(=O)(=O)c2ccc(Br)cc2)c1)NOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(S(=O)(=O)n3ccc(/C=C/C(=O)NOC4CCCCO4)c3)cc2)cn1
Temperature: 90 °C
Yield: 81.8 %

Procedure:
(E)-3-[1-(4-Bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (0.95 g) and [5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-carbamic acid tert-butyl ester (1.00 g) are dissolved under an inert gas atmosphere in dimethylethylenglycole (35 mL), and Pd(PPh3)3Cl2 (0.22 g) and a sodium carbonate solution (2.21 g dissolved in 21 water) is added and it is heated for 0.5 h at 90° C. After cooling the mixture is diluted with water, extracted with chloroform, and the combined organic phases are dried and evaporated. The residue is purified by silica gel flash chromatography CHCl3/THF (4:1). 0.97 g of the title compound are obtained with a melting point of 140-146° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[C:36]([O:40][CH2:41][CH3:42])(=[O:39])[CH:37]=[CH2:38]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:41]([O:40][C:36](=[O:39])[CH:37]=[CH:38][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)[CH3:42]
Reactant: OCc1ccc(Br)cc1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1ccc(CO)cc1

Procedure:
4-Bromobenzyl alcohol (10.5 g, 56.1 mmol), triphenylphosphine (0.5 g, 1.9 mmol) and palladium acetate (0.5 g, 2.2 mmol) were stirred at reflux in ethyl acrylate (20 mL) and triethylamine (100 mL) for 72 hours, then allowed to cool. The reaction mixture was filtered through celite (Diatomaceous Earth), then concentrated. The crude solid was purified by chromatography on silica gel (20% v/v ethyl acetate in petroleum ether) to afford the title compound as an oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH2:13][CH3:14])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:15]([NH2:18])[CH:16]=[CH2:17].C(=O)([O-])O.[Na+]>>[CH2:15]([NH:18][C:2]1[N:3]=[C:4]([NH:12][CH2:13][CH3:14])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1)[CH:16]=[CH2:17]
Reactant: C=CCN
Reactant: CCNc1nc(Cl)nc2c(C)csc12
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NCC)c2scc(C)c2n1
Yield: 64.1 %

Procedure:
In a sealed tube were heated 273 mg (1.2 mmol) of 2-chloro-4-ethylamino-7-methylthieno[3,2-d]pyrimidine and 1.10 g (19.2 mmol) of allylamine at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate (50 ml×2). The organic layer was washed with brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/2) to give 191 mg (yield: 64.3%) of the title compound.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.[F:8][C:9]1[CH:10]=[C:11]([C:16]2[CH2:20][CH:19]([CH2:21][N:22]3[CH:26]=[CH:25][N:24]=[N:23]3)[O:18][N:17]=2)[CH:12]=[CH:13][C:14]=1F>CN(C)C=O>[F:8][C:9]1[CH:10]=[C:11]([C:16]2[CH2:20][CH:19]([CH2:21][N:22]3[CH:26]=[CH:25][N:24]=[N:23]3)[O:18][N:17]=2)[CH:12]=[CH:13][C:14]=1[N:3]1[CH:7]=[CH:6][CH:5]=[N:4]1
Reactant: c1cn[nH]c1
Reactant: Fc1ccc(C2=NOC(Cn3ccnn3)C2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc(C2=NOC(Cn3ccnn3)C2)ccc1-n1cccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.2 %

Procedure:
A slurry of sodium hydride (60% in oil, 44 mg, 1.1 mM) in anhydrous N,N-dimethylformamide (1 ml) was stirred under an atmosphere of nitrogen and treated dropwise with a solution of pyrazole (76 mg, 1.1 mM) in anhydrous N,N-dimethylformamide (1 ml) at 0°. The mixture was allowed to warm to ambient temperature over 20 minutes, then a solution of (5RS)-3-(3,4-difluorophenyl)-5-(1,2,3-triazol-1-yl-methyl)-4,5-dihydroisoxazole (264 mg, 1 mM) in anhydrous N,N-dimethylformamide (2 ml) added, and the mixture stirred at 70° for 16 hours. After cooling, the mixture was partitioned between aqueous sodium bicarbonate solution (40 ml) and ethyl acetate (40 ml), and the organic extract washed with water (40 ml) and brine (40 ml). After drying (magnesium sulfate) and evaporation, the crude product was chromatographed on a 20 g silica Mega Bond Elut® column, eluting with ethyl acetate. Relevant fractions were combined to give the desired product (141 mg).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[CH:10][CH:9]=1)=[O:6].O.[NH2:25][NH2:26]>CO>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH:25][NH2:26])=[O:2])=[CH:9][CH:10]=1
Reactant: COC(=O)CC(=O)Nc1ccc(OCc2cccc(F)c2)cc1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)CC(=O)Nc1ccc(OCc2cccc(F)c2)cc1
Reaction time: 8 h

Procedure:
A suspension of 0.35 g (1.1 mmol) of N-[4-(3-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester in 7 ml methanol is treated with 83 mg (1.7 mmol) of hydrazine hydrate. The reaction mixture is refluxed for 2 h, then another portion of 300 mg (6 mmol) of hydrazine hydrate is added and reflux is pursued for another 8 h. The mixture is cooled and hold overnight in the frig. The precipitate is filtered off and recrystallised from methanol to yield 0.043 g (12%) of filthy, colorless needles. MS: m/e=318.3 (M++H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[C:10]1([CH2:16][CH2:17][NH2:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>CO>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH:18][CH2:17][CH2:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: NCCc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)cc(NCCc2ccccc2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
A mixture of 4,6-dichloro-2-pyrimidinamine (815 mg, 5.0 mmol), (2-phenylethyl)amine (665 mg, 5.5 mmol) and triethylamine (1.0 g, 10 mmol) in CH3OH (20 mL) was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was subjected to flash chromatography on SiO2 (eluent: 1/1 EtOAc/petroleum ether) to afford the title compound (1.0 g, 81%) as light yellow solid. LC-MS (ES) m/z=249 [M+H]+.
Reaction SMILES: Cl.Cl[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[CH:21])[CH:15]=3)=[N:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[N+:22]([O-:24])=[O:23].[CH3:25][O-:26].[Na+]>O>[C:20]([C:16]1[CH:15]=[C:14]([NH:13][C:7]2[C:6]3[C:11](=[CH:12][C:3]([O:26][CH3:25])=[C:4]([N+:22]([O-:24])=[O:23])[CH:5]=3)[N:10]=[CH:9][N:8]=2)[CH:19]=[CH:18][CH:17]=1)#[CH:21]
Reactant: C#Cc1cccc(Nc2ncnc3cc(Cl)c([N+](=O)[O-])cc23)c1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: C#Cc1cccc(Nc2ncnc3cc(OC)c([N+](=O)[O-])cc23)c1

Procedure:
(7-Chloro-6-nitroquinazolin-4-yl)-(3-ethynyl-phenyl)-amine hydrochloride (100 mg, 0.306 mmol and dry sodium methoxide (120 mg, 2.22 mmol) were stirred in 2 mL of dry 2-methylpyrrolidin-1-one for 8 hours at 30° C. To the cooled reaction mixture 0.93 mL of 3N and 1 mL of water were added. The mixture was diluted with 60 mL of water and extracted with two time 60 mL of ethyl acetate. The pooled organic layers were washed with three times 50 mL of water and 50 mL of brine, dried with magnesium sulfate, filtered and vacuum evaporated to afford the title product as a solid; 80 mg (82%); mp 213°-218° C. dec.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:12]Br>[Fe]>[Br:12][C:6]1[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=[C:2]([F:1])[C:7]=1[CH3:8]
Reactant: Cc1ccc([N+](=O)[O-])cc1F
Reactant: BrBr
Agent: [Fe]
Product: Cc1c(F)cc([N+](=O)[O-])cc1Br
Temperature: 100 °C
Yield: 23.2 %

Procedure:
To 3-fluoro-4-methylnitrobenzene (4.0 gm, 25.8 mmol) was added bromine (5.2 gm, 32 mmol) and iron powder (100 mg). The mixture was heated under a condenser at 100° C. for 40 hr and then poured into ice water containing enough sodium sulfite to quench the excess bromine. The aqueous layer was extracted twice with ether and the ether layers were washed with brine, dried over sodium sulfate, combined and evaporated. The residue was purified by FC (10-20% ethyl acetate/hexanes) to afford 1.4 gm of the title compound as a white solid (the major and highest Rf isomer). NMR (CDCl3): δ 2.41 (d, 3H, J=3 Hz), 7.85 (dd, 1H, J=2.1 and 9 Hz), 8.24 (dd, 1H, J=1.8 and 2.1 Hz).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]1[CH2:7][N:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[NH:5][CH2:4]1.[CH3:19][S:20]([C:23]1[N:28]=[C:27]([C:29](Cl)=[O:30])[CH:26]=[CH:25][N:24]=1)(=O)=O.[OH-].[Na+]>ClCCl>[CH3:18][N:2]([CH3:1])[CH:3]1[CH2:7][N:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:5]([C:29]([C:27]2[CH:26]=[CH:25][N:24]=[C:23]([S:20][CH3:19])[N:28]=2)=[O:30])[CH2:4]1
Reactant: CS(=O)(=O)c1nccc(C(=O)Cl)n1
Reactant: CN(C)C1CNN(C(=O)Cc2ccc(F)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CSc1nccc(C(=O)N2CC(N(C)C)CN2C(=O)Cc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1-(4-dimethylamino-pyrazolidin-1-yl)-2-(4-fluorophenyl)-ethanone, 22, (2.5 g, 10 mmol) in dichloromethane (20 mL) is added 2-methylsulfonyl-pyrimidine-4-carbonyl chloride (3.7 g, 20 mmol) followed by dropwise addition of a 1.0 N aqueous solution of sodium hydroxide (35 mL). The mixture is vigorously stirred at room temperature for 12 hours. The reaction is diluted with dichloromethane (100 mL) and washed with water (100 mL). The aqueous layer is back-extracted with dichloromethane (100 mL). The combined organic layers are washed with a saturated aqueous solution of sodium bicarbonate (100 mL) and brine (100 mL), dried, filtered and concentrated in vacuo. The resulting crude material is purified over silica (1:1 hexane/ethyl acetate to 100% ethyl acetate) to afford the desired product.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)=O>>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:6]1[C:5]([C:3]([OH:2])=[O:4])=[CH:10][C:9]([C:11]2[S:13][CH:24]=[C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)[N:12]=2)=[CH:8][CH:7]=1)([O-:22])=[O:21]
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1cccs1
Product: O=C(O)c1cc(-c2nc(-c3cccs3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 47 %

Procedure:
2′-Nitro-4-(4-thiophen-2-yl-thiazol-2-yl)-biphenyl-2-carboxylic acid (120 mg, 47%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-(2-bromoacetyl)thiophene (available from Maybridge) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 8.51 (d, J=1.7 Hz, 1H), 8.10-8.20 (m, 3H), 7.71 (t, J=8.1 Hz, 1H), 7.57-7.67 (m, 3H), 7.41 (t, J=8.3 Hz, 2H), 7.15 (t, J=4.6 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([C:10]([OH:12])=O)=[CH:7][CH:6]=1)=[O:4].S(Cl)(Cl)=O.O.[NH2:18][NH2:19]>>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([C:10]([NH:18][NH2:19])=[O:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)O)s1
Reactant: NN
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(C(=O)NN)s1
Yield: 72 %

Procedure:
The known procedure disclosed in the literature (J. Heterocyclic Chem., 28, 17, (1991).) was followed using 5-methoxycarbonyl-2-thiophenecarboxylic acid, thionyl chloride and hydrazine monohydrate to give 144 mg of a white solid (yield 72%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].[CH:14]([NH2:16])=O>>[OH:13][CH2:12][C:10]1[CH:11]=[C:2]2[C:3]([C:4](=[O:5])[NH:16][CH:14]=[N:1]2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(CO)cc1N
Reactant: NC=O
Product: O=c1[nH]cnc2cc(CO)ccc12
Temperature: 180 °C

Procedure:
A mixture of 2.0 g (19.1 mmole) of methyl 2-amino-4-hydroxymethlybenzoate in 4 ml of formamide is heated in an oil bath of 180° C. for three hours. The mixture is cooled and triturated with 70 ml of boiling ethyl acetate. The ethyl acetate is then decanted from the dark oil and cooled in a freezer overnight to precipitate 0.7 g 205-12° C. mp; 40% yield. 1H NMR (d6-DMSO, 300 MHz) δ 8.08 (s, 1H), 8.06 (d, 1H), 7.60 (s, 1H), 7.45 (d, 1H), 5.48 (bs, 1H), 4.65 (s, 2H), 3.35 (bs, 1H). EI MS, [M]+=176.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]1[CH:27]=[CH:26][CH:25]=[CH:24][C:6]=1[O:7][CH2:8][CH2:9][NH:10][CH:11]([CH3:23])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([S:21][CH3:22])[CH:14]=1)[CH3:3].[OH:28]O>C(O)C>[ClH:1].[CH2:2]([O:4][C:5]1[CH:27]=[CH:26][CH:25]=[CH:24][C:6]=1[O:7][CH2:8][CH2:9][NH:10][CH:11]([CH3:23])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([S:21]([CH3:22])=[O:28])[CH:14]=1)[CH3:3]
Reactant: CCOc1ccccc1OCCNC(C)Cc1ccc(OC)c(SC)c1
Reactant: OO
Agent: Cl
Solvent: CCO
Product: CCOc1ccccc1OCCNC(C)Cc1ccc(OC)c(S(C)=O)c1

Procedure:
In 30 ml of ethanol was dissolved 1.0 g of 4-{2-[2-(2-ethoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylthio)anisole hydrochloride and then 0.5 g of an aqueous 35% hydrogen peroxide solution was added to the solution with stirring. After stirring the mixture for 18 hours at room temperature, ethanol was distilled off under reduced pressure and the remaining sticky product was dispersed in 20 ml of water and extracted with 100 ml of ethyl acetate. The ethyl acetate layer was washed three times each time with 20 ml of water and after acidifying the solution with 0.2 ml of concentrated hydrochloric acid, the solvent was distilled off under reduced pressure. The remaining sticky material was applied to a silica gel column chromatography and eluted using a mixture of ethyl acetate and methanol (4:1 by volume ratio). The sticky product obtained was crystallized by the addition of 3 ml of isopropanol and the crystals thus formed were recovered by filtration to provide 0.4 g of 4-{2-[2-(2-ethoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylsulfinyl)anisole hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.[N:29]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH3:16][C:6]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:2]([CH3:1])[N:3]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:23][CH2:24][N:25]([C:35]([N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:36])[CH2:26][CH2:27]2)=[O:20])[N:5]=1
Reactant: O=C(Cl)N1CCCCC1
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Product: Cc1nc(OCC(=O)N(C)C2CCN(C(=O)N3CCCCC3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 31 and 1-piperidinecarbonyl chloride in the same manner as in Example 32.