Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].S([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+].OS(O)(=O)=O>O>[F:14][C:8]1[CH:7]=[CH:6][C:5]([S:2]([OH:4])=[O:3])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1F
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(S(=O)O)ccc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 72 %

Procedure:
264 mmol 5-Chlorosulfonyl-2-fluoro-benzoic acid (CAS: 37098-75-2) was added portionwise onto a solution of 1.98 mol sodium sulfite in 1 L of water. The reaction mixture was kept under basic conditions by the addition of the proper amount of 20% NaOH and was stirred at room temperature for 45 minutes. After such time the reaction mixture was cooled down with an ice bath and was then acidified by the addition of 20% H2SO4 solution until reaching pH 2. Water was evaporated and 600 ml methanol was added. The mixture was stirred overnight and filtrated. The filtrate was evaporated and dried to yield the title compound as a white solid (72%). MS (m/e): 203.0 ([M−H, 100%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[CH:6][C:7]=1[CH:8]=[CH2:9].C(N(C(C)C)CC)(C)C.[CH3:20][Si:21]([CH3:38])([CH3:37])[CH2:22][CH2:23][O:24][C:25](ON1C2C=CC=CC=2N=N1)=[O:26]>CN(C)C=O.O>[CH3:20][Si:21]([CH3:38])([CH3:37])[CH2:22][CH2:23][O:24][C:25](=[O:26])[NH:10][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH2:9])=[C:2]([Cl:1])[CH:3]=1
Reactant: C=Cc1ccc(N)cc1Cl
Reactant: C[Si](C)(C)CCOC(=O)On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=Cc1ccc(NC(=O)OCC[Si](C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 3-chloro-4-vinyl-phenylamine (3.4 g) in N,N-dimethylformamide (44 mL) containing diisopropylethylamine (5.8 mL) is added 1-[2-(trimethylsilyl)-ethoxycarbonyl-oxy]benzotriazole (7.1 g) and the mixture is stirred at room temperature under an atmosphere of argon for three days. The solution is then diluted with water and extracted three times with diethyl ether. The combined organic extracts are washed successively with water, saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue is chromatographed over silica gel (10% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a yellow oil.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1([CH3:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10](=O)[CH2:9]1.[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:7][C:8]1([CH3:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH2:10][CH2:9]1
Reactant: CC1(C)CC(=O)Nc2ccccc21
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC1(C)CCNc2ccccc21
Yield: 93 %

Procedure:
To a stirred solution of LiAlH4 (1.0 M in THF, 35 mL, 35 mmol), was added a solution of 1a. (2.17 g, 12.4 mmol) in THF (10 mL) for 5 min at 0° C. under nitrogen. The resulting mixture was warmed gradually to reflux, and heated at reflux for 5.5 h. To the cooled mixture with stirring, was added sat'd Na2SO4 dropwise till the complete decomposition of LiAlH4. The mixture was filtered, and rinsed with EtOAc. The organic was washed with H2O, brine, dried (MgSO4), and concentrated to dryness. It was purified by flash chromatography (silica gel, 0-20% EtOAc in hexanes) to give pure 1b (1.86 g, yield: 93%). LC-MS ESI 162 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][CH2:11][C:12]2([C:16]([O:18]CC)=[O:17])[CH2:15][CH2:14][CH2:13]2)=[C:5]([CH3:21])[C:4]=1[CH3:22].[OH-].[K+]>C(O)C>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][CH2:11][C:12]2([C:16]([OH:18])=[O:17])[CH2:13][CH2:14][CH2:15]2)=[C:5]([CH3:21])[C:4]=1[CH3:22]
Reactant: CCOC(=O)C1(CNc2cc(C)c(OC)c(C)c2C)CCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(C)cc(NCC2(C(=O)O)CCC2)c(C)c1C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a solution of ethyl 1-((4-methoxy-2,3,5-trimethylpheny-lamino)methyl)cyclobutane-carboxylate (500 mg) in ethanol (10 mL), was added a KOH solution (2.5 mL). The mixture was left overnight and the ethanol was evaporated. After addition of water, the mixture was acidified with HCl (3 M) to reach a pH of 1-2. The aqueous phase was extracted with ethylacetate and the organic phase was dried with Na2SO4 and evaporated to give 1-((4-methoxy-2,3,5-trimethylphenyl-amino)-methyl)cyclobutane carboxylic acid (440 mg ) as a foam, which was used for next step. 10 mL of the foam was mixed with toluene (10 mL) and phosphoric acid (1 mL). The mixture was heated up in an oil bath, and after 30 min, the mixture was cooled and quenched with water. Dichloromethane was used to extract the aqueous phase several times. The organic phase was then combined, dried and evaporated to give a solid, which was passed through a column (Hexane: EtOAc; 5:2-5:4) to give 6′-methoxy-5′,7′,8′-trimethyl-1′H-spiro[cyclobutane-1,3′-quinolin]-4′(2′H)-one as a yellow solid. 1H-NMR, (300 MHz, CDCl3) δ=4.18 (s, 1H), 3.6 (s, 3H), 3.53(s, 2H), 2.58(s, 3H), 2.515-2.322 (m, 2H), 2.25 (s, 3H), 2.05 (s, 3H), 2.022-1.769 (m, 4H). ppm. 13C-NMR, (75 MHz, CDCl3) δ=197.89, 147.22, 136.52, 131.29, 118.77, 114.58, 60.48, 50.64, 47.26, 25.89, 14.9, 14.48, 13.78, 12.91 ppm. MS: m/z 260.2 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH:18]=[C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:17])[C:11]2=[N:10]1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH:18]=[C:12]2[CH:13]=[N+:14]([O-:27])[CH:15]=[C:16]([F:17])[C:11]2=[N:10]1
Reactant: Fc1cncc2cn(-c3c(Cl)cccc3Cl)nc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: [O-][n+]1cc(F)c2nn(-c3c(Cl)cccc3Cl)cc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.5 %

Procedure:
To a cooled (0° C.) solution of 2-(2,6-dichlorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine (5.4 g, 19.1 mmol) in DCM (100 mL) was added mCPBA (5.2 g, 30.0 mmol). The reaction mixture was stirred for 1.5 hours, warmed to room temperature, and stirred for a further 16 hours. Sodium thiosulfate (sat. aq.) was added and the layers were partitioned. The organic layer was washed with sodium hydrogen carbonate (sat. aq.) and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was triturated with ether to afford the title compound as a beige solid (5.04 g, 89% yield). LCMS (Method C): RT=2.45 min, m/z: 298 [M+H+].
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=2)=O)=[C:4]1[CH3:23])[CH3:2].C(N1C2C(=CC=CC=2)C(C(C2C(C(O)=O)=NC=CC=2)=O)=C1C)C.[C:47]1([NH:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2([N:53]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:19]3[CH2:20][O:21]2)=[C:4]1[CH3:23])[CH3:2]
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: CCn1c(C)c(C(=O)c2ncccc2C(=O)O)c2ccccc21
Agent: CCn1c(C)c(C(=O)c2cccnc2C(=O)O)c2ccccc21
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCn1c(C)c(C2(N(c3ccccc3)c3ccccc3)OCc3cccnc32)c2ccccc21
Reaction time: 8 h

Procedure:
A mixture containing 4.5 g. of an isomer mixture comprising 2-[(1-ethyl-2-methyl-3-indolyl)carbonyl]-3-pyridinecarboxylic acid and 3-[(1-ethyl-2-methyl-3-indolyl)carbonyl]-2-pyridinecarboxylic acid, 2.5 g. of diphenylamine and 30 ml. of acetic anhydride was stirred 6.5 hours, then treated with one ml. of pyridine and allowed to stand overnight. The reaction mixture was poured into 750 ml. of water and the resulting solid product was purified by column chromatography affording 7-(1-ethyl-2-methyl-3-indolyl)-7-(diphenylamino)furo[3,4-b]pyridine-(5(7H)-one as a light orange solid, m.p. 132.5°-136° C. A toluene solution of the product contacted with acidic clay or phenolic resin developed an orange image.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([NH2:26])=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13](B2OC(C)(C)C(C)(C)O2)=[CH:12][CH:11]=3)[CH2:3][CH2:2]1.Br[C:28]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:29]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[CH3:34][C:33]1[C:28]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([NH2:26])[C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:16]3)=[C:29]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:42])([F:43])[F:44])[CH:36]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: CC1(C)OB(c2ccc3nc(N)c(N4CCOCC4)cc3c2)OC1(C)C
Reactant: Cc1cccc(-c2cccc(C(F)(F)F)c2)c1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(-c2cccc(C(F)(F)F)c2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1

Procedure:
A solution of 3-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (50 mg, 0.141 mmol, prepared as in Example 2, Step 1-2), 2-bromo-3-methyl-3′-(trifluoromethyl)biphenyl (66.5 mg, 0.211 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (13.42 mg, 0.028 mmol), potassium phosphate (90 mg, 0.422 mmol) and PdCl2(dppf)-CH2Cl2 adduct (5.15 mg, 7.04 mmol) in ethanol (1206 μL)/water (201 μL) was heated in a sealed tube in the microwave at 140° C. for 20 min. The reaction was then quenched with water and the aqueous layer was extracted with EtOAc. The organic layer was then washed with water and brine (3× ea.), dried over Na2SO4 and concentrated in vacuo to remove the solvent. The crude material was purified by column chromatography with 0-70% (10% MeOH/DCM)/DCM to afford 6-(3-methyl-3′-(trifluoromethyl)biphenyl-2-yl)-3-morpholinoquinolin-2-amine MS (ESI, pos. ion) m/z: 464 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[NH:11][C:12](=[O:36])[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[N:29]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)=[CH:15][CH:14]=1.C(O)=O.C([O-])=O.[K+]>[Pt].O1CCCC1.C(O)C>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:11][C:12](=[O:36])[C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[N:29]=[C:28]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:15][CH:14]=2)[CH:4]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Agent: [Pt]
Agent: O=C[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O=CO
Solvent: CCO
Product: Cc1ccc(N)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Yield: 84.9 %

Procedure:
A stirred mixture of N-(2-methyl-5-nitrophenyl)-4-[(4-phenylquinazolin-2-yl)amino]benzamide (500 mg, 1.05 mmol), formic acid (140 μL, 3.71 mmol), potassium formate (312 mg, 3.71 mmol) and 5% platinum on carbon (150 mg, catalytic) in tetrahydrofuran (10 mL) and ethanol (10 mL) was heated to reflux for 1 h. The mixture was filtered while hot through Celite and washed with hot ethanol. Water was added until the mixture became cloudy, then the volatile solvents were removed on a rotary evaporator. The solid was collected by filtration to give N-(5-amino-2-methylphenyl)-4-[(4-phenylquinazolin-2-yl)amino]benzamide (397 mg, 85%). 1H NMR (400 MHz, DMSO-d6): δ 10.20 (s, 1H), 9.46 (s, 1H), 8.15 (d, 2H), 7.97 (d, 2H), 7.84 (m, 5H), 7.65 (m, 3H), 7.42 (m, 1H), 6.89 (d, 1H), 6.65 (d, 1H), 6.39 (dd, 1H), 2.08 (s, 3H). MS (EI) for C28H23N5O: 446.1 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([CH2:9][CH3:10])[N:6]([CH2:11][CH3:12])[N:5]=1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(O[C@H:27]1[NH:30][C:29](=[O:31])[C@@H:28]1[C@H:32]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH3:33])(=O)C.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH2:11]([N:6]1[C:7]([CH2:9][CH3:10])=[CH:8][C:4]([C:1]([CH2:2][C@H:27]2[NH:30][C:29](=[O:31])[C@@H:28]2[C@H:32]([O:34][Si:35]([C:38]([CH3:39])([CH3:41])[CH3:40])([CH3:37])[CH3:36])[CH3:33])=[O:3])=[N:5]1)[CH3:12]
Reactant: CCc1cc(C(C)=O)nn1CC
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1cc(C(=O)C[C@H]2NC(=O)[C@@H]2[C@@H](C)O[Si](C)(C)C(C)(C)C)nn1CC
Reaction time: 0.75 h
Yield: 46.8 %

Procedure:
3-Acetyl-1,5-diethylpyrazole (1.65 g) in dry tetrahydrofuran (THF) (50 ml) under an argon atmosphere was cooled in an acetone/solid carbon dioxide bath and then treated with a 1M solution of lithium bis(trimethylsilyl)amide (19.8 ml). The mixture was stirred for 45 minutes and then (3R,4R)-4-acetoxy-3-[(R)-1-tert-butyldimethylsilyloxyethyl]azetidinone (2.84 g) in dry THF (10 ml), added by syringe over ca. 1 minute. The mixture was stirred in the cold for 5 h. Saturated aqueous ammonium chloride was then added, followed by ethyl acetate. The layers were separated and the aqueous layer was re-extracted with ethyl acetate. The combined ethyl acetate layers were washed with saturated brine, dried and evaporated. Chromatography on silica gel, eluting with ethyl acetate/hexane mixtures gave the title compound (1.82 g); υmax(CH2Cl2) 3412, 2957, 2885, 2857, 1761, 1677, 1473, and 1376 cm−1; δ(CDCl3) 0.078 (6H, s), 0.88 (9H, s), 1.21 (3H,d, J 6.3 Hz), 1.29 (3H, t, J 7.6 Hz), 1.45 (3H, t, J 7.3 Hz), 2.63 (2H, q, J 7.3 Hz), 2.90 (1H, dd, J 1.6 & 4.9 Hz), 3.15 (1H, dd, J 10.0 & 17.0 Hz), 3.50 (1H, dd, J 3.6 & 17.0 Hz), 4.06-4.25 (4H, m), 6.09 (1H, s), 6.56 (1H, s). (Found m/z 393.2445. C20H35N3O3Si requires m/z 393.2448).
Reaction SMILES: [C:1]1([CH2:7][C@:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([OH:21])[CH2:9]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:28]1[CH:32]=[N:31][CH:30]=[N:29]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:1]1([CH2:7][C@:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([OH:21])[CH2:9][N:28]2[CH:32]=[N:31][CH:30]=[N:29]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@](O)(Cc2ccccc2)c2ccccc2)cc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O[C@@](Cc1ccccc1)(Cn1cncn1)c1ccccc1
Yield: 50.6 %

Procedure:
A mixture of 87 g (0.23 mol) of (2R)-1,2-diphenyl-2-hydroxy-3-tosyloxy-propane, 70 g (1 mol) of 1,2,4-triazole, 70 g (0.5 mol) of potassium carbonate and 800 ml of acetonitrile is refluxed for 16 hours with stirring. The reaction mixture is then poured into water, and the product which precipitates out is filtered off under suction. In order to remove any undesired biproducts which are still present, the product is dissolved in chloroform and filtered through a silica gel column, a mixture of chloroform/ethyl acetate=1:1 being used as eluent. The eluate is evaporated under reduced pressure. In this fashion, 32.5 g (51% of theory) of (2R)-1,2-diphenyl-2-hydroxy-3-(1,2,4-triazol-1-yl)-propane are obtained in the form of a solid of melting point 134° C. [α]D20 =-2.7° (c=2.75/CHCl3)
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1B(O)O.Br[C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].C(=O)([O-])[O-].[K+].[K+]>O.C1COCC1.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>[CH3:10][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:10])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Reactant: Cc1ccccc1B(O)O
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: C1CCOC1
Product: Cc1ccccc1-c1ccc(-c2ccccc2C)c([N+](=O)[O-])c1

Procedure:
5.46 g (4.7 mmol) of Pd(PPh3)4 are added to a well-stirred, degassed suspension of 155 g (1140 mmol) of o-tolylboronic acid, 133.4 g (474.9 mmol) of 2,5-dibromonitrobenzene and 305.3 g (1435 mmol) of potassium carbonate in a mixture of 250 ml of water and 250 ml of THF, and the mixture is heated under reflux for 20 h. After cooling, the organic phase is separated off, washed three times with 200 ml of water and once with 200 ml of saturated, aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo in a rotary evaporator. The grey residue is recrystallised from hexane. The deposited crystals are filtered off with suction, washed with a little MeOH and dried in vacuo; yield: 50.5 g, 97% of theory; purity: 99.2% according to HPLC.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([C:17]([OH:19])=O)[O:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[OH:44][CH:45]([C:58]1[CH:63]=[CH:62][C:61](/[C:64](=[N:66]/O)/[NH2:65])=[CH:60][CH:59]=1)[CH2:46][N:47]1[CH2:52][CH2:51][CH2:50][C@H:49]([C:53]([O:55]CC)=[O:54])[CH2:48]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.Cl>CN(C=O)C.C(OCC)(=O)C.CC#N>[OH:44][CH:45]([C:58]1[CH:59]=[CH:60][C:61]([C:64]2[N:66]=[C:17]([C:11]3[O:10][N:9]=[C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=4)[C:12]=3[C:13]([F:14])([F:15])[F:16])[O:19][N:65]=2)=[CH:62][CH:63]=1)[CH2:46][N:47]1[CH2:52][CH2:51][CH2:50][C@H:49]([C:53]([OH:55])=[O:54])[CH2:48]1
Reactant: Cc1cccc(-c2noc(C(=O)O)c2C(F)(F)F)n1
Reactant: CCOC(=O)[C@H]1CCCN(CC(O)c2ccc(/C(N)=N/O)cc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cccc(-c2noc(-c3nc(-c4ccc(C(O)CN5CCC[C@H](C(=O)O)C5)cc4)no3)c2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 3-(6-methylpyridin-2-yl)-4-(trifluoromethyl)isoxazole-5-carboxylic acid (100 mg, 0.367 mmol) and DIEA (0.128 mL, 0.735 mmol) in DMF (3 mL) was added BOP—Cl (103 mg, 0.404 mmol). After 15 minutes, (3S)-ethyl 1-(2-hydroxy-2-(4-((Z)—N′-hydroxycarbamimidoyl)phenyl)ethyl)piperidine-3-carboxylate, (refer to Preparation 14B) (136 mg, 0.404 mmol) was added. The reaction mixture was stirred at room temperature. After 1 hour, 1M TBAF/THF (0.367 mL, 0.367 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated NaCl. The organic layer was dried with MgSO4, filtered, and concentrated. The resulting material was purified by on a silica gel cartridge using an EtOAc/hexanes gradient. The peak with the desired mass was isolated by LCMS. This residue was dissolved in MeCN and treated with 6N HCl overnight. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 6 mg of (3S)-1-(2-hydroxy-2-(4-(5-(3-(6-methylpyridin-2-yl)-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid as a TFA salt. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.14 (2H, d, J=8.35 Hz), 7.81 (1H, t, J=7.69 Hz), 7.63 (3H, t, J=7.25 Hz), 7.39 (1H, d, J=7.91 Hz), 5.12-5.24 (1H, m), 3.93 (1H, d, J=12.74 Hz), 3.70-3.86 (1H, m), 3.57 (1H, d, J=11.86 Hz), 3.32-3.44 (1H, m), 3.24-3.32 (2H, m), 2.73-3.12 (2H, m), 2.48-2.56 (3H, m), 1.74-2.32 (2H, m), 1.41-1.65 (1H, m). MS (m+1)=544. HPLC Peak RT=2.96 minutes (Analytical Method A). Purity=90%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].S(OOS([O-])(=O)=O)([O-])(=O)=[O:14].[K+].[K+].S(=O)(=O)(O)O>>[CH3:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[C:7](=[O:12])[O:14][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: Cc1cccc2c1NC(=O)C2=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cccc2oc(=O)c(=O)[nH]c12

Procedure:
32.2 parts of 7-methylisatin are introduced into a solution of 56 parts of potassium peroxydisulfate in 450 parts of 92% strength sulfuric acid at from 0° C. to 10° C. The mixture is then stirred for a few minutes, after which it is poured onto ice. The product is filtered off and dried, giving 31.4 parts of 5-methyl-2,3-dioxo-1,4-benzoxazine, of melting point 247°-249° C.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:17][CH:18]1[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20][NH:19]1.[Cl-].[NH4+]>C(#N)C>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:19]2[CH2:20][CH2:21][CH:22]([CH3:25])[CH2:23][CH2:24][CH:18]2[CH3:17])[C:7]=1[F:8]
Reactant: CC1CCNC(C)CC1
Reactant: Fc1c(Cl)ncnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Product: CC1CCC(C)N(c2ncnc(Cl)c2F)CC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 97.2 %

Procedure:
Into 3 ml of acetnitrile were added 0.2 g of 4,6-dichloro-5-fluoropyrimidine, 0.50 g of potassium carbonate and 0.24 g of 2,5-dimethylhexahydro-1H-azepine hydrochloride, and the mixture was stirred for 5 hours at 80° C. The reaction mixture was cooled to near room temperature, a saturated ammonium chloride aqueous solution was added therein, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.3 g of 1-(6-chloro-5-fluoro pyrimidin-4-yl)-2,5-dimethylhexahydro-1H-azepine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:30](I)[CH3:31]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH2:30][CH3:31])[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:20]2[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=2)=[CH:4][CH:3]=1
Reactant: CCI
Reactant: N#Cc1ccc(-c2nc(-c3ccccc3)[nH]c2Sc2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1c(-c2ccccc2)nc(-c2ccc(C#N)cc2)c1Sc1ccc(Cl)cc1
Reaction time: 0.08 h

Procedure:
To 4-{5-[(4-chlorophenyl)thio]-2-phenyl-1H-imidazol-4-yl}benzonitrile (Example 2, 10 mg) in THF (1 mL) was added NaH (60% wt, 15 mg) at 0° C. After stirring for 5 min, EtI (0.05 mL) was added. The reaction was stirred at 50° C. overnight, then quenched with aq NH4Cl to adjust the pH to 6-8. The product was extracted with EtOAc and the combined extracts were washed with water, brine, dried over MgSO4, filtered, and concentrated. The residue was subject to silica column chromatography (0-15% EtOAc in hexanes) to give the title compound. LCMS: m/z 416 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:30]=[CH:29][C:12]([C:13]2[O:14][C:15]3[C:20]([C:21](=[O:25])[C:22]=2[O:23][CH3:24])=[C:19]([OH:26])[CH:18]=[C:17]([O:27][CH3:28])[CH:16]=3)=[CH:11][C:10]=1[O:31][CH3:32])C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:30]=[CH:29][C:12]([C:13]2[O:14][C:15]3[C:20]([C:21](=[O:25])[C:22]=2[O:23][CH3:24])=[C:19]([OH:26])[CH:18]=[C:17]([O:27][CH3:28])[CH:16]=3)=[CH:11][C:10]=1[O:31][CH3:32]
Reactant: COc1cc(O)c2c(=O)c(OC)c(-c3ccc(OCc4ccccc4)c(OC)c3)oc2c1
Agent: [Pd]
Solvent: CCO
Product: COc1cc(O)c2c(=O)c(OC)c(-c3ccc(O)c(OC)c3)oc2c1
Reaction time: 1 h
Yield: 85.1 %

Procedure:
A solution of 0.86 g of 4'-(benzyloxy)-5-hydroxy-3,3',7-trimethoxyflavone in 30 ml of ethanol was hydrogenated in the presence of 50 mg of 5% by weight palladium-charcoal at room temperature under atmospheric pressure. After 1 hour, the catalyst was filtered off and the filtrate was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane. There was obtained 0.58 g (90% yield) of 4',5-dihydroxy-3,3',7-trimethoxyflavone as yellow crystals: m.p. 171°-173° C.