Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:29][C:28]=1[NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:31]3[CH:30]=[CH:29][C:28]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[C:27]([O:26][CH3:25])[CH:32]=3)[C:10]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(C)C
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)OC(C)(C)C

Procedure:
cis-3-Iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (10 g, 22.66 mmol), tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (9.49 g, 27.17 mmol), palladium tetrakistriphenyphosphine (1.57 g, 1.36 mmol) and sodium carbonate (5.76 g, 54.38 mmol) were mixed with ethylene glycol dimethyl ether (180 mL) and water (90 mL). The reaction mixture was heated at reflux overnight. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by preparative thin layer column chromatography using dichloromethane/methanol (80:20) as mobile phase to give cis-tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)carbamate (10.859 g, 89%). 1H NMR (DMSO-d6) δ 1.49 (s, 9H), 1.58 (m, 2H), 1.71 (m, 2H), 2.08 (m, 2H), 2.17 (s, 3H), 2.45 (m, 4H), 2.38 (m, 4H), 2.45 (m, 3H), 3.87 (s, 3H), 4.80 (m, 1H), 7.22 (m, 2H), 7.91 (d, J=8.14, 1H), 8.04 (s, 1H), 8.22 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:3]=1.[OH:15]O>CC(O)=O>[CH3:1][C:2]1[CH:7]=[CH:6][N+:5]([O-:15])=[C:4]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])[CH:3]=1
Reactant: Cc1ccnc(NC(=O)C(C)(C)C)c1
Reactant: OO
Solvent: CC(=O)O
Product: Cc1cc[n+]([O-])c(NC(=O)C(C)(C)C)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
To a solution of N-(4-methylpyridin-2-yl)pivalamide (10 g, 52 mmol) in AcOH (300 ml) was added H2O2 (7.0 ml, 68 mmol) dropwise at 0° C. The mixture was stirred overnight at 70° C. The reaction mixture was quenched with water, extracted with ethyl acetate (200 mL×3) and washed with saturated Na2SO3 solution. The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum. The residue was purified by chromatography on silica gel (5% ethyl acetate in petroleum ether) to afford 4-methyl-2-pivalamidopyridine 1-oxide (8.4 g, 77%). 1H NMR (CDCl3, 300 MHz) δ 10.38 (br s, 1H), 10.21 (br s, 1H), 8.34 (s, 1H), 8.26 (d, J=6.9 Hz, 1H), 6.83 (d, J=6.9 Hz, 1H), 2.37 (s, 3H), 1.33 (s, 9H).
Reaction SMILES: [CH3:1][C@@H:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4](=[O:13])[C@H:3]1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].[Br:22]N1C(=O)CCC1=O>CN(C=O)C.[NH4+].[Cl-]>[Br:22][C:11]1[CH:10]=[CH:9][C:7]2[NH:8][C@@H:2]([CH3:1])[C@H:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:4](=[O:13])[NH:5][C:6]=2[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@@H]1Nc2ccccc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C[C@@H]1Nc2ccc(Br)cc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 95.7 %

Procedure:
To a 0° C. solution of tert-butyl(2S,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (107.0 mg, 367 μmol) in DMF (2.45 ml) was added a solution of N-bromosuccinimide (68.6 mg, 386 μmol) in DMF (1.22 ml), dropwise over 5 min. The reaction was stirred at 0° C. for 30 min, then diluted with sat. aq. NH4Cl and extracted with EtOAc. The combined organic layers were washed with H2O, sat. aq. NaHCO3, and sat. aq. NaCl, dried over Na2SO4, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(2S,3S)-7-bromo-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (130 mg, 96%) as a white solid. MS m/z 392/394 (MNa)+.
Reaction SMILES: [C:1]1([C@@H:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>ClCCl>[C:16]([O:9][C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])(=[O:18])[CH3:17]
Reactant: C[C@H](O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
In a 25 ml nitrogen-purged flask, with exclusion of air and moisture, 8.28 mmol (1.01 g, 1.00 ml) of (S)-1-phenylethanol (Fluka, 99% ee), 12.4 mmol (1.50 equ., 983 mg, 1.00 ml) of pyridine and 15 ml of dichloromethane are charged and cooled down to 0° C. (ice bath). With stirring, 10.8 mmol (1.30 equ., 1.10 g, 1.02 ml) of acetic anhydride is added dropwise over 10 min. Within a period of 12 h, the mixture is warmed up to room temperature and successively extracted twice each with 20 ml of 1 M aqueous hydrochloric acid solution, saturated sodium hydrogencarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, separated from the desiccant by filtration and freed from solvent in a rotary evaporator. The crude product was purified by chromatography over silica gel (mobile solvent: hexane:ethyl acetate=9:1). The product fractions are combined and freed from solvent in a rotary evaporator. After drying in an oil-pump vacuum, a clear liquid remains (1.25 g, 7.62 mmol, 92%). Analytics: 1H-NMR (CDCl3, 200 MHz): δ=1.52 (d) 3J=6.6 Hz [3H], 2.06 (s) [3H], 5.94 (q) 3J=6.6 Hz [1H], 7.24-7.38 (m) [5H]; 13C-{1H}-NMR (CDCl3, 50 MHz): δ=21.4 (s), 22.2 (s), 72.3 (s), 126.1 (s), 127.9 (s), 128.5 (s), 141.7 (s), 170.3 (s); MS (EI, 70 eV, pos. ions): m/z (% rel. int.): 164 (25) [M+], 122 (77), 107 (36), 105 (69), 104 (100), 103 (24), 79 (27), 78 (27), 77 (43), 51 (24), 43 (90); EA: C: 72.95% (calc. 73.15%), H: 7.28% (calc. 7.37%); GC (Hewlett Packard 5890, 25 m fused silica, 0.25 inner diameter, 2,6-dimethyl-3-pentyl-β-CD (95% methyl-/5% phenylpolysiloxane), FID, 80° C., 4° C. min−1, 120° C. 0.2 min iso, 0.63 bar hydrogen): 99.8% ee.
Reaction SMILES: [C:1]1([O:11][C:12]2[S:18][CH:17]3[N:14]([C:15](=[O:19])[CH2:16]3)[C:13]=2[C:20]([O:22]CC2C=CC([N+]([O-])=O)=CC=2)=[O:21])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+:37]>O1CCOCC1.O.[Pd]>[C:1]1([O:11][C:12]2[S:18][CH:17]3[N:14]([C:15](=[O:19])[CH2:16]3)[C:13]=2[C:20]([O-:22])=[O:21])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Na+:37]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)C1=C(Oc2cccc3ccccc23)SC2CC(=O)N12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C([O-])C1=C(Oc2cccc3ccccc23)SC2CC(=O)N12

Procedure:
A mixture of a solution of 800 mg of 4-nitrobenzyl 3-(1-naphthyloxy)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate in dioxan and 150 mg of sodium bicarbonate in water, and 10% palladium/charcoal was hydrogenated at 50 psi at 25° for 60 minutes.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:37]([C:34]2[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=2)(=[O:39])=[O:38])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3nccs3)cc2)c1
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccc(Cl)cc2)c1

Procedure:
The title compound of Step B was prepared from {3-[(4-thiazol-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester of Step A and 4-chlorobenzenesulfonyl chloride following the method described in Example 3, Step B with a reaction time of 96 h. MS 584 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([OH:12])=[C:7]([C:9](=[O:11])[CH3:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][O:20][CH2:21][CH2:22][OH:23]>C(Cl)(Cl)Cl>[OH:12][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][O:23][CH2:22][CH2:21][O:20][CH3:19])=[CH:8][C:7]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)c1cc(CCl)ccc1O
Reactant: COCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: COCCOCc1ccc(O)c(C(C)=O)c1
Reaction time: 24 h
Yield: 17.8 %

Procedure:
A mixture of 5'-(chloromethyl)-2'-hydroxyacetophenone (1.85 g, 10.0 mmol), potassium carbonate (1.38, 10.0 mmol), 2-methoxyethanol (0.91 g, 12.0 mmol) and 10 mL chloroform was stirred 24 hours, filtered, and the filtrate concentrated in vacuo to give a residue. The residue was purified by flash chromatography eluting with 30:70 ethyl acetate:hexane to give 0.40 g (18%) product as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([S:14](Cl)(=[O:16])=[O:15])=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=[C:4]2[CH:3]=1.Cl.[F:19][C:20]1([F:24])[CH2:23][NH:22][CH2:21]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([S:14]([N:22]3[CH2:23][C:20]([F:24])([F:19])[CH2:21]3)(=[O:16])=[O:15])=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=[C:4]2[CH:3]=1
Reactant: FC1(F)CNC1
Reactant: CC(C)c1nc2cc(Br)ccn2c1S(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)c1nc2cc(Br)ccn2c1S(=O)(=O)N1CC(F)(F)C1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
7-Bromo-2-isopropylimidazo[1,2-a]pyridine-3-sulfonylchloride (500 mg, 1.481 mmol) obtained in step 1 was dissolved in acetonitrile (5.0 mL), and the solution was stirred at 50° C. for 30 minutes after adding 3,3-difluoroazetidine hydrochloride (230 mg, 1.78 mmol) and triethylamine (0.413 ml, 2.96 mmol). The reaction mixture was allowed to cool to room temperature, and a sodium hydrogen carbonate aqueous solution was added. The precipitated solid was collected by filteration to give 7-bromo-3-(3,3-difluoroazetidin-1-ylsulfonyl)-2-isopropylimidazo[1,2-a]pyridine (546 mg, yield 94%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:20].[Br:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26](Br)[CH:27]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[Br:21][C:22]1[CH:27]=[C:26]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([CH3:1])[C:3](=[O:20])[CH2:4]3)[CH:25]=[N:24][CH:23]=1
Reactant: Brc1cncc(Br)c1
Reactant: CN1C(=O)Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
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: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CN1C(=O)Cc2cc(-c3cncc(Br)c3)ccc21
Temperature: 120 °C

Procedure:
To 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one (1.0 g, 3.66 mmol), prepared as described in Example 3a, was added 3,5-dibromopyridine (2.6 g, 11 mmol), 1,2-dimethoxyethane (10.0 mL), and 2 M aqueous sodium carbonate (4.00 mL, 8.0 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at, which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (2.0 g, 0.220 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 120° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane, and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 3.55%) to furnish 5-(5-bromo-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 303.0133 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 3.27 (s, 3H), 3.62 (s, 2H), 6.94 (d, J=8.1 Hz, 1H), 7.48 (s, 1H), 7.50 (d, J=8.1 Hz, 1H), 8.01 (t, J=1.9 Hz, 1H), 8.64 (d, J=2.0 Hz, 1H), 8.73 (d, J=1.6 Hz, 1H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:15]=3[CH:22]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH:23]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH3:25])[CH3:24].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[CH:23]([N:26]1[CH2:31][CH2:30][N:29]([C:19]([C:17]2[O:18][C:14]3[CH:13]=[CH:12][C:11]([O:10][CH:7]4[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]4)=[CH:22][C:15]=3[CH:16]=2)=[O:21])[CH2:28][CH2:27]1)([CH3:25])[CH3:24]
Reactant: CC(C)N1CCNCC1
Reactant: CC(C)N1CCC(Oc2ccc3oc(C(=O)O)cc3c2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(Oc2ccc3oc(C(=O)N4CCN(C(C)C)CC4)cc3c2)CC1
Yield: 55.9 %

Procedure:
In a flask were mixed together the above prepared 5-(1-isopropyl-piperidin-4-yloxy)-benzofuran-2-carboxylic acid (0.220 g, 0.549 mmol, corrected for purity), 1-isopropylpiperazine (0.084 g, 1.2 eq.), (benzotriazol-1-yloxy)-tris-(dimethylamino)-phosphonium hexafluorophosphate (0.291 g, 1.2 eq.) and 2.4 eq. of N-ethyldiisopropyl-amine (0.225 mL) in 2.2 mL of abs. THF and allowed to react during one night at ambient temperature. Pouring onto crashed ice/AcOEt/NH4Cl-solution, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, NEt3/AcOEt=4/96) produced 0.127 g of the title compound as light yellow oil.
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)C.[Cl:17][C:18]1[CH:32]=[CH:31][C:21]([O:22][C:23]2[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:32]=[CH:31][C:21]([O:22][C:23]2[CH:30]=[CH:29][C:26]([CH2:27][NH:28][C:4]3[C:5](=[O:16])[C:6](=[O:15])[C:7]=3[NH:8][C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)=[CH:25][CH:24]=2)=[CH:20][CH:19]=1
Reactant: NCc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CCOc1c(Nc2cccnc2)c(=O)c1=O
Product: O=c1c(NCc2ccc(Oc3ccc(Cl)cc3)cc2)c(Nc2cccnc2)c1=O
Yield: 68 %

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridin-3-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 1A and 4-(4-chlorophenoxy)-benzylamine.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C([O-])([O-])=O.[K+].[K+].[CH2:20]([C:22]([CH3:24])=[O:23])C>>[CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:20][CH:22]2[CH2:24][O:23]2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1ccc(O)cc1
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCOc1ccc(OCC2CO2)cc1

Procedure:
A mixture of 24.41 g of 4-pentoxyphenol, 56 g of K2CO3, 34.7 ml of epicholorohydrin and 500 ml of methyl ethyl ketone was refluxed overnight. Solvent and solid were removed to yield a residue which was distilled by a Kugelrohr adaptor to give the title compound, bp 175°/0.01 mmHg.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[CH:14]2)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH2:20]1[CH2:24]OC[CH2:21]1>CCOC(C)=O>[Si:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH:20]([CH3:24])[CH3:21])[N:15]=[CH:14]2)([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:5])[CH3:4]
Reactant: C1CCOC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)n1ncc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20 %

Procedure:
Sodium hydride (60% oil dispersion, 211 mg, 5.28 mmol) was added to a solution of 5-{[tert-butyl(dimethyl)silyl]oxy}-1H-indazole (Preparation 41, 1.09 g, 4.40 mmol) in THF (10 mL) and stirred at room temperature for 15 minutes. The solution was then heated at 50° C. for 18 hours, then at reflux for 8 hours. The reaction mixture was diluted with EtOAc and washed with water, 0.5 N aqueous citric acid solution and brine, then dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography eluting with 0 to 10% EtOAc in heptane to yield the title compound as a clear oil (261 mg, 20%):
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([OH:18])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=O.Cl.[NH2:20][OH:21]>N1C=CC=CC=1>[Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([OH:18])[CH:14]=[CH:13][C:3]=1[C:4](=[N:20][OH:21])[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1
Reactant: NO
Reactant: Cc1ccc(C(=O)c2ccc(O)c(Cl)c2Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(C(=NO)c2ccc(O)c(Cl)c2Cl)cc1

Procedure:
A mixture of 2,3-dichloro-4-hydroxy-4'-methylbenzophenone and 12.5 g of hydroxylamine hydrochloride in 200 ml of pyridine is refluxed for 2 hours. Thereafter the pyridine is evaporated off under vacuum and the residue is partitioned between ethyl acetate and 5% hydrochloric acid. The ethyl acetate extract is, successively, washed with water, dried and concentrated to dryness leaving 2,3-dichloro-4-hydroxy-4'-methylbenzophenone oxime.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.Cl.[NH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([OH:27])[C:21]=1[OH:28].CCN(CC)CC>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([OH:27])[C:21]=1[OH:28]
Reactant: NCc1ccc(O)c(O)c1O
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1NC(=O)c2ccc(Br)cc2C1=CNCc1ccc(O)c(O)c1O
Yield: 28.9 %

Procedure:
To a mixture of 6-Bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (200 mg, 0.71 mmol) and 4-aminomethyl-benzene-1,2,3-triol hydrochloride salt (139.6 mg, 1 mmol) in N,N-dimethylformamide (DMF) (10 mL) is added Et3N (0.25 mL, 1.83 mmol). The resulting precipitate is filtered to give 83 mg (28.9%) of the title compound as a dark brown solid. (ESI) m/z 403.0 (M−H)−1. 1H NMR (DMSO-d6) δ 4.53 (d, 2H, J=6 Hz), 6.29 (d, 1H, J=8 Hz), 6.55 (d, 1H, J=8 Hz), 7.28 (d, 1H, J=8 Hz), 7.85 (d, 1H, J=8 Hz), 8.05 (s, 1H), 8.39 (s, 1H), 8.67 (d, 1H, J=12 Hz), 8.80 (s, 1H), 9.18 (s, 1H), 10.63-10.68 (m, 1H), 11.05 (s, 1H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].Cl[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18].Cl>CN(C=O)C.CCCCCC>[Cl:16][C:15]1[C:10]([O:6][CH2:5][C:4]([F:8])([F:7])[F:3])=[C:11]([N+:17]([O-:19])=[O:18])[CH:12]=[CH:13][CH:14]=1
Reactant: OCC(F)(F)F
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=[N+]([O-])c1cccc(Cl)c1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
According to the procedure of J. T. Gupton et al, Can. J. Chem. 63, 3037 (1985), a suspension of hexane-washed sodium hydride (8.4 g, 0.21 mol) in DMF (250 mL) was added to 2,2,2-trifluoroethanol (22.1 mL, 0.3 mol) dropwise in 200 mL of DMF at room temperature over 60 minutes (excessive frothing occurs if added too fast). After stirring an additional 30 minutes 2,3-dichloronitrobenzene (38 g, 0.20 mol) was added in one portion. The resulting mixture was stirred at room temperature for 2 hours. The reaction was then poured into 1N HCl (500 mL) and extracted with Et2O (2×500 mL). The combined Et2O layers were washed first with water (200 mL) and finally with saturated brine (200 mL). After drying (MgSO4), the ether was concentrated to yield 47 g (90% based on dichloronitrobenzene) of 3-chloro-2-(2,2,2-trifluoroethoxy)nitrobenzene as a yellow liquid (b.p. 85° C./0.3 mmHg), which was used without further purification.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=4[C:30]([O:32][CH3:33])=[O:31])[O:25][C:26]=3[CH3:27])=[C:18]([O:40][CH3:41])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[CH2:42]([P:51](=[O:58])([O:55][CH2:56][CH3:57])[O:52][CH2:53][CH3:54])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH2:56]([O:55][P:51](/[CH:42]=[CH:1]/[C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=4[C:30]([O:32][CH3:33])=[O:31])[O:25][C:26]=3[CH3:27])=[C:18]([O:40][CH3:41])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1)([O:52][CH2:53][CH3:54])=[O:58])[CH3:57]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COC(=O)c1ccccc1-c1nc(COc2ccc(COc3nn(-c4ccccc4)cc3C=O)cc2OC)c(C)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3C(=O)OC)oc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 50.8 %

Procedure:
To a mixture of methyl 2-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate (0.65 g), tetraethyl methylenediphosphonate (0.37 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.060 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl 2-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoate as a colorless oil (0.41 g, yield 49%) from a fraction eluted with ethyl acetate-hexane (4:1, v/v).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([NH:5][CH2:6][C:7]1[C:8]([F:19])=[CH:9][C:10]([Cl:18])=[C:11]([CH:17]=1)[C:12]([N:14]=[C:15]=[O:16])=O)=[O:4].[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH:30]C(OC(C)(C)C)=O)=[CH:25][C:24]=1[C:38]([F:41])([F:40])[F:39].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:10]1[C:11]([C:12]2[NH:14][C:15](=[O:16])[N:29]([C:26]3[CH:27]=[CH:28][C:23]([F:22])=[C:24]([C:38]([F:39])([F:40])[F:41])[CH:25]=3)[N:30]=2)=[CH:17][C:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:21])([F:20])[F:1])=[C:8]([F:19])[CH:9]=1
Reactant: CC(C)(C)OC(=O)NNc1ccc(F)c(C(F)(F)F)c1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)c(F)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1cc(-c2nn(-c3ccc(F)c(C(F)(F)F)c3)c(=O)[nH]2)c(Cl)cc1F)C(F)(F)F
Yield: 32.4 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-fluorobenzoyl isocyanate (Intermediate-69, 0.400 g), tert-butyl 2-[4-fluoro-3-(trifluoromethyl)phenyl]hydrazinecarboxylate (Intermediate-80, 0.400 g), DCM (20 mL) and TFA (5.0 mL) to afford 0.200 g of the desired product.