Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:32]2[CH2:44][CH2:43][C:42]3[N:41]4[C:36]([CH2:37][CH2:38][CH2:39][CH2:40]4)=[CH:35][C:34]=3[C:33]2=[O:45])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:28][N:27]([CH3:29])[CH2:26]3)=[CH:21][N:20]=2)[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=1)(=O)C.[OH-].[Li+]>C1COCC1.C(O)(C)C.O>[OH:4][CH2:5][C:6]1[C:7]([N:32]2[CH2:44][CH2:43][C:42]3[N:41]4[C:36]([CH2:37][CH2:38][CH2:39][CH2:40]4)=[CH:35][C:34]=3[C:33]2=[O:45])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:28][N:27]([CH3:29])[CH2:26]3)=[CH:21][N:20]=2)[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CN(C)C4)cn3)c(=O)n(C)c2)ccnc1N1CCc2c(cc3n2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: CN1CC(c2ccc(Nc3cc(-c4ccnc(N5CCc6c(cc7n6CCCC7)C5=O)c4CO)cn(C)c3=O)nc2)C1
Temperature: 30 °C
Reaction time: 1 h
Yield: 29.5 %

Procedure:
A mixture of 244d (90 mg, 0.15 mmol) and lithium hydroxide (60 mg, 1.5 mmol) in THF/i-propanol (5:3, 8 mL) and water (2 mL) was stirred at 30° C. for 1 h. The mixture was evaporated in vacuo and the residue was diluted with water (3 mL). It was then extracted with ethyl acetate (20 mL×2). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 244 (25 mg, 30%) as white solid. MS-ESI: [M+H]+ 566.4. 1H NMR (500 MHz, CDCl3) δ 8.74 (d, J=2.5 Hz, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.16 (d, J=2.0 Hz, 1H), 7.91 (s, 1H), 7.87 (d, J=2.0 Hz, 1H), 7.59-7.57 (m, 1H), 7.35 (d, J=5.0 Hz, 1H), 6.85-6.83 (m, 1H), 6.33 (s, 1H), 5.04-5.01 (m, 1H), 4.67-4.65 (m, 1H), 4.44-4.39 (m, 1H), 4.33-4.29 (m, 1H), 3.95-3.91 (m, 1H), 3.86-3.83 (m, 2H), 3.76-3.74 (m, 1H), 3.73 (s, 3H), 3.62-3.59 (m, 1H), 3.16-3.13 (m, 2H), 3.02-2.95 (m, 2H), 2.84-2.83 (m, 2H), 2.39 (s, 3H), 2.05-2.02 (m, 2H), 1.90-1.87 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([O:20]CC)=[O:19])=[CH:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O1CCCC1>C(O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc2cccc(NC(=O)OC(C)(C)C)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cccc2cc(C(=O)O)[nH]c12
Temperature: 50 °C
Reaction time: 3 h
Yield: 94.4 %

Procedure:
A mixture of ethyl 7-[(tert-butoxycarbonyl)amino]-1H-indole-2-carboxylate (2.65 g), 1N aqueous sodium hydroxide solution (22.0 mL), tetrahydrofuran (20 mL) and ethanol (30 mL) was stirred at 50° C. for 3 hr. The reaction mixture was concentrated, and water was added to the residue. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water, and dried to give the title compound (2.27 g, yield 94%) as colorless crystals. melting point>246° C. (decomposition).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.[CH3:11][O:12][C:13]1[CH:17]=[C:16]([C:18](Cl)=[O:19])[O:15][N:14]=1.C(N(CC)CC)C.O>ClCCl>[O:1]1[CH2:6][CH2:5][N:4]([C:18]([C:16]2[O:15][N:14]=[C:13]([O:12][CH3:11])[CH:17]=2)=[O:19])[C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2
Reactant: c1cc2c(cn1)NCCO2
Reactant: COc1cc(C(=O)Cl)on1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc(C(=O)N2CCOc3ccncc32)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 10 ml flask, 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (100 mg, 0.73 mmol) and 3-methoxy-isoxazol-5-carbonyl chloride (131 mg, 0.80 mmol) were dissolved in dichloromethane. Triethylamine (0.51 ml, 3.65 mmol) was added thereto and then stirred at room temperature for 2 hours. After completion of the reaction by adding water dropwise, the reaction mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on amine silica eluting with a solvent of dichloromethane:methanol=30:1. The fractions containing the product were collected and evaporated to obtain the target compound 43, i.e., (2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-(3-methoxy-isoxazol-5-yl)-methanone, as pale-brown solid (149 mg, 78%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[N:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([NH:27][CH2:28][C@@H:29]3[C@H:34]([CH3:35])[CH2:33][CH2:32][CH2:31][NH:30]3)=[N:24][C:23]=2[CH:36]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([NH:27][CH2:28][C@@H:29]3[C@H:34]([CH3:35])[CH2:33][CH2:32][CH2:31][N:30]3[C:7]([C:6]3[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[C:11]3[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[N:12]=3)=[O:9])=[N:24][C:23]=2[CH:36]=1
Reactant: Cc1ccc(-c2ccnc(C)n2)c(C(=O)O)c1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1nc2cc(Cl)ccc2o1
Product: Cc1ccc(-c2ccnc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-methyl-2-(2-methylpyrimidin-4-yl)benzoic acid and 5-chloro-N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 490 [M+1]+.
Reaction SMILES: C([O:4][CH:5]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:8]=2[N:7]([CH3:23])[C:6]1=[O:24])(=O)C.C(C1N=C(C2C=CC=CC=2Cl)C2C=CC(C(F)(F)F)=CC=2N(C)C1=O)(=O)C1C=CC=CC=1>>[CH3:23][N:7]1[C:6](=[O:24])[CH:5]([OH:4])[N:11]=[C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:9]2[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:8]1=2
Reactant: CC(=O)OC1N=C(c2ccccc2)c2cc(Cl)ccc2N(C)C1=O
Agent: CN1C(=O)C(C(=O)c2ccccc2)N=C(c2ccccc2Cl)c2ccc(C(F)(F)F)cc21
Product: CN1C(=O)C(O)N=C(c2ccccc2)c2cc(Cl)ccc21

Procedure:
When the above procedure is carried out and in place of 205 g. of O-acetyl temazepam there is used a corresponding quantity of 3-benzoyl-5-(o-chlorophenyl)-1,3-dihydro-1-methyl-8-trifluoromethyl-2H-1,4-benzodiazepine-2-one or 1,3-dihydro-1-methyl-7-nitro-3-phenacetyl-5-(p-trifluoromethylphenyl)-2H-1,4-benzodiazepine-2-one, there is obtained the corresponding 5-(o-chlorophenyl)-7-trifluoromethyl and 5-(p-trifluoromethylphenyl)-7-nitro analog of temazepam, respectively, in high yield and purity.
Reaction SMILES: C(OC([N:8]([C@H:17]1[CH2:21][CH2:20][C@@H:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[CH2:18]1)[O:9]C(OC(C)(C)C)=O)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:28][C:24]1[CH:23]=[C:22]([C@@H:19]2[CH2:20][CH2:21][C@H:17]([NH:8][OH:9])[CH2:18]2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)ON(C(=O)OC(C)(C)C)[C@H]1CC[C@@H](c2cccc(F)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: ON[C@H]1CC[C@@H](c2cccc(F)c2)C1
Temperature: 0 °C
Yield: 64 %

Procedure:
To a solution of the compound prepared in Step 5, above (3.2 g, 17 mmol), PPh3 (6.06 g, 22 mmol), and N,O-di-tert-butoxycarbonylhydroxylamine (4.5 g, 18 mmol) in THF (15 ml), cooled to −40° C., was added dropwise a solution of diethylazodicarboxylate (3.8 ml, 22 mmol) in THF (10 ml). The reaction mixture was warmed to room temperature overnight and the solvent removed under reduced pressure. Chromatography on silica gel (ethyl acetate/hexane, 1:9) gave 6.7 g of the crude N,O-di-tert-butoxycarbonyl-N-[cis-3-(3-fluorophenyl)cyclopentyl]hydroxylamine. To a stirred solution of the protected hydroxylamine obtained as above in CH2Cl2 (40 ml), cooled to 0° C., was slowly added trifluoroacetic acid (12.5 ml). The reaction mixture was allowed to warm to room temperature for 6 hours and then solvent was evaporated off. The resultant residue was covered with saturated aqueous NaHCO3 (50 ml) and extracted with CH2Cl2 (2×100 ml). The combined extracts were washed with brine (50 ml) and dried over MgSO4, and solvent was removed under reduced pressure. Chromatography on silica gel (ethyl acetate/hexane, 1:2) afforded the title compound (1.9 g, 64% yield) as a yellow solid.
Reaction SMILES: [C:1]([C:9]1[N:13](C)[N:12]=[N:11][N:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C#N)C1C=CC=CC=1.[N-]=[N+]=[N-].[NH4+]>>[CH2:1]([C:9]1[NH:10][N:11]=[N:12][N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1nnnc1C(=O)c1ccccc1
Agent: [N-]=[N+]=[N-]
Agent: [NH4+]
Solvent: N#CCc1ccccc1
Product: c1ccc(Cc2nnn[nH]2)cc1

Procedure:
Another process for the preparation of 5-benzoyl-1-methyltetrazole is known from J. Amer. Chem. Soc. 1963, 85, 2967-2976. Benzyl cyanide is reacted with ammonium azide to give 5-benzyltetrazole and then oxidized with chromium trioxide to give 5-benzoyltetrazole. The methylation to 5-benzoyl-1-methyltetrazole takes place with diazomethane. This synthesis route is likewise disadvantageous as regards safety and economical aspects.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH2:12](O)[C:13]([Cl:16])([Cl:15])[Cl:14].C(Cl)CCl.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[Cl:14][C:13]([Cl:16])([Cl:15])[CH2:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[CH2:2][Br:1]
Reactant: OCC(Cl)(Cl)Cl
Reactant: O=C(O)c1ccccc1CBr
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: O=C(OCC(Cl)(Cl)Cl)c1ccccc1CBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.7 %

Procedure:
To a suspension of 2-(bromomethyl)benzoic acid (1.0 g, 4.65 mmol), β-trichloroethanol (0.54 mL, 5.58 mmol) and DMAP (0.057 g, 0.465 mmol) in DCM (20 mL) was added EDC×HCl (1.34 g, 6.98 mmol) at 0° C. The solution was stirred at 0° C. for 0.5 h and thereafter allowed to reach rt and stirred overnight. Water was added and the phases were separated through a phase separator. The organic portion was concentrated and the crude was submitted to flash chromatography using heptane and EtOAc (90/10) as eluent to yield the titled compound (0.80 g, 50%) as an oil; 1H NMR (400 MHz, CDCl3): δ 4.99 (s, 2H), 5.08 (s, 2H), 7.46 (m, 1H), 7.60 (m, 2H), 8.13 (d, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH3:16])=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7])([O-])=O.[NH4+].[Cl-]>CO.O.[Fe]>[NH2:1][C:4]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH3:16])=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7]
Reactant: CCCOc1ccc([N+](=O)[O-])c(C(N)=O)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CCCOc1ccc(N)c(C(N)=O)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a mixture of 2-nitro-5-propoxy-benzamide (1.20 g, 5.36 mmol) in MeOH-H2O (v/v, 3:1, 60 mL) was added NH4Cl (2.84 g, 53.6 mmol) and Fe (2.99 g, 53.6 mmol). The resulting mixture was stirred at 60° C. for 3 h. After the reaction was completed, the mixture was cooled to room temperature and the iron was filtered off. The filtrate was concentrated to 15 mL and the formed precipitate was collected and dried in vacuo to give 1.02 g of ii-a as a pale yellow solid (98%). LCMS m/z=1781 (M−16), 195.1 (M+1) (Method B) (retention time=1.46 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]2[N:19]3[N:20]=[C:21](S(C)(=O)=O)[N:22]=[C:18]3[N:17]=[C:16]([CH3:27])[CH:15]=2)[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:11])([F:10])[F:9].[O-:28][CH2:29][CH3:30].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]2[N:19]3[N:20]=[C:21]([O:28][CH2:29][CH3:30])[N:22]=[C:18]3[N:17]=[C:16]([CH3:27])[CH:15]=2)[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: CC[O-]
Reactant: Cc1cc(Nc2cc(F)c(C(F)(F)F)c(F)c2)n2nc(S(C)(=O)=O)nc2n1
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc2nc(C)cc(Nc3cc(F)c(C(F)(F)F)c(F)c3)n2n1
Temperature: 120 °C

Procedure:
Intermediate 12 (0.29 g, 0.712 mmol) was added to sodium ethoxide (ALDRICH, 0.145 g, 2.136 mmol) in ethanol (5 mL). The mixture was heated under microwave irradiation at 120° C. for 30 minutes. Solvent was removed under vacuum and the crude mixture was purified by flash chromatography (Si, eluting Hexane/EtOAc mixtures from 90:10 to 0:100%) to yield the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>O.COCCO>[C:12]1([NH:11][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: Cl
Solvent: O
Solvent: COCCO
Product: O=[N+]([O-])c1cnccc1Nc1ccccc1

Procedure:
A solution of 4-chloro-3-nitropyridine (II: R′=4-aza, halogen=Cl) (3.22 g, 0.020 mol), aniline (III: R1′=H) (1.85 mL, 0.020 mol) and conc. HCl (0.17 mL, 0.02 mol) in 1:1 water/2-methoxyethanol (40 mL) was refluxed for 18 hours, then concentrated to dryness. The residue was partitioned between saturated aqueous NaHCO3 and EtOAc, and the organic portion was worked up to give an oil which was chromatographed on silica gel. Petroleum ether eluted foreruns, while EtOAc/petroleum ether (1:1) gave 4-(N-phenylamino)-3-nitropyridine (VI: R′=4-aza, R1′=H) (2.02 g, 41%); mp (EtOAc/petroleum ether) 119° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:34]=[CH:33][C:9]([NH:10]/[C:11](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)/[C:12]3[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)[N:3]=[CH:2]1.O.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(O)(=O)C.O1CCOCC1>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:34]=[CH:33][C:9]([NH:10]/[C:11](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)/[C:12]3[CH:13]=[CH:14][C:15]([CH2:18][NH:19][C:36](=[O:38])[CH3:37])=[CH:16][CH:17]=3)=[CH:8][CH:7]=2)[N:3]=[CH:2]1
Reactant: NCc1ccc(/C(Nc2ccc(-c3c[nH]cn3)cc2)=C2/C(=O)Nc3ccc([N+](=O)[O-])cc32)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC(=O)NCc1ccc(/C(Nc2ccc(-c3c[nH]cn3)cc2)=C2/C(=O)Nc3ccc([N+](=O)[O-])cc32)cc1

Procedure:
3-{(Z)-1-[4-(1H-imidazol-4-yl)anilino]-1-(4-aminomethyl-phenyl)methylidene}-5-nitro-2-indolinone×H2O is stirred into dry dioxane together with 1.2 equivalents of acetic anhydride and a few drops of glacial acetic acid overnight at ambient temperature. The mixture is evaporated down in vacuo and the evaporation residue is triturated with ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:31])([C@H:16]([S:18][C@@H:19]1[CH2:24][O:23][C@@H](C2C=CC=CC=2)[O:21][CH2:20]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C([O-])(O)=O.[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:31])([C@H:16]([S:18][CH:19]([CH2:20][OH:21])[CH2:24][OH:23])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[C@@H](S[C@H]1CO[C@H](c2ccccc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
In 3.5 ml of methanol were dissolved 353 mg of (2R,3R)-2-(2,4-difluorophenyl)-3-[[trans-2-phenyl-1,3-dioxan-5-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol as described in Example 40, and 0.35 ml of a 4N HC1-dioxane solution were added to the solution, followed by stirring of the resulting mixture at room temperature for 30 minutes. To the reaction mixture were added 250 mg of a NaHCO3 powder, and the mixture was stirred for 10 minutes, followed by filtration of the reaction mixture and concentration of the filtrate under reduced pressure. The thus obtained oil was subjected to column chromatography using 5 g of silica gel and eluted with 10% methanol-ethyl acetate to obtain 179 mg (yield: 88%) of the title compound as a viscous oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[CH3:12][C:13]1[N:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[O:19][C:16]1[CH:15]=[CH:14][C:13]([CH3:12])=[N:18][CH:17]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Cc1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2C)cn1
Temperature: 110 °C

Procedure:
The mixture of 1-chloro-2-methyl-4-nitrobenzene (17.2 g), 6-methylpyridin-3-ol (12 g) and Cs2CO3 (39 g) in DMF (150 mL) was heated at 110° C. for 4 h. The solid was filtered and water (100 mL) and EtOAc (200 mL) were added. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained yellow solid was used for the next step directly.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([SH:20])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:21]([O:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:33][S:20][C:15]2[C:12]3[CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10][C:11]=3[CH:18]=[CH:17][C:16]=2[Cl:19])=[CH:35][CH:36]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(S)c2CC1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(OCc4ccccc4)cc3)c2CC1
Yield: 67.3 %

Procedure:
Dissolve 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (706 mg, 1.84 mmol) in methanol (20 mL). Add potassium hydroxide (3.5 g, 55 mmol) and heat the mixture at reflux for 3h. Cool to ambient temperature. Pour reaction in saturated aqueous NH4Cl solution. Extract three times with EtOAc. Combine organic extracts, dry over Na2SO4 and concentrate in vacuo to obtain crude 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (602 mg, 100%). Dissolve 3-tert-butoxycarbonyl-7-chloro-6mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (282 mg, 0.9 mmol) in acetone (30 mL). Add 4-benzyloxybenzyl chloride (251 mg, 1.08 mmol), potassium carbonate (powder) (373 mg, 2.7 mmol) and potassium iodide (powder) (15 mg, 0.1 mmol) and reflux for 16 h. Cool the reaction to ambient temperature, dilute with acetone, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 17:3) to give 6-(4-benzyloxybenzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (309 mg, 67%). MS (ES+) m/z: 510 (M+H)+.
Reaction SMILES: [H-].[Na+].[Br-].[C:4]([CH2:7][CH2:8][CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:6])=[O:5].[CH:30]([CH2:32][CH:33]1[O:40][CH:36]2[CH2:37][CH2:38][CH2:39][CH:35]2[CH:34]1/[CH:41]=[CH:42]/[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=O.[OH-].[Na+]>CS(C)=O>[C:4]([CH2:7][CH2:8][CH2:9][CH2:10]/[CH:30]=[CH:32]\[CH:33]1[O:40][CH:36]2[CH2:37][CH2:38][CH2:39][CH:35]2[CH:34]1/[CH:41]=[CH:42]/[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])([OH:6])=[O:5]
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCC/C=C/C1C(CC=O)OC2CCCC21
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCC/C=C/C1C(/C=C\CCCCC(=O)O)OC2CCCC21
Temperature: 0 °C

Procedure:
A mixture of 0.194 g. (0.007952 mole) of sodium hydride (free of mineral oil) and 5.5 ml. of dimethylsulfoxide is heated to 70° C. until gas evolution ceases under a nitrogen atmosphere. The resulting solution is cooled below room temperature and treated with a solution of 1.400 g. (0.00316 mole) of 4-carboxybutyltriphenyl phosphonium bromide [E. J. Corey et al., J. Am. Chem. Soc., 91, 5675 (1969)] in 6 ml. of dimethylsulfoxide. To the resulting red solution is added 0.738 g. (0.00263 mole) of 2-(formylmethyl)-3-(1-trans-octenyl)-1,1-dioxolano cyclopentane in 2 ml. of dimethylsulfoxide and the mixture is stirred at room temperature for 2.25 hours. The mixture is poured into ice water, sodium hydroxide solution is added to pH 12, and the neutral materials are extracted with diethyl ether. The basic phase is acidified with dilute hydrochloric acid and is extracted with diethyl ether. The organic phase is washed with water and saturated brine, dried (Na2SO4), and evaporated to a semicrystalline mass. The latter is triturated with hot hexane, the solids are filtered off, and the filtrate is evaporated to yield an oil. IR: 1705, 1040, 970, 722 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:28][C:29]([C:31]2[C:32](=[O:44])[N:33]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[N:34]=[CH:35][CH:36]=2)=[O:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:16]=[C:17](I)[C:10]=12.[N:45]1([C:51]([C:53]2[CH:58]=[CH:57][C:56](B(O)O)=[CH:55][CH:54]=2)=[O:52])[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[F:1][C:2]1[CH:3]=[C:4]([NH:28][C:29]([C:31]2[C:32](=[O:44])[N:33]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[N:34]=[CH:35][CH:36]=2)=[O:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:16]=[C:17]([C:56]3[CH:55]=[CH:54][C:53]([C:51]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[O:52])=[CH:58][CH:57]=3)[C:10]=12
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCOCC1
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: COCCOC
Product: COc1ccc(Cn2nc(-c3ccc(C(=O)N4CCOCC4)cc3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 70 °C

Procedure:
To a small round bottom flask was added N-(3-fluoro-4-(3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (30 mg, 0.0425 mmol), 4-(morpholine-4-carbonyl)phenylboronic acid (20.0 mg, 0.0849 mmol), and Pd(PPh3)4 (2.45 mg, 0.00212 mmol) and the mixture was dissolved in 3:1 DME:aqueous 2N Na2CO3 (2 mL). The mixture was stirred at 70° C. until the reaction was determined to be complete by LC/MS (1-18 hours). The reaction mixture was then partitioned between ethyl acetate (15 mL) and water (30 mL). The organic layer washed with brine, dried over Na2SO4 and evaporated to afford crude product. Purified by silica gel column chromatography (Biotage 12M) eluting with 1-5% MeOH/CHCl3 to give the desired product. Yield: 40.2 mg, 81%. LRMS (APCI pos) m/e 770.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:16]=2[F:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:28][OH:29].N1C=CC=CC=1.O>C(OCC)(=O)C.CCCCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:16]=2[F:25])=[N:28][OH:29])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2cccc(C(F)(F)F)c2F)CC1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N1CCC(C(=NO)c2cccc(C(F)(F)F)c2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
A mixture of 4-(2-Fluoro-3-trifluoromethyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (9.00 g, 24.0 mmol), hydroxylamine hydrochloride (2.00 g, 28.8 mmol) and pyridine (50 mL) was stirred at room temperature under nitrogen overnight. The yellow reaction solution was poured into cold water (500 mL) and the mixture aged at 0° C. for 1 h. The product was collected by filtration, washed with water, and dried under vacuum at 50° C. to afford 9.54 g of a while solid. Trituration of the solid with hot 25% ethyl acetate/heptane afforded 8.50 g (91%) of the desired product as a white solid. Proton NMR showed product to be a 3.8 to 1 mixture of isomers.