Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:10]2[CH2:11][C:12]3[C:17]([CH:9]12)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH2:18]([C:25]1[CH:26]=[CH:27][C:28]([O:31][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]2[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1C2Cc3ccccc3C21
Reactant: Oc1ccc(Cc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@H]1Cc2ccccc2[C@H]1Oc1ccc(Cc2ccccc2)cc1
Yield: 38.7 %

Procedure:
The title compound was prepared in a similar manner to Preparation 18 from (±)N-tert-butoxycarbonyl-1,2-iminoindane (2 g, 8.7 mmol), 4-benzylphenol (1.59 g, 8.7 mmol), pyridinium p-toluenesulfonate (30 mg) and chloroform (50 ml). After a reaction time of 3 h, the reaction was diluted with chloroform (50 ml) then washed sequentially with saturated aq. sodium bicarbonate, water and brine. After drying over Na2 SO4, volatiles were removed in vacuo and the residue subjected to column chromatography on neutral alumina eluting with 10% diethyl ether in hexanes to afford the title compound (1.4 g) as a foam
Reaction SMILES: Cl.[C@@H:2]12[N:9]([CH2:10][C@@H:11]([C:13]3[C:14]([CH3:23])=[C:15]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:22])[O:17][CH2:16]4)[OH:12])[C@@H:6](CC1)[CH2:5][NH:4][CH2:3]2.[CH3:24][C@@H:25]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([CH:35]3[CH2:37][O:36]3)[CH:32]=2)[C:27](=[O:38])[O:26]1.CCN(C(C)C)C(C)C>C(O)C>[OH:36][CH:35]([C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:38])[O:26][C@H:25]([CH3:24])[CH2:34]2)[CH2:37][N:4]1[CH2:3][CH2:2][N:9]([CH2:10][C@@H:11]([OH:12])[C:13]2[C:14]([CH3:23])=[C:15]3[C:19](=[CH:20][CH:21]=2)[C:18](=[O:22])[O:17][CH2:16]3)[CH2:6][CH2:5]1
Reactant: C[C@@H]1Cc2cc(C3CO3)ccc2C(=O)O1
Reactant: Cc1c([C@@H](O)CN2[C@@H]3CC[C@H]2CNC3)ccc2c1COC2=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1c([C@H](O)CN2CCN(CC(O)c3ccc4c(c3)C[C@@H](C)OC4=O)CC2)ccc2c1COC2=O
Temperature: 80 °C

Procedure:
To a solution of (R)-5-(1-hydroxy-2-(piperazin-1-yl)ethyl)-4-methylisobenzofuran-1(3H)-one (INTERMEDIATE 12) (150 mg, 0.54 mmol) in ethanol (2 mL) was added (3R)-3-Methyl-6-(oxiran-2-yl)-3,4-dihydro-1H-isochromen-1-one (INTERMEDIATE 23) (110 mg, 0.54 mmol) and Hunig's base (95 uL, 0.54 mmol). The mixture was heated to 80° C. for 20 hours. The solvent was removed using rotary evaporation and the crude oil was purified via by silica gel chromatography (0-7% MeOH in DCM) to yield (3R)-6-(1-hydroxy-2-(4-((S)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperazin-1-yl)ethyl)-3-methylisochroman-1-one as a diastereomeric mixture.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:19])[N:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:5]=[CH:6][C:7]=1Cl.[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][OH:26])=[CH:23][CH:22]=1.[OH-].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:3](=[O:19])[N:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:5]=[CH:6][C:7]=1[O:26][CH2:25][C:24]1[CH:27]=[CH:28][C:21]([Cl:20])=[CH:22][CH:23]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccc(C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=c1c(Cl)c(OCc2ccc(Cl)cc2)cnn1-c1ccc(C(F)(F)F)cc1
Yield: 72.4 %

Procedure:
In 50 ml of N,N-dimethylformamide were dissolved 2.0 g (6.5 m mol) of 4,5-dichloro-2-(4-trifluoromethylphenyl)-3(2H)-pyridazinone and 0.92 g (6.5 m mol) of p-chlorobenzyl alcohol, and thereto was added 0.51 g of powdery potassium hydroxide. Then, the procedures in Synthesis Example 2 were repeated to give 1.94 g of the intended compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][N:3]=1.[CH2:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>C(OCC)(=O)C>[CH2:13]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([Cl:12])=[N:4][N:3]=2)[CH2:22][C:21]1=[O:26])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: O=C1CNCCN1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=C1CN(c2nnc(Cl)c3ccccc23)CCN1Cc1ccccc1

Procedure:
1,4-dichlorophthalazine (500 mg, 2.51 mmol), 1-benzylpiperazin-2-one (526 mg, 2.76 mmol), potassium carbonate (521 mg, 3.01 mmol), and N-methylpyrrolidinone (3 mL) were heated at 110° for 8 hours. The reaction was taken up in ethyl acetate (80 mL) and washed with aqueous K2CO3 (10%), water, and saturated sodium chloride. The organics were dried (MgSO4) and evaporated to give an orange oil. Chromatography over silica gel with a gradient of hexanes/0-40% ethyl acetate gave an off-white solid. MS (M+H)+=353.9.
Reaction SMILES: [Cl:1]Cl.[CH3:3][N:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)[CH:7]=[CH:6][C:5]1=[O:16]>C(O)(=O)C>[Cl:1][C:6]1[C:5](=[O:16])[N:4]([CH3:3])[CH:9]=[C:8]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)[CH:7]=1
Reactant: ClCl
Reactant: Cn1cc(-c2cnccn2)ccc1=O
Solvent: CC(=O)O
Product: Cn1cc(-c2cnccn2)cc(Cl)c1=O

Procedure:
About 1.2 ml of condensed chlorine gas is introduced into a reaction mixture comprising 1-methyl-5-(2-pyrazinyl)-2-pyridone (3.2 g) dissolved in 200 ml of glacial acetic acid. After all the chlorine is added, stirring is stopped and the solid product filtered, washed with ether and air dried. The dried solid is suspended in distilled H2O to which saturated potassium carbonate is added until the pH is greater than 7. The resulting white solid is filtered, recrystallized from isopropanol, and NMR and IR indicate that it is the desired 3-chloro-1-methyl-5-(2-pyrazinyl)-2-pyridone compound, M.P. 197°-198° C.
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.[NH:25]([C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][C:35]=1[O:43][CH3:44])=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[C:26]1([NH:25][C:32](=[O:33])[C:34]2[CH:39]=[CH:38][C:37]([C:2]3[C:10]4[C:5](=[N:6][CH:7]=[N:8][C:9]=4[NH2:11])[N:4]([C@H:12]4[CH2:17][CH2:16][C@H:15]([N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)[CH2:14][CH2:13]4)[N:3]=3)=[CH:36][C:35]=2[O:43][CH3:44])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1cc(B(O)O)ccc1C(=O)Nc1ccccc1
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1C(=O)Nc1ccccc1

Procedure:
trans-3-Iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (266 mg, 0.604 mmol), 4-(anilinocarbonyl)-3-methoxyphenylboronic acid (180 mg, 0.664 mmol), palladium tetrakistriphenyphosphine (42 mg, 0.036 mmol) and sodium carbonate (154 mg, 1.449 mmol) were mixed with ethylene glycol dimethyl ether (8 mL) and water (4 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 flash column chromatography using dichloromethane/methanol (95:5) as mobile phase to give trans-N1-phenyl-4-{4-amino-1-[-4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxybenzamide (226 mg, 69%). 1H NMR (CDCl3) δ 1.58 (m, 4H), 2.17 (m, 7H), 2.32 (s, 3H), 2.52 (m, 2H), 2.69 (2.69, 3H), 4.16 (s, 3H), 4.78 (m, 1H), 5.49 (bs, 2H), 7.14 (m, 1H), 7.43 (m, 4H), 7.69 (m, 2H), 8.44 (m, 2H), 9.77 (s, 1H). LC/MS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min.(B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.5 mL/min.): MH+=541.2, Rt=2.61 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[S:11].[C:21](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[N:12][C:13](=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[S:11][CH3:21]
Reactant: O=C([O-])[O-]
Reactant: O=C(NC(=S)Nc1c(Cl)cccc1Cl)c1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CSC(=NC(=O)c1ccccc1)Nc1c(Cl)cccc1Cl
Yield: 85 %

Procedure:
19.5 g (0.06 M) of N-(2,6-dichlorophenyl)-N'-benzoyl thiourea, 5.5 g (0.04 M) of ground potassium carbonate, 5.1 ml (0.08 M) of methyliodide and 200 ml of acetone are boiled in a reflux for 4 hours under energetic shaking. The acetone is distilled off. 200 ml of water are added to the residue and it is then filtered. The sediment on the filter is washed to a neutral pH. After drying 20.2 g (99% of the theoretical yield) of N-(2,6-dichlorophenyl)-N'-benzoyl-S-methylisothiourea are obtained with melting point 127-129° C. This product being recrystallized from ethyl alcohol gives the corresponding isothiourea with a melting point of 128°-130° C. and 85% yield of the theoretical one.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[F:10].N1C=CN=C1.[Cl-].[CH:17]([SiH:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])([CH3:19])[CH3:18]>CN(C=O)C>[F:8][C:7]1[CH:6]=[C:5]([O:9][Si:20]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:17]([CH3:19])[CH3:18])[CH:4]=[C:3]([F:10])[C:2]=1[NH2:1]
Reactant: Nc1c(F)cc(O)cc1F
Reactant: CC(C)[SiH](C(C)C)C(C)C
Agent: [Cl-]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1cc(F)c(N)c(F)c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A mixture of 4-amino-3,5-difluorophenol (580 mg), imidazole (354 mg), triisopropylsilane chloride (848 mg) and DMF (12 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a pale-brown oil (1.0 g).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:4]=[CH:3]1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:17][C:3]1[C:2](=[O:1])[NH:7][C:6]([C:8]([F:9])([F:10])[F:11])=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(=O)[nH]c1C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(Br)c(=O)[nH]c1C(F)(F)F
Temperature: 80 °C
Yield: 74.9 %

Procedure:
To a solution of ethyl 6-oxo-2-(trifluoromethyl)-1,6-dihydropyridine-3-carboxylate (Organic Process Research and Development 1997, 1, 370-378; 0.10 g) in carbon tetrachloride was added N-bromosuccinimide (0.083 g). The mixture was heated at 80° C. for 24 h. Evaporation and the purification by flash column chromatography gave the subtitle compound as a colourless solid (0.10 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1.[Cl:12][C:13]1[CH:14]=[C:15](I)[N:16]2[C:21]=1[CH:20]=[N:19][C:18]([S:22][CH3:23])=[N:17]2.C(=O)([O-])[O-].[Na+].[Na+].O>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.O1CCOCC1>[Cl:12][C:13]1[CH:14]=[C:15]([C:6]2[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:16]2[C:21]=1[CH:20]=[N:19][C:18]([S:22][CH3:23])=[N:17]2
Reactant: CSc1ncc2c(Cl)cc(I)n2n1
Reactant: COc1ccc(B(O)O)cn1
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: C1COCCO1
Solvent: O
Product: COc1ccc(-c2cc(Cl)c3cnc(SC)nn23)cn1
Temperature: 60 °C
Yield: 81 %

Procedure:
2-Methoxypyridine-5-boronic acid (116 mg, 0.758 mmol), Tetrakis(triphenylphosphine)palladium(0) (46 mg, 0.040 mmol) and 5-Chloro-7-iodo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.152 g, 0.467 mmol) were placed in a vial, followed by 1,4-Dioxane (3.00 mL) and 2.00 M of Sodium carbonate in Water (1.00 mL, 2.00 mmol). The sample was frozen, placed under vacuum, sealed, warmed, refrozen, evacuated, then placed under nitrogen and heated in a 60° C. block. When complete, the sample was partitioned between EtOAc and water (30 mL each), the aq. extracted (EtOAc 3×20 mL) and the comb. organics washed with brine. Purification (ISCO, 12 g, 0-30% EtOAc:Hex) afforded 5-Chloro-7-(6-methoxy-pyridin-3-yl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.116 g, 81%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH2:7])[CH:3]=1.[I-].[K+].[Cl:10][C:11]1[CH:12]=[C:13]([C:18]([C:20]2[N:29]=[C:28](Cl)[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)=[O:19])[CH:14]=[CH:15][C:16]=1[F:17].O>CN(C=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:18]([C:20]2[N:29]=[C:28]([NH:7][C:4]3[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=3)[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)=[O:19])[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: Cc1cc(N)n[nH]1
Reactant: O=C(c1ccc(F)c(Cl)c1)c1nc(Cl)c2ccccc2n1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Nc2nc(C(=O)c3ccc(F)c(Cl)c3)nc3ccccc23)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
To a mixture of 5-methyl-1H-pyrazol-3-amine (0.26 g, 2.68 mmol), potassium iodide (0.26 g, 1.57 mmol), and TEA (0.45 mL, 3.23 mmol) in DMF (30 mL) was added (3-chloro-4-fluorophenyl)(4-chloroquinazolin-2-yl)methanone (0.495 g, 1.54 mmol) and the mixture was stirred at rt overnight. Water was added and the precipitated solid was collected by filtration to afford crude (3-chloro-4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone (458 mg) which was used directly in the next step. LC-MS (ESI) m/z 382 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].N1C=CC=CC=1.O[C:23]1[CH:32]=[C:31]2[C:26]([C:27](=[O:34])[C:28]([CH3:33])=[CH:29][O:30]2)=[CH:25][CH:24]=1>O>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:23]1[CH:32]=[C:31]2[C:26]([C:27](=[O:34])[C:28]([CH3:33])=[CH:29][O:30]2)=[CH:25][CH:24]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1coc2cc(O)ccc2c1=O
Solvent: c1ccncc1
Solvent: O
Product: Cc1coc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under nitrogen atmosphere, 0.23 ml of trifluoromethansulfonic anhydride was added at 0° C. to 3 ml solution of pyridine with 120 mg of 7-hydroxy-3-methyl-4H-chromen-4-one, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and extracted with ethyl acetate. Ethyl acetate layer was washed with saturated saline solution, and then dried with anhydrous sodium sulfate. After distilling out the solvents under reduced pressure, residues were separated and purified with silicagel chromatography (hexane/ethyl acetate=10/1) to obtain 183 mg of the above compound as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([NH:5][C:6]1[NH:7][C:8](=O)[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[N:18]=1)=[O:4].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:8]1[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[N:18]=[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:21])([CH3:20])[CH3:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)C(=O)Nc1nc2[nH]c3ccccc3c2c(=O)[nH]1
Product: CC(C)(C)C(=O)Nc1nc(Cl)c2c(n1)[nH]c1ccccc12
Yield: 59 %

Procedure:
In a 50 mL R.B.F. was placed 5 (56 mg, 0.17 mmol) and phosphoryl trichloride (15 mL). The mixture was stirred and heated at reflux for 4 hours. The phosphoryl trichloride was evaporated under reduced pressure using a vacuum aspirator. The resulting residue was cooled in an ice and water mixture, and neutralized with ammonium hydroxide solution to yield a precipitate that was filtered and dried over P2O5. The filterate was extracted with chloroform and dried over sodium sulfate. The dry precipitate and filterate were combined and evaporated to provide 35 mg of 6 as a brown solid in 59% yield. Compound 6 was used without further purification for the subsequent step. TLC Rf 0.65 (chloroform-methanol 10:1); mp 234° C.; 1H NMR (DMSO-d6) δ 1.24 (s, 9H, C(CH3)3), 7.36-8.17 (m, 4H, Ar—H), 10.25 (s, 1H, 2-NH, exch), 12.55 (s, 1H, 9-NH, exch). Anal. Calculated (C15H15ClN4O. 0.15H2O): C, 58.98; H, 5.04; N, 18.34; Cl, 11.60. Found: C, 59.00; H, 5.09; N, 17.97; Cl, 11.83.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:20])[O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1)([CH3:5])[CH3:4].N1C=CC=CC=1.[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>ClCCl>[N+:27]([C:30]1[CH:31]=[CH:32][C:33]([S:36]([O:1][CH2:2][C:3]([CH3:4])([C:6]2[O:10][N:9]=[C:8]([NH:11][C:12]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:20])[CH:7]=2)[CH3:5])(=[O:38])=[O:37])=[CH:34][CH:35]=1)([O-:29])=[O:28]
Reactant: CC(C)(CO)c1cc(NC(=O)Oc2ccccc2)no1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(COS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1cc(NC(=O)Oc2ccccc2)no1
Temperature: 35 °C
Reaction time: 15 h
Yield: 59.5 %

Procedure:
To a stirred solution of phenyl 5-(1-hydroxy-2-methylpropan-2-yl)isoxazol-3-ylcarbamate (prepared as described in Example 131A steps 1 through 4) (250 mg, 0.91 mmol) and pyridine (0.15 mL, 1.81 mmol) in dichloromethane (5 mL) at 0° C., was added dropwise, 4-nitrophenylsulfonyl chloride (245 mg, 1.08 mmol) in dichloromethane (3 mL). The reaction mixture was warmed to 35° C. and stirred for a further 15 h. Concentration under reduced pressure gave the crude product which was purified via silica gel column chromatography (eluting with 20% ethyl acetate in petroleum ether) to afford 2-methyl-2-(3-(phenoxycarbonylamino)isoxazol-5-yl)propyl 4-nitrobenzenesulfonate (250 mg, 60%) as a yellow solid. 1H NMR (400 MHz, CDCl3) 88.36-8.39 (m, 2H), 8.01-8.03 (m, 2H), 7.88 (m, 1H), 7.43-7.45 (m, 2H), 7.21-7.31 (m, 3H), 6.54 (s, 1H), 4.19 (s, 2H), 1.38 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cl:14]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:1][C:2]1[C:3]([CH3:13])=[C:4]([Cl:14])[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cc(Br)c(C)cc1O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(C)c(Cl)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
To a solution of methyl 5-bromo-2-hydroxy-4-methylbenzoate (4.54 g) in DMF (34.0 mL) was added N-chlorosuccinimide (2.47 g), and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (5.20 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[F:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][NH:29][CH3:30])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][N:29]([CH3:30])[CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]2)=[CH:26][CH:25]=1
Reactant: CNCc1ccc(F)cc1
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Product: CN(CCn1cnc(-c2cc(C(=O)O)ccn2)c1)Cc1ccc(F)cc1
Yield: 23 %

Procedure:
The title compound was prepared in 23% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate and 4-fluoro-N-methylbenzylamine according to the procedure for the preparation of Example 58. 1H NMR (400 MHz, DMSO): δ 2.18 (3H, s), 2.69 (2H, t, J=6 Hz), 3.51 (2H, s), 4.00 (1H, t, J=5.7 Hz), 4.15 (1H, t, J=5.9 Hz), 7.03 (2H, t, J=8.9 Hz), 7.20 (2H, dd, J=8.7 Hz and 2.8 Hz), 7.52 (1H, s), 7.72 (1H, d, J=1.7 Hz), 7.78 (1H, s), 8.26 (1H, s), 8.46 (1H, d, J=4.3 Hz). [M+H] Calc'd for C19H19FN4O2, 355. Found, 355.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[O:5][C:6]=1Br.Cl[Zn][CH3:14]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[O:5][C:6]=1[CH3:14]
Reactant: C[Zn]Cl
Reactant: COC(=O)c1cc(Br)c(Br)o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)c(C)o1
Reaction time: 10 h
Yield: 72 %

Procedure:
To a solution of methyl 4,5-dibromo-2-furancarboxylate (4.5 g, 15.85 mmol) and BIS(TRIPHENYLPHOSPHINE)PALLADIUM(II) CHLORIDE (0.38 g, 0.541 mmol) in THF (100 mL) at RT was added chloro(methyl)zinc (15 mL, 30 mmol) dropwise. After stirring for 10 h, the reaction was quenched with NH4Cl (sat'd) (50 mL). The mixture was extracted with EtOAc (50 mL×3), and the collected organic layers were dried over MgSO4. Solvent was removed under vacuum and the resulting residue was purified via column chromatography (silica, EtOAc/Hex 10-20%) to give the title compound (2.5 g, 72%) as a white solid: LC-MS (ES) m/z 220 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([O:18][CH3:19])[CH:10]=1)C1C=CC=CC=1.[H][H]>O1CCCC1.CO.[C].[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]=1[O:18][CH3:19]
Reactant: [H][H]
Reactant: COc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(O)ccc1N
Reaction time: 8 h

Procedure:
1-Benzyloxy-3-methoxy-4-nitrobenzene (11.0 g) was dissolved in tetrahydrofuran (100 ml)-methanol (100 ml), and then 10% palladium carbon (5.0 g) was added thereto, followed by replacing with hydrogen inside the system and stirring overnight. After replacing with nitrogen inside the system, the reaction mixture was filtered to remove the catalyst, which was washed with tetrahydrofuran, ethyl acetate and methanol in this order. The filtrate was concentrated under a reduced pressure to give a residue, which was dried in vacuum to provide the titled compound (5.88 g, quantitatively) as brown powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH:19](=O)[CH2:20][CH3:21]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:13]([CH2:19][CH2:20][CH3:21])[CH2:12][CH2:11][CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1
Reactant: CCC=O
Reactant: COC(=O)C1=Cc2cc(Br)ccc2NCCCC1
Solvent: O
Product: CCCN1CCCCC(C(=O)OC)=Cc2cc(Br)ccc21
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a solution of methyl 9-bromo-2,3,4,5-tetrahydro-1H-1-benzoazonin-6-carboxylate (2.0 g) in 1,27-dichloroethane (20 ml) were added propion aldehyde (1.87 g) and triacetoxy sodium borohydride (4.11 g) and the mixture was stirred overnight. Water was added and the mixture was extracted with ethyl acetate, after which it was washed with aqueous saturated sodium bicarbonate solution and saturated brine, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give methyl 9-bromo-1-propyl-2,3,4,5-tetrahydro-1H-1-benzoazonin-6-carboxylate (2.15 g) as a yellow oily material.