Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:11]I>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH3:11])[N:7]=1
Reactant: CI
Reactant: Nc1ccc(O)nn1
Agent: [Na+]
Agent: [OH-]
Product: Cn1nc(N)ccc1=O
Temperature: 85 °C
Reaction time: 2.5 h
Yield: 23.9 %

Procedure:
A mixture of 6-aminopyridazin-3-ol (2 g, 18.00 mmol), NaOH (0.720 g, 18.00 mmol) and MeI (1.126 mL, 18.00 mmol) was stirred for 2.5 hr at 85° C. under Ar. The reaction mixture was concentrated. The crude material was purified by silica gel column chromatography (NH3 1%/CH2Cl2/MeOH 4-7%) to afford the title product (538 mg, 4.30 mmol, 24% yield) as a yellow solid. tR: 0.25 min (LC-MS 2); ESI-MS: 126 [M+H]+ (LC-MS 2); Rf=0.36 (CH2Cl2/MeOH 9:1).
Reaction SMILES: C(O[C:4](=[O:14])[C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:12]Br)C.[C:15]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>CC(O)C>[C:15]([C:19]1[CH:20]=[CH:21][C:22]([N:23]2[CH2:12][C:6]3[C:5](=[C:10]([OH:11])[CH:9]=[CH:8][CH:7]=3)[C:4]2=[O:14])=[CH:24][CH:25]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)c1c(O)cccc1CBr
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: CC(C)O
Product: CC(C)(C)c1ccc(N2Cc3cccc(O)c3C2=O)cc1
Reaction time: 0.17 h

Procedure:
2-Bromomethyl-6-hydroxy-benzoic acid ethyl ester (2.005 g), and 4-t-butylaniline (1.616 g) were put into 4 microwave reaction tubes along with 4.2 mL of iPrOH in each tube. The tubes were subjected to 170° C., 10 min of microwave. The resulting precipitate was collected via filtration and washed with iPrOH to obtain 2-(4-t-butyl-phenyl)-7-hydroxy-2,3-dihydro-isoindol-1-one as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][NH:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([CH3:26])[N:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH:9]2[CH2:15][CH2:14][CH:13]1[CH2:12][N:11]([C:21]([C:20]1[C:19]([CH3:26])=[N:18][C:17]([NH2:16])=[CH:25][CH:24]=1)=[O:22])[CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(N)ccc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Product: Cc1nc(N)ccc1C(=O)N1CC2CCC(C1)N2C(=O)OC(C)(C)C
Yield: 88.1 %

Procedure:
Following general amide formation method 1, 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (279 mg, 1.31 mmol, 1.0 eq) was combined with 6-amino-2-methylnicotinic acid (200 mg, 1.31 mmol, 1.0 eq) which gave 3-(6-Amino-2-methyl-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (400 mg) in 88% yield. MS m/z 346.6 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1.[N+:17]([O-])([OH:19])=[O:18]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: CC(Cc1ccccn1)c1ccc(Br)cc1
Product: CC(Cc1ccccn1)c1ccc(Br)cc1[N+](=O)[O-]

Procedure:
2-(p-Bromophenyl)-1-(2-pyridyl)propane (11.5 g., 0.043 mole) is heated in 80 ml. of concentrated nitric acid (specific gravity 1.42, 69-71%) for 4.5 hr. at 80°C. The solution is cooled, quenched in 300 g. of ice, made alkaline with sodium hydroxide, and extracted with ethyl acetate. The extract washed with water and brine, dried over sodium sulfate, and evaporated affords 12.2 g. (88%) of oily nitrated product of sufficient purity to be used in following "step d". Distillation provides analytically pure 2-(4-bromo-2-nitrophenyl)-1-(2-pyridyl)propane, b.p. 172°-176°C. (0.2 mm. Hg.), nD 29 1.5968.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:12][S:13]([C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[C:18]([F:24])[CH:17]=2)(=[O:15])=[O:14])[N:3]=1.[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH:27]([NH2:34])[CH2:26]1>O1CCOCC1>[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH:27]([NH:34][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[NH:12][S:13]([C:16]3[CH:21]=[C:20]([F:22])[C:19]([F:23])=[C:18]([F:24])[CH:17]=3)(=[O:15])=[O:14])[N:3]=2)[CH2:26]1
Reactant: NC1COc2ccccc21
Reactant: O=S(=O)(Nc1cccc2nc(Cl)ccc12)c1cc(F)c(F)c(F)c1
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cccc2nc(NC3COc4ccccc43)ccc12)c1cc(F)c(F)c(F)c1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
N-(2-Chloro-quinolin-5-yl)-3,4,5-trifluoro-benzenesulfonamide (150 mg, 0.402 mmol) was dissolved in 5 mL dioxane. Argon was bubbled through the solution for 2 minutes to remove oxygen. rac-2,3-Dihydro-benzofuran-3-ylamine (CAS 109926-35-4, 82 mg, 0.607 mmol), sodium tert.-butylate (97 mg, 1.01 mmol), 1,1′-bis(diphenylphosphin)ferrocen (33 mg, 0.06 mmol) and 1,1′-bis(diphenylphosphin)ferrocen-palladium(II) chloride (16 mg, 0.02 mmol) were added. The reaction mixture was stirred in a sealed tube at 120° C. for 6 hours. The solvent was evaporated and the residue purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0->70:30 gradient). The title compound was obtained as a yellow foam (100 mg, 53%), MS: m/e 472.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]([Cl:8])=[CH:3][CH:4]=[C:5]([CH3:7])[CH3:6].Br[CH:10]([C:16]#[N:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[Ca+2]>C(O)C>[C:16]([C:10]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:4]([CH:3]=[C:2]([Cl:8])[Cl:1])[C:5]1([CH3:7])[CH3:6])#[N:17]
Reactant: CC(C)=CC=C(Cl)Cl
Reactant: CCOC(=O)C(Br)C#N
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Product: CCOC(=O)C1(C#N)C(C=C(Cl)Cl)C1(C)C
Yield: 56.5 %

Procedure:
A mixture of 1,1-dichloro-4-methylpenta-1,3-diene (30.2 parts) and ethyl bromocyanoacetate (19.2 parts) is heated in ethanol (100 parts by volume) at 77°-80° C. for 6 hours in the presence of cupric chloride (1.34 parts) and calcium carbonate (10 parts). The crude ethyl 1-cyano-3-(2',2'-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylate is isolated as described in Examples 13-24. The product has a strength of 61.0% and a cis-cyano/trans-cyano ratio of 85.2:14.8. The yield is 56.5%.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH2:13][C:12]3([CH2:18][CH2:17]N(C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[O:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=C1CC[C:30]2([O:34][CH2:33][CH2:32][O:31]2)CC1>>[C:1]1([C:7]#[C:8][C:9]2[CH2:13][C:12]3([CH2:14][CH2:15][C:30]4([O:34][CH2:33][CH2:32][O:31]4)[CH2:17][CH2:18]3)[O:11][N:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(C#Cc1ccccc1)=NO2
Reactant: C=C1CCC2(CC1)OCCO2
Product: C(#Cc1ccccc1)C1=NOC2(CCC3(CC2)OCCO3)C1
Yield: 44.9 %

Procedure:
The title compound was synthesized using the same method described for Compound 1b but using Compound 31a instead of N-Boc-4-methylenepiperidine. After the usual work-up procedure, the title product was purified by automated RP chromatography (Isolera®TM-Biotage; gradient buffer NH4HCO3-MeCN from 40-60 a 20-80. Yield: 44.9%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[C:16](Cl)=[O:17].S1C=CC=C1C(Cl)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:16](=[O:17])[C:15]2[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=[C:13]([F:12])[CH:14]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1cc(F)cc(C(F)(F)F)c1
Agent: O=C(Cl)c1cccs1
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1cc(F)cc(C(F)(F)F)c1

Procedure:
4-Fluoro-3-nitro-phenylamine was reacted with 3-fluoro-5-trifluoromethyl-benzoyl chloride according to the procedure of Example 256a substituting 3-fluoro-5-trifluoromethyl-benzoyl chloride for thiophene-2-carbonyl chloride to provide N-(4-Fluoro-3-nitro-phenyl)-3-fluoro-5-trifluoromethyl-benzamide which was then reacted according to the procedures of Examples 256b and 256c to provide the title product.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:27]2[C:28]([CH3:44])=[CH:29][C:30]([O:33][CH2:34][C:35]3([C:39]([O:41]CC)=[O:40])[CH2:38][CH2:37][CH2:36]3)=[N:31][CH:32]=2)[CH:7]=[CH:8][C:9]=1[C:10]1[N:11]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1>CO>[Cl:3][C:4]1[CH:5]=[C:6]([C:27]2[C:28]([CH3:44])=[CH:29][C:30]([O:33][CH2:34][C:35]3([C:39]([OH:41])=[O:40])[CH2:36][CH2:37][CH2:38]3)=[N:31][CH:32]=2)[CH:7]=[CH:8][C:9]=1[C:10]1[N:11]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:12]=[C:13]([C:15]([F:18])([F:16])[F:17])[N:14]=1
Reactant: CCOC(=O)C1(COc2cc(C)c(-c3ccc(-c4nc(C(F)(F)F)cn4COCC[Si](C)(C)C)c(Cl)c3)cn2)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(OCC2(C(=O)O)CCC2)ncc1-c1ccc(-c2nc(C(F)(F)F)cn2COCC[Si](C)(C)C)c(Cl)c1
Yield: 100.8 %

Procedure:
Methanol (4.3 mL) and 1N aqueous sodium hydroxide solution (1.7 mL) were added to ethyl 1-{[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylate (213 mg), and the mixture was refluxed for 1 hour. Methanol was distilled off under reduced pressure, and the residue was neutralized by 1N hydrochloric acid. The mixture was extracted with ethyl acetate, the organic layer was washed with a saturated brine, and dried over anhydrous magnesium sulfate. After concentrating the mixture under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 95:5) to obtain 1-{[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylic acid (205 mg).
Reaction SMILES: N[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[Br-:12].[Na+].S(=O)(=O)(O)O.[N+]([O-])([O-])=O.[Na+]>O.S([O-])([O-])(=O)=O.[Cu+2]>[Br:12][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: [Br-]
Reactant: CCOC(=O)c1csc(N)n1
Agent: [Cu+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: CCOC(=O)c1csc(Br)n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 19.3 %

Procedure:
Acording to literature reference (Kelly, T. R.; Lang, F. J. Org. Chem. 1996, 61, 4623–4633), crude ethyl 2-amino-4-thiazolecarboxylate (19.0 g, 111 mmol) is combined with sodium bromide (46.7 g, 444 mmol) and copper (II) sulfate (52.4 g, 333 mmol). A portion of 9N sulfuric acid (225 mL) is then added and the reaction mixture is cooled in an ice/salt bath. A solution of sodium nitrate (8.35 g, 122 mmol) in water (100 mL) is added drop wise to this reaction mixture over 30 minutes while maintaining the reaction temperature at 0° C. Once the addition is complete, the reaction mixture is stirred at 0° C. for 30 minutes and at 25° C. for an additional 1.5 hours. A portion of water (300 mL) is then added and the reaction mixture extracted with diethyl ether. Subsequently, the aqueous layer is made basic (pH 9) by addition of 20% sodium hydroxide and then extracted a second time with diethyl ether. The combined organic extracts are dried over sodium sulfate and concentrated. The crude product is purified by column chromatography (20% ethyl acetate in hexanes) to afford 5.06 g of ethyl 2-bromo-4-thiazolecarboxylate.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[C:15]([N:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[C:14]([CH2:30][O:31][C:32]2[CH:37]=[C:36]([CH:38]([CH3:40])[CH3:39])[CH:35]=[CH:34][C:33]=2[CH3:41])=[C:13]([CH3:42])[N:12]=1)[CH3:2].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:11]1[N:12]=[C:13]([CH3:42])[C:14]([CH2:30][O:31][C:32]2[CH:37]=[C:36]([CH:38]([CH3:39])[CH3:40])[CH:35]=[CH:34][C:33]=2[CH3:41])=[C:15]([N:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)[N:16]=1)[CH3:10]
Reactant: CCc1cccc(CC)c1-c1nc(C)c(COc2cc(C(C)C)ccc2C)c(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1cccc(CC)c1-c1nc(C)c(COc2cc(C(C)C)ccc2C)c(N2CCNCC2)n1

Procedure:
To tert-butyl 4-{2-(2,6-diethylphenyl)-5-[(5-isopropyl-2-methylphenoxy)methyl]-6-methylpyrimidin-4-yl}piperazine-1-carboxylate (228 mg, 0.40 mmol) is added trifluoroacetic acid (2 mL). Gas evolution ensues and rapidly subsides. Toluene (10 mL) is added and removed under reduced pressure. The resulting residue is dissolved in EtOAc (25 mL) and extracted with saturated potassium carbonate (10 mL) followed by brine (10 mL), dried over sodium sulfate, filtered and evaporated at reduced pressure to obtain the title compound as a colorless oil. LC/MS (Method 3), M+H=473.2, Rt=2.35 min.; 1H NMR (CDCl3) δ=7.26 (d, 1H), 7.12 (d, 3H), 6.83 (me, 2H), 4.99 (s, 2H), 3.49 (m, 8H), 2.91 (m, 1H), 2.56, (s, 3H), 2.42 (q, 4H) 2.24 (s, 3H), 1.42 (s, 9H), 1.28 (d, 6H), 1.13 (t, 6H).
Reaction SMILES: O.C(=O)([O-])[O-].[Na+].[Na+].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.Br[C:20]1[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:22]([NH:33][C:34]([C:36]2[CH:37]=[N:38][CH:39]=[C:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:41]=2)=[O:35])[CH:21]=1>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.COCCOC>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:20]1[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])=[C:22]([NH:33][C:34]([C:36]2[CH:37]=[N:38][CH:39]=[C:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:41]=2)=[O:35])[CH:21]=1
Reactant: COc1ccccc1B(O)O
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1cncc(-c2ccccc2)c1
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
Solvent: O
Product: COc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2cncc(-c3ccccc3)c2)c1
Temperature: 25 °C
Yield: 57.5 %

Procedure:
Water (0.6 mL), sodium carbonate (70 mg), 2-methoxyphenylboronic acid (40 mg), and tetrakis(triphenylphosphine)palladium(0) (13 mg) were added to an ethylene glycol dimethyl ether (2.0 mL) suspension of tert-butyl 4-bromo-2-(5-phenylpyridine-3-carboxamido)benzoate (0.10 g), followed by heating to reflux under a nitrogen atmosphere for 1 hour. After cooling the reaction mixture to room temperature, the insoluble substance was removed by filtration, and a 10% aqueous solution of citric acid and ethyl acetate were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 91-80% hexane/ethyl acetate] to obtain 61 mg of tert-butyl 4-(2-methoxyphenyl)-2-(5-phenylpyridine-3-carboxamido)benzoate as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]([OH:9])[C:6]2[O:10][CH:11]=[CH:12][C:5]=2[CH2:4]1)[CH3:2].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1F>>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:9][CH:7]1[CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][C:5]2[CH:12]=[CH:11][O:10][C:6]1=2
Reactant: Fc1ccccc1Br
Reactant: CCN1Cc2ccoc2C(O)C1
Product: CCN1Cc2ccoc2C(Oc2ccccc2Br)C1

Procedure:
The same method as in Example 1 was conducted using 5-ethyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridin-7-ol (Reference Example 34) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2-bromo-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:5]=1[C:19]1[N:23]([C@H:24]2[CH2:28][CH2:27][O:26][CH2:25]2)[N:22]=[CH:21][C:20]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30])([O-:3])=[O:2].Br[C:35]1[C:36]([CH3:46])=[N:37][C:38]([O:42][CH:43]([CH3:45])[CH3:44])=[CH:39][C:40]=1[CH3:41].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[CH:43]([O:42][C:38]1[N:37]=[C:36]([CH3:46])[C:35]([C:8]2[CH:7]=[CH:6][C:5]([C:19]3[N:23]([C@H:24]4[CH2:28][CH2:27][O:26][CH2:25]4)[N:22]=[CH:21][C:20]=3[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=2)=[C:40]([CH3:41])[CH:39]=1)([CH3:45])[CH3:44]
Reactant: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1ccc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
Reactant: Cc1cc(OC(C)C)nc(C)c1Br
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1ccc(-c2c(C)cc(OC(C)C)nc2C)cc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Ethyl 5-[2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate obtained in Preparation Example 7-(2) (70 mg) was dissolved in a mixed solution of 1,4-dioxane (1 mL) and water (0.2 mL), and 3-bromo-6-isopropyloxy-2,4-dimethylpyridine (41.1 mg), Pd(PPh3)4 (17.7 mg) and cesium carbonate (150 mg) were added. The reaction mixture was stirred at 110° C. overnight. After returning the reaction mixture to room temperature, the reaction mixture was purified by silica gel column chromatography (ethyl acetate/n-heptane, 10 to 50% to 100%) to give the title compound (66.5 mg).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[NH2:11][CH:12]([CH:17]1[CH2:22][CH:21]2[CH:19]([C:20]2([F:24])[F:23])[CH2:18]1)[C:13]([O:15][CH3:16])=[O:14].C(N(CC)CC)C.CCOC(C)=O.CCCCCC>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:11][CH:12]([CH:17]2[CH2:18][CH:19]3[CH:21]([C:20]3([F:23])[F:24])[CH2:22]2)[C:13]([O:15][CH3:16])=[O:14])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: COC(=O)C(N)C1CC2C(C1)C2(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)C(NS(=O)(=O)c1ccc(Cl)s1)C1CC2C(C1)C2(F)F
Temperature: 25 °C
Yield: 13.6 %

Procedure:
5-Chlorothiophene-2-sulfonyl chloride (1.26 g, 4.82 mmol) was added dropwise (5 min) as a solution in CH2Cl2 (10 mL) to a 0° C. solution of methyl amino(6,6-difluorobicyclo[3.1.0]hex-3-yl)acetate (0.9 g, 4.38 mmol) in CH2Cl2 (10 mL) and triethylamine (1.22 mL, 8.77 mmol). The solution was allowed to warm to 25° C. overnight (19 h). An aliquot was taken and TLC (1:4 EtOAc-hexane) indicated that the reaction was complete. It was diluted in CH2Cl2 (100 mL) and the organic layer was washed with 1N HCl (20 mL) and saturated aqueous NaCl (20 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain a crude off-yellow solid (1.69 g). The crude product was purified by the Biotage Flash™ 40 chromatography instrument, eluent: 1:4 EtOAc-hexanes, to afford methyl {[(5-chlorothien-2-yl)sulfonyl]amino}(6,6-difluorobicyclo[3.1.0]hex-3-yl)acetate as a colorless oil (0.230 g, 12.23%). Mass Spectrum (−ESI): 384 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-])=O.O(CC)[C:12]([S-])=[S:13].[K+]>>[SH:13][C:12]1[O:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:1]=1
Reactant: CCOC(=S)[S-]
Reactant: O=[N+]([O-])c1ccccc1O
Agent: [K+]
Product: Sc1nc2ccccc2o1

Procedure:
In Scheme 3, substituted phenol E can be nitrated to give the corresponding ortho-nitrophenol F. This material can then be reduced to provide the ortho-aminophenol G. The aminophenol G can subsequently be reacted with potassium ethyl xanthate (potassium (carbodithiolatooxy)ethane) to produce the cyclized 2-mercaptobenzoxazole H. Reaction of the 2-mercaptobenzoxazole H with a chlorinating agent, such as thionyl chloride, affords the desired 2-chlorobenzoxazole J.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH:7]=[CH:6][CH2:5][N:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]1=[O:17].[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.S(Cl)(Cl)(=O)=O>ClCCl.N1C=CC=CC=1>[CH2:10]([O:9][N:4]1[CH2:5][CH:6]=[CH:7][CH2:8][C@@H:2]([NH:1][S:25]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[C:3]1=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N[C@@H]1CC=CCN(OCc2ccccc2)C1=O
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1[C@H](NS(=O)(=O)c2ccc(F)cc2)CC=CCN1OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.2 %

Procedure:
To a solution of 551 mg of 3-(R)-amino-1-benzyloxy-1,3,4,7-tetrahydro-azepin-2-one from example 1 Step D in 4 mL of dichloromethane and 4 mL of pyridine was added 565 mg of 4-fluorophenyl sulfonyl chloride. The reaction was stirred at room temperature for 24 hours, and an additional 495 mg of the sulfonyl chloride was added. The reaction was stirred for an additional 24 hours, and then the reaction was extracted with ethyl acetate. The mixture was washed with 5% HCl(aq.), NaHCO3(aq.), and NaCl(aq.) solutions. The aqueous layers were re-extracted with ethyl acetate, and the organic layers combined and dried over Na2SO4(s). Filtration and solvent removal gave a light brown solid. Dilution with ethyl ether, filtration, washing of the solids with ethyl ether and drying gave 548 mg of a light brown solid. MS: 391 (M+H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[Si:8]([O:15][CH2:16][C@@H:17]([N:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][N:35]=[C:34](S(C)(=O)=O)[N:33]=2)=[CH:28][C:27]1=[O:42])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]>CC(N(C)C)=O.O>[Si:8]([O:15][CH2:16][C@@H:17]([N:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([NH:7][CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[N:33]=2)=[CH:28][C:27]1=[O:42])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=1)([C:11]([CH3:14])([CH3:12])[CH3:13])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(F)c(Cl)c1)n1ccc(-c2ccnc(S(C)(=O)=O)n2)cc1=O
Reactant: NC1CCOCC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(F)c(Cl)c1)n1ccc(-c2ccnc(NC3CCOCC3)n2)cc1=O
Temperature: 120 °C
Yield: 92.1 %

Procedure:
Tetrahydro-2H-pyran-4-amine (0.45 g, 4.5 mmol) was added to (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (0.48 g, 0.89 mmol) in DMA (4 mL) in a microwave vial. The mixture was heated at 120° C. for 1 hour in a microwave. The reaction mixture was diluted with water and extracted with EtOAc. The EtOAc was washed three times with dilute aqueous NaCl, water, twice with brine, dried over MgSO4, filtered, and evaporated to yield the desired (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.46 g, 0.82 mmol, 92% yield) as a film.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[C:11](Cl)(=[O:13])[CH3:12]>ClC(Cl)C>[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:11](=[O:13])[CH3:12])(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccccc1N
Reactant: CC(=O)Cl
Solvent: CC(Cl)Cl
Product: CC(=O)Nc1ccccc1C(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice cold slurry of the 1-(2-amino-phenyl)-ethanone (2 g, 14.79 mmol) in dichloroethane (10 mL), acetyl chloride (1.22 g, 16.2 mmol) was added slowly. The reaction mixture was warmed to room temperature and stirred for 2 h. After completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (2×25 mL). The combined organic layers were washed with an aq. solution of 5% NaHCO3 followed by water and brine, then dried over anhydrous sodium sulphate and concentrated to dryness. The obtained residue was purified by column chromatography using 2% ethyl acetate in hexane to obtain the title compound as off-white solid which directly used for the next reaction.