Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([CH:12]2C(=O)OC(C)(C)[O:14][C:13]2=[O:21])[CH2:9][CH:10]=[CH2:11])[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.O>CCOC(C)=O>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:9][CH:10]=[CH2:11])[CH2:12][C:13]([OH:21])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CCC(c1cccc(O)c1)C1C(=O)OC(C)(C)OC1=O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCC(CC(=O)O)c1cccc(O)c1
Temperature: 25 °C
Yield: 97 %

Procedure:
A solution of 43.1 (3.4 g, 12 mmol) in 10:1 DMF/water (48 mL) was stirred overnight at 90° C. The mixture was cooled to room temperature, diluted with EtOAc, washed with 1 N HCl and brine, dried (MgSO4), and concentrated to afford 43.2 (2.4 g) as a pink oil. The crude product was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:12])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Se](=O)=[O:14]>O1CCOCC1>[O:12]=[C:3]1[NH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:11]=[C:2]1[CH:1]=[O:14]
Reactant: Cc1nc2ccccc2[nH]c1=O
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: O=Cc1nc2ccccc2[nH]c1=O

Procedure:
A mixture of 3-methyl-1H-quinoxalin-2-one (0.5 g) and selenium dioxide (0.728 g, 2.1 eq) in dry dioxane (33 mL) was stirred at reflux under nitrogen for 30 min. After cooling, the dark-brown mixture was concentrated under reduced pressure and the residue was purified by FC (AcOEt) to give the title compound as an orange solid.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:22][CH3:23])[CH:19]=2)[C:14]1=[O:24])[CH2:10][CH2:11][CH3:12]>CN(C)C=O.CCOC(C)=O>[CH2:9]([CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:22][CH3:23])[C:19]=2[Cl:1])[C:14]1=[O:24])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCC1Cc2cc(OC)ccc2C1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCC1Cc2c(ccc(OC)c2Cl)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.4 %

Procedure:
N-Chlorosuccinimide (505 mg, 3.8 mmol) was added to a solution of 2-butyl-5-methoxy-1-indanone (825 mg, 3.8 mmol) in anhydrous dimethylformamide (3.8 mL) and the resulting solution was stirred under nitrogen and at room temperature overnight. The reaction mixture was diluted with EtOAc (50 mL), washed with 5% aqueous NaHCO3 (20 ml), water (3×50 mL) and brine (10 mL), dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by column chromatography on EM silica gel 60 (2320-400 mesh, 2.75×29 cm), eluting with CH2Cl2, to afford 2-butyl-4-chloro-5-methoxy-1-indanone (148 mg) as an oil.
Reaction SMILES: Cl.[N:2]1([C:7]([C:9]2([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=O)[CH2:6][CH2:5][CH2:4][CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[N:2]1([CH2:7][C:9]2([NH2:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NC1(C(=O)N2CCCC2)CCCCC1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Product: NC1(CN2CCCC2)CCCCC1

Procedure:
1-(Pyrrolidin-1-ylcarbonyl)cyclohexanamine hydrochloride was added under ice-cooling to a THF solution of LAH, followed by heating under reflux for 3 hours. Sodium hydroxide aqueous solution and sodium sulfate were added to the reaction liquid, followed by filtering. By concentrating the filtrate under a reduced pressure, 1-(pyrrolidin-1-ylmethyl)cyclohexanamine was obtained.
Reaction SMILES: [O:1]=[C:2]1[C:14]2[C:13]([C:15](O)=[O:16])=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C(Cl)(=O)C(Cl)=O.Cl.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([OH:46])[CH:33]([NH2:45])[CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)=[CH:28][CH:27]=1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH:32]([OH:46])[CH:33]([NH:45][C:15]([C:13]2[C:14]3[C:2](=[O:1])[C:3]4[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=4)[C:9]=3[CH:10]=[CH:11][CH:12]=2)=[O:16])[CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)=[CH:30][CH:31]=1
Reactant: O=C(O)c1cccc2c1C(=O)c1ccccc1-2
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1cccc2c1C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
To a solution of 9-oxo-9H-fluorene-1-carboxylic acid (144 mg, 0.64 mmol) in tetrahydrofuran (5 ml) were added oxalyl chloride (0.11 ml, 1.72 mmol) and N,N-dimethylformamide (0.01 ml), and the mixture was stirred at room temperature for 30 min. The reaction solution was evaporated under reduced pressure. To a solution of the residue in ethyl acetate (5 ml) were added (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.43 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was, stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (137 mg, 61%).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=3[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].CCOC(C)=O.Cl>O1CCOCC1.O>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=3[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CN(c2nc3cc(O)ccc3n2C)C2CCC(C(C)(C)C)CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1c(N(Cc2ccc(C(=O)O)cc2)C2CCC(C(C)(C)C)CC2)nc2cc(O)ccc21
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of the title compound of Example 15 Step A (0.09 mmol, 40 mg) in 1 mL of dioxane was added LiOH (1 mmol, 24 mg) in 0.5 mL of H2O. The reaction mixture was stirred at 40° C. for 1 h. The reaction mixture was taken up in dilute pH 7 buffer and EtOAc, and acidified with 2 N HCl until two clear layers formed after agitation. The organic layer was collected and the aqueous layer was washed 2× with EtOAc. The combined organic layers were dried with Na2SO4 and concentrated under reduced pressure to afford the acid as a beige solid. HPLC A: 2.01 min.
Reaction SMILES: C1CO[C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22](O)C=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.Cl[C:28]1N=C(NC2C=CC=C(O)C=2)C(F)=C[N:29]=1.N1C=CC=C(CN)C=1>>[F:18][C:17]1[C:12]([NH:11][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([OH:2])[CH:4]=2)=[N:13][C:14]([NH:19][CH2:20][C:25]2[CH:28]=[N:29][CH:22]=[CH:23][CH:24]=2)=[N:15][CH:16]=1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Agent: NCc1cccnc1
Product: Oc1cccc(Nc2nc(NCc3cccnc3)ncc2F)c1
Yield: 62 %

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine (50 mg, 0.21 mmol) and 3-pyridylmethylamine (68 mg, 0.63 mmol) gave 5-fluoro-N4-(3-hydroxyphenyl)-N2-(3-pyridylmethyl)-2,4-pyrimidinediamine (40 mg, 62%). 1H NMR (CDCl3): δ 4.40 (d, J=6.3 Hz, 2H), 5.60 (br, 1H), 6.62-6.70 (m, 3H), 7.05 (br, 1H), 7.14 (t, J=8.1 Hz, 1H), 7.30 (dd, J=5.1 and 7.8 Hz, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.80 (d, J=3.3 Hz, 1H), 8.49 (d, J=4.5 Hz, 1H), 8.66 (s, 1H); 19F NMR (282 MHz, CDCl3): 6-169.52; LCMS: ret. time: 9.41 min.; purity: 99.25%; MS (m/e): 312.01 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:18])=[CH:4][C:5](=[O:17])[N:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:7]=1.OC1C(C#N)=CNC(=O)C=1.CS(O[CH:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1)(=O)=O.C(C1C=NC(N2CCC(CS([O-])(=O)=O)CC2)=NC=1)CC>>[Cl:1][C:2]1[C:3]([O:18][CH:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]2)=[CH:4][C:5](=[O:17])[N:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:7]=1
Reactant: N#Cc1ccc(-n2cc(Cl)c(O)cc2=O)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: CCCc1cnc(N2CCC(CS(=O)(=O)[O-])CC2)nc1
Agent: N#Cc1c[nH]c(=O)cc1O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(C#N)c(F)c3)cc2Cl)CC1

Procedure:
The intermediate was prepared according to the procedures described in Example 221 substituting 4-(5-chloro-4-hydroxy-2-oxopyridin-1(2H)-yl)-2-fluorobenzonitrile for 4-hydroxy-6-oxo-1,6-dihydropyridine-3-carbonitrile and tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate for 1-(5-propylpyrimidin-2-yl)piperidin-4-ylmethanesulfonate in Step B. MS (ESI) 392 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[N:4]=1)#[N:2].[C:11]([O-])(=[O:13])[CH3:12].[Na+].C(OC(=O)C)(=O)C>[Ni]>[C:11]([NH:2][CH2:1][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[N:4]=1)(=[O:13])[CH3:12]
Reactant: COc1cccc(C#N)n1
Reactant: CC(=O)[O-]
Agent: [Ni]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1cccc(CNC(C)=O)n1
Reaction time: 5.5 h

Procedure:
A mixture of 1.0 g (7.46 mmole) of 2-cyano-6-methoxypyridine, 0.37 g (4.48 mmole) of sodium acetate, 25 ml of acetic anhydride and about 1.0 g of Raney nickel was hydrogenated on a Paar apparatus for about 5.5 hours. The mixture was filtered, and then evaporated with warming in vacuo to provide 2-acetamidomethyl-6-methoxypyridine. The structural assignment was supported by infrared spectral analysis.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.N(C(OCC)=O)=NC(OCC)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:17]2[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:16]=2[Cl:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2Cl)CC1
Yield: 80.4 %

Procedure:
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (3.32 g), 2-chloro-4-nitrophenol (2.36 g) and triphenylphosphine (5.11 g) in dichloromethane (60 ml), diethyl azodicarboxylate (3.10 ml) was added dropwise with stirring under ice-cooling, and the resulting mixture was stirred at room temperature for 18 hours and then evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (5:2) as the eluent to afford the title compound (3.90 g, yield: 76%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][C:13](=[CH:16][O:17]C)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C1(C)C=CC=CC=1.C(O)=O.[OH-].[K+]>CO>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH:16]=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: COC=C1CCC(c2ccc(C(=O)OC)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O=CO
Product: COC(=O)c1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 123 g of 4-[4-(methoxymethylidene)cyclohexyl]benzoic acid methyl ester 1000 ml of toluene and 500 ml of formic acid was stirred vigorously at room temperature overnight. The formic acid phase was separated. The toluene phase was washed neutral with water, dried over sodium sulfate, filtered and concentrated. The crude trans/cis-mixture obtained was dissolved in 600 ml of methanol. The solution was added dropwise at 3° C. within 10 minutes to 1.2 1 of 0.1N methanolic potassium hydroxide solution while gassing with nitrogen. The reaction mixture was stirred at 3° C. for a further 1 hour, then poured on to ice/water and extracted with diethyl ether. The organic phases were washed neutral with water, dried over sodium sulfate, filtered and concentrated. Recrystallization of the residue from tert. butyl methyl ether yielded 88.5 g of 4-(trans-4-formylcyclohexyl)benzoic acid methyl ester with m.p. 84°-85° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:21][C:22]([F:25])([F:24])[F:23])(=O)=O.O>CN(C=O)C>[F:23][C:22]([F:25])([F:24])[CH2:21][N:6]1[CH:5]=[C:4]([NH2:1])[CH:8]=[N:7]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cnn(CC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.1 %

Procedure:
To a suspension of 4-nitro-1H-pyrazole (500 mg) and potassium carbonate (1.22 g) in DMF (5 mL) was added dropwise 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.54 g). The reaction mixture was stirred at room temperature for 4 hr, water was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A suspension of the obtained residue and palladium on carbon (1 g) in methanol (30 mL) was stirred at room temperature for 12 hr under a hydrogen atmosphere, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (490 mg).
Reaction SMILES: N(OC(C)(C)C)=O.[Br:8][C:9]1[CH:15]=[CH:14][C:12](N)=[C:11]([S:16][CH3:17])[C:10]=1[CH3:18].[CH3:19][S:20]SC>[Cu]>[CH3:18][C:10]1[C:11]([S:16][CH3:17])=[C:12]([S:20][CH3:19])[CH:14]=[CH:15][C:9]=1[Br:8]
Reactant: CSSC
Reactant: CSc1c(N)ccc(Br)c1C
Agent: [Cu]
Agent: CC(C)(C)ON=O
Product: CSc1ccc(Br)c(C)c1SC
Temperature: 50 °C
Reaction time: 4 h

Procedure:
14.8 g (129 mmol) of tert-butyl nitrite and 20 g of copper powder are initially charged in 50 ml of dimethyl disulfide, and a solution of 20 g (86 mol) of 4-bromo-3-methyl-2-methylthioaniline in 100 ml of dimethyl disulfide is added dropwise at from 50 to 55° C. The mixture is subsequently stirred at 50° C. for 4 hours. For work-up, the solid is filtered off with suction and the filtrate is diluted with methylene chloride and extracted with dilute hydrochloric acid. The organic phase is washed with saturated aqueous NaHCO3 solution, dried over sodium sulfate, filtered off and concentrated. Excess dimethyl disulfide is removed under oil pump vacuum.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16](I)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].B(O)(O)[C:26]1[CH:31]=[CH:30][C:29]2[O:32][CH2:33][O:34][C:28]=2[CH:27]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[O:32]1[C:29]2[CH:30]=[CH:31][C:26]([C:16]3[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:9]4[CH:8]=[CH:7][C:6]5[O:1][CH2:2][CH2:3][O:4][C:5]=5[CH:10]=4)[CH:17]=3)=[CH:27][C:28]=2[O:34][CH2:33]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: Ic1ccnc(Nc2ccc3c(c2)OCCO3)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: c1cc(-c2ccc3c(c2)OCO3)cc(Nc2ccc3c(c2)OCCO3)n1
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
In a 5 mL vial were added (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-iodo-pyridin-2-yl)-amine (Example 2(b), 75 mg, 0.2 mmol), tetrakis (triphenylphosphine) palladium (0) (Aldrich Chemical Company) (12 mg, 0.011 mmol) and 1,2-dimethoxyethane (2 mL). After stirring under nitrogen for 10 min, aqueous Na2CO3 (22 mg in 0.5 mL of water) and 3,4-(methylenedioxy)phenylboronic acid (Aldrich Chemical Company) (42 mg, 0.25 mmol) were introduced. The reaction was heated in the Smith Microwave Synthesizer at 150° C. for 10 min. The residue was partitioned between EtOAc and brine. The aqueous layer was extracted with EtOAc and the combined EtOAc layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification on a Biotage 40 S column (4:1 hexane:EtOAc) gave the title compound as a light-yellow solid. MS (ESI, pos. ion) m/z: 349 (M+1). Mp: 116.0-118.0° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].CO.[BH4-].[Na+].CC(C)=O>C(OCC)(=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:10])[CH3:9]
Reactant: CC(=O)c1ccccc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CO
Product: CC(O)c1ccccc1Br
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To the mixture of 2′-bromoacetophenone (3.9 g, 20 mmol) and methanol (50 ml), sodium borohydride (600 mg, 16 mmol) was added at 0° C. (an outer temperature), and the obtained reaction mixture was stirred at the same temperature for 30 minutes. Acetone was added to the reaction mixture at the same temperature, followed by the addition of water and ethyl acetate at the same temperature. The organic layer was separated and washed with saturated saline. The solvents were evaporated under reduced pressure from the organic layer, and then the obtained residue was filtered with NH-silica gel (heptane:ethyl acetate=1:1), thereby obtaining the entitled compound (3.9 g, 98%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[Cl:11]([O-])(=O)=O.[K+]>Cl.O>[Cl:11][C:7]1[C:2]([OH:1])=[N:3][CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=1
Reactant: [O-][Cl+2]([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(O)nc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1cnc(O)c(Cl)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 230.4 %

Procedure:
The procedure of Koch and Schnatterer, Synthesis ,1990, 499-501 was followed. To 2-hydroxy-5-nitropyridine (70.0 g, 0.5 mol) in 12 N hydrochloric acid was added dropwise a solution of potassium chlorate (21.4 g, 0.18 mol) in H2O (300 mL) at a rate such that the temperature remained ≤60° C. The mixture was allowed to stir for a further 30 minutes at ca. 50° C., then allowed to cool to ambient temperature, then was further cooled in an ice bath. The yellow solid was collected by filtration, washed with cold H2O, and dried under vacuum at 50° C. to afford 3-chloro-2-hydroxy-5-nitropyridine (72.4 g, 83%) as a yellow powder. To phosphorus oxychloride (37.4 mL, 0.4 mol) at 0° C. was added quinoline (23.6 mL, 0.2 mol), followed by 3-chloro-2-hydroxy-5-nitropyridine (70 g, 0.4 mol) from above. The mixture was heated at 120° C. for 2.5 hours, during which time it became a dark liquid. After cooling to 100° C., H2O (150 mL) was added cautiously, and the mixture was cooled to 0° C. The precipitated solid was collected by filtration, washed with cold H2O, and dried under vacuum at 50° C. to afford 2,3-dichloro-5-nitropyridine (68.6 g, 89%). To 2,3-dichloro-5-nitropyridine (68.5 g, 0.39 mol) in a mixture of H2O (800 mL) and acetic acid (160 mL) were added bits of metallic iron with stirring until the starting material was consumed (TLC analysis). The mixture was filtered, and the filter cake was washed repeatedly with EtOAc. The aqueous filtrate was extracted with EtOAc and the organic fractions were combined and concentrated. The residue was chromatographed (silica gel; MeOH: CHCl3, 0.5:99.5 to 1:99) to afford the title compound (44.5 g, 70%) as a light orange powder: MS (CI/NH3) m/z 163 and 165 (M+H+), 180 and 182 (M+NH4)+.
Reaction SMILES: O1CCCC1.CN(OC)[C:8](=[O:17])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH2:16].[C:20]([O:24][C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1Br)=[O:26])([CH3:23])([CH3:22])[CH3:21].C([Li])CCC>C(OC(=O)C)C.O.CCCCCC>[NH2:16][C:10]1[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=1[C:8]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][NH:27][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])=[O:17]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1Br
Reactant: CON(C)C(=O)c1cc(Cl)ccc1N
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccccc1C(=O)c1cc(Cl)ccc1N
Yield: 27 %

Procedure:
3,5-Trans-N-(2-fluorobenzyl)-5-(2-tert-butoxycarbonylaminomethylphenyl)-7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (1) A tetrahydrofuran (30 ml) solution of N-methyl-N-methyloxy-2-amino-5-chlorobenzamide (4.3 g) and N-tert-butoxycarbonyl-2-bromobenzylamine (3.82 g) was cooled to −78° C. To the solution was gradually added dropwise a hexane solution of n-butyl lithium (1.6 mol/L) (42 ml). To the mixture were then added water (100 ml) and acetic acid ethyl ester (100 ml). The organic layer was washed with water and dried over anhydrous MgSO4. The solvent was then distilled off. The residual oily compound was purified by means of a silica gel column chromatography to give a yellow solid product, which was recrystallized from n-hexane-isopropyl ether. The crystals were collected by filtration to afford 2-amino-2′-tert-butoxycarbonylaminomethyl-5-chlorobenzophenone (1.3 g) as a pale yellow crystalline product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:10]=[C:9]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH:23]([CH3:25])[CH3:24])=[CH:4][CH:3]=1.[CH3:26][S:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28].C([O-])([O-])=O.[K+].[K+].COCCOC>CCOC(C)=O.Cl[Pd]Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].O>[CH:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([S:27]([CH3:26])(=[O:29])=[O:28])[CH:35]=3)=[CH:3][CH:4]=2)[CH:12]=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:10]=1)([CH3:25])[CH3:24]
Reactant: CC(C)c1ccccc1-c1nc(C(C)(C)O)cn1-c1ccc(Br)cc1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)c1ccccc1-c1nc(C(C)(C)O)cn1-c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
To a 50 mL round bottom flask attached with Vigreux column and magnetic stir bar was added 2-[1-(4-Bromo-phenyl)-2-(2-isopropyl-phenyl)-1H-imidazol-4-yl]-propan-2-ol (297 mg, 743 μmol), 3-methylsulfonylphenyl boronic acid (193 mg, 968 μmol), PdCl2 dppf (60 mg, 10 mol %), K2CO3 (310 mg, 2.23 mmol), 1,2-dimethoxyethane (14 mL) and H2O (4 mL). The reaction solution was allowed to stir at 80° C. for 2 hrs. The reaction solution was diluted with EtOAc (150 mL) and filtered through a Celite padded Buchner funnel to remove spent Pd. The filtrate was transferred to a separatory funnel and washed with aq NH4Cl (100 mL) and aq NaCl (100 mL). The organic phase was dried over Na2SO4, filtered, concentrated on the Rotavapor and chromatographed through a 25 g SiO2 column using a mobile phase gradient of 100% Hx to 90% EtOAc to afford 303 mg (86% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 8.14 (s, 1H), 8.02 (d, 1H), 7.89 (d, 1H), 7.89 (d, 1H), 7.78 (d, 2H), 7.72 (t, 1H), 7.37-7.34 (m, 3H), 7.26 (d, 2H), 7.18-7.16 (m, 2H), 4.84 (s, 1H), 3.26 (s, 3H), 2.85 (sept, 1H), 1.50 (6H), 0.96 (d, 6H); MS (ES): 475.4 [M+H]+, 497.5 [M+Na].
Reaction SMILES: P(Cl)(Cl)[Cl:2].[CH2:5]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH3:8]>CCCCCC.C(OCC)C>[ClH:2].[CH2:5]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH3:8]
Reactant: ClP(Cl)Cl
Solvent: CCCCNCCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: Cl

Procedure:
A solution of 68.7 g (0.5 mole) of phosphorus trichloride in dry hexane or diethyl ether is added slowly to a stirred solution of 363.6 g (3.0 moles) of dibutylamine in the same solvent. A voluminous precipitate of dibutylamine hydrochloride is formed, the temperature remaining between 10° and 40° C. After all the phosphorus trichloride has been added, the mixture is boiled and refluxed for between 30 minutes and 2 hours. The mixture is then cooled to room temperature and filtered to separate it from 280 g (1.7 moles) of dibutylamine hydrochloride. The solvent is then stripped off at reduced pressure in a rotary evaporator.