Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12]Br)[C:5]([O:7][CH3:8])=[O:6].O.O.C([N+]([O-:23])(CC)CC)C.O>CS(C)=O.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]=[O:23])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC[N+]([O-])(CC)CC
Reactant: COC(=O)c1ccc(CBr)c(F)c1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(C=O)c(F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
Methyl 3-fluoro-4-bromomethylbenzoate (80 mg, 0.32 mmol), described in J. Med. Chem., 35(5) 877 (1992), was dissolved in a mixture of anhydrous dimethyl sulfoxide (4.5 ml) and anhydrous dichloromethane (3 ml). To the solution cooled to 0° C. was added dropwise with stirring triethylamine N-oxide dihydrate (180 mg, 1.62 mmol) and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and this mixture was partitioned between a mixture of ethyl acetate and hexane (1:1) and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was chromatographed on a silica gel column using ethyl acetate-hexane (1:10) as the eluant to give methyl 3-fluoro-4-formylbenzoate (29 mg, yield 48%) as a white solid. NMR spectrum (400 MHz, CDCl3) δ ppm: 3.97 (3H, s), 7.85 (1H, d, J=11 Hz), 7.9-8.0 (2H, m), 10.43 (1H, s). Mass spectrum m/z (EI): 182 (M+, 100%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH:10]=[C:11]([S:14][CH3:15])SC)=[CH:5][CH:4]=1.O.[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][CH:20]=1>C(O)(=O)C>[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=3)=[CH:10][C:11]([S:14][CH3:15])=[N:26]2)=[CH:21][CH:20]=1
Reactant: NNc1ccc(F)cc1
Reactant: CSC(=CC(=O)c1ccc(SC)cc1)SC
Solvent: CC(=O)O
Solvent: O
Product: CSc1ccc(-c2cc(SC)nn2-c2ccc(F)cc2)cc1
Temperature: 100 °C
Reaction time: 7 h
Yield: 22.1 %

Procedure:
A mixture of 1-[4-(methylthio)phenyl]-3,3-bis-(methylthio)-2-propen-1-one (2.7 g) and 4-fluorophenylhydrazine hydrate (1.8 g) in acetic acid (15 ml) was stirred at 100 ° C. for 7 hours. The solvent was evaporated and the residue was dissolved in ethanol. The insoluble material was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (25 g) eluting with chloroform to give an oil of 1-(4-fluorophenyl)-3-(methylthio)-5-[4-(methylthio)phenyl]pyrazole (0.73 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9](=[O:12])[C:8]2[CH:7]=[C:6](/[CH:13]=[CH:14]/[C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH:5]=[CH:4][C:3]1=2.CC1(C)CCC(=O)C2C=C(/C=C/C3C=[CH:48][C:44]([C:45]([OH:47])=O)=CC=3)C=CC1=2.BrC[C:53](OCC)=[O:54]>C1C=CC=CC=1.[Zn]>[CH3:26][C:2]1([CH3:1])[CH2:11][CH2:10][C:9]([OH:12])([C:53]([O:47][CH2:45][CH2:44][CH3:48])=[O:54])[C:8]2[CH:7]=[C:6](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)CBr
Reactant: CC1(C)CCC(=O)c2cc(/C=C/c3ccc(C(=O)O)cc3)ccc21
Reactant: CCOC(=O)c1ccc(/C=C/c2ccc3c(c2)C(=O)CCC3(C)C)cc1
Agent: [Zn]
Solvent: c1ccccc1
Product: CCCOC(=O)C1(O)CCC(C)(C)c2ccc(/C=C/c3ccc(C(=O)OCC)cc3)cc21

Procedure:
To a refluxing solution of 0.75 g (11.5 mmol) of granular zinc in 5.0 mL of benzene was added a solution of ethyl (E)-4-[2-(5,5-dimethyl-5,6,-dihydro-naphthalen-8(7H)-one-2-yl)ethenyl]-benzoate (Compound A2) in 5.0 mL of benzene followed by 0.27 g (0.18 mmol) of ethyl bromoacetate. The resulting mixture was refluxed for 24 h. The reaction was cooled, filtered through celite. The filtrate was washed with 10% HCl, sat. aqueous NaHCO3 and brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica, 10% ethyl acetate in hexane) to afford the title compound as a white solid.
Reaction SMILES: Br[CH2:2][C@@H:3]1[CH2:9][C@:8]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:10][C@H:4]1[CH2:5][CH2:6][C@H:7]2[NH:17][CH2:18][C:19]1[CH:24]=[C:23]([O:25][C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:21][C:20]=1[O:30][CH:31]1[CH2:33][CH2:32]1.[Na].[CH3:35][S:36]([OH:38])=[O:37].[ClH:39]>CN(C)C=O.C(OCC)(=O)C.O>[ClH:39].[ClH:39].[CH:31]1([O:30][C:20]2[CH:21]=[CH:22][C:23]([O:25][C:26]([F:29])([F:27])[F:28])=[CH:24][C:19]=2[CH2:18][NH:17][C@@H:7]2[CH2:6][CH2:5][C@@H:4]3[NH:10][C@@:8]2([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][C@H:3]3[CH2:2][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:32][CH2:33]1
Reactant: FC(F)(F)Oc1ccc(OC2CC2)c(CN[C@@H]2CC[C@@H]3N[C@@]2(c2ccccc2)C[C@H]3CBr)c1
Reactant: CS(=O)O
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)C[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2NCc1cc(OC(F)(F)F)ccc1OC1CC1
Temperature: 110 °C

Procedure:
(1R*,2R*,5S*,6R*)-6-(Bromomethyl)-2-(2-cyclopropoxy-5-(trifluoromethoxy)benzylamino)-1-phenyl-8-azabicyclo[13.2.1]octane (Example 20; 200 mg, 0.38 mmol) was dissolved in N,N-dimethylformamide (5 mL) and the solution treated with the sodium salt of methanesulfinic acid (388 mg, 3.8 mmol). The resulting suspension was heated at 110° C. for 1 hour, then cooled and poured into water (50 mL). The mixture was extracted with ethyl acetate (2×20 mL), the extracts were dried (MgSO4) and then concentrated to give a gum. This was purified by silica chromatography to give the pure free base, which was dissolved in ethyl acetate (10 mL). Ethereal hydrogen chloride (2 mL, 1M) solution was added and the solid formed was removed by filtration and recrystallized from methanol/diethyl ether to give the title compound as a white powder (120 mg, 0.20 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C([N:14]=C=NCCCN(C)C)C.[Cl-].[NH4+].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:14])=[O:5]
Reactant: Nc1c(Cl)cccc1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cccc(Cl)c1N
Reaction time: 6 h
Yield: 50.4 %

Procedure:
To 2-amino-3-chlorobenzoic acid (1.72 g, 10 mmol) in DMF (5 mL) were added hydroxybenzatriazole (2.0 g, 13 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.3 g, 12 mmol), ammonium chloride (2.3 g, 42 mmol), and DIEA (7.5 ml, 42 mmol). The mixture was purged with nitrogen and was stirred for 6 h. The mixture was then poured into water and extracted with EtOAc (3×50 mL). The combined extracts were washed with brine (2×20 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was treated with DCM (10 mL) resulting in a precipitate that was collected by filtration to afford 2-amino-3-chlorobenzamide (860 mg). LCMS (ESI) m/z 171 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:23])[NH:8][CH2:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])=[C:5]([C:24](O)=[O:25])[CH:4]=[N:3]1.CCOC(C(C#N)=NOC([N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.N1CCOCC1>CN(C=O)C>[CH3:16][C:15]1[O:14][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:12][C:11]=1[CH2:10][CH2:9][NH:8][C:7]([C:6]1[N:2]([CH3:1])[N:3]=[CH:4][C:5]=1[C:24]([N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)=[O:25])=[O:23]
Reactant: Cc1oc(-c2ccccc2)nc1CCNC(=O)c1c(C(=O)O)cnn1C
Reactant: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCN1
Product: Cc1oc(-c2ccccc2)nc1CCNC(=O)c1c(C(=O)N2CCOCC2)cnn1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 1-methyl-5-(2-(5-methyl-2-phenyloxazol-4-yl)ethylcarbamoyl)-1H-pyrazole-4-carboxylic acid (40 mg, 113 μmol) in DMF (1 mL) were added COMU (58.0 mg, 135 μmol) and N,N-diisopropylethylamine (14.6 mg, 19.7 μL, 113 μmol) at 0-5° C. After 10 min the suspension became a clear solution and subsequently morpholine (11.8 mg, 135 μmol) and N,N-diisopropylethylamine (14.6 mg, 19.7 μL, 113 μmol) were added. The ice bath was removed after 10 min and the mixture was stirred at RT for 3 h. The product was obtained after purification by preparative HPLC using an acetonitrile/water (containing 0.1% formic acid) gradient as off-white waxy solid (31 mg, 73.2 μmol, 64.9%).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([N:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]3=[O:20])[CH:11]=[CH:12][C:5]=2[N:4]=1)[CH3:2].[F:21][C:22]([F:31])([F:30])[C:23]1[N:24]=[C:25]([CH2:28]O)[S:26][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCOC)=O)=NC(OCCOC)=O>C1COCC1.O>[CH2:1]([C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([N:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:28][C:25]4[S:26][CH:27]=[C:23]([C:22]([F:31])([F:30])[F:21])[N:24]=4)=[CH:15][C:14]3=[O:20])[CH:11]=[CH:12][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccc(-n3ccc(O)cc3=O)cc2n1C
Reactant: OCc1nc(C(F)(F)F)cs1
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2ccc(-n3ccc(OCc4nc(C(F)(F)F)cs4)cc3=O)cc2n1C
Reaction time: 3 h
Yield: 27.1 %

Procedure:
To a solution of 1-(2-ethyl-1-methyl-1H-benzo[d]imidazol-6-yl)-4-hydroxypyridin-2(1H)-one (400 mg), (4-(trifluoromethyl)-1,3-thiazol-2-yl)methanol (544 mg) and triphenylphosphine (1.17 g) in THF (35 ml) was added bis(2-methoxyethyl) azodicarboxylate (1.04 g) at room temperature. After 3 h, the mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/MeOH), followed by recrystallization from IPA-IPE to give the title compound (175 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12](=[O:16])[NH:13][CH2:14][CH3:15])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1.[N:35]1[CH:40]=[CH:39][CH:38]=[N:37][C:36]=1[C:41](O)=[O:42].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:14]([NH:13][C:12]([NH:11][C:8]1[S:9][C:10]2[C:2]([NH:1][C:41]([C:36]3[N:37]=[CH:38][CH:39]=[CH:40][N:35]=3)=[O:42])=[CH:3][C:4]([C:17]3[CH:18]=[N:19][C:20]([N:23]4[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]4)=[N:21][CH:22]=3)=[CH:5][C:6]=2[N:7]=1)=[O:16])[CH3:15]
Reactant: O=C(O)c1ncccn1
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(N)c2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(NC(=O)c3ncccn3)c2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.8 %

Procedure:
Ethyl 1-[5-[7-amino-2-(ethylcarbamoylamino)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (159 mg, 0.27 mmol), pyrimidine-2-carboxylic acid (64.2 mg, 0.52 mmol) and diisopropylethylamine (271 mg, 2.1 mmol) were dissolved in DMF (5 mL). The reaction was purged with N2 then HATU (197 mg, 0.5 2 mmol) was added and the reaction stirred at rt for 18 h. The DMF was removed under reduced pressure and the resulting residue diluted with water and extracted with EtOAc. During the work up a solid precipitated which was collected by filtration and dried in the vacuum oven to provide the crude product (100 mg, 66% yield).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[NH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28]>CN(C=O)C>[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: NCCCCO
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(Cl)nc2ccccc2c1NCCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
Triethylamine (31 g, 0.31 mol) was added to a solution of 2,4-dichloro-3-nitroquinoline (50 g of 90% pure material) in anhydrous DMF (400 mL). 4-Amino-1-butanol (21 mL, 0.23 mol) was added in portions over a period of ten minutes, and the reaction was stirred at room temperature overnight and then partitioned between deionized water (1.5 L) and ethyl acetate (800 mL). The organic layer was separated, and a precipitate formed. The precipitate was collected by filtration, and the filtrate was concentrated under reduced pressure to provide a solid. The two solids were dried under vacuum to provide 44.34 g of 4-(2-chloro-3-nitroquinolin-4-ylamino)butan-1-ol.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[Cl:12][C:5]1[CH:4]=[CH:3][C:2]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:7][C:6]=1[C:8]([F:11])([F:10])[F:9]
Reactant: FC(F)(F)c1cc(Br)ccc1Cl
Reactant: C1CNCCN1
Product: FC(F)(F)c1cc(N2CCNCC2)ccc1Cl
Yield: 78.2 %

Procedure:
Beginning with 5-bromo-2-chlorobenzotrifluoride (602 mg) and piperazine (1 g), 480 mg of the title compound was recovered by the procedure described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:56][N:57]1[CH2:62][CH2:61][NH:60][CH2:59][C:58]1=[O:63].ClCl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:60]1[CH2:61][CH2:62][N:57]([CH3:56])[C:58](=[O:63])[CH2:59]1)=[O:24])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: CN1CCNCC1=O
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)c2ccc(C(=O)NCc3nc4cc(Cl)ccc4[nH]3)cc2Cl)CC1=O
Yield: 9 %

Procedure:
Prepared analogously to Example 1g from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, TBTU, diisopropylethylamine, and 1-methylpiperazin-2-one in DMF. Yield: 9%; C21H19C12N5O3 (460.32); mass spectrum: (M+H)+=460/462/464 (chlorine isotope).
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:16]1([C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:23][CH:24]=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.C([BH3-])#N>ClCCl.CO>[C:16]1([C:22]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:23][CH2:24][N:5]2[CH2:6][CH2:7][N:2]([C:8]3[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=3)[CH2:3][CH2:4]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=CC=C(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: N#Cc1ccc(N2CCN(CC=C(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.3 %

Procedure:
A suspension of 4-piperazin-1-ylbenzonitrile hydrochloride (1.30 g, 5.00 mmol) and 3,3-diphenylacrylaldehyde (1.56 g, 7.50 mmol)) in dichloromethane (10 mL) and methanol (10 mL) was neutralized to pH 5 with diisopropylethylamine, treated with polymer-supported cyanoborohydride (2.47 mmol/g, 6 g, 14.82 mmol), shaken at room temperature for 24 hours, and filtered. The resin was washed with 1:1 dichloromethane/methanol (10 mL×3) and the combined filtrates were concentrated. The concentrate was purified by silica gel chromatography eluting with a gradient from 10%-50% ethyl acetate/hexanes to provide the desired product (1.60 g, 84%). MS (CI) m/e 380 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[CH3:15][N:16]([CH3:34])[C:17]([C:19]1[CH:24]=[CH:23][C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][N:20]=1)=[O:18].C(=O)([O-])[O-].[K+].[K+]>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>[C:10]([C:4]1[C:3]([O:13][CH3:14])=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([C:17]([N:16]([CH3:34])[CH3:15])=[O:18])=[N:20][CH:21]=2)[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=1)(=[O:12])[CH3:11]
Reactant: CN(C)C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1c(C(C)=O)cc(Cl)c(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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(C(C)=O)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (0.38 g, 1.4 mmol) and N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (from PepTech, 0.46 g, 1.6 mmol) in 1,4-dioxane (6 mL), potassium carbonate (0.38 g, 2.7 mmol) in water (2 mL) was added. The reaction mixture was bubbled with N2. Tetrakis(triphenylphosphine)palladium(0) (0.095 g, 0.082 mmol) was added and the reaction was stirred overnight at 100° C. The reaction was diluted with water, extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated and purified on silica gel (eluting with 0-100% EtOAc in hexanes) to give the desired product. LCMS calculated for C18H20ClN2O3 (M+H)+: m/z=347.1; Found: 347.1
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([S:16][CH3:17])[N:10]3[N:9]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:33])C=1.CCCCCC.C(OCC)(=O)C>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([S:16]([CH3:17])=[O:33])[N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CSc1cccc2c(-c3ccncn3)c(-c3ccc(F)cc3)nn12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CS(=O)c1cccc2c(-c3ccncn3)c(-c3ccc(F)cc3)nn12
Reaction time: 1 h

Procedure:
To a stirred solution of 2-(4-fluorophenyl)-7-methylthio-3-(4-pyrimidinyl)pyrazolo[1,5-α]pyridine (Example 6, 0.246 g, 0.73 mmol) in chloroform (20 mL) was added, dropwise, a solution of of m-chloroperbenzoic acid (57–86%, 0.221 g, 0.73–1.1 mmol) in chloroform (10 mL). After 1 hour, the reaction was quenched by the addition of aqueous potassium carbonate (20 mL), and the organic phase was separated. The aqueous phase was further extracted with chloroform (2×20 mL) and the combined chloroform phases were dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the solvent was evaporated to give a light brown solid. Chromatography on silica gel eluting with a hexane/ethyl acetate gradient (0–30% ethyl acetate) gave the title compound as the major product, 0.170 g (66%). 1H NMR (DMSO-d6): δ 3.11 (s, 3H), 7.13 (d, J=5.4 Hz, 1H), 7.33 (t, J=8.8 Hz, 2H), 7.50 (d, J=7.0 Hz, 1H), 7.63 (dd, J=5.7, 8.6 Hz, 2H), 7.76 (dd, J=7.4, 8.1 Hz, 1H), 8.50 (d, J=8.8 Hz, 1H), 8.60 (d, J=5.5 Hz, 1H). 9.20 (s, 1H), APESI+MS m/z 353 (M+1)−.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[C:15]([O:19][C:20](=[O:23])[CH2:21][NH2:22])([CH3:18])([CH3:17])[CH3:16]>N1C=CC=CC=1>[C:15]([O:19][C:20](=[O:23])[CH2:21][NH:22][S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
4-Nitrobenzenesulfonyl chloride (46.3 g) was added to a solution of glycine t-butyl ester hydrochloride (35 g) in pyridine (200 ml). The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated. The residue was washed with water and then a mixture of hexane and ethyl acetate (9:1) and dried to give the title compound (61.4 g) having the following physical data.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl.C(OCC)(=O)C>[CH3:32][S:33]([O:1][CH:2]1[CH2:3][CH2:4][C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])=[CH:6][CH:7]1[NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:15])(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1C=C(c2ccncc2[N+](=O)[O-])CCC1O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1C=C(c2ccncc2[N+](=O)[O-])CCC1OS(C)(=O)=O
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of (+/−)-tert-butyl 6-hydroxy-3-(3-nitropyridin-4-yl)cyclohex-2-enylcarbamate (1.0 equiv.) and triethyl amine (1.5 equiv.) in CH2Cl2 (0.2 M) was added methanesulfonyl chloride (1.2 equiv.) at 0° C. The mixture was stirred for 2 hours at that temperature. The reaction mixture was diluted with ethyl acetate, and washed with sat NaCl. The organic was dried with MgSO4, filtered and concentrated to give (+/−)-2-(tert-butoxycarbonylamino)-4-(3-nitropyridin-4-yl)cyclohex-3-enyl methanesulfonate (85%), which was used in the next step without further purification. LC/MS (m/z): MH+=414.0, Rt=0.82
Reaction SMILES: [NH2:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1.[C:26]([Cl:30])(=[O:29])[O:27][CH3:28].C(OCC)C>C(Cl)Cl>[ClH:30].[CH3:28][O:27][C:26]([NH:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:29]
Reactant: Nc1[nH]c(-c2ccc(F)cc2)nc1-c1ccccc1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: COC(=O)Nc1[nH]c(-c2ccc(F)cc2)nc1-c1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
To a solution of 5-amino-2-(4-fluorophenyl)-4-phenylimidazole (63 mg) and pyridine (40 mg) in methylene chloride (5 ml) was added methyl chlorocarbonate (28 mg) under ice-cooling and the mixture was stirred at room temperature overnight. To the reaction mixture was added diethyl ether, and the solvent was removed under reduced pressure. The resulting residue was triturated with diethyl ether and the powder was collected by filtration. The powder was treated with hydrogen chloride-methanol solution to obtain 5-methoxycarbonylamino-2-(4-fluorophenyl)-4-phenylimidazole hydrochloride (67 mg) as colorless powder.