Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([C:16](=O)/[CH:17]=[CH:18]/[N:19](C)C)=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:23]N>CCO>[Si:1]([O:8][CH2:9][C:10]1[C:11]([C:16]2[NH:23][N:19]=[CH:18][CH:17]=2)=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CN(C)/C=C/C(=O)c1ncccc1CO[Si](C)(C)C(C)(C)C
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCc1cccnc1-c1ccn[nH]1
Temperature: 80 °C
Yield: 89.4 %

Procedure:
To (E)-1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-3-(dimethylamino)prop-2-en-1-one (crude, 350 mg, 1.09 mmol, 1 eq.) in EtOH (5 mL) was added hydrazine (140 mg, 4.36 mmol, 4 eq.). The mixture was heated at 80° C. for 2 h, cooled, concentrated, and purified on silica gel using EtOAc as eluent to give 3-((tert-butyldimethylsilyloxy)methyl)-2-(1H-pyrazol-5-yl)pyridine (282 mg, 90%) as a white solid. LRMS (M+H+) m/z 290.1
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](OS(C(F)(F)F)(=O)=O)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:31]4[CH:32]=[CH:33][C:34]5[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH:30]=4)[C:15]=3[O:14]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(OS(=O)(=O)C(F)(F)F)c3O2)cc1
Reactant: OB(O)c1ccc2ccccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccc5ccccc5c4)c3O2)cc1
Yield: 35.9 %

Procedure:
Treatment of (±)-(7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.32 mmol) with 2-naphthaleneboronic acid (0.86 g, 4.97 mmol), tetrakis(triphenylphosphine)palladium(0) (0.38 g, 0.33 mmol), and potassium phosphate (1.41 g, 6.64 mmol) generally according to the procedure described for Intermediate 50 provided 0.513 g (36%) of (±)-[7-(2-naphthyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf=0.42 (silica, ethyl acetate:hexanes 1:3); Anal. calcd. for C26H22O4S: C, 72.54; H, 5.15. Found: C, 72.04; H, 5.04.
Reaction SMILES: Cl.C(Cl)Cl.[CH3:5][C:6]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=[N:20][OH:21])[C:17]([NH2:19])=[O:18].O>C1(C)C=CC=CC=1>[CH3:5][C:6]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1/[C:16](=[N:20]\[OH:21])/[C:17]([NH2:19])=[O:18]
Reactant: Cc1ccc(C)c(OCc2ccccc2C(=NO)C(N)=O)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C)c(OCc2ccccc2/C(=N\O)C(N)=O)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.8 %

Procedure:
Conc. hydrochloric acid (2 ml) and methylene chloride (5 ml) were added to 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-hydroxyiminoacetamide (Z=at least 98%) (0.50 g, 1.68 mmol), and the mixture was stirred at room temperature for 15 hours. After stirring, water (5 ml) and toluene (5 ml) were added. The resulting crystals were separated by filtration and dried to give (E)-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-hydroxyiminoacetamide (0.48 g, Yield: 96.0%) as colorless crystals.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([CH3:34])[CH:28]=4)[N:21]=3)[CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:22]2[CH:23]=[C:24]([CH3:26])[N:25]=[C:20]([N:18]3[CH:19]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=4)[N:16]=[CH:17]3)[N:21]=2)=[CH:28][C:29]=1[CH3:34]
Reactant: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-n2cnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-n2cnc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 63.8 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{1-[6-(4-chloro-3-methyl-phenyl)-4-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.53 g) in dichloromethane (5 ml) was added TFA (5 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (10 ml), diethylether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried. Further purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (THF/heptane) yielded the title compound as a white solid (0.3 g, 68%). MS (ISP) 440.1 [(M+H)+]; mp 219° C. (dec.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:15]#[C:16][CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([N:32]=[C:33]([C:35]3[C:40]([CH3:41])=[CH:39][CH:38]=[CH:37][C:36]=3[CH3:42])[N:34]=2)[CH:31]=1>CN(C=O)C>[CH3:41][C:40]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:42])[C:35]=1[C:33]1[N:34]=[C:29]2[CH:28]=[CH:27][C:26]([CH2:25][O:1][C:2]3[CH:3]=[CH:4][C:5]([C@@H:8]([C:15]#[C:16][CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=3)=[CH:31][N:30]2[N:32]=1
Reactant: Cc1cccc(C)c1-c1nc2ccc(CCl)cn2n1
Reactant: CC#C[C@@H](CC(=O)OCC)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc3nc(-c4c(C)cccc4C)nn3c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
To a solution of (S)-ethyl 3-(4-hydroxyphenyl)hex-4-ynoate (WO05/086661) (0.2 g, 0.87 mmol) in DMF (20 mL) is added Cs2CO3 (0.84 g, 2.59 mmol) and 6-(chloromethyl)-2-(2,6-dimethylphenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.187 g, 0.69 mmol). The reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is poured into ice cold water and extracted with EtOAc (3×50 mL). The combined organic extracts are washed with water (2×50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The crude material is purified by combiflash silica gel chromatography eluting with 13% EtOAc in hexane to give the title compound as colourless liquid (0.225 g, 55%). LCMS m/z 468 (M+H)+.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[C:14]2[O:13][CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)=O>CO.[OH-].[Na+]>[NH2:5][C:6]1[C:14]2[O:13][CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Nc1cccc2c1OCC2)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1cccc2c1OCC2
Yield: 96.2 %

Procedure:
A solution of 7-(trifluoroacetylamino)-2,3-dihydrobenzofuran (D2) (1.6 g) in methanol (30 ml) and 10% NaOH (3 ml) was heated to reflux for 24h. The mixture was evaporated under reduced pressure and partitioned between ethyl acetate and water. The organic phase was dried (Na2SO4) and the solvent evaporated under reduced pressure to give the title compound (900 mg, 96%) as a pale orange oil, which crystallised on standing.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.O.C(Cl)(Cl)Cl>[CH2:16]([N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]1=[O:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1cccn(Cc2ccccc2)c1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
To a stirring reaction mixture of 3-methoxypyridine-2-one (0.2 g, 1.6 mmol) and K2CO3 (0.66 g, 4.8 mmol) in DMF (8 mL) was added benzyl bromide (0.33 g, 1.92 mmol) dropwise in a condenser equipped round bottom flask. Reaction mixture was then heated to 100° C. After overnight stirring, reaction mixture was cooled down and diluted with water (40 mL) and CHCl3 (50 mL). Organic layer was washed with water (3×40 mL), brine (1×30 mL) and dried over Na2SO4 and solvent was evaporated in vacuo to yield pure 141b (0.26 g, 75%) as a colorless oil without any further purification needed. 1H NMR (400 MHz, CDCl3) δ 7.26 (m, 5H), 6.85 (dd, J=6.9, 1.7 Hz, 1H), 6.54 (dd, J=7.5, 1.6 Hz, 1H), 6.03 (m, 1H), 5.13 (s, 2H), 3.76 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 157.94, 150.05, 136.31, 128.56, 128.01, 127.74, 127.70, 111.82, 104.83, 104.81, 55.64, 51.64.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=2)=[N:6][CH:7]=1.[C:19]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:19][O:14][C:12]1[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=[C:8]([C:5]2[N:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc(-c2nc(O)cc(C(F)(F)F)n2)nc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(C(F)(F)F)nc(-c2ccc(N)cn2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of compound of example 15 (0.100 g, 0.390 mmol) in DMF (3 mL), was added K2CO3 (0.080 g, 0.58 mmol) and stirred at 25° C. for 10 minutes. To the reaction mixture methyl iodide (0.083 g, 0.58 mmol) was added slowly and stirred at 25° C. for 1 hour. DMF was removed under vacuum and reaction mass quenched with water, extracted with ethyl acetate (3×10 mL), dried over sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 8% methanol in chloroform as an eluent to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH2:13][C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[N:19][NH:20]2)=[CH:16][CH:15]=1>CCO.C(O)(=O)C>[NH:20]1[C:21]2[C:17](=[CH:16][CH:15]=[C:14]([N:13]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[CH:22]=2)[CH:18]=[N:19]1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Reactant: Nc1ccc2cn[nH]c2c1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)C(=Nc1ccc3cn[nH]c3c1)C(=O)N2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 25.3 %

Procedure:
To a mixture of 5-methylisatin (80.5 mg, 0.5 mmol) and 6-aminoindazole (66.5 mg, 0.5 mmol) in EtOH (2 mL) was added 1 drops of acetic acid. The resulting mixture was capped and microwaved 30 min at 120° C. After cooling to rt, it was stirred for 5 min at rt and the resulting precipitate was collected by suction filtration to give the title compound (35 mg, 28%) as an orange red solid. 1H NMR indicated a 80:20 mixture of E/Z isomers. 1H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H, NH), 10.89 (s, 1H, NH), 8.10 (s, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.15 (d, J=7.2 Hz, 1H), 7.07 (s, 1H), 6.81-6.74 (m, 2H), 6.17 (s, 1H), 2.49 (s, 3H, CH3); MS ESI 277.0 [M+H]+, calcd for [C16H12N4O+H]+ 277.1.
Reaction SMILES: [NH:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:12]([Cl:15])(=[O:14])[CH3:13]>C(#N)C>[ClH:15].[C:12]([O:10][CH2:9][CH2:8][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:14])[CH3:13]
Reactant: OCCNc1ccccc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CC#N
Product: CC(=O)OCCNc1ccccc1
Temperature: 22 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
2-Anilinoethanol (137 g, 1.0 mol) was mixed with acetonitrile (300 ml) and concentrated hydrochloric acid (100 ml), and the reaction mixture was evaporated to dryness. The residue was dissolved in acetonitrile (1000 ml); acetyl chloride (89 ml, 1.25 mol) was added and the reaction mixture was stirred at room temperature (22° C.) for 16 hours. The mixture was evaporated to dryness under reduced pressure and the resulting solid was triturated with ethyl ether (1000 ml). The solid was removed by filtration and dried to yield 197 g (91.3%) of product.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[NH:4][N:3]=1.[OH-].[K+].Cl[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([C:23]#[N:24])[CH2:19][CH2:18]1)=[O:16]>CN(C)C=O.O>[CH3:1][C:2]1[N:3]([CH2:14][C:15]([N:17]2[CH2:18][CH2:19][CH:20]([C:23]#[N:24])[CH2:21][CH2:22]2)=[O:16])[N:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[CH:6]=1
Reactant: Cc1cc(C(F)(F)F)[nH]n1
Reactant: N#CC1CCN(C(=O)CCl)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(C#N)CC1
Temperature: 7.5 °C
Reaction time: 8 h

Procedure:
A solution of 3-methyl-5-trifluoromethylpyrazole (9.3 g, 62 mmol) and 45% aqueous potassium hydroxide solution (7.79 g, 62 mmol) in N,N-dimethylformamide (25 mL) was cooled to 5° C., and 1-(2-chloroacetyl)-4-piperidinecarbonitrile (i.e. the product of Example 8, Step A or A1) (11.2 g, 60 mmol) was added. The reaction mixture was stirred for 8 h at 5-10° C., then diluted with water (100 mL), and filtered. The filter cake was washed with water and dried at 50° C. in a vacuum-oven to give 15 g of the title compound as a solid containing 3% of its regioisomer, i.e. 1-[2-[3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinecarbonitrile.
Reaction SMILES: OS(O)(=O)=O.[N+:6]([O-:9])(O)=[O:7].[CH2:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=1[O-:18])[CH3:11]>>[CH2:10]([C:12]1[CH:17]=[C:16]([N+:6]([O-:9])=[O:7])[CH:15]=[CH:14][N+:13]=1[O-:18])[CH3:11]
Reactant: CCc1cccc[n+]1[O-]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCc1cc([N+](=O)[O-])cc[n+]1[O-]
Temperature: 80 °C

Procedure:
Concentrated H2SO4 (1826.0 g, 18.660 mol) and fuming HNO3 (1174.0 g, 18.640 mol) are mixed at 0° C. Then 573.8 g (4.7 mol) 2-ethyl-pyridine-1-oxide are added to the mixture over 1 h. The resulting mixture is heated to 80° C. for 3 h. After cooling to RT, the mixture is slowly poured into the crushed ice with fierce stirring. The aqueous layer is extracted with DCM (6×1.0 L), the combined layer is dried over anhydrous Na2SO4. The solvent is removed in vaccuo to afford the title compound. Yield: 700.0 g (89%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][OH:15])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:20]=1.O>C1COCC1>[CH3:26][O:25][C:23](=[O:24])[C:22]1[CH:27]=[CH:28][C:19]([O:15][CH2:14][C:9]2[N:10]([CH3:13])[N:11]=[N:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:20][CH:21]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)nnn2C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
A solution of [5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-methanol (380 mg, 2.02 mmol) in THF (5.5 mL) was added dropwise at 0° C. to a suspension of NaH (55% in oil, 88 mg, 2.02 mmol) in THF (2.7 mL) and the reaction mixture was then stirred at room temperature for 30 min. Then a solution of methyl 6-chloronicotinate (346 mg, 2.02 mmol) in THF (5.5 mL) was added dropwise at 0° C. and the reaction mixture stirred at room temperature for 16 h. The mixture was then poured into water extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (449 mg, 72%) as a white solid. MS: m/e=343.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:24])=[O:23])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc(NS(=O)(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to general procedure for sulfonylation of 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile using benzenesulfonyl chloride (70 μL, 0.55 mmol) to provide N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]benzene sulfonamide (0.046 g).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH3:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][O:8][NH:7]1>C(OCC)C>[CH3:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][O:8][N:7]1[C:3](=[O:4])[NH:2][CH3:1]
Reactant: CC1NOCCc2ccccc21
Reactant: CN=C=O
Solvent: CCOCC
Product: CNC(=O)N1OCCc2ccccc2C1C
Reaction time: 8 h

Procedure:
A solution of 1.37 g. of methylisocyanate in 10 ml. of diethyl ether was added dropwise to a solution of 1.96 g. of 1-methyl-1,2,4,5-tetrahydro-3,2-benzoxazepine in 30 ml. of diethyl ether under stirring at 0°-5° C. After standing overnight the solution was evaporated to dryness and the oily residue was distilled at 160° C./0.02 mm Hg. Yield 2.41 g.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[CH2:12][C:11]([CH3:14])([CH3:13])[O:10][CH:9](O)[C:8]2=[O:16])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:42][C:43]1[CH:44]=[C:45]([CH:48]=[CH:49][C:50]=1[N:51]1[CH:55]=[C:54]([CH3:56])[N:53]=[CH:52]1)[CH:46]=O>>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[CH2:12][C:11]([CH3:14])([CH3:13])[O:10]/[C:9](=[CH:46]\[C:45]3[CH:48]=[CH:49][C:50]([N:51]4[CH:55]=[C:54]([CH3:56])[N:53]=[CH:52]4)=[C:43]([F:42])[CH:44]=3)/[C:8]2=[O:16])=[CH:4][CH:3]=1
Reactant: CC1(C)CN(Cc2ccc(F)cc2)C(=O)C(O)O1
Reactant: Cc1cn(-c2ccc(C=O)cc2F)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=S(Cl)Cl
Product: Cc1cn(-c2ccc(/C=C3\OC(C)(C)CN(Cc4ccc(F)cc4)C3=O)cc2F)cn1

Procedure:
44.7 mg of the title compound was obtained from 4-(4-fluorobenzyl)-2-hydroxy-6,6-dimethylmorpholin-3-one, thionyl chloride, triphenylphosphine, and 3-fluoro-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde in the same manner as in Example 7.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([F:19])[CH:18]=1)[NH2:15].C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(N(C)C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:16]=[C:17]([F:19])[CH:18]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1cc(F)cc(F)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=[N+]([O-])c1cccnc1Nc1cc(F)cc(F)c1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a degassed solution of 2-chloro-3-nitro-pyridine (2.7 g, 17.03 mmol) and 3,5-difluoro aniline (2.0 g, 15.5 mmol) in dimethylacetamide (50 mL) was added cesium carbonate (10 g, 30.98 mmol) and was further degassed with nitrogen for 10 min. To the mixture was added xanthophos (448 mg, 0.77 mmol) and Pd2 (dba)3 (851 mg, 0.92 mmol) and stirred at 100° C. for 16 h. After completion of the reaction, water (100 mL) was added and the mixture extracted with EtOAc (500 mL). The organic phase was dried over sodium sulfate and concentrated to provide the crude material, which was purified by column chromatography using 0-5% EtOAc in hexane to yield N-(3,5-difluorophenyl)-3-nitro-pyridin-2-amine: LC-MS (ESI) m/z 250.1 [M−H]−.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]([O:9][CH3:10])[C:5]([O:7][CH3:8])=[O:6].O[N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.N#N>C(Cl)Cl.O>[O:22]=[C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:21])[N:12]1[O:1][CH2:2][CH2:3][C@H:4]([O:9][CH3:10])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)[C@H](CCO)OC
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@H](CCON1C(=O)c2ccccc2C1=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 42.6 %

Procedure:
To a solution of (S)-methyl 4-hydroxy-2-methoxybutanoate (46b, 1.48 g, 10.0 mmol) in CH2Cl2 (25.0 mL) was added 2-hydroxyisoindoline-1,3-dione (1.63 g, 10.0 mmol) and triphenylphosphine (3.93 g, 15.0 mmol). The resultant mixture was cooled to 0° C. and diisopropylazodicarboxylate (2.95 ml, 15.0 mmol) was slowly added drop wise under N2 atmosphere. The reaction mixture was stirred at ambient temperature for 48 h. To the reaction mixture, H2O (100 mL) was added and extracted with CH2Cl2. The organic layers washed with brine. Dried over anhydrous Na2SO4, filtered and concentrated to provide yellow oil, which was purified by flash chromatography (50% EtOAc-hexane) to afford (S)-methyl 4-(1,3-dioxoisoindolin-2-yloxy)-2-methoxybutanoate (46c, 1.25 g, 42%) as light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.98-2.10 (m, 1H) 2.23-2.37 (m, 1H) 3.51 (s, 3H) 3.79 (s, 3H) 4.24 (dd, J=9.47, 3.66 Hz, 1H) 4.31-4.40 (m, 2H) 7.74-7.82 (m, 2H) 7.81-7.90 (m, 2H).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:12]([F:13])=[C:11]([C:14](O)=[O:15])[C:10]([F:17])=[C:9]([F:18])[C:5]=1[C:6]([OH:8])=[O:7].Cl.FC1(CO)C(F)=CC(F)=C(F)C1CO>O.C1(C)C=CC=CC=1.C(COC)OC>[C:6]([C:5]1[C:9]([F:18])=[C:10]([F:17])[C:11]([CH2:14][OH:15])=[C:12]([F:13])[C:4]=1[F:3])([OH:8])=[O:7]
Reactant: O=C(O)c1c(F)c(F)c(C(=O)O)c(F)c1F
Agent: Cl
Agent: OCC1C(F)=C(F)C=C(F)C1(F)CO
Agent: [BH4-]
Solvent: COCCOC
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)c1c(F)c(F)c(CO)c(F)c1F
Temperature: 50 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
Into a 200 ml flask, 2.58 g of sodium borohydride and 25 g of dimethoxyethane were charged at room temperature and the obtained mixture was heated to 50° C. A mixed solution of 6.1 g of 2,3,5,6-tetrafluoroterephthalic acid and 20 g of dimethoxyethane was added dropwise to the mixture over 1 hour while stirring at the same temperature to effect the reaction for 7 hours at 60° C. After adding 25 g of toluene to the reaction mixture and cooling the obtained mixture at 25° C., 8.5 g of 35% by weight aqueous hydrochloric acid was added thereto dropwise over 1 hour at 25 to 30° C. and the resultant mixture was stirred and kept for 6 hours at 25 to 30° C. To the obtained mixture, 30 g of water was added. After leaving the mixture at rest, the mixture was separated to an organic layer and an aqueous layer. The aqueous layer was extracted twice with 30 g of ethyl acetate and the obtained oil layers were mixed with the organic layer previously obtained. The organic layer after mixing was washed with 10 g of a saturated potassium carbonate and then 10 g of water, and the organic layer was concentrated to obtain the solid containing 2,3,5,6-tetrafluorobenzenedimethanol. The yield of 2,3,5,6-tetrafluorobenzenedimethanol was 33%. Alternatively, 4-carboxy-2,3,5,6-tetrafluorobenzyl alcohol was formed as by-products in the yield of 29%, and a raw material 2,3,5,6-tetrafluoroterephthalic acid remained in 38%.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)#[N:24]>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)=[CH:3][C:2]=1[C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([C:23]#[N:24])[CH:30]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cccc(C#N)c4)c3)cnc2c1F
Yield: 79.9 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol (100 mg, 0.36 mmol) and 3-cyanophenylboronic acid (79 mg, 0.54 mmol) were coupled using the procedure in Example 30 to afford 2′-fluoro-5′-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]biphenyl-3-carbonitrile (112 mg, 80%) as a white solid: δH (360 MHz, CDCl3) 1.74 (6H, s), 2.02 (1H, s), 7.20 (1H, dd, J 7 and 7), 7.37 (1H, dd, J 9 and 9), 7.54-7.63 (3H, m), 7.70-7.73 (2H, m), 7.82 (1H, d, J 9), 7.89 (1H, s), 8.04 (1H, d, J 7); m/z (ES+) 390 (100%, [MH]+).