Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:21][O:20][C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 13.1 %

Procedure:
A mixture of methyl thiosalicylate (0.56 g, 3.4 mmol), 2-cyano-6-methoxypyridine (0.45 g, 3.4 mmol), triethylamine (0.70 ml, 5.0 mmol) and toluene (50 ml) was refluxed for 48 hrs as described in Example 1. The reaction mixture was concentrated under reduced pressure and recrystallized from ethanol to give the titled compound (0.12 g, 13%) as crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[N:20][C:7]2[O:8][C:9]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:10]=3[N:11]([CH3:14])[C:12](=[O:13])[C:6]=2[CH:5]=1)([O-])=O>C(O)(=O)C.Cl>[NH2:1][C:4]1[CH:21]=[N:20][C:7]2[O:8][C:9]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:10]=3[N:11]([CH3:14])[C:12](=[O:13])[C:6]=2[CH:5]=1
Reactant: Cc1ccc2c(c1)Oc1ncc([N+](=O)[O-])cc1C(=O)N2C
Agent: Cl
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)Oc1ncc(N)cc1C(=O)N2C
Reaction time: 3 h

Procedure:
To a suspension of 3-nitro-6,9-dimethylpyrido[2,3-b][1,5]benzoxazepin-5(6H)-one (1.6 g, 5.6 mmol) in acetic acid (30 ml) was added a solution of stannous chloride dihydrate (10 g, 44 mmol) in conc. hydrochloric acid (13 ml). After stirring the mixture for 3 hours, the precipitated product was filtered and washed with ether. The product was then dissolved in water, basified with 2N sodium hydroxide, extracted with ether and ethyl acetate, dried (anhydrous magnesium sulfate), and concentrated. Crystallization from ethanol/hexane provided 0.82 g (57% of theory) of pure product as tan needles, m.p. 191°-193° C.
Reaction SMILES: NC1C=CC(OC2N=CN=C(N)C=2)=C(F)C=1.FC1C=CC(CC(N=C=O)=O)=CC=1.COC1C=CC(C[NH:37][C:38]2[N:43]=[CH:42][N:41]=[C:40]([O:44][C:45]3[CH:50]=[CH:49][C:48]([NH:51][C:52]([NH:54][C:55](=[O:64])[CH2:56][C:57]4[CH:62]=[CH:61][C:60]([F:63])=[CH:59][CH:58]=4)=[O:53])=[CH:47][C:46]=3[F:65])[CH:39]=2)=CC=1>C1COCC1>[NH2:37][C:38]1[N:43]=[CH:42][N:41]=[C:40]([O:44][C:45]2[CH:50]=[CH:49][C:48]([NH:51][C:52]([NH:54][C:55](=[O:64])[CH2:56][C:57]3[CH:62]=[CH:61][C:60]([F:63])=[CH:59][CH:58]=3)=[O:53])=[CH:47][C:46]=2[F:65])[CH:39]=1
Reactant: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Agent: Nc1ccc(Oc2cc(N)ncn2)c(F)c1
Agent: O=C=NC(=O)Cc1ccc(F)cc1
Solvent: C1CCOC1
Product: Nc1cc(Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)ncn1
Yield: 55.6 %

Procedure:
The title compound was prepared from 6-(4-amino-2-fluorophenoxy)pyrimidin-4-amine (92 mg, 0.42 mmol) and 0.36 M 2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound D of Example 11, 1.3 mL, 0.45 mmol) in THF as described above for Example 11. The crude product was purified by trituration using 1:1 EtOH/H2O followed by absolute EtOH. The product was vacuum dried to give the title compound (100 mg, 60%). A second, slightly less pure crop of the product (45 mg, 27%) was obtained by extracting the combined filtrates and washing with EtOAc. 1H NMR (DMSO-d6) δ 10.99 (s, 1H), 10.50 (s, 1H), 8.01 (s, 1H), 7.65 (dd, 1H, J=12.6, 2.1 Hz), 7.33 (dd, 2H, J=8.1, 6.0 Hz), 7.28 (dd, 1H, J=8.6, 2.0 Hz), 7.22 (dd, 1H, J=8.8, 8.8 Hz), 7.17-7.12 (m, 2H), 6.89 (br s, 2H), 5.80 (s, 1H), 3.71 (s, 2H); MS(ESI+) m/z 400.09 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][CH2:11][CH:12]2[CH2:14][O:13]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)[CH2:26][CH2:25]2)[CH3:23])=[CH:18][CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)C>[Cl:1][C:2]1[N:3]([CH2:10][CH2:11][CH:12]([OH:13])[CH2:14][O:36][C:33]2[CH:32]=[CH:31][C:30]([N:27]3[CH2:26][CH2:25][CH:24]([N:22]([C:19]4[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=4)[CH3:23])[CH2:29][CH2:28]3)=[CH:35][CH:34]=2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: CN(c1ccc(Cl)cc1)C1CCN(c2ccc(O)cc2)CC1
Reactant: O=[N+]([O-])c1cn(CCC2CO2)c(Cl)n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN(c1ccc(Cl)cc1)C1CCN(c2ccc(OCC(O)CCn3cc([N+](=O)[O-])nc3Cl)cc2)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
2-Chloro-4-nitro-1-(2-oxiranylethyl)-1H-imidazole (810 mg) was suspended in ethanol (20 ml) and 4-{4-[N-(4-chlorophenyl)-N-methylamino]piperidin-1-yl}phenol (982 mg) and tripotassium phosphate (200 mg) were added thereto, followed by stirring at 70° C. overnight. Thereafter the reaction solution was cooled to room temperature, and filtered through Celite to remove insoluble matter and, then the residue was washed with ethyl acetate. The filtrate and liquid were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:1) and recrystallized from methylene chloride-ethyl acetate to afford the title compound as a yellow solid (486 mg).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:16])[CH2:9][C:10]([CH3:15])([CH3:14])[O:11]2)=[CH:6][CH:5]=1.Cl[CH2:18][S:19][CH2:20]OCSCCl>C([N+](CCCC)(CCCC)CCCC)CCC.S([O-])(O)(=O)=O.ClCCl>[CH3:18][S:19][CH2:20][O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:16])[CH2:9][C:10]([CH3:14])([CH3:15])[O:11]2)=[CH:6][CH:5]=1
Reactant: ClCSCOCSCCl
Reactant: CC1(C)CC(=O)c2ccc(O)cc2O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CSCOc1ccc2c(c1)OC(C)(C)CC2=O
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
A mixture of 20 ml of a 10% sodium hydroxide solution, 40 ml of dichloromethane, 0.5 g (2 millimoles) of tetrabutyl-ammonium-hydrogensulfate and 10 millimoles of 7-hydroxy-2,2-dimethyl-4-chromanone is intensively stirred for 30 minutes. To the mixture 2.4 g (2.1 ml, 25 millimoles) of chloromethyl-thiomethyl-ether are added, the reaction mixture is stirred for 20 minutes at room temperature and worked up according to Example 12. Thus 2.0 g of the desired compound are obtained in the form of an orange oil, yield 79%.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][CH:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH2:9]2)=[CH:5][CH:4]=1)#[N:2].[OH-:21].[K+]>C(O)(C)(C)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH2:9]2)=[CH:19][CH:20]=1)(=[O:21])[NH2:2]
Reactant: [OH-]
Reactant: N#Cc1ccc(OC2CCN(c3ccncc3)C2)cc1
Agent: [K+]
Solvent: CC(C)(C)O
Product: NC(=O)c1ccc(OC2CCN(c3ccncc3)C2)cc1
Yield: 57.8 %

Procedure:
A mixture of 4-[3-(4-cyanophenoxy)-1-pyrrolidinyl]pyridine (269 mg) and powdered potassium hydroxide (568 mg) in t-butanol (10 ml), under an atmosphere of argon, was heated under reflux for 18 hours. The mixture was filtered hot. The filtercake was washed with water and ethanol to give 4-[3-(4-carbamoylphenoxy)-1-pyrrolidinyl]pyridine (166 mg) as a colourless solid, mp 298-300° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7])([O-:3])=[O:2].CO[C:15](OC)([N:17]([CH3:19])[CH3:18])[CH3:16]>>[CH3:18][N:17]([CH2:15][CH:16]=[N:8][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:19]
Reactant: COC(C)(OC)N(C)C
Reactant: NC(=O)c1ccccc1[N+](=O)[O-]
Product: CN(C)CC=NC(=O)c1ccccc1[N+](=O)[O-]
Temperature: 120 °C

Procedure:
2-Nitrobenzamide (12.4 g, 75 mmol) was dissolved to dimethylacetamide-dimethylacetal (25 mL ) and heated to 120° C. for 2 hours. Upon cooling, the reaction was passed through a short silica column, eluting with ethyl acetate. The crystals that formed in the collected eluent were collected by filtration and rinsed with diethyl ether to provide N-[(dimethylamino)ethylidene]-2-nitrobenzamide (7.73 g).
Reaction SMILES: [N:1]1([C:7]([NH:9][C:10]2[CH:11]=[C:12]([C:16]3[N:25]=[C:24]([NH:26][C:27]4[CH:28]=[C:29]5[C:33](=[CH:34][CH:35]=4)[N:32](C(OC(C)(C)C)=O)[N:31]=[CH:30]5)[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[CH:13]=[CH:14][CH:15]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:32]1[C:33]2[C:29](=[CH:28][C:27]([NH:26][C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:16]([C:12]4[CH:11]=[C:10]([NH:9][C:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[O:8])[CH:15]=[CH:14][CH:13]=4)[N:25]=3)=[CH:35][CH:34]=2)[CH:30]=[N:31]1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)N5CCOCC5)c4)nc4ccccc34)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1)N1CCOCC1

Procedure:
To tert-butyl 5-(2-(3-(morpholine-4-carboxamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (25 mg, 0.044 mmol) was added a solution of 1:1 TFA:CH2Cl2 (2 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the product triturated with ethyl ether to afford N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)morpholine-4-carboxamide. (24 mg, 100%)
Reaction SMILES: [NH2:1][C@@H:2]([C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9](I)=[CH:8][C:7]=1[F:13])=[O:4].C(N(CC)CC)C.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31]>C(OCC)C.[Cu](I)I>[NH2:1][C@@H:2]([C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:34]#[C:33][Si:30]([CH3:32])([CH3:31])[CH3:29])=[CH:8][C:7]=1[F:13])=[O:4]
Reactant: C#C[Si](C)(C)C
Reactant: C[C@@H](c1ccccc1)[C@H](N)C(=O)Nc1ccc(I)cc1F
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C[C@@H](c1ccccc1)[C@H](N)C(=O)Nc1ccc(C#C[Si](C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.9 %

Procedure:
A solution of (2S,3S)-2-amino-N-(2-fluoro-4-iodo-phenyl)-3-phenyl-butyramide (1.00 g, 2.51 mmol) in triethylamine (1.5 mL, 10.8 mmol) was thoroughly degassed with argon, bis-dichlorotriphenylphosphine palladium(II) (20.3 mg, 0.05 mmol) added followed by copper iodide (9.8 mg, 0.05 mmol) and trimethylsilylacetylene (277 mg, 2.77 mmol) and the mixture stirred under argon at ambient temperature for 3 hours. Additional triethylamine (1.5 mL, 10.8 mmol) was added to form a stirrable reaction mixture and stirring continued for an additional 20 hours. The reaction mixture was diluted with diethyl ether and a small amount of Celite added prior to filtration through Celite. The Celite was eluted with diethyl ether (4×20 mL) and the combined organic filtrates concentrated in vacuo. The resulting green oil was dissolved in a small amount of diethyl ether and diluted with hexanes (10 mL) to induce crystallization. The product was isolated by filtration, washed with hexanes and dried in vacuo to afford (2S,3S)-2-amino-N-(2-fluoro-4-trimethylsilanylethynyl-phenyl)-3-phenyl-butyramide as a grey solid (610 mg, 66%). A second crop of product was obtained by reprocessing of the mother liquors from the initial crystallization (168 mg, 18%).
Reaction SMILES: [H-].[Na+].[S:3]([NH:13][C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1)([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[Br:25][CH2:26][CH2:27][CH2:28][CH2:29]Br.C(OCC)(=O)C>CN(C)C=O>[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][N:13]([S:3]([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)(=[O:4])=[O:5])[C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1ccc(NS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N(CCCCBr)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5 %

Procedure:
To 0.892 g (0.0372 mol) of sodium hydride resulting from washing 1.11-1.12 g of an 80% oil dispersion with hexanes under nitrogen was added 26 mL of dry dimethylformamide. To the stirred mixture was added dropwise over a 21 min period through an addition funnel a solution of 10.00 g (0.0313 mol) of ethyl 4-tosylaminobenzoate (Baker, B. R.; Santi, D. V.; Shapiro, H. S. J. Pharm. Sci.. 1964, 53, 1317) in 52 mL of dry dimethylformamide and then 3 mL of rinse dimethylformamide. When the stirred mixture had cooled to room temperature, to it was added at one time 27.74 g (0.128 mol) of 1,4-dibromobutane. The stirred mixture was heated for 4 h 45 min with a bath maintained near 80° C. and was allowed to cool to room temperature and stand under nitrogen overnight. The mixture was concentrated under vacuum at 40° C. to an oil/solid mixture; yield, 22.37 g. To the mixture was added 100 mL of ethyl acetate, and undissolved solid was collected by suction filtration. The filtrate was purified by a flash chromatography column consisting of 700 g of Silica Gel 60 with 6:1 hexane/ethyl acetate as the eluting solvent. The major fractions of clean product were combined and concentrated under vacuum to a colorless oil that solidified to a white solid; yield, 10.91 g (77%): NMR (Me2SOd6) δ 1.29 (t, 3H), 1.3-1.5 (m, 2H), 1.7-1.9 (m, 2H), 2.37 (s, 3H), 3.47 (t, 2H), 3.60 (t, 2H), 4.29 (q, 2H), 7.23 (d, 2H), 7.3-7.5 (AA'BB', 4H), 7.91 (d, 2H). An additional 5% yield was obtained from later column fractions.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[N:20]=[CH:19][C:18]([CH2:21][C:22]([O:24]CC)=O)=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH:27]3[CH2:29][CH2:28]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH3:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[N:20]=[CH:19][C:18]([CH2:21][C:22]([NH2:30])=[O:24])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH:27]3[CH2:28][CH2:29]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: CCOC(=O)Cc1ccc(Nc2cc(C3CC3)nc(-c3cccc(Cl)c3)n2)nc1
Product: NC(=O)Cc1ccc(Nc2cc(C3CC3)nc(-c3cccc(Cl)c3)n2)nc1
Temperature: 100 °C
Reaction time: 23 h
Yield: 44.9 %

Procedure:
A 10-mL vial was charged with ethyl 2-(6-((2-(3-chlorophenyl)-6-cyclopropylpyrimidin-4-yl)amino)pyridin-3-yl)acetate (0.070 g, 0.17 mmol) and NH3 (4.9 mL, 7N in methanol, 34.2 mmol). The vial was sealed and the resulting mixture was stirred at 100° C. for 23 h. The crude reaction solution concentrated under reduced pressure. The residue was absorbed on silica (2 g) then purified by chromatography on silica using dichloromethane/methanol (10:0 to 9:1) as eluent to afford the title compound (0.029 g, 45%) as a white solid. M.p. 232-235° C. 1H NMR (DMSO-d6, 500 MHz) δ 10.10 (s, 1H), 8.31-8.29 (m, 1H), 8.27 (dt, J=7.5, 2.0 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.75-7.69 (m, 1H), 7.67 (dd, J=8.5, 2.0 Hz, 1H), 7.60 (br s, 1H), 7.58-7.52 (m, 2H), 7.50 (br s, 1H), 6.93 (br s, 1H), 3.37 (s, 2H), 2.07 (septet, J=4.5 Hz, 1H), 1.14-1.09 (m, 2H); 1.06-1.00 (m, 2H); APCI MS m/z 380 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:13]([F:16])([F:15])[F:14])=[N:5][N:6]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:7]=1[Cl:8].O.[SH-:18].[Na+].O>CN(C)C=O>[C:9]([N:6]1[C:7]([Cl:8])=[C:3]([CH2:2][SH:18])[C:4]([C:13]([F:16])([F:15])[F:14])=[N:5]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)n1nc(C(F)(F)F)c(CBr)c1Cl
Reactant: [SH-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)n1nc(C(F)(F)F)c(CS)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
43.5 g (136.1 mmoles) of 4-bromomethyl-1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole was added to a solution of 21.8 g of sodium hydrosulfide hydrate (purity: 70%, 272.2 mmoles) dissolved in 300 ml of N,N-dimethylformamide. The mixture was stirred at room temperature overnight to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with diethyl ether. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 32.3 g (yield: 87.0%) of (1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanethiol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:16])[C:9](=[O:15])[N:10]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:5]2=[CH:4][CH:3]=1.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B1OC(C)(C)C(C)(C)O1)#[N:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:12]1([CH2:11][N:10]2[C:5]3[C:6](=[N:7][C:2]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[C:17]#[N:18])=[CH:3][CH:4]=3)[N:8]([CH3:16])[C:9]2=[O:15])[CH2:14][CH2:13]1
Reactant: CC1(C)OB(c2ccccc2C#N)OC1(C)C
Reactant: Cn1c(=O)n(CC2CC2)c2ccc(Cl)nc21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cn1c(=O)n(CC2CC2)c2ccc(-c3ccccc3C#N)nc21
Temperature: 90 °C

Procedure:
5-chloro-1-(cyclopropylmethyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1-4) (35 mg, 0.138 mmol), 2-cyanophenylboronic acid pinacol ester (79 mg, 0.345 mmol), cesium carbonate (135 mg, 0.414 mmol), and bis(tri-t-butylphosphine)palladium(0) (7 mg, 0.014 mmol) were added to a microwave vial, and purged with nitrogen. Dioxane (1.1 ml) and water (0.3 ml) were added and the suspension was heated at 90° C. overnight. The reaction was cooled to room temperature, diluted with methanol, and passed through a syringe filter. The solution was purified using reverse phase chromatography (10-100%, 0.1% TFA in H2O/Acetonitrile) and the desired fractions were collected and concentrated to produce 2-[1-(cyclopropylmethyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]benzonitrile (1-5). HRMS (M+H)+: observed=305.1403, calculated=305.1397.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.C([Li])CCC.[O:18]=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:19]1([OH:18])[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Fc1ccccc1-n1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2nccn2-c2ccccc2F)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
1-(2-Fluorophenyl)imidazole (484 mg, 2.99 mmol) was dissolved in a tetrahydrofuran (5 mL) under an atmosphere of argon. The reaction mixture was cooled to −78° C. n-Butyllithium (2.2 mL of 1.6 M, 3.58 mmol) in hexanes was slowly added and the resulting mixture was stirred at −78° C. for 1 hour. tert-Butyl 4-oxopiperidine-1-carboxylate (892.2 mg, 4.48 mmol) was then added as a solution in tetrahydrofuran (2 mL). The reaction mixture was allowed to slowly warm to room temperature and stir for 10 days. The crude material was evaporated to dryness and taken to the next step without further purification. ESI-MS m/z calc. 361.2, found 362.1 (M+1)+. Retention time 1.12 minutes (3 min run).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].Cl.[CH2:10]([O:17][NH2:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CCOCC.O.S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:10]([O:17][NH:18][S:5]([CH2:4][CH2:3][CH2:2][Cl:1])(=[O:7])=[O:6])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NOCc1ccccc1
Reactant: O=S(=O)(Cl)CCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: O
Product: O=S(=O)(CCCCl)NOCc1ccccc1
Yield: 41 %

Procedure:
3-Chloropropylsulfonyl chloride 1 (30.28 g, 0.17 mol), O-benzylhydroxylamine hydrochloride (27.3 g, 0.17 mol), potassium carbonate (50 g, 0.36 mol) and tetrabutylammonium sulfate (about 500 mg) are reacted in a mixture of ether (1L) and water (100 ml) for 24 hours at room temperature and the reaction mixture was extracted with ethyl acetate. The extract was subjected to column chromatography on silica gel. From the fraction eluted with a mixture of ethyl acetate/n-hexane (1:4), 18.4 g (41%) of crude N-benzyloxy-3-chloropropylsulfonamide (intermediate 3g) was obtained as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:17])C=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1cccnc1Br
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cccc(F)c1Br
Temperature: 50 °C
Reaction time: 18 h
Yield: 80.2 %

Procedure:
A mixture of 2-bromo-3-fluoropyridine (1.0 g, 5.7 mmol) and 3-chloroperbenzoic acid (1.5 g, 7.4 mmol) in chloroform (3.5 mL) was stirred at 50° C. for 18 hours, cooled down to room temperature and filtered. The filtrate was concentrated under reduced pressure to give a residue that was purified by flash chromatography (Si—PPC, MeOH:EtOAc, gradient 0:100 to 5:95) to give 2-Bromo-3-fluoropyridine 1-oxide as a white solid (878 mg, 80%). 1H NMR (400 MHz, CHCl3-d): δ 8.25 (dt, J=6.6, 1.3 Hz, 1H); 7.25-7.17 (m, 1 H); 7.06 (ddd, J=8.7, 6.6, 1.3 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8]
Reactant: O=C1CCC(c2cc(Cl)c(O)c(Cl)c2)=NN1
Solvent: CC(=O)O
Product: O=c1ccc(-c2cc(Cl)c(O)c(Cl)c2)n[nH]1

Procedure:
3 In acetic acid heated to 70° C. was suspended 4.3 g. of 6-(3,5-dichloro-4-hydroxyphenyl)-4,5-dihydro-3(2H)pyridazinone. The resulting suspension was then treated in the manner as in Example 1 - 3 to give 3.7 g. of the desired product of m.p. above 300° C.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][CH3:3].[H-].[Na+].F[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:14]1[N:18]([CH3:19])[C:17]2[CH:20]=[CH:21][C:22]([C:24]([F:27])([F:26])[F:25])=[CH:23][C:16]=2[N:15]=1.[Cl-].[NH4+]>CN(C=O)C>[CH3:19][N:18]1[C:17]2[CH:20]=[CH:21][C:22]([C:24]([F:27])([F:26])[F:25])=[CH:23][C:16]=2[N:15]=[C:14]1[C:13]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[O:4][CH2:1][CH2:2][CH3:3]
Reactant: Cn1c(-c2ccncc2F)nc2cc(C(F)(F)F)ccc21
Reactant: CCCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCOc1cnccc1-c1nc2cc(C(F)(F)F)ccc2n1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.6 %

Procedure:
To a mixture of 0.36 g of 1-propanol and 6 ml of DMF was added 0.24 g of 60% sodium hydride (oily) under ice cool, and the mixture was stirred for 10 minutes. 2-(3-fluoropyridin-4-yl)-1-methyl-5-trifluoromethyl-1H-benzimidazole (0.35 g) was added, then, the mixture was heated up to room temperature and further stirred for 1 hour. A saturated ammonium chloride aqueous solution was poured, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.36 g of 1-methyl-2-(3-propoxypyridin-4-yl)-5-trifluoromethyl-1H-benzimidazole (hereinafter, referred to as present active compound 10).
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[N:18]=[C:17]([O:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[CH:16]=[CH:15][CH:14]=1.C1C[O:28][CH2:27]C1>>[CH3:23][N:22]([CH3:24])[CH2:21][CH2:20][O:19][C:17]1[N:18]=[C:13]([CH:27]=[O:28])[CH:14]=[CH:15][CH:16]=1
Reactant: CN(C)CCOc1cccc(Br)n1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CN(C)CCOc1cccc(C=O)n1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
n-BuLi 2.5 M in hexane (1.2 mL, 3 mmol, 3 eq) was added at −70° C. to a solution of the product from the previous step, N-{2-[(6-bromo-2-pyridinyl)oxy]ethyl}-N,N-dimethylamine (245 mg, 1 mmol) in dry THF (10 mL). The reaction mixture was stirred at −70° C. for 1 h 30 min. Ethyl formate (freshly distilled over P2O5) was added at −70° C., and the reaction mixture was stirred at −70° C. for 2 hours. The reaction was quenched with addition of water. The reaction mixture was extracted with 3 portions of DCM. Combined organic phase were dried with MgSO4, filtrated and evaporated to give the desired product, 6-[2-(dimethylamino)ethoxy]-2-pyridinecarbaldehyde (192 mg, 0.988 mmol, 99%).