Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26](OS(C)(=O)=O)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.O>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([O:9][C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: Oc1cc(F)ccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)ccc2Cl)CC1
Temperature: 80 °C
Yield: 65.3 %

Procedure:
To a stirred solution of 2-chloro-5-fluorophenol (6 g, 0.0413 mole) in DMF (20 mL) was added cesium carbonate (26.89 g, 0.00827 mole) followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (11.54 g, 0.04137 mole). The reaction mixture was heated at 80° C. for overnight. The mixture was then diluted with water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 230-400 mesh (2% ethyl acetate in hexane) to afford 8.9 g (65%) of 4-(2-chloro-5-fluoro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 330.12 (M+1)+, 100%. A solution of 4-(2-chloro-5-fluoro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (8.9 g, 0.027 mole) in ethyl acetate.HCl (10 mL) was stirred at ambient temperature for 2 hours. The reaction mixture was then concentrated under reduced pressure and the resulting residue was washed with ether to afford 6.54 g (92%) of. LCMS: 230.07 (M+1)+, 100%, 1H NMR (DMSO-d6): δ 9.6-9.1 (bs, 2H), 7.55-7.45 (t, 1H), 7.35-7.2 (d, 1H), 6.9-6.8 (t, 1H), 4.9-4.7 (s, 1H), 3.26-3.0 (s, 4H), 2.2-2.06 (s, 2H), 2.0-1.8 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[C:7]=1[C:19]#[N:20].[N:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=1)=[C:25]=[O:26]>CN(C)C=O.C(OCC)(=O)C>[C:19]([C:7]1[C:8]2[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:9]=2[CH:17]=[CH:18][C:6]=1[O:5][C:4]1[CH:21]=[CH:22][CH:23]=[C:2]([NH:1][C:25](=[O:26])[NH:24][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:35])([F:37])[F:36])=[CH:29][CH:28]=2)[CH:3]=1)#[N:20]
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c(C#N)c2s1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)Nc4ccc(OC(F)(F)F)cc4)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.3 %

Procedure:
N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (150 mg, 0.462 mmol) produced in Example 12(ii) was dissolved in N,N-dimethylformamide (2 mL), 1-isocyanato-4-(trifluoromethoxy)benzene (91 μL, 0.60 mmol) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=80/20→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from diisopropyl ether to give the title compound (147 mg, 60%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7]([C:9]3[C:13]([N+:14]([O-])=O)=[CH:12][NH:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1>C(O)C.[Pd]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7]([C:9]3[C:13]([NH2:14])=[CH:12][NH:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])c1c[nH]nc1-c1nc2cc(Cl)ccc2[nH]1
Agent: [Pd]
Solvent: CCO
Product: Nc1c[nH]nc1-c1nc2cc(Cl)ccc2[nH]1
Reaction time: 3 h
Yield: 143.8 %

Procedure:
A solution of 5-chloro-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole [91 mg, Example 239(a)] in ethanol (40 mL), under nitrogen, was treated with palladium on carbon (spatula tip, 5%). The mixture was stirred under hydrogen for 3 hours and then filtered through Celite. The filter pad was washed well with dichloromethane. The combined filtrate and washings were evaporated to give 3-(5-chloro-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine (116 mg). LC-MS (METHOD A): RT=2 minutes; 234 (M+H)+. (b) 3-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine
Reaction SMILES: ClC(Cl)(Cl)C(C1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[F:24])[NH:7][CH:6]=1)=O.CO.C1COCC1.[OH-].[Na+].C[CH2:37][O:38][C:39]([CH3:41])=[O:40]>>[F:24][C:16]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:15]=1[O:14][C:12]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:7][CH:6]=[C:41]([C:39]([O:38][CH3:37])=[O:40])[C:13]=12
Reactant: O=C(c1c[nH]c2nccc(Oc3ccc([N+](=O)[O-])cc3F)c12)C(Cl)(Cl)Cl
Reactant: CCOC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c[nH]c2nccc(Oc3ccc([N+](=O)[O-])cc3F)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
To a solution of 2,2,2-trichloro-1-(4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanone (490 mg, 1.17 mmol, See: Step A of Example 270) in a mixed solvent (10 mL of MeOH and 10 mL of THF) was added 1 N NaOH (10 mL, 10 mmol). The reaction mixture was stirred at room temperature for 3 h, and diluted with EtOAc (30 mL). The organic layer was washed with sat. aq. NaHCO3, solution, dried and concentrated in vacuo to give the desired product (235 mg, 61%) as a light brown solid. MS(ESI+) m/z 332.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([O:13]C)=[O:12])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl>[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([OH:13])=[O:12])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)c1n[nH]c2ncc(Br)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1n[nH]c2ncc(Br)cc12
Temperature: 90 °C
Yield: 92.6 %

Procedure:
A suspension of methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (VII) (70 mg, 0.27 mmol) in aqueous 1N NaOH solution (20 mL) was heated at 90° C. for 3 h until the solution became clear. The solution was then cooled to 0° C. and acidified with a 10% HCl solution. The solids formed were filtered, washed with cold water and dried at room temperature under vacuum to give 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (VIII) as a white solid (60 mg, 0.25 mmol, 92% yield). 1H NMR (CDCl3) δ ppm 8.58 (d, J=3.01 Hz, 1H), 8.66 (d, J=3.01 Hz, 1H); ESIMS found for C7H4BrN3O2 m/z 242.1 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[CH:4]=[N:3]1.C(OC([NH:15][C:16]1[S:20][C:19]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[N:18][C:17]=1[C:29](O)=[O:30])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:15][C:16]1[S:20][C:19]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[N:18][C:17]=1[C:29]([NH:7][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:30]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1cc(N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1cc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)cn1
Yield: 70 %

Procedure:
Following the procedures as described in Example 113, 1-methyl-1H-pyrazol-4-amine, 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid and HATU were reacted to give 102 as a white solid (45 mg, 70%) over two steps. 1H NMR (400 MHz, DMSO) δ 9.78 (s, 1H), 8.00 (d, J=37.3, 1H), 7.70-7.47 (m, 4H), 7.28 (t, J=8.4, 2H), 3.81 (d, J=12.5, 3H). ESIMS m/z=336.1 (M+1)
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[C:14]([Cu])#[N:15]>CN(C=O)C>[C:14]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1)#[N:15]
Reactant: N#C[Cu]
Reactant: Cc1ccc2nc(C)cc(Br)c2c1
Solvent: CN(C)C=O
Product: Cc1ccc2nc(C)cc(C#N)c2c1
Yield: 55.5 %

Procedure:
First, 4-bromo-2,6-dimethylquinoline (5.0 g) and CuCN (4.82 g) were added to DMF (70 ml) and were allowed to react for 6 hours at a temperature of 140° C. Ice was poured to the reaction solution and the produced precipitate was removed through filtering. The filtrate was extracted using ethyl acetate, the solvent was removed under reduced pressure, and the residue was purified through column chromatography (silica gel, hexane/ethyl acetate=4/1) to obtain 4-cyano-2,6-dimethylquinoline (2.14 g) represented by the following chemical formula (47).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:13]([CH:21]([CH3:23])[CH3:22])[C:14]1[CH:19]=[N:18][CH:17]=[C:16]([Cl:20])[N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.CN([CH:28]=[O:29])C>>[CH2:6]([N:13]([CH:21]([CH3:23])[CH3:22])[C:14]1[N:15]=[C:16]([Cl:20])[C:17]([CH:28]=[O:29])=[N:18][CH:19]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)N(Cc1ccccc1)c1cncc(Cl)n1
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)N(Cc1ccccc1)c1cnc(C=O)c(Cl)n1
Reaction time: 0.25 h
Yield: 70 %

Procedure:
Phosphoryl chloride (5.6 mL) was added dropwise to DMF (12 mL) at 0° C. The mixture was stirred for 15 min, and a solution of N-benzyl-6-chloro-N-(1-methylethyl)pyrazin-2-amine (3.40 g) in DMF (3 mL) was added dropwise thereto. The mixture was stirred at 100° C. for 13 hr, water (50 mL) was added at 0° C., and the mixture was stirred at room temperature for 1 hr. The mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 5-420% ethyl acetate/hexane) to give the title compound (2.42 g, 70%) as a pale-yellow oil.
Reaction SMILES: Cl.[CH2:2]([NH:6][CH2:7][CH2:8][CH2:9]Cl)[CH:3]([CH3:5])[CH3:4].[CH3:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:21]=[C:22]=[S:23]>>[CH3:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:21]=[C:22]1[N:6]([CH2:2][CH:3]([CH3:5])[CH3:4])[CH2:7][CH2:8][CH2:9][S:23]1
Reactant: CC(C)CNCCCCl
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Agent: Cl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCCCN1CC(C)C

Procedure:
3-Aminopropanol was reacted with butyraldehyde according to Method B9a, Step 1 to afford 2-isopropyltetrahydro,1,3-oxazine. The oxazine was reduced according to Method B9a, Step 2 to give N-isobutyl-3-hydroxypropylamine. The 3-hydroxypropylamine was reacted with SOCl2 according to Method B9a, Step 3 to give N-isobutyl-3-chloropropylamine HCl salt. The 3-chloropropylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to afford 2-(2-methyl-4-nitrophenylimino)-3-isobutyltetrahydro-1,3-thiazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH2:11]([O:13][CH:14]([O:23][CH2:24][CH3:25])[C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:12]>N1CCCCC1.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[C:16]([C:15]([CH:14]([O:13][CH2:11][CH3:12])[O:23][CH2:24][CH3:25])=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: COc1ccccc1C=O
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1ccccc1OC)C(=O)C(OCC)OCC

Procedure:
A solution of 2-methoxybenzaldehyde (2.7228 g), ethyl 4,4-diethoxyacetoacetate (4.3648 g) and piperidine (4 or 5 drops) in benzene (20 ml) was refluxed under azeotropic dehydration for 3 hours. The resultant solution was washed with water and dried. The solvent was removed from the extract to give oily ethyl 2-(2-methoxybenzylidene)-4,4-diethoxyacetoacetate. The mixture of the compound obtained above and ethyl 3-aminocrotonate (2.5832 g) was heated in an oil bath (about 100° C.) for 7 hours. After cooling, the reaction mixture was extracted with diethyl ether, and the extract was washed with water twice and dried over magnesium sulfate. The solvent was removed to give a red oil. The oil was purified by a column chromatography on silica gel with an eluent (benzene:ethyl acetate=20:1) to give diethyl 2-methyl-4-(2-methoxyphenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (5.0779 g). The product was recrystallized from n-hexane to give pale yellowish prisms, m.p. 105° to 107° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([C:14]2[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=2)[N:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>CC(N(C)C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[N:3][C:4]=2[C:14]1[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=1)([CH3:13])[CH3:12]
Reactant: C1COCCN1
Reactant: CC(C)n1cnc2c(-c3cnc(N)nc3)nc(Cl)nc21
Solvent: CC(=O)N(C)C
Product: CC(C)n1cnc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc21
Temperature: 94 °C
Yield: 58 %

Procedure:
To a solution of 5-(2-chloro-9-isopropyl-9H-purin-6-yl)-pyrimidin-2-ylamine (2.84 mmol) in dimethyl acetamide (18 ml) was added morpholine (2.84 mmol). The reaction mixture was stirred while being heated on an oil bath maintained at 94° C. for 12 h. The reaction was monitored for the absence of starting material by LC-MS. The crude material was directly loaded onto a preparative HPLC column and purified by chromatography to give 5-(9-isopropyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine in a yield of 58%. 1H NMR, DMSO-d6: 9.53 (s, 2H), 8.32 (s, 1H), 7.30 (bs, 2H), 4.72 (m, 1H), 3.78 (m, 4H), 3.73 (m, 4H), 1.55 (d, 6H). m/z: 341.17 [MH]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[CH2:10][C@@H:11]([NH:25]C(OC(C)(C)C)=O)[C:12]([NH:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>C(Cl)Cl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[CH2:1]([O:8][C:9](=[O:33])[CH2:10][C@@H:11]([NH2:25])[C:12]([NH:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CC(=O)OCc1ccccc1)C(=O)N[C@H](CO)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](CC(=O)OCc1ccccc1)C(=O)N[C@H](CO)Cc1ccccc1
Reaction time: 2.5 h

Procedure:
To a solution of N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-(t-butoxycarbonylamino) succinamic acid benzyl ester (389 mg, 0.851 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (1 mL). After 2.5 h at ambient temperature, the solvent was removed in vacuo to give 3(R)-amino-N-(1(S)-benzyl-2-hydroxyethyl)succinamic acid benzyl ester trifluoroacetate salt as a yellow foam that was placed with 3-(biphenyl-4-yl-)2,5-dimethoxytetrahydrofuran (182 mg, 0.641 mmol) in HOAc (1 mL) and heated to 50° C. After 2 hours, the mixture was allowed to cool, carefully stirred with saturated aqueous NaHCO3 (25 mL), and extracted into CHCl3 (3×15 mL). The combined organic layers were dried over Na2SO4 and evaporated to give a brown oil, 685 mg. Flash column chromatography with 10% MeOH/CH2Cl2 as eluant provided 276 mg (64%) of N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-(3-(biphenyl-4-yl)-1H-pyrrol-1-yl)succinamic acid benzyl ester as a yellow solid. 1H NMR (CDCl3): δ 7.70-7.48 (m, 10H), 7.44 (dd, 2H, J=7.2, 7.8 Hz), 7.38-7.12 (m, 5H), 7.08-6.98 (m, 2H), 6.89 (bm, 1H), 6.63 (dd, 1H, J=2.5, 2.5 Hz), 6.54 (dd, 1H, J=1.2, 1.2 Hz), 5.76 (d, 1H, J=7.5 Hz), 5.10 (dd, 2H, J=12.1, 15.9 Hz), 4.95 (dd, 1H, J=5.0, 8.7 Hz), 4.34-4.00 (bm, 1H), 3.66 (dd, 1H, J=3.7, 11.2 Hz), 3.49 (dd, 1H, J=5.3, 11.2 Hz), 3.37 (dd, 1H, J=5.0, 16.8 Hz), 3.18 (dd, 1H, J=8.7, 16.8 Hz), 2.74 (ddd, 2H, J=6.5, 13.7, 15.9Hz). IR(KBr): 3314, 3029, 2925, 1731, 1658, 1548, 1495, 1355, 1196, 1165, 761, 698 cm−1; Anal. calculated for C36H34N2O4.0.5 H2O: C, 76.17; H, 6.22; N, 4.94. Found: C, 76.24; H, 6.18; N, 4.97.
Reaction SMILES: Br[C:2]1[C:3]([F:15])=[C:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[C:5]([F:8])=[CH:6][CH:7]=1.C([O-])(=O)C.[K+].[B:21]1(B2OCC(C)(C)CO2)[O:26]CC(C)(C)C[O:22]1>O1CCOCC1>[F:15][C:3]1[C:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[B:21]([OH:26])[OH:22]
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Reactant: Fc1ccc(Br)c(F)c1-c1cccnc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: OB(O)c1ccc(F)c(-c2cccnc2)c1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
A mixture of 3-(3-bromo-2,6-difluorophenyl)pyridine (2.97 g, 11 mmol), potassium acetate (2.16 g, 22 mmol) and bis(neopentyl glycolato)diboron (2.86 g, 12.7 mmol) in 1,4-dioxane (30 ml) was heated at 90° C. for 16 h. The reaction was cooled, filtered (washing the filter cake with a small quantity of diethyl ether) and the filtrate concentrated in vacuo. The residue was partitioned between diethyl ether (100 ml) and 1M sodium hydroxide (100 ml) and the organics discarded. The aqueous was washed with more diethyl ether and then cooled in an ice-water bath. The pH was adjusted to approximately 6 with 36% hydrochloric acid, and allowed to stand for 1 h. The resulting solid was collected by filtration and dried under vacuum to afford 2,4-difluoro-3-(pyridin-3-yl)benzeneboronic acid (2.2 g, 85%) as a grey solid: m/z (ES+) 236 (M++H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([CH3:17])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:19]([CH3:18])(=[O:21])=[O:20])=[C:12]([CH3:17])[CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)N1CCN(c2ccc(N)c(C)c2)CC1
Solvent: c1ccncc1
Product: CC(=O)N1CCN(c2ccc(NS(C)(=O)=O)c(C)c2)CC1

Procedure:
1-Acetyl-4-(4-amino-3-methylphenyl)piperazine (7.89 g) was dissolved in pyridine (130 ml). Methanesulphonyl chloride (7.9 ml) was added dropwise with stirring. The mixture was reduced in volume after 2 hours by evaporation and then stirred overnight. The resulting slurry was partitioned between water (125 ml) and dichloromethane (100 ml), and the aqueous layer was further extracted with dichloromethane (2×100 ml), 5% methanol in dichloromethane (2×100 ml), and ethyl acetate (2×125 ml). The combined organic layers were dried (sodium sulphate) and evaporated, and the residue was chromatographed in 5% methanol in dichloromethane over t.l.c. grade silica, the product-containing fractions, after evaporation, yielding a foam (5.93 g), Rf 0.29 (5% methanol/dichloromethane/silica), used directly in step (D). A small sample from a second run was recrystallized from ethyl acetate/hexane, m.p. 153°-4°.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)[C:15]([C:16](=O)[CH:17]=[CH:18]N(C)C)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH:30]1([NH:35][C:36]([NH2:38])=[NH:37])[CH2:34][CH2:33][CH2:32][CH2:31]1.CC(C)([O-])C.[K+].O>O1CCCC1>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=4)[C:15]([C:16]4[CH:17]=[CH:18][N:38]=[C:36]([NH:35][CH:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[N:37]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N=C(N)NC1CCCC1
Reactant: CN(C)C=CC(=O)c1c(-c2ccncc2)nn2c(NC3CCCC3)cccc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: c1cc(NC2CCCC2)n2nc(-c3ccncc3)c(-c3ccnc(NC4CCCC4)n3)c2c1
Temperature: 25 °C
Yield: 75 %

Procedure:
A solution of 1-[7-(cyclopentylamino)-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone (0.3 g, 0.94 mmol) in N,N-dimethylformamide dimethyl acetal (10 mL) was heated at reflux for 3 days. The mixture was allowed to cool to room temperature. Water was added and the resulting mixture was extracted with ethyl acetate. The ethyl acetate phase was dried (magnesium sulfate), filtered and concentrated. The resulting residue was purified by flash chromatography (7:3 ethyl acetate-acetone) to give 1-[7-(cyclopentylamino)-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (0.23 g, 65%) as a colored syrup which was used in the next step without further purification. To a solution of 1-[7-(cyclopentylamino)-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (0.10 g, 0.27 mmol) in tetrahydrofuran (10 mL) was added cyclopentyl guanidine hydrochloride (0.06 g, 0.38 mmol) followed by potassium tert-butoxide (0.085 g, 0.76 mmol). The resulting mixture was heated at reflux for 12 hours. Upon cooling to room temperature, water was added. The mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with brine, dried (magnesium sulfate), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (1:9 methanol-dichloromethane) to give the title compound (89 mg, 75%) as a white solid. 1H NMR (CDCl3): δ 8.64 (d, 2H), 8.04 (d, 1H), 7.58 (m, 3H), 7.28 (t, 1H), 6.32 (d, 1H), 6.02 (d, 1H), 5.95 (d, 1H), 5.03 (d, 1H), 4.22 (m, 1H), 3.97 (m, 1H), 1.2–2.2 (m, 16H); MS m/z 440 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:13][C@@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([O:17][CH3:18])=[O:16])[C:5]([CH2:11]O)=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.S(Cl)([Cl:26])=O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:13][C@@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([O:17][CH3:18])=[O:16])[C:5]([CH2:11][Cl:26])=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C[C@H](Cc1cc(C)c2[nH]ncc2c1CO)C(=O)OC
Solvent: ClCCl
Product: COC(=O)C[C@H](Cc1cc(C)c2[nH]ncc2c1CCl)C(=O)OC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99 %

Procedure:
(S)-dimethyl 2-((7-methyl-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate (180 mg, 0.56 mmol) was dissolved in dichloromethane (4.0 mL). 2M Thionyl chloride in dichloromethane (4.0 mL, 8.0 mmol) was added to the mixture. Reaction stirred at room temperature for 2.5 hours. Mixture was concentrated. Residue was treated with toluene and then concentrated by roto-vap. Residue was dissolved in dichloromethane and then concentrated to dryness Title compound was obtained as amber solid in 99% yield. MS m/e (M+H)+=339.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([NH2:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][N:22]=[CH:21][C:20]=2[CH2:24][CH2:25][C:26](O)=[O:27])=[CH:15][CH:14]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([NH:11][C:26](=[O:27])[CH2:25][CH2:24][C:20]2[CH:21]=[N:22][O:23][C:19]=2[C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)CCc1cnoc1-c1ccc(Cl)cc1
Reactant: COc1cccc(C(C)N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(C(C)NC(=O)CCc2cnoc2-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
A mixture of 1-(3-methoxyphenyl)ethylamine (0.32 g), 3-[5-(4-chlorophenyl)-4-isoxazolyl]propionic acid (0.45 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.33 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.40 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-[1-(3-methoxyphenyl)ethyl]-3-[5-(4-chlorophenyl)-4-isoxazolyl]propionamide (0.61 g, yield 88%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 89–90° C.