Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[CH3:27][CH:28]1[CH2:32][C:31]2[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:30]=2[O:29]1.C(N(CC)CC)C.N1C=CC=CC=1>O1CCCC1.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][C:2]1[N:3]([C:34]2[CH:35]=[CH:36][C:30]3[O:29][CH:28]([CH3:27])[CH2:32][C:31]=3[CH:33]=2)[C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC1Cc2cc(B(O)O)ccc2O1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCc1nc(C)n(-c2ccc3c(c2)CC(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), (2-methyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (0.5 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (2.0 g) in tetrahydrofuran (15 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.68 g, 49%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=O)[CH:4]=[N:3]1.[Cl-].[Li+].[CH3:30][O:31][CH2:32][CH2:33][NH:34][CH2:35][CH2:36][O:37][CH3:38].C(N(C(C)C)CC)(C)C.CCCP(=O)=O>O1CCCC1.C(OCC)(=O)C>[CH3:30][O:31][CH2:32][CH2:33][N:34]([CH2:35][CH2:36][O:37][CH3:38])[C:25]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([NH:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:17]=[C:11]2[CH:10]=1)=[O:24])=[O:27]
Reactant: COCCNCCOC
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Agent: CCCP(=O)=O
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCN(CCOC)C(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 84.8 %

Procedure:
A suspension of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid with 1 eq. lithium chloride (80 mg, 0.198 mmol), bis(2-methoxyethyl)amine (87 ul, 0.59 mmole), diisopropylethylamine (104 ul, 0.59 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 291 ul, 0.494 mmol) in tetrahydrofurane (4 ml) is stirred for 2.5 hours at 70° C. giving after 20 min a light yellow solution. The cooled solution is diluted with ethyl acetate, washed once with sat. aqueous sodium carbonate solution, once with 1N aqueous hydrochloric acid, once with brine, dried with magnesium sulfate and the solvent is evaporated to dryness affording N4,N4-bis(2-methoxyethyl)-1-methyl-N5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (80 mg, 84.8%) as a colorless waxy solid. MS: m/z=478.2 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:22])=[N:8][N:9]([C:11]2[C:16]([CH2:17][O:18][CH:19]3[CH2:21][CH2:20]3)=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:10]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>O1CCCC1.[O-2].[Mn+4].[O-2]>[CH:19]1([O:18][CH2:17][C:16]2[C:11]([N:9]3[CH:10]=[C:6]([CH:4]=[O:3])[C:7]([CH3:22])=[N:8]3)=[N:12][CH:13]=[CH:14][CH:15]=2)[CH2:20][CH2:21]1
Reactant: CCOC(=O)c1cn(-c2ncccc2COC2CC2)nc1C
Agent: [Mn+4]
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1nn(-c2ncccc2COC2CC2)cc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a solution of 1-(3-cyclopropoxymethyl-pyridin-2-yl)-3-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (410 mg, 1.03 mmol) in tetrahydrofuran (0.15 M) at 0° C. under nitrogen, 1.0 M lithium aluminum hydride in tetrahydrofuran (1.2 equiv) is added. The mixture is stirred at room temperature for 1 h and saturated aqueous solution of ammonium chloride is added and the aqueous layer is extracted with ethyl acetate. The organic layer is separated, dried over sodium sulfate and the solvent eliminated under reduced pressure. The crude material is dissolved in dichloromethane (14 mL) and manganese (IV) oxide (1.2 g, 13.9 mmol) is added. The mixture is stirred at room temperature overnight and then filtered through a pad of celite and the solvent is evaporated under reduced pressure. The crude is passed through a pad of silica gel (eluent: ethyl acetate and dichloromethane). The solvent is eliminated under reduced pressure to yield 90 mg of the title product. MS (m/z): 258 (M+1).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH2:6][C:7]1([CH2:20][OH:21])[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1.I[CH3:27]>C1COCC1>[F:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH2:6][C:7]1([CH2:20][O:21][CH3:27])[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)(Cc2ccccc2F)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1(Cc2ccccc2F)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (80 mg, 60% in mineral oil, 1.99 mmol) was added to a solution of tert-butyl 3-(2-fluorobenzyl)-3-(hydroxymethyl)piperidine-1-carboxylate (0.43 g, 1.33 mmol) in THF (5 ml) and the reaction mixture was stirred at room temperature for 20 mins. Iodomethane (0.125 ml, 1.99 mmoL) was added to the flask, and the reaction was allowed to stir at room temperature for 16 hrs. The reaction was quenched with water (5 ml) and was extracted using ethyl acetate (20 ml) three times. The ethyl acetate layers were combined, dried over sodium sulfate, filtered, and concentrated. The crude mixture was purified using flash chromatography (0-60% ethyl acetate in hexane) to give the titled compound (0.415 g).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH3:27][S:28][C:29]1[N:30]=[CH:31][C:32]([NH2:35])=[N:33][CH:34]=1.N1C=CC=CC=1>CN(C)C=O.C(Cl)Cl>[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([NH:35][C:32]2[CH:31]=[N:30][C:29]([S:28][CH3:27])=[CH:34][N:33]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CSc1cnc(N)cn1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CSc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
A solution of 3-cyclopentyl-2(R)-(4-methanesulfonylphenyl)-propionic acid (prepared as in Example 3, 1.21 g, 4.07 mmol) and N,N-dimethylformamide (5 drops) in methylene chloride (10 mL) was cooled to 0° C. The reaction mixture was then treated with oxalyl chloride (0.53 mL, 6.10 mmol), and the resulting reaction mixture was stirred at 0° C. for 1 h. The solution was then concentrated in vacuo, and the orange-brown gel was dissolved in methylene chloride. The resulting solution was added dropwise via an addition funnel at 0° C. to a solution of 5-methylsulfanyl-pyrazin-2-ylamine (prepared as in Example 4, 0.58 g, 4.07 mmol) in methylene chloride (10 mL) and pyridine (0.36 mL, 4.48 mmol). The reaction mixture was stirred at 0° C. for 30 min and then was allowed to warm to 25° C. where it was stirred for 3 h. The reaction mixture was quenched with a 1N aqueous citric acid solution (10 mL) and was stirred for 15 min. The reaction was then diluted with ethyl acetate (75 mL) and a 1N aqueous citric acid solution (50 mL). The layers were separated, and the organic layer was then washed with a saturated aqueous sodium bicarbonate solution (50 mL), water (50 mL), and a saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 1/1 ethyl acetate/hexanes) afforded 3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-N-(5-methylsulfanyl-pyrazin-2-yl)-propionamide (0.864 g, 51%) as a white foam: mp 71–77° C. (foam to gel); (ES)+-HRMS m/e calcd for C20H25N3O3S2 (M+H)+ 420.1410, found 420.1415.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[C:15]([CH2:25][S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[CH2:19][CH2:18][CH2:17]2.[N:35]1([CH2:40][CH:41](O)[CH2:42][CH2:43][CH2:44][CH3:45])[CH:39]=[CH:38][N:37]=[CH:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[N:35]1([CH2:40][CH:41]([O:13][C:14]2[C:15]([CH2:25][S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[C:16]3[C:21](=[CH:22][CH:23]=2)[C:20](=[O:24])[CH2:19][CH2:18][CH2:17]3)[CH2:42][CH2:43][CH2:44][CH3:45])[CH:39]=[CH:38][N:37]=[CH:36]1
Reactant: CCCCC(O)Cn1ccnc1
Reactant: O=C1CCCc2c1ccc(O)c2CS(=O)(=O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCC(Cn1ccnc1)Oc1ccc2c(c1CS(=O)(=O)c1ccccc1)CCCC2=O
Reaction time: 120 h
Yield: 62 %

Procedure:
Diethyl azodicarboxylate (0.16 mL, 0.99 mmol) was added over 10 min to a mixture of 6-Hydroxy-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone (300 mg, 0.99 mmol), 1-(1H-imidazol-1-yl)-2-hexanol (166 mg, 1.08 mmol), triphenylphosphine (259 mg, 0.99 mmol) and tetrahydrofuran (2 mL) under nitrogen. The resulting mixture was stirred for 5 d, whereupon it was concentrated and the residue was purified by dry-flash column chromatography (SiO2, 1-9% 2-propanol-dichloromethane) to give 6-{[1-(1H-imidazol-1-ylmethyl)pentyl]oxy}-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone as a colorless foam, 283 mg, 62% yield. NMR spectrum was consistent with structure. MS EI: M+• 466.1919 (M+• 466.1926).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10](Cl)[CH:9]=2)[C:3]=1[C:15]([NH2:17])=O.FC(F)[O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][C:22]=1O>CCO.N1CCCCC1>[C:3]([C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:4]2[NH:5][N:6]=[C:2]([N:1]=[CH:25][C:24]3[CH:27]=[CH:28][C:21]([OH:20])=[CH:22][CH:23]=3)[C:3]=2[C:15]#[N:17])=[CH:9][CH:10]=1)([CH3:15])([CH3:4])[CH3:2]
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C)c1ccc(Nc2[nH]nc(N=Cc3ccc(O)cc3)c2C#N)cc1

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in EtOH and 4-(difluoromethoxy)-3-hydroxybenzaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH3:29][N:30]([CH3:40])[C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>>[CH3:29][N:30]([CH3:40])[C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:12]=3)[CH2:7][CH2:6]2)=[O:36])=[CH:33][CH:32]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3ccc(N(C)C)cc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-(dimethylamino)benzoyl chloride: ESMS m/e: 527.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([N:21]=[C:22]([N:24](C)C)[CH3:23])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.Cl.N[OH:29]>CO>[Br:1][C:2]1[N:3]=[C:4]([N:21]=[C:22]([NH:24][OH:29])[CH3:23])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: NO
Reactant: CC(=Nc1nc(Br)cnc1N1CCN(C(=O)OC(C)(C)C)CC1)N(C)C
Agent: Cl
Solvent: CO
Product: CC(=Nc1nc(Br)cnc1N1CCN(C(=O)OC(C)(C)C)CC1)NO
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.9 %

Procedure:
A 100 mL round bottom flask was charged with tert-butyl 4-(5-bromo-3-((1-(dimethylamino)ethylidene)amino)pyrazin-2-yl)piperazine-1-carboxylate (2.8 g, 6.6 mmol) and methanol (25 mL). To the above solution was added hydroxylamine hydrochloride (0.76 g, 10.9 mmol) in one portion. The mixture was stirred at room temperature for 16 h. Work-up: the solvent was evaporated. The resulting crystalline solid was washed with water and collected by filtration. The solid was washed with ethanol (100 mL) and dried, to afford 2.3 g (84%) of the product as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH3:22][C:23]1[C:24]([C:34](Cl)=[O:35])=[N:25][N:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:27]=1>>[CH3:22][C:23]1[C:24]([C:34]([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[O:35])=[N:25][N:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:27]=1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: Cc1nn(-c2ccccc2)nc1C(=O)Cl
Product: Cc1nn(-c2ccccc2)nc1C(=O)N1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 58 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 5-methyl-2-phenyl-2H-1,2,3-triazole-4-carbonyl chloride and conditions outlined in procedure N. M.p.=275-280° C.; 300 MHz 1H NMR (CDCl3) δ 8.07 (d, J=7.5 Hz, 1H), 7.99 (d, J=7.5 Hz, 2H), 7.80 (d, J=7.5 Hz, 1H), 7.68 (t, J=8.4 Hz, 1H), 7.48 (m, 3H), 7.37 (m, 1H), 4.65 (m, 2H), 3.67 (t, 1H), 3.39 (m 1H), 3.01 (s, 2H), 2.57 (s, 3H), 2.30 (brm, 2H), 1.96 (m, 2H); LCMS: 487 [M+H].
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16](C=O)[CH2:15][CH2:14]1.Cl.C(Cl)(Cl)Cl>CO>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: O=CN1CCN(CCSc2nc3ccccc3[nH]2)CC1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: c1ccc2[nH]c(SCCN3CCNCC3)nc2c1
Temperature: 40 °C
Reaction time: 3 h
Yield: 137.2 %

Procedure:
1-[2-(benzimidazol-2-ylthio)ethyl]-4-formylpiperazine (1.92 kg) was suspended in methanol (4.5 kg), and 12N hydrochloric acid (2.9 kg) was added, and the mixture was stirred at 40° C. for 3 hours. To the reaction solution was added chloroform (17 kg), and the precipitated crystals were collected by filtration. The crystals were washed with chloroform to give 2.38 kg of 1-[2-(benzimidazol-2-ylthio)ethyl]piperazine.3 hydrochloride (yield 97%) as colorless crystalline powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:17]1[N:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[N:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(Cl)nn1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Product: Cc1ccc(-n2cc(C#Cc3cccc(Cl)c3)nc2C)nn1

Procedure:
The title compound, MS: m/e=309.3 (M+H+), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 3-chloro-6-methyl-pyridazine.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]=O)=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][CH2:2]1.[CH3:14][CH:15]([CH3:19])[C:16](=[O:18])[CH3:17].[OH-].[Na+]>CO>[O:1]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]=[CH:17][C:16](=[O:18])[CH:15]([CH3:19])[CH3:14])=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc2c(c1)OCCCO2
Reactant: CC(=O)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C(=O)C=Cc1ccc2c(c1)OCCCO2
Reaction time: 24 h

Procedure:
The MeOH (5 mL) solution of 3,4-dihydro-2H-1,5-benzodioxepine-7-carbaldehyde (445 mg) and 3-methyl-2-butanone (195 mg) was treated with aq. sodium hydroxide (1N, 1 ml) and the mixture was stirred for 24 hours. The reaction was partitioned between 10 ml water and 40 ml ethyl acetate. The organic layer was then sequentially washed with aq. hydrochloric acid (1N, 20 ml), water (20 ml), and Brine (20 ml) and then concentrated under reduced pressure. The residue was purified with flash chromatography on silica (33% ethyl acetate in hexane) to give the desired product as a white crystal.
Reaction SMILES: Cl[C:2]1[C:3]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]2)=[N:4][C:5]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1.C(P(C12CC3CC(CC(C3)C1)C2)[C:43]12[CH2:52]C3CC(CC(C3)[CH2:44]1)C2)CCC.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:52]1([C:2]2[C:3]([N:24]3[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:34])[CH3:35])[CH2:25]3)=[N:4][C:5]([N:8]3[C:16]4[CH:15]=[C:14]([C:17]5[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=5)[N:13]=[CH:12][C:11]=4[CH:10]=[N:9]3)=[CH:6][CH:7]=2)[CH2:43][CH2:44]1
Reactant: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(Cl)c(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C3CC3)c(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)n1
Temperature: 105 °C
Reaction time: 72 h
Yield: 367 %

Procedure:
A mixture of tert-butyl N-[(3S)-1-[3-chloro-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3-piperidyl]carbamate (0.2225 mmol; 115.9 mg), potassium cyclopropyl trifluoroborate (0.3337 mmol; 50.90 mg), butyldi-1-adamantylphosphine (0.06674 mmol; 25.19 mg), cesium carbonate (0.6674 mmol; 217.4 mg) and palladium(II) acetate (0.04449 mmol; 9.994 mg) in water (0.5 mL) and Toluene (4.5 mL) was purged with Argon for 1 minute. The reaction mixture in a pressure tube was stirred at 105° C. for 3 days. The layers were separated. The organic later was concentrated. The residue was purified on silica eluted with 0 to 5% MeOH in DCM to afford tert-butyl N-[(3S)-1-[3-cyclopropyl-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3-piperidyl]carbamate (129 mg, ˜100%).
Reaction SMILES: [C:1]([Cl:5])(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:25][O:26][CH2:27][O:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1CO>O1CCCC1>[CH3:25][O:26][CH2:27][O:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:1][Cl:5]
Reactant: ClC(Cl)(Cl)Cl
Reactant: COCOc1ccccc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCOc1ccccc1CCl
Yield: 57 %

Procedure:
16.4 ml of carbon tetrachloride, followed by 44.5 g of triphenylphosphine were added, whilst ice-cooling, to a solution of 23.8 g of 2-methoxymethoxybenzyl alcohol in 240 ml of tetrahydrofuran, and the resulting mixture was heated under reflux for 5 hours. At the end of this time, the mixture was cooled, insoluble materials were filtered off and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 9:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 15.5 g (yield 57%) of the title compound as a colorless liquid.
Reaction SMILES: [NH:1]([C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=O)[NH2:2].[C:18]([C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1)#[N:19]>C(O)CCC>[N:21]1[CH:22]=[CH:23][CH:24]=[N:25][C:20]=1[C:18]1[NH:2][N:1]=[C:3]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[N:19]=1
Reactant: N#Cc1ncccn1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c(-c3ncccn3)n2)CC1

Procedure:
A mixture of tert-butyl 4-(hydrazinocarbonyl)piperidine-1-carboxylate (10.1 g, 41.5 mmol) and 2-cyanopyrimidine (4.36 g, 41.5 mmol) in 1-butanol (20 mL) was heated to reflux for 48 hours. The mixture was concentrated, suspended in ether, and filtered to give tert-butyl 4-(5-pyrimidin-2-yl-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate as a solid. MS (M+H+): 331.2 observed; 1H-NMR (400 MHz, CD3OD): δ 8.92 (d, J=4.0 Hz, 2H), 7.52 (t, J=4.0 Hz, 1H), 4.18-4.15 (m, 2H), 3.14-3.08 (m, 1H), 2.98 (br.s, 2H), 2.07-2.01 (m, 2H), 1.85-1.77 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]5[CH:24]=[C:25]([NH2:29])[CH:26]=[CH:27][CH:28]=5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N([O-])=O.[Na+].[N-:42]=[N+:43]=[N-].[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.O.O.CCOCC>[N:29]([C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[NH:22][C:18]1[N:17]=[C:16]([C:15]2[C:14]([C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[N:13][N:12]3[C:7]([NH:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:8][CH:9]=[CH:10][C:11]=23)[CH:21]=[CH:20][N:19]=1)=[N+:42]=[N-:43]
Reactant: COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(Nc3cccc(N)c3)n2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(Nc3cccc(N=[N+]=[N-])c3)n2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 23 %

Procedure:
The following transformation was performed in the dark. To a cold (0° C.) solution of N′-{[7-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-1,3-benzenediamine (16.5 mg, 0.03 mmol) in acetic acid/water (80/20, 1 mL) was added aqueous sodium nitrite (0.32 mL of a stock solution prepared by dissolving 200 mg of sodium nitrite in 25 mL water, 0.04 mmol). The resultant dark solution was stirred at 0° C. for 15 minutes. Aqueous sodium azide (0.11 mL of a stock solution prepared by dissolving 200 mg of sodium azide in 10 mL of water, 0.04 mmol) was added and the resultant solution was stirred for 1.5 hours over which time it was allowed to warm to room temperature. Ether was added and the solution made basic by dropwise addition of saturated aqueous sodium bicarbonate. The organic layer was washed with brine. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over magnesium sulfate. Filtration and concentration gave a solid residue which was purified by flash chromatography (4:1 to 2:1 hexanes-ethyl acetate) to provide 3-[2-(3-azidoanilino)-4-pyrimidinyl]-N-cyclopentyl-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine (4 mg, 23%) as a tinted solid. 1H NMR (CDCl3): δ 8.12 (d, 1 H), 7.71 (d, 1 H), 7.60-7.56 (m, 3 H), 7.33-7.25 (m, 3 H), 6.98 (d, 2H), 6.70 (d, 1 H), 6.54 (d, 1 H), 6.05-6.04 (m, 2 H), 4.00 (m, 1 H), 3.87 (s, 3 H), 2.13 (m, 2 H), 1.85-1.58 (m, 6 H); MS m/z 518 (M+1).