Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](=[O:46])[NH:25][CH:26]([C:32]3[CH:33]=[C:34]([C:39]4[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=4)[CH:35]=[C:36]([F:38])[CH:37]=3)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:53]1([CH3:76])[CH:58]=[CH:57][C:56]([S:59]([O:62][CH2:63][CH2:64]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:61])=[O:60])=[CH:55][CH:54]=1>CN(C)C=O>[F:38][C:36]1[CH:37]=[C:32]([CH:26]([NH:25][C:24]([C@@H:20]2[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)[CH2:19]2)=[O:46])[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:33]=[C:34]([C:39]2[CH:40]=[CH:41][C:42]([O:45][CH2:64][CH2:63][O:62][S:59]([C:56]3[CH:57]=[CH:58][C:53]([CH3:76])=[CH:54][CH:55]=3)(=[O:61])=[O:60])=[CH:43][CH:44]=2)[CH:35]=1
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cc(F)cc(-c2ccc(O)cc2)c1
Reactant: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cc(F)cc(-c2ccc(OCCOS(=O)(=O)c3ccc(C)cc3)cc2)c1
Temperature: 25 °C
Reaction time: 70 h
Yield: 11.5 %

Procedure:
178.0 mg (0.28 mmol) 4-(3-{(R)-3-[1-(5-fluoro-4′-hydroxy-biphenyl-3-yl)-2-methoxycarbonyl-ethylcarbamoyl]-piperidin-1-yl}-3-oxo-propyl)-piperidine-1-carboxylic acid tert-butyl ester (example 17d) were dissolved in 10.7 ml N,N-dimethylformamide. 272 mg (0.84 mmol) cesium carbonate and 154.6 mg (0.42 mmol) ethylene glycol bis-p-toluenesulfonate were added. The mixture was stirred at room temperature for 70 hours and concentrated. The remainder was taken up with saturated ammonium chloride solution and ethyl acetate. The aqueous phase was extracted with 3×20 ml ethyl acetate. The extracts were dried over sodium sulfate and concentrated. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-95/5) gave 167 mg which were further purified by HPLC to yield 27 mg (11%) tert-butyl 4-{3-[(3R)-3-({1-[5-fluoro-4′-(2-{[(4-methylphenyl)sulfonyl]oxy}ethoxy)biphenyl-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:5][C:4]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[C:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:40])C=CC=CC=1>O1CCCC1>[CH3:16][O:15][C:13](=[O:14])[CH:12]([OH:40])[C:4]1[S:5][C:6]2[C:11]([C:2](=[O:1])[C:3]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: COC(=O)Cc1sc2ccccc2c(=O)c1-c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(O)c1sc2ccccc2c(=O)c1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
Under a nitrogen atmosphere, the compound obtained in (1) above (0.16 mmol, 50 mg) was dissolved in tetrahydrofuran (3.0 mL), and the solution was cooled to −78° C. Then, 0.24 mL of lithium hexamethyldisilazide (a 1.0 M solution) was added thereto dropwise, and stirred for 10 min. A Davis reagent (0.32 mmol, 84 mg) was added to the resulting solution, and stirred for 30 min. After the disappearance of the starting materials was confirmed by thin-layer chromatography, the reaction was terminated by adding a saturated aqueous ammonium solution to the reaction solution. Then, the organic substances were extracted with ethyl acetate, and the obtained organic layer was dried over magnesium sulfate. The solvents were evaporated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (0.15 mmol, 50 mg) was obtained in a 95% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=1[Cl:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([C:33]2[N:41]3[C:36]([CH:37]=[N:38][C:39](O)=[N:40]3)=[CH:35][CH:34]=2)[CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([NH:21][C:39]2[N:38]=[CH:37][C:36]3=[CH:35][CH:34]=[C:33]([C:29]4[CH:30]=[CH:31][CH:32]=[C:27]([S:24]([CH3:23])(=[O:26])=[O:25])[CH:28]=4)[N:41]3[N:40]=2)[CH:18]=[CH:17][C:16]=1[Cl:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(N)ccc1Cl
Reactant: CS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(Nc2ncc3ccc(-c4cccc(S(C)(=O)=O)c4)n3n2)ccc1Cl

Procedure:
This example was prepared by using (R)-2-(5-Amino-2-chloro-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (J. Med. Chem. 2007, 50, 4353) and 7-(3-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol as described in Example 1255c. 1H-NMR (CDCl3) δ 8.7 (brs, 1H), 8.6 (m, 1H), 8.4 (d, J=8.0 Hz, 1H), 8.0 (d, J=8.0 Hz, 1H), 7.7 (t, 1H), 7.5-7.0 (m, 5H), 4.1-3.9 (m, 3H), 3.5-3.2 (m, 2H), 3.0 (s, 3H), 2.2 (m, 3H), 1.9 (m, 1H); LC/MS (ESI+): 598 (M+H).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:3]#[N:4].[C:11]([CH2:19][C:20](=O)[CH3:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)C.CCCCCC>[NH2:4][C:3]1[C:19]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:20]([CH3:21])[NH:1][C:2]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: N#CC(N)c1ccccc1
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1[nH]c(-c2ccccc2)c(N)c1C(=O)c1ccccc1

Procedure:
Starting from 2-amino-2-phenylacetonitrile and benzoylacetone, the open-chain intermediate compound is obtained, melting at 134°-135° C. (from diethyl ether/hexane). The title compound is obtained in a 60% overall yield. M.P. 285°-290° C. (from methanol/diethyl ether). The free base melts at 203°-5° C. (from methanol).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH:11]1([C:14]#[N:15])[CH2:13][CH2:12]1.Cl[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>O1CCCC1>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:19][CH:20]=1
Reactant: COc1ccc(CCl)cc1
Reactant: N#CC1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CC2(C#N)CC2)cc1
Reaction time: 0.33 h

Procedure:
Sodium bis(trimethylsilyl)amide (2 M in tetrahydrofuran (THF), 37.5 mL, 75.0 mmol) was slowly added to a solution of cyclopropanecarbonitrile (3.35 g, 49.9 mmol) in THF (30 mL) at room temperature. The reaction mixture was stirred for 20 minutes and then a solution 1-chloromethyl-4-methoxy-benzene (7.83 g, 50.0 mmol) in THF was added. The mixture was heated to reflux for 3 hours and then quenched with a saturated aqueous solution of ammonium chloride (50 mL). The separated aqueous layer was extracted three times with ethyl acetate (50 mL). The combined organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and evaporated to dryness to give crude 1-(4-methoxy-benzyl)-cyclopropanecarbonitrile, which was used directly in the next step.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[C:7]([NH:9][C:10]([NH:22][CH3:23])=[N:11][CH2:12][CH2:13][S:14][CH2:15][C:16]1[NH:20][CH:19]=[N:18][C:17]=1[CH3:21])#[N:8]>O>[C:7]([NH:9][C:10]([NH:22][CH3:23])=[N:11][CH2:12][CH2:13][S:14]([CH2:15][C:16]1[NH:20][CH:19]=[N:18][C:17]=1[CH3:21])=[O:2])#[N:8]
Reactant: CNC(=NCCSCc1[nH]cnc1C)NC#N
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CNC(=NCCS(=O)Cc1[nH]cnc1C)NC#N
Reaction time: 1.5 h

Procedure:
Sodium metaperiodate (1.85 g, 8.68 m.mol.) was added to a stirred, cooled (5°) solution of N-cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine (2.085 g, 8.27 m.mol.) in water (83 ml). After 90 minutes stirring at 5° thin layer chromatography indicated almost complete disappearance of starting material. The solution was allowed to stand overnight at room temperature to complete the reaction, then evaporated under reduced pressure to dryness, with azeotroping with n-propanol. The residue was boiled with isopropanol (60 ml), filtered hot, and the filtrate was evaporated to dryness to give the crude product as a glass. This was purified by charcoaling in methanol (40 ml), filtration and dilution with ether to 1500 ml. The liquid was decanted from the flocculent precipitated glass which was kept under a further 1500 ml ether to become semicrystalline, then filtered and allowed to stand overnight in air. The hardened glass was stirred with cold methanol (25 ml) filtered from insoluble crude product and and inorganics (0.28 g. m.p. 190°) and to the filtrate was carefully added ether (to 500 ml) so that two layers formed. On standing undisturbed for three days there separated off white crystals of N-cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylsulphinyl)ethyl]guanidine (1.55 g), m.p. 185°-186.5° C. Found: C,44.57; H,6.08; N, 31.18; S,11.91% C10H16N6OS requires C, 44.76; H, 6.01; N,31.32; S,11.95%.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.Cl[CH2:19][CH2:20][OH:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]3([C:10]([F:13])([F:11])[F:12])[O:21][CH2:20][CH2:19][O:14]3)=[N:6][C:5]=2[CH:15]=1
Reactant: OCCCl
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)C1(c2nc3cc(Cl)c(Cl)cc3[nH]2)OCCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(5,6-DiChloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (1.14 g; 4.02 mmol), 2-chloroethanol (0.83 mL; 12.4 mmol) and potassium carbonate (1.68 g; 12.2 mmol) were dissolved in DMF (18 mL). The reaction mixture was stirred for 18 hrs at ambient temperature, then diluted with ethyl acetate (80 mL), washed with water (50 mL) and brine (2×50 mL). The extracts were dried over Na2SO4, filtered, concentrated to a light brown solid and the light brown solid purified by column chromatography (SiO2; 30% ethyl acetate/hexanes) to yield the title compound as a tan solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[CH3:12]I.O>O1CCCC1>[CH3:12][O:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(C)(C)CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCC(C)(C)C(=O)OC
Temperature: 60 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
A solution of methyl 3-hydroxy-2,2-dimethylpropionate (25.0 g) in tetrahydrofuran (300 ml) was added dropwise to a suspension composed of a 60% oil suspension of sodium hydride (8.32 g) and tetrahydrofuran (100 ml) under ice cooling, and the mixture was stirred at 60° C. for 1 hour. Methyl iodide (53.7 g) was added to the reaction mixture, and the resultant mixture was stirred at room temperature for 2 hours. Water was carefully added to conduct extraction twice with methylene chloride. After the resultant organic layer was washed with saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resultant oil was distilled to obtain the title compound (12.8 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:18][O:17]C(C)(C)[O:15][CH2:14]2)=[C:4](Cl)[N:3]=1.[CH3:22][CH:23]([CH3:25])[O-:24].[Na+].Cl.C(=O)(O)[O-].[Na+]>C(O)(C)C.O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]([CH2:14][OH:15])[CH2:18][OH:17])=[C:4]([O:24][CH:23]([CH3:25])[CH3:22])[N:3]=1
Reactant: CC(C)[O-]
Reactant: CC1(C)OCC(CCn2cnc3c(Cl)nc(N)nc32)CO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)Oc1nc(N)nc2c1ncn2CCC(CO)CO
Reaction time: 0.42 h

Procedure:
A solution of 2-amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (0.25 g, 0.8 mmol) in isopropanol (2.5 ml) containing sodium isopropoxide (0.5M) was stirred at 60° for 25 minutes. After cooling, hydrochloric acid (5M, 0.3 ml) and water (0.7 ml) were added and the solution was stirred for 15 minutes at room temperature. The solution was neutralised by addition of aqueous sodium bicarbonate and the solvent was removed. The residue was extracted with chloroform-ethanol (2:1) and the solution purified by column chromatography on silica gel eluting with chloroform-methanol (7:1) to afford 2-amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)-6-isopropoxypurine which was crystallised from chloroform-carbon tetrachloride (0.18 g, 76%), m.p. 111.5-113.5° C.; δH [(CD3)2SO] 1.34 (6H, d, J 6.3 Hz, C(CH3)2), 1.45 (1H, m, 3′-H), 1.74 (2H, q, J 7.2 Hz, 2′-H), 3.3-3.5 (4H, AB part of ABX, 2×4′-H), 4.06 (2H, t, J 7.3 Hz, 1′-H), 4.40 (2H, br, 2×OH), 5.49 (1H, septet, J 6.3 Hz, CH(CH3)2), 6.27 (2H, s, 2-NH2), and 7.83 (1H, s, 8-H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11](Cl)=[O:12].[CH3:14][O:15][C:16]1[CH:22]=[C:21]([B:23]2[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]2)[CH:20]=[CH:19][C:17]=1[NH2:18].C(N(C(C)C)C(C)C)C>ClCCl>[CH3:14][O:15][C:16]1[CH:22]=[C:21]([B:23]2[O:24][C:25]([CH3:30])([CH3:31])[C:26]([CH3:29])([CH3:28])[O:27]2)[CH:20]=[CH:19][C:17]=1[NH:18][C:11]([C:3]1[N:2]([CH3:1])[C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:12]
Reactant: Cn1c(C(=O)Cl)cc2ccccc21
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.1 %

Procedure:
To a solution containing 1-methyl-1H-2-indolecarbonyl chloride (5.44 g, 0.0281 mol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (7.00 g, 0.0281 mol) in anhydrous dichloromethane (150 mL), N-ethyl-N,N-diisopropylamine (4.9 mL, 0.0309 mol) was added dropwise at 0° C. and the resulting solution was stirred at ambient temperature under an atmosphere of nitrogen for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water (150 mL) and ethyl acetate (150 mL), The organic phase was washed with brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (1:6)) as mobile phase to yield N2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-2-indolecarboxamide (8.0 g, 0.0197 mol) as a white solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:39])[CH:13]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31](=[O:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:25][CH:24]=3)[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[BH4-].[Na+]>CCO>[OH:38][CH:31]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([CH:13]([C:12]([NH:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[CH:1]=[N:2][CH:3]=[CH:4]3)=[O:39])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(OCC(=O)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(OCC(O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-2-(4-(2-oxo-2-phenylethoxy)phenyl)propylcarbamate (E275) in EtOH was added NaBH4 and the solution was stirred for 20 min at room temperature. The mixture was then poured into NaHCO3(sat) and extracted with CH2Cl2. The combined organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 5% MeOH/CH2Cl2) gave pure tert-butyl 2-(4-(2-hydroxy-2-phenylethoxy)phenyl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E276).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:10]2[CH:11]=[C:12](Br)[CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[CH3:16])[CH3:2].[C:18]([Cu])#[N:19].[C-]#N.[Na+]>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:10]2[CH:11]=[C:12]([C:18]#[N:19])[CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[CH3:16])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)Cc1c(C)oc2ccc(Br)cc12
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1c(C)oc2ccc(C#N)cc12
Temperature: 165 °C
Yield: 77.3 %

Procedure:
A mixture of (5-bromo-2-methyl-benzofuran-3-yl)-acetic acid ethyl ester (6.8 g, 22.9 mmol) and CuCN (3.1 g, 34.3 mmol) in anhydrous DMF (20 mL) is heated for 16 h at reflux (165° C.) under an argon atmosphere. After cooling to room temperature a solution of NaCN (5.8 g, 114 mmol) in water (30 mL) is added. The reaction mixture is partitioned between water and toluene, the layers are separated and the aqueous phase is extracted with toluene. The combined organic layers are washed with a 10% aqueous NaCN solution and brine, dried over Na2SO4, filtered and concentrated at reduced pressure to afford the title compound as a brown solid (4.31 g, 17.7 mmol, 77%). 1H NMR (400 MHz, CDCl3, 298 K): δ=7.82 (d, J=1.7 Hz, 1H), 7.51-7.43 (m, 2H), 4.16 (q, J=7.1 Hz, 2H), 3.59 (s, 2H), 2.46 (s, 3H), 1.26 (t, J=7.1 Hz, 3H). MS (ES+): 244 (M(C14H13NO3)+H)+.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:20]1([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH2:29][NH2:30])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH2:29][NH:30][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: NCc1cccc(-c2ccccc2)c1
Product: c1ccc(-c2cccc(CNc3nccc(-n4cnc5ccccc54)n3)c2)cc1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 3-phenylbenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 378.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.60 (s, 1H); 8.44 (br s, 1H); 8.09 (br s, 1H); 7.85 (m, 1H); 7.65 (s, 1H); 7.59 (d, J=7.3 Hz, 2H); 7.56 (m, 1H); 7.41-7.49 (m, 4H); 7.36 (m, 3H); 6.85 (d, J=5.2 Hz, 1H); 5.83 (br s, 1H); 4.83 (d, J=5.9 Hz, 2H).
Reaction SMILES: C(OC([N:8]1[CH:12]2[CH2:13][CH2:14][CH:9]1[CH:10]([C:38]([OH:40])=O)[CH:11]2[NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=[C:29]([CH3:37])[CH:28]=2)=[CH:21][CH:20]=1)(=[O:18])=[O:17])=O)(C)(C)C.[NH2:41][OH:42].C(O)(C(F)(F)F)=O.C(Cl)Cl>>[OH:42][NH:41][C:38]([CH:10]1[CH:11]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:21][CH:20]=2)(=[O:17])=[O:18])[CH:12]2[NH:8][CH:9]1[CH2:14][CH2:13]2)=[O:40]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)NC3C(C(=O)O)C4CCC3N4C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Reactant: NO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(S(=O)(=O)NC3C4CCC(N4)C3C(=O)NO)cc2)c2ccccc2n1

Procedure:
According to the procedure of Example 24, Step 3, 0.05 g (0.088 mmol) of 3-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-7-aza-bicyclo[2.2.1]heptane-2,7-dicarboxylic acid 7-tert-butyl ester (Example 37, Step 5) and hydroxylamine, followed by treatment with TFA:CH2Cl2 (1:1, 0.2 mL) for 15 min, gave 3-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-7-aza-bicyclo[2.2.1]heptane-2-carboxylic acid hydroxyamide as a hygroscopic solid (0.0189 g, 37.2%). MS: 483 (M+H)+
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)[C:15]([C:16](=[O:18])[CH3:17])=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.CO[CH:28](OC)[N:29]([CH3:31])[CH3:30]>>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:19]4[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=4)[C:15]([C:16](=[O:18])[CH:17]=[CH:28][N:29]([CH3:31])[CH3:30])=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1c(-c2ccncc2)nn2c(NC3CCCC3)cccc12
Solvent: O
Product: CN(C)C=CC(=O)c1c(-c2ccncc2)nn2c(NC3CCCC3)cccc12
Temperature: 25 °C
Yield: 65 %

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: I[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1.[F:20][C:21]([F:43])([F:42])[C:22]([NH:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=1)=[O:23]>>[F:20][C:21]([F:42])([F:43])[C:22]([NH:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[CH2:12][CH2:11][CH2:10][C@H:9]3[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=2)=[CH:29][CH:28]=1)=[O:23]
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccc(I)cc1
Reactant: CC1(C)OB(c2ccc(CCNC(=O)C(F)(F)F)cc2)OC1(C)C
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccc(-c2ccc(CCNC(=O)C(F)(F)F)cc2)cc1
Yield: 39.8 %

Procedure:
(+,−) Trans propane-2-sulfonic acid [2-(4-iodo-phenyl)-cyclopentyl]-amide (100 mg, 0.25 mmol, prepared in example 2) and 2,2,2-Trifluoro-N-{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-acetamide (105 mg, 0.31 mmol) were treated as described in example 6. The reaction was purified by radial chromatography eluting with 70:30 hexanes:ethyl acetate to afford 48 mg (39%) of the title compound as a white solid. The NMR was consistent with the assigned structure.