Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:9]=[CH:10][C:5]=2[N:4]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:3]=1.[C:23]([Si:27]([CH3:45])([CH3:44])[O:28][CH:29]1[CH2:34][CH2:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH2:30]1)([CH3:26])([CH3:25])[CH3:24].P(=O)([O-])[O-].[K+].[K+]>C1COCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:12]([NH:11][C:8]1[N:9]=[CH:10][C:5]2[N:4]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:3]=[C:2]([C:32]3[CH2:33][CH2:34][CH:29]([O:28][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:44])[CH3:45])[CH2:30][CH:31]=3)[C:6]=2[N:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCNc1ncc2c(n1)c(Br)cn2-c1ccc(F)cc1
Reactant: CC1(C)OB(C2=CCC(O[Si](C)(C)C(C)(C)C)CC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=[PH]([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCCNc1ncc2c(n1)c(C1=CCC(O[Si](C)(C)C(C)(C)C)CC1)cn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 80.9 %

Procedure:
A mixture of 7-bromo-N-butyl-5-(4-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (0.11 g, 0.3 mmol), tert-butyldimethyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enyloxy)silane (0.15 g, 0.45 mmol), potassium phosphonate (0.083 g, 0.60 mmol), tetrakis(triphenylphosphine)palladium (0.035 g, 0.03 mmol) in THF (4 mL) and water (1 mL) was stirred at room temperature for 1 min, then was heat at 150° C. for 1 h under microwave irradiation. The reaction mixture was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc (3×). The combined organic layer was dried (Na2SO4), concentrated, and purified by ISCO to provide the desired product (0.12 g, 83%). 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 7.41-7.34 (m, 2H), 7.32 (s, 1H), 7.20 (t, J=8.5 Hz, 2H), 7.17-7.12 (m, 1H), 4.97 (t, J=5.6 Hz, 1H), 4.09-3.95 (m, 1H), 3.49 (dd, J=13.3, 6.5 Hz, 2H), 2.68-2.44 (m, 3H), 2.35-2.23 (m, 1H), 2.03-1.94 (m, 1H), 1.86-1.74 (m, 1H), 1.72-1.59 (m, 2H), 1.52-1.39 (m, 2H), 0.97 (t, J=7.3 Hz, 3H), 0.92 (s, 9H), 0.10 (s, 6H); MS m/z 495.3 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:32])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][CH2:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:9]=2)[C:6]2[CH:28]=[CH:29][CH:30]=[CH:31][C:5]=2[N:4]=1.C(O)C.[F:36][CH2:37][CH:38]1[CH2:40][O:39]1.C(N(CC)C(C)C)(C)C>O>[F:32][CH:2]([F:1])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][CH2:21][CH:22]3[CH2:23][CH2:24][N:25]([CH2:40][CH:38]([OH:39])[CH2:37][F:36])[CH2:26][CH2:27]3)[N:9]=2)[C:6]2[CH:28]=[CH:29][CH:30]=[CH:31][C:5]=2[N:4]=1
Reactant: FC(F)c1nc2ccccc2n1-c1cc(N2CCOCC2)nc(NCC2CCNCC2)n1
Reactant: FCC1CO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: OC(CF)CN1CCC(CNc2nc(N3CCOCC3)cc(-n3c(C(F)F)nc4ccccc43)n2)CC1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-yl-N-(piperidin-4-ylmethyl)pyrimidin-2-amine (100 mg) and ethanol (2 mL) were added 2-(fluoromethyl)oxirane (19 μL) and N,N-diisopropyl ethylamine (79 μL), and the mixture was stirred in a microwave reactor at 120° C. for 1 hour. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by amino silica gel column chromatography (ethyl acetate:hexane) to obtain 1-{4-[({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}amino)methyl]piperidin-1-yl}-3-fluoropropan-2-ol (81 mg) as a white powder.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.[C:9]([C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([N:6]2[CH2:5][C@H:4]([CH3:8])[NH:3][C@H:2]([CH3:1])[CH2:7]2)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(c2ccc(C(C)(C)C)cc2)C[C@H](C)N1
Temperature: 100 °C
Yield: 37.3 %

Procedure:
To a solution of cis-2,6-dimethylpiperazine (1 g, 8.7 mmol) in toluene (35 mL) was added 4-(tert-butyl)bromobenzene (1.86 g, 8.7 mmol), followed by BINAP (0.81 g, 1.3 mmol) and t-BuONa (1.5 g, 15.6 mmol) in one portion each. The resulting mixture was degassed twice. To the mixture was added Pd2(dba)3 (0.79 g, 0.87 mmol) in one portion and the mixture was heated to 100° C. overnight. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (3×100 mL), washed with water (1×100 mL), and brine (1×50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-20% MeOH in dichloromethane) to afford 0.8 g 1-(4-tert-Butyl-phenyl)-cis-3,5-dimethyl-piperazine. 1H NMR (400 MHz, CDCl3) δ 7.29-7.26 (m, 2H), 6.88-6.86 (m, 2H), 3.49-3.46 (m, 2H), 3.08-3.00 (m, 2H), 2.33-2.27 (m, 2H), 2.15 (1H, br), 1.29 (s, 9H), 1.13 (d, 6H).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]([Cl:33])[CH:20]=[C:21]([CH:32]=1)[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].CN>O1CCCC1>[NH2:3][O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]([Cl:33])[CH:20]=[C:21]([CH:32]=1)[C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23]
Reactant: O=C(OCc1ccccc1)c1cc(Cl)cc(OCCCON2C(=O)c3ccccc3C2=O)c1
Agent: CN
Solvent: C1CCOC1
Product: NOCCCOc1cc(Cl)cc(C(=O)OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 79.8 %

Procedure:
To a solution of phthalimide 27 (1.00 g, 2.15 mmol) in tetrahydrofuran (20 mL) was added a 40% aqueous solution of methylamine (0.148 mL, 1.72 mmol). After stirring 25 minutes at 0° C., the reaction was evaporated in vacuo, the residue partitioned between methylene chloride and water, and the organic layer dried over Na2SO4 and filtered. The evaporated filtrate was then purified by chromatography on silica gel (40% ethyl acetate in hexanes) giving product 28 (0.576 g, 80%). 1H NMR (300 MHz, CDCl3) δ 7.62 (t, 1H, J=1.6 Hz), 7.48 (dd, 1H, J=2.4 Hz, 1.4 Hz), 7.45-7.32 (m, 5H), 7.08 (t, 1H, J=2.1 Hz), 5.35 (s, 2H), 4.07 (t, 2H, J=6.3 Hz), 3.82 (t, 2H, J=6.3 Hz), 2.07 (pentet, 2H, J=6.3 Hz).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[Cs+].[Cs+].N1CCC[C@H]1C(O)=O>CS(C)=O.[Cu]I>[N:11]1([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][CH:3]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C1CCNC1
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: c1cc2ccc(N3CCCC3)cc2[nH]1
Temperature: 94 °C
Reaction time: 20 h
Yield: 56.1 %

Procedure:
A solution of 6-bromo-1H-indole (300 mg, 1.53 mmol) in DMSO (2 mL) was placed in a 10 mL sealed tube and sparged with nitrogen. Pyrrolidine (1.09 g, 15.33 mmol) was then added, followed by the addition of cesium carbonate (1 g, 3.07 mmol), copper (I) iodide (30 mg, 0.16 mmol), and L-proline (200 mg, 1.74 mmol). The resulting solution was stirred for 20 hours at 94° C. The reaction mixture was then quenched by the addition of iced water (30 mL). The resulting solution was extracted with ethyl acetate (3×100 mL) and the organic layers were combined, dried (MgSO4) and concentrated. The residue was purified by column chromatography using a 1:2 ethyl acetate/petroleum ether solvent system to give 160 mg (47%) of 6-(pyrrolidin-1-yl)-1H-indole as a tan crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[C:22]3[C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:24])[C:13]=3[CH:12]=[CH:11][C:10]=2[NH:25][C:26](=[O:29])[CH2:27]Cl)=[O:7])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[O:41]1[C:45]2([CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[O:44][CH2:43][CH2:42]1.C(OCC)(=O)C>O1CCCC1.CCO.CCCCCC>[CH3:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[C:22]3[C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:24])[C:13]=3[CH:12]=[CH:11][C:10]=2[NH:25][C:26](=[O:29])[CH2:27][N:48]2[CH2:49][CH2:50][C:45]3([O:44][CH2:43][CH2:42][O:41]3)[CH2:46][CH2:47]2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)Nc2c(NC(=O)CCl)ccc3c2C(=O)c2ccccc2C3=O)cc1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2c(NC(=O)CN3CCC4(CC3)OCCO4)ccc3c2C(=O)c2ccccc2C3=O)cc1
Reaction time: 0.12 h
Yield: 55 %

Procedure:
Compound CC-12 (0.86 g, 2 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and to the solution was added successively with DIPEA (1 ml, 6 mmole) and 1,4-dioxa-8-azaspiro[4.5]decane (1.03 ml, 8 mmole) under stirring for 5 to 10 minutes. This mixture was heated under reflux for 16 hours. After the completion of the reaction, the mixture was filtered, and the filtrate was concentrated by reduced pressure concentrator (such as Vacuum Evaporator). The residue was extracted with ethyl acetate for several times. The extract was dried on magnesium sulfate, and concentrated under reduced pressure. The crude product was washed with ethyl acetate/hexane. Finally, the crude product was recrystallized in hot ethanol to obtain a brown compound CC-40. Mol. Wt.: 539.5785 (C31H29N3O6); Rf: 0.34 (ethyl acetate:n-hexane=1:2); Yield: 55%; Mp.: 197-198° C. (EtOH); HRMS (EI) m/z: calcd [M]+, 539.2056 (C31H29N3O6+); found, 539.2051; 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 1.39 (d, J=5.4 Hz, 8H, —CH2—), 2.43 (s, 3H, —CH3), 3.15 (s, 2H, —CH2N—), 3.77 (s, 4H, —CH2—), 7.41 (d, J=7.8 Hz, 1H, Ar—H), 7.88-7.91 (m, 2H, Ar—H), 8.06 (d, J=8.1 Hz, 2H, Ar—H), 8.10-8.19 (m, 2H, Ar—H), 8.26 (d, J=8.7 Hz, 1H, Ar—H), 8.70 (d, J=8.7 Hz, 1H, Ar—H), 10.03 (s, 1H, Ar—NH—), 10.60 (s, 1H, Ar—NH—); 13C-NMR (75 MHz, DMSO-d6) δ (ppm): 20.88, 33.68, 51.35, 61.29, 63.34, 63.52, 105.58, 125.90, 126.28, 126.32, 126.91, 127.75, 127.86, 128.18, 129.18, 129.40, 130.44, 132.29, 134.13, 134.38, 134.44, 140.32, 142.46, 166.29 (NCO), 169.31 (NCO), 181.44 (CO), 183.81 (CO).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[CH:10][C:5]2=[CH:4][N:3]=1.[I:11]N1C(=O)CCC1=O>CN(C=O)C>[I:11][C:10]1[C:5]2[C:6](=[N:7][C:2]([CH3:1])=[N:3][CH:4]=2)[NH:8][N:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ncc2cn[nH]c2n1
Solvent: CN(C)C=O
Product: Cc1ncc2c(I)n[nH]c2n1
Temperature: 80 °C

Procedure:
2.180 g (purity 73%, approx. 11.82 mmol) of 6-methyl-1H-pyrazolo[3,4-d]pyrimidine and 3.987 g (17.72 mmol) of N-iodosuccinimide were dissolved in 30 ml of DMF and the mixture was heated at 80° C. for 2 h. After cooling, the mixture was concentrated on a rotary evaporator and the residue was stirred with dichloromethane, filtered off with suction and dried under high vacuum. 7.950 g (38% purity, 100% of theory) of the target compound were obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[CH:4][CH:3]=1.Cl.[CH2:14]([O:16][C:17](=[O:21])[CH2:18][NH:19][CH3:20])[CH3:15].[H-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:14]([O:16][C:17]([C:18]1[N:19]([CH3:20])[C:2]2[CH:3]=[CH:4][N:5]=[CH:6][C:7]=2[C:8]=1[OH:10])=[O:21])[CH3:15]
Reactant: CCOC(=O)c1cnccc1Cl
Reactant: CCOC(=O)CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(O)c2cnccc2n1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 28.9 %

Procedure:
To a stirred solution of ethyl 4-chloro-nicotinate (2.05 g, 11.0 mmol) and sarcosine ethyl ester hydrochloride (4.75 g, 30.9 mmol) in anhydrous DMF (40 ml), under an argon atmosphere, was added sodium hydride (59.6 mmol, 60% in dispersion oil, 2.39 g) in portions over 20 minutes. On complete addition the mixture was heated at 80° C. for 1.5 hours. Potassium carbonate (1.52 g, 11.0 mmol) was then added and the mixture heated for a further 2 hours. The reaction mixture was then quenched by the addition of water (50 ml) and subsequently concentrated to provide a residue. The residue was partitioned between ethyl acetate (100 ml) and water (100 ml). The layers were separated, the aqueous phase was cooled to 0° C. and the pH adjusted to 7 by the addition of concentrated HCl. The aqueous phase was aged overnight and the resulting precipitate was filtered, washed with water and dried under vacuum at 60° C. to give a white solid (700 mg, 15%). LCMS (method B): RT=1.82 min, M+H+=221.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:26][CH2:25][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([CH:22]4[CH2:24][CH2:23]4)[CH2:16]3)[CH2:14][CH2:13]2)[C:9]([NH2:11])=[O:10])=[C:4]([F:27])[CH:3]=1.[N:28]1[C:37]2[C:32](=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:22]1([N:17]2[CH2:16][C:15]3([CH2:25][CH2:26][N:12]([CH:8]([C:5]4[CH:6]=[CH:7][C:2]([C:33]5[CH:34]=[CH:35][CH:36]=[C:37]6[C:32]=5[CH:31]=[CH:30][CH:29]=[N:28]6)=[CH:3][C:4]=4[F:27])[C:9]([NH2:11])=[O:10])[CH2:13][CH2:14]3)[O:20][CH2:19][C:18]2=[O:21])[CH2:24][CH2:23]1
Reactant: NC(=O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Reactant: OB(O)c1cccc2ncccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(=O)C(c1ccc(-c2cccc3ncccc23)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Yield: 21 %

Procedure:
A solution of 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide (0.273 mmol) in dry 1,4-dioxane (1.5 mL) was treated with quinolin-5-ylboronic acid (0.300 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.014 mmol) and 2M aq potassium carbonate (0.818 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture irradiated in a Biotage Initiator Microwave at 120° C. for 15 min. The resulting black mixture was diluted with water (50 mL) and brine (20 mL) and was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-9% methanol/dichloromethane) and chiral HPLC (Chromegachiral CC4, methanol) followed by lyophilization from water (w/25% acetonitrile) afforded the title compound as a white solid in >99% ee (30 mg, 21% yield). MS(ES)+ m/e 489.5 [M+H]+, αD=+38 deg (c=0.05, methanol).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[C:15]1([CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:22][CH2:23][NH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:24][CH2:23][CH2:22][CH:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)#[N:2]
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: CC(C)OC(=NC#N)c1cccnc1
Solvent: CO
Product: N#CNC(=NCCC(c1ccccc1)c1ccccc1)c1cccnc1
Reaction time: 1 h
Yield: 62.5 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.60 g, 3.2 mmol) was dissolved in methanol (10 ml), and 3,3-diphenylpropylamine (0.74 g, 3.5 mmol) was added. The mixture was stirred at .room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 50 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure and crystallized from methanol-diethyl ether to give the title compound (0.68 g, 2.0 mmol, yield: 63%) as colorless powder.
Reaction SMILES: C([O:4][C@@H:5]1[CH2:9][N:8]([C:10]2[CH:15]=[CH:14][N:13]3[N:16]=[CH:17][C:18]([C:19]([O:21]CC)=[O:20])=[C:12]3[N:11]=2)[C@@H:7]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH2:6]1)(=O)C.[OH-].[Na+].Cl>CO.O1CCOCC1>[F:30][C:26]1[CH:25]=[C:24]([C@H:7]2[CH2:6][C@H:5]([OH:4])[CH2:9][N:8]2[C:10]2[CH:15]=[CH:14][N:13]3[N:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[C:12]3[N:11]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cnn2ccc(N3C[C@@H](OC(C)=O)C[C@@H]3c3cccc(F)c3)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)c1cnn2ccc(N3C[C@@H](O)C[C@@H]3c3cccc(F)c3)nc12
Temperature: 25 °C
Reaction time: 60 h
Yield: 100.6 %

Procedure:
A mixture of ethyl 5-((2R,4S)-4-acetoxy-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (225 mg, 0.546 mmol) and NaOH (131 mg, 1.64 mmol) in MeOH (1.0 mL) was stirred at ambient temperature for 60 hours followed by 3 hours at 60° C. The mixture was cooled to ambient temperature and 4M HCl in dioxane (1 mL) was added. The mixture was concentrated and the residue was treated with DCM. The mixture was filtered through Celite and concentrated to afford 5-((2R,4S)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (188 mg, 10% yield) as a white solid. MS (apci) m/z=343.0 (M+H).
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:25]1[N:26]=[CH:27][S:28][CH:29]=1)\[C:5]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([O-:22])=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[CH2:13][S:14][C@H:9]12)=[O:6].[Na+].Br[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:34](=[O:35])[O:33]1.Cl.C(OCC)(=O)C>CN(C)C=O>[CH3:1][O:2]/[N:3]=[C:4](/[C:25]1[N:26]=[CH:27][S:28][CH:29]=1)\[C:5]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([O:22][CH:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:34](=[O:35])[O:33]3)=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: O=C1OC(Br)c2ccccc21
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(COC(N)=O)CS[C@H]12)c1cscn1
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC3OC(=O)c4ccccc43)=C(COC(N)=O)CS[C@H]12)c1cscn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.4 %

Procedure:
Sodium 7-[(Z)-2-methoxyimino-2-(thiazol-4-yl)-acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylate (100 mg) was dissolved in dimethylformamide (1 ml). 3-Bromophthalide (69 mg) was added to the solution. After stirring for one hour at room temperature, the reaction mixture was added to a mixture of dil. HCl (10 ml) and ethyl acetate (20 ml). The resulting ethyl acetate layer was separated, washed successively with dil. HCl (10 ml) and saturated aqueous NaCl (10 ml×2), dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (2 ml) and the solution was added dropwise to a petroleum ether-diethyl ether mixture (100 ml) with stirring. Resulting crystals well filtered, and dried under reduced pressure to give the title compound (45 mg).
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38](=[O:50])[CH2:39][C:40]([NH:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[F:49])=[O:41])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:32])[C:16]([CH2:19][N:20]([CH2:28][CH2:29][O:30][CH3:31])C(=O)OC(C)(C)C)=[CH:17][N:18]=3)[S:13][C:6]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38](=[O:50])[CH2:39][C:40]([NH:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[F:49])=[O:41])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:32])[C:16]([CH2:19][NH:20][CH2:28][CH2:29][O:30][CH3:31])=[CH:17][N:18]=3)[S:13][C:6]=12
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5F)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCNCc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5F)cc4F)c3s2)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
To a solution of 354 (230 mg, 0.325 mmol) in DCM (3 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature overnight then concentrated. The residue was partitioned between EtOAc and NaHCO3 saturated solution. The organic layer was collected, dried and concentrated. The residue was purified via Biotage (0-50% MeOH/EA; 10 g SNAP column) to afford a reddish solid which was purified again by flash column chromatography (eluent MeOH/EA, 20-25%) to give a yellowish solid which was triturated with ether to afford the title compound 355 (80 mg, 0.132 mmol, 40.5% yield) as an off-white solid. HNMR (dmso) d (ppm) 1H: 10.53 (s, 1H), 10.01 (s, 1H), 8.47 (d, 1H, J=5.5 Hz), 7.95 (m, 1H), 7.85-7.81 (m, 2H), 7.46 (t, 1H, J=8.8 Hz), 7.39 (d, 1H, J=10.9 Hz), 7.15-7.09 (m, 2H), 6.91 (s, 1H), 6.65 (d, 1H, J=5.5 Hz), 3.81 (s, 3H), 3.72 (s, 2H), 3.58 (s, 2H), 3.35 (t, 2H, J=5.6 Hz), 3.20 (s, 3H), 2.64 (t, 2H, J=5.6 Hz). MS: 607.2 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH:10]=O)=[CH:4][CH:3]=1.[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10][N:31]2[CH2:32][CH2:33][CH:28]([C:24]3[CH:23]=[C:22]([NH:21][C:19](=[O:20])[CH:18]([CH3:17])[CH3:34])[CH:27]=[CH:26][CH:25]=3)[CH2:29][CH2:30]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1cccc(Oc2ccc(Cl)cc2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc(Oc4ccc(Cl)cc4)c3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 3-(4-chlorophenoxy)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 463.2 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:40])[C@@H:22]([C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:31]([Cl:39])[CH:30]=3)[CH2:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:16]2)[CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[CH2:14][N:15]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:40])[C@@H:22]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:31]([Cl:39])[CH:30]=2)[CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:16]1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3cccc(N)c3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.7 %

Procedure:
(3-{3-[2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-phenyl)-carbamic acid tert-butyl ester (prepared in Example 57, 501 mg, 0.83 mmol) was dissolved in methylene chloride (5 mL) and trifluoroacetic acid (500 μL) was added. The reaction stirred at 25° C. for 3 h. The reaction was concentrated in vacuo to half the reaction volume, diluted with toluene and concentrated in vacuo to dryness. The reaction was dissolved in ethyl acetate (25 mL), washed with a saturated aqueous sodium bicarbonate solution (2×10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate and concentrated in vacuo to give the desired product, N-[1-(3-amino-benzyl)-1H-pyrazol-3-yl]-2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (348 mg, 83%) as an off white powder: ESI-LRMS m/e calcd for C25H29ClN4O3S [M+] 500.16, found 501.20 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.06-1.21 (m, 2H, CH2), 1.41-1.92 (m, 8H, 4×CH2), 2.14-2.32 (m, 1H, CH), 3.25 (s, 3H, SO2CH3), 3.53-3.68 (m, 1H, CH), 5.02 (s, 2H, NCH2), 6.45-6.55 (m, 1H, Ar), 6.56-0.665 (m, 2H, Ar), 6.68 (s, 1H, Ar), 7.00-7.14 (m, 1 H, Ar), 7.32 (s, 1H, Ar), 7.45 (d, Jo=7.8 Hz. 1H, Ar), 7.60 (s, 1H, Ar), 7.75-8.23 (m, 2H, Ar and NH).