Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NCC1C=NC=CC=1.Cl.Cl.[CH3:11][C:12]1[S:13][CH:14]=[C:15]([CH2:17][NH2:18])[N:16]=1.[F:19][C:20]1[CH:41]=[CH:40][C:23]([CH2:24][N:25]2[C:29](=[O:30])[N:28]([C:31]3[S:35][C:34]([C:36](O)=[O:37])=[C:33]([CH3:39])[CH:32]=3)[CH:27]=[N:26]2)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:41]=[CH:40][C:23]([CH2:24][N:25]2[C:29](=[O:30])[N:28]([C:31]3[S:35][C:34]([C:36]([NH:18][CH2:17][C:15]4[N:16]=[C:12]([CH3:11])[S:13][CH:14]=4)=[O:37])=[C:33]([CH3:39])[CH:32]=3)[CH:27]=[N:26]2)=[CH:22][CH:21]=1
Reactant: Cc1nc(CN)cs1
Reactant: Cc1cc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Agent: Cl
Agent: NCc1cccnc1
Product: Cc1nc(CNC(=O)c2sc(-n3cnn(Cc4ccc(F)cc4)c3=O)cc2C)cs1
Yield: 80 %

Procedure:
Following the procedure as described in Example 31, making variations as required to replace 3-(aminomethyl)pyridine with 1-(2-methyl-1,3-thiazol-4-yl)methylamine dihydrochloride to react with 5-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-3-methylthiophene-2-carboxylic acid, the title compound was obtained as a colorless solid in 80% yield: mp 148-150° C.; 1H NMR (300 MHz, CDCl3) δ 7.71 (s, 1H), 7.40-7.33 (m, 2H), 7.07-6.99 (m, 2H), 7.03 (s, 1H), 6.89 (s, 1H), 6.50 (t, J=4.9 Hz, 1H), 4.96 (s, 2H), 4.62 (d, J=4.9 Hz, 2H), 2.69 (s, 3H), 2.50 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.7, 162.6 (d, JC-F=247.1 Hz), 162.2, 151.8, 150.4, 140.0, 134.5, 132.4, 131.2 (d, JC-F=3.3 Hz), 130.3 (d, JC-F=8.3 Hz), 126.1, 120.4, 115.7 (d, JC-F=21.7 Hz), 115.0, 48.9, 40.0, 19.1, 16.0; MS (ES+) m/z 444.1 (M+1).
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][N+:7]1[C:12](Cl)=[CH:11][C:10]([NH2:14])=[CH:9][N:8]=1.C(#N)C.[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][N+:7]1[C:12]([O:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][C:10]([NH2:14])=[CH:9][N:8]=1
Reactant: C[n+]1ncc(N)cc1Cl
Reactant: Oc1ccccc1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: c1ccncc1
Solvent: CC#N
Product: C[n+]1ncc(N)cc1Oc1ccccc1

Procedure:
12.2 parts of 1-methyl-4-amino-6-chloropyridazinium perchlorate in 150 parts of acetonitrile is stirred with 5 parts of phenol and 4 parts of pyridine for 4 hours at 80°C. The reaction mixture is filtered and the filtrate is concentrated at subatmospheric pressure. About 200 parts of water is added. 5.5 parts (36.6% of theory) of 1-methyl-4-amino-6-phenoxypyridazinium perchlorate is obtained; C11H12O5N3Cl, melting point 182° to 184°C after having been recrystallized from water.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].[CH:10]([O:12]CCCC)=[CH2:11].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.CCOC(C)=O.Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:10](=[O:12])[CH3:11])=[C:3]([CH3:9])[CH:4]=1
Reactant: C=COCCCC
Reactant: Cc1cc(F)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(F)cc1C
Temperature: 80 °C
Yield: 48.4 %

Procedure:
To a solution of 2-bromo-5-fluorotoluene (5 g, 26.5 mmol) in DMF (65 ml) and water (15 ml) was added butyl vinyl ether (6.6 g, 65.9 mmol), palladium acetate (0.18 g, 0.8 mmol), 1,3-bis(diphenylphosphino)propane (0.72 g, 1.75 mmol) and potassium carbonate (4.4 g, 31.8 mmol). The reaction was heated at 80° C. for 48 h under nitrogen. The cooled reaction mixture was diluted with EtOAc (˜250 ml) and concentrated HCl added and shaken. Further EtOAc and water were added to obtain an easier separation of the 2 layers. The organic layer was washed with brine, dried (MgSO4), and concentrated. The residue was purified on a plug of silica eluting with 3% EtOAc/isohexane to give the title compound as an oil (1.95 g, 49%). 1H NMR (400 MHz, d6-DMSO) δ 2.45 (3H, s), 2.54 (3H, s), 7.13–7.17 (2H, m), 7.89–7.93 (1H, m).
Reaction SMILES: C1C=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])C2=CC=1)=[O:8].[C:14]([OH:17])(=[O:16])[CH3:15]>[OH-].[OH-].[Pd+2]>[CH3:5][C:7]([CH2:9][C:10]([CH2:15][C:14]([OH:17])=[O:16])=[O:11])=[O:8]
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: CC(=O)O
Agent: [Pd+2]
Agent: [OH-]
Product: CC(=O)CC(=O)CC(=O)O
Temperature: 25 °C

Procedure:
Compound 77 (0.302 g, 0.44 mmol) was dissolved in glacial acetic acid (20 mL). Pd(OH)2 (80 mg) was added and the mixture was charged with H2 (160 psi) in a Parr hydrogenator and stirred over night at room temperature. The reaction was found to be complete according to TLC (product stains bright purple after staining with ninhydrin). Pd(OH)2 was filtered off and the solvent was removed in vacuo to afford the pure product 78 as the triacetate salt.
Reaction SMILES: [CH:1]([C:4]1[C:5]([CH:25]([OH:27])[CH3:26])=[C:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:7]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:5]([C:25](=[O:27])[CH3:26])=[C:6]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[C:7]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:8]([CH:10]([CH3:11])[CH3:12])[CH:9]=1)([CH3:2])[CH3:3]
Reactant: CCCCCc1c(C(C)C)cc(C(C)C)c(C(C)O)c1-c1ccc(F)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCCc1c(C(C)C)cc(C(C)C)c(C(C)=O)c1-c1ccc(F)cc1
Reaction time: 0.75 h
Yield: 98.7 %

Procedure:
A mixture of 3,5-diisopropyl-2-(1-hydroxyethyl)-6-pentyl-4′-fluoro-1,1′-biphenyl (Example 192, 13.7 g, 37.1 mmol), Celite (26 g), and pyridinium chlorochromate (14.9 g, 69.3 mmol) in dichloromethane (750 mL) was stirred for 45 minutes. The mixture was diluted with ethyl acetate (750 mL) and hexane (1.5 L) and filtered through a plug of silica (100 mm×2″) topped with Celite (100 mm×0.5″). Elution was continued with ethyl acetate:hexanes (1:1 mixture, 3L×2). The combined filtrates were concentrated in vacuo to afford the desired product as a white solid (13.5 g, 99%). 1H NMR (300 MHz, CDCl3): δ 0.75-0.80 (m, 3H), 1.06-1.31 (m, 18H), 1.95 (s, 3H), 2.33-2.39 (m, 2H), 2.78 (septet, J=7.0 Hz, 1H), 3.18 (septet, J=7.0 Hz, 1H), 7.03-7.09 (m, 2H), 7.17-7.22 (m, 2H) 7.26 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 13.75, 22.02, 24.32, 24.37, 28.99, 29.10, 29.28, 30.60, 31.04, 32.06, 33.03, 114.85 (d, J=20.8 Hz, 2C), 122.06, 132.03 (d, J=7.3 Hz, 2C), 135.52 (d, J=2.4 Hz, 1C) 135.58, 135.76, 140.13, 140.85, 147.66 161.99 (d, J=246.6 Hz, 1C), 208.23. EI-MS: calculated for C25H33OF 368; found 368 (M+). Anal. calc for C25H33OF: C, 80.86; H, 8.96. Found: C, 81.04; H, 9.06. Rf=0.65 (9:1 hexanes:ethyl acetate). HPLC: (C-18, A=0.05% aqueous trifluoroacetic add, B=CH3CN; linear gradient: 75%-100% B over 30 min; 254 nm, 1 mL/min): R.T. 22.7 min (94.0 area %). mp 123.0-124.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH:12]=[O:13])=[N:9][C:8]([C@@H:14]([NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]3[C:18]=1[N:19]=[CH:20][N:21]3[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[CH3:15])=[CH:7]2.[OH:35]OS([O-])=O.[K+].O.[OH-].[NH4+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]([OH:35])=[O:13])=[N:9][C:8]([C@@H:14]([NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]3[C:18]=1[N:19]=[CH:20][N:21]3[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)[CH3:15])=[CH:7]2
Reactant: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(C=O)n4)ncnc32)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(C(=O)O)n4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinoline-1-carbaldehyde 5 (1.67 g, 3.53 mmol, 1 eq) in DMF (40 mL) at RT, oxone (6.5 g, 10.59 mmol, 3 eq) was slowly added and the resulting mixture was stirred at RT overnight. The reaction was complete based on TLC analysis. The reaction mixture was poured into water (50 mL) and neutralized with concentrated ammonium hydroxide to adjust the pH value to 7-8. The mixture was stirred at RT for 30 min and then extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-5% MeOH-DCM) to afford the product (S)-8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinoline-1-carboxylic acid 10.
Reaction SMILES: [NH:1]1[C:5]([NH:6][C:7]([C:9]2[C:17](=[O:18])[N:16]3[C:12]([S:13][C:14]4[CH:22]=[C:21](CCC)[C:20]([N+:26]([O-:28])=[O:27])=[CH:19][C:15]=43)=[N:11][CH:10]=2)=[O:8])=[N:4][N:3]=[N:2]1.N1C(NC(C2C(=O)N3[C:40]([S:41]C4C=C(OC)C([N+]([O-])=O)=CC=43)=NC=2)=O)=NN=N1.N1C(NC(C2C(=O)N3C(SC4C=C(OCC)C([N+]([O-])=O)=CC=43)=NC=2)=O)=NN=N1.N1C(NC(C2C(=O)N3C(SC4C=C(O)C([N+]([O-])=O)=CC=43)=NC=2)=O)=NN=N1.N1C(NC(C2C(=O)N3C(SC4C=C(Cl)C([N+]([O-])=O)=CC=43)=NC=2)=O)=NN=N1.N1C(NC(C2C(=O)N3C(SC4C=C(F)C([N+]([O-])=O)=CC=43)=NC=2)=O)=NN=N1>>[NH:1]1[C:5]([NH:6][C:7]([C:9]2[C:17](=[O:18])[N:16]3[C:12]([S:13][C:14]4[CH:22]=[C:21]([S:41][CH3:40])[C:20]([N+:26]([O-:28])=[O:27])=[CH:19][C:15]=43)=[N:11][CH:10]=2)=[O:8])=[N:4][N:3]=[N:2]1
Reactant: COc1cc2sc3ncc(C(=O)Nc4nnn[nH]4)c(=O)n3c2cc1[N+](=O)[O-]
Reactant: CCCc1cc2sc3ncc(C(=O)Nc4nnn[nH]4)c(=O)n3c2cc1[N+](=O)[O-]
Agent: CCOc1cc2sc3ncc(C(=O)Nc4nnn[nH]4)c(=O)n3c2cc1[N+](=O)[O-]
Agent: O=C(Nc1nnn[nH]1)c1cnc2sc3cc(Cl)c([N+](=O)[O-])cc3n2c1=O
Agent: O=C(Nc1nnn[nH]1)c1cnc2sc3cc(F)c([N+](=O)[O-])cc3n2c1=O
Product: CSc1cc2sc3ncc(C(=O)Nc4nnn[nH]4)c(=O)n3c2cc1[N+](=O)[O-]

Procedure:
N-(5-tetrazolyl)-7-nitro-8-methyl-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboximide; N-(5-tetrazolyl)-7-nitro-8-n-propyl-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxamide; N-(5-tetrazolyl)-7-nitro-8-methoxy-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxamide; N-(5-tetrazolyl)-7-nitro-8-ethoxy-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxamide; N-(5-tetrazolyl)-7-nitro-8-hydroxy-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxamide; N-(5-tetrazolyl)-7-nitro-8-chloro-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxamide; and N-(5-tetrazolyl)-7-nitro-8-fluoro-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxamide.
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)=[O:7])=[CH:4][CH:3]=1.[CH2:27]([C:31]1[CH:36]=[CH:35][C:34]([CH:37]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45][CH:46]([CH3:48])[CH3:47])=[CH:41][CH:40]=2)Cl)=[CH:33][CH:32]=1)[CH:28]([CH3:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:45]([C:42]1[CH:43]=[CH:44][C:39]([CH:37]([C:34]2[CH:35]=[CH:36][C:31]([CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:32][CH:33]=2)[O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([C:8]3[CH:9]=[C:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:11]4[C:16]=3[CH:15]=[CH:14][CH:13]=[CH:12]4)=[O:7])=[CH:25][CH:26]=2)=[CH:40][CH:41]=1)[CH:46]([CH3:48])[CH3:47]
Reactant: CC(C)Cc1ccc(C(Cl)c2ccc(CC(C)C)cc2)cc1
Reactant: CCOC(=O)CCCc1cc(C(=O)c2ccc(O)cc2)c2ccccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCc1cc(C(=O)c2ccc(OC(c3ccc(CC(C)C)cc3)c3ccc(CC(C)C)cc3)cc2)c2ccccn12
Temperature: 25 °C
Reaction time: 20 h
Yield: 15.9 %

Procedure:
A mixture of ethyl 4-[1-(4-hydroxybenzoyl)indolizin-3-yl]butyrate (334 mg), bis(4-isobutylphenyl)chloromethane (599 mg) and potassium carbonate (394 mg) in N,N-dimethylformamide (5 ml) was stirred at room temperature for 20 hours. The reaction mixture was filtered and the filtrate was poured into a mixture of ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel eluting with n-hexane and ethyl acetate (3:1) to give ethyl 4-[1-[4-[bis(4-isobutylphenyl)methoxy]benzoyl]indolizin-3-yl]butyrate (95 mg) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[Cl:13]>C(O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[Cl:13]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Cl
Solvent: CCO
Product: COC(=O)c1cc(N)ccc1Cl
Yield: 74.7 %

Procedure:
2-Chloro-5-nitro-benzoic acid methyl ester 15 (4.3 g, 20.2 mmol), SnCl2-2H2O (45.5 g, 201.8 mmol) and ethanol (100 mL) were combined into a sealed pressure vial and was sonicated for 2 hr. The solvent was concentrated and the residue was dissolved in EtOAc, washed with NaHCO3, brine, dried over MgSO4 and filtered. The solvent was evaporated to give the desired product 16 (2.8 g, 73%).
Reaction SMILES: C1(S(O)(=O)=O)C=CC=CC=1.C(OC([NH:18][CH2:19][C@@:20]1([CH2:28][C:29]([OH:31])=[O:30])[CH2:26][C@H:25]2[C@@H:21]1[CH:22]=[C:23]([CH3:27])[CH2:24]2)=O)(C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[NH2:18][CH2:19][C@@:20]1([CH2:28][C:29]([OH:31])=[O:30])[CH2:26][C@H:25]2[C@@H:21]1[CH:22]=[C:23]([CH3:27])[CH2:24]2
Reactant: CC1=C[C@H]2[C@@H](C1)C[C@@]2(CNC(=O)OC(C)(C)C)CC(=O)O
Agent: O=S(=O)(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1=C[C@H]2[C@@H](C1)C[C@@]2(CN)CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
[(1S,5R,6R)-6-tert-butoxycarbonylaminomethyl-3-methylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid benzenesulfonic acid (5.8 g, 16.4 mmol) was suspended in methylene chloride (50 mL). To the suspension, triethylamine (4.6 ml, 32.7 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The resulting solid was collected by filtration and washed with isopropanol to obtain the compound of interest as a white solid (2.0 g, 63%).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[S:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.N(OCCCC)=O>>[C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:15]1[S:14][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccccc1-c1ccccc1
Reactant: c1ccsc1
Agent: CCCCON=O
Product: c1ccc(-c2ccccc2-c2cccs2)cc1
Reaction time: 192 h
Yield: 34.8 %

Procedure:
In a 4-l Erlenmeyer flask were placed 100 g (0.600 mole) of Pfalz and Bauer o-aminobiphenyl, m.p. 49°-51° C., 3000 ml (38.2 moles) of thiophene and 90 ml (0.80 mole) of n-butyl nitrite. The mixture was thoroughly stirred and then allowed to stand at room temperature for eight days. Unreacted thiophene was removed by distillation. The residue was distilled at reduced pressure to give 49.4 g (34.8%) of 2-(o-biphenylyl)thiophene b.p. 138°-155° C. (0.1 mm), ND20 1.6465.
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.C(OCC)(=O)C.[Zn]>[NH2:1][C:4]1[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: N#Cc1cccc(Oc2ncccc2[N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#Cc1cccc(Oc2ncccc2N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The crude reaction mixture from 106a was dissolved in ethanol (4 mL) and ethyl acetate (1 mL). Zinc dust (1.3 g, 20 mmol) was added to the mixture along with ammonium chloride (300 mg, 5.7 mmol). The mixture was shaken at rt for 18 h. The reaction mixture was filtered over Celite®, and concentrated to afford mainly 106b which was used in the next step without further purification. [M+H]+=212.32.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[CH:13][C:14]([C:17]#[N:18])=[N:15][CH:16]=2)[CH2:7][CH2:6]1.[N-:24]=[N+:25]=[N-:26].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Br:1][C:2]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[N:15][C:14]([C:17]3[N:24]=[N:25][NH:26][N:18]=3)=[CH:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cnc(N2CCC(Oc3cc(F)ccc3Br)CC2)cn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(Br)c(OC2CCN(c3cnc(-c4nn[nH]n4)cn3)CC2)c1
Reaction time: 3 h

Procedure:
To a solution of 5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]pyrazine-2-carbonitrile from Step 5 (0.200 g, 0.530 mmol) in DMF (2 mL) was added sodium azide (0.070 g, 1.06 mmol) and ammonium chloride (0.284 g, 5.30 mmol). After a period of 3 h at 130° C., the reaction mixture was cooled and partitioned between ethyl acetate and brine. The organic phase was separated, dried over sodium sulfate and evaporated. To the crude product was added a mixture of ether-hexane (1:1). The resulting solid was filtered to provide the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[N:19]=[CH:18][CH:17]=[N:16]1.N1N(C2C=CC=CC=2C(O)=O)N=CC=1.Cl.N[C@H]1CCC[C@@H]1O.CCN(C(C)C)C(C)C>>[OH:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[N:16]=[CH:17][CH:18]=[N:19]1
Reactant: O=C(N[C@H]1CCC[C@H]1O)c1ccccc1-n1nccn1
Agent: Cl
Agent: N[C@H]1CCC[C@@H]1O
Agent: O=C(O)c1ccccc1-n1nccn1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CCC[C@@H]1O)c1ccccc1-n1nccn1

Procedure:
Prepared according to the procedure for N-[(1S,2R)-2-hydroxycyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 10) from 2-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS number 1001401-62-2; 531 mg, 2.81 mmol), (1S,2S)-2-aminocyclopentan-1-ol hydrochloride (CAS number 68327-04-8; 368 mg, 2.67 mmol) and DIPEA (1401 μl, 8.02 mmol) to afford the title compound.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[O:8]2)[CH2:4][CH2:3]1.[C:17]1([C:23]2[N:24]=[CH:25][C:26]([NH:29][C:30](=O)[O:31]C3C=CC=CC=3)=[N:27][CH:28]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CS(C)=O.CN(C)CC1C=CC=CC=1>C(#N)C.O>[O:16]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2([CH2:6][CH2:7][N:2]([C:30]([NH:29][C:26]3[CH:25]=[N:24][C:23]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:28][N:27]=3)=[O:31])[CH2:3][CH2:4]2)[O:8]1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Reactant: O=C(Nc1cnc(-c2ccccc2)cn1)Oc1ccccc1
Agent: CN(C)Cc1ccccc1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CC#N
Product: O=C1OC2(CCN(C(=O)Nc3cnc(-c4ccccc4)cn3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Spiro[isobenzofuran-1(3H),4′-piperidine]-3-one hydrochloride (515 mg) and phenyl N-(5-phenyl-2-pyrazinyl)carbamate (583 mg) were dissolved into dimethyl sulfoxide (2.6 mL), followed by dropwise addition of dimethylbenzylamine (0.33 mL). The temperature of the resultant mixture was raised up to 50° C., and the mixture was stirred for one hour. The reaction mixture was cooled to room temperature, and acetonitrile/water (1:2) mixture solution (7.8 mL) was dropwise added. At the time when 0.2 mL of the mixture solution was added, seed crystal was added. The resultant mixture was stirred at room temperature for 6 hours. The yielded colorless crystals were collected by filtration, washed with acetonitrile/water (1:1) and dried in vacuum at room temperature for 15 hours to obtain the above-identified compound (793 mg) as crude colorless crystals. Crude crystals (26 g) prepared by the repetition of the above procedure were suspended in water-saturated isopropyl acetate (143 mL). The mixture was seeded with seed crystal and stirred at room temperature for 18 hours. The yielded crystals were collected by filtration, washed with isopropyl acetate (20 mL) and dried in vacuum at 30° C. for 15 hours to obtain the above-identified compound in the crystal form D (25.2 g) as colorless crystals (melting point; 206° C. measured without correction by the use of Melting Point B-545 distributed by Buchi Company).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: N#Cc1ccc(N(c2ccc([N+](=O)[O-])cc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl)amino]pyrimidine and 4-fluoronitrobenzene
Reaction SMILES: [C@@H:1]1([N:10]2[CH:15]=[C:14]3[CH:16]=[CH:17][C:18](=[O:20])[N:19]=[C:13]3[NH:12][C:11]2=[O:21])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3].P(Cl)(Cl)(Cl)=O.[CH2:27](OP(OCC)(OCC)=O)C>>[C@@H:1]1([N:10]2[CH:15]=[C:14]3[CH:16]=[CH:17][C:18](=[O:20])[N:19]([CH3:27])[C:13]3=[N:12][C:11]2=[O:21])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: CCOP(=O)(OCC)OCC
Reactant: O=c1ccc2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c(=O)[nH]c-2n1
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c(=O)ccc2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c(=O)nc21
Temperature: 0 °C

Procedure:
A solution of 560 mg of 3-β-D deoxyribofuranosyl-2,7-dioxopyrido[2,3-d]pyrimidine (a) in 5 ml of triethylphosphate was cooled to 0° C. and 613 mg of phosphorus oxychloride was added thereto. After the mixture was made to undergo a reaction for 6 hours, 1 g of ice was added to effect a hydrolysis. The reaction mixture was concentrated at reduced pressure and the resulting residue was dissolved in 1 ml of distilled water. The purification of the product was carried out by column chromatography on DEAE-Sephadex A-25 (HCO3 -form) by use of a linear gradient of triethylammonium bicarbonate to obtain 575 mg of 3-(5'-O-phosphoryl-β-D-2'-deoxyribofuranosyl)-2,7-dioxopyrido[2,3-d]pyrimidine (b).
Reaction SMILES: [CH2:1]([CH:4]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3]>[Pd].CO>[CH2:1]([CH:4]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: C=CCC1CCCC(=O)N1
Agent: [Pd]
Solvent: CO
Product: CCCC1CCCC(=O)N1

Procedure:
Ex-30d) The 6-allyl-piperidine-2-one product of Example 30c is reduced with palladium on carbon in methanol under hydrogen to give the 6-n-propyl-piperidine-2-one.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[C:7]#[N:8])[CH:2]=[CH2:3].[H][H].C(OCC)(=O)C.CCCCCC>C(O)C.[Pd]>[OH:12][C:11]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: [H][H]
Reactant: C=CCc1cc(C#N)ccc1O
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCc1cc(C#N)ccc1O
Reaction time: 1.33 h
Yield: 99.6 %

Procedure:
A Parr hydrogenation shaker was charged with a solution of 29.76 g (187 mmol) of the product of Step A in 100 mL of ethanol and 3.00 g of a 10% palladium on carbon catalyst was added. The flask was mounted in the hydrogenation appartus, freed of air, pressurized with hydrogen (40 psig) and shaken 80 minutes. At the end of this preiod, TLC analysis (15% ethyl acetate/hexane) indicated that the reaction was complete and the reaction mixture was filtered and evaporated. The product was dried in vacuo to afford 30.01 g (99%) of the title compound as a yellow oil.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[H-].[Na+].C[O:7][C:8]([C:10]1([CH3:13])[CH2:12][CH2:11]1)=O.CO>C1COCC1.O>[CH3:13][C:10]1([C:8](=[O:7])[CH2:2][C:1]#[N:3])[CH2:12][CH2:11]1
Reactant: CC#N
Reactant: COC(=O)C1(C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C(=O)CC#N)CC1
Reaction time: 0.17 h

Procedure:
Add acetonitrile (87 mL, 1.6 mol) to a suspension of sodium hydride (66 g, 1.6 mol) in THF (700 mL) at room temperature and stir 10 minutes. Then add 1-methyl-cyclopropanecarboxylic acid methyl ester (90.0 g, 0.78 mol) and reflux the white slurry for 3 hours. Cool the mixture, then add methanol (200 mL) and pour the mixture over water (500 mL). Separate the phases and reduce the pH of the aqueous phase with 1.0N HCl until pH 3-4. Extract the aqueous phase with diethyl ether (2×350 mL), combine the organic layers and wash with aqueous sodium chloride. Dry over sodium sulfate, filter, and concentrate under reduced pressure to give 3-(1-methyl-cyclopropyl)-3-oxo-propionitrile as yellow oil. 1H NMR (CDCl3): 3.59 (s, 2H), 1.37 (s, 3H), 1.30 (q, J=4 Hz, 2H), 0.86 (q, J=4 Hz, 2H).