Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:29]([F:32])([F:31])[F:30])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C:22]([N+:26]([O-])=O)([CH3:25])[CH2:23][OH:24])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.CO.[Zn]>[NH2:26][C:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:7][CH2:6][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]3)[C:13]=2[C:29]([F:31])([F:32])[F:30])[CH:18]=1)([CH3:25])[CH2:23][OH:24]
Reactant: CC(CO)(c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1)[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: CC(N)(CO)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-[6-(trans-4-tert-Butyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-2-nitro-propan-1-ol (57 mg, 0.00012 mol) was dissolved in acetic acid (0.50 mL, Fisher), followed by addition of zinc (76 mg, 0.0012 mol, Aldrich) dust in small portions at room temperature. The reaction mixture was then allowed to stir at room temperature for 1.5 hours. The reaction was diluted with methanol, filtered and evaporated. The white solid was taken up in methylene chloride, washed with 1N NaOH, washed with water, dried with magnesium sulfate, filtered and evaporated. 45 mg of product isolated (85%). MS: m/z=424.57 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm: 8.20 (dd, J=9.3, 1.5 Hz, 1H), 7.90-7.95 (m, 1H), 7.89 (d, J=1.8 Hz, 1H), 7.63 (dd, J=9.2, 2.1 Hz, 1H), 7.31 (d, J=9.0 Hz, 1H), 4.24-4.34 (m, 1H), 3.77 (d, J=10.5 Hz, 1H), 3.68 (d, J=10.5 Hz, 1H), 2.14-2.23 (m, 2H), 1.94-2.13 (m, 3H), 1.81-1.92 (m, 2H), 1.48-1.59 (m, 5H), 1.24-1.38 (m, 1H), 1.03-1.19 (m, 3H), 0.88 (s, 9H).
Reaction SMILES: [C:1]([N:9]=[C:10]1[NH:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:18]=2)[O:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[CH:34]=[C:33]([CH2:35][CH2:36][CH2:37][NH2:38])[N:32]=[CH:31]1>N1C=CC=CC=1>[C:1]([NH:9][C:10]([NH:14][CH2:13][CH:12]([OH:11])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:18]=1)=[N:38][CH2:37][CH2:36][CH2:35][C:33]1[N:32]=[CH:31][NH:30][CH:34]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C1NCC(COc2cccc(CN3CCCCC3)c2)O1)c1ccccc1
Reactant: NCCCc1c[nH]cn1
Solvent: c1ccncc1
Product: O=C(NC(=NCCCc1c[nH]cn1)NCC(O)COc1cccc(CN2CCCCC2)c1)c1ccccc1

Procedure:
1.97 g (5 mmol) of 2-benzoylimino-5-[(3-piperidinomethylphenoxy)methyl]oxazolidine and 0.69 g (5.5 mmol) of 3-(imidazol-4-yl)propylamine are together heated under reflux in 30 ml of pyridine for 8 hours. The solvent is distilled off under vacuum, and the reaction product is isolated and purified by a method analogous to Method A.
Reaction SMILES: C(O)C.[NH2:4][C:5]1C=[C:12]([F:14])[C:11]([CH3:15])=[CH:10][C:6]=1C(O)=O.C[Si](C=[N+]=[N-])(C)C.[CH2:23]([O:25][C:26](=[O:28])[CH3:27])C>>[CH3:23][O:25][C:26](=[O:28])[C:27]1[C:5]([NH2:4])=[CH:6][CH:10]=[C:11]([CH3:15])[C:12]=1[F:14]
Reactant: Cc1cc(C(=O)O)c(N)cc1F
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCO
Product: COC(=O)c1c(N)ccc(C)c1F
Reaction time: 16 h

Procedure:
Dissolve in ethylacetate (1 mL) and ethanol (1 mL) 6-Amino-2-fluoro-3-methyl-benzoic acid and 2-Amino-4-fluoro-5-methyl-benzoic acid (240 mg, 1.42 mmol) and add (trimethylsilyl) diazomethane (0.7 mL, 1.4 mmol, 2M in hexane) at room temperature and stir the solution for 16 h. Remove the solvent under reduced pressure. Chromatograph the residue over silica gel, eluting with hexanes/ethyl acetate (10:1), to afford the titled compound (50 mg). 1H NMR (CDCl3, 300 MHz) δ 2.13 (d, J=2.4 Hz, 3H), 3.9 (s, 3H), 6.39 (dd, J=0.8, 8.5 Hz, 1H), 7.04 (t, J=8.1 Hz, 1H). MS (ES+): 184 (M+H).
Reaction SMILES: [CH:1]1([C:7](=[NH:17])[NH:8][CH2:9][C:10](OC(C)(C)C)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:18][CH2:19]CCl>FC(F)(F)C(O)=O>[Cl:18][C:19]1[N:17]=[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[NH:8][C:9]=1[CH:10]=[O:11]
Reactant: ClCCCl
Reactant: CC(C)(C)OC(=O)CNC(=N)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1[nH]c(C2CCCCC2)nc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
tert-Butyl N-[cyclohexyl(imino)methyl]glycinate (830 mg) was dissolved in a solution (10%, 15 ml) of trifluoroacetic acid in 1,2-dichloroethane and the mixture was stirred at room temperature for 1 day. The reaction mixture was concentrated under reduced pressure. The residue was suspended in toluene, phosphorus oxychloride (3.21 ml) was added and the mixture was stirred at 80° C. for 30 min. DMF (2.67 ml) was added and the mixture was stirred at 100° C. for 5 hr. The reaction mixture was ice-cooled, basified by pouring into an aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (495 mg).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[C:18]2[C:26]2[C:27]([CH3:32])=[N:28][O:29][C:30]=2[CH3:31])=[CH:13][CH:12]=1>CN(C=O)C>[Br:8][C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:16][CH:15]=2)[C:18]=1[C:26]1[C:27]([CH3:32])=[N:28][O:29][C:30]=1[CH3:31]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(-n2c(-c3c(C)noc3C)cc3ccccc32)cc1
Solvent: CN(C)C=O
Product: COc1ccc(-n2c(-c3c(C)noc3C)c(Br)c3ccccc32)cc1
Temperature: 25 °C
Yield: 98 %

Procedure:
NBS (59 mg, 0.33 mmol) was added to a cooled (0° C.) solution of 4-(1-(4-methoxyphenyl)-1H-indol-2-yl)-3,5-dimethylisoxazole (105 mg, 0.33 mmol) in 5 ml of DMF. The temperature was allowed to warm to RT and the mixture was stirred at RT for 30 min DMF was evaporated. DCM and water were added and the phases were separated. After evaporation of the solvents, the residue was purified by flash chromatography with heptane/EtOAc 9:1 to provide 4-(3-bromo-1-(4-methoxyphenyl)-1H-indol-2-yl)-3,5-dimethylisoxazole in 98% yield. ES/MS m/z: 365.14 (M+H), 363.30 (M−H).
Reaction SMILES: [F:1][C@@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.C(OC([NH:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])=[N:36][C:35]=1[C:46](O)=[O:47])=O)(C)(C)C>>[NH2:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])=[N:36][C:35]=1[C:46]([NH:23][C:18]1[CH:19]=[N:20][N:21]([CH3:22])[C:17]=1[C@@H:5]1[CH2:6][CH2:7][C@@H:8]([NH2:9])[C@@H:2]([F:1])[CH2:3][O:4]1)=[O:47]
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2F)nc1C(=O)O
Product: Cn1ncc(NC(=O)c2nc(-c3ccccc3F)sc2N)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3R,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 24), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 5-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)thiazole-4-carboxylic acid (Example 7) gave 186 as the hydrochloride salt as a white solid (38 mg, 71%). 1H NMR (400 MHz, d6-DMSO) δ 9.47 (s, 1H), 8.60-8.40 (m, 3H), 8.19-8.13 (m, 1H), 7.71 (s, 1H), 7.49-7.35 (m, 3H), 5.40-5.23 (m, 1H), 4.87 (d, J=10.5 Hz, 1H), 4.28 (ddd, J=32.0, 14.5, 4.7 Hz, 1H), 4.07 (ddd, J=23.4, 14.5, 2.8 Hz, 1H), 3.80 (s, 3H), 3.78-3.60 (m, 1H), 2.19-1.82 (m, 4H). LCMS (ES+) m/z 449 (M+1). Alkyl NH2 not observed.
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([CH:14]=[O:15])[CH:13]=1)[N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:9]=[C:8]2[C:24]#[N:25]>C1COCC1>[Cl:4][C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([CH:14]([OH:15])[CH3:1])[CH:13]=1)[N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:21])[CH3:23])[CH:9]=[C:8]2[C:24]#[N:25]
Reactant: C[Mg]Br
Reactant: C[Si](C)(C)CCOCn1cc(C#N)c2cc(Cl)cc(C=O)c21
Solvent: C1CCOC1
Product: CC(O)c1cc(Cl)cc2c(C#N)cn(COCC[Si](C)(C)C)c12
Temperature: -20 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
Methylmagnesium bromide (0.334 mL, 1.002 mmol) was added to a −20° C. solution of 5-chloro-7-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carbonitrile (305 mg, 0.911 mmol) in THF (10 mL). The reaction was stirred 1 hour at −20° C., and TLC indicated that reaction was about 50% complete and no longer progressing. More methylmagnesium bromide (0.304 mL, 0.911 mmol) was added and the reaction was stirred an additional 1 hour at −20° C. The reaction was quenched by addition of HCL(1N, 10 mL) and then water (30 mL) was added and the reaction was extracted with ethyl acetate (3×20 mL). The organic layers were washed with brine (20 mL), dried with MgSO4 and evaporated. The residue was purified by chromatography on SiO2 with 20% ethyl acetate/hexanes to provide (±)-5-chloro-7-(1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carbonitrile (224 mg, 0.638 mmol, 70.1% yield) as a clear oil. 1H-NMR (CDCl3, 400 MHz) δ 7.66 (d, J=2.0 Hz, 1H), 7.62 (s, 1H), 7.47 (d, J=2.0 Hz, 1H), 5.83 (d, J=11.3 Hz, 1H), 5.56 (pentet, J=6.3 Hz, 1H), 5.48 (d, J=11.3 Hz, 1H), 3.46 (app t, J=8.5 Hz, 2H), 2.27 (d, J=6.1 Hz, 1H), 1.66 (d, J=6.5 Hz, 3H), 0.86 (app t, J=8.3 Hz, 2H), −0.07 (s, 9H). LC/MS (HPLC method 4): tR=3.57 min, 373.16(MNa)+.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH:16]=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:4]1.[N:17]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[C:23]#[N:24])=[C:18]=[O:19]>O1CCOCC1>[N:11]1[C:10]2[NH:14][CH:15]=[CH:16][C:9]=2[C:8]([N:5]2[CH2:6][CH2:7][C@@H:3]([N:2]([CH3:1])[C:18]([NH:17][C:20]3[CH:27]=[CH:26][CH:25]=[C:22]([C:23]#[N:24])[CH:21]=3)=[O:19])[CH2:4]2)=[N:13][CH:12]=1
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: CN[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Solvent: C1COCCO1
Product: CN(C(=O)Nc1cccc(C#N)c1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1

Procedure:
A solution of (R)—N-methyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine (50 mg, 0.230 mmol) and 3-isocyanatobenzonitrile (37 mg, 0.257 mmol) in 1,4-dioxane (1 mL) was refluxed overnight. The volatiles were removed under vacuum and the residue was purified by flash chromatography to give the title compound. MS (m/z): 362 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:6][CH2:5][C:4](=O)[CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C([O-])(=O)C.[NH4+:18]>CCO>[NH2:18][C:4]1[CH2:5][CH2:6][C:2]([CH3:13])([CH3:1])[C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: [NH4+]
Reactant: CCOC(=O)C1C(=O)CCC1(C)C
Agent: CC(=O)[O-]
Solvent: CCO
Product: CCOC(=O)C1=C(N)CCC1(C)C
Temperature: 85 °C
Yield: 86.1 %

Procedure:
A mixture of ethyl 2,2-dimethyl-5-oxocyclopentanecarboxylate (3.426 g) and ammonium acetate (14.33 g) in EtOH (100 mL) was heated at 85° C. (bath) for 1 hour. The contents were concentrated. The residue was partitioned between water and DCM. The organic phase was separated. The aqueous solution was extracted with DCM. The combined DCM solutions were washed with water and dried (Na2SO4). Upon filtration and concentration, solid ethyl 2-amino-5,5-dimethylcyclopent-1-enecarboxylate (2.933 g) was yielded. The ethyl 2-amino-5,5-dimethylcyclopent-1-enecarboxylate was mixed with ammonium formate (5.054 g) and formamide (7 mL) and heated at 150° C. for 16 hours. The mixture was diluted with water and extracted with 5:1 DCM-IPA. The combined extracts were dried (Na2SO4) and concentrated to give 5,5-dimethyl-6,7-dihydro-3H-cyclopenta[d]pyrimidin-4(5H)-one as a viscous oil (1.185 g). 5,5-Dimethyl-6,7-dihydro-3H-cyclopenta[d]pyrimidin-4(5H)-one (1.063 g) was dissolved in acetonitrile (20 mL) with POCl3 (1.78 mL). The mixture was heated at 80° C. for 10 hours. The mixture was cooled to 0° C. 50% KOH (15.3 mL) was added dropwise. t-Butyl piperazine-1-carboxylate (3.615 g) was added. The mixture was heated at 80° C. for 24 hours. The contents were concentrated. Water was added. The mixture was extracted with DCM (2×) and dried (Na2SO4). The crude material was purified with flash chromatography to give tert-butyl 4-(5,5-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (1.021 g). 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.57 (s, 1H), 3.56-3.54 (m, 4H), 3.37-3.34 (m, 4H), 2.90 (t, J=7.3 Hz, 2H), 1.89 (t, J=7.3 Hz), 3H) 1.48 (s, 9H), 1.40 (s, 6H). MS: 333.2 (M+1).
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[NH:10][C:9]([C:14]34[CH2:21][CH2:20][C:17]([CH:22]=C)([CH2:18][CH2:19]3)[O:16][CH2:15]4)=[N:8][C:7]=2[N:6]([CH2:24][CH2:25][CH3:26])[C:5]1=[O:27])[CH2:2][CH3:3].[O:28]1CCOCC1>CC(O)(C)C.O.O=[Os](=O)(=O)=O>[O:27]=[C:5]1[N:6]([CH2:24][CH2:25][CH3:26])[C:7]2[N:8]=[C:9]([C:14]34[CH2:21][CH2:20][C:17]([CH:22]=[O:28])([CH2:18][CH2:19]3)[O:16][CH2:15]4)[NH:10][C:11]=2[C:12](=[O:13])[N:4]1[CH2:1][CH2:2][CH3:3]
Reactant: C1COCCO1
Reactant: C=CC12CCC(c3nc4c([nH]3)c(=O)n(CCC)c(=O)n4CCC)(CC1)CO2
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)(C)O
Solvent: O
Product: CCCn1c(=O)c2[nH]c(C34CCC(C=O)(CC3)OC4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1,3-Dipropyl-8-(1-vinyl-2-oxa-bicyclo[2.2.2]oct-4-yl)-3,7-dihydro-purine-2,6-dione (400 mg, 1.08 mmol) was suspended in 8 ml of dioxane and 1 ml of a 2.5% solution of OsO4 in t-BuOH was added, followed by 3 ml of H2O. After 10 min, NaIO4 was added and the reaction mixture was stirred at rt for 3 h. It was then diluted with H2O and extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated to afford the aldehyde intermediate, 4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-oxa-bicyclo[2.2.2]octane-1-carbaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.[CH2:21]([O:28][C:29]1[C:34]([CH3:35])=[CH:33][C:32]([C:36]([C:38]2[CH:43]=[C:42](Cl)[N:41]=[CH:40][N:39]=2)=[O:37])=[CH:31][C:30]=1[CH3:45])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:21]([O:28][C:29]1[C:30]([CH3:45])=[CH:31][C:32]([C:36]([C:38]2[N:39]=[CH:40][N:41]=[C:42]([N:17]3[CH2:18][CH2:19][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:15][CH2:16]3)[CH:43]=2)=[O:37])=[CH:33][C:34]=1[CH3:35])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc(C)c1OCc1ccccc1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c(OCc5ccccc5)c(C)c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
200 mg (0.730 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 240 mg (0.680 mmol) (4-benzyloxy-3,5-dimethyl-phenyl)-(6-chloro-pyrimidin-4-yl)-methanone and 0.400 mL (2.30 mmol) DIPEA were combined in 2.0 mL DMF and stirred for 3 h at RT. The mixture was added to ice water, the precipitate was suction filtered and dried.
Reaction SMILES: Cl.C([O:6][C:7](=[O:20])[CH2:8][N:9]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][C:11]([CH3:19])=[N:10]1)(C)(C)C>C1COCC1>[CH2:17]([O:16][C:14]([C:13]1[N:9]([CH2:8][C:7]([OH:20])=[O:6])[N:10]=[C:11]([CH3:19])[CH:12]=1)=[O:15])[CH3:18]
Reactant: CCOC(=O)c1cc(C)nn1CC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C)nn1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
6 N Hydrochloric acid (4 mL, 24.00 mmol) was added to a solution of ethyl 1-(2-tert-butoxy-2-oxoethyl)-3-methyl-1H-pyrazole-5-carboxylate (324 mg, 1.21 mmol) in THF (4 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (206 mg).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]=[C:6]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[C:16]([C:17]3[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[C:18]=3[O:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:10]=2[CH:9]=1)[CH3:7])C.C1COCC1.[Li+].[OH-]>CO>[CH2:30]([O:29][C:18]1[C:19]([CH:26]([CH3:28])[CH3:27])=[CH:20][C:21]([CH:23]([CH3:24])[CH3:25])=[CH:22][C:17]=1[C:16]1[C:10]2[CH:9]=[C:8]([C:6]([CH3:7])=[CH:5][C:4]([OH:34])=[O:3])[S:12][C:11]=2[CH:13]=[CH:14][CH:15]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCOc1c(-c2cccc3sc(C(C)=CC(=O)OCC)cc23)cc(C(C)C)cc1C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOc1c(-c2cccc3sc(C(C)=CC(=O)O)cc23)cc(C(C)C)cc1C(C)C
Temperature: 25 °C

Procedure:
A mixture of 0.450 mmol of 3-[4-(2-n-butoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH (2N aqueous) was refluxed for 2 hours. After cooling at room temperature, the mixture was acidified to pH=2 and extracted with ethyl acetate. The organic layer was dried over MgSO4 and after evaporation of the solvents, the crude acid was recrystallized from acetonitrile. 3-[4-(2-n-butoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoic acid was isolated as a white solid.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[C:11]([CH2:19][CH2:20][CH3:21])[C:10]=1[CH2:22]O)([OH:8])[C:4]([F:7])([F:6])[F:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O>ClCCl>[CH3:18][O:17][CH2:16][O:15][C:12]1[C:11]([CH2:19][CH2:20][CH3:21])=[C:10]2[C:9](=[CH:14][CH:13]=1)[C:3]([C:4]([F:6])([F:5])[F:7])([C:2]([F:1])([F:24])[F:25])[O:8][CH2:22]2
Reactant: CCCc1c(OCOC)ccc(C(O)(C(F)(F)F)C(F)(F)F)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CCCc1c(OCOC)ccc2c1COC2(C(F)(F)F)C(F)(F)F
Reaction time: 8 h
Yield: 92.8 %

Procedure:
To a solution of 1,1,1,3,3,3-hexafluoro-2-[2-(hydroxymethyl)-4-(methoxymethoxy)-3-propylphenyl]propan-2-ol (1.29 g, 3.43 mmol) and triphenylphosphine (1.98 g, 7.55 mmol) in dichloromethane (15 mL), diethyl azodicarboxylate (2.2 mol/L toluene solution, 4.67 mL, 10.27 mmol) was added under ice-cold conditions and the mixture was stirred overnight. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by silica-gel column chromatography (hexane/ethyl acetate) and the title compound (1.14 g, 93%) was obtained as colorless oil.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:10]3[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]([C:21]1[CH:22]=[N:23][N:24]([CH3:29])[C:25]=1[C:26](O)=[O:27])=[O:20].CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1.C(=O)(O)[O-].[Na+]>[CH3:29][N:24]1[C:25]([C:26](=[O:27])[NH:15][C:12]2[CH:13]=[CH:14][N:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:16]=[C:10]3[CH:11]=2)=[C:21]([C:19]([O:18][CH3:17])=[O:20])[CH:22]=[N:23]1
Reactant: COC(=O)c1cnn(C)c1C(=O)O
Reactant: Nc1ccn2nc(-c3ccccc3)nc2c1
Agent: CCCP(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.5 %

Procedure:
A solution of 2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylamine (1.534 g, 7.3 mmol), 4-(methoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (1.61 g, 8.76 mmol), propylphosphonic anhydride (50% in ethyl acetate, 10.7 ml, 18.2 mmol) and diisopropylethylamine (5.1 ml, 29.2 mmol) in tetrahydrofurane (54 ml) is stirred at 70° C. for 1.25 hr giving a white suspension. The cooled suspension is poured in sat. aqueous sodium bicarbonate solution (200 ml), stirred at room temperature for 15 min and the solid is collected by filtration, washed with water and dried affording methyl 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylate (2.596 g, 94.5%) as a white solid. mp.: 243-7° C. MS: m/z=377.2 (M+H+).
Reaction SMILES: [IH:1].[CH3:2][N:3]1[C:8](=[O:9])[N:7]2[CH:10]=[N:11][C:12]([C:13](SC)=[NH:14])=[C:6]2[N:5]=[N:4]1.[NH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>>[IH:1].[CH3:2][N:3]1[C:8](=[O:9])[N:7]2[CH:10]=[N:11][C:12]([C:13](=[NH:14])[NH:17][CH2:18][C:19](=[O:20])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:6]2[N:5]=[N:4]1
Reactant: NCC(=O)c1ccccc1
Reactant: CSC(=N)c1ncn2c(=O)n(C)nnc12
Agent: I
Product: Cn1nnc2c(C(=N)NCC(=O)c3ccccc3)ncn2c1=O
Yield: 34 %

Procedure:
Using the general procedure, the title compound was synthesized from methyl 3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbimidothioate hydroiodide and aminoacetophenone, using a reaction time for the amidine formation of 3.5 hours. Yield 34%. δH (DMSO-d6): 9.69 (2H, m), 9.51 (1H, bs), 9.22 (1H, s), 8.07-8.05 (2H, m), 7.78-7.73 (1H, m), 7.65-7.61 (2H, m), 5.24 (2H, d, J=6.0), 4.06 (3H, s).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([C:15]#[N:16])[N:14]=1)[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=O.[CH3:32][NH2:33].O>CCO>[CH3:32][NH:33][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([C:15]#[N:16])[N:14]=1)[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[CH:8]2)=[O:2]
Reactant: COC(=O)c1nc(C#N)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: CN
Solvent: CCO
Solvent: O
Product: CNC(=O)c1nc(C#N)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 80 °C

Procedure:
A mixture of 1-benzyl-8-cyano-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.085 mmol) and methylamine (1 mL, 2M in THF) in 2 mL of EtOH was heated in a sealed tube at 80° C. for 4 h. After cooling to r.t., 3 mL of water was added. The resulting suspension was filtered, and the crude solid was purified by silica gel chromatography (0-20% EtOAc/CH2Cl2+1% AcOH) to give 13 mg of the title compound as a white solid. MS: (+) m/z 411.01 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]12(O)[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2.OS(O)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:9]12([C:6]3[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[OH:8])[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Yield: 73.6 %

Procedure:
To a mixture of 4-bromophenol (34.60 g, 200 mmol) and 1-adamantanol (30.45 g, 200 mmol) in 100 mL of anhydrous CH2Cl2 at room temperature was added dropwise over 10–15 minutes concentrated H2SO4 (11 mL). After 1.5 hours a thick suspension resulted and the reaction was allowed to continue for a total of 24 hours. The suspension was carefully poured into ice water and neutralized with solid NaHCO3. The resulting layers were separated and the aqueous layer extracted with CH2Cl2 (2×). The combined organics were washed with brine, dried (MgSO4) and filtered. The solvent was removed under reduced pressure and the resulting solid was purified on silica gel (hexane:ethyl acetate 85:15), the impure fractions were further purified by recrystallization from hexane and the two lots combined to give 45.2 g (74%) of 2-(1-adamantyl)-4-bromophenol. 1H NMR (300 MHz; CDCl3): δ 1.77 (s, 6H), 2.08 (s, 9H), 4.81 (s, 1H), 6.53 (d, J=8.4 Hz, 1H), 7.14 (dd, J1=8.7 Hz, J2=2.4 Hz, 1H), 7.29 (d, J=2.4 Hz, 1H).