Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].O>CN(C)C=O.C(OCC)(=O)C>[CH2:27]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCBr
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 70 °C
Reaction time: 10 h

Procedure:
To a suspension of 1-(4-Hydroxyphenyl)-4-tert-butoxycarbonylpiperazine (3 g) and potassium carbonate (0.82 g) in N,N-dimethylformamide (15 ml) was added octyl bromide (1.87 ml). The mixture was stirred for 10 hours at 70° C. The reaction mixture was added to a mixture of water and ethyl acetate. The organic layer was taken, and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel, and eluted with (hexane : ethyl acetate=9:1). The fractions containing the object compound were combined, and evaporated under reduced pressure to give 1-(4-n-Octyloxyphenyl)-4-tert-butoxycarbonylpiperazine (2.71 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:28]([N:31]2[CH:35]=[N:34][N:33]=[N:32]2)=[CH:27][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C@@:9]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].I.[CH2:37]([O:39][CH2:40][CH2:41][N:42]1[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[N:44]=[C:43]1[N:51]1[CH2:57][CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)[CH3:38]>>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:28]([N:31]2[CH:35]=[N:34][N:33]=[N:32]2)=[CH:27][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C@:9]([CH2:12][CH2:13][N:54]2[CH2:55][CH2:56][CH2:57][N:51]([C:43]3[N:42]([CH2:41][CH2:40][O:39][CH2:37][CH3:38])[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=4[N:44]=3)[CH2:52][CH2:53]2)([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:8]1)=[O:6]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccc(Cl)c(Cl)c2)C1
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Agent: I
Product: CCOCCn1c(N2CCCN(CC[C@]3(c4ccc(Cl)c(Cl)c4)CCN(C(=O)c4cc(-n5cnnn5)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 47.3 using (S)-1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt to give the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:6][CH:7]=1.[NH3:18]>>[NH2:18][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: N
Reactant: FC(F)(F)c1cccc(-c2ccc(Cl)nn2)c1
Product: Nc1ccc(-c2cccc(C(F)(F)F)c2)nn1
Temperature: 200 °C

Procedure:
A 12.5 g sample of 3-chloro-6-[3-(trifluoromethyl)phenyl]pyridazine was placed in a steel cylinder with liquid ammonia and the sealed cylinder (bomb) was heated at 200° C. The chilled cylinder was opened and the ammonia allowed to evaporate. The solid residue was heated and stirred with chloroform, then filtered. The filtrate was concentrated and the residue recrystallized, first from chloroform-hexane, then twice from chloroform to give 1.8 g of 3-amino-6-[3-(trifluoromethyl)phenyl]pyridazine as white crystals, mp 143°-145° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14]I)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].II.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.Br[C:48]1[CH:53]=[CH:52][N:51]=[C:50]([O:54][CH3:55])[CH:49]=1>[Zn].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].O.CCOC(C)=O.CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:48]1[CH:53]=[CH:52][N:51]=[C:50]([O:54][CH3:55])[CH:49]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H](CI)NC(=O)OC(C)(C)C
Reactant: COc1cc(Br)ccn1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: II
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@H](Cc1ccnc(OC)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
Dry DMF (30 mL) was added to zinc dust (2.78 g, 42.6 mmol) in a flame dried bottom flask under N2. (R)-Methyl 2-(tert-butoxycarbonylamino)-3-iodopropanoate (3.85 g, 11.7 mmol) was added followed by a catalytic amount of iodine (1.06 g, 0.10 mmol). The mixture was stirred at ambient temperature for 0.5 h. Pd2(dba)3 (487 mg, 0.050 mmol), S—Phos (437 g, 0.100 mmol) and 4-bromo-2-methoxypyridine (2.00 g, 10.6 mmol) were added. The reaction mixture was heated at 60° C. for 6 h and then cooled to ambient temperature. EtOAc (200 mL) and water (200 mL) were added. The organic phase was separated, washed with water (300 mL×3) and brine (300 mL×1), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane/EtOAc=2:1) to afford (S)-methyl 2-(tert-butoxycarbonylamino)-3-(2-methoxypyridin-4-yl)propanoate (2.4 g, 73% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[NH:12]1[C:16]2[CH:17]=[CH:18][C:19]([CH:21]=O)=[CH:20][C:15]=2[N:14]=[N:13]1.N1CCCCC1>CCO>[NH:12]1[C:16]2[CH:17]=[CH:18][C:19](/[CH:21]=[C:5]3/[C:6](=[O:11])[NH:7][C:8]4[C:4]/3=[CH:3][C:2]([NH2:1])=[CH:10][CH:9]=4)=[CH:20][C:15]=2[N:14]=[N:13]1
Reactant: O=Cc1ccc2[nH]nnc2c1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: Nc1ccc2c(c1)/C(=C\c1ccc3[nH]nnc3c1)C(=O)N2
Temperature: 90 °C
Yield: 20.4 %

Procedure:
A scintillation vial was charged with 5-aminoindolin-2-one (37 mg, 0.247 mmol), 1H-benzo[d][1,2,3]triazole-5-carbaldehyde (40 mg, 0.272 mmol), piperidine (2.5 uL, 0.025 mmol) and EtOH (2 mL). The reaction was then heated to 90° C. for 2 hrs. The EtOH was removed in vacuo and the residue loaded onto a silica gel column eluting with 92:8 CH2Cl2/MeOH to give 14 mg, 20% of a red solid. 1H NMR (400 MHz, d6-DMSO) δ 15.96 (bs, 1H), 10.15 (s, 1H), 8.21 (bs, 1H), 8.02 (bs, 1H), 7.73 (bs, 1H), 7.67 (s, 1H), 6.87 (s, 1H), 6.59-6.47 (m, 2H), 4.65 (bs, 2H); MS ESI 278.0 [M+H]+, calcd for [C15H11N5O+H]+ 278.10.
Reaction SMILES: [C:1]12([C:11]3[CH:50]=[CH:49][C:14]([O:15][C:16]4[CH:17]=[CH:18][C:19]5[N:23]=[C:22]([CH2:24][O:25][C:26]6[CH:31]=[CH:30][C:29]([CH2:32][CH:33]([O:38][CH2:39][C:40]7[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=7)[C:34]([O:36]C)=[O:35])=[CH:28][CH:27]=6)[N:21]([CH3:47])[C:20]=5[CH:48]=4)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH-].[Na+].Cl.C(=O)([O-])O.[Na+]>O.O1CCCC1.CO>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:15][C:16]4[CH:17]=[CH:18][C:19]5[N:23]=[C:22]([CH2:24][O:25][C:26]6[CH:31]=[CH:30][C:29]([CH2:32][CH:33]([O:38][CH2:39][C:40]7[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=7)[C:34]([OH:36])=[O:35])=[CH:28][CH:27]=6)[N:21]([CH3:47])[C:20]=5[CH:48]=4)=[CH:49][CH:50]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: COC(=O)C(Cc1ccc(OCc2nc3ccc(Oc4ccc(C56CC7CC(CC(C7)C5)C6)cc4)cc3n2C)cc1)OCc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cn1c(COc2ccc(CC(OCc3ccc(F)cc3)C(=O)O)cc2)nc2ccc(Oc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
A mixture of methyl 3-[4-[6-(4-adamantan-1-ylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-(4-fluorobenzyloxy)propionate (0.25 g), aqueous 2N sodium hydroxide solution (2 ml) and methanol (5 ml) was stirred at room temperature for 2 hours. To the reaction mixture was added tetrahydrofuran (5 ml) and the mixture was stirred for 4 hours. The reaction mixture was poured into water and neutralized with hydrochloric acid and sodium hydrogencarbonate and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The ethyl acetate was evaporated under reduced pressure. The residue crystallized in ethyl acetate and the crystals were isolated by filtration to afford the title compound (0.23 g, mp 148-149° C.).
Reaction SMILES: O[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[N:6][CH:5]=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(-c2nccnc2O)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2nccnc2Cl)cc1
Reaction time: 4 h

Procedure:
The 2-hydroxy-3-p-methoxyphenylpyrazine is refluxed (120°-130° C.) with excess phosphorus oxychloride under stirring for 3-5 hours. The solution is evaporated to dryness at 50° C. in vacuo, cooled, ice is added, then treated with 10% sodium hydroxide solution, extracted with a suitable solvent such as diethyl ether, the ethereal solution washed with water and evaporated. The crude product is crystallized from a suitable solvent such as ethanol to give 2-chloro-3-p-methoxyphenylpyrazine.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:9])[C@@H:6]([CH3:8])[NH2:7])[CH2:2][CH3:3].[NH:10](C(OCC1C=CC=CC=1)=O)[C@H:11]([C:23](O)=[O:24])[CH2:12][C:13](=[O:22])[O:14]CC1C=CC=CC=1>>[CH2:1]([O:4][C:5](=[O:9])[C@@H:6]([CH3:8])[NH:7][C:23](=[O:24])[C@H:11]([CH2:12][C:13](=[O:14])[OH:22])[NH2:10])[CH2:2][CH3:3]
Reactant: CCCOC(=O)[C@@H](C)N
Reactant: O=C(C[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Product: CCCOC(=O)[C@@H](C)NC(=O)[C@@H](N)CC(=O)O

Procedure:
This compound was prepared from 1.7 g D-alanine propyl ester and 3.6 g Z-Asp(OBzl) in a manner similar to Example 11 (A). Yield: 1.6 g.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][N:12]=1.CNN(NC)C(Cl)=[S:23].[C:27](=[O:30])([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:11][N:12]([CH3:13])[C:27](=[S:23])[OH:30].[OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][N:12]=1
Reactant: O=C([O-])[O-]
Reactant: CNN(NC)C(=S)Cl
Agent: COc1ccnc(-c2cc([N+](=O)[O-])ccc2O)c1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(O)=S

Procedure:
The compound from step (a) above (24.2 mmol), N,N-dimethylaminothiocarbamoyl chloride (37 mmol) in dimethyl formamide (250 ml) were stirred rapidly in the presence of potassium carbonate (60 mmol) for 24 hours, adding more potassium carbonate (1 g) after 18 hours. The mixture was acidified (to pH4) with dilute hydrochloric acid and extracted with ethyl acetate (3 times). The combined extracts were washed with water (4 times), dried (anhydrous sodium sulphate) and evaporated to yield a brown solid, which was triturated with ether, and filtered to give the sub-title compound.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[N:6]=1)=[N+]=[N-].O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1>[CH3:19][S:16]([C:13]1[CH:12]=[CH:11][C:10]([N:7]2[CH:8]=[CH:9][C:5]([CH2:4][NH2:1])=[N:6]2)=[CH:15][CH:14]=1)(=[O:17])=[O:18]
Reactant: CS(=O)(=O)c1ccc(-n2ccc(CN=[N+]=[N-])n2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-n2ccc(CN)n2)cc1
Reaction time: 8 h

Procedure:
To a solution of 3-azidomethyl-1-(4-methanesulfonyl-phenyl)-1H-pyrazole (75 mg, 0.27 mmol, 1.00 equiv) in 1,4-dioxane (5 mL) was added water (0.5 mL) and triphenylphosphine resin (0.11 g, 3 mol/g, 200-400 mesh, 1.2 equiv). The suspension was stirred overnight. Filtration and concentration afforded C-[1-(4-methanesulfonyl-phenyl)-1H-pyrazol-3-yl]-methylamine as a colorless solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20](=[O:22])[CH3:21])=[CH:12][CH:11]=1.[Cl:23][C:24]1[CH:25]=[C:26]([C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])[CH:27]=[C:28]([Cl:30])[CH:29]=1.Cl>O1CCCC1>[Br:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20](=[O:22])[CH2:21][C:31]([C:26]2[CH:27]=[C:28]([Cl:30])[CH:29]=[C:24]([Cl:23])[CH:25]=2)([OH:36])[C:32]([F:35])([F:34])[F:33])=[CH:12][CH:11]=1
Reactant: CC(=O)c1ccc(Br)c2ccccc12
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(CC(O)(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(Br)c2ccccc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
Lithium diisopropylamide (Aldrich Chemical Company, 2M in tetrahydrofuran/ethylbenzene, 4 mL, 7.94 mmol) was added to tetrahydrofuran (4 mL) at −78° C. A solution of 1-(4-bromo-1-naphthalenyl)ethanone (1.8 g, 7.22 mmol) in tetrahydrofuran (4 mL) was added dropwise to the mixture. When the addition was complete the mixture was stirred for 30 min at −78° C. Then a solution of 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone (1.75 g, 7.20 mmol) in tetrahydrofuran (4 mL) was added dropwise to the mixture at such a rate that the temperature of the reaction mixture did not exceed −55° C. The mixture was allowed to warm to ambient temperature over 120 min. The mixture was then poured into 1N hydrochloric acid (100 mL) and extracted with ethyl acetate (2×100 mL). The combined extracts were dried and evaporated. Chromatography on silica gel (eluted with 1:9 ethyl acetate/hexanes) and crystallization from hexanes gave the title product as a white solid (1.1 g, 40% yield) melting at 74.5-75° C. (after recrystallization from hexanes).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([O:9]CC)=[O:8])[CH:4]=[C:3]([C:12]([O:14][CH2:15]C)=[O:13])[CH:2]=1.[OH-].[K+]>C(O)C>[CH3:15][O:14][C:12]([C:3]1[CH:2]=[N:1][CH:6]=[C:5]([C:7]([OH:9])=[O:8])[CH:4]=1)=[O:13]
Reactant: CCOC(=O)c1cncc(C(=O)OCC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)c1cncc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of diethyl 3,5-pyridinedicarboxylate [prepared according to the procedure of J. C. Speelman and R. M. Kellogg, J. Org. Chem., 1990, 55 (2), pages 647-653; 64.19 g, 0.248 mol] in ethanol (650 mL) were added KOH pellets (14.56 g, 0.260 mol). The reaction mixture was stirred overnight at ambient temperature. Evaporation of solvent afforded a white solid that was rinsed with dichloromethane, and then dissolved in water. The aqueous solution was extracted with ether, and then acidified to pH 3. The resultant white precipitate was collected by filtration and dried to afford pyridine-3,5-dicarboxylic acid monomethyl ester (33.70 g). A portion of this material (10.00 g, 51.3 mmol) was dissolved in dry tert-butanol (300 mL) and treated sequentially with triethylamine (7.85 mL, 56.4 mmol) and diphenyl phosphoryl azide (11.5 mL, 53.4 mmol). The mixture was refluxed for 90 minutes, and then stirred at ambient temperature overnight. Solvent was removed under reduced pressure and the residue was partitioned between water and dichloromethane. The layers were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried and concentrated. Chromatography on silica gel eluting with a mixture of pentane and ethyl acetate (3:1, v/v) gave 5-tert-butoxycarbonylamino-nicotinic acid ethyl ester (4.79 g). This ester was dissolved in methanol (45 mL) and treated with 1 N NaOH (54 mL, 54 mmol). After stirring 2 hours, volatiles were evaporated under reduced pressure and the residue was treated with 1 N HCl until the resultant slurry reached pH 3. The precipitate was collected by filtration, washed with water, and dried to afford 5-tert-butoxycarbonylamino-nicotinic acid (4.21 g): 1H NMR (300 MHz, DMSO-d6) δ 13.39 (br, s, 1H), 9.82 (s, 1H), 8.78 (d, J=2.5 Hz, 1H), 8.69 (d, J=1.9 Hz, 1H), 8.45-8.50 (m, 1H), 1.50 (s, 9H); 13C NMR (75 MHz, DMSO-d6) δ 166.2, 152.7, 143.4, 143.2, 136.2, 126.3, 124.9, 80.0, 27.9; MS (ESI) m/z 239 (M+H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[N:14]([CH3:30])[C:15](=[O:29])[C:16]([O:19]CC3C=CC(OC)=CC=3)=[CH:17][N:18]=2)[CH:8]=1)(=O)=O.[CH:33]1[C:42]2[CH:41]=[CH:40][CH:39]=[C:38](B(O)O)[C:37]=2[CH:36]=[CH:35][N:34]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH:33]1[C:42]2[C:37](=[C:38]([C:7]3[CH:8]=[C:9]([C:13]4[N:14]([CH3:30])[C:15](=[O:29])[C:16]([OH:19])=[CH:17][N:18]=4)[CH:10]=[CH:11][CH:12]=3)[CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][N:34]=1
Reactant: OB(O)c1cccc2cnccc12
Reactant: COc1ccc(COc2cnc(-c3cccc(OS(=O)(=O)C(F)(F)F)c3)n(C)c2=O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1c(-c2cccc(-c3cccc4cnccc34)c2)ncc(O)c1=O
Temperature: 120 °C
Yield: 43 %

Procedure:
To a solution of 50.0 mg (0.106 mmol) 3-{5-[(4-methoxybenzyl)oxy]-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl}phenyl trifluoromethanesulfonate in 2 ml THF was added 7.8 mg (0.011 mmol) 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane adduct, 18.3 mg (0.106 mmol) isoquinoline-5-boronic acid, and 300 μl (0.300 mmol) 1 M Cs2CO3. The reaction mixture was heated to 120° C. for 20 min in the microwave, then extracted with 10 ml EtOAc, and concentrated in vacuo. The oil was dissolved in 1 ml CH2Cl2, 1 ml TFA was added, and then concentrated in vacuo. Purification by mass-guided high throughput purification gave 15 mg (43% yield) of 2-(3-isoquinolin-5-ylphenyl)-5-hydroxy-3-methylpyrimidin-4(3H)-one. 1H NMR δ (ppm)(DMSO-d6): 9.62 (1 H, s), 8.58 (1 H, s), 8.34 (1 H, d, J=8.04 Hz), 7.97-7.86 (3 H, m), 7.74-7.66 (4 H, m), 7.57 (1 H, s), 2.54 (3 H, s). HRMS (ESI positive) tale (M+H)+=330.1237. Found 330.1237.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[C:34]([CH3:36])[N:35]=[C:9]23)[CH2:4][CH2:3]1.[N+](=[CH:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N-]>C([O-])(=O)C.[Rh+].C1(C)C=CC=CC=1>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:12]2[C:13](=[O:14])[N:8]([CH:5]3[CH2:6][CH2:7][CH:2]([O:1][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:3][CH2:4]3)[C:9]3[N:10]([N:33]=[C:34]([CH3:36])[N:35]=3)[C:11]=2[CH2:30][CH2:31][CH3:32])=[CH:17][CH:18]=1)#[N:29]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(O)CC2)c2nc(C)nn12
Agent: [Rh+]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(OCC(=O)OCC)CC2)c2nc(C)nn12
Reaction time: 1 h
Yield: 76 %

Procedure:
To a mixture of 4′-{[4-(4-hydroxycyclohexyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1.2 g), rhodium(I) acetate (0.055 g) and toluene (40 mL) was added dropwise ethyl diazoacetate (1.2 mL) at 80° C., and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography to give the title compound as a colorless solid (1.1 g, 76%).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[CH:25][N:24]=1.N1C=C(B(O)O)C=NC=1>>[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@H:11]([N:13]5[CH2:14][CH2:18][CH2:15][CH2:16][CH2:17]5)[CH2:10]4)[S:8][C:4]=3[CH:3]=2)=[CH:25][N:24]=1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: COc1ncc(B(O)O)cn1
Agent: OB(O)c1cncnc1
Product: COc1ncc(-c2ccc3nc([C@H]4C[C@H](N5CCCCC5)C4)sc3c2)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, except for substituting the compound of Example 44A for the compound of Example 1E, and substituting 2-methoxypyrimidine-5-boronic acid for pyrimidine-5-boronic acid. 1H NMR (500 MHz, CDCl3) δ ppm 8.78 (s, 2H) 8.07 (d, J=8.54 Hz, 1H) 7.98 (d, J=1.53 Hz, 1H) 7.60 (dd, J=8.39, 1.68 Hz, 1H) 4.09 (s, 3H) 3.80-3.92 (m, 1H) 3.07-3.24 (m, 1H) 2.55-2.73 (m, 4H) 2.26-2.47 (m, 4H) 1.57-1.80 (m, 4H) 1.43-1.53 (m, 2H). MS: (M+H)+=381.
Reaction SMILES: [CH2:1]([C:16]1[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=1)[O:19][CH:20]([CH2:24][CH3:25])[C:21](O)=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].S(Cl)([Cl:31])=O>ClCCl>[CH2:1]([C:16]1[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=1)[O:19][CH:20]([CH2:24][CH3:25])[C:21]([Cl:31])=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCCc1cccc(OC(CC)C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCc1cccc(OC(CC)C(=O)Cl)c1

Procedure:
2-(3-Pentadecylphenoxy)butanoic acid (7.8 g, 0.02 mol) (CAS Registry Number 14230-52-5) and thionyl chloride (50 ml) were heated under reflux on a steam-bath for 1 h. The resulting yellow solution was allowed to cool before being distilled under reduced pressure to leave a yellow oil. The oil was dissolved in dichloromethane (50 ml) and the solution was distilled under reduced pressure to remove volatiles. The residual 2-(3-pentadecylphenoxy)butanoyl chloride was used without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[F:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C@@:16]1([C@@H:19]([OH:21])[CH3:20])[CH2:18][O:17]1.C(O)(=O)C(O)=O>CS(C)=O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C@:16]([OH:17])([C@H:19]([OH:21])[CH3:20])[CH2:18][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: C[C@H](O)[C@]1(c2cc(F)ccc2F)CO1
Reactant: c1nc[nH]n1
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@@H](O)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
1,2,4-Triazole (274 mg; 3.89 mmol) is dissolved in DMSO (3 ml). Sodium hydride (124 mg; 60% suspension in paraffin; 3.24 mmol) is added and the reaction mixture is heated to 70° C. for one hour. The reaction mixture is cooled to room temperature and 1(S)-[2(S)-(2,5-Difluoro-phenyl)-oxiranyl]-ethanol (275 mg; 1.3 mmol) dissolved in DMSO (2 ml) is added slowly over a period of 10 minutes. The reaction mixture is then heated to 70° C. for three hours. The solvent is evaporated. The residue is taken-up in ethyl acetate (10 ml) and water (5 ml). The phases are separated. The aqueous layer is extracted 3 times with ethyl acetate (3 times 5 ml). The combined organic phases are washed twice with water (2 times 5 ml). The organic phase is dried over sodium sulfate. The solids are filtered off and the solvent is removed under reduced pressure. The crude product is dissolved in ethyl acetate (16 ml). Oxalic acid (164 mg; 1.3 mmol) is added and the solution is stirred for 30 minutes. The mixture is stored at 0° C. overnight. The crystalline (2R,3R)-2-(2,5-Difluoro-phenyl)-1-[1,2,4]triazol-1-yl-butane-2,3-diol oxalate salt is filtered off. The crystals are washed with hexanes and dried under vacuum. The desired compound is obtained as a white powder (337 mg); yield 66.7% with an optical purity higher than 95% (no other isomer is visible in NMR).