Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]2=[N:17][CH:18]=[C:19]([CH:21]=[O:22])[N:20]=[C:15]2[CH:14]=1.[BH4-].[Na+]>O1CCOCC1.CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][OH:22])[N:20]=[C:15]2[CH:14]=1
Reactant: COc1ccc2c(c1)c(-c1cc3nc(C=O)cnc3n1COCC[Si](C)(C)C)cn2C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: COc1ccc2c(c1)c(-c1cc3nc(CO)cnc3n1COCC[Si](C)(C)C)cn2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
6-(5-Methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde (5.03 g, 11.5 mmol, prepared using D from Preparation #C.1. with (E)-styrylboronic acid and E) in 1,4-dioxane (65 mL) and EtOH (13 mL) was treated with NaBH4 (0.436 g, 11.5 mmol) then stirred overnight at rt. The reaction mixture was concentrated under reduced pressure then the residue was partitioned between EtOAc (125 mL) and saturated aqueous NaHCO3 (100 mL). The layers were separated then the aqueous layer was extracted with EtOAc (75 mL). The combined organic layers were extracted with brine (50 mL) then dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The material was purified by flash chromatography on neutral alumina with 8:2 DCM/EtOAc then 7:3 DCM/EtOAc then finally EtOAc to give (6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanol (3.19 g, 63%): LC/MS (Table 2, Method a) Rt=2.76 min; MS m/z 439 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[NH2:8][CH:9]([C:15](O)=[O:16])[CH2:10][CH2:11][C:12]([OH:14])=[O:13]>[OH-].[Na+]>[CH2:1]([N:5]1[C:15](=[O:16])[CH:9]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])[NH:8][C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN=C=O
Reactant: NC(CCC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCCN1C(=O)NC(CCC(=O)O)C1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
n-Butyl isocyanate (7.5 g, 0.075 mole) was added dropwise to a stirred solution of DL-glutamic acid (7.35 g, 0.05 mole) in aqueous sodium hydroxide (4.0 g, in 50 ml) at 0° C. The mixture was stirred at 0° C. for 2 hours then left to rise to room temperature overnight. The mixture was filtered and the filtrate acidified with concentrated hydrochloric acid (50 ml) and heated on a steam-bath for 30 minutes. The solution was cooled whence crystals separated which were collected at the pump and recrystallised from methanol to give prisms, m.p. 130.5° C. Yield 8.7 g=76%.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:9])=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.CS(C)=O.[O:14]1[C:16]2[CH2:17][CH2:18][CH2:19][C:15]1=2>[Pd].O1CCCC1>[NH2:9][C:3]1[C:2]([CH3:1])=[CH:7][N:6]([CH:18]2[CH2:19][CH:15]([OH:14])[CH:16]=[CH:17]2)[C:5](=[O:8])[N:4]=1
Reactant: C1CC2=C(C1)O2
Reactant: Cc1c[nH]c(=O)nc1N
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cc1cn(C2C=CC(O)C2)c(=O)nc1N
Reaction time: 1.5 h
Yield: 24.4 %

Procedure:
50 g (0.4 mol) of 5-methylcytosine are added to a solution of the palladium(0) catalyst (1.6 mol %) prepared in situ as described above in 200 ml of dry tetrahydrofuran/200 ml of dry dimethylsulfoxide at 5° C. 49.2 g (0.6 mol) of epoxycyclopentene, dissolved in 100 ml of tetrahydrofuran, are added dropwise to this suspension, while stirring (1.5 hours). The mixture is stirred at room temperature for 3 days and then concentrated, and the residue is stirred with 2N sodium carbonate solution, filtered off and washed with water and acetone. 20.2 g (24.4% of theory) of 4-amino-5-methyl-1-[(1RS,4SR)-4-hydroxy-cyclopent-2-en-1-yl]pyrimidin-2(1H)-one of melting point 241°-245° C. are obtained. Chromatography (silica gel, methylene chloride/methanol 3/1) of the neutralized mother liquor gives, in addition to 5-methylcytosine (14.95 g, melting point 264°-269° C.) a further 9.87 g (11.9% of theory) of the title compound; total yield: 36.3% of theory. 1H NMR (270 MHz, d6 -DMSO); δ[ppm]: 7.23 (s, 1H), 7.12 (s, broad, 1H), 6.70 (s, broad, 1H), 6.09 (m, 1H), 5.74 (m, 1H), 5.45 (m, 1H), 5.17 (s, 1H), 4.61 (m, 1H), 2.71 (m, 1H), 1.81 (s, 3H), 1.27 (m, 1H).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]([CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]3[CH:24]=[CH:25][CH:26]=[CH:27][C:10]=3[CH2:9][O:8][C:7]=2[CH:28]=1.[CH3:29][C:30]1[N:35]=[C:34]2[NH:36][C:37]([CH2:39][CH3:40])=[N:38][C:33]2=[C:32]([CH3:41])[CH:31]=1>>[CH3:29][C:30]1[N:35]=[C:34]2[N:36]([CH2:2][C:3]3[CH:4]=[CH:5][C:6]4[CH:12]([CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11]5[CH:24]=[CH:25][CH:26]=[CH:27][C:10]=5[CH2:9][O:8][C:7]=4[CH:28]=3)[C:37]([CH2:39][CH3:40])=[N:38][C:33]2=[C:32]([CH3:41])[CH:31]=1
Reactant: CCc1nc2c(C)cc(C)nc2[nH]1
Reactant: CCOC(=O)C(C(=O)OCC)C1c2ccccc2COc2cc(CO)ccc21
Product: CCOC(=O)C(C(=O)OCC)C1c2ccccc2COc2cc(Cn3c(CC)nc4c(C)cc(C)nc43)ccc21
Yield: 29 %

Procedure:
The same procedures as in Steps C and D of Example 1 were repeated using 367 mg of Compound 23-a and 250 mg of 5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine to give 150 mg (31%) of the product as an oily substance.
Reaction SMILES: I[C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]([C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])[C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[NH:23]1[C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2B(O)O)=[N:26][N:25]=[N:24]1.[OH-].[Na+]>CO.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:19][CH2:18][CH2:17][CH2:16][C:15]([N:7]([C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[NH:23][N:24]=[N:25][N:26]=2)=[CH:22][CH:21]=1)=[O:20]
Reactant: CCCCC(=O)N(Cc1ccc(I)cc1)[C@H](C(=O)O)C(C)C
Reactant: OB(O)c1ccccc1-c1nnn[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O)C(C)C
Temperature: 70 °C
Yield: 85.1 %

Procedure:
Nitrogen is bubbled for 5 min. To a mixture made up of 0.20 g (0.48 mmol) of N-(4-iodobenzyl)-N-valeryl-L-valine, 0.115 g (0.61 mmol) of 2-(1H-tetrazol-5-yl)phenylboronic acid, 0.017 g (0.024 mmol) of bis(triphenylphosphine)palladium chloride and 0.115 g (2.87 mmol) of NaOH in 2.4 mL of methanol and 0.7 mL of water are added. The reaction is heated to 70° C. under nitrogen atmosphere. Once 3 h has elapsed the reaction is considered to be completed and the methanol is distilled. The crude product is treated with 25 mL of HCl 1N and 25 mL of AcOEt. The AcOEt phase is dried with anhydrous sodium sulphate and after distilling the solvent the crude product obtained is purified by silica gel chromatography (eluent AcOEt/heptane/AcOH 1.5:5:0.2) to provide 0.178 g (85%) of Valsartan.
Reaction SMILES: [OH:1][C:2]([CH3:8])([CH2:6][OH:7])[C:3](=[O:5])[CH3:4].[CH3:9][C:10]([CH3:12])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCCC(C)C>[CH3:9][C:10]1([CH3:12])[O:1][C:2]([C:3](=[O:5])[CH3:4])([CH3:8])[CH2:6][O:7]1
Reactant: CC(=O)C(C)(O)CO
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCC(C)C
Solvent: O
Product: CC(=O)C1(C)COC(C)(C)O1
Yield: 92 %

Procedure:
A mixture of 3,4-dihydroxy-3-methylbutan-2-one (4.13 g, 35 mmol), acetone (25 ml) and p-toluenesulfonic acid monohydrate (33 mg, 0.18 mmol) in isohexane (75 ml) was heated in a Dean-Stark apparatus for 10 h. The solvent was removed by distillation at atmospheric pressure and the residue purified by chromatography on silica gel. Elution with 50% ether in isohexane afforded 1-(2,2,4-trimethyl-[1,3]dioxolan-4-yl)ethanone as a pale yellow liquid (5.1 g, 92%): δH (360 MHz, d6-DMSO) 1.29 (3H, s), 1.34 (3H, s), 1.36 (3H, s), 2.20 (3H, s), 3.69 (1H, d, J 9), 4.18 (1H, d, J 9).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Sn:8]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:10][CH2:11][CH3:12])[N:3]=1.CCN(CC)CC.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>O>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Sn:8]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:10][CH2:11][CH3:12])[N:3]=2)[CH2:31][CH2:30]1
Reactant: CN1CCNCC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(Br)n1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(N2CCN(C)CC2)n1
Temperature: 100 °C
Yield: 67.2 %

Procedure:
To a solution of 2-bromo-6-(tributylstannyl)pyridine (2.0 g, 4.47 mmol) in Et3N (3.12 mL, 22.37 mmol) and was added 1-methyl piperazine (2 ml, 17.89 mmol). The reaction was heated at 100° C. for 24 h then cooled to RT, diluted with water, and extracted with EtOAc. The combined organic layer were washed with brine, dried and concentrated. The residue was purified with silica gel chromatography to give 1-methyl-4-(6-(tributylstannyl)pyridin-2-yl)piperazine (1.4 g, 70.3%). MS (ESI, pos. ion) m/z: 466.2 (M+1); 1H-NMR (CDCl3, 300 MHz) δ 7.3 (1H, t), 6.8 (1H, d), 6.5 (1H, d), 3.6 (4H, t), 2.5 (4H, t), 2.4 (3H, s), 1.5-1.7 (6H, m), 1.2-1.5 (6H, m), 1.0-1.2 (6H, q), 0.8-0.9 (9H, q).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:9](=[O:12])[NH:10][N:11]=2)[CH:5]=[N:6][C:7]=1[Cl:8].Cl[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[N:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:4]([C:9](=[O:12])[N:10]([CH2:14][C:15]3[CH:20]=[N:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=3)[N:11]=2)[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: FC(F)(F)c1ccc(CCl)cn1
Reactant: Nc1c(Cl)ncn2c(=O)[nH]nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c(Cl)ncn2c(=O)n(Cc3ccc(C(F)(F)F)nc3)nc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.6 %

Procedure:
To a stirred solution of 8-amino-7-chloro-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (1.41 g, 7.6 mmol) in DMF (10 mL) at room temperature under argon was added 5-(chloromethyl)-2-(trifluoromethyl)pyridine (1.78 g, 9.1 mmol), followed by K2CO3 (2.1 g, 15.2 mmol). The resulting mixture was stirred at room temperature for 5 h. Analysis by HPLC/MS indicated that the reaction was complete. Water (50 mL) was added to the reaction mixture. The solid precipitate was collected by filtration and was washed with water (10 mL×3). After the resulting solid was dried under vacuum, the title compound (2.4 g) was obtained as an off-white solid. HPLC/MS: retention time 2.43 min, [M+H]30 =345. 1H NMR (CDCl3): δ 8.81 (s, 1H), 8.12 (s, 1H), 7.92 (d, J=7.0 Hz, 1H), 7.69 (d, J=7.0 Hz, 1H), 5.21 (s, 2H), 4.42 (s, 2H). N-alkylation, rather than O-alkylation, was demonstrated by the presence of a 13C NMR resonance at 46.9 ppm.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[Cl:27][C:22]1[CH:21]=[C:20]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:25]=[CH:24][C:23]=1[F:26]
Reactant: Fc1ccc(Br)cc1Cl
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2cccc3[nH]ccc23)cc1Cl
Temperature: 75 °C
Reaction time: 15 h
Yield: 69.6 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 3.00 g, 12.34 mmol), and 4-bromo-2-chloro-fluorobenzene (2.58 g, 12.34 mmol) in THF (42 mL)) were added Palladium catalyst Pd(PPh3)4 (0.428 g, 0.37 mmol) and the freshly prepared sodium hydroxide solution (1.50 g, 37.02 mmol in 17 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 75° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 2.11 g (70%) of the product 4-(3-chloro-4-fluoro-phenyl)-1H-indole as a white solid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].O1CCCC1.[F:9][C:10]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:11]=1[C:12](Cl)=[O:13]>ClCCl>[F:9][C:10]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:11]=1[C:12]([N:2]([CH3:3])[CH3:1])=[O:13]
Reactant: CNC
Reactant: O=C(Cl)c1cc(I)ccc1F
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(I)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Add a 2.0 M solution of dimethylamine in tetrahydrofuran (5 mL, 10.1 mmol) to a solution of 2-fluoro-5-iodobenzoylchloride (1.3 g, 4.6 mmol) in dichloromethane (20 mL) and stir at room temperature for 0.5 h. Sequentially wash the reaction mixture with a 1 N hydrochloric acid (50 mL), a 1 N sodium hydroxide (50 mL), and an aqueous saturated solution of sodium chloride (50 mL). Dry (sodium sulfate), filter, and concentrate to give the title compound as a white solid (1.3 g, 98%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:11]1[CH:13]([CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:12]1.Cl>CS(C)=O.O1CCCC1>[CH2:3]([O:10][CH2:12][CH:13]([CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1)[OH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: C(CCCCCCC1CCCCC1)CCCCCOCC1CO1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: OC(COCCCCCCCCCCCCC1CCCCC1)COCc1ccccc1
Temperature: 60 °C
Yield: 78.9 %

Procedure:
In 100 ml of dimethylsulfoxide is suspended 1.4 g of sodium hydride, to which 9.73 g of benzyl alcohol is added dropwise at room temperature with stirring. After the addition is over, the mixture is gradually heated to 60° C. and stirred at that temperature for 40 minutes. Then, a solution of 9.7 g of 1,2-epoxy-3-(12-cyclohexyldodecyloxy)propane in 50 ml of tetrahydrofuran is added dropwise to the mixture and the resulting mixture is stirred at 60° C. for 2 hours. The thus obtaind reaction mixture is then neutralized with dilute hydrochloric acid and extracted with hexane-ethyl acetate (1:1). The extract layer is washed with water, dried and concentrated. The residue is purified by silica gel column chromatography to yield 10.2 g of the captioned compound as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9]O)=[CH:4][N:3]=1.N1C=CC=CC=1.P(Cl)(Cl)([Cl:19])=O.Cl>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][Cl:19])=[CH:4][N:3]=1
Reactant: OCc1cnc(Cl)c(Cl)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: ClCc1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
To a stirred solution of 2,3-dichloro-5-hydroxymethylpyridine (4.4 g, 25 mmol) and pyridine (2.61 g, 33 mmol) in dichloromethane (75 mL) was added rapidly phosphorous oxychloride (4.91 g, 32 mmol). An exothermic reaction sufficient to boil the reaction mixture ensued. After stirring at room temperature for 2 h, 1 N HCl aqueous solution (50 mL) was carefully added to the reaction mixture and the stirring continued for 10 min. The organic phase was separated and the aqueous phase extracted with dichloromethane (50 mL). The combined organic phase was washed successively with water (25 mL), 1 N aqueous NaOH solution (25 mL) and saturated aqueous NaCl solution (25 mL), dried over anhydrous MgSO4, filtered, and concentrated to give 3.80 g of the desired 2,3-dichloro-5-chloromethylpyridine as yellow oil (77.4% yield) which solidified upon standing at room temperature. GC-MS: mass calcd for C6H5Cl2NO [M]+ 178. Found 178
Reaction SMILES: [CH3:1][C:2](/[CH:4]=[N:5]/O)=O.[CH3:7][C:8]([CH2:10][C:11]([C:13]([F:16])([F:15])[F:14])=[O:12])=O.C(O)(=O)C.[OH-].[Na+]>[Zn].O>[CH3:7][C:8]1[NH:5][CH:4]=[C:2]([CH3:1])[C:10]=1[C:11](=[O:12])[C:13]([F:16])([F:15])[F:14]
Reactant: CC(=O)/C=N/O
Reactant: CC(=O)CC(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Cc1c[nH]c(C)c1C(=O)C(F)(F)F
Temperature: 25 °C
Yield: 14.6 %

Procedure:
According to the literature procedure (Chiswell, B. Inorganica Chimica Acta. 1972, 629), a mixture of anti-pyruvic aldehyde 1-oxime (1.3 g, 15 mmol), 1,1,1-trifluoro-2,4-pentadione (1.85 mL, 15 mmol), glacial acetic acid (12 mL) and H2O (3.0 mL) was stirred vigorously at room temperature. To this flask, zinc dust (3 g) was added slowly keeping the temperature below 60° C. After addition, the resulting brown solution was heated under reflux condition for 2 hours. After cooling down to room temperature, the reaction mixture was basified by an addition of 2 M aqueous NaOH, then filtered. The filtrate was extracted with CH2Cl2 (20 mL×3), the combined organic layer dried over MgSO4, and concentrated iii vacito. The residue was purified by flash chromatography (1-3:1 CH2Cl2-Hexane) to afford the subtitle compound (0.42 g, 15% yield) as an oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:15]=[CH:14][C:13]=1[OH:25].[C:26](Cl)(=[O:30])[C:27]([CH3:29])=[CH2:28]>N1C=CC=CC=1>[C:26]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:15]=[CH:14][C:13]=1[OH:25])(=[O:30])[C:27]([CH3:29])=[CH2:28]
Reactant: C=C(C)C(=O)Cl
Reactant: CCCCCCCc1ccc(O)c(CCCCCCCCCCO)c1
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCCCCCCCCCCc1cc(CCCCCCC)ccc1O

Procedure:
2-(10-Hydroxydecyl)-4-heptylphenol (0.1 mol) prepared according to Example 3a is reacted with methacryloyl chloride (0.1 mol) in 300 ml of pyridine at 5° C. to give 2-(10-methacryloyloxydecyl)-4-heptylphenol.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[CH:3]=1.C(B(CC)[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)C.CN(C=O)C>O>[I:8][C:4]1[CH:3]=[C:2]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Ic1cccc(I)c1
Reactant: CCB(CC)c1cccnc1
Solvent: O
Solvent: CN(C)C=O
Product: Ic1cccc(-c2cccnc2)c1

Procedure:
A solution of 1,3-diiodobenzene (1.10 g, 3.3 mmol), 3-(diethylboryl)pyridine (0.48 g, 3.3 mmol), tetrakis(triphenlyphosphine)palladium(0) (0.010 g, 0.0086 mmol) potassium carbonate (0.922 g, 6.64 mmol), in mixed solvent of 3 mL DMF and 1 mL water, was heated at 150° C. for 5 minutes under microwave irradiation. The reaction mixture was quenched with H2O (30 mL), then extracted with EtOAc (3×30 mL) and the combined organic extracts washed with brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude purified by liquid chromatography on silica gel using an ISCO single channel system (Hexane/EtOAc=9/1 to 1/9) to afford 3-(3-iodophenyl)pyridine as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:19](=[O:20])[N:11]3[CH2:12][CH2:13][CH2:14][CH:15]([C:16]([OH:18])=[O:17])[N:10]3[C:9]=2[C:21]2[CH:26]=[CH:25][N:24]=[C:23]([S:27][CH3:28])[N:22]=2)=[CH:4][CH:3]=1.[N+](=[CH2:31])=[N-]>C(OCC)C.C(OCC)(=O)C.C(OCC)C>[CH3:31][O:17][C:16]([C@@H:15]1[CH2:14][CH2:13][CH2:12][N:11]2[C:19](=[O:20])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[C:9]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([S:27][CH3:28])[N:22]=3)[N:10]12)=[O:18]
Reactant: C=[N+]=[N-]
Reactant: CSc1nccc(-c2c(-c3ccc(F)cc3)c(=O)n3n2C(C(=O)O)CCC3)n1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)[C@@H]1CCCn2c(=O)c(-c3ccc(F)cc3)c(-c3ccnc(SC)n3)n21
Reaction time: 0.08 h
Yield: 98 %

Procedure:
To a solution of 2-(4-fluorophenyl)-3-(2-methylsulfanylpyrimidin-4-yl)-1-oxo-5,6,7,8-tetrahydro-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid, 30, in diethyl ether/ethyl acetate (2.5:1, 7o mL) is added freshly generated diazomethane in diethyl ether (5 mL). The reaction is stirred for 5 minutes then quenched by the addition of HOAc (0.5 mL). The resulting solution is washed with NaHCO3, brine, dried, and concentrated in vacuo to afford 1 g (98% yield) of the desired product as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([CH3:23])([CH3:22])[NH:5][C:6](=[O:21])[C@H:7]([CH2:16][O:17][C:18]#[C:19][CH3:20])[NH:8]C(OC(C)(C)C)=O.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>C(Cl)Cl>[F:28][C:27]([F:30])([F:29])[C:25]([OH:31])=[O:26].[CH3:1][O:2][C:3](=[O:24])[C:4]([CH3:23])([CH3:22])[NH:5][C:6](=[O:21])[C@H:7]([CH2:16][O:17][C:18]#[C:19][CH3:20])[NH2:8]
Reactant: CC#COC[C@H](NC(=O)OC(C)(C)C)C(=O)NC(C)(C)C(=O)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC#COC[C@H](N)C(=O)NC(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
Purified N-tert-butoxycarbonyl O-propynyl-L-seryl α,α-dimethylglycine methyl ester 14 (2.27 g, 6.63 mmol) was dissolved in 50% (v/v) TFA in CH2Cl2 and the reaction mixture stirred for 1 h 10 min at room temperature. The solvent and bulk of excess TFA were evaporated and CH2Cl2 (3×20 mL) added and evaporated. Diethyl ether (25 mL) was added causing a white solid to precipitate on standing. The Et2O was decanted off and the residue washed with more Et2O (2×25 mL). After decantation of the Et2O the residue was dried under high vacuum affording the title compound as a white solid (2.10 g, 89%); 1H NMR (200 MHz, DMSO-d6) δ 8.95 (s, 1H, NH), 8.31 (br s, 3H, NH3+), 4.20 (d, J=2.4 Hz, 2H, CH2CCH), 4.02 (dd, J=5.8, 3.8 Hz, 1H, CαH or CHH), 3.88-3.67 (m, 2H, CH2 or CαH/CHH), 3.57 (s, 3H, OCH3), 3.52 (t, J=2.3 Hz, 1H, CCH), 1.39 (s, 3H, CH3), 1.36 (s, 3H, CH3); 13C NMR (75 MHz, DMSO-d6) δ 173.9, 165.7, 158.3 (q, JCF=31 Hz), 117.2 (q, JCF=298 Hz), 79.5, 78.0, 68.0, 58.1, 55.5, 52.1, 52.0, 24.7; HRMS (m/z): M+ calcd. for C11H19N2O4, 243.1344. found, 243.1335; Anal. Calcd. for C13H19F3N2O6: C, 43.82; H, 5.38; N, 7.86. Found: C, 43.8; H, 5.4; N, 7.8.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[C:4]([F:14])[C:3]=1[F:15].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C)C(=O)C>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[C:4]([F:14])[C:3]=2[F:15])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)S(=O)(=O)c1ccc(F)c(F)c1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC(=O)N(C)C
Product: CC(C)S(=O)(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1F
Temperature: 90 °C

Procedure:
To 7.6 mmol 1,2,3-trifluoro-4-(propane-2-sulfonyl)-benzene in 20 ml N,N-dimethylacetamide was added 15.9 mmol tert-butyl-1-piperazine carboxylate, and the mixture was heated at 90° C. for 1 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 1:2) to afford the title compound.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:4]([CH3:18])=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16].[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:14]([N:6]1[C:5]2=[C:4]([CH3:18])[N:3]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:2]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7]1=[O:13])[CH:15]([CH3:17])[CH3:16]
Reactant: Nc1ccccc1
Reactant: COc1ccc(Cn2c(Cl)c3c(=O)n(C)c(=O)n(CC(C)C)c3c2C)cc1
Product: COc1ccc(Cn2c(Nc3ccccc3)c3c(=O)n(C)c(=O)n(CC(C)C)c3c2C)cc1
Temperature: 150 °C

Procedure:
5-chloro-1-isobutyl-6-(4-methoxybenzyl)-3,7-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (12 mg, 0.03 mmol) is placed in a Biotage microwave tube, and then aniline (0.22 mL) is added. The mixture was heated at 150° C. for 3 h., and then purified by a semi-preparative HPLC to give 4 mg of pure product. MS (ESI) m/z 447.3 [M+H]+.