Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:17](=O)[NH:18][C:19]1[CH:20]=[C:21]2[C:37](=[O:38])[NH:36][N:35]=[CH:34][C:23]3=[C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[NH:25][C:26]([CH:27]=1)=[C:22]23)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(C)(C)C.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>C(Cl)Cl>[F:44][C:43]([F:46])([F:45])[C:41]([OH:47])=[O:42].[NH2:7][C@@H:8]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:17][N-:18][C:19]1[CH:20]=[C:21]2[C:37](=[O:38])[NH:36][N:35]=[CH:34][C:23]3=[C:24]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[NH:25][C:26]([CH:27]=1)=[C:22]23
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CCc1ccccc1)C[N-]c1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 84 %

Procedure:
Preparation of example 54 from the title compound of Example 53 (30 mg, 0.056 mmol) and 45% TFA in CH2Cl2 (1 mL) was carried out analogously to Example 20. Isolation, also in an analogous manner, afforded the title compound (26 mg, 0.047 mmol) as a yellow powder in 84% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[C:3]=1N.Cl.N([O-])=[O:19].[Na+].F[B-](F)(F)F.[H+]>C(O)(=O)C.O>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:2]([CH3:1])[C:3]=1[OH:19]
Reactant: Cc1cccc(Oc2ccccc2F)c1N
Reactant: O=N[O-]
Agent: Cl
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc(Oc2ccccc2F)c1O
Yield: 50.1 %

Procedure:
A solution of 2-methyl-6-(2-fluorophenoxy)aniline (27 g) in a mixture of conc. hydrochloric acid (26 ml) and water (85 ml), aqueous solution (15 ml) of sodium nitrite (8.6 g) and 42% fluoroboric acid (27 ml) were treated in a similar manner to that of Example 5-(1). To the resultant diazonium salt was added glacial acetic acid (500 ml), and the mixture was refluxed under heating for 6 hours. After cooling, the reaction mixture was evaporated, and water was added to the residue. The mixture was extracted with n-hexane, and the extract was washed with water and saturated aqueous sodium bicarbonate, dried and evaporated. To the oily residue were added 20% aqueous sodium hydroxide and ethanol, and the mixture was refluxed under heating for an hour, and then evaporated. Water was added to the residue, washed with n-hexane, acidified with conc. hydrochloric acid and extracted with n-hexane. The extract was washed with water, dried and evaporated. The residue was subjected to column chromatography on silica gel (220 g) and eluted with benzene to give oily 6-(2-fluorophenoxy)-o-cresol (13.6 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:11]1[C:12]([CH3:17])=[N:13][S:14][C:15]=1[NH2:16].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:17][C:12]1[C:11]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[C:15]([NH2:16])[S:14][N:13]=1
Reactant: Cc1nsc(N)c1Br
Reactant: OB(O)c1cccnc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1nsc(N)c1-c1cccnc1

Procedure:
3-pyridylboronic acid (127.3 mg, 1.036 mmol), 4-bromo-3-methyl-isothiazol-5-amine (100 mg, 0.518 mmol), Na2CO3 (777 μL of 2 M, 1.554 mmol), palladium triphenylphosphane (29.93 mg, 0.0259 mmol) in dioxane (6 mL) was heated at 110° C. in a microwave for 30 min. The mixture was concentrated in vacuo and the residue was loaded on a SCX column, washed with DCM/MeOH mixtures before the product was eluted with a 2M solution of ammonia in MeOH. The eluent was concentrated in vacuo to yield 3-methyl-4-(pyridin-3-yl)isothiazol-5-amine as a pale yellow oil that was used in next step without further purification. MS (ES+) 192.0.
Reaction SMILES: [OH-].[Li+].[CH3:3][S:4]([O:7][C:8]1[C:9]([O:20][CH3:21])=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13](C(=O)C)[N:12]=[CH:11]2)(=[O:6])=[O:5].O>O1CCCC1.CO>[CH3:3][S:4]([O:7][C:8]1[C:9]([O:20][CH3:21])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[CH:11]2)(=[O:5])=[O:6]
Reactant: COc1c(OS(C)(=O)=O)ccc2c1cnn2C(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(OS(C)(=O)=O)ccc2[nH]ncc12
Reaction time: 1 h
Yield: 93.8 %

Procedure:
A 2M-aqueous lithium hydroxide solution (0.352 ml, 0.704 mmol) was added to a solution of 1-acetyl-4-methoxy-1H-indazol-5-yl methanesulfonate (100 mg, 0.352 mmol) in a mixture of tetrahydrofuran (1.0 ml) and methanol (1.0 ml) at room temperature. After 1 hour, the resulting mixture was poured into water (10 ml) and extracted with ethyl acetate (20 ml×2), and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 4-methoxy-1H-indazol-5-yl methanesulfonate (80 mg, 94%).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[N:7][N:6]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:5]=1[C:17](OCC)=[O:18])([O-:3])=[O:2].[BH4-].[Na+].[Cl-].[NH4+].Cl>O1CCCC1.C(OCC)(=O)C.CO>[N+:1]([C:4]1[CH:8]=[N:7][N:6]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:15])[CH3:16])[C:5]=1[CH2:17][OH:18])([O-:3])=[O:2]
Reactant: CCOC(=O)c1c([N+](=O)[O-])cnn1COCC[Si](C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ncc([N+](=O)[O-])c1CO
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89.6 %

Procedure:
To a 0° C. solution of 4-nitro-2-(2-trimethylsilanyl-ethoxymethyl)-2H-pyrazole-3-carboxylic acid, ethyl ester (10 g, 31.7 mmol) in tetrahydrofuran (200 mL) was added methanol (24 mL) followed by sodium borohydride (9.59 g, 8 eq) in one portion. The resulting mixture was stirred at 0° C. for 20 minutes. The reaction mixture was then added to a mixture of saturated aqueous ammonium chloride solution (600 mL) and ethyl acetate (800 mL) in an ice-bath. A solution of 4 N HCl was added with stirring at 0° C. to adjust the pH of the aqueous layer to about 4. The organic layer was separated and washed with brine (1×500 mL), dried over magnesium sulfate, filtered and concentrated to give the title compound (7.76 g) as a reddish oil. M+=273.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:9]2[CH:10]=[N:11][C:12]([C:15]([OH:18])([CH3:17])[CH3:16])=[N:13][CH:14]=2)=[C:4]([F:19])[C:3]=1[CH:20]1[CH2:24][CH2:23][CH2:22][O:21]1.O1CCOCC1.[CH2:31]([NH:33][C:34]([NH:36][C:37](SC)=NC(=O)NCC)=[O:35])[CH3:32].C([O-])(O)=O.[Na+]>OS(O)(=O)=O>[CH2:31]([NH:33][C:34]([NH:36][C:37]1[NH:1][C:2]2[C:3]([CH:20]3[CH2:24][CH2:23][CH2:22][O:21]3)=[C:4]([F:19])[C:5]([C:9]3[CH:10]=[N:11][C:12]([C:15]([OH:18])([CH3:16])[CH3:17])=[N:13][CH:14]=3)=[CH:6][C:7]=2[N:8]=1)=[O:35])[CH3:32]
Reactant: CCNC(=O)N=C(NC(=O)NCC)SC
Reactant: CC(C)(O)c1ncc(-c2cc(N)c(N)c(C3CCCO3)c2F)cn1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)O)nc3)c(F)c(C3CCCO3)c2[nH]1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a stirring suspension of 2-[5-(4,5-diamino-2-fluoro-3-tetrahydrofuran-2-yl-phenyl)pyrimidin-2-yl]propan-2-ol (21) (111.3 g, 334.9 mmol) and 1,4-dioxane (556.5 mL, Sigma-Aldrich 360481) was added 1-ethyl-3-(N-(ethylcarbamoyl)-C-methylsulfanyl-carbonimidoyl)urea (10) (93.36 g, 401.9 mmol, CB Research and Development) followed by a pH 3.5 buffer (1.113 L), prepared by dissolving NaOAc trihydrate (158.1 g) in 1N aqueous H2SO4 (1.100 L). The reaction mixture was stirred at reflux overnight (HPLC showed complete conversion), cooled to room temperature, and poured portion-wise (frothing) into a stirring solution of aqueous saturated NaHCO3 (2.23 L) giving pH 8-9. This was stirred for 30 minutes, the solid was collected by filtration, washed copiously with water to neutral pH, and then more sparingly with EtOH. The solid was dried under reduced pressure giving 22 as an off-white yellowish solid (135.2 g, 94% yield; 99% HPLC purity). LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 429.58 (2.03 min). 1H NMR (300 MHz, MeOD) δ 8.95 (d, J=1.6 Hz, 2H), 7.45 (d, J=6.5 Hz, 1H), 5.38 (br.s, 1H), 4.27 (dd, J=14.9, 7.1 Hz, 1H), 4.01 (dd, J=15.1, 7.0 Hz, 1H), 3.37-3.29 (m, 2H), 2.55 (br.s, 1H), 2.19-2.07 (m, 2H), 2.02-1.82 (br.s, 1H), 1.63 (s, 6H), 1.21 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:20])[CH:3]=1.[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[O:28][CH:29]([CH3:31])[CH3:30].C(=O)([O-])O.[Na+]>O1CCOCC1.O.C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:25]=[CH:26][C:27]([O:28][CH:29]([CH3:30])[CH3:31])=[C:22]([F:21])[CH:23]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:20])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1/C=C/C(=O)c1ccc(=O)n(C)c1
Reactant: CC(C)Oc1ccc(B(O)O)cc1F
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: O=C([O-])O
Solvent: C1=CCCC=CCC1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(OC(C)C)c(F)c1

Procedure:
In analogy to example 203, step 1, 5-[(E)-3-(4-chloro-2-methyl-phenyl)-acryloyl]-1-methyl-1H-pyridin-2-one was reacted with 3-fluoro-4-isopropoxyphenylboronic acid in the presence of chloro(1,5-cyclooctadiene)rhodium(I) dimer and sodium hydrogencarbonate in 1,4-dioxane and water at 60° C. to give the title compound as a colourless solid, MS (ESI+): m/z=442.2 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]#[N:18])=[CH:9]2)=[CH:5][CH:4]=1)=[O:2].[OH-:19].[Na+]>CO.O1CCCC1.[Ag]=O>[C:17]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:6]2[O:7][C:3]([C:1]([OH:19])=[O:2])=[CH:4][CH:5]=2)[CH:9]=1)#[N:18]
Reactant: [OH-]
Reactant: N#Cc1cn(-c2ccc(C=O)o2)c2ccccc12
Agent: O=[Ag]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cn(-c2ccc(C(=O)O)o2)c2ccccc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a suspension of 1-(5-formylfuran-2-yl)-1H-indole-3-carbonitrile (0.085 g) in methanol (4 mL) and tetrahydrofuran (4 mL) were added silver oxide (0.1 g) and 2 mol/L aqueous sodium hydroxide solution (0.27 mL), this mixture was stirred at room temperature for 6 hours. The insoluble material of reaction mixture was removed by filtration, and the filtrate was concentrated under reduced pressure. To this residue were added water (15 mL) and 2 mol/L hydrochloric acid solution (2 mL), this mixture was extracted with ethyl acetate. This organic layer was washed with brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give the title compound (0.023 g).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][C:20]([OH:22])=[O:21])=[C:9]2[CH3:23])=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36]O)[CH:31]=1.C(N(CC)CC)C>C1C=CC=CC=1.O1CCCC1.O>[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][O:21][C:20](=[O:22])[CH2:19][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[N:8]([C:6](=[O:7])[C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:9]=2[CH3:23])[CH:31]=1
Reactant: OCc1cccnc1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(CC(=O)OCc1cccnc1)c(C)n2C(=O)c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 79.7 %

Procedure:
A mixture of 3.0 g of 1-(p-chlorobenzoyl)-2-methyl-5-methoxy-3-indolylacetic acid and 3.0 g of thionyl chloride was refluxed in 70 ml of benzene for 3 hours. After cooling, the solvent was distilled off under reduced pressure to leave a residue. The residue was dissolved in 20 ml of tetrahydrofuran. This solution was added to a solution of 1.0 g of 3-pyridylmethanol in 70 ml of tetrahydrofuran under cooling. To this mixture was carefully added 0.95 g of triethylamine and stirring was continued for 2 hours at room temperature. After the reaction was complete, the solvent was removed by distillation under reduced pressure to leave a residue. After addition of water to the residue, an oily substance was obtained and extracted with chloroform. The extract was applied on a column of silica gel and the adsorbate was eluted with ether to give crystals. Recrystallization of the crystals from a mixed solvent of ethyl acetate ester and ether yielded 3.0 g of 1-(p-chlorobenzoyl)-2-methyl-5-methoxy-3-indolylacetic acid-3 -pyridylmethyl ester, melting at 116°-118° C. Analysis--Calculated for C25H21ClN2O4 : C, 66.89; H, 4.72; N, 6.24. Found: C, 67.06; H, 4.68; N, 6.11.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Br:15])[CH:13]=2)[NH:8][N:7]=1)=[O:5])C.[H-].[Na+].[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>CN(C)C=O>[Br:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[N:7]=[C:6]2[C:4]([OH:3])=[O:5]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1n[nH]c2ccc(Br)cc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(O)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
2.19 g of 5-bromo-1H-indazole-3-carboxylic acid ethyl ester was dissolved in 40 mL of dimethylformamide, added with 391 mg of 60% sodium hydride (oil-based) and 2.38 g of trityl chloride, and stirred at room temperature for 1 hour. After adding a saturated aqueous ammonium chloride, the reaction solution was extracted with ethyl acetate, and the resultant organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated. The resultant residue was dissolved in a solution of 20 mL of ethanol, 20 mL of tetrahydrofuran and 15 mL of 5N sodium hydroxide aqueous, and stirred at 60° C. for 2 hours. After allowing to cool to room temperature, the reaction solution was neutralized by adding 1N hydrochloric acid, extracted with a mixed solvent of ethyl acetate:tetrahydrofuran=1:1, and the resultant organic layer was washed with saturated brine and dried over magnesium sulfate. After evaporated the solvent, the generated crystals were washed with diethyl ether and filtered to afford 3.3 g of the title compound as pale yellow crystals.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:18]=[CH:19][N:20]=2)[N:5]=[C:6]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:7]=1.[NH2:21][C:22]1[N:27]=[C:26]([N:28]2[CH2:32][CH2:31][CH2:30][CH:29]2[CH2:33][OH:34])[CH:25]=[CH:24][CH:23]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>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].O1CCOCC1>[OH:34][CH2:33][CH:29]1[CH2:30][CH2:31][CH2:32][N:28]1[C:26]1[N:27]=[C:22]([NH:21][C:2]2[C:3]3[N:4]([CH:18]=[CH:19][N:20]=3)[N:5]=[C:6]([C:8]3[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=3)[C:11]([O:13][CH3:14])=[O:12])[CH:7]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1cccc(-c2cc(Br)c3nccn3n2)c1
Reactant: Nc1cccc(N2CCCC2CO)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1cccc(-c2cc(Nc3cccc(N4CCCC4CO)n3)c3nccn3n2)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 69.4 %

Procedure:
A mixture of methyl 3-(8-bromoimidazo[1,2-b]pyridazin-6-yl)benzoate (200 mg, 0.6 mmol), (1-(6-aminopyridin-2-yl)pyrrolidin-2-yl)methanol (176 mg, 0.9 mmol), Pd2(dba)3 (36 mg, 0.06 mmol), BINAP (152 mg, 0.24 mmol), Cs2CO3 (592 mg, 1.8 mmol) and dioxane (10 mL) was heated to 100° C. with stirring for 16 h under N2. The solvent was removed in vacuo and the resulting mixture was purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=20:1) to give methyl 3-(8-(6-(2-(hydroxymethyl)pyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (185 mg, 69%) as a yellow solid. LC-MS: [M+H]+, 223.2, [2M+H]+, 445.2, tR=1.737 min.
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([OH:18])[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])[CH3:6].Cl[C:21]1[N:22]=[CH:23][C:24]([C:27]([N:29]([CH3:31])[CH3:30])=[O:28])=[N:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[F:1][CH:2]([F:19])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18][C:21]2[CH:26]=[N:25][C:24]([C:27](=[O:28])[N:29]([CH3:30])[CH3:31])=[CH:23][N:22]=2)[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])[CH3:6]
Reactant: COC(=O)c1cc(O)cc(O[C@@H](C)COC(F)F)c1
Reactant: CN(C)C(=O)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(O[C@@H](C)COC(F)F)c1
Temperature: 140 °C
Reaction time: 5 h
Yield: 77.5 %

Procedure:
A mixture of methyl 3-[(2S)-1-(difluoromethoxy)propan-2-yl]oxy-5-hydroxy-benzoate (0.25 g, 0.91 mmol), 5-chloro-N,N-dimethyl-pyrazine-2-carboxamide (168 mg, 0.91 mmol) and potassium carbonate (250 mg, 1.81 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 140° C. for 5 hours. The mixture was reduced in vacuo and ethyl acetate (50 mL) added. The mixture was washed with water (50 mL), brine (50 mL), dried (MgSO4) and reduced in vacuo. The residue was chromatographed on silica, eluting with 20 to 70% ethyl acetate in isohexane, to give the desired compound (0.3 g).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:13]([OH:15])=O)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:3])[CH3:2].Cl.Cl.[CH2:18]([O:20][C:21](=[O:31])[C@H:22]([CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:30])[NH2:29])[NH2:23])[CH3:19].C(N(CC)CC)C.ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH3:19][CH2:18][O:20][C:21]([C@@H:22]([NH:23][C:13]([C@@H:5]([NH:4][C:1]([CH3:2])=[O:3])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:15])[CH2:24][CH2:25][CH2:26][N:27]=[C:28]([NH2:30])[NH2:29])=[O:31]
Reactant: CCOC(=O)[C@@H](N)CCCNC(=N)N
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](Cc1ccccc1)NC(C)=O
Temperature: -15 °C
Reaction time: 5 h

Procedure:
0.829 g (4 mmols) of N-acetyl-L-phenylalanine are dissolved in 40 ml of dimethylformamide. 1.10 g (4 mmols) of finely powdered L-arginine ethyl ester dihydrochloride, 0.56 ml (4 mmols) of triethylamine and 0.69 g (6 mmols) of N-hydroxysuccinimide are added and the mixture is cooled to -15° C. After adding 0.91 g (4.4 mmols) of dicyclohexylcarbodiimide, the mixture is stirred at -5° C. for 7 hours, at 5° C. overnight and at room temperature for 5 hours. The precipitate is filtered off and the solution is concentrated almost to dryness in vacuo on a rotary evaporator. After taking up the residue in 80 ml of water, the pH of the solution is adjusted to 6.0 with triethylamine and the solution is discharged onto a column (1.5×40 cm) of Cm- "Sephadex" (Trade Mark) C-25, equilibrated with 0.05 M triethylammonium acetate of pH 6.0. Elution is carried out with a linear gradient increasing to 0.2 M triethylammonium acetate of pH 6.0 (720 ml; 50 ml/hour; size of fraction: 8 ml). Fractions 75-110, which, according to spotting on filter paper and spraying with Sakaguchi reagent, contains most of the eluted material, is lyophilised. 0.5 ml of ethanol is added to the combined residues and the product is precipitated with 60 ml of ethyl acetate. The precipitate is dried over phosphorus pentoxide in a desiccator.
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH2:14][OH:15])[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.CS(C)=O.C(OC(=O)C)C>ClCCl>[C:4]([O:3][C:1]([NH:8][C@H:9]([CH:14]=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13])=[O:2])([CH3:6])([CH3:7])[CH3:5]
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of the commercially available (Advanced Chem Tech) Boc-L-leucinol (0.78 g, 3.6 mmol) in anhydrous dichloromethane (17.5 ml) was added triethyl amine (2 ml, 14.36 mmol) and the mixture was cooled to 0° C. Dimethyl sulfoxide (17.5 ml) was added followed by sulfur trioxide pyridine complex (2.3 g, 14.36 mmol) and the reaction was stirred for two hours. TLC in 1:1 ethylacetate:hexanes confirmed the completion of the reaction. The reaction mixture was concentrated and the remaining residue diluted with ethylacetate. The ethylacetate layer was washed with 1M hydrochloric acid (2×75 ml) followed by saturated sodium bicarbonate solution (2×75 ml) and brine (75 ml). The organic layer was dried (sodium sulfate), filtered and concentrated to yield 775 mg of product.
Reaction SMILES: [O:1]([C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]2[C@@H:24]([CH2:25][CH2:26][C@@H:27]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[OH:28])[C:23](=[O:36])[N:22]2[C:37]2[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][CH2:45][NH:46][S:47]([CH3:50])(=[O:49])=[O:48])=[CH:39][CH:38]=2)=[CH:17][CH:16]=1)[C@@H:2]1[O:10][C@H:9]([C:11]([O:13]C)=[O:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]>CO.O.C(N(CC)CC)C>[O:1]([C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]2[C@@H:24]([CH2:25][CH2:26][C@@H:27]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[OH:28])[C:23](=[O:36])[N:22]2[C:37]2[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][CH2:45][NH:46][S:47]([CH3:50])(=[O:49])=[O:48])=[CH:39][CH:38]=2)=[CH:17][CH:16]=1)[C@@H:2]1[O:10][C@H:9]([C:11]([OH:13])=[O:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: COC(=O)[C@H]1O[C@@H](Oc2ccc([C@@H]3[C@@H](CC[C@H](O)c4ccc(F)cc4)C(=O)N3c3ccc(CCCNS(C)(=O)=O)cc3)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCCc1ccc(N2C(=O)[C@H](CC[C@H](O)c3ccc(F)cc3)[C@H]2c2ccc(O[C@@H]3O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]3O)cc2)cc1

Procedure:
A solution of 9a in methanol/water/triethylamine (1:7:2, 1 mL) was stirred at room temperature for approximately 1 h. The volatiles were evaporated in vacuo and the crude residue purified by preparative reversed phase high performance liquid chromatography on YMC Pack Pro C18 phase (gradient elution; 10-65% acetonitrile/water as eluent, 0.1% TFA modifier) to give the title compound (2b; m/z (ES) 735 (M+Na)+, 685 (M−OH)+, 509 (M-sugar-OH)+; HRMS (ES) m/z calc'd for C34H39FN2O11S (MH+) 703.2337, found 703.2337.
Reaction SMILES: C=CCCCCCC.CC(C1C=CC=CC=1)=C.C1=CCCCCCC1.C12CC(CC1)C=C2.CC1CC[C@@H](C(C)=C)CC=1.[CH3:43][C@H:44]1[C:49](=[O:50])[CH2:48][C@H:47]([C:51]([CH3:53])=[CH2:52])[CH2:46][CH2:45]1>>[CH:51]([CH:47]1[CH2:48][C:49](=[O:50])[CH:44]([CH3:43])[CH2:45][CH2:46]1)([CH3:53])[CH3:52]
Reactant: C=C(C)[C@@H]1CC[C@@H](C)C(=O)C1
Agent: C1=CC2CCC1C2
Agent: C1=CCCCCCC1
Agent: C1=C\CCCCCC/1
Solvent: C=CCCCCCC
Product: CC1CCC(C(C)C)CC1=O
Yield: 99 %

Procedure:
The yields of the hydrogenated products were determined by gas chromatography (GC). Hydrogenation of terminal alkenes such as 1-octene and α-methylstyrene proceeded readily within 24 hours at room temperature with excellent yields (see Table 1, entries 5-7). Internal alkenes trans-2-octene, cis-cyclooctene, and norbornylene were also hydrogenated at room temperature (see Table 1, entries 8-10). Hydrogenation of (R)-(+)-limonene occurred selectively at the terminal position; the internal tri-substituted C═C bond was not hydrogenated (see Table 1, entry 11). At room temperature, hydrogenation of (+)-dihydrocarvone occurred only at the C═C bond, affording 5-isopropyl-2-methylcyclohexanone in 99% yield (see Table 1, entry 12).