Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([C:19]#[N:20])[N:4]=1.Cl.[NH2:24][OH:25].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[OH:25][NH:24][C:19]([C:5]1[N:4]=[C:3]([C:2]([F:21])([F:22])[F:1])[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][CH:10]=2)[N:6]=1)=[NH:20]
Reactant: NO
Reactant: N#Cc1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(NO)c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
A stirred mixture of 4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile (example B.2) (1.0 g, 3.15 mmol), hydroxylamine hydrochloride (0.81 g, 11.7 mol) and sodium carbonate (0.67 g, 6.32 mol) in water (15 mL) and ethanol (15 mL) was heated under reflux conditions for 2 h. The ethanol was removed partly and the mixture stirred at room temperature for 0.5 h. The precipitate was collected by filtration, washed with water and dried to yield the title compound (1.08 g, 98%) as a light brown solid. MS (ISP) 351.1 [(M+H)+]; mp 224° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:15])[C:10]([N:12]([CH3:14])[CH3:13])=[O:11])[C:5](F)=[N:6][CH:7]=1.[NH3:16]>C(O)C>[NH2:16][C:5]1[C:4]([C:9](=[O:15])[C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: CN(C)C(=O)C(=O)c1cc(Br)cnc1F
Reactant: N
Solvent: CCO
Product: CN(C)C(=O)C(=O)c1cc(Br)cnc1N

Procedure:
2-(5-Bromo-2-fluoro-pyridin-3-yl)-N,N-dimethyl-2-oxo-acetamide (948 mg, 3.45 mmol) was treated with saturated ammonia solution in ethyl alcohol (10 mL) in a sealed vial at 50° C. for 1 h. The reaction was complete and the mixture was dried in vacuo and used crude in the next step. MS: m/z 272 (M+H+).
Reaction SMILES: [CH3:1]I.[OH:3][C:4]1[C:11]([I:12])=[CH:10][C:7]([C:8]#[N:9])=[C:6]([S:13][CH3:14])[N:5]=1>O1CCOCC1.C(=O)([O-])[O-].[Ag+2]>[I:12][C:11]1[C:4]([O:3][CH3:1])=[N:5][C:6]([S:13][CH3:14])=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: CSc1nc(O)c(I)cc1C#N
Reactant: CI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1nc(SC)c(C#N)cc1I
Temperature: 60 °C
Reaction time: 5 h
Yield: 68 %

Procedure:
905 μl (2 eq) of methyl iodide and 2.1 g (1.05 eq) of silver carbonate are added successively to a solution of 2.12 g (7.26 mmol) of 6-hydroxy-5-iodo-2-(methylthio)nicotinonitrile in 20 ml of 1,4-dioxane. The reaction medium is stirred at 60° C. for 5 hours. The solid is filtered and the residue rinsed thoroughly with methanol. The filtrate is evaporated and the residue purified by silica column chromatography (4:6 dichloromethane/cyclohexane as eluent) to yield 1.52 g (68%) of 5-iodo-6-methoxy-2-(methylthio)nicotinonitrile in the form of a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[CH3:10][O:11][C:12](=[O:24])/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.CN(C=O)C.Cl>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:10][O:11][C:12](=[O:24])[CH:13]=[CH:14][C:15]1[CH:16]=[CH:17][C:18]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=2[CH3:9])=[CH:19][CH:20]=1
Reactant: Cc1cc(O)ccc1Br
Reactant: COC(=O)/C=C/c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc(-c2ccc(O)cc2C)cc1
Temperature: 80 °C
Yield: 20 %

Procedure:
A mixture of 4-bromo-3-methyl-phenol (460 mg, 2.01 mmol), [4-(E-3-methoxy-3-oxo-1-propen-1-yl)phenyl]boronic acid (486 mg, 2.21 mmol), tetrakis(triphenylphosphine)palladium(0) (232 mg, 0.201 mmol) cesium carbonate (1.31 g, 4.02 mmol) and DMF (4.8 mL) is heated to 80° C. for 4.5 hours. The reaction is cooled to room temperature and diluted with water and acidified with 1 N HCl. The resulting solution is extracted with ether. The combined organic layers are dried over anhydrous magnesium sulfate and are purified via flash chromatography eluting with 15% ethyl acetate/heptane to give the title compound (108 mg, 20%). ES/MS m/e 267.3 (M−1).
Reaction SMILES: [C:1]1(=[O:15])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](O)=[O:12])[C:4](=[O:14])[CH:3]=[CH:2]1.S(Cl)([Cl:18])=O>>[C:1]1(=[O:15])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([Cl:18])=[O:12])[C:4](=[O:14])[CH:3]=[CH:2]1
Reactant: O=C(O)CCCCCN1C(=O)C=CC1=O
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CCCCCN1C(=O)C=CC1=O

Procedure:
The 6-maleimidocaproic acid is reacted with excess thionyl chloride at 50° C. for three hours, and then the excess thionyl chloride is distilled off to leave 6-maleimidocaproic chloride.
Reaction SMILES: C(OCC)(=O)C.[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[O:19][C:18]([CH3:21])([CH3:20])[N:17]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@@H:16]2[CH2:29][F:30])=[CH:11][CH:10]=1)#[CH:8].Cl/[C:32](=[N:38]/[OH:39])/[C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])O.[Na+]>CN(C)C=O>[C:25]([O:24][C:22]([N:17]1[C@H:16]([CH2:29][F:30])[C@@H:15]([C:12]2[CH:11]=[CH:10][C:9]([C:7]3[O:39][N:38]=[C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:8]=3)=[CH:14][CH:13]=2)[O:19][C:18]1([CH3:21])[CH3:20])=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: C#Cc1ccc([C@H]2OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]2CF)cc1
Reactant: CCOC(=O)/C(Cl)=N\O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ccc([C@H]3OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]3CF)cc2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
To an ethyl acetate (20 ml) solution of (4S,5R)-tert-butyl 5-(4-ethynylphenyl)-4-(fluoromethyl)-2,2-dimethyloxazolidine-3-carboxylate (1.35 g, 4.0 mmol) is added a dimethylformamide solution of (E)-ethyl 2-chloro-2-(hydroxyimino)-acetate (12.5 ml, 1.5 g, 2.5 equiv). Sodium hydrogen carbonate (3.5 g) is added to the solution and it is allowed to stir overnight at room temperature. The mixture is filtered and diluted with ethyl acetate (100 ml). After washing with water (4×25 ml) the organic phase is concentrated to give the crude product, which is purified on silica gel using a gradient of ethyl acetate in hexanes (0% to 20% ethyl acetate) to give the title compound (567 mg): 1H NMR (400 MHz, CDCl3) 1.43-1.56 (m, 14 H) 1.62 (s, 3 H) 1.74 (br. s., 3 H) 4.50 (q, J=7.24 Hz, 3 H) 5.20 (d, J=7.33 Hz, 1 H) 6.96 (s, 1 H) 7.60 (d, J=8.34 Hz, 2 H) 7.86 (d, J=8.59 Hz, 2 H), m/z (Cl) 449 ([M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([F:16])[CH:11]=[C:12]([F:15])[CH:13]=2)[C:8]([S:17]([CH2:20][C:21]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[O:22])(=[O:19])=[O:18])=[CH:7]1.C([N:40]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[N:41]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C.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>[NH:40]1[CH:44]=[C:43]([C:2]2[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=2)[CH2:5][N:6]2[C:14]3[C:9](=[C:10]([F:16])[CH:11]=[C:12]([F:15])[CH:13]=3)[C:8]([S:17]([CH2:20][C:21]([NH:23][C:24]3[CH:28]=[C:27]([CH3:29])[O:26][N:25]=3)=[O:22])(=[O:18])=[O:19])=[CH:7]2)[CH:42]=[N:41]1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc(NC(=O)CS(=O)(=O)c2cn(Cc3cccc(Br)c3)c3cc(F)cc(F)c23)no1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(NC(=O)CS(=O)(=O)c2cn(Cc3cccc(-c4cn[nH]c4)c3)c3cc(F)cc(F)c23)no1
Temperature: 80 °C
Reaction time: 8 h
Yield: 2.1 %

Procedure:
In a 5 mL microwave vial, 2-((1-(3-bromobenzyl)-4,6-difluoro-1H-indol-3-yl)sulfonyl)-N-(5-methyl-isoxazol-3-yl)acetamide (20 mg, 0.38 mmol), prepared in Example 1, was dissolved in DMF (2 mL). PdCl2(PPh3)2 (1.0 mg, 0.001 mmol), 1-Boc-pyrazole-4-boronic acid pinacol ester (20 mg, 0.68 mmol), and 2 N aqueous sodium carbonate (1 mL) were added and stirred at 80° C. overnight. The reaction was cooled to ambient temperature. Water (2 mL) was added and the mixture was extracted with ethyl acetate (2×3 mL). The organics were combined, dried over magnesium sulfate and concentrated in vacuo to give an oily residue which was purified on a Gilson Prep HPLC system (5-95% acetonitrile:water (0.1% TFA) over 6 min) to afford the title compound (4.0 mg, 0.008 mmol, 21% yield) as a white solid. LCMS>98% 220 nm, RT=0.79 min, m/z=512 (m+1). 1H NMR (400 MHz, DMSOD6) 12.97 (s, 1H), 11.33 (s, 1H), 8.38 (s, 1H), 8.16, (s, 1H), 7.91 (s, 1H), 7.61 (s, 1H), 7.49-7.55 (m, 2H), 7.28 (t, J=8.0 Hz, 1H), 7.18 (d, J=10.8 Hz, 1H), 7.00 (d, J=7.6 Hz, 1H), 6.48 (s, 1H), 5.52 (s, 2H), 4.48 (s, 2H), 2.35 (s, 3H).
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1[CH:7]=[C:8]([OH:20])[C:9]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=2)=[N:10][C:11]=1[CH3:12].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:33][O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:34][CH3:35])[N:25]=[CH:24][CH:23]=[C:22]2[O:20][C:8]1[C:9]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=2)=[N:10][C:11]([CH3:12])=[C:6]([CH3:5])[CH:7]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1ccnc(-c2nc(C)c(C)cc2O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3cc(C)c(C)nc3-c3cc(C)ccn3)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
Dimethyl sulfoxide (2 ml) was added to 5,6,4′-trimethyl-[2,2′]bipyridin-3-ol (50 mg), 4-chloro-6,7-dimethoxyquinoline (157 mg), and cesium carbonate (229 mg), and the mixture was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (42 mg, yield 45%).
Reaction SMILES: [CH3:1][C:2]([CH3:15])=[C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH3:4].[H][H]>CO.[Pd]>[CH3:1][CH:2]([CH3:15])[CH:3]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][CH:14]=1)[CH3:4]
Reactant: [H][H]
Reactant: COC(=O)c1ccc(C(C)=C(C)C)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(C(C)C(C)C)cc1
Yield: 97 %

Procedure:
To a solution methyl 4-(3-methylbut-2-en-2-yl)benzoate (0.2 g, 1.0 mmol) in methanol (30 mL) was added Pd/C (0.50 g). The reaction mixture was stirred at room temperature for 3 hour at 4 atm of hydrogen, after the reaction, it was filtered, and the filtrate was removed in vacuo to give pure product methyl 4-(3-methylbutan-2-yl)benzoate (0.20 g, 100%) as the colorless oil.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:46])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:34](=[O:45])[NH:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[C:39]([CH3:44])[CH:38]=3)[C:32]=2[Cl:33])[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C(O)C.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:46])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:34](=[O:45])[NH:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[C:39]([CH3:44])[CH:38]=3)[C:32]=2[Cl:33])[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2c(Cl)c(C(=O)NCc3ccc(F)c(C)c3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(CNC(=O)c2nn3c(-c4cc(F)c5c(c4C)CCCO5)c([C@H](OC(C)(C)C)C(=O)O)c(C)nc3c2Cl)ccc1F
Temperature: 60 °C

Procedure:
To a solution of (2S)-ethyl 2-(tert-butoxy)-2-(3-chloro-2-((4-fluoro-3-methylbenzyl)carbamoyl)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (22 mg, 0.034 mol, 1 equiv) in ethanol (0.45 mL) and water (0.22 mL) was added lithium hydroxide monohydrate (7 mg, 0.168 mmol, 5 equiv). The reaction was heated in an oil bath at 60° C. for 16 h. After cooling to ambient temperature, the reaction was filtered and loaded directly onto reverse phase HPLC (acetonitrile/TFA eluent). The desired compound was isolated as an off white solid (2.4 mg, 11% yield). 1H NMR (500 MHz, CDCl3) δ 7.19-7.15 (m, 2H), 7.14-7.10 (m, 1H), 7.00-6.94 (m, 1H), 6.86 (d, J=10.6 Hz, 1H), 5.08 (s, 1H), 4.57 (d, J=6.3 Hz, 2H), 4.36-4.32 (m, 2H), 2.81 (s, 3H), 2.77-2.72 (m, 2H), 2.27 (d, J=1.7 Hz, 3H), 2.20-2.14 (m, 2H), 1.88 (s, 3H), 1.22 (s, 9H); 19F NMR (471 MHz, CDCl3) δ 119.29 (s, 1F), −139.22 (s, 1F); LCMS (ESI, M+1): 627.5.
Reaction SMILES: B(F)(F)F.CCOCC.[Li+].[C-:11]#[C:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O:19]1[C:21]2([CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[CH2:20]1>C1COCC1>[OH:19][C:21]1([CH2:20][C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]1
Reactant: [C-]#Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Agent: FB(F)F
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(CC#Cc2ccccc2)CC1
Temperature: -75 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
Boron trifluoride diethyl etherate (0.131 mL, 1.03 mmol) followed by lithium phenylacetylide (1M in THF, 1.03 mL, 1.03 mmol) was dropped into a solution of Compound 256a (200 mg, 0.938 mmol) in THF (5 mL) stirred at −75° C. under nitrogen atmosphere. Stirring and cooling were kept on for 2 h and after overnight stirring at r.t., the reaction mixture was quenched with water and EtOAc. The combined extracts were washed, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (EtOAc—Petroleum Ether 85:15) affording the title product (272 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][C:3]=1[Cl:9].[CH2:10]([SH:12])[CH3:11].[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:12][CH2:10][CH3:11])=[CH:4][C:3]=1[Cl:9]
Reactant: Fc1ccc(Br)c(Cl)c1
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCSc1ccc(Br)c(Cl)c1
Reaction time: 4 h
Yield: 64.8 %

Procedure:
To a solution of 1-bromo-2-chloro-4-fluorobenzene (24.8 g, 119 mmol) and ethanethiol (10.6 mL, 143 mmol) in N,N-dimethylformamide (150 mL) was added sodium hydride (60% in oil, 6.00 g, 150 mmol) at room temperature by small portions, and the resulting mixture was stirred for 4 hr. The reaction mixture was diluted with ethyl acetate, washed twice with water and once with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane) to give the title compound (19.4 g, yield 65%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17](=O)[C:16]3[C:15]([C:19](OCC)=[O:20])=[CH:14][CH:13]=[CH:12][C:11]=3[NH:10][CH:9]2[C:24]2N(C)C=CN=2)=[CH:4][CH:3]=1.O.[NH2:31][NH2:32]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3=[N:31][NH:32][C:19](=[O:20])[C:15]4[CH:14]=[CH:13][CH:12]=[C:11]([C:16]=43)[NH:10][CH:9]2[C:24]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]=[CH:9][CH:8]=[CH:17]3)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(F)cc1)C(c1nccn1C)N2
Reactant: NN
Solvent: CO
Solvent: O
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccc3ncccc3c1)C2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 25 %

Procedure:
A mixture of ethyl 3-(4-fluorophenyl)-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (260 mg, 0.59 mmol) in 85% hydrazine monohydrate (1 mL) and methanol (5 mL) was stirred at room temperature for 4 h. The resulting mixture was filtered and washed by water (20 mL) and methanol (5 mL) to obtain the title compound as a white solid (61 mg, yield 25%). LC-MS (ESI) m/z: 409(M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 4.52-4.55 (d, J=9.6 Hz, 1H), 4.98-5.01 (d, J=9.6 Hz, 1H), 6.97-7.01 (m, 2H), 7.19-7.22 (m, 3H), 7.41-7.43 (d, J=7.6 Hz, 1H), 7.46-7.50 (m, 1H), 7.54 (s, 1H), 7.59-7.63 (t, J=7.6 Hz, 1H), 7.77-7.79 (m, 1H), 7.84 (s, 1H), 7.91-7.93 (m, 1H), 8.24-8.26 (d, J=7.6 Hz, 1H), 8.85-8.86 (m, 1H), 12.20 (s, 1H).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([OH:18])(=[O:17])[C:14]([CH3:16])=[O:15].[OH-].[K+:20]>CO>[O:15]=[C:14]([CH:16]=[CH:11][CH:10]=[CH:9][CH:8]=[CH:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:13]([O-:18])=[O:17].[K+:20]
Reactant: CC(=O)C(=O)O
Reactant: O=CC=CC=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])C(=O)C=CC=CC=Cc1ccccc1
Temperature: 2.5 °C

Procedure:
A solution of 5-phenyl-2,4-pentadienal (6.70 g) and pyruvic acid (3.0 mL) in 5 mL of methanol was stirred and chilled to 0-5° C. in an ice bath. To the chilled solution was added a solution of 35 mL of potassium hydroxide (3.5 g) in 10 mL of methanol dropwise over a period of 30 minutes. The remaining methanolic potassium hydroxide was added rapidly and the ice bath was removed. The reaction was allowed to warm to room temperature and stirred for another hour. The flask was then refrigerated overnight. The solid was collected by filtration, washed with 15 mL of methanol three times, 15 mL of ether and then air dried to afford 6.69 g of potassium 2-oxo-8-phenyl-3,5,7-octatrienoate as a yellow solid. 1H NMR (DMSO-d6, 300 MHz), δ(ppm) 7.52 (d, 2H), 7.32 (m, 3H), 7.10 (m, 2H), 6.83 (dd, 2H), 6.57 (dd, 1H), 6.13 (d, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:40]=[CH:39][C:12]([CH2:13][N:14]([CH2:35][CH2:36][CH2:37][CH3:38])[C:15](=[O:34])[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([O:31][CH2:32][CH3:33])[C:26]([O:28]CC)=[O:27])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C(#N)C.O.[OH-].[K+]>[CH2:1]([O:8][C:9]1[CH:40]=[CH:39][C:12]([CH2:13][N:14]([CH2:35][CH2:36][CH2:37][CH3:38])[C:15](=[O:34])[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([O:31][CH2:32][CH3:33])[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCN(Cc1ccc(OCc2ccccc2)cc1)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Agent: [K+]
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CCCCN(Cc1ccc(OCc2ccccc2)cc1)C(=O)COc1ccc(C[C@H](OCC)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
To a solution of ethyl(2S)-3-(4-{2-[[4-(benzyloxy)benzyl](butyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate (0.116 g, 0.21 mmol) in acetonitrile (10 mL) was added aqueous 0.10 M LiOH (5 mL) and the reaction mixture was stirred at room temperature overnight. The solvent volume was reduced in vacuo and the remaining aqueous phase was diluted with water and aqueous 1 M KOH and washed with diethyl ether (2×50 mL). The aqueous phase was acidified with 5% HCl and extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo to afford 0.070 g (63%) of a colourless oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:11](=[O:22])[NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[CH:8][C:9]=1[CH3:10])=[O:4].O[Li].O>C1COCC1.O>[OH:21][C:17]1[CH:16]=[C:15]([CH2:14][CH2:13][NH:12][C:11]([C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([CH3:10])[CH:8]=2)=[O:22])[CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1sc(C(=O)NCCc2cccc(O)c2)cc1C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NCCc2cccc(O)c2)sc1C(=O)O
Yield: 69.5 %

Procedure:
A solution of 5-[2-(3-hydroxy-phenyl)-ethyl-carbamoyl]-3-methyl-thiophene-2-carboxylic acid methyl ester (260 mg, 0.81 mmol) in THF/water (8 ml/4 ml) was treated with LiOH.H2O (171 mg, 4.1 mmol) at 40° C. for 1.5 h. The reaction mixture was quenched with 1N HCl and extracted with EtOAc. The layers were separated. The organic layer was washed with brine, then dried over Na2SO4 and concentrated under reduced pressure to afford the desired product (172 mg, 70% yield).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(OC(C)(C)C)=O.C(N(C(C)C)CC)(C)C.[CH3:23][CH:24]([S:26](Cl)(=[O:28])=[O:27])[CH3:25]>C(Cl)Cl>[CH3:23][CH:24]([S:26]([N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)(=[O:28])=[O:27])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-BOC-piperazine (0.617 mmol) and diisopropylethylamine (0.679 mmol) in 0.5 mL of methylene chloride was added to a 4 mL vial. Propane-2-sulfonyl chloride (0.679 mmol) was added to the vial, and the reaction mixture was shaken overnight at room temperature. When the reaction was complete, it was diluted with 1.5 mL of methylene chloride and extracted with 1 mL of 1N solution of hydrogen chloride followed by 1 mL of 10% potassium carbonate solution. The organic layer was concentrated in vacuo. The residue was dissolved in 0.5 mL of tetrahydrofuran and 4M solution of hydrogen chloride in dioxane (0.5 mL). The solution was shaken overnight at room temperature then concentrated in vacuo to give 1-(propane-2-sulfonyl)-piperazine.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.CN(C=O)C.[CH2:16]1COC[CH2:17]1>>[CH2:16]([N:5]1[CH:6]=[N:7][C:8]2[C:4]1=[N:3][CH:2]=[N:1][C:9]=2[NH2:10])[CH3:17]
Reactant: C1CCOC1
Reactant: Nc1ncnc2nc[nH]c12
Solvent: CN(C)C=O
Product: CCn1cnc2c(N)ncnc21
Yield: 43 %

Procedure:
Coupling of 2b with adenine in THF in the presence of Ph3P and DEAD formed the desired N9 -substituted derivative 1a in only 5% yield. The low yield may be due to the insolubility of adenine in THF. After replacement of THF with DMF, compound 1a was produced in 43% yield without any detection of the N7 - derivative or the N9 -ethyladenine.
Reaction SMILES: [I:1][C:2]1[N:3]=[N:4][C:5](I)=[CH:6][CH:7]=1.[CH3:9][O-:10].[Na+].O>CO>[CH3:9][O:10][C:5]1[N:4]=[N:3][C:2]([I:1])=[CH:7][CH:6]=1
Reactant: C[O-]
Reactant: Ic1ccc(I)nn1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(I)nn1
Temperature: 25 °C
Reaction time: 13 h
Yield: 86 %

Procedure:
To 2.73 g (8.23 mmol) of 3,6-diiodopyridazine were added 80 ml of methanol and 3.17 g (16.46 mmol) of 28 wt % of sodium methylate in methanol, and the mixture was stirred at room temperature for 13 hours. Water was added to the reaction mixture, and the solution was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica-gel column chromatography (200 ml of silica gel, hexane:ethyl acetate=8:1) to give 1.661 g (7.04 mmol) of 3-methoxy-6-iodopyridazine (yield: 86%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:8][N:7]([C:9]([O:11]C(C)(C)C)=O)[C@H:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:5]1.[N:20]1[CH:25]=[C:24]([C:26]2[CH:34]=[CH:33][C:29](C(O)=O)=[CH:28][CH:27]=2)[CH:23]=[N:22][CH:21]=1>>[CH3:1][O:2][N:3]=[C:4]1[CH2:8][N:7]([C:9](=[O:11])[C:29]2[CH:28]=[CH:27][C:26]([C:24]3[CH:25]=[N:20][CH:21]=[N:22][CH:23]=3)=[CH:34][CH:33]=2)[C@H:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:5]1
Reactant: O=C(O)c1ccc(-c2cncnc2)cc1
Reactant: CON=C1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)OC)N(C(=O)c2ccc(-c3cncnc3)cc2)C1
Yield: 68 %

Procedure:
Following the general methods as outlined in Example 4, starting from 1-tert-butyl 2-methyl (2S,4EZ)-4-(methoxyimino)-1,2-pyrrolidinedicarboxylate and 4-(5-pyrimidinyl)benzoic acid, the title compound was obtained, after flash-chromatography, as a mixture of two isomers as an oil in 68% yield (93.0% purity by HPLC).