Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCC[O-])C.[Na+].[Na].[NH2:9][C:10]1[N:15]=[C:14]([NH2:16])[C:13]([CH:17]=O)=[CH:12][N:11]=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[CH2:27][C:28]#[N:29]>C(OCCO)C>[NH2:9][C:10]1[N:11]=[CH:12][C:13]2[CH:17]=[C:27]([C:21]3[C:20]([Cl:19])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:26])[C:28]([NH2:29])=[N:16][C:14]=2[N:15]=1
Reactant: N#CCc1c(Cl)cccc1Cl
Reactant: Nc1ncc(C=O)c(N)n1
Agent: CCOCC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOCCO
Product: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1

Procedure:
(Prepared by the method of U.S. Pat. No. 3,534,039). To a solution of sodium 2-ethoxyethoxide prepared from 0.14 g of sodium and 60 mL of 2-ethoxyethanol was added 2.07 g of 2,4-diamino-5-pyrimidinecarboxaldehyde and 2.79 g of 2,6-dichlorophenylacetonitrile. The mixture is heated at reflux for 4 hours, cooled, and the insoluble product washed with diethylether to give 2,7-diamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidine, mp 325-332° C. (MS).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Br)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.[CH2:25]([NH2:28])[C:26]#[CH:27].[I-].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:28][CH2:25][C:26]#[CH:27])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1
Reactant: C#CCN
Reactant: Fc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CBr)n1-2
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCNCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Preparation 19, 8-fluoro-1-(bromomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine in dimethylformamide is reacted at room temperature with propargylamine in the presence of potassium iodide to give 8-fluoro-1-[[(2-propynyl)amino]methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 22 8-(Trifluoromethyl)-1-[[(2-propynyl)amino]methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+]>ClCCl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Cl-].[Ru+2]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(C)c1
Agent: [Ru+2]
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Product: Cc1cccc(C(C)O)c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
Tris(triphenylphosphine)ruthenium(II) chloride (3.8 mg, 4 μmol, 1 mol %) and a chiral ligand (M=Ru, R=i-Pr, Ar=C6H5—, 2.6 μmol, 0.65 mol %) were dissolved in dichloromethane (3 mL) under nitrogen atmosphere, and then heated and stirred for 0.5 h at 40° C. After the mixture was cooled to room temperature, m-methylacetophenone (0.4 mmol), dichloromethane (2 mL) and an aqueous solution of lithium hydroxide (0.4 mL, 0.2 M) were added thereto. Thereafter, the reaction system was placed in an autoclave, and stirred for 24 h under H2 (20 atm) at 0° C. The solvent was removed under reduced pressure, and the resultants were separated by column chromatography (silica gel column; eluent: ethyl acetate/petroleum ether=1/5). Accordingly, pure 1-(m-methylphenyl)ethanol was obtained and the ee value (ee=99.0%) was measured by GC analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:20][CH2:21][C:22]([N:24]3[CH2:29][CH2:28][CH:27]([C:30](=[O:32])[CH3:31])[CH2:26][CH2:25]3)=[O:23])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3=[N:17][CH:18]=[CH:19][N:9]23)=[CH:4][CH:3]=1.[CH3:33][Mg+].[Br-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:20][CH2:21][C:22]([N:24]3[CH2:25][CH2:26][CH:27]([C:30]([OH:32])([CH3:33])[CH3:31])[CH2:28][CH2:29]3)=[O:23])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3=[N:17][CH:18]=[CH:19][N:9]23)=[CH:4][CH:3]=1
Reactant: CC(=O)C1CCN(C(=O)CCC2(c3ccc(Cl)cc3)c3ccccc3-c3nccn32)CC1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(O)C1CCN(C(=O)CCC2(c3ccc(Cl)cc3)c3ccccc3-c3nccn32)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(1-{3-[5-(4-chlorophenyl)-5H-imidazo[2,1-a]isoindol-5-yl]propanoyl}piperidin-4-yl)ethanone (25 mg) in THF (0.8 mL) at −78° C. was added a solution of MeMgBr (0.028 mL, 3 M in ether). The cooling bath was then removed and the reaction mixture was stirred at room temperature for 30 minutes. It was then cooled back to −78° C., 0.15 mL more Grignard solution added, cooling bath removed and was stirred at room temperature for 20 minutes. Reaction was quenched with saturated aqueous NH4Cl, partitioned between saturated aqueous NH4Cl and CH2Cl2. Aqueous layer was extracted with CH2Cl2 (2×). Combined organic layers were dried over Na2SO4 and concentrated. Purification by reversed phase HPLC (21×100 mm Phenomenex Gemini, 15-75% MeCN/water containing 0.05% NH4OH over 20 min at 20 mL/min) afforded title compound as a white solid. HRMS. Found, 464.2099; calcd for (M+H)+, 464.2099. 1H NMR (500 MHz, CDCl3): δ 7.86 (d, J=7.58 Hz, 1 H); 7.43-7.38 (m, 1 H); 7.36-7.26 (m, 4 H); 7.25-7.19 (m, 1 H); 7.11 (d, J=8.54 Hz, 2 H); 6.96 (d, J=9.11 Hz, 1 H); 4.59 (d, J=13.19 Hz, 1 H); 3.34 (d, J=13.18 Hz, 1 H); 3.12-3.04 (m, 1 H); 2.89-2.82 (m, 1 H); 2.68-2.59 (m, 1 H); 2.36-2.29 (m, 1 H); 1.71-1.55 (m, 3 H); 1.41-1.34 (m, 1 H); 1.16-1.10 (m, 6 H); 1.09-0.92 (m, 1 H); 0.93-0.83 (m, 1 H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]([OH:9])[C:6]2[S:10][C:11]([CH3:13])=[CH:12][C:5]=2[CH2:4]1)[CH3:2].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1F>>[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:9][CH:7]1[CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][C:5]2[CH:12]=[C:11]([CH3:13])[S:10][C:6]1=2
Reactant: CCN1Cc2cc(C)sc2C(O)C1
Reactant: Fc1ccccc1Br
Product: CCN1Cc2cc(C)sc2C(Oc2ccccc2Br)C1

Procedure:
The same method as in Example 1 was conducted using 5-ethyl-2-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 32) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2-bromo-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: C([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12](/[CH:16]=[C:17](\[CH3:23])/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:11][C:10]=1[F:24])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[F:15][C:14]1[CH:13]=[C:12]([CH2:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:11]=[C:10]([F:24])[C:9]=1[OH:8]
Reactant: [H][H]
Reactant: CCOC(=O)/C(C)=C/c1cc(F)c(OCc2ccccc2)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)Cc1cc(F)c(O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution (E)-ethyl 3-(4-(benzyloxy)-3,5-difluorophenyl)-2-methylacrylate (8) (1.4 g, 4.21 mmol) in ethanol (25 mL) was added Pd/C (140 mg, 10% Degussa type). A balloon of hydrogen gas was added and the reaction was evacuated and back-filled with hydrogen three times. The reaction was stirred under a hydrogen balloon overnight at room temperature, filtered through a pad of celite and concentrated in vacuo to give ethyl 3-(3,5-difluoro-4-hydroxyphenyl)-2-methylpropanoate (9).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C1(C)C=CC(S(O[CH2:21][C@@H:22]2[O:24][CH2:23]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:21][C@@H:22]2[O:24][CH2:23]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)ccc1OC[C@H]1CO1
Temperature: 60 °C
Reaction time: 24 h
Yield: 59.1 %

Procedure:
A mixture of 5-bromo-2-hydroxybenzaldehyde (68.75 g), (R)-glycidyl 4-toluenesulphonate (65 g) and potassium carbonate (47.3 g) in dry dimethylformamide (1.5 L) was stirred and heated at 60° C. under nitrogen for 24 hours, then cooled and allowed to stand at ambient temperature for 24 hours. The mixture was poured into water (2 L) then extracted with ether (4×400 ml). The combined extracts were washed with brine (4×500 ml), dried over magnesium sulphate, and the solvent removed in vacuo to give an oil which was purified by flash chromatography over silica eluting with a 4:1 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate. Appropriate fractions were combined and the solvent removed in vacuo to give an oil, which on trituration with ether (150 ml) gave (R)-5-bromo-2-(2,3-epoxypropoxy)benzaldehyde as a colourless solid (43.3 g).
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH2:7][CH2:8][C:9]1[C:10]([NH2:25])=[N:11][C:12](=[O:24])[N:13]([CH:23]=1)[C@@H:14]1[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[C@H:15]1[OH:16])=O.[OH-].[NH4+]>O>[NH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:10]([NH2:25])=[N:11][C:12](=[O:24])[N:13]([CH:23]=1)[C@@H:14]1[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[C@H:15]1[OH:16]
Reactant: Nc1nc(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1CCCNC(=O)C(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: NCCCc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)nc1N
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 97.6 %

Procedure:
5-[3-(trifluoroacetamido)propyl]cytidine (0.69 g, 1.74 mmol) was dissolved in DI H2O (8.5 mL). After complete dissolution, concentrated ammonium hydroxide (NH4OH) (8.5 mL) was added to the reaction mixture. The reaction solution was stirred at ambient temperature for 2-3 h and then concentrated under reduced pressure giving the crude product as yellow-orange residue. The crude product was dissolved in deionized H2O (10 mL) and AG50W-X8 resin (2.5 g) was added to the solution. The suspension was stirred for 15 min and filtered over a bed of AG50W-X8 resin (2.5 g). The resin was washed with DI H2O and the product was then eluted off of the resin by washing the resin with deionized H2O/conc. NH4OH, 4:1, collecting fractions (monitored by TLC). Removal of solvent from the appropriate fractions afforded 0.51 g (98%) of 5-(3-aminopropyl)cytidine as light tan solid, which was confirmed by 1H-NMR.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[C:9]1[N:14]=[CH:13][C:12](/[C:15](/[C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[C:16](\[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)/[CH2:17][CH3:18])=[CH:11][CH:10]=1>C1COCC1>[CH3:1][NH:2][CH2:3][CH2:4][O:5][C:9]1[N:14]=[CH:13][C:12](/[C:15](/[C:25]2[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=2)=[C:16](\[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)/[CH2:17][CH3:18])=[CH:11][CH:10]=1
Reactant: CNCCO
Reactant: CC/C(=C(\c1ccc(O)cc1)c1ccc(Cl)nc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCNC)nc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a stirred solution of 2-(methylamino)ethanol (672 mg, 10 eq) in 20 mL anhydrous THF was added NaH (373 mg, 8.0 eq) at 0° C. The mixture was stirred at rt for 1 h, then to the mixture was added (Z)-4-(1-(6-chloropyridin-3-yl)-2-phenylbut-1-enyl)phenol (300 mg, 1 eq, made from example 1). The reaction was heated at reflux for 16 h, cooled, quenched with sat. NH4Cl, and extracted with CH2Cl2. The extract was dried, concentrated, and purified by column chromatography to give the desired product (200 mg, 60% yield). 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.18-7.20 (m, 2H), 7.08-7.16 (m, 3H), 7.01-7.06 (m, 3H), 6.77 (d, J=8.4 Hz, 1H), 6.28 (d, J=8.4 Hz, 1H), 4.28 (t, J=5.2 Hz, 2H), 2.93 (t, J=5.2 Hz, 2H), 2.46-2.55 (m, 5H), 0.92 (t, J=7.6 Hz, 3H); m/z=375 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=O)[CH3:14])[CH3:2].N1CCC[C@H]1C(O)=O.[NH2:25][C:26]1[C:31]([CH:32]=O)=[CH:30][CH:29]=[CH:28][N:27]=1>CCO>[CH2:1]([O:3][C:4](=[O:16])[CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:32][C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1)[CH3:2]
Reactant: Nc1ncccc1C=O
Reactant: CCOC(=O)C=CCCCCCCC(C)=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C=CCCCCCCc1ccc2cccnc2n1
Temperature: 110 °C

Procedure:
A mixture of 28-3 (4.1 g, 18.3 mmol), proline (2.7 g, 23.8 mmol), and 1-3 (2.9 g, 23.8 mmol ) in 50 mL EtOH was heated at 110° C. for 24 hr. The reaction mixture was concentrated and purified by silica gel chromatography (EtOAc, 100%) to afford the desired product 28-4 as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][O:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]2)[C:10]=1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:30][CH2:31][CH2:32][C:33](Cl)=[O:34].C(N(CC)CC)C.O>ClCCl>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][O:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([N:27]3[CH2:30][CH2:31][CH2:32][C:33]3=[O:34])[CH2:23][CH2:22]2)[C:10]=1[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCCBr
Reactant: Cc1c(CO[C@H]2CC[C@H](N)CC2)nc2ccccc2c1OCc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(CO[C@H]2CC[C@H](N3CCCC3=O)CC2)nc2ccccc2c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
To a solution of trans-4-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}cyclohexaneamine (300 mg) in dichloromethane (5 mL) were added 4-bromo butanoic acid chloride (0.11 mL) and triethylamine (0.15 mL) under ice-cooling, followed by stirring at the same temperature for 45 minutes. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was dissolved in THF, and 60% sodium hydride (50 mg) was added thereto. The reaction mixture was stirred at room temperature for 2 hours, followed by stirring for another 15 hours while heating it in an oil bath at 60° C. 60% sodium hydride (50 mg) was added to the reaction mixture, followed by stirring for 4 hours while heating it in an oil bath at 60° C. The reaction mixture was cooled to room temperature, and water was then added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=100/0˜95/5). The solvent was evaporated under reduced pressure, and the residue was then dried under vacuum at room temperature to obtain 161 mg of 1-(trans-4-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}cyclohexyl)pyrrolidin-2-one as a yellow oily substance.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:26])[CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[C:18]1[N:23]=[N:22][C:21](OC)=[CH:20][CH:19]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:28][NH2:29]>>[C:1]([NH:5][CH2:6][CH:7]([OH:26])[CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[C:18]1[N:23]=[N:22][C:21]([NH:28][NH2:29])=[CH:20][CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(-c2ccc(OC)nn2)c(OCC(O)CNC(C)(C)C)c1
Reactant: NN
Solvent: O
Product: COc1ccc(-c2ccc(NN)nn2)c(OCC(O)CNC(C)(C)C)c1

Procedure:
A stirred mixture of 6-[2-(3-t-butylamino-2-hydroxypropoxy)-4-methoxyphenyl]-3-methoxypyridazine (0.36 g, 0.001 mole) and hydrazine hydrate (8 ml) was heated under reflux for 2 hours. Excess of hydrazine hydrate was removed under reduced pressure and 6-[2-(3-t-butylamino-2-hydroxypropoxy)-4-methoxyphenyl]-3-hydrazino pyridazine was isolated by crystallisation from ethanol-ether
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:32][CH:33]([C:38]#[N:39])[C:34]([NH:36][CH3:37])=[O:35].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:38]([CH:33]([NH:32][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:29])([F:31])[F:30])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:34]([NH:36][CH3:37])=[O:35])#[N:39]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CNC(=O)C(N)C#N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CNC(=O)C(C#N)NC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 26.1 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 20 mg, 0.046 mmol), (R/S)-2-amino-2-cyano-N-methylacetamide (7.87 mg, 0.070 mmol), 4-methylmorpholine (18.76 mg, 0.185 mmol), and HATU (22.92 mg, 0.060 mmol) were added to DMF (2 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.5 min) to provide (R/S)-2-cyano-2-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)-N-methylacetamide (8 mg, 0.012 mmol, 26.5% yield) as a mixture of diastereomers. LCMS=527.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.12-8.28 (2 H, m), 7.48-7.78 (7 H, m), 5.40-5.58 (1 H, m), 5.27 (1 H, s), 2.80 (3 H, s); HPLC peak RT=9.4 min (Method A).
Reaction SMILES: C(O)C.C([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:21])[C@@H:18]([OH:20])[CH3:19])[CH2:13][CH2:12]1)C1C=CC=CC=1.C1CCCCC=1.O.O.[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32]>O1CCCC1.[Pd]>[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].[OH:20][C@@H:18]([CH3:19])[C:17]([N:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1)=[O:21]
Reactant: C[C@H](O)C(=O)N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: C1=CCCCC1
Solvent: C1CCOC1
Product: C[C@H](O)C(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Ethanol (350 kg), Palladium (10% on activated carbon) (8.40 kg, 7.89 mol) and (S)-1-(4-benzylpiperazin-1-yl)-2-hydroxypropan-1-one 5 (70.0 kg, 282 mol) were charged to a reactor and the mixture was purged with nitrogen and heated to reflux. Cyclohexene (70.0 kg, 852 mol) was slowly added. The reaction mixture was heated to reflux and stirred for 24 h. After cooling to ambient temperature, the mixture was filtered through a pad of CELITE® and the cake was washed with ethanol (20 kg). The filtrate was cooled to 10-15° C. and a solution of oxalic acid dihydrate (36.0 kg, 286 mol) in tetrahydrofuran (156 kg) was slowly added at a rate to maintain the reaction temperature at 10-20° C. After aging for 2 h, the solid was collected by filtration, washed with ethanol (100 kg) and dried under reduced pressure at 50-55° C. to afford (S)-2-hydroxy-1-(piperazin-1-yl)propan-1-one oxalate salt V (58.2 kg, 83%). 1H NMR (300 MHz, D2O) δ 4.73-4.51 (m, 1H), 3.93-3.59 (m, 4H), 3.26 (dd, J=8.8, 4.0 Hz, 4H), 1.27 (d, J=6.7 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[C:14](=O)[NH:13][N:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[C:11]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=2)=[N:12][N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(OC)cc(-c2n[nH]c(=O)c3cc(OC)ccc23)c1
Product: COc1cc(OC)cc(-c2nnc(Cl)c3cc(OC)ccc23)c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-(3,5-dimethoxyphenyl)-7-methoxy-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33]>>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1
Reactant: COc1ccccc1Br
Product: COc1ccccc1C(=O)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1

Procedure:
This compound is prepared by method C using compound 12e and 2-bromoanisole
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[C:9]([CH:10]=CC2C=CC=CC=2)=[CH:8][C:7]([F:18])=[C:6]([F:19])[C:5]=1[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27].CC([OH:33])(C)C.C[N+]1([O-])CCOCC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.C(OCC)(=O)C.O>[CH3:1][O:2][C:3](=[O:28])[C:4]1[C:9]([CH:10]=[O:33])=[CH:8][C:7]([F:18])=[C:6]([F:19])[C:5]=1[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27]
Reactant: COC(=O)c1c(C=Cc2ccccc2)cc(F)c(F)c1Nc1ccccc1Cl
Reactant: CC(C)(C)O
Agent: C[N+]1([O-])CCOCC1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(C=O)cc(F)c(F)c1Nc1ccccc1Cl
Reaction time: 1 h
Yield: 755.5 %

Procedure:
A mixture of 2-(2-chlorophenylamino)-3,4-difluoro-6-styrylbenzoic acid methyl ester (1.20 g, 3.00 mmol), 2.5% OSO4 solution in t-BuOH (2.0 mL, 0.165 mmol) and NMO (0.435 g, 3.60 mmol) in 30 mL of 1:1 THF/water was stirred for 1 hour. Sodium periodate (0.963 g, 4.50 mmol) was added. After 1 hour, the reaction mixture was diluted with ethyl acetate and water and the layers separated. The organic layer was dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography (1:1 methylene chloride/hexanes) gave 0.406 g (42%) pure desired product.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[N:10][N:9]3[C:12]([C:15]4[CH:16]=[C:17]([NH:21][C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[O:23])[CH:18]=[CH:19][CH:20]=4)=[CH:13][N:14]=[C:8]3[CH:7]=2)[CH:3]=[N:2]1.[C:30](#[N:34])[CH:31]=[CH:32][CH3:33].N12CCCN=C1CCCCC2>C(#N)C.CO>[C:30]([CH2:31][CH:32]([N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[N:10][N:9]3[C:12]([C:15]4[CH:16]=[C:17]([NH:21][C:22]([NH:24][CH2:25][C:26]([F:28])([F:27])[F:29])=[O:23])[CH:18]=[CH:19][CH:20]=4)=[CH:13][N:14]=[C:8]3[CH:7]=2)[CH:3]=[N:2]1)[CH3:33])#[N:34]
Reactant: CC=CC#N
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cn[nH]c4)cnn23)c1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CC(CC#N)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of N-{3-[7-(1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea (15 mg, 0.037 mmol) and 2-butenenitrile (3.8 mg, 0.056 mmol) in acetonitrile (0.5 mL) and methanol (0.2 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (5.6 μL, 0.037 mmol). The mixture was stirred at 60° C. overnight. The reaction mixture was stirred at 60° C. overnight. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=469.1.