Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[OH-].[K+].[CH3:12][O:13][CH2:14]Cl>N1C=CC=CC=1>[F:1][CH:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]1([CH2:12][O:13][CH3:14])[OH:9]
Reactant: COCCl
Reactant: Oc1ccc(F)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Product: COCC1(O)C=CC(F)=CC1F
Yield: 71 %

Procedure:
To a reaction mixture containing 2,4-difluorophenol (25, 2 g, 15.37 mmol) in 30 mL of dry pyridine was added powdered KOH (0.854 g, 15.25 mmol) and methoxymethyl chloride (1.6 g, 19.37 mmol) and this reaction mixture was heated under reflux for 3.5 hours (FIG. 2E). The reaction was cooled and partitioned between 1 M NaOH and ethyl ether (2×30 mL). The organic solution was washed with 1 M HCl (2×20 mL), water, and then dried (MgSO4), filtered, and the solvent removed under vacuo to afford a oily residue. The crude product was purified by column chromatography (EtOAc:hexanes; 5:95) to afford the desired product as a pale yellow oil in 71% yield. 1H NMR (CDCl3) δ7.1-7.16 (m, 1 H, ArH), 6.78-6.88 (m, 2 H, ArH), 5.15 (s, 2 H, CH2), 3.52 (s, 3 H, CH3).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)[CH2:20][C:21]([OH:23])=[O:22].N1C=CC=CC=1.N1CCCCC1>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH:17]=[CH:20][C:21]([OH:23])=[O:22])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C(O)CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=CC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 100 °C

Procedure:
A mixture of N-benzyloxycarbonyl-4-formylpiperidine (10 g), malonic acid (4.2), pyridine (4 ml) and piperidine (0.4 ml) was heated at 100° C. for 2 hours. The reaction mixture was allowed to cool and was diluted with ethyl acetate (100 ml). The solution was washed with 2M HCl (2×100 ml), dried and evaporated to dryness. The residue was triturated with isohexane to give the title compound, yield 13.5 g. NMR (DMSOd6): 1.2 (m, 2H) 1.7 (m, 2H) 2.35 (m, 1H) 2.85 (m, 2H) 4 (d, 2H) 5.05 (s, 2H) 5.75 (d, 1H) 6.75 (m, 1H) 7.35 (m, 5H) 12.25 (broad peak, 1H)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:19][C:14]3=[N:15][CH:16]=[CH:17][N:18]=[C:13]3[C:12]=2[CH2:20][CH2:21][CH2:22][NH2:23])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C.O>O1CCCC1.C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:19][C:14]3=[N:15][CH:16]=[CH:17][N:18]=[C:13]3[C:12]=2[CH2:20][CH2:21][CH2:22][NH:23][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1ccc(-c2[nH]c3nccnc3c2CCCN)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(-c2[nH]c3nccnc3c2CCCNS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 3-(6-(4-tert-butylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)propylamine [0.0324 mmol, Example 35] in tetrahydrofuran (1.5 mL) was treated with methanesulfonyl chloride (0.0324 mmol) and triethylamine (0.0788 mmol). The solution was stirred at room temperature for 12 hours and water and ethyl acetate were added. The layers were separated and the organic solution was dried over magnesium sulfate. The drying agent was filtered and the solvent was evaporated. The residue was purified by column chromatography (silica gel, ethyl acetate followed by 10% methanol in ethyl acetate) to give the title compound as a yellow solid. MS: 387 (MH+). HPLC (Method C): RT=3.23 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:12][C:13]3[CH:24]=[CH:23][C:16]4[N:17]=[C:18](S(C)=O)[S:19][C:15]=4[CH:14]=3)=[CH:10][N:11]=2)[N:8]=1.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32].CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:12][C:13]3[CH:24]=[CH:23][C:16]4[N:17]=[C:18]([NH:25][C@@H:26]5[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]5[OH:32])[S:19][C:15]=4[CH:14]=3)=[CH:10][N:11]=2)[N:8]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: COc1ccc2ncc(Cc3ccc4nc(S(C)=O)sc4c3)n2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc2ncc(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)n2n1
Temperature: 140 °C
Reaction time: 24 h
Yield: 32.9 %

Procedure:
A mixture of 6-((6-methoxyimidazo[1,2-b]pyridazin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (320 mg, 0.89 mmol), (1R,2R)-2-amino cyclohexanol (308 mg, 2.68 mmol) and DIEA (231 mg, 1.79 mmol) in NMP (11 mL) was stirred for 1 d at 140° C. The mixture was cooled to rt and water (50 mL) was added. The mixture was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50:1 to 10:1 DCM/MeOH, then further purified by preparative HPLC to afford (1R,2R)-2-((6-((6-methoxyimidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol as a brown solid (120 mg, 33%). 1H NMR (300 MHz, DMSO-d6) δ 7.97 (d, J=9.6 Hz, 1H), 7.83 (d, J=7.5 Hz, 1H), 7.61 (s, 1H), 7.44 (s, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.18 (d, J=9.9 Hz, 1H), 6.82 (d, J=9.6 Hz, 1H), 4.72 (d, J=5.4 Hz, 1H), 4.23 (s, 2H), 3.95 (s, 3H), 3.52-3.49 (m, 1H), 3.39-3.36 (m, 1H), 2.05-2.01 (m, 1H), 1.90-1.86 (m, 1H), 1.65-1.59 (m, 2H), 1.28-1.14 (m, 4H). LCMS (ESI) m/z 410 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](O)=[O:14])=[C:6]([CH2:18][CH2:19][CH3:20])[C:5]=1[OH:21])(=[O:3])[CH3:2].Cl.[NH2:23][OH:24].C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:23][OH:24])=[O:14])=[C:6]([CH2:18][CH2:19][CH3:20])[C:5]=1[OH:21])(=[O:3])[CH3:2]
Reactant: NO
Reactant: CCCc1c(OCCCCC(=O)O)ccc(C(C)=O)c1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1c(OCCCCC(=O)NO)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Four and six-tenths grams of 5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentanoic acid were converted to the corresponding acid chloride according to the procedure of Example 55. The resulting acid chloride and 1.05 g. of hydroxylamine hydrochloride were dissolved in 50 ml. of methylene chloride, after which were added 4.15 ml. of triethylamine in about 50 ml. of methylene chloride. After stirring overnight at room temperature, the methylene chloride was removed by evaporation and the residue was partitioned between ethyl acetate and dilute hydrochloric acid. The layers were separated, and the ethyl acetate solution was evaporated in vacuo. The residue was dissolved in diethyl ether and the solution was extracted with dilute sodium hydroxide solution. The aqueous basic solution was then made acidic with dilute hydrochloric acid and the solution was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and evaporated to dryness. The residue was crystallized from methylene chloride/hexane to provide 400 mg. of the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].C(=O)([O-])[O-].[K+].[K+].CCN(C(C)C)C(C)C.[CH2:25]([O:27][CH:28]([O:31][CH2:32][CH3:33])[CH2:29]Br)[CH3:26]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:29][CH:28]([O:31][CH2:32][CH3:33])[O:27][CH2:25][CH3:26])=[CH:4][C:3]=1[F:9]
Reactant: Oc1ccc(Cl)c(F)c1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(COc1ccc(Cl)c(F)c1)OCC
Temperature: 100 °C
Reaction time: 16 h
Yield: 104.6 %

Procedure:
To 4-chloro-3-fluorophenol (3.66 g, 25 mmol) in DMF (30 ml) at room temperature was added potassium carbonate (6.91 g, 50.0 mmol), DIEA (8.73 ml, 50.0 mmol) and then bromoacetaldehyde diethylacetal (7.52 ml, 50.0 mmol). The mixture was stirred at 100° C. for 16 hr. The mixture was cooled to room temperature and then quenched with water and extracted with EtOAc two times, dried over magnesium sulfate, filtered, concentrated. The residue was purified via Biotage (0-20% AcOEt/heptane; SNAP25 column) giving 13a (6.87 g, quant) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])[NH:5][C:6](=[O:25])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14](=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([C:21](=[NH:23])[NH2:22])=[CH:17][CH:16]=2)[CH:8]=1.C(Cl)Cl.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[C:21]([C:18]1[CH:17]=[CH:16][C:15]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[C:6]([NH:5][C@H:4]([C:3]([O:2][CH3:1])=[O:34])[CH2:26][C:27]([OH:29])=[O:28])=[O:25])=[O:24])=[CH:20][CH:19]=1)(=[NH:22])[NH2:23]
Reactant: COC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c1cccc(NC(=O)c2ccc(C(=N)N)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](CC(=O)O)NC(=O)c1cccc(NC(=O)c2ccc(C(=N)N)cc2)c1
Reaction time: 3 h
Yield: 75 %

Procedure:
A solution of N-[m-(p-amidinobenzamido)benzoyl]-3-(t-butoxycarbonyl)-L-alanine methyl ester hydroidide in CH2Cl2 /trifluoroacetic acid is left to stand at room temperature for 3 hours. After removal of the solvent and recrystallization of the residue from ethanol/ether there is obtained (S)-3-[m-(p-amidinobenzamido)benzamido]-3-(methoxycarbonyl)propionic acid trifluoroacetate in the form of a colourless solid. Yield: 75%, m.p. 132°-134° C. (decomposition). MS: 413 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].[H-].[Na+].[CH:20]1([N:25]2[CH2:30][CH2:29][CH:28](OS(C)(=O)=O)[CH2:27][CH2:26]2)[CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C=O)C.CC(OC)(C)C.O.[OH-].[Na+]>[CH:20]1([N:25]2[CH2:30][CH2:29][CH:28]([O:17][C:14]3[CH:15]=[CH:16][C:11]([C:5]4([CH2:4][N:2]([CH3:1])[CH3:3])[CH2:6][CH2:7][O:8][CH2:9][CH2:10]4)=[CH:12][CH:13]=3)[CH2:27][CH2:26]2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CS(=O)(=O)OC1CCN(C2CCCC2)CC1
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CC1(c2ccc(OC3CCN(C4CCCC4)CC3)cc2)CCOCC1
Temperature: 75 °C
Reaction time: 1 h
Yield: 12.2 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (487 mg, 2.07 mmol) in DMF (2 ml) was added to a solution of NaH (100 mg, 2.5 mmol) in DMF (2 ml) at room temperature under N2. The reaction was stirred for 1 hr and a solution of methanesulfonic acid 1-cyclopentyl-piperidin-4-yl ester (409 mg, 1.65 mmol) in DMF (1.5 ml) was slowly added. The reaction was heated to 75° C. and stirred for 6 hrs. The reaction was allowed to cool to room temperature and diluted with TBME (20 ml), water (10 ml) and 5M NaOH solution (10 ml). The organic layer was washed with 2.5M NaOH (2×20 ml), brine (2×20 ml), dried over MgSO4, filtered and concentrated in vacuo. The crude reaction was purified by column chromatography, eluting with DCM:MeOH:NH3 (98:1:1) to give the title compound as a white solid (78 mg, 12%). 1H NMR (400 MHz, CDCl3) δ7.20 (d, 2H), 6.87 (d, 2H), 4.28 (m, 1H), 3.75 (dt, 2H), 3.55 (td, 2H), 2.89-2.76 (m, 2H), 2.52 (p, 1H), 2.40 (s, 2H), 2.37-2.25 (m, 2H), 2.14-1.94 (m, 4H), 1.96 (s, 6H), 1.93-1.77 (m, 6H), 1.76-1.34 (m, 6H).
Reaction SMILES: N([O-])=O.[Na+].[C:5]1([C@@H:11]([NH:13][C:14]2[N:19]=[C:18]([N:20]3[C:24]4[CH:25]=[CH:26][C:27]([NH2:29])=[CH:28][C:23]=4[N:22]=[CH:21]3)[CH:17]=[CH:16][N:15]=2)[CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N-:30]=[N+:31]=[N-].[Na+]>O.C(O)(=O)C.C(OCC)(=O)C>[C:5]1([C@@H:11]([NH:13][C:14]2[N:19]=[C:18]([N:20]3[C:24]4[CH:25]=[CH:26][C:27]([N:29]=[N+:30]=[N-:31])=[CH:28][C:23]=4[N:22]=[CH:21]3)[CH:17]=[CH:16][N:15]=2)[CH3:12])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(N)ccc32)n1)c1ccccc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](Nc1nccc(-n2cnc3cc(N=[N+]=[N-])ccc32)n1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
A solution of 12 mg of NaNO2 in 0.5 mL of H2O was added to a 5° C. solution of 56 mg of 2-[(S)-1-phenylethylamino]-4-[5-aminobenzimidazol-1-yl]pyrimidine in 2 mL acetic acid. The solution was cooled to 0° C. and stirred for 0.5 hours. A solution of 16.5 mg NaN3 in 0.5 mL H2O was added and stirred for one hour. The solution was diluted with 100 mL of ethyl acetate and washed with water, saturated NaHCO3 and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with methanol in methylene chloride to give 53 mg of the title compound. RF: 0.6 (5% MeOH in CH2Cl2). 1H NMR (400 MHz, 1:1 CD3OD/CDCl3): δ 1.60 (d, J=7.0 Hz, 3H), 5.12 (q, J=7.0 Hz, 1H), 6.8 (m, 1H), 6.95 (d, J=6 Hz, 1H), 7.2-7.45 (m, 6H), 7.72 (m, 1H), 8.33 (br s, J=6.5 Hz, 1H), 8.74 (m, 1H). Mass Spectrum (CH3CN-TFA-NH4HCO2-ESI): 357.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([CH3:10])=[CH2:9])[CH2:4][CH:3]=1.B1([O-])OO1.[OH2:15].[OH2:16].O.O.[Na+].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH3:1][C:2]12[O:15][CH:7]1[CH2:6][CH:5]([C:8]1([CH3:10])[O:16][CH2:9]1)[CH2:4][CH2:3]2
Reactant: C=C(C)[C@H]1CC=C(C)CC1
Reactant: O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CC1(C2CCC3(C)OC3C2)CO1
Temperature: 60 °C
Reaction time: 12 h
Yield: 96.9 %

Procedure:
Limonene (1.36 g, 10 mmol) was dissolved in toluene (25 ml), and a composition containing sodium perborate tetrahydrate (15.4 g, 100 mmol) and acetic anhydride (10.2 g, 100 mmol) was added thereto. The mixture was stirred at 60° C. After 12 hours, the reaction solution was washed with water to thereby completely remove acetic acid and sodium acetate, which were generated as by-products, and the remaining H2O2. Toluene was distilled off from the organic phase by distillation, and as a result, 1.63 g (97% yields) of limonene diepoxide with a GC purity of 98% was obtained.
Reaction SMILES: O1CCCO[CH:2]1[CH2:7][CH2:8][C:9]1[C:10]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:17]=[CH:16][C:11]=2[N:12]=[C:13]([NH2:15])[N:14]=1.ClC1N=C(C2CC2)C2N=C(C3C=CC(F)=CC=3)C=CC=2N=1>>[CH:8]1([C:9]2[C:10]3[N:19]=[C:18]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[CH:17]=[CH:16][C:11]=3[N:12]=[C:13]([NH2:15])[N:14]=2)[CH2:7][CH2:2]1
Reactant: Nc1nc(CCC2OCCCO2)c2nc(-c3ccc(F)cc3)ccc2n1
Agent: Fc1ccc(-c2ccc3nc(Cl)nc(C4CC4)c3n2)cc1
Product: Nc1nc(C2CC2)c2nc(-c3ccc(F)cc3)ccc2n1

Procedure:
The procedure for the synthesis of 4-(2-[1,3]dioxan-2-yl-ethyl)-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidin-2-ylamine was repeated, except for the use of 2-chloro-4-cyclopropyl-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidine instead of 2-chloro-4-(2-[1,3]dioxan-2-yl-ethyl)-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidine. The compound was characterized as follows: MS (m/z) 281.0 [M+H]+; HPLC Rt=2.96 minutes (Method A).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:11]2[CH:22]=[N:21][C:14]3[O:15][CH2:16][C:17](=[O:20])[N:18]([CH3:19])[C:13]=3[CH:12]=2)=[O:10])=[C:4]([Cl:24])[CH:3]=1.[F:25][C:26]([Si](C)(C)C)([F:28])[F:27].[F-].C[N+](C)(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:11]2[CH:22]=[N:21][C:14]3[O:15][CH2:16][C:17](=[O:20])[N:18]([CH3:19])[C:13]=3[CH:12]=2)([OH:10])[C:26]([F:28])([F:27])[F:25])=[C:4]([Cl:24])[CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C(=O)c1cnc2c(c1)N(C)C(=O)CO2)c1ccc(Br)cc1Cl
Agent: C[N+](C)(C)C
Agent: [F-]
Product: CC(c1ccc(Br)cc1Cl)C(O)(c1cnc2c(c1)N(C)C(=O)CO2)C(F)(F)F

Procedure:
In analogy to Example 1, step 3, 7-[2-(4-bromo-2-chloro-phenyl)-propionyl]-1-methyl-1H-pyrido[2,3-b][1,4]oxazin-2-one was reacted with (trifluoromethyl)trimethylsilane and tetramethylammonium fluoride to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=477.0 [M−H+].
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1Cl.C(=O)([O-])[O-].[K+].[K+].[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:23][CH2:22]1>C(#N)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:23][CH2:22]1
Reactant: Clc1cc(Cl)c(Cl)nn1
Reactant: COc1ccccc1N1CCN(CCCCN)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccccc1N1CCN(CCCCNc2cc(Cl)nnc2Cl)CC1
Yield: 54.2 %

Procedure:
9.25 g (0.050 mol) of 3,4,6-trichloropyridazine are stirred with 6.90 g (0.050 mol) of powdered anhydrous potassium carbonate and 13.15 g (0.050 mol) of 1-(4-aminobutyl)-4-(2-methoxyphenyl)piperazine in 1350 ml of dry acetonitrile at room temperature for 96 hours. The mixture is subsequently filtered with suction, and the filtrate is concentrated in vacuo. The residue is taken up in ethanol, and the trihydrochloride of 3,6-dichloro-4-((4-(4-(2-methoxyphenyl)-1-piperazinyl)butyl)amino)pyridazine of m.p.: 155°-170° C. is precipitated with ethereal HCl; yield: 54.2% of theory.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([S:9][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.C([Li])CCC.[CH3:22][C:23](N(C)C)=[O:24]>O1CCCC1>[C:23]([C:12]1[S:11][C:10]([S:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)=[CH:14][CH:13]=1)(=[O:24])[CH3:22]
Reactant: CC(=O)N(C)C
Reactant: FC(F)(F)c1cccc(Sc2cccs2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Sc2cccc(C(F)(F)F)c2)s1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(3-trifluoromethylphenylthio)thiophene (4.0 g) in dry tetrahydrofuran (30 ml) at -30° C. under nitrogen, was added dropwise n-butyllithium (9.2 ml, 2.5M) and the solution left to stir at -30° C. for 2 hours. Dimethylacetamide (2.8 ml) was then added dropwise and the reaction mixture stirred at -30° C. for a further hour, allowed to warm to room temperature and stirred over night. The reaction mixture was quenched with 2N HCl (100 ml), extracted with ether (2×100 ml), dried over MgSO4 and evaporated to give a brown oil. The oil was flash chromatographed on a Sorbsil C60-40/60H column using 30% ether-hexane to give a colourless oil which crystallised on standing.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[C:6]=1[CH3:22])=[O:4].[Br:23]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[CH:18][CH:19]=2)[C:6]=1[CH2:22][Br:23])=[O:4]
Reactant: COC(=O)c1cc(Br)c(=O)n(Cc2ccc(C#N)cc2)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)c(=O)n(Cc2ccc(C#N)cc2)c1CBr
Yield: 90.8 %

Procedure:
A mixture of 5-bromo-1-(4-cyano-benzyl)-2-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (2.05 g, 5.68 mmol), N-bromosuccinimide (1.11 g, 6.25 mmol), and benzoyl peroxide (0.14 g, 0.568 mmol) in CCl4 (60 mL) was refluxed for 16 h. The solvent was evaporated in vacuo, and the residue was chromatographed (0-45% EtOAc/hexanes) to give 2.27 g of the title compound as a white solid. 1H NMR (CDCl3, 200 MHz): δ=8.42 (s, 1H), 7.65 (d, 2H, J=8.2 Hz), 7.20-7.40 (m, 2H), 5.69 (br s, 2H), 4.87 (br s, 2H), 3.91 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C:8]3[C:13]([O:14][C:15]=2[CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.Cl.N1C=CC=CC=1>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C:8]3[C:13]([O:14][C:15]=2[CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: COc1ccc2c(c1)Oc1ccccc1C2
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Oc1ccc2c(c1)Oc1ccccc1C2
Yield: 96.3 %

Procedure:
A solid mixture of 3-methoxy-9H-xanthene 9 (5.84 g, 27.5 mmole) and pyridine hydrochloride (42 g, 363 mmole) was heated at 200-210° for 2 hrs. The resulting reaction mixture was cooled to about 70° and treated with water, while a precipitate formed. The orange colored solid was filtered on a Buchner funnel, washed with water, and dried in vacuo, yielding the crude 3-hydroxy-9H-xanthene 10 (5.25 g, 96%). No major oxidation took place when crude 10 was stored in a desiccator under argon in the dark. Thus, the crude xanthene 10 was used for silylation without further purification. No 1H NMR or 1R were taken.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].C([O-])(=O)C.[C:29]([C:31]1[CH:36]=[CH:35][C:34]([N:37]2[C:41](C3C=C(C(NCC[N+]4(C)CCCC4)=O)C(=O)N(C4C=CC=C(C(F)(F)F)C=4)C=3C)=[CH:40][CH:39]=[N:38]2)=[CH:33][CH:32]=1)#[N:30].O.O.O.P([O-])([O-])(O)=O.[K+].[K+].CC1(C)C(C)(C)OB(C2N(C3C=CC(C#N)=CC=3)N=CC=2)O1>CN(C=O)C.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[C:29]([C:31]1[CH:32]=[CH:33][C:34]([N:37]2[C:41]([C:2]3[CH:3]=[C:4]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:5](=[O:19])[N:6]([C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=4)[C:7]=3[CH3:8])=[CH:40][CH:39]=[N:38]2)=[CH:35][CH:36]=1)#[N:30]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cc(C(=O)NCC[N+]2(C)CCCC2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1cc(I)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 55 °C

Procedure:
Ethyl 5-iodo-6-methyl-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylate (synthesised according to WO2005/026123, Example 63 (b)) (9.02 g, 20 mmol), 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzonitrile (synthesised according to WO2009/061271, Example 1 intermediate) (8.85 g, 30.00 mmol), potassium hydrogenphosphate trihydrate (13.69 g, 60.00 mmol) and 1,1′-bis(di-tert-butylphosphino) ferrocene palladium dichloride (0.918 g, 1.40 mmol) were suspended in DMF (100 mL) in a 250 mL round-bottomed flask and the mixture was purged with argon. Then 1,1″-bis(di-tert-butylphosphino) ferrocene palladium dichloride (0.918 g, 1.40 mmol) was added and the reaction mixture was heated to 55° C. under vigorous stirring. After 30 and 90 min more 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzonitrile (1.4 g, 4.74 mmol and 2.5 g, 8.47 mmol) was added.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][C:18]([CH3:28])([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:19]=O.O>C1(C)C=CC=CC=1>[CH3:19][C:18]([CH3:28])([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)/[CH:17]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(C)(C=O)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/C(C)(C)Cc1ccccc1
Reaction time: 0.5 h

Procedure:
A suspension (17.8 g, 445 mmol) of 60% sodium hydride in liquid paraffin was suspended in toluene (300 ml), and a solution of ethyl diethylphosphonoacetate (99.8 g, 445 mmol) in toluene (50 ml) was added at room temperature. The mixture was stirred for 30 min. A solution of 2,2-dimethyl-3-phenylpropanal (see Tetrahedron Lett., 1273-1275 (1973)) (60.16 g, 370.8 mmol) in toluene (50 ml) was dropwise added, and the mixture was stirred at room temperature for 2 hrs. The reaction solution was poured into water, and the mixture was extracted twice with diethyl ether. The recovered organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=20/1-9/1) to give the objective substance.