Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Br:9][C:10]1[C:11]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[N:12][C:13](Cl)=[N:14][CH:15]=1.Cl>C(#N)C.O1CCOCC1>[Br:9][C:10]1[C:11]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[N:12][C:13]([NH:1][C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)=[N:14][CH:15]=1
Reactant: OCCCCNc1nc(Cl)ncc1Br
Reactant: Nc1cccc(O)c1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: OCCCCNc1nc(Nc2cccc(O)c2)ncc1Br

Procedure:
A reaction mixture of 327 mg (3.0 mmol) of 3-aminophenol and 864 mg (3.1 mmol) of 4-(5-bromo-2-chloro-pyrimidin-4-ylamino)-butan-1-ol in 9 ml of acetonitrile is mixed with 0.75 ml of a 4 M solution of hydrochloric acid in dioxane, and it is stirred under reflux overnight. After the cooling, the reaction mixture is filtered, and the filtrate is completely concentrated by evaporation. The oil that is obtained is recrystallized from ethyl acetate/ethanol. The solid is filtered off and then dissolved in water. By adding triethylamine, the solution is made basic and extracted with ethyl acetate (2×). The combined organic phases are dried (Na2SO4), filtered and concentrated by evaporation. 444 mg (1.2 mmol, corresponding to 40% of theory) of the product is obtained.
Reaction SMILES: C(N(CC)C(C1C=C(C2C=NN(CCCO)C=2)C=CC=1NC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(O)OCC)=CC=2OC)N=1)=O)C.[F:50][C:51]1[C:52]([C:95](=[O:98])[NH:96][CH3:97])=[C:53]([NH:66][C:67]2[C:72]([C:73]([F:76])([F:75])[F:74])=[CH:71][N:70]=[C:69]([NH:77][C:78]3[CH:92]=[CH:91][C:81]([CH2:82][P:83](=[O:90])([O:87]CC)[O:84][CH2:85][CH3:86])=[CH:80][C:79]=3[O:93][CH3:94])[N:68]=2)[CH:54]=[CH:55][C:56]=1[C:57]1[CH:58]=[N:59][N:60]([CH2:62][CH2:63][CH2:64][OH:65])[CH:61]=1>>[F:50][C:51]1[C:52]([C:95](=[O:98])[NH:96][CH3:97])=[C:53]([NH:66][C:67]2[C:72]([C:73]([F:75])([F:76])[F:74])=[CH:71][N:70]=[C:69]([NH:77][C:78]3[CH:92]=[CH:91][C:81]([CH2:82][P:83](=[O:87])([OH:90])[O:84][CH2:85][CH3:86])=[CH:80][C:79]=3[O:93][CH3:94])[N:68]=2)[CH:54]=[CH:55][C:56]=1[C:57]1[CH:58]=[N:59][N:60]([CH2:62][CH2:63][CH2:64][OH:65])[CH:61]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c(F)c3C(=O)NC)n2)c(OC)c1)OCC
Agent: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(CC)CC)n2)c(OC)c1
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c(F)c3C(=O)NC)n2)c(OC)c1
Yield: 98.9 %

Procedure:
Prepared analogously to Compound 3A using diethyl (4-{[4-({3-fluoro-4-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-(methylcarbamoyl)phenyl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 27B, 200 mg, 282 μmol) to afford 190 mg of the title compound (99%). 1H NMR (400 MHz, CD3OD) δ=8.31 (s, 1H), 8.20 (s, 1H), 7.93 (s, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.04 (s, 1H), 6.69 (d, J=7.3 Hz, 1H), 4.37 (t, J=6.8 Hz, 2H), 3.91 (s, 3H), 3.81 (quin, J=7.0 Hz, 2H), 3.62 (t, J=6.1 Hz, 2H), 2.95 (s, 1H), 2.90 (s, 4H), 2.14 (quin, J=6.5 Hz, 2H), 1.15 (t, J=7.1 Hz, 3H). MS (ESI): m/z=682.19 [M+H]+. UPLC: tR=1.11 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[OH-].[Na+].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[C:14]([O:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc(C=O)cc1O
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C=O)cc1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred suspension of 3-hydroxy-4-methoxybenzaldehyde (50 g) in water (200 mL) at between 0° and 5° C. is treated dropwise with an aqueous solution of sodium hydroxide (200 mL; 20% w/v), followed at between 0° and 5° C. by benzoyl chloride (38 mL). The reaction mixture is stirred at between 0° and 5° C. for 1 hour and then it is allowed to warm to room temperature and is stirred for a further period of 2 hours. The resulting solution is extracted with dichloromethane (2×200 mL) and the combined extract is washed with water (200 mL), dried over magnesium sulfate and concentrated, to give 2-methoxy-5-formylphenyl benzoate (35.2 g), m.p. 70°-72° C.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:24])=[C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[C:17]([CH3:23])[CH:16]=3)[N:11]=2)[S:8][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[CH2:25]([CH:27]1[O:29][CH2:28]1)Cl>C(O)(C)C.[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+]>[CH3:23][C:17]1[CH:16]=[C:15]([C:12]2[N:11]=[C:10]([C:7]3[S:8][CH:9]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6]=3[CH3:24])[O:14][N:13]=2)[CH:20]=[C:19]([CH3:21])[C:18]=1[O:22][CH2:25][CH:27]1[CH2:28][O:29]1
Reactant: Cc1cc(-c2noc(-c3scc(CC(C)C)c3C)n2)cc(C)c1O
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1cc(-c2noc(-c3scc(CC(C)C)c3C)n2)cc(C)c1OCC1CO1
Temperature: 25 °C
Reaction time: 15 h
Yield: 63.9 %

Procedure:
To a solution of 4-[5-(4-isobutyl-3-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenol (515 mg, 1.50 mmol) in isopropanol (20 mL), 3 N aq. NaOH (5 mL) followed by epichlorohydrine (473 mg, 5.12 mmol) is added and the mixture is stirred at rt for 15 h. Another portion of epichlorohydrine (473 mg, 5.12 mmol) is added and stirring is continued for 24 h. The mixture is diluted with sat. aq. Na2CO3 and is then extracted with DCM (4×75 mL). The combined organic extracts are dried (Na2SO4), filtered and evaporated. The residue is purified by CC on silica gel eluting with heptane:EA 4:1 to give rac-3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-5-(4-isobutyl-3-methyl-thiophen-2-yl)-[1,2,4]oxadiazole (382 mg) as a white powder; LC-MS: tR=1.22 min, [M+1]=399.28.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][C@@H:8]([O:25][CH3:26])[C@@H:9]([N:13](C(OCC1C=CC=CC=1)=O)[CH3:14])[CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:27])[CH2:7][C@@H:8]([O:25][CH3:26])[C@@H:9]([NH:13][CH3:14])[CH:10]([CH3:11])[CH3:12])([CH3:3])([CH3:2])[CH3:4]
Reactant: CO[C@H](CC(=O)OC(C)(C)C)[C@H](C(C)C)N(C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CN[C@@H](C(C)C)[C@@H](CC(=O)OC(C)(C)C)OC

Procedure:
To a solution of t-butyl-(3R,4S)-4-(N-benzyloxycarbonyl-N-methylamino)-3-methoxy-5-methyl-hexanoate (3.855 g, 10.17 mmol) in 100 ml methanol was added 10% Pd/C (0.541 g) and the mixture was hydrogenated until completion of the deprotection (tlc control). The catalyst was removed by filtration and the filtrate concentrated in vacuo. The resulting amorphous solid (2.49 g) can be crystallized from ether by adding a solution of HCl in dioxane.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][N:28]=2)(O)[CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[Cl-].[Na+].O>[CH:21]1([CH:20]=[C:19]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)[C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][N:28]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CS(=O)(=O)c1ccc(C(O)(CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3[nH]2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
A mixture of 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-1-(5-methanesulfonyl-pyridin-2-yl)-ethanol (0.12 g, 0.23 mmol) and tetrabutylammonium fluoride in tetrahydrofuran (1 M, 4.6 mL, 4.6 mmol) was stirred for 3 h at room temperature. After cooling to room temperature, the mixture was poured into brine (15 mL), extracted with ethyl acetate (2×100 mL), washed with a saturated aqueous ammonium chloride solution (3×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-[2-cyclopentyl-1-(5-methanesulfonyl-pyridin-2-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (84 mg, 100%) which was used in the next step without purification: LC/MS m/e calcd for C20H21N3O2S [M+H]+ 368.47, observed 368.1.
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[CH2:4][CH2:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C1C=CC([As](C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C[Sn](C)(C)[C:39]1[CH:40]=[N:41][CH:42]=[C:43]([Cl:45])[CH:44]=1>CN1C(=O)CCC1.CCOC(C)=O.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]>[Cl:45][C:43]1[CH:44]=[C:39]([C:2]2[C:3](=[O:17])[CH2:4][CH2:5][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH:40]=[N:41][CH:42]=1
Reactant: C[Sn](C)(C)c1cncc(Cl)c1
Reactant: CS(=O)(=O)c1ccc(C2=C(Br)C(=O)CC2)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(C2=C(c3cncc(Cl)c3)C(=O)CC2)cc1
Temperature: 60 °C
Yield: 30.9 %

Procedure:
To a degassed r.t. solution of 2-bromo-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one (0.630 g, 2.0 mmol), Pd2 (dba)3 (0.037 g, 0.04 mmol), and AsPh3 (0.098 g, 0.32 mmol) in 5 mL NMP was added a degassed NMP solution (5 mL) of 3-trimethylstannanyl-5-chloropyridine (~2.0 mmol). The resulting mixture was heated to 60° C. for 16 h. The mixture was then cooled to r.t., diluted with EtOAc, washed with water and brine, dried over MgSO4, and concentrated to dryness. The residue was purified by flash chromatography (80% EtOAc/hexanes) followed by a CH2Cl2 /Et2O swish to provide 0.215 g of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)([C:14]#[N:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:24].[NH4+]>S(=O)(=O)(O)O>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)([C:14]([NH2:15])=[O:24])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1(Nc2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: NC(=O)C1(Nc2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 71 %

Procedure:
To 1-Benzyl-4-(4-chloro-phenylamino)-piperidine-4-carbonitrile (1.97 g, 6.05 mmol) was added concentrated sulfuric acid (50 ml). The reaction stirred at room temperature as an orange homogeneous solution. After 24 hours the reaction was cooled to 0° C. and very slowly poured into concentrated ammonium hydroxide in ice. The precipitate was filtered and washed with water to give a white solid (202 mg, 71%).
Reaction SMILES: Br[CH:2]([CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([SH:20])=[CH:16][CH:15]=1>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([S:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)[CH2:8][CH2:9][CH2:10][CH3:11])[CH3:7]
Reactant: COc1ccc(S)cc1
Reactant: CCCCC(Br)C(=O)OCC
Product: CCCCC(Sc1ccc(OC)cc1)C(=O)OCC
Yield: 98 %

Procedure:
2-(4-Methoxy-phenylsulfanyl)-hexanoic acid ethyl ester was prepared according to the general method as outlined in Example 1. Starting from ethyl 2-bromo,hexanoate (7 g, 32 mmol) and 4-methoxybenzenethiol (4.2 g, 30 mmol), 8.3 g of the product was isolated. Yield 98%; Light yellow oil; MS: 283 (M+H)+.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1)[NH2:3].[F:13][C:14]([F:27])([F:26])[C:15](=O)[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=O>>[N:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:2]([C:4]3[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][OH:12])=[CH:8][CH:9]=3)[N:3]=[C:15]([C:14]([F:13])([F:26])[F:27])[CH:16]=2)=[CH:20][CH:21]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccncc1
Reactant: NNc1ccc(CCO)cc1
Agent: Cl
Product: OCCc1ccc(-n2nc(C(F)(F)F)cc2-c2ccncc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from 2-(4-hydrazinophenyl)ethanol hydrochloride and 4,4,4-trifluoro-1-pyridin-4-ylbutane-1,3-dione: MS (ESI) m/z 334 [M+H]+, 1H-NMR (CDCl3) δ 8.60-8.58 (2H, m), 7.28-7.24 (4H, m), 7.14-7.12 (2H, m), 6.88 (1H, s), 3.90-3.86 (2H, m), 2.92 (2H, t, J=6.6 Hz), 1.52 (1H, br.s).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]2[CH2:33][C@@H:32]([C:34]3[CH:45]=[CH:44][C:37]4[O:38][C:39]([CH3:43])([CH3:42])[O:40][CH2:41][C:36]=4[CH:35]=3)[O:31][C:30]2=[O:46])[CH:15]=[CH:16][CH:17]=1.C(O)(C)C>ClCCl>[CH3:42][C:39]1([CH3:43])[O:38][C:37]2[CH:44]=[CH:45][C:34]([C@H:32]3[O:31][C:30](=[O:46])[N:29]([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][C:14]4[CH:13]=[C:12]([NH:11][C:9]([NH:8][C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=5)=[O:10])[CH:17]=[CH:16][CH:15]=4)[CH2:33]3)=[CH:35][C:36]=2[CH2:41][O:40]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(N)c4)C(=O)O3)ccc2O1
Reactant: O=C=Nc1cccc(I)c1
Solvent: ClCCl
Solvent: CC(C)O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)Nc5cccc(I)c5)c4)C(=O)O3)ccc2O1
Reaction time: 5 h
Yield: 76.6 %

Procedure:
3-Iodophenylisocyanate (500 mg) was added to a solution of (5R)-3-{6-[2-{[(3-aminophenyl)methyl]oxy}ethoxy]hexyl}-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (700 mg) in dichloromethane (14 ml) and the mixture was stirred at 20° under nitrogen for 5 h. Isopropanol (14 ml) was added and the mixture was stirred for 16 h. The solvent was evaporated in vacuo to give a residue that was purified by Biotage. Elution with EtOAc-PE (2:1) gave the title compound (800 mg). LCMS RT=4.02 min, ES+ve 744 (MH)+.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]2[CH:14]=[C:13]([C:15]3[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([NH:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[N:16]=3)[S:12][C:11]=2[CH:33]=1)=[O:6].C1COCC1.[ClH:39]>CO.O>[ClH:21].[ClH:39].[ClH:21].[Cl:21][C:20]1[C:15]([C:13]2[S:12][C:11]3[CH:33]=[C:7]([C:5]([OH:6])=[O:4])[CH:8]=[CH:9][C:10]=3[CH:14]=2)=[N:16][C:17]([NH:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]2)=[N:18][CH:19]=1
Reactant: COC(=O)c1ccc2cc(-c3nc(NCCCN4CCN(C)CC4)ncc3Cl)sc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CN1CCN(CCCNc2ncc(Cl)c(-c3cc4ccc(C(=O)O)cc4s3)n2)CC1
Temperature: 25 °C
Yield: 67 %

Procedure:
Aqueous LiOH solution (2.0 M, 2.8 mL) is added to a stirred suspension of 2-{5-chloro-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-6-carboxylic acid methyl ester (0.840 g, 1.80 mmol) in MeOH (20 mL)/THF (20 mL)/H2O (6 mL), the resultant mixture is heated at 70° C. for 4.5 hours. While heating the solution, 5.0 N HCl (3.4 mL) is added in one portion then the solution is allowed to cool to ambient temperature to from a suspension. After filtration, the solid is dried in a vacuum oven at 60° C. for 4 hours to give the title compound (0.64 g, 67% yield). ES+(m/z) 446 (35Cl) and 448 (37Cl) [M+H].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:23])[CH:9]=[C:10]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:24].[C:25]([O-:28])(=[O:27])C.[Na+].[C]=O>COCCOC.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:22][C:17]1[CH:16]=[C:15]([C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:25]([OH:28])=[O:27])=[C:3]([CH3:24])[CH:4]=2)=[O:23])[CH:20]=[C:19]([Cl:21])[CH:18]=1
Reactant: Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Reactant: CC(=O)[O-]
Agent: [Fe+2]
Agent: [Pd+2]
Agent: [C]=O
Solvent: COCCOC
Solvent: O
Product: Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)O
Temperature: 25 °C
Yield: 58.2 %

Procedure:
To a solution of 4.85 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butene-1-one representing mixed geometrical isomers (isomeric ratio of 8:1) that was synthesized according to Synthetic Examples 1 and 2 and 1.36 g of sodium acetate in 20 mL of 1,2-dimethoxyethane and 20 mL of water in an autoclave, 0.25 g of 1,1′-bis(diphenylphosphino) ferrocene and 50 mg of palladium(II) acetate were added, the mixture was stirred for 5.5 hours at 110° C. in an atmosphere of carbon monoxide at 1.0 MPa. After that, the temperature was cooled to room temperature to isolate solid matter by filtration, diluted hydrochloric acid was added to extract with ethyl acetate, and then an organic layer was dehydrated and dried with saturated saline followed by anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified using silica gel column chromatography that was eluted with ethyl acetate-hexane (1:5) followed by crystallization from a mixed solvent of hexane and a small amount of ethyl acetate to obtain 2.6 g of aimed product as white solid.
Reaction SMILES: C1(N2C=C(Cl)C(Cl)[C:9](=[O:15])N2)C=CC=CC=1.[C:16]1([N:22]2[C:27](=[O:28])[C:26]([Cl:29])=[C:25](Cl)[CH:24]=[N:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CO>[C:16]1([N:22]2[C:27](=[O:28])[C:26]([Cl:29])=[C:25]([O:15][CH3:9])[CH:24]=[N:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1NN(c2ccccc2)C=C(Cl)C1Cl
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1cnn(-c2ccccc2)c(=O)c1Cl
Yield: 95 %

Procedure:
The title compound was prepared according to the method of (S. Cho et al. described in J. Het. Chem., (1996), 33, 1579-1582), starting with the N-phenyl-dichloropyridazinone. A mixture of 2-phenyl-4,5-dichloro-3(2H)-pyridazinone (1 g, 4.1 mmol) and finely powdered, anhydrous K2CO3 (580 mg, 4.2 mmol) in 50 mL of methanol was heated at reflux for 5 hours and concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The acetate layer was washed with water, and brine to provide 2-phenyl-4-chloro-5-methoxy-3(2H)-pyridazinone (yield: 920 mg, 95%). 1H NMR (300 MHz, DMSO-d6) δ 4.15 (s, 3H), 7.50 (m, 5H), 8.43 (s, 1H). MS (DCI/NH3) m/z 237 (M+H)+, 254 (M+NH4)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:14]2[CH:15]=[CH:16][C:11]([CH3:10])=[C:12]([N+:20]([O-:22])=[O:21])[CH:13]=2)[CH:7]=1
Reactant: Cc1ccc(B(O)O)cc1[N+](=O)[O-]
Reactant: COc1ccnc(Br)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccnc(-c2ccc(C)c([N+](=O)[O-])c2)c1
Temperature: 80 °C
Reaction time: 7 h
Yield: 95.1 %

Procedure:
To a suspension of 2-bromo-4-methoxypyridine (2.5 g), 4-methyl-3-nitrophenylboronic acid (3.37 g) and tetrakis(triphenylphosphine)-palladium (768 mg) in 1,2-dimethoxyethane (100 ml) was added 2M aqueous solution of sodium carbonate (18.6 ml). The mixture was stirred at 80° C. for 7 hours under a nitrogen atmosphere, then cooled to room temperature and diluted with ethyl acetate. The organic layer was separated, washed with water and brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. Methanol was added to the residue. The precipitate was collected by filtration and dried under reduced pressure to give 4-(4-methoxypyridin-2-yl)-2-nitrotoluene (3.09 g).
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[Cl:46])=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1>O1CCCC1>[Cl:46][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[CH2:39][C:28]1[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=1
Reactant: Clc1ccccc1Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: C1CCOC1
Product: O=c1[nH]nc(Cc2ccccc2Cl)cc1O

Procedure:
Prepared in the same way as 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(2-chlorophenyl)methyl]pyridazine (Intermediate 53) except that the solvent used for the hydrogenation was tetrahydrofuran and the product was recrystallised from a mixture of MTBE and heptanes.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([NH:16][C:17]([C:19]4[N:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]5=[N:21][CH:20]=4)=[O:18])[CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:28][CH3:29])=[N:8]2)=[N:2]1.Br[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1.O.[OH-].[Cs+]>CN(C=O)C>[CH2:28]([C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([C:19]2[N:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]3=[N:21][CH:20]=2)=[O:18])[N:7]([CH2:6][C:3]2[CH:4]=[CH:5][N:1]([CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[CH2:35][CH2:34]3)[N:2]=2)[N:8]=1)[CH3:29]
Reactant: CCc1nn(Cc2cc[nH]n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reactant: CC(C)(C)OC(=O)N1CCN(CCBr)CC1
Agent: [Cs+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nn(Cc2ccn(CCN3CCN(C(=O)OC(C)(C)C)CC3)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reaction time: 0.5 h

Procedure:
To a solution of N-(1-((1H-pyrazol-3-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (40.0 mg; 0.104 mmol) in dry DMF (0.5 mL) was added tert-butyl 4-(2-bromoethyl)piperazine-1-carboxylate (30.4 mg; 0.104 mmol) and cesium hydroxide hydrate (17.4 mg; 0.104 mmol). The mixture was stirred under a nitrogen atmosphere for 30 minutes. The mixture was filtered, washing with methanol and ethyl acetate, and the solvent was removed under reduced pressure. The residue (a mixture of two regioisomers) was purified by preparative thin layer chromatography on silica, eluting with 10% methanol in dichloromethane. The desired isomer tert-butyl 4-(2-(3-((3-ethyl-4-(imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate was isolated (21.5 mg) along with some of the alternate isomer.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.I[CH:14]([CH2:16][CH3:17])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH:14]([CH2:16][CH3:17])[CH3:15])[CH:6]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: CCC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(C)Oc1cccc(CC(=O)OC)c1
Temperature: 65 °C

Procedure:
To 3-hydroxyphenyl acetic acid methyl ester (27.3 g, 165 mmol) in acetone (200 mL) was added 2-iodobutane (55 mL, 478 mmol) and potassium carbonate (83 g, 601 mmol). The mixture was heated at 65° C. for 48 hrs and filtered through a Celite® pad. The filtrate was concentrated in vacuo and the residue was diluted with dichloromethane and water. The aqueous phase was extracted with dichloromethane (3×100 mL). The combined extracts were washed with saturated sodium chloride (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford (3-sec-butoxy-phenyl)-acetic acid methyl ester. To a solution of (3-sec-butoxy-phenyl)-acetic acid methyl ester in methanol (200 mL) was added 10N sodium hydroxide solution (50 mL). The reaction mixture was stirred at 60° C. for 4 hrs. The solvent was evaporated and the mixture was acidified to pH=3 by addition of 6N hydrogen chloride solution. The aqueous phase was extracted with dichloromethane (3×100 m]L). The combined extracts were washed with saturated aqueous sodium chloride solution (80 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford (3-sec-butoxy-phenyl) acetic acid (25 g, 73% yield) as a light brown oil.