Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1([CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([O:19]C)=[CH:11][C:10]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[OH-].[Na+]>[CH2:1]([O:8][C:9]1([CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[CH2:11][C:10]1=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC1=CC(=O)C(CCC(C)C)(OCc2ccccc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CCC1(OCc2ccccc2)C(=O)CC(=O)c2ccccc21
Yield: 92.4 %

Procedure:
A solution of Example 12A (26 mg, 0.074 mmol) in methanol (0.25 mL) and 1 N NaOH (0.25 mL) was stirred at 40° C. for 6 hours. The solution was concentrated in vacuo. Column chromatography on silica (7% methanol/dichloromethane) afforded the title compound (23 mg, 91%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.29-0.46 (m, 1H), 0.69 (dd, J=13.97, 6.62 Hz, 6H), 0.80-0.95 (m, 1H), 1.25-1.41 (m, 1H), 1.97 (m, 1H), 2.27 (m, 1H), 3.83 (d, J=10.66 Hz, 1H), 4.04-4.20 (m, 1H), 5.89 (s, 1H), 7.18-7.42 (m, 5H), 7.44-7.59 (m, 1H), 7.71 (br. s, 2H) 7.94 (br. s, 1H), 11.76 (s, 1H); MS (ESI) m/z 337.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][CH2:14][NH2:15])=[CH:8][CH:7]=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12][CH2:13][CH2:14][NH:15][C:18](=[O:19])[O:20][CH2:21][CH3:22])=[CH:10][CH:11]=1
Reactant: CC(C)=CCOc1ccc(SCCN)cc1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)NCCSc1ccc(OCC=C(C)C)cc1

Procedure:
In the same manner, 2-[4-(3-methyl-2-butenoxy)phenylthio]ethylamine is reacted with ethyl chloroformate to yield ethyl N-{2-[4-(3-methyl-2-butenoxy)phenylthio]ethyl}carbamate (compound 77, Table A).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH:18][C:17]=1[C:32](=[O:38])[C:33]([CH3:37])([CH3:36])[CH2:34][CH3:35].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH:18][C:17]=1[CH:32]([OH:38])[C:33]([CH3:37])([CH3:36])[CH2:34][CH3:35]
Reactant: CCC(C)(C)C(=O)c1cc(OCc2ccc(OC)cc2)ccc1-c1cc(OC)ccc1F
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(C)(C)C(O)c1cc(OCc2ccc(OC)cc2)ccc1-c1cc(OC)ccc1F
Reaction time: 0.17 h
Yield: 95.1 %

Procedure:
Under a nitrogen atmosphere, to a suspension of lithium aluminum hydride (28.2 mg) in THF (5.7 mL) was added dropwise a solution of 1-(2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)-[1,1′-biphenyl]-2-yl)-2,2-dimethylbutan-1-one (162.2 mg) in THF (1.9 mL) at 0° C., and the mixture was stirred for 10 min. To the reaction mixture was added a small portion of sodium sulfate decahydrate at 0° C., and the mixture was filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (155 mg) as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Cl:21])C(=O)C1>CN(C=O)C>[C:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]([F:12])([F:13])[F:11])[C:6]=1[Cl:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C(F)(F)F)n[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CC(C)(C)c1[nH]nc(C(F)(F)F)c1Cl

Procedure:
Following protocol L, 5-tert-butyl-3-trifluoromethyl-1H-pyrazole was treated with NCS in DMF to yield title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:16]=[C:17](\[CH3:20])/[CH2:18]O)[CH:5]=[C:6]([F:15])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:40]1(=[O:50])[NH:44][C:43](=[O:45])[C:42]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:41]12.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4](/[CH:16]=[C:17](\[CH3:20])/[CH2:18][N:44]2[C:40](=[O:50])[C:41]3[C:42](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:43]2=[O:45])[CH:5]=[C:6]([F:15])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C/C(=C\c1cc(F)c(Oc2ccccc2)c(F)c1)CO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C/C(=C\c1cc(F)c(Oc2ccccc2)c(F)c1)CN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of (E)-3-(3,5-difluoro-4-phenoxyphenyl)-2-methylprop-2-en-1-ol (Intermediate 93.1) (410 mg, 1.49 mmol) in dry toluene (7.45 mL) under N2 was added PPh3 and phthalimide. The resulting solution was cooled to 0° C. and diethyl azodicarboxylate (DEAD, 0.748 mL) was added dropwise over several minutes. The reaction was allowed to warm to room temperature and stirred overnight. After diluting with EtOAc (20 mL), the organic layer was washed with water (2×30 mL), brine (30 mL) and dried over Na2SO4. After removal of solvent, the resulting residue was applied to a silica gel column (15% EtOAc in hexanes) to yield 385 mg of the title compound (63%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1.Cl>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][NH:20]4)=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncccc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Agent: Cl
Product: COc1ccc(Nc2ncccc2-c2nc(C)nc3[nH]cnc23)cn1
Yield: 94.7 %

Procedure:
A solution of 6-methoxy-N-(3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)pyridin-3-amine (95.3 mg, 228 μmol) in 2N aqueous HCl (2.0 mL, 4 mmol) was heated briefly at 100° C. in an oil bath, and then the heater was turned off and the mixture allowed to slowly cool. The solution was concentrated and purified by SCX ion exchange chromatography washing with MeOH and eluting off with 2N NH3/MeOH to give N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)pyridin-2-amine (72 mg, 95% yield) as an orange solid. 1H NMR (400 MHz, d6-DMSO) δ 13.60 (br. s., 1H); 12.68 (s, 1H); 9.80 (dd, J=7.82, 1.96 Hz, 1H); 8.60 (s, 1H); 8.54 (d, J=2.69 Hz, 1H); 8.31 (dd, J=4.65, 1.96 Hz, 1H); 8.20 (dd, J=8.92, 2.81 Hz, 1H); 7.00 (dd, J=7.95, 4.77 Hz, 1H); 6.85 (d, J=8.80 Hz, 1H); 3.85 (s, 3H); 2.86 (s, 3H). m/z (ESI, +ve) 334.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:49])[CH2:4][CH2:5][C:6]1[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:29]=[CH:28][C:22]3[C:23](=[O:27])[CH:24]=[CH:25][O:26][C:21]=3[C:20]=2[CH2:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46].O1C2C(=CC=CC=2)C(=O)C=C1>[Pd].CO.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:49])[CH2:4][CH2:5][C:6]1[C:7]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46])=[CH:8][CH:9]=[CH:10][C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:29]=[CH:28][C:22]2[C:23](=[O:27])[CH2:24][CH2:25][O:26][C:21]=2[C:20]=1[CH2:30][CH2:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COC(=O)CCCCCOc1cccc(CCCCCCOc2ccc3c(=O)ccoc3c2CCCc2ccccc2)c1CCC(=O)OC
Agent: [Pd]
Agent: O=c1ccoc2ccccc12
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CCCCCOc1cccc(CCCCCCOc2ccc3c(c2CCCc2ccccc2)OCCC3=O)c1CCC(=O)OC
Yield: 38 %

Procedure:
A 1.0 g (1.49 mmol) sample of 2-[(6-methoxy-6-oxohexyl)oxy]-6-[6-[[4-oxo-8-(3-phenylpropyl)-4H-1-benzopyran-7-yl]oxy]hexyl]benzenepropanoic acid methyl ester from the preceding example was catalytically hydrogenated over 10% palladium on carbon, in 30 mL of 1:1 methanol-ethyl acetate, at room temperature and 1 atmosphere, using thin-layer chromatography to monitor the reduction of the starting chromone. The catalyst was filtered and the filtrate was concentrated in vacuo giving an oily product which was purified by flash-chromatography. There was obtained 0.38 g (38%) of the title chromanone as a colorless oil.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH:2]1[C@H:7]1[CH:11]=[CH:10][CH2:9][C@H:8]1[C:12]([OH:14])=[O:13].[N+](=[CH2:17])=[N-]>CO>[CH3:17][O:13][C:12]([C@H:8]1[C@@H:7]([CH:2]2[S:3][CH2:4][CH2:5][CH2:6][S:1]2)[CH:11]=[CH:10][CH2:9]1)=[O:14]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)[C@@H]1CC=C[C@@H]1C1SCCCS1
Solvent: CO
Product: COC(=O)[C@@H]1CC=C[C@@H]1C1SCCCS1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
214 mg (0.93 mmole) of cis-3-(1,3-dithian-2-yl)-4-cyclopentene-2-carboxylic acid (as prepared in example 4) are dissolved in 3 ml. of dried methanol. To the cooled mixture (0° C), there is added an ethereal solution of diazomethane up to persistente yellow colour. The solution is stirred for 3 hours at room temperature, the solvent is evaporated under reduced pressure and the oily residue is purified by column chromatography (eluant C6H6 /CH3CO2C2H5 : 80/20) to yield cis-methyl-3-(1,3-dithian-2-yl)-4-cyclopentene-2-carboxylate.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[F:8][CH:9]([F:12])[CH2:10][OH:11].F[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[S:21][C:22]2[C:27]([N:28]=1)=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][N:23]=2>O>[F:8][CH:9]([F:12])[CH2:10][O:11][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[S:21][C:22]2[C:27]([N:28]=1)=[CH:26][C:25]([C:29]([F:32])([F:30])[F:31])=[CH:24][N:23]=2
Reactant: OCC(F)F
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)cnc2s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)COc1cnccc1-c1nc2cc(C(F)(F)F)cnc2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.1 %

Procedure:
To a mixture of 51 mg of sodium hydride (60% dispersion in mineral oil) and 2 ml of DMF was added at room temperature a mixture of 0.10 g of 2,2-difluoro-ethanol and 1 ml of DMF. This mixture was stirred at room temperature for 15 minutes, then, cooled with ice. Next, to this was added a mixture of 0.29 g of 2-(3-fluoropyridin-4-yl)-6-(trifluoromethyl)thiazolo[5,4-b]pyridine and 10 ml of DMF, and the resultant mixture was stirred for 0.5 hours under ice cool, further for 0.5 hours at room temperature. To the reaction mixture was added water, and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, to obtain 0.27 g of 2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-6-(trifluoromethyl)thiazolo[5,4-b]pyridine (hereinafter, referred to as the present compound 13).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].OS(O)(=O)=O>C(COC)OC.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.CCCCCC>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[F:9])=[CH:4][N:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: Nc1ncc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: COCCOC
Solvent: CCCCCC
Product: Nc1ncc(-c2ccccc2F)cn1
Temperature: 25 °C

Procedure:
To a solution of 2-amino-5-bromo-pyrimidine 9 (49.40 g, 284 mmol) in dimethoxyethane (500 mL) were added 2-fluorophenylboronic acid 10 (43.66 g, 312 mmol), 2.0 M aqueous sodium carbonate solution (285 mL, 570 mmol) and tetrakis(triphenylphosphine)palladium (0) (3.28 g, 2.84 mmol). The mixture was stirred at reflux for 2 hr. The reaction mixture was cooled to ambient temperature and slowly poured into 10% H2SO4 (600 mL), which was added with hexane (300 mL). The acidic aqueous layer was separated, and the insoluble material and the organic layer was extracted with 10% H2SO4 (200 mL×2). The combined acidic aqueous layers were washed with EtOAc (200 mL), neutralized with K2CO3 to give a precipitate of the title compound and an inorganic salt, which were washed with water (3000 mL) to afford the title compound 11 as a white solid. The white solid was dissolved in hot THF (500 mL). The insoluble material was filtered off and concentrated in vacuo. The residual solid was washed with IPE to afford the title compound 11 as crystals.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]2[N:11]([C:15]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]4[CH2:30][CH2:29][CH:28]([C:31](O)=[O:32])[CH2:27][CH2:26]4)[N:19]=3)=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:4])=[O:3].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH:70]1[CH2:75][CH2:74][CH:73]([OH:76])[CH2:72][CH2:71]1>CN(C=O)C.O>[OH:76][CH:73]1[CH2:74][CH2:75][N:70]([C:31]([CH:28]2[CH2:29][CH2:30][CH:25]([NH:24][C:20]3[N:19]=[C:18]([C:15]4[N:11]5[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])[C:10]5=[N:17][CH:16]=4)[CH:23]=[CH:22][N:21]=3)[CH2:26][CH2:27]2)=[O:32])[CH2:71][CH2:72]1
Reactant: CS(=O)(=O)CCCOc1cccn2c(-c3ccnc(NC4CCC(C(=O)O)CC4)n3)cnc12
Reactant: OC1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)CCCOc1cccn2c(-c3ccnc(NC4CCC(C(=O)N5CCC(O)CC5)CC4)n3)cnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
A solution of 4-{4-[8-(3-methanesulfonyl-propoxy)-imidazo[1,2-a]pyridine-3-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid (0.09 g) in DMF (3 mL) was treated with BOP (0.126 g), and the mixture stirred at RT for 15 min DIEA (0.1 mL) and piperidin-4-ol (29 mg) were added, and the mixture stirred at RT overnight. The reaction mixture was then diluted with water and stirred at RT for 30 min, permitting the product to precipitate. The resulting solid was filtered, washed with water, dried, and titurated with EtOAc. The product was filtered, dried at 50° C. under vacuum overnight to provide (4-hydroxy-piperidin-1-yl)-(4-{4-[8-(3-methanesulfonyl-propoxy)-imidazo[1,2-a]pyridin-3-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanone (compound 5, 71 mg).
Reaction SMILES: [C:1]([NH:24][CH:25]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:26]([O:28]C)=[O:27])(=[O:23])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH3:22].[OH-].[Na+].Cl>CO>[C:1]([NH:24][CH:25]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:26]([OH:28])=[O:27])(=[O:23])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH3:22]
Reactant: CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)NC(CC(C)C)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)NC(CC(C)C)C(=O)O
Temperature: 50 °C
Yield: 86.2 %

Procedure:
To a solution of methyl 2-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoate (610 mg, 1.34 mmol) in MeOH (15 mL) was added 2 M NaOH (30 mL). The reaction mixture was heated (50° C., 16 h), cooled (RT), and acidified with 2 M HCl to pH=1. The mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by silica chromatography, (MeOH:DCM, 0-10%) to afford 2-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoic acid (0.51 g, 89%) as a light yellow solid. Mass calculated for C28H43NO3=441.65. found: [M+H]+=442.1.
Reaction SMILES: [C:1]1([C:7](=[C:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[CH2:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)[C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.CCO.[OH-].[Na+]>Cl.CCOC(C)=O>[C:1]1([C:7](=[C:18]2[CH2:19][C:20]([CH3:27])([CH3:26])[CH2:21][C:22]([CH3:25])([CH3:24])[CH2:23]2)[C:8]2[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccccc2)c2ccc(C(=O)O)cc2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
A mixture of 20, THF (15 mL), EtOH (15 mL) is charged with 1 N aqueous NaOH (20 mL) and heated to reflux. After 4 h the reaction was allowed to cool to room temperature and then diluted with 1 N aqueous HCl (30 mL) and EtOAc (50 mL). The organic fraction was washed with water (2×40 mL) and brine (40 mL) then dried (Na2SO4). After concentrating, the solid was triturated with hexane (25 mL), filtered and air-dried to afford 770 mg (86%) of the title compound 21 as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.82 (s, 1H), 7.86 (d, J=8.2 Hz, 2H), 7.16-7.29 (m, 7H), 1.90 (s, 2H), 1.88 (s, 2H), 1.26 (s, 2H), 0.88 (s, 12H). LCMS (ESI): m/z 347 (M−H)−. Anal. Calcd for C24H28O2: C, 82.69; H, 8.12. Found: C, 82.48; H, 8.14.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5]CC)=O.[C:12]1([NH:18][NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CO.C[O-].[Na+]>C(O)CCC>[C:20]1([N:19]2[C:1](=[O:9])[CH2:2][C:3](=[O:5])[N:18]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: c1ccc(NNc2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCO
Product: O=C1CC(=O)N(c2ccccc2)N1c1ccccc1
Temperature: 100 °C
Yield: 68.7 %

Procedure:
Three point six five (3.65) grams (22.8 mmol) of diethyl malonate and 4.00 g (21.7 mmol) of 1,2-diphenylhydrazine were dissolved in 10 ml of n-butanol, then 4.61 g (23.9 mmol) of a 28% methanol solution of sodium methoxide was added thereto, and the reaction system was heated at 100° C. for 10 hours. Subsequently the solvent was distilled off under reduced pressure, 10 ml of water was added thereto and stirred, and then the reaction solution was filtered. An activated carbon was added to the recovered filtrate and stirred for 30 minutes. After stirring, the solution was filtered again to recover the filtrate. Four (4) ml of hydrochloric acid was added to the filtrate, and the precipitated solid was recovered by filtration. Thus, 3.76 g (yield: 60%) of 1,2-diphenyl-3,5-pyrazolidinedione was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:14](SC)=[N:15][CH2:16][Si](C)(C)C)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)#[N:2].[Cl:23][C:24]1[CH:29]=[C:28]([C:30]([C:32]([F:35])([F:34])[F:33])=[CH2:31])[CH:27]=[C:26]([Cl:36])[N:25]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[Cl:23][C:24]1[CH:29]=[C:28]([C:30]2([C:32]([F:33])([F:34])[F:35])[CH2:31][C:14]([C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[N:12][CH:11]=[N:10]4)=[C:3]([CH:4]=3)[C:1]#[N:2])=[N:15][CH2:16]2)[CH:27]=[C:26]([Cl:36])[N:25]=1
Reactant: C=C(c1cc(Cl)nc(Cl)c1)C(F)(F)F
Reactant: CSC(=NC[Si](C)(C)C)c1ccc(-n2cncn2)c(C#N)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(C2=NCC(c3cc(Cl)nc(Cl)c3)(C(F)(F)F)C2)ccc1-n1cncn1
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To the crude solution of methyl 3-cyano-4-(1H-1,2,4-triazol-1-yl)-N-[(trimethylsilyl)methyl]benzenecarbimidothioate (Japanese patent application JP2008-143120) was added 2,6-dichloro-4-(3,3,3-trifluoroprop-1-en-2-yl)pyridine (0.15 g) and the resultant mixture was cooled to −10° C. Additionally, a solution of tetrabutylammonium fluoride (0.70 mL of 1.0 M in THF) in THF was added over 10 minutes under argon atmosphere. The reaction mixture was stirred for 30 minutes at the same temperature and returned to room temperature gradually, and then stirred 3 hours. Water was added to the reaction liquor, and aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous brine, and subsequently dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain 5-[3-(2,6-dichloropyridin-4-yl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]-2-(1H-1,2,4-triazol-1-yl)benzonitrile (0.14 g) at a yield of 46%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].C1(C)C=CC(S(O[CH2:35][C:36]([F:39])([F:38])[F:37])(=O)=O)=CC=1>CN(C)C=O.CS(C)=O>[F:37][C:36]([F:39])([F:38])[CH2:35][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:9])=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)c1ccc(OCC(F)(F)F)cc1
Temperature: 130 °C
Reaction time: 0.75 h

Procedure:
A mixture of benzyl 4-hydroxyphenyl ketone (12.5 g; 0.059 mol), potassium carbonate (11.2 g; 0.08 mol) and sodium iodide (0.5 g) in dimethylformamide (80 ml) was heated to 130° C. At this temperature, 2,2,2-trifluoroethyl p-toluenesulphonate (16.4 g; 0.066 mol), dissolved in dimethyl sulphoxide (30 ml), was added dropwise over 30 minutes. It was then stirred for 45 minutes at a 130° C. After cooling, the reaction mixture was poured into ice-water (500 ml) and the precipitate separated. This was recrystallised from diisopropyl ether/hexane to give pure benzyl 4-(2,2,2-trifluoroethoxy)phenyl ketone.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[C:9](O)(=O)[CH2:10]C.S(=O)(=O)(O)O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[OH-].[NH4+]>O.[N+]([O-])([O-])=O.[Ag+]>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][C:7]=1[CH2:9][CH3:10]
Reactant: CCC(=O)O
Reactant: Clc1ccc(Cl)nn1
Agent: [Ag+]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: O
Product: CCc1cc(Cl)nnc1Cl
Temperature: 60 °C
Yield: 54.3 %

Procedure:
To a suspension of 3,6-dichloropyridazine (11.25 g, 0.076 mol, 1.0 eq), silver nitrate (6.41 g, 0.038 mol, 0.5 eq), propionic acid (8.39 g, 0.113 mol, 1.5 eq) in water (125 mL) at 50° C. was added a solution of sulfuric acid (11.54 mL, 0.227 ml. 3.0 eq) in water (125 mL). The solution was heated to 60° C. and then a solution of ammonium persulfate (51.7 g, 0.227 mol, 3.0 eq) was added in slowly in 20 minutes. The solution was then heated to 75° C. for 30 minutes. The reaction solution was poured into ice water and adjusted to pH 7 with 30% ammonium hydroxide solution. The mixture was extracted with dichloromethane (3×), and the extracts washed with water, brine, dried with sodium sulfate and concentrated in vacuo. The resulting residue was purified using an ISCO chromatography system (120 g silica cartridge, 5% ethyl acetate in heptane) to provide the compound 3,6-dichloro-4-ethylpyridazine (7.3 g, 54% yield). LC/MS, m/e 177.15 (M+1). HPLC Rt, 2.03 min. Waters Sunfire C18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.