Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25].O>CS(C)=O>[CH2:25]([N:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=[CH2:17]
Reactant: C=CCCCCCCCBr
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 0.25 h
Yield: 81.6 %

Procedure:
1-(8,9-Oxidononyl)-3,7-dimethylxanthine was synthesized as follows: A mixture of theobromine (17.64 g, 98 mmol) and sodium hydride (2.35 g, 98 mmol) in dimethylsulfoxide (250 ml) was stirred for 15 minutes. 9-Bromo-1-nonene (20.0 g, 98 mmol) was added and stirring continued for 3 days. The reaction mixture was poured into water (300 ml) and extracted with dichloromethane (4×200 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution (2×150 ml), dried over sodium sulfate, and the solvents evaporated under vacuum. The residue was crystallized (dichloromethane-ether) to give 1-(8-nonenyl)-3,7-dimethylxanthine (24.34 g, 99% yield) as white crystals.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH2:12]([S:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][N:18]=1)[CH:13]([CH3:15])[CH3:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:12]([S:16][C:17]1[N:18]=[CH:19][C:20]([C:23]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:24]=2)=[CH:21][CH:22]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CSc1ccc(C#N)cn1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)CSc1ccc(-c2nc(=O)c3ccccc3s2)cn1
Yield: 24.4 %

Procedure:
A mixture of methyl thiosalicylate (1.01 g, 6.0 mmol), 2-isobutylthio-5-cyanopyridine (1.03 g, 5.0 mmol), triethylamine (0.98 ml, 7.0 mmol) and toluene (10 ml) was refluxed under nitrogen atmosphere for 20 hrs. The reaction mixture was concentrated. The residue was subjected to a silica gel column chromatography, eluted with ethyl acetate-hexane (2:1, v/v) and recrystallized from ethyl acetate-isopropylether to give the titled compound (0.40 g, 23%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12]CC=C)[O:8][C:7](=[O:16])[CH:6]=[CH:5]2.CCN([C:22]1[CH:23]=CC=C[CH:27]=1)CC>CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:23][CH:22]=[CH2:27])[C:11]=1[OH:12])[O:8][C:7](=[O:16])[CH:6]=[CH:5]2
Reactant: CCN(CC)c1ccccc1
Reactant: C=CCOc1cc2oc(=O)ccc2cc1C
Solvent: CCCCCC
Product: C=CCc1c(O)c(C)cc2ccc(=O)oc12

Procedure:
A solution of 6-methyl-7-hydroxycoumarin (IV) (11.4 g) in diethylaniline (80 ml) was refluxed for 2 h. After cooling the solution was diluted with n-hexane (500 ml) yielding a precipitate, which was collected by filtration, washed several times with n-hexane and crystallized from EtOAc, yielding 6-methyl-7-hydroxy-8-allylcoumarin (VII) (6.3 g; m.p. 161°-2° C.). ##STR13##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C([N-]C(C)C)(C)C.[Li+].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:23](Cl)=[O:24].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:23]([C:22]1[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:20]([O:19][CH3:18])[CH:21]=1)=[O:24]
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)cc1OC
Temperature: 0 °C
Yield: 50.4 %

Procedure:
A solution of 3,5-dichloro-4-methyl-pyridine (2.06 g, 12.7 mmol) in dry tetrahydrofuran (30 ml) was cooled down to −78° C., then a 1.8 M solution of lithium diisopropylamide in tetrahydrofuran (7.4 ml, 13.3 mmol) was added dropwise under stirring, keeping the temperature below −70° C. The resulting solution was stirred for 30 min., then a solution of 3,4-dimethoxy-benzoyl chloride (2.55 g, 12.7 mmol) in dry tetrahydrofuran (20 ml) was added dropwise, maintaining the temperature below −70° C. After stirring for 15 minutes, ice (20 g) was added, followed by further 500 ml of water. The mixture was extracted with ethyl acetate (2×50 ml), the combined organic layers were dried over sodium sulphate and evaporated under reduced pressure to give an oil that was purified by flash chromatography (Eluent:ethyl acetate/petroleum ether from 10/90 to 30/70 v:v). 2.1 grams (6.4 mmol, 52% yield) of the title compound were obtained as a white solid.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=1[CH2:27][O:28][CH3:29].FC1C=C(F)C=CC=1N>>[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[CH:22][C:21]=1[CH2:27][O:28][CH3:29]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: COCc1cc(N)ccc1F
Agent: Nc1ccc(F)cc1F
Agent: [Na+]
Product: COCc1cc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)ccc1F
Yield: 46.6 %

Procedure:
The product is prepared according to the procedure described in example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 900 mg of 4-fluoro-3-(methoxymethyl)aniline prepared previously, in place of the 2,4-difluoroaniline. 168 mg of N-[4-fluoro-3-(methoxymethyl)phenyl]-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH:1]1([S:4][C:5]([F:18])([F:17])[C:6]2([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=3[F:16])[CH2:8][O:7]2)[CH2:3][CH2:2]1.[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH:1]1([S:4][C:5]([F:18])([F:17])[C:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])([OH:7])[CH2:8][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[CH2:3][CH2:2]1
Reactant: Fc1ccc(C2(C(F)(F)SC3CC3)CO2)c(F)c1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: OC(Cn1cncn1)(c1ccc(F)cc1F)C(F)(F)SC1CC1
Temperature: 55 °C
Reaction time: 1.5 h
Yield: 39.8 %

Procedure:
To a solution of 2-[(cyclopropylthio) (difluoro)-methyl]-2-(2,4-difluorophenyl)oxirane (5.0 g, 0.017 mol) in DMSO (70 ml), 1,2,4-triazole (3.48 g, 0.05 mol) and potassium carbonate (6.95 g, 0.05 mol) were added, followed by stirring at 55° C. for 1.5 hours. After the completion of the reaction, water was added to the reaction mixture. The resulting mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated saline and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue so obtained was crystallized from isopropyl ether—ethyl acetate, whereby 1-(cyclopropylthio)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol (2.35 g, yield: 32%) was obtained as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][CH:8]([OH:22])[CH2:9][C@H:10]([OH:21])[CH2:11][O:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].O[C@H:25]1[CH2:30]C(=O)O[C@H](COC(=O)C2C=CC=CC=2)[CH2:26]1.COC(=O)C[C@H]1C[C@@H](COC(=O)C2C=CC=CC=2)OC(C)(C)O1>>[C:1]([O:5][C:6](=[O:23])[CH2:7][C@H:8]1[CH2:9][C@@H:10]([CH2:11][O:12][C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:21][C:25]([CH3:30])([CH3:26])[O:22]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(O)C[C@H](O)COC(=O)c1ccccc1
Reactant: O=C1C[C@H](O)C[C@@H](COC(=O)c2ccccc2)O1
Agent: COC(=O)C[C@H]1C[C@@H](COC(=O)c2ccccc2)OC(C)(C)O1
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](COC(=O)c2ccccc2)OC(C)(C)O1

Procedure:
89.3%; (5S)-6-benzoyloxy-3,5-dihydroxyhexanoic tert-butyl ester: 8.8%; (2S,4R)-4-hydroxy-6-oxo-2-[(benzoyloxy)methyl]tetrahydro-2H-pyran: 0.1%; 2-[(4R,6S)-2,2-dimethyl-6-benzoyloxymethyl-1,3-dioxan-4-yl]acetic methyl ester: undetected.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[Cl:19]N1C(=O)CCC1=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH2:18][Cl:19])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cccc2c(-c3ccc(F)cc3)nccc12
Product: Fc1ccc(-c2nccc3c(CCl)cccc23)cc1

Procedure:
1-(4-Fluorophenyl)-5-methylisoquinoline was reacted with N-chlorosuccinimide in the same way as in step (a) of Example 2 to afford 1-(4-flurophenyl)-5-chloromethylisoquinoline as colorless needles having a melting point of 109.5° to 111.5° C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:21])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15](Cl)[N:14]=2)[CH2:3][CH2:2]1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[CH2:25][CH2:24]1>C(Cl)Cl.CO>[Cl:19][C:18]1[C:13]([NH:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:21])=[N:14][C:15]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([CH2:29][N:26]3[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]3)=[CH:36][CH:35]=2)=[N:16][CH:17]=1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: O=C(NC1CC1)c1ccccc1Nc1nc(Cl)ncc1Cl
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC4CC4)n3)cc2)CC1
Yield: 38 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from N-cyclopropyl-2((2,5-dichloropyrimidin-4-yl)amino)benzamide and 4-((4-methylpiperazin-1-yl)methyl)aniline in 38% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.64 (d, 1H, J=8.5 Hz), 8.11 (s, 1H), 7.50 (d, 2H, J=8.2 Hz), 7.44 (m, 2H), 7.25 (d, 2H, J=8.2 Hz), 7.07 (t, 1H, J=7.5 Hz), 6.38 (bs, 1H), 3.50 (s, 2H), 2.93 (q, 1H, J=3.4 Hz), 2.55 (bs, 8H), 2.35 (s, 3H), 0.92 (m, 2H), 0.65 (m, 2H); MS (ESI): 492.1 [M+H]+.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:15]=[CH:14][O:13][N:12]=1)([O-:3])=[O:2].[CH2:18]([NH2:20])[CH3:19]>>[N+:1]([CH:4]=[C:5]([NH:20][CH2:18][CH3:19])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:15]=[CH:14][O:13][N:12]=1)([O-:3])=[O:2]
Reactant: CCN
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1ccon1
Product: CCNC(=C[N+](=O)[O-])NCCSCc1ccon1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-(3-isoxazolylmethylthio)-ethylamino]ethylene (see Example 31 (ii) with ethylamine by the procedure of Example 8(ii) gives the title product.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])[CH3:2].C([O:18][C:19]([NH:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]([CH2:37][CH3:38])([CH2:35][CH3:36])[C:31]([O:33][CH3:34])=[O:32])[CH2:25][CH2:24]1)=O)(C)(C)C>>[CH2:35]([C:30]([CH2:29][N:26]1[CH2:25][CH2:24][CH:23]([CH2:22][NH:21][C:19]([N:6]2[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]([CH:1]([CH3:3])[CH3:2])[C:5]2=[O:13])=[O:18])[CH2:28][CH2:27]1)([CH2:37][CH3:38])[C:31]([O:33][CH3:34])=[O:32])[CH3:36]
Reactant: CCC(CC)(CN1CCC(CNC(=O)OC(C)(C)C)CC1)C(=O)OC
Reactant: CC(C)n1c(=O)[nH]c2ccccc21
Product: CCC(CC)(CN1CCC(CNC(=O)n2c(=O)n(C(C)C)c3ccccc32)CC1)C(=O)OC

Procedure:
The title compound was prepared according to the procedure described in Step 2 of Example 8 from 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one and Methyl 2-[(4-{[(tert-butoxycarbonyl)amino}methyl}piperidin-1-yl)methyl]-2-ethylbutanoate (step 1 of Example 13).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]=[C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:7][C:6]=2[CH:17]=1.[H-].[Na+].I[CH3:21]>CN(C)C=O.O>[CH3:21][O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]=[C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:7][C:6]=2[CH:17]=1
Reactant: CCOC(=O)CC1=COc2ccc(O)cc2O1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC1=COc2ccc(OC)cc2O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.8 g (12.75 mmol) of the ester obtained in Step B are dissolved in 30 ml of anhydrous N,N-dimethylformamide. 0.61 g (16 mmol) of sodium hydride is then added slowly to the reaction mixture previously cooled to 0° C. After 30 minutes of stirring under argon and at 0° C., 2.28 g (16 mmol) of iodomethane are added to the reaction medium. After 4 hours of stirring at ambient temperature, the solvent is evaporated in vacuo; the residue obtained is then taken up in water and then extracted with ethyl acetate. The organic phase, dried over magnesium sulphate and then filtered, is concentrated under reduced pressure. The title ester is obtained pure in the form of a white solid after passage over a silica column (eluant: ethyl acetate/petroleum ether: 30/70).
Reaction SMILES: C(O[C:4](=[N:14][CH3:15])[CH2:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[F:13])C.[C:16]([NH2:22])(=[O:21])[C:17]([NH:19][NH2:20])=O.N>CN1CCOCC1.ClCCl>[F:12][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([F:13])[C:6]=1[CH2:5][C:4]1[N:14]([CH3:15])[C:17]([C:16]([NH2:22])=[O:21])=[N:19][N:20]=1
Reactant: NNC(=O)C(N)=O
Reactant: CCOC(Cc1c(F)cccc1F)=NC
Agent: N
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cn1c(Cc2c(F)cccc2F)nnc1C(N)=O

Procedure:
320 mg (1.5 mmol) of 1-ethoxy-2-(2,6-difluorophenyl)-1-(N-methylimino)-ethane and 155 mg (1.5 mmol) of oxalic acid monoamide monohydrazide are dissolved under a nitrogen atmosphere in 5 ml of N-methylmorpholine and the whole is heated under reflux for 41 hours. After cooling, the reaction mixture is diluted with 20 ml of dichloromethane and extracted by shaking in succession twice with water, twice with 2N hydrochloric acid and again with water The last three acidic aqueous phases obtained are combined, rendered alkaline with concentrated ammonia solution and extracted three times with dichloromethane. The combined organic phases are dried over magnesium sulphate and concentrated. Recrystallisation of the crude product from ethanol yields 102 mg (27% of the theoretical yield) of the desired 5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxamide which melts at 189°-190°.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH3:28])[C:7](=[O:27])[CH:8]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.B(Br)(Br)Br.O>C(Cl)Cl.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH3:28])[C:7](=[O:27])[CH:8]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(C2=NC(Cc3ccccc3Cl)C(=O)N(C)c3ccc(Cl)cc32)cc1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CN1C(=O)C(Cc2ccccc2Cl)N=C(c2ccc(O)cc2)c2cc(Cl)ccc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 8.1 %

Procedure:
(Z)-7-chloro-3-(2-chlorobenzyl)-5-(4-methoxyphenyl)-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one (230 mg, 0.524 mmol) was dissolved in methylene chloride (5 mL) and cooled to −78° C. under nitrogen. Boron tribromide (54 μL 0.576 mmol) was added dropwise. The mixture turned orange. It was kept at −78° C. for 2 h then allowed to warm to RT. Tlc indicated no reaction after 6 hr. An additional equivalent of boron tribromide was added. The mixture was left stirring overnight at RT. Carefully added water (2 mL) then brine (2 mL). The aqueous layer was extracted twice with methylene chloride. The combined organic layers were dried over magnesium sulfate then filtered and the solvent evaporated. The residue was chromatographed on silica gel eluting with 30-50% ethyl acetate in hexanes to give (Z)-7-chloro-3-(2-chlorobenzyl)-5-(4-hydroxyphenyl)-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one as a yellow solid (18 mg). 1H NMR (300 MHz, CDCl3) δ 3.4 (s, 3H), 3.6-3.8 (m, 2H), 3.8-3.9 (m, 1H), 6.8 (d, 2H), 7.1-7.6 (m, 9H); ESI m/z measured 425.0828 [M+H+], calculated 425.0824.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@H:5]([CH2:7]O)[CH2:4][CH2:3]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[CH3:9][C:2]1([CH3:1])[O:6][C@H:5]([CH2:7][N:33]2[C:29](=[O:39])[C:30]3[C:31](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:32]2=[O:34])[CH2:4][CH2:3]1
Reactant: CC1(C)CC[C@@H](CO)O1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CC[C@@H](CN2C(=O)c3ccccc3C2=O)O1
Temperature: 8 °C

Procedure:
To a stirred solution of (S)-(5,5-dimethyltetrahydrofuran-2-yl)methanol (14 g, 108 mmol) and PPh3 (33.8 g, 129 mmol) in THF (140 ml) under N2 was added phthalimide (17.40 g, 118 mmol) to give a suspension. The mixture was cooled to 8° C. and DIAD (27.2 ml, 140 mmol) was added dropwise over 30 mins keeping internal T<10° C. The resulting white slurry was diluted with water (100 ml) and extracted with EtOAc (100 ml). The organics were washed with sat. NaHCO3 (100 ml), brine (100 ml) and dried (MgSO4) and concentrated under reduced pressure. Purification by chromatography on silica eluting with 0-20% EtOAc/iso-hexane afforded the title compound as a white crystalline solid;
Reaction SMILES: [CH:1]([P:4]1(=[O:12])[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[CH2:6][O:5]1)=[C:2]=[CH2:3].CC1(C)COP(C#CC)(=O)[O:16]C1.O.NN.Cl>>[CH2:1]([P:4]1(=[O:12])[O:5][CH2:6][C:7]([CH3:10])([CH3:11])[CH2:8][O:9]1)[C:2]([CH3:3])=[O:16]
Reactant: CC#CP1(=O)OCC(C)(C)CO1
Reactant: C=C=CP1(=O)OCC(C)(C)CO1
Agent: Cl
Agent: NN
Solvent: O
Product: CC(=O)CP1(=O)OCC(C)(C)CO1
Yield: 57.5 %

Procedure:
A solution mixture of II and III obtained in Reference Example 1 was stirred under cooling with ice and 510 g (10.2 mol) of hydrazine monohydrate was dropwise added thereto. After the completion of dropwise addition, the solution mixture was stirred for 30 minutes (the reaction was completed in ten minutes), and 11.2 kg of 10% by weight hydrochloric acid was added thereto. The solution mixture was stirred for one hour at room temperature and 5.0 kg of the solvent was distilled off. The solution was subjected to salting-out by addition of 1.38 kg of sodium chloride and extracted 2 times with 15.8 kg of chloroform. The chloroform layers were combined and dried over anhydrous sodium sulfate, followed by filtration. The solvent was distilled off, and the residue was dissolved in 3.5 kg of toluene and cooled with ice. The crystal thus precipitated was collected by filtration by means of suction and washed with 1.0 kg of toluene cooled and dried to obtain 1,000 g (yield: 57.5% through 4 steps) of the desired product of 2-acetonyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane as colorless crystal.
Reaction SMILES: [C:1]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:28][C:29]1([CH3:45])[O:34][CH:33]([C:35]([NH:37][CH2:38][CH2:39][C:40](O)=[O:41])=[O:36])[C:32]([CH3:44])([CH3:43])[CH2:31][O:30]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH3:28][C:29]1([CH3:45])[O:34][CH:33]([C:35]([NH:37][CH2:38][CH2:39][C:40]([O:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[NH:20][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:41])=[O:36])[C:32]([CH3:44])([CH3:43])[CH2:31][O:30]1
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1ccccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1ccccc1OC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 72 %

Procedure:
A solution of 303 mg of 2-oleoylaminophenol, mg of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid, 227 mg of dicyclohexylcarbodiimide and 122 mg of 4-dimethylamino pyridine in 15 ml of toluene was heated under reflux for 2 hours. After cooling the reaction mixture, the crystals formed were filtered. The filtrate was concentrated and the residue obtained was subjected to silica gel column chromatography to obtain 445 mg of the title compound (yield: 72%).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27](C(F)(F)F)=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[F:35][C:36]([F:47])([F:46])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O>>[F:35][C:36]([F:47])([F:46])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:14]1[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:8])[CH3:9])[C:4]([OH:3])=[O:34])[C:11]([C:36]([F:47])([F:46])[F:35])=[C:12]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:13]=1
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: OB(O)c1ccccc1C(F)(F)F
Product: CC(C)CC(C(=O)O)c1cc(-c2ccccc2C(F)(F)F)cc(-c2ccccc2)c1C(F)(F)F

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 2-trifluoromethyl-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.86-0.97 (m, 6H), 1.54 (dt, J=13.39, 6.63 Hz, 1H), 1.75-1.85 (m, 1H), 2.01 (ddd, J=13.94, 7.95, 7.70 Hz, 1H), 3.78 (t, J=7.83 Hz, 1H), 7.36 (s, 1H), 7.38 (d, J=7.34 Hz, 1H), 7.45-7.53 (m, 2H), 7.56-7.62 (m, 2H), 7.67-7.78 (m, 5H); Calcd for C26H22ClF6O2 (M+Na) 503.44, Found 503.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N:15]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([O:22][C:23]([F:32])([F:31])[CH:24]([F:30])[O:25][C:26]([F:29])([F:28])[F:27])=[N:16]1.ClC1C=CC=C(C(OO)=[O:41])C=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9]([CH2:10][C:11]([F:12])([F:14])[F:13])=[O:41])=[CH:4][C:3]=1[N:15]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([O:22][C:23]([F:31])([F:32])[CH:24]([F:30])[O:25][C:26]([F:28])([F:29])[F:27])=[N:16]1
Reactant: COc1cc(OC(F)(F)C(F)OC(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COc1cc(OC(F)(F)C(F)OC(F)(F)F)nn1-c1cc(S(=O)CC(F)(F)F)c(C)cc1F
Reaction time: 1 h
Yield: 96.9 %

Procedure:
0.2 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-methoxy-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole was dissolved in 10 mL of chloroform, and 92 mg of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for one hour under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.20 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-5-methoxy-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole.