Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:3]=1/[CH:4]=[N:5]/O.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:13])([F:14])[F:15])=[CH:7][C:3]=1[C:4]#[N:5]
Reactant: O/N=C/c1cc(OC(F)(F)F)ccc1F
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: N#Cc1cc(OC(F)(F)F)ccc1F
Yield: 82.6 %

Procedure:
To a solution of E-2-fluoro-5-trifluoromethoxy-benzaldehyde oxime (47.5 g, 213 mmol) in THF (400 mL) was added triethylamine (65.0 mL, 466 mmol). The mixture was cooled in an ice bath and trifluoroacetic anhydride (32.8 mL, 236 mmol) was added at such a rate that the temperature was kept <30° C. After 1 h at rt all volatiles were evaporated (40° C., 200 mbar). The oily residue was partitioned (ether/water), the organic phase was dried over sodium sulfate and concentrated. Distillation (24 mbar, T=80-83° C.) afforded the title compound (36.1 g, 83%) that was sufficiently pure to be used in the next step. MS: m/e=205 [M]+.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22]O)[CH:19]=2)=[CH:11][C:3]=1[C:4]([N:6]([CH2:9]C)CC)=[O:5].NC1C=CC(Br)=CC=1[C:27](NC)=[O:28].CC1(C)C(C)(C)OB(C2C=NN(CCCCO)C=2)O1>>[NH2:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][CH2:27][OH:28])[CH:19]=2)=[CH:11][C:3]=1[C:4]([NH:6][CH3:9])=[O:5]
Reactant: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Reactant: CNC(=O)c1cc(Br)ccc1N
Agent: CC1(C)OB(c2cnn(CCCCO)c2)OC1(C)C
Product: CNC(=O)c1cc(-c2cnn(CCCCO)c2)ccc1N
Yield: 17 %

Procedure:
Prepared analogously to Compound 3C using 2-amino-5-bromo-n-methyl-benzamide (Compound 8D, 300 mg, 1.31 mmol) and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]butan-1-ol (Compound 14C, 383 mg, 1.44 mmol) to afford 64 mg of the title compound (17%). 1H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 7.54 (s, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.32 (dd, J=2.0, 8.6 Hz, 1H), 6.71 (d, J=8.3 Hz, 1H), 6.13 (br. s., 1H), 5.43 (br. s., 2H), 4.20 (t, J=6.9 Hz, 2H), 3.65-3.72 (m, 2H), 3.01 (d, J=5.1 Hz, 3H), 2.01 (quin, J=7.3 Hz, 2H), 1.58-1.67 (m, 3H).
Reaction SMILES: C(OCC)C.[C:6]([C:10]1[CH:15]=[CH:14][C:13]([Mg]Br)=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7].[CH:18]([C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][CH:25]=[CH:24]2)([CH3:20])[CH3:19]>O1CCCC1>[C:6]([C:10]1[CH:15]=[CH:14][C:13]([C:26]2[CH:25]=[CH:24][C:23]3[C:28](=[CH:29][CH:30]=[C:21]([CH:18]([CH3:20])[CH3:19])[CH:22]=3)[N:27]=2)=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)c1ccc2ncccc2c1
Reactant: CC(C)(C)c1ccc([Mg]Br)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)c1ccc2nc(-c3ccc(C(C)(C)C)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40.6 %

Procedure:
To a cooled (ice bath) 2M diethyl ether solution of 4-tert-butylphenylmagnesium bromide (15 ml, 0.03 mol) was added dropwise under argon 15 ml of a tetrahydrofuran solution of 6-isopropylquinoline (5.13 g, 0.03 mol). The resulting mixture was refluxed for 5 hours, stirred at room temperature for 12 hours and quenched with water (80 ml). The yellow precipitate obtained was then filtered and washed with hexane. Crystallization in hexane:chloroform 40:1 yielded 3.7 g of pure (+)-2-(4-tert-butylphenyl)-6-isopropylquinoline (40% yield). 1H NMR(CDCl3): 8.2 (m, ArH, 4H), 7.84 (m, ArH, 1H), 7.60 (m, ArH, 4H), 3.12 (s, CH(Me)2, 1H), 1.4 (s, CH(Me)2 and C(Me)3, 15H); Mass/Cl—NH3: MH− 304.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(N(CC)CC)C.[P:16](Cl)(Cl)([O:18][CH2:19][CH2:20][CH3:21])=[O:17]>CCOCC>[P:16]1([O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1)([O:18][CH2:19][CH2:20][CH3:21])=[O:17]
Reactant: CCCOP(=O)(Cl)Cl
Reactant: Oc1ccccc1O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCOP1(=O)Oc2ccccc2O1
Yield: 101.8 %

Procedure:
Pyrocatechol (0.856 g, 7.77 mM) was dissolved in 32 ml of ether and, using 1.573 g (15.54 mM) of triethylamine and 1.484 g (7.77 mM) of n-propyl dichlorophosphate, the reaction was carried out at -30° C. to -25° C. and the reaction mixture treated in the same manner as in Reference Example 1. There was obtained 1.695 g (95.6% yield) of n-propyl o-phenylene phosphate as a viscous oil (slightly turbid).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(N(CC)CC)C.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(OCC)(=O)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([O:11][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc([N+](=O)[O-])c(Br)c1
Reaction time: 6 h

Procedure:
Combine 3-bromo-4-nitrophenol (1 eq.), triethylamine (1.1 eq.) and tert-butyldimethylsilyl chloride (1.1 eq.) in methylene chloride at 0° C. After about 6 hours, pour the reaction mixture into ethyl acetate, wash with brine, dry the organic layer over Na2SO4 and then concentrate. Purify to give 3-bromo-4-nitro-1-tert-butyldimethylsilyloxybenzene.
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([O:40][CH3:41])=[O:39])=[CH:34][CH:33]=1)(C(OCC=C)=O)[C:18]([O:20]CC=C)=[O:19])#[N:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:18]([CH:17]([CH2:16][CH2:15][CH2:14][CH2:13][C:11]#[N:12])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([O:40][CH3:41])=[O:39])=[CH:34][CH:33]=1)([OH:20])=[O:19]
Reactant: C=CCOC(=O)C(CCCCC#N)(CCc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O=CO
Product: COC(=O)c1ccc(CCC(CCCCC#N)C(=O)O)cc1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
A solution of 7.45 ml (53.42 mmol) of triethylamine and 1.53 ml (40.47 mmol) of formic acid in 67 ml of dioxane is added to a solution of 6.92 g (16.19 mmol) of diallyl 2-(4-cyanobutyl)-2-[2-(4-methoxycarbonylphenyl)ethyl]malonate, 594 mg (2.26 mmol) of triphenylphosphine and 145 mg (0.64 mmol) of palladium acetate in 67 ml of dioxane at room temperature. The reaction mixture is then stirred at 100° C. for 12 hours. After conversion is complete, the reaction solution is cooled and the solvent is removed in vacuo. The residue is taken up in ethyl acetate and water and acidified with 1 N hydrochloric acid, and the organic phase is separated off. The aqueous phase is extracted three more times with ethyl acetate, and the organic phases are then combined, washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solution is concentrated in vacuo. The resulting crude product is purified by flash chromatography on silica gel [mobile phase: cyclohexane/ethyl acetate (with 1% formic acid) 2:1→1:3]. 2.1 g (43% of theory) of a colorless solid are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11]C)=O.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:1]2[C:2]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:8][C:9]2=[O:11])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COC(=O)Cc1ccccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)Cc3ccccc32)CC1
Reaction time: 0.5 h
Yield: 130.2 %

Procedure:
Methyl 2-aminophenylacetate (3.0 g, 18.2 mmol) and 1-tert-butoxycarbonyl-4-piperidone (4.5 g, 22.6 mmol) were set stirring in 50 mL of CH2Cl2 under an atmosphere of nitrogen. Sodium triacetoxyborohydride (5.4 g, 25.5 mmol) was added followed by 1 mL of acetic acid. After 20 h at rt the mixture was quenched by the slow addition of saturated NaHCO3. After stirring for 30 min, the organics were separated, dried (MgSO4), and evaporated to afford 7.5 g of a purple oil. Purification by column chromatography (silica, 10-50% EtOAc/hexanes) gave 3.9 g (62%) of the title compound. TLC (silica, 25% EtOAc/hexanes): Rf=0.15. 1H NMR (400 MHz, CDCl3): 7.25 (m, 2H), 7.01 (m, 2H), 4.40 (m, 1H), 3.53 (s, 2H), 2.83 (m, 2H), 2.32 (m, 2H), 1.70 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([O:16]CC)=[O:15])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([CH2:20][CH3:21])[C:3]=1[C:22]([NH2:24])=[O:23].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](OC)=O)=[CH:29][CH:28]=1.[O-]CC.[Na+].CC(O)=O>C(O)C>[Cl:13][C:12]1[CH:11]=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=[C:8]([Cl:19])[C:7]=1[N:6]1[C:2]2=[N:1][C:34]([CH2:33][C:30]3[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)=[N:24][C:22](=[O:23])[C:3]2=[C:4]([CH2:20][CH3:21])[NH:5]1
Reactant: COC(=O)Cc1ccc(OC)cc1
Reactant: CCOC(=O)c1cc(Cl)c(-n2nc(CC)c(C(N)=O)c2N)c(Cl)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1[nH]n(-c2c(Cl)cc(C(=O)O)cc2Cl)c2nc(Cc3ccc(OC)cc3)nc(=O)c1-2
Yield: 75.1 %

Procedure:
Part D: To a stirred solution of 500 mg (1.35 mmol) of 5-amino-3-ethyl-1-(2,6-dichloro-4-carboethoxyphenyl)pyrazole-4-carboxamide in 10 mL ethanol was added 1.45 g (8.1 mmol) of methyl 4-methoxyphenylacetate followed by 2.6 mL (8.1 mmol) of 2.66 M sodium ethoxide in ethanol. The reaction was heated at relux for 18 h and then 10% aq. HOAc was added. After stirring an additional hour at relux, the heat was removed and the reaction solution was poured into ice water, stirred 10 min. and filtered. The solid was washed with water and diethyl ether and dried to give 480 mg (75%) of 1-(2,6-dichloro-4-carboxyphenyl)-3-ethyl-6-(4-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one, mp 277° C. Mass Spec.: (ES−) 471 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:25]([NH:31][NH2:32])(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:32][NH:31][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[O:22])[N:14]=2)[CH:4]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: CC(C)(C)C(=O)NN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NNC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: -60 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
In a 50 mL, 3-neck round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.2 g, 1.0 eq.) was dissolved in EtOAc (20 mL) and cooled to −60° C. where pivalohydrazide (0.08 g, 1.2 eq.) was introduced dropwise. T3P (50% in EtOAc) (0.4 mL, 4 eq.) was added dropwise followed by DIPEA (0.4 mL, 4 eq.) and the reaction mixture was stirred for 1 h at −60° C. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3% methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-pivaloylacrylohydrazide (0.11 g, yield: 43%);
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[C@@H:23]([OH:38])[C@@H:24]([NH:34][C:35](=[O:37])[CH3:36])[CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][C:40]([CH3:42])=O.COC(C)=C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:10][C@@H:9]1[C@H:23]1[O:38][C:40]([CH3:42])([CH3:39])[N:34]([C:35](=[O:37])[CH3:36])[C@H:24]1[CH2:25][C:26]1[CH:27]=[C:28]([F:33])[CH:29]=[C:30]([F:32])[CH:31]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CO[C@@H]2C[C@H]([C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(C)=O)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: CC(C)=O
Agent: C=C(C)OC
Solvent: ClCCl
Product: COc1ccc(CO[C@@H]2C[C@H]([C@H]3OC(C)(C)N(C(C)=O)[C@H]3Cc3cc(F)cc(F)c3)N(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 1 h
Yield: 607.3 %

Procedure:
Add to a solution of (2R,4R)-2-[(1S,2S)-2-acetylamino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-4-(4-methoxy-benzyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (5.64 g, 10.55 mmol) in dichloromethane (25 mL) and acetone (25 mL) p-toluene sulfonic acid pyridine salt (0.245 g, 1 mmol) and 2-methoxy propene (4.6 mL, 49 mmol). Stir 60 min and concentrate. Dissolve in ethyl acetate and wash with saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry (magnesium sulfate) and purify (silica gel chromatography, eluting with hexanes/ethyl acetate mixtures) to give the title compound as a foam (3.49 g, 61%).
Reaction SMILES: [OH-].[Li+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[C:13]([O:15]CC)=[O:14]>O.CO>[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)c1cnc2ccccc2n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cnc2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of lithium hydroxide (20.0 mg, 0.84 mmol) in water (1 mL), ethyl quinoxaline-2-carboxylate (20.0 mg, 0.99 mmol) in methanol (3 mL) was added. The solution was left to stir at room temperature for 2 h. The solution was concentrated in vacuo. This cream solid residue was dissolved in water and made acidic with concentrated hydrochloric acid. The organic material was extracted into ethyl acetate. The organic layers were dried with anhydrous sodium sulphate, filtered, and concentrated in vacuo to yield quinoxaline-2-carboxylic acid as a white solid.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[Cl:12][C:13]1[CH:18]=[C:17]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COC(=O)c1cc(Br)oc1C
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2cccc(Cl)c2)oc1C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
A mixture of methyl 5-bromo-2-methyl-3-furancarboxylate (2.2 g), 3-chlorophenylboronic acid (1.9 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 15% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (2.3 g, 92%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH:11]1[O:16][C:15](=[O:17])[CH:14]=[CH:13][CH2:12]1.I[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.Cl>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.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C@@H:11]1[O:16][C:15](=[O:17])[CH2:14][C@@H:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:12]1
Reactant: O=C1C=CCC(CCc2ccc(Cl)cc2Cl)O1
Reactant: Ic1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C1C[C@@H](c2ccccc2)C[C@H](CCc2ccc(Cl)cc2Cl)O1
Temperature: 80 °C

Procedure:
A mixture of compound (1a) (270 mg, 1.0 mmol), iodobenzene (224 mg, 1.1 mmol), triethylamine (160 μl, 1.1 mmol) and tetrakis(triphenylphosphine)palladium 10 mg) was placed under argon nd heated at 80° C. for 16 hours. The dark mixture was cooled and distributed between ethyl acetate (100 ml) and 1N HCl (100 ml). The organic layer was separated and washed with water (2×50 ml), dried and evaporated. The residue was purified by flash chromatography on silica gel using CHCl3 acetone, 20:1 (V:V) as eluant.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:10]([CH3:17])([CH3:16])[C:9]=2/[CH:18]=[CH:19]/[CH:20](O)[CH2:21][CH:22]([OH:27])[CH2:23][C:24]([OH:26])=[O:25])=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][C:12]([CH3:14])([CH3:15])[CH2:11][C:10]([CH3:17])([CH3:16])[C:9]=2/[CH:18]=[CH:19]/[C@@H:20]2[O:25][C:24](=[O:26])[CH2:23][C@@H:22]([OH:27])[CH2:21]2)=[CH:6][CH:7]=1
Reactant: CC1(C)CC(c2ccc(F)cc2)=C(/C=C/C(O)CC(O)CC(=O)O)C(C)(C)C1
Solvent: Cc1ccccc1
Product: CC1(C)CC(c2ccc(F)cc2)=C(/C=C/[C@H]2C[C@H](O)CC(=O)O2)C(C)(C)C1

Procedure:
The 3,5-dihydroxycarboxylic acid from Step 10 (9.0 g, 23 mmoles) and 250 ml of toluene were refluxed in a Dean-Stark apparatus for 1.5 hours. The toluene was removed in vacuo and the residue chromatographed on silica gel using hexane/ethyl acetate (3/1) as the eluent. The product was recrystallized from ether/hexane. M.P. 121°-122° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)[CH:5]=[N:6][CH:7]=1.CN(C(O[N:27]1N=[N:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.NC1C=CC=CC=1N>CN(C=O)C.O>[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([NH:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[O:18]
Reactant: O=C(O)CCCCCC(=O)Nc1cncc(Br)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccccc1NC(=O)CCCCCC(=O)Nc1cncc(Br)c1
Temperature: 35 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
To a solution of 7-((5-bromopyridin-3-yl)amino)-7-oxoheptanoic acid (1.0 g, 3.2 mmol) in DMF (30 mL) was added HBTU (1.8 g, 4.7 mmol), DIEA (0.82 g, 6.3 mmol), 1,2-diaminobenzene (1.04 g, 9.6 mmol). The solution was stirred at 35° C. for 2 h. After TLC showed the reaction was completed, 50 mL water was added to the solution. The mixture was stirred at room temperature, for 30 min. Then the mixture was filtered to give the crude product as a yellow solid. The crude product was recrystallized by methanol to give product as a yellow solid (yield 55.9%).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[CH2:7]([O:14][C:15]([CH:17]1[CH2:22][CH2:21][CH:20]([CH2:23]O)[CH2:19][CH2:18]1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N(C(N(C)C)=O)=NC(N(C)C)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:7]([O:14][C:15]([CH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[CH2:19][CH2:18]1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCC(F)(F)F
Reactant: O=C(OCc1ccccc1)C1CCC(CO)CC1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)C1CCC(COCC(F)(F)F)CC1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 94.6 %

Procedure:
2,2,2-Trifluoro-ethanol (288 μL, 4.03 mmol) was added to a mixed solution of 4-hydroxymethyl-cyclohexanecarboxylic acid benzyl ester (100 mg, 0.403 mmol), 1,1′-azobis(N,N-dimethylformamide) (139 mg, 0.805 mmol) and tributyl-phosphine (199 μL, 0.805 mmol) in toluene (1.2 mL) at 0° C. The mixture was stirred at 65° C. for 1.5 hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 4-(2,2,2-trifluoro-ethoxymethyl)-cyclohexanecarboxylic acid benzyl ester as a colorless liquid (126 mg, 95%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([Cl:14])[C:5]=1[C:15]1[CH:19]=[C:18]([S:20][CH3:21])[NH:17][N:16]=1.[F:22][C:23](I)([F:25])[F:24].O>CN(C)C=O>[Cl:14][C:6]1[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=[C:4]([Cl:3])[C:5]=1[C:15]1[CH:19]=[C:18]([S:20][CH3:21])[N:17]([C:23]([F:25])([F:24])[F:22])[N:16]=1
Reactant: FC(F)(F)I
Reactant: CSc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nn1C(F)(F)F
Temperature: 25 °C

Procedure:
Sodium hydride was added dropwise to a suspension of 0.5 g of 3-(2,6-dichloro-4-trifluoromethylphenyl)-5(methylsulfenyl)pyrazole (compound 16) in 5 ml of anhydrous N,N-dimethylformamide at 0° C., and the mixture was stirred at room temperature. An excess of trifluoromethyl iodide was introduced into the reaction mixture, and the resulting mixture was stirred for 3 hours with the reactor closed. The reaction mixture was poured into water, followed by extraction with ether, washing with brine and drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel (eluent: chloroform/hexane=1/20), giving 0.2 g of the desired product in the form of light brown oil (yield 33.3%).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH2:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:17]([NH:23][C:8](=[O:9])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCN
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CCCCCCNC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, off-white solid, m.p. 100° C. and MS: m/e=296.4 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl chloride and hexylamine.