Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([CH3:19])[C:4]=1[NH:20][C:21]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[C:28](=O)[CH2:27][CH2:26]2)=[O:22])[CH3:2].C([O-])(=O)C.[Na+].Cl.[NH2:39][OH:40]>C(O)C.O>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([F:18])([C:10]([F:11])([F:13])[F:12])[C:14]([F:15])([F:17])[F:16])[CH:6]=[C:5]([CH3:19])[C:4]=1[NH:20][C:21]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[C:28](=[N:39][OH:40])[CH2:27][CH2:26]2)=[O:22])[CH3:2]
Reactant: NO
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc2c(c1)CCC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc2c(c1)CCC2=NO
Yield: 92.8 %

Procedure:
N-[2-Ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]-1-oxoindane-5-carboxamide (2.4 g) was dissolved in ethanol (40 ml), and sodium acetate (0.85 g) and hydroxylamine hydrochloride (0.43 g) were added thereto, and then stirred and heated at reflux temperature for 2 hours. The reaction solution was brought back to room temperature and diluted with water. The resulting crystals were collected by filtration and dried to obtain N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]-1-(hydroxyimino) indane-5-carboxamide (2.3 g, yield 91%).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CC(C)([O-])C.[K+].F[C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(C1C=CC=CC=1)(=O)C>C1COCC1.CCCCCCC>[CH2:1]([O:9][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][C:18]=1[C:26]([F:27])([F:28])[F:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCO
Reactant: CC(=O)c1ccc(F)c(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CC(=O)c1ccccc1
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(C(C)=O)cc1C(F)(F)F
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 325.8 %

Procedure:
A solution of n-octanol (13.3 g, 0.102 mol), in THF (224 mL) was treated with 1.0 M potassium t-butoxide in THF (112 mL, 1.1 equiv) at room temperature and heated to 65° C. After 15 minutes, a solution of 1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone (21 g, 1.0 equiv) in THF (224 mL) was charged slowly over 30 minutes. Vigorous gas evolution was noted during the addition. The reaction was monitored by HPLC and deemed complete after 1.5 h. The reaction mixture was cooled to ambient temperature, treated with 10% aqueous citric acid (250 mL), extracted with MTBE (2×500 mL), dried, and concentrated to afford the product (31.99 g, 99.3%, 88.1% AUC by HPLC). This reaction was repeated with slight modification as described above (reducing the amount of THF used to dissolve the acetophenone to 3 mL/g from 10.7 mL/g with improved control of gas evolution) on a 100 g scale to give 137.1 g, >100% yield). The two lots were combined and purified by column chromatography using silica-gel (1 kg), eluted with 10% ethyl acetate: 90% heptane to afford the title product (105 g, 75% yield) as a pale yellow color oil. Impure fractions were collected and provided 22.8 g (16.3% yield) of the product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[CH:13]=[CH:14][C:15]([OH:17])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:21](Cl)(=O)[C:22](Cl)=O.[CH3:27][N:28]([CH:30]=O)[CH3:29]>C1COCC1>[N:28]1([CH2:29][C:22]2[CH:21]=[CH:5][C:4]([NH:1][C:15](=[O:17])/[CH:14]=[CH:13]/[C:12]3[CH:18]=[CH:19][CH:20]=[C:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)[CH:11]=3)=[CH:9][CH:8]=2)[CH2:30][CH2:10][CH2:6][CH2:7][CH2:27]1
Reactant: CN(C)C=O
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C=Cc1cccc(-c2cccc([N+](=O)[O-])c2)c1
Solvent: C1CCOC1
Product: O=C(/C=C/c1cccc(-c2cccc([N+](=O)[O-])c2)c1)Nc1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In THF (10 ml) was dissolved 3-(3-nitrophenyl)cinnamic acid (0.54 g), and to the solution were added oxalyl chloride (0.35 ml) and a drop of DMF. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in THF (20 ml), and to the solution were added 1-(4-aminobenzyl)piperidine (0.38 g) and triethylamine (0.34 ml) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, and to the mixture was added water (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give (E)-N-[4-(piperidinomethyl)-phenyl]-3-(3-nitrophenyl)cinnamamide (Compound 75) (0.65 g) as pale yellow crystals.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(O[SiH](OCC)OCC)C.N[CH2:16][CH2:17][CH2:18][Si:19]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Rh].[Rh].[Rh].[Rh].C1(C)C=CC=CC=1>[CH2:1]([NH2:4])[CH:2]=[CH2:3].[NH2:4][CH:17]([CH3:16])[CH2:18][Si:19]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]
Reactant: CCO[Si](CCCN)(OCC)OCC
Agent: [Rh]
Agent: CCO[SiH](OCC)OCC
Agent: [C-]#[O+]
Solvent: Cc1ccccc1
Solvent: C=CCN
Product: CCO[Si](CC(C)N)(OCC)OCC
Temperature: 110 °C

Procedure:
A three-neck flask equipped with a reflux condenser, stirring rod and thermometer was charged with 14 grams of allylamine (0.25 mole), 41 grams of triethoxy silane (0.25 mole), 0.32 gram of 1,5-cycloctadiene (2.9×10-3 mole) and 30 ml. of toluene, and heated in an oil bath maintained at a temperature of 110° C. When the temperature of the mixture reached 85° C., 0.22 gram of tetrarhodium dodecacarbonyl (2.9×10-4 mole) was added to the mixture as a catalyst. About 60 minutes after the addition of the catalyst, the reaction temperature reached 110° C. At the end of the period the reaction mixture was subjected to gas chromatography analysis. It was found that gamma-aminopropyl triethoxy silane was obtained in a yield of 78% on an allylamine basis, while the yield of beta-aminopropyl triethoxy silane was 5.6% on an allylamine basis.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C:8]#[C:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([OH:4])(=[O:6])=[O:3].[OH:6][CH2:7][C:8]#[C:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24]
Reactant: CS(=O)(=O)Cl
Agent: O=C(c1ccccc1F)c1cc(Cl)ccc1C#CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O
Temperature: 0 °C

Procedure:
Dropwise 13 ml (0.17 mole) of methanesulfonyl chloride was added to a solution of 28.9 g (0.1 mole) of 3-hydroxy-1-[4-chloro-2-(2-fluorobenzoyl)phenyl]propyne and 24.4 ml (0.175 mole) of triethylamine in 300 ml of methylene chloride which was cooled to 0° C. The mixture was washed with ice water, cold 1N hydrochloric acid, cold saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. Concentration of the methylene chloride solution gave a brown oil which was crystallized from ether to give a yellow solid. Recrystallization from a mixture of ether and petroleum ether gave off-white prisms, mp 95°-96° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23](O)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.[N:32]1(OC(N(C)C)=[N+](C)C)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40]C=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)[CH:60]=[O:61]>>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:32]3[CH2:36][CH2:37][CH:38]([O:61][CH3:60])[CH2:39][CH2:40]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Reactant: CN(C)C=O
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc3[nH]2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-methoxy piperidine(commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:12])[CH:3]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[F:46][CH:47]([F:50])[CH2:48][NH2:49]>ClCCCl.ClC(Cl)C>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([NH:49][CH2:48][CH:47]([F:50])[F:46])=[O:8])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(O)c1cc(F)c(Cl)cc1F
Reactant: NCC(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(F)F)c1cc(F)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-chloro-2,5-difluorobenzoic acid (1.28 g, 6.64 mmol), N,N-diisopropylethylamine (3.5 mL, 20 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (3.07 g, 8.07 mmol) in 1,2-dichloroethane (20 mL) was stirred for 10 min. at room temperature prior to the addition of a solution of 2,2-difluoroethanamine (538 mg, 6.64 mmol) in dichloroethane (2 mL). The resulting solution was stirred for 1 h. at room temperature. LCMS data indicated that the major reaction component was the desired product. The crude reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with methanol in dichloromethane (0-10%) to afford the desired product. LCMS (M+H)+: m/z=256.0.
Reaction SMILES: [CH3:1][CH:2]1[N:9]2[CH:10]=[N:11][C:12]3[CH:13]([CH2:17][C:18]([OH:20])=O)[C:14](=[O:16])[CH:15]=[C:7]([C:8]=32)[NH:6][CH2:5][CH2:4][C:3]1=[O:21].[NH2:22][C:23]1[N:28]=[CH:27][C:26]2[CH2:29][C:30]3([CH2:40][C:25]=2[CH:24]=1)[C:38]1[C:33](=[N:34][CH:35]=[CH:36][CH:37]=1)[NH:32][C:31]3=[O:39].C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:1][CH:2]1[N:9]2[CH:10]=[N:11][C:12]3[CH:13]([CH2:17][C:18]([NH:22][C:23]4[N:28]=[CH:27][C:26]5[CH2:29][C:30]6([CH2:40][C:25]=5[CH:24]=4)[C:38]4[C:33](=[N:34][CH:35]=[CH:36][CH:37]=4)[NH:32][C:31]6=[O:39])=[O:20])[C:14](=[O:16])[CH:15]=[C:7]([C:8]=32)[NH:6][CH2:5][CH2:4][C:3]1=[O:21]
Reactant: Nc1cc2c(cn1)CC1(C2)C(=O)Nc2ncccc21
Reactant: CC1C(=O)CCNC2=CC(=O)C(CC(=O)O)c3ncn1c32
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1C(=O)CCNC2=CC(=O)C(CC(=O)Nc3cc4c(cn3)CC3(C4)C(=O)Nc4ncccc43)c3ncn1c32
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (8-methyl-2,7-dioxo-5,6,7,8-tetrahydro-4H-imidazo[1,5,4-fg][1,6]benzodiazocin-1(2H)-yl)acetic acid (66 mg, 0.23 mmol, described in Intermediate 14), (±)-3-amino-5,7-dihydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (71 mg, 0.28 mmol, described in intermediate 3), N,N,N′,N′-bis(tetramethylene)chloroformamidinium hexafluorophosphate (153 mg, 0.46 mmol), and N,N-diisopropylethylamine (0.20 mL, 1.15 mmol) in THF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (3×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])=[C:4]([F:24])[CH:3]=1.C(O)(=O)C>C(O)C.[Fe]>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:24])=[C:5]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])[CH:6]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc([N+](=O)[O-])c(Cl)cc2F)c1=O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N)c(Cl)cc2F)c1=O
Yield: 93.9 %

Procedure:
Under a nitrogen atmosphere a solution of 3.0 grams (8.2 mmole) of 3-(4-chloro-2-fluoro-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione, and 20 mL of acetic acid in 80 mL of ethanol was stirred, and 1.8 grams (32 mmole) of iron powder was added. The reaction mixture was then heated under reflux for one hour, after which analysis by thin layer chromatography (TLC) indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The concentrate was then taken up in 50 mL of aqueous 5% sodium bicarbonate solution and 100 mL of ethyl acetate. The mixture was filtered through diatomaceous earth, and the filter cake was washed with 20 mL of water and three 50 mL portions of ethyl acetate. The filtrate was placed in a separatory funnel and 100 mL of aqueous 5% sodium bicarbonate solution was added. The aqueous phase was separated and the organic phase was washed with 50 mL of aqueous saturated sodium bicarbonate solution, then with 50 mL of aqueous saturated sodium chloride solution. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 2.6 grams of 3-(5-amino-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:8][CH2:7][O:6][C:4](=[O:5])[CH2:3]1.[IH:10].[N+](=[CH2:13])=[N-]>CC(O)=O>[CH3:1][C:2]([CH3:9])([CH2:8][CH2:7][I:10])[CH2:3][C:4]([O:6][CH3:13])=[O:5]
Reactant: C=[N+]=[N-]
Reactant: I
Reactant: CC1(C)CCOC(=O)C1
Solvent: CC(=O)O
Product: COC(=O)CC(C)(C)CCI

Procedure:
3,3-dimethyl-δ-valerolactone was treated with HI in HOAc, followed by diazomethane to give methyl 3,3-dimethyl-5-iodo-pentanoate. This material and the aldehyde from U.S. Pat. No. 4,851,409, Example 24, Step 1 were assembled using Method L. The thiol was from Example 80, Step 4. This compound showed signals at m/e 548 (M+I) and 570 (M+Na) in a fast atom bombardment mass spectrometer (FAB-MS).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:31])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][N:24]=4)=[CH:17][CH:16]=3)[CH:7]=2)[CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:55][NH:56][CH3:57].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C.O>[CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:31])[C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][N:56]([CH3:57])[CH3:55])=[CH:25][N:24]=4)=[CH:19][CH:20]=3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccc(CO)cn2)cc1
Reactant: CNC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccc(CN(C)C)cn2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.2 %

Procedure:
To N-cyclopropyl-3-[(4-{[5-(hydroxymethyl)pyridin-2-yl]methoxy}benzoyl)amino]-4-methylbenzamide (100 mg, 0.232 mmol) in DCM (10 mL) was added Dess-Martin periodinane (197 mg, 0.464 mmol) and the reaction was stirred at room temperature for 3 h. The reaction was diluted with DCM (40 mL), washed with 2N NaOH (3×15 mL) and then a saturated brine solution (20 mL). The DCM solution of the aldehyde was dried with magnesium sulphate and then concentrated under reduced pressure to approximately 10 mL. To this solution was added dimethylamine (2M in THF, 0.13 mL, 0.260 mmol), acetic acid (2 drops) and titanium iso-propoxide (132 mg, 0.464 mmol). The mixture was stirred at room temperature for 1 h and then sodium triacetoxyborohydride (123 mg, 0.580 mmol) was added. The reaction was stirred for 18 h at room temperature. Water (4 drops) was added and the reaction was evaporated to dryness. The residue was purified by basic preparative HPLC to give the title compound as a white solid (30 mg, 28%); NMR Spectrum: (DMSOd6) 0.62 (m, 2H), 0.75 (m, 2H), 2.21 (s, 6H), 2.31 (s, 3H), 2.90 (m, 1H), 3.48 (s, 2H), 5.83 (s, 2H), 7.22 (d, 2H), 7.38 (d, 1H), 7.57 (d, 1H), 7.68 (dd, 1H), 7.81 (m, 1H), 7.85 (d, 1H), 8.04 (d, 2H), 8.42 (d, 1H), 8.57 (s, 1H), 9.88 (s, 1H); Mass Spectrum: M+H+ 459.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8]([C:10]1[N:19]([CH3:20])[C:18](=[O:21])[C:17]2[CH2:16][CH2:15][CH2:14][NH:13][C:12]=2[C:11]=1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:9].[H-].[Na+].IC.[C:43](OCC)(=O)C>C1COCC1>[F:38][C:2]([F:37])([F:1])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:34])([F:36])[F:35])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8]([C:10]1[N:19]([CH3:20])[C:18](=[O:21])[C:17]2[CH2:16][CH2:15][CH2:14][N:13]([CH3:43])[C:12]=2[C:11]=1[C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)=[O:9]
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1c(-c2ccc(F)cc2)c2c(c(=O)n1C)CCCN2
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1c(-c2ccc(F)cc2)c2c(c(=O)n1C)CCCN2C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In THF (3 ml) was dissolved N-[3,5-bis(trifluoro methyl)benzyl]-8-(4-fluorophenyl)-1,2,3,4,5,6-hexahydro-N,6-dimethyl-5-oxo-7-pyrido[4,3-b]pyridinecarboxamide (Example 27)(68 mg). To the solution were added sodium hydride (60% oil) (6 mg) and iodomethane (1.5 ml). The mixture was stirred for 15 hours at room temperature. To the reaction mixture was added ethyl acetate, and the mixture was washed with water and dried, then the solvent was distilled off to give the above-titled compound as colorless crystals (39 mg), m.p.230°-232° C. (recrystallized from ethyl acetate-ethyl ether)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][NH:32][CH:33]=2)O1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:8]2([C:5]3[CH:6]=[CH:7][C:2]([C:29]4[CH:30]=[N:31][NH:32][CH:33]=4)=[CH:3][CH:4]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:15][CH:16]=1
Reactant: Clc1ccc(C2(c3ccc(Br)cc3)CCNCC2)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: Clc1ccc(C2(c3ccc(-c4cn[nH]c4)cc3)CCNCC2)cc1

Procedure:
4-(4-Bromo-phenyl)-4-(4-chloro-phenyl)-piperidine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. LC/MS: (PS-A3) Rt 7.22 [M+H]+ 338.08. 1H NMR (Me-d3-OD) δ 2.64-2.74 (4H, m), 3.22-3.25 (4H, m), 7.33-7.45 (6H, m 7.65 (2H, d), 8.37 (2H, s).
Reaction SMILES: [CH3:1][CH:2]([CH3:23])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH:19]([OH:22])[CH2:20][OH:21].[C:24](Cl)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1>[C:24]([O:21][CH2:20][CH:19]([OH:22])[CH2:18][O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:23])[CH3:1])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)CCCCCCCCCCCCCCOCC(O)CO
Solvent: c1ccncc1
Product: CC(C)CCCCCCCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.3 %

Procedure:
A mixture of 2.0 g (6.06 mmole) of 1-(15-methylhexadecyloxy)-2,3-propanediol, 2.54 g (9.09 mmole) of trityl chloride and 20 ml of pyridine was stirred at room temperature for 2 days, and then pyridine was distilled off. To the residue was added 50 ml of ethyl acetate and the ethyl acetate solution was washed with 1N hydrochloric acid, water and saturated sodium bicarbonate solution, in order, and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (100 g) and eluted with hexane-ethyl acetate (20:1) to give 2.3 g of crude 1-(trityloxy)-3-(15-methylhexadecyloxy)-2-propanol. This product was treated by following the procedure of that of Reference Example 12 to give 1.0 g (yield: 39%) of the desired product.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH:15]=2)=[CH:9][C:8]=1[CH3:34])C.[OH-].[Na+].Cl>C(O)C>[CH2:30]([O:29][C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH:17]=1)[O:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:35])=[O:3])=[C:8]([CH3:34])[CH:9]=1)[CH:31]([CH3:33])[CH3:32]
Reactant: CCOC(=O)COc1ccc(Oc2cc(C#CCN3CCOCC3)cc(OCC(C)C)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Oc2cc(C#CCN3CCOCC3)cc(OCC(C)C)c2)ccc1OCC(=O)O
Reaction time: 16 h

Procedure:
{4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenoxy]-2-methyl-phenoxy}-acetic acid ethyl ester (260 mg; 0.56 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness and purified by prep HPLC (method B). Yield: 180 mg; 72%. HPLC-MS: m/z: 454.6 (M+H)+; Rt: 1.77 min. δH (400 MHz; CDCl3) 1.01 (d, 6H), 2.02-2.10 (m, 1H), 2.28 (s, 3H), 3.10-3.55 (m, 4H), 3.68 (d, 2H), 3.93-4.07 (m, 4H), 4.10 (s, 2H), 4.67 (s, 2H), 6.47 (m, 1H), 6.57-6.59 (m, 1H), 6.66-6.69 (m, 1H), 6.71 (d, 1H), 6.79 (dd, 1H), 6.86 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18][CH2:19][CH2:20][CH3:21])[N:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:14]=2[CH:28]=1.ClC1C=CC=C(C(OO)=[O:38])C=1.S(OS([O-])=O)([O-])=O.[Na+].[Na+]>ClCCl>[CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18]([CH2:19][CH2:20][CH3:21])=[O:38])[N:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:14]=2[CH:28]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCSc1nc2ccc(OCCCCCC(=O)OC)cc2n1-c1ccccc1
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCS(=O)c1nc2ccc(OCCCCCC(=O)OC)cc2n1-c1ccccc1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
80 mg of 6-[[1-phenyl-2-propylmercapto-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was dissolved in 2 ml of dichloromethane, mixed with 56 mg of m-chloroperbenzoic acid (about 60%), and the mixture was stirred for 10 minutes at 20° C. It was mixed with sodium disulfite solution, extracted twice with dichloromethane, the combined organic phases were washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 30 mg was obtained.