Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](Cl)=[O:12])=[CH:5][CH:4]=1.Cl.[CH3:17][NH:18][O:19][CH3:20].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:20][O:19][N:18]([CH3:17])[C:11](=[O:12])[CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:15])([F:14])[F:1])=[CH:4][CH:5]=1
Reactant: O=C(Cl)CCc1ccc(C(F)(F)F)cc1
Reactant: CNOC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)CCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
To a mixture of 3.034 g (13 mmol) 3-(4-Trifluoromethyl-phenyl)-propionyl chloride (CAS: 539855-79-3) and 1.4 g (14.1 mmol) N,O-Dimethylhydroxylamine hydrochloride in 55 mLl chloroform, under argon, was added dropwise 2.28 mL (28 mmol) pyridine at 0° C. The solution was allowed to warm to RT and was stirred for 2 hour. The mixture was washed with 1N HCl (50 mL). The organic layer was washed once with 1N NaOH. The organic phases was dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude oil was purified with flash column chromatography on silica gel eluting with a gradient formed from heptane and ethylacetate to provide 2.1 g (63%) of title compound as colorless oil. MS (m/e): 262.0 (MH+).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]2[C:22](F)=[CH:21][CH:20]=[CH:19][C:18]=2F)[C:9]=1[C:10]#[N:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]=1[CH2:10][NH2:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1c(Nc2c(F)cccc2F)cccc1Oc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NCc1c(Nc2ccccc2)cccc1Oc1ccccc1
Temperature: 25 °C

Procedure:
The product of example 1b above, 2-phenoxy-6-(2,6-difluorophenylamino)benzonitrile, (0.34 g, 1.06 mmol) was dissolved in dry tetrahydrofuran (40 mL) and stirred under argon in a room temperature water bath. Lithium aluminum hydride (0.384 g, 10.1 mmol) was added, and the reaction mixture was heated to 65° C. for 0.5 hour. The reaction mixture was cooled to room temperature and anhydrous sodium sulfate was added followed by quenching by the addition of a freshly prepared saturated solution of anhydrous sodium sulfate. The solvent was evaporated and the residue triturated with ethyl acetate, filtered and evaporated. Flash chromatography on silica gel eluted with 40% methylene chloride/hexane to which 3% methanol was added followed by Gilson hplc purification gave the title compound as a white amorphous solid. mp 113–116° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:28](O)=[O:29])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:31]([O:38][CH2:39][CH2:40][NH:41][CH:42]1[CH2:46][CH2:45][CH2:44]C1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[Si:31]([O:38][CH2:39][CH2:40][N:41]([CH:42]1[CH2:46][CH2:45][CH2:44]1)[C:28]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]=1)=[O:29])([C:34]([CH3:35])([CH3:36])[CH3:37])([CH3:32])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)OCCNC1CCCC1
Reactant: O=C(O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[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: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)C1CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a stirred solution mixture of 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (283) (300 mg, 0.74 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclobutyl-amine (8e) (204 mg, 0.89 mmol) in dimethylformamide (5 mL) were added N,N-diisopropylethylamine (0.4 mL, 2.22 mmol) and HATU (423 mg, 1.11 mmol). After stirring at room temperature for 1 h, water (50 mL) was added and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic part was washed with water (3×50 mL) and brine (2×30 mL) and dried and concentrated. The crude product was purified by Combi-Flash column (eluted at 20-30% ethyl acetate in hexane) to get 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclobutyl-amide (292) (420 mg, 91.94%) as a yellow sticky solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[C:5]([C:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH:9]=2)[C:4]([CH3:15])=[N:3]1.[C:16](OC(=O)C)(=[O:18])C>C(O)=O>[CH3:1][N:2]1[C:6]([NH:7][CH:16]=[O:18])=[C:5]([C:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH:9]=2)[C:4]([CH3:15])=[N:3]1
Reactant: Cc1nn(C)c(N)c1C1=CCC(C)CC1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: Cc1nn(C)c(NC=O)c1C1=CCC(C)CC1
Reaction time: 2 h

Procedure:
To a suspension of 1,3-dimethyl-4-(4-methyl-1-cyclohexen-1-yl)-5-(1H)-pyrazolamine (24.5 g; 0.119 mole) in 99% formic acid (245 ml), acetic acid anhydride (64.14 g, 0.628 mole) is added at a temperature of about 20° C. Then the mixture is heated to 80°-90° C. and kept at this temperature for about 2 hours. After distillation of the solvent under vacuum, the residue is taken up with water and the pH is adjusted to about 8 with aqueous sodium carbonate. The solution is extracted with methylene chloride and the organic layer is washed with water and then dried over sodium sulfate. After distillation of the solvent, the crude product of the title is recovered and crystallized from the mixture t.butylmethyl-ether and hexane. M.p. 97°-99° C.
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][NH:5][C:6](=[O:33])[CH2:7][CH:8]1[N:14]([C:15](=[O:22])[C:16]2C=CN=CC=2)[CH2:13][C:12]2[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=2[N:10]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:9]1=[O:32].C(OC(=O)C)(=O)C>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:15]([N:14]1[CH2:13][C:12]2[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=2[N:10]([CH2:27][C:28]([CH3:30])([CH3:31])[CH3:29])[C:9](=[O:32])[CH:8]1[CH2:7][C:6]([NH:5][CH2:4][C:3]1[CH:34]=[CH:35][CH:36]=[CH:37][C:2]=1[F:1])=[O:33])(=[O:22])[CH3:16]
Reactant: CC(C)(C)CN1C(=O)C(CC(=O)NCc2ccccc2F)N(C(=O)c2ccncc2)Cc2ccccc21
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N1Cc2ccccc2N(CC(C)(C)C)C(=O)C1CC(=O)NCc1ccccc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 83.9 %

Procedure:
To a solution of the compound (0.15 g) obtained in Example 1B (1) in pyridine (6 ml) were added acetic anhydride (0.20 g) and 4-dimethylaminopyridine (0.05 g), and the mixture was stirred at room temperature for 14 hrs. The solvent was evaporated, and the residue was purified by silica gel column chromatography and recrystallized from hexane-ethyl acetate to give the title compound (0.11 g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:35][CH2:36][CH2:37][CH3:38])[N:14]([CH2:15][CH2:16][CH2:17][N:18]([CH2:23][C:24]3[CH:25]=[C:26]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]=[CH:28][CH:29]=3)[CH2:19][CH2:20][CH2:21]Cl)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[CH2:39]([NH:41][CH3:42])[CH3:40]>>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:35][CH2:36][CH2:37][CH3:38])[N:14]([CH2:15][CH2:16][CH2:17][N:18]([CH2:23][C:24]3[CH:25]=[C:26]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]=[CH:28][CH:29]=3)[CH2:19][CH2:20][CH2:21][N:41]([CH2:39][CH3:40])[CH3:42])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCNC
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN(CCCCl)Cc1cccc(CC(=O)OC)c1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN(CCCN(C)CC)Cc1cccc(CC(=O)OC)c1

Procedure:
The title compound was prepared by the method of example 11 step (x) using the product of example 11 step (ix) (627 mg) and N-ethylmethylamine (1 ml) as a white solid 65 mg.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9](=[O:11])[CH3:10])=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[Br-:12].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C(OCC)(=O)C>C(O)(=O)C.C1COCC1.C1CCCCC1>[Br:12][CH2:10][C:9]([C:8]1[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=1)=[O:11]
Reactant: CC(=O)c1ncnn1C(C)C
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)n1ncnc1C(=O)CBr
Temperature: 75 °C
Yield: 36 %

Procedure:
To a solution of 1-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-ethanone (10 g, 65.3 mmol) in acetic acid (1 mL) and THF (100 mL) was added a solution of PTT (phenyltrimethylammonium tribromide, 24.5 g, 65.3 mmol) in THF (100 mL) over 20 min. The reaction mixture was heated at 75° C. before cooling to RT. The resultant mixture was concentrated in vacuo and the products partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo to give a residue which was subjected to flash chromatography (SiO2, gradient 0 to 20% ethyl acetate in cyclohexane) to give 2-Bromo-1-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-ethanone as an oil (5.4 g, 36%). 1H NMR δ (ppm) (CDCl3): 7.98 (1H, s), 5.53-5.42 (1H, m), 4.69 (2H, s), 1.52 (6H, d, J=6.63 Hz).
Reaction SMILES: [F:1][C:2]1[C:3]([O:24][CH3:25])=[C:4]([C:8](=[CH:21][CH2:22][CH3:23])[CH2:9][C:10]([OH:20])([C:16]([F:19])([F:18])[F:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[C:3]([O:24][CH3:25])=[C:4]([CH:8]([CH2:21][CH2:22][CH3:23])[CH2:9][C:10]([OH:20])([C:16]([F:19])([F:18])[F:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CCC=C(CC(O)(C(=O)OCC)C(F)(F)F)c1cccc(F)c1OC
Agent: [Pd]
Solvent: CO
Product: CCCC(CC(O)(C(=O)OCC)C(F)(F)F)c1cccc(F)c1OC
Yield: 100 %

Procedure:
698 mg (2.56 mmol) of 1,1′-bi-2-naphthol are admixed with 2.56 ml (1.28 mmol) of a 0.5 M titanium tetraisopropoxide solution in toluene and the red solution is stirred at room temperature for 2 hours. 4.26 g (21.9 mmol) of 2-fluoro-6-(1-methylenbutyl)anisole and 5.7 ml (44 mmol) of ethyl trifluoropyruvate are added and the mixture is heated at 140° C. for 18 hours. After cooling it is immediately purified by column chromatography on silica gel (hexane/ethyl acetate 0-15%) to give 5.82 g of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hept-4-enoate. 2.6 g (7.1 mmol) of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hept-4-enoate are dissolved in 65 ml of methanol and the solution is admixed with 260 mg of palladium on carbon (10%). The suspension is shaken under a hydrogen atmosphere at atmospheric pressure for 4 hours until the hydrogen uptake is 155 ml. The mixture is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. Removal of the solvent gives 2.6 g of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)heptanoate. 2.6 g (7.1 mmol) of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-heptanoate in 150 ml of diethyl ether are cooled to −10° C. and over 15 minutes 520 g (14.2 mmol) of solid lithium aluminum hydride are added in portions. The mixture is stirred at −15° C. for 1.5 hours, followed by dropwise addition in succession of ethyl acetate and water and by a further hour of stirring until a readily filterable precipitate is formed. The suspension is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo. Separation by column chromatography on silica gel (hexane/diisopropyl ether 0-15%) yields 2.1 g of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)heptanal as a mixture of the diastereomers.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11](=[O:37])[O:12][C:13]([OH:36])([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[C:14]=3[CH2:15][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:38][N:39]([CH2:41][CH2:42][CH2:43]O)[CH3:40].CN(C)CCO>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11](=[O:37])[O:12][C:13]([O:36][CH2:43][CH2:42][CH2:41][N:39]([CH3:40])[CH3:38])([C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)[C:14]=3[CH2:15][C:16]3[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccc(C2(O)OC(=O)C(c3ccc4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OC)c2)cc1
Reactant: CN(C)CCCO
Agent: CN(C)CCO
Solvent: ClCCl
Product: COc1ccc(C2(OCCCN(C)C)OC(=O)C(c3ccc4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 125 mL dichloromethane was added 3-Benzo[1,3]dioxol-5-yl-5-hydroxy-5-(4-methoxy-phenyl)-4-(3,4,5-trimethoxy-benzyl)-5H-furan-2-one 3.0 g (5.92 mmol), giving a suspension. N,N-dimethyl-propanolamine 2 g (19.4 mmol) was added, and the mixture was purged with anhydrous HCl gas until saturated. After an hour at room temperature, additional N,N-dimethylethanolamine 1 g (9.69 mmol) was added, followed by stirring for 24 hours at room temperature. The mixture was evaporated in vacuo and the residue was suspended in ethyl ether. The ether suspension was washed exhaustively with 4 N NaOH, followed by water and saturated sodium chloride solution. The ether phase was dried over anhydrous magnesium sulfate, filtered, and diluted with hexane, giving a solid. Filter and dry in vacuo, giving a white solid, 1.65 g. The product was identified by 1H NMR, MS [M--H]+ =592 Da.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2([OH:17])[CH2:15][CH2:14][O:13][CH:12]2[CH3:16])=[CH:8][C:9]=1[NH2:10])=[O:4].CO[CH:20]([N:23]([CH3:25])[CH3:24])OC>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2([OH:17])[CH2:15][CH2:14][O:13][CH:12]2[CH3:16])=[CH:8][C:9]=1[N:10]=[CH:20][N:23]([CH3:25])[CH3:24])=[O:4]
Reactant: COC(=O)c1sc(C2(O)CCOC2C)cc1N
Reactant: COC(OC)N(C)C
Product: COC(=O)c1sc(C2(O)CCOC2C)cc1N=CN(C)C

Procedure:
3-Amino-5-(3-hydroxy-2-methyltetrahydrofuran-3-yl)thiophene-2-carboxylic acid methyl ester and dimethoxymethyldimethylamine were reacted by method B. The product with the molecular weight of 312.39 (C14H20N2O4S) was obtained in this way; MS (ESI): 313 (M+H+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13][C:14]([CH3:16])=O.O.S([O-])([O-])(=O)=O.[Mg+2].C(O)(=O)C>C(O)C>[CH2:19]([O:18][C:12](=[O:17])[CH:13]=[C:14]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)[CH3:16])[CH3:20]
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C=C(C)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
3-Trifluoromethylaniline (2.50 g, 15.5 mmol) and ethyl acetoacetate (2.32 g, 17.8 mmol) are dissolved in absolute ethanol in a 500 ml round bottom flask equipped with a stir bar and a reflux condenser. Magnesium sulphate monohydrate (2.58 g, 18.6 mmol) and glacial acetic acid (14 mg, 0.23 mmol) are added. The suspension is stirred rigorously at reflux for 16 hours under an argon atmosphere. The crude reaction mixture is cooled to room temperature, filtered and concentrated in vacuo to give an oil. The oil is chromatographed over silica gel with cyclohexane/ethyl acetate mixtures as eluent to yield a pale yellow oil which is analytically pure.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=[CH:32][CH:31]=1)[CH:5]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:18]=1)[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].Cl.C(=O)([O-])O.[Na+]>C(OCC)C.[Cl-].[Zn+2].[Cl-].O>[OH:3][CH:4]([C:30]1[CH:31]=[CH:32][C:33]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=[CH:34][CH:35]=1)[CH:5]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:18]=1)[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: O=C(OCc1ccccc1)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1ccc(Oc2ccccn2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: O
Solvent: CCOCC
Product: O=C(OCc1ccccc1)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of zinc chloride (3.19 g, 23.4 mmol) in diethyl ether (100 ml) was added sodium borohydride (1.77 g, 67.1 mmol), and the mixture was stirred at room temperature for 30 min. Insoluble material was filtered off, and to the filtrate was added a solution of benzyl 3-oxo-3-[4-(pyridin-2-yloxy)phenyl]-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate (6.5 g, 11.7 mmol) in diethyl ether (50 ml) at 0° C. The mixture was stirred for 30 min. and 1N hydrochloric acid was added to stop the reaction. After neutralization with saturated aqueous sodium hydrogen carbonate, water (200 ml) was added and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:1) to give the objective substance (4.78 g, 73%).
Reaction SMILES: CN(C)C=O.C(O)(=O)C.[OH:10][CH2:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH:15]1[C:20]([O:22][CH3:23])=[O:21].C(N(CC)CC)C.Br[CH2:32][CH2:33][S:34][C:35]1[S:36][CH:37]=[CH:38][CH:39]=1>C(OCC)(=O)C.O>[OH:10][CH2:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:32][CH2:33][S:34][C:35]2[S:36][CH:37]=[CH:38][CH:39]=2)[CH2:16][CH:15]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: BrCCSc1cccs1
Reactant: COC(=O)C1CNCCC1CCCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: COC(=O)C1CN(CCSc2cccs2)CCC1CCCO
Temperature: 75 °C
Reaction time: 2.5 h

Procedure:
To 3.1 mL of an N,N-dimethylformamide solution containing 0.12 g of methyl 4-(3-hydroxypropyl)piperidine-3-carboxylate acetate, 0.19 mL of triethylamine and 0.14 g of 2-((2-bromoethyl)thio)thiophene were added, and the mixture was stirred at 70 to 80° C. for 2.5 hours. Water and ethyl acetate were added thereto, and the organic layer was separated. The organic layer was washed sequentially with water and an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=50:1] to obtain 0.10 g of a brown oily substance, methyl 4-(3-hydroxypropyl)-1-(2-(2-thienylthio)ethyl)piperidine-3-carboxylate.
Reaction SMILES: S(O[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][C:25]#[C:26][C:27]1[CH:28]=[C:29]([CH:40]=[CH:41][CH:42]=1)[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])(C1C=CC(C)=CC=1)(=O)=O.C(=O)(O)[O-].[Na+].[N-:48]=[N+:49]=[N-:50].[Na+]>CN(C)C=O.O>[N:48]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][C:25]#[C:26][C:27]1[CH:28]=[C:29]([CH:40]=[CH:41][CH:42]=1)[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])=[N+:49]=[N-:50]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOCC#Cc2cccc(C(=O)OCc3ccccc3)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCOCCOCCOCCOCC#Cc1cccc(C(=O)OCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a 1000-mL round-bottom flask, was placed a solution of benzyl 3-(1-(tosyloxy)-3,6,9,12-tetraoxapentadec-14-yn-15-yl)benzoate (35.4 g, 59.30 mmol, 1.00 equiv) in N,N-dimethylformamide (400 mL), sodium bicarbonate (10 g, 119.05 mmol, 2.00 equiv), sodium azide (11 g, 169.23 mmol, 3.00 equiv). The resulting solution was stirred overnight at 80° C. The resulting solution was diluted with 200 mL of water. The resulting solution was extracted with 3×100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×100 mL of NaHCO3 aq. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 25 g (90%) of benzyl 3-(1-azido-3,6,9,12-tetraoxapentadec-14-yn-15-yl)benzoate as brown oil.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5].[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]([C:30](O)=[O:31])=[CH:24]2>>[CH2:13]([C@H:3]([NH:2][C:30]([C:25]1[NH:26][C:27]2[C:23]([CH:24]=1)=[CH:22][C:21]([Cl:20])=[CH:29][CH:28]=2)=[O:31])[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCC(O)CC1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCC(O)CC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
(S)-2-Amino-1-(4-hydroxy-piperidin-1-yl)-3-phenyl-propan-1-one hydrochloride (0.8 mmol) and 5-chloro-1H-indole-2-carboxylic acid (0.9 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, 48 hour reaction time) and the product purified by chromatography on silica gel eluted with 50, 75 and 100% ethyl acetate in hexanes followed by trituration from 1:1 ether-hexanes. Yield 266 mg, 76%; HPLC (60/40) 4.09 minutes (99%); PBMS 426/428 (MH+, 100%);
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([O:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14]([N:18]=[CH:19][N:20]([CH:22](C)[CH3:23])[CH3:21])=[C:13]([CH3:25])[CH:12]=2)[S:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(OC2C(C)=CC(/N=C/N3CCCCC3)=C(C)C=2)SN=1)(C)(C)C.C(C1N=C(OC2C(C(F)(F)F)=CC(/N=C/N3CCCCC3)=C(C)C=2)SN=1)(C)(C)C.C(C1N=C(OC2C(C(F)(F)F)=CC(N=CN(CC)C)=C(C)C=2)SN=1)(C)(C)C.C(C1N=C(OC2C(C(F)(F)F)=CC(N=CN(C(C)C)C)=C(C)C=2)SN=1)(C)(C)C.C(C1N=C(OC2C(Cl)=CC(N=CN(C(C)C)C)=C(C)C=2)SN=1)(C)(C)C.C(C1N=C(OC2C(Cl)=CC(N=CN(CC)C)=C(C)C=2)SN=1)(C)(C)C.C(C1N=C(OC2C(Cl)=CC(/N=C/N3CCCCC3)=C(C)C=2)SN=1)(C)(C)C>>[C:1]([C:5]1[N:9]=[C:8]([O:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14]([N:18]=[CH:19][N:20]([CH2:22][CH3:23])[CH3:21])=[C:13]([CH3:25])[CH:12]=2)[S:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Oc2nc(C(C)(C)C)ns2)c(C)cc1N=CN(C)C(C)C
Agent: CCN(C)C=Nc1cc(C(F)(F)F)c(Oc2nc(C(C)(C)C)ns2)cc1C
Agent: CCN(C)C=Nc1cc(Cl)c(Oc2nc(C(C)(C)C)ns2)cc1C
Agent: Cc1cc(Oc2nc(C(C)(C)C)ns2)c(C(F)(F)F)cc1/N=C/N1CCCCC1
Product: CCN(C)C=Nc1cc(C)c(Oc2nc(C(C)(C)C)ns2)cc1C

Procedure:
(A-2) N′-{4-[(3-(tert-butyl)-1,2,4-thiadiazol-5-yl)oxy]-2,5-dimethylphenyl}-N-isopropyl-N-methylimidoformamide; (A-3) 4-[(3-(tert-butyl)-1,2,4-thiadiazol-5-yl)oxy]-2,5-dimethyl-N-[(1E)-piperidin-1-ylmethylene]aniline; (A-4) 4-[(3-(tert-butyl)-1,2,4-thiadiazol-5-yl)oxy]-2-methyl-N-[(1E)-piperidin-1-ylmethylene]-5-(trifluoromethyl)aniline; (A-5) N′-{4-[(3-(tert-butyl)-1,2,4-thiadiazol-5-yl)oxy]-2-methyl-5-(trifluoromethyl)phenyl}-N-ethyl-N-methylimidoformamide; (A-6) N′-{4-[(3-(tert-butyl)-1,2,4-thiadiazol-5-yl)oxy]-2-methyl-5-(trifluoromethyl)phenyl}-N-isopropyl-N-methylimidoformamide; (A-7) N′-{4-[(3-(tert-butyl)-1,2,4-thiadiazol-5-yl)oxy]-5-chloro-2-methylphenyl}-N-isopropyl-N-methylimidoformamide; (A-8) N′-{4-[(3-(tert-butyl)-1,2,4-thiadiazol-5-yl)oxy]-5-chloro-2-methylphenyl}-N-ethyl-N-methylimidoformamide; (A-9) 4-[(3-(tert-butyl)-1,2,4-thiadiazol-5-yl)oxy]-5-chloro-2-methyl-N-[(1E)-piperidin-1-ylmethylene]aniline.