Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I.[Cl-].[NH4+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:24])[CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)cc2)CC1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN(c1ccc(F)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 109.1 %

Procedure:
To an N,N-dimethylformamide solution (5 ml) of tert-butyl 4-[(4-fluorophenyl)amino]piperidine-1-carboxylate (250 mg, 0.850 mmol) synthesized in Reference Synthesis Example 23, sodium hydride (37 mg, 0.93 mmol, purity 60%) and methyl iodide (58 μL, 0.93 mmol) were added at room temperature and the resultant solution was stirred at room temperature for 15 hours. After completion of the reaction, saturated ammonium chloride aqueous solution was added, and extraction with ethyl acetate was performed from the resultant mixture. The resultant organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product of tert-butyl 4-[(4-fluorophenyl)(methyl)amino]piperidine-1-carboxylate (286 mg). Subsequently, to the obtained tert-butyl 4-[(4-fluorophenyl)(methyl)amino]piperidine-1-carboxylate (130 mg, 0.420 mmol), 4 M hydrogen chloride/1,4-dioxane solution (2 mL) was added and the resultant mixture was stirred at room temperature for 1 day. After completion of the reaction, the resultant solid was collected by filtration and washed with dichloromethane. To the obtained solid, water was added and pH of the resultant solution was adjusted to 9 with 1 M sodium hydroxide aqueous solution, followed by extraction from the resultant mixture with ethyl acetate and chloroform. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (62 mg, yield 72%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:9]=[C:10]([NH:15][CH:16]=O)[CH:11]=[C:12]([F:14])[CH:13]=1>C1COCC1>[F:7][C:8]1[CH:9]=[C:10]([CH:11]=[C:12]([F:14])[CH:13]=1)[NH:15][CH3:16]
Reactant: O=CNc1cc(F)cc(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNc1cc(F)cc(F)c1
Reaction time: 8 h
Yield: 86.8 %

Procedure:
A solution of 3,5-difluoroaniline (5.0 g, 38.7 mmol) in HCOOH (15 mL) was heated to reflux for 4 h. The mixture was poured into ice-water and stirred for 0.5 h. The white solid was collected by filtration, and dried under vacuum to give 4.8 g (79%) of crude N-(3,5-difluorophenyl)formamide. To the solution of LiAlH4 (3.0 g, 78.9 mmol) in dry THF (50 mL) was added a solution of N-(3,5-difluorophenyl)formamide (4.8 g, 30.6 mmol) in dry THF (50 mL) at r.t. The mixture was stirred overnight and then quenched with addition of water (3.0 mL), aqueous 10% NaOH (3.0 mL), and water (9.0 ml). The reaction mixture was filtered and extracted with EtOAc. Organics were dried (Na2SO4), and concentrated to give 3.8 g (86%) of the title compound as a pale brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[S:31]([CH3:34])(=[O:33])=[O:32]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:27]4[CH:28]=[CH:29][C:30]([S:31]([CH3:34])(=[O:32])=[O:33])=[C:25]([F:24])[CH:26]=4)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Cl)ncc3o2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(S(C)(=O)=O)c(F)c4)ncc3o2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 3-fluoro-4-methylsulfonyl-phenylboronic acid following a procedure analogous to that described for Example 1. LC (method 4): tR=1.71 min; Mass spectrum (ESI+): m/z=475 [M+H]+.
Reaction SMILES: [Mg].[Br:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.[Cl:10][Si:11](Cl)([Cl:13])[Cl:12]>C(OCC)C>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([Si:11]([Cl:13])([Cl:12])[Cl:10])=[CH:5][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: Cl[Si](Cl)(Cl)Cl
Agent: [Mg]
Solvent: CCOCC
Product: Cl[Si](Cl)(Cl)c1ccc(Br)cc1
Reaction time: 8 h

Procedure:
Freshly activated magnesium (8.5 g, 0.35 mol) was slowly added over a period of four hours to a solution of 1,4-dibromobenzene (80 g, 0.34 mol) in 200 mL of diethylether, keeping the temperature below 30° C. The reaction mixture was stirred for 8 hours and then slowly added to a mixture of tetrachlorosilane (100 mL, 0.87 mol) in diethylether (50 mL) within 12 hours. The mixture was stirred for 12 hours, and unreacted tetrachlorosilane and diethylether were removed in vacuum. The remaining liquid was fractionally distilled through a Vigreux column under reduced pressure to provide 4-bromophenyltrichlorosilane as an oil (350 μHg/85° C.-37 g/37%). 1HNMR(400 MHz, CDCl3): δ 7.69 (4H, dd). 13CNMR (100 MHz, CDCl3): δ 134.6, 131.9, 130.4, 128.2. GC-MS: 290 (M+).
Reaction SMILES: [BH3-]C#N.[Na+].C([OH:9])(C)(C)C.I[CH:11]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O=O>O.CC(N=NC(C#N)(C)C)(C#N)C>[C:14]1([CH2:13][CH2:12][CH:11]([OH:9])[CH2:20][CH2:21][CH2:22][CH3:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCCC(I)CCc1ccccc1
Reactant: CC(C)(C)O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=O
Agent: [BH3-]C#N
Solvent: O
Product: CCCCC(O)CCc1ccccc1
Reaction time: 13 h
Yield: 93 %

Procedure:
A reaction vessel (50 ml, a two-neck, eggplant type flask) is subjected to nitrogen gas purging. NaBH3CN (1.0 mmol, 62.8 mg), AIBN (0.005 mmol, 0.8 mg) and Bu2(t-Bu)SnCl (0.025 mmol, 8.1 mg, 7 μl) are added to tert-butanol (2 ml). Then, 3-iodo-1-phenylheptane (0.5mmol, 151.1mg, 115 μl) is added. The introduction of nitrogen gas is discontinued, a nitrogen gas-filled black butyl rubber balloon is set instead, and using a syringe, oxygen (0.75 mmol, 18 ml) is bubbled into the solution. Thereafter, the reaction vessel is immersed in an oil bath at 60° C. After 13 hours, heating is discontinued and the reaction mixture is diluted with pure water (10 ml) and extracted with ether (15 ml×4). The organic solution is dried over anhydrous magnesium sulfate and the solvent is distilled off. The residue is purified by column chromatography (silica gel 4 g, ethyl acetate/hexane 20%) to provide 1phenyl-3-heptanol (89.4 mg, 93%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=1)\[C:13]([OH:15])=O)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:63][C@H:64]1[C@@H:67]([CH2:68][N:69]2[N:73]=[N:72][C:71]([CH3:74])=[N:70]2)[NH:66][C:65]1=[O:75]>C(Cl)Cl.CN(C=O)C>[C:25]([O:24][C:22]([NH:21][C:18]1[S:19][CH:20]=[C:16](/[C:12](=[N:11]/[O:10][C:7]([CH3:9])([CH3:8])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:29])/[C:13]([NH:63][C@@H:64]2[C:65](=[O:75])[NH:66][C@@H:67]2[CH2:68][N:69]2[N:73]=[N:72][C:71]([CH3:74])=[N:70]2)=[O:15])[N:17]=1)=[O:23])([CH3:27])([CH3:28])[CH3:26]
Reactant: Cc1nnn(C[C@H]2NC(=O)[C@H]2N)n1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nnn(C[C@H]2NC(=O)[C@H]2NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c2csc(NC(=O)OC(C)(C)C)n2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
Prepared in an analogous manner to example 4, step 3 using (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (130 mg, 0.302 mmol), DIPEA (158 μL, 0.906 mmol) and HATU (138 mg, 0.362 mmol) in DCM:DMF (2:1, 3.0 mL) at 0° C. followed by a solution of (3S,4R)-3-amino-4-((5-methyl-2H-tetrazol-2-yl)methyl)azetidin-2-one (55 mg, 0.30 mmol) in DCM:DMF (2:1, 3.0 mL). After stirring at rt for 1 h it was concentrated in vacuo, dissolved in EtOAc, washed with water then brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (Acetone-DCM), affording the title compound (179 mg, 99%) as a solid. LCMS: Rt=0.93 min, m/z=594.3 (M+1) Method 2m_acidic.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH:19]2[O:23]C2CCCCO2)[C:10]([NH:12][C:13]([NH:15][CH3:16])=[O:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH:19]2[OH:23])[C:10]([NH:12][C:13]([NH:15][CH3:16])=[O:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC(=O)NC(=O)C(CC1CCCC1OC1CCCCO1)c1ccc(Cl)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CNC(=O)NC(=O)C(CC1CCCC1O)c1ccc(Cl)c(Cl)c1
Temperature: 55 °C
Yield: 84.6 %

Procedure:
A solution of 1-{2-(3,4-dichloro-phenyl)-3-[2-(tetrahydro-pyran-2-yloxy)-cyclopentyl]-propionyl}-3-methyl-urea (45 mg, 0.10 mmol) in ethanol (1.01 mL) was treated with pyridinium p-toluenesulfonate (2.5 mg, 0.01 mmol). The reaction mixture was heated to 55° C. for 5 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 100% ethyl acetate) afforded the 1-[2-(3,4-dichloro-phenyl)-3-(2-hydroxy-cyclopentyl)-propionyl]-3-methyl-urea (30.4 mg, 83.4%) as a white solid: mp 62–64° C.; FAB-HRMS m/e calcd for C16H20Cl2N2O3 (M+H)+ 359.0929, found 359.0929.
Reaction SMILES: [OH:1][C:2]1([C:12]2[N:16]([S:17]([N:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[C:15]([C:23]([O:25][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])=[CH2:24])=[N:14][C:13]=2[CH3:36])[C@H:9]2[C@H:5]([O:6][C:7]([CH3:11])([CH3:10])[O:8]2)[CH2:4][O:3]1.[BH4-].[Na+]>C(O)C>[OH:1][C@@H:2]([C@H:9]1[C@@H:5]([CH2:4][OH:3])[O:6][C:7]([CH3:11])([CH3:10])[O:8]1)[C:12]1[N:16]([S:17]([N:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[C:15]([C:23]([O:25][Si:26]([CH:30]([CH3:31])[CH3:32])([CH:27]([CH3:29])[CH3:28])[CH:33]([CH3:34])[CH3:35])=[CH2:24])=[N:14][C:13]=1[CH3:36]
Reactant: C=C(O[Si](C(C)C)(C(C)C)C(C)C)c1nc(C)c(C2(O)OC[C@H]3OC(C)(C)O[C@H]32)n1S(=O)(=O)N(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C=C(O[Si](C(C)C)(C(C)C)C(C)C)c1nc(C)c([C@@H](O)[C@@H]2OC(C)(C)O[C@@H]2CO)n1S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a 0° C. solution of 5-((3aR,6aR)-4-hydroxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-N,N,4-trimethyl-2-(1-(triisopropylsilyloxy)vinyl)-1H-imidazole-1-sulfonamide (2.09 g, 3.83 mmol) in ethanol (70 ml) was added granular NaBH4 (1.4 g, 38.32 mmol) in a few portions. After 2 hours, the reaction was warmed to room temperature for 30 minutes, then concentrated. The residue was redissolved in water (40 ml) and ethyl acetate (40 ml). The biphasic mixture was stirred vigorously for 10 minutes, then the layers were separated. The aqueous layer was washed with ethyl acetate (2×40 ml) and the combined organics were washed with brine (30 ml), then dried over MgSO4 and concentrated. The crude foam was purified by flash chromatography over silica (5% methanol:dichloromethane eluent) to provide 5-((R)-hydroxy((4S,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-N,N,4-trimethyl-2-(1-(triisopropylsilyloxy)vinyl)-1H-imidazole-1-sulfonamide (1.88 g, 90% yield) as a 3:1 mixture of inseparable diasteromers at the benzylic position: M+1=547.4.
Reaction SMILES: Br[C:2]1[C:3]([C:29]#[N:30])=[C:4]([CH:26]=[CH:27][CH:28]=1)[O:5][C:6]1[CH:24]=[CH:23][C:9]([C:10]([NH:12][CH2:13][C:14]2[C:15]([OH:22])=[N:16][C:17]([CH3:21])=[CH:18][C:19]=2[CH3:20])=[O:11])=[CH:8][C:7]=1[Cl:25].[N:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[Cl:25][C:7]1[CH:8]=[C:9]([CH:23]=[CH:24][C:6]=1[O:5][C:4]1[CH:26]=[CH:27][CH:28]=[C:2]([C:34]2[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=2)[C:3]=1[C:29]#[N:30])[C:10]([NH:12][CH2:13][C:14]1[C:15]([OH:22])=[N:16][C:17]([CH3:21])=[CH:18][C:19]=1[CH3:20])=[O:11]
Reactant: Cc1cc(C)c(CNC(=O)c2ccc(Oc3cccc(Br)c3C#N)c(Cl)c2)c(O)n1
Reactant: OB(O)c1ccncc1
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: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2ccc(Oc3cccc(-c4ccncc4)c3C#N)c(Cl)c2)c(O)n1
Temperature: 90 °C
Reaction time: 12 h
Yield: 69.7 %

Procedure:
To a solution of 4-(3-bromo-2-cyanophenoxy)-3-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (500 mg, 1.03 mmol), pyridin-4-ylboronic acid (150 mg, 1.2 mmol), sodium carbonate (425 mg, 3.07 mmol) in 1,4-dioxane (20 mL) and water (5 mL) was added tetrakis(triphenylphosphine)palladium(0) (118 mg, 0.1 mmol). The reaction mixture was stirred at 90° C. under nitrogen atmosphere for 12 hours. After the reaction, it was allowed to cool to room temperature, and concentrated in vacuo, then diluted with ethyl acetate, washed with water. The organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give the pure product 3-chloro-4-(2-cyano-3-(pyridin-4-yl)phenoxy)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (348 mg, 70%). LRMS (M+H+) m/z: calcd 484.13. found 484. 1H NMR (300 MHz, d6-DMSO): δ 11.48 (s, 1H), 8.75 (d, J=6.0 Hz, 2H), 8.55 (t, J=4.5 Hz, 1H), 8.15 (s, 1H), 7.94-7.91 (m, 1H), 7.76 (t, J=7.8 Hz, 1H), 7.67-7.65 (m, 2H), 7.44 (d, J=7.5 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 5.86 (s, 1H), 4.29 (d, J=4.8 Hz, 2H), 2.16 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: [CH3:1][Si:2]([CH3:20])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][CH2:4][CH2:5][CH2:6][C:7](O)=[O:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+].Cl>O1CCCC1.ClCCl>[CH3:20][Si:2]([CH3:1])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8]
Reactant: CCCCCCCCCC[Si](C)(C)CCCCC(=O)O
Agent: Cl
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCCCCCC[Si](C)(C)CCCCCO

Procedure:
Under nitrogen, 17.1 g (56.9 mmol) of 6,6-dimethyl-6-sila-n-hexadecanoic acid, dissolved in 20 ml of absolute tetrahydrofuran, is added dropwise to 5.4 g (142 mmol) of lithium aluminum hydride in 150 ml of absolute tetrahydrofuran (caution being exercised due to hydrogen evolution). The resultant mixture is stirred at 60° for 18 hrs., then cooled to about 10°; and injected into a cold (about 10°) saturated aqueous of sodium-potassium tartrate. Dichloromethane is added and the mixture acidified with dilute hydrochloric acid (2 N). The organic phase is separated, washed with saturated aqueous sodium bicarbonate solution, then dried over anh. sodium sulfate, filtered and the filtrate concentrated to obtain the crude title product of this step as an oily residue. The oily residue is distilled in a kugelrohr apparatus and the fraction collecting at 108° to 115° and 0.19 to 0.13 mm Hg to obtain refined title product of this step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[C:7]([CH:9]1[CH2:14][CH2:13][N:12](C(C(F)(F)F)=O)[CH2:11][CH2:10]1)=[O:8])([O-:3])=[O:2].[N+](C1C=CC=CC=1C(C1CCN(C(C(F)(F)F)=O)CC1)=O)([O-])=O.[N+](C1C=CC(C(C2CCN(C(C(F)(F)F)=O)CC2)=O)=CC=1)([O-])=O.[ClH:70]>C(O)(C)C>[ClH:70].[N+:1]([C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[C:7]([CH:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)C1CCN(C(=O)C(F)(F)F)CC1
Agent: Cl
Agent: O=C(c1ccc([N+](=O)[O-])cc1)C1CCN(C(=O)C(F)(F)F)CC1
Agent: O=C(c1ccccc1[N+](=O)[O-])C1CCN(C(=O)C(F)(F)F)CC1
Solvent: CC(C)O
Product: O=C(c1cccc([N+](=O)[O-])c1)C1CCNCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 42 %

Procedure:
To a suspension of 2.8 g (8.48 mol) of 4-(3-nitrobenzoyl)-1-trifluoromethylcarbonylpiperidine, 4-(2-nitrobenzoyl)-1-trifluoromethylcarbonylpiperidine, and 4-(4-nitrobenzoyl)-1-trifluoromethylcarbonylpiperidine mixture (62:33:5) in isopropanol (60 mL) was added HCl 37% (10 mL). The reaction mixture was refluxed for 8 h and rapidly a complete dissolution was observed. Then, the solution was allowed to cool to room temperature and post-agitated for 4 h. The precipitate was filtered, rinsed with isopropanol (2×5 mL) and ethyl ether (5 mL). Drying under vacuum at 50° C. afforded pure 4-(3-nitrobenzoyl)piperidine HCl (956 mg, 42%).
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=1)[CH3:2].C(N(CC)CC)C.[O:22]1C[CH2:25][CH2:24][CH2:23]1.C([O-])(=O)C=C.[Cl-]>C1(C)C=CC=CC=1.O>[C:23]([O:10][CH2:9][CH2:8][C:7]1[CH:11]=[CH:12][C:4]([N:3]([CH2:1][CH3:2])[CH2:13][CH3:14])=[CH:5][CH:6]=1)(=[O:22])[CH:24]=[CH2:25]
Reactant: CCN(CC)c1ccc(CCO)cc1
Reactant: C1CCOC1
Agent: C=CC(=O)[O-]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: C=CC(=O)OCCc1ccc(N(CC)CC)cc1
Temperature: 0 °C

Procedure:
In a three-aperture flask, 5.43 g (28.1 mmol) of p-diethylaminophenethyl alcohol, 6.26 g (61.8 mmol) of triethylamine, and 30 mL of dehydrated tetrahydrofuran were poured, and the mixture was stirred under an argon atmosphere and an ice-cooling condition. Then, 5.09 g (56.2 mmol) of chloride acrylate was delivered by drops into the reaction solution for 30 minutes. Upon completion of the dripping, the reaction solution was further stirred for 5 hours. The reaction solution was poured to 100 mL of water and then an extract was obtained therefrom by using toluene, followed by washing with water three times. The toluene solution was dried with anhydrous magnesium sulfate, and then the solvent was distilled away to purify the toluene solution by silica gel chromatography using a mixture solvent of hexane/ethyl acetate (9/1) as an eluent to thereby synthesize 3.17 g (yield: 46% by mass) of p-diethylaminophenethyl acrylate of the exemplified compound No. 21 represented by the following structural formula.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]([F:15])([F:14])[F:13])=[N:8][N:9]([CH3:11])[CH:10]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[CH3:11][N:9]1[CH:10]=[C:6]([CH2:4][OH:3])[C:7]([C:12]([F:13])([F:14])[F:15])=[N:8]1
Reactant: CCOC(=O)c1cn(C)nc1C(F)(F)F
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: Cn1cc(CO)c(C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 16 h
Yield: 100.7 %

Procedure:
Dissolve 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.74 g, 7.83 mmol) in tetrahydrofuran (100 mL) and cool to 0° C. Add diisobutylaluminum hydride (47.0 mL, 47.0 mmol, 1 M in toluene) dropwise over 15 min. Allow the reaction mixture to warm to room temperature over 16 hr. Partition between ethyl acetate (100 mL) and saturated aqueous potassium sodium tartrate solution (50 mL) and stir at room temperature for another 16 hr. Separate the organic layer; dry (sodium sulfate), filter and concentrate to give (1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol (1.42 g, 100%). 1H-NMR (400 MHz, CDCl3) δ 7.42 (s, 1H), 4.63 (s, 2H), 3.90 (s, 3H), 1.80 (bs, 1H).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([C:11]2[N:15]([NH2:16])[C:14]([CH3:18])([CH3:17])[O:13][N:12]=2)[CH:7]=[C:8]([CH3:10])[CH:9]=1.[CH2:19]([C:21]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24])[CH3:20].O>C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C.C(Cl)(Cl)Cl>[CH3:3][C:4]1[CH:5]=[C:6]([C:11]2[N:15]([NH:16][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:21]=3[CH2:19][CH3:20])[C:14]([CH3:18])([CH3:17])[O:13][N:12]=2)[CH:7]=[C:8]([CH3:10])[CH:9]=1
Reactant: Cc1cc(C)cc(C2=NOC(C)(C)N2N)c1
Reactant: CCc1c(OC)cccc1C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1c(OC)cccc1C(=O)NN1C(c2cc(C)cc(C)c2)=NOC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.8 %

Procedure:
A 20% aqueous solution of NaOH (275 mg, 1.37 mmol) was added to a solution of 3-(3,5-dimethyl-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-ylamine (200 mg, 0.91 mmol) in 2 mL of toluene. 2-Ethyl-3-methoxybenzoyl chloride (199 mg, 1 mmol) was then added to the mixture. The reaction was stirred at room temperature for 2 hours, and then heated at 50° C. for 1 hour. TLC indicated 3 spots. Water, dilute NaOH, and CHCl3 were then added to the reaction mixture. The organic phase was separated, dried over MgSO4, and the solvent removed in vacuo. The residue was triturated with 10% ether in hexane. Filtration and air-drying of the resultant solid provided 100 mg (29% yield) of N-[3-(3,5-dimethyl-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-2-ethyl-3-methoxy-benzamide, 1H-NMR (300 MHz, CDCl3) δ (ppm): 7.42 (s, 2H), 7.11 (s, 1H), 7.11 (t, 1H), 6.9 (d, 1H), 6.67 (d, 1H), 3.81 (s, 3H), 2.55 (q, 2H), 2.34 (s, 6H), 1.7 (br s, 6H), 1.05 (t, 3H), Rf=0.5 (1:1 ethyl acetate:hexane).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[C].[Pd]>[CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cc2ccccc2)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(Cc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
389 mg of 2-benzyl-5-nitropyridine was dissolved in ethyl acetate and 153 mg of 10% palladium carbon was added thereto. Then the resulting mixture was stirred under a hydrogen gas stream at room temperature under atmospheric pressure for 30 minutes. Then the reaction mixture was filtered through celite. After distilling off the solvent under reduced pressure, 333 mg of the title compound was obtained as an amber oily substance.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Br[CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CS(C)=O>[CH3:16][C:15]([CH3:17])=[CH:14][CH2:13][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: CC(C)=CCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCC=C(C)C)cc1
Yield: 83 %

Procedure:
A mixture of 4-hydroxybenzoic acid, methyl ester (17.0 mL, 66 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA), 1-bromo-3-methylbut-2-ene (12.0 g, 79 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) and potassium carbonate (23.0 g, 164 mmol) in DMSO (25 mL) was stirred at room temperature for 24 hours. EtOAc (150 mL) was added, and the mixture was washed with water (25×3 mL) and brine (25×2 mL) and dried over MgSO4. The solvent was removed, and the product was purified by CombiFlash® silica gel column chromatography, eluent with hexane/EtOAc, 90/10 to give T45.1 (12.0 g, yield 83%). 1H NMR (500 MHz, CDCl3) δ ppm 7.99 (2H, d, J=8.8 Hz), 6.92 (2H, d, J=8.8 Hz), 5.42-5.58 (1H, m), 4.57 (2H, d, J=6.8 Hz), 3.89 (3H, s), 1.81 (3H, s), 1.76 (3H, s).