Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C@H:9]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)[NH:8][CH2:7][CH2:6]2.[CH3:27][NH:28][C:29]([C@@H:31](OS(C1C=CC(C)=CC=1)(=O)=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30].[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(CC(C)=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C@H:9]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)[N:8]([C@H:31]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:29]([NH:28][CH3:27])=[O:30])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)[C@H](CCc1ccc(C(F)(F)F)cc1)NCC2
Reactant: CNC(=O)[C@@H](OS(=O)(=O)c1ccc(C)cc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: CNC(=O)[C@@H](c1ccccc1)N1CCc2cc(OC)c(OC)cc2[C@@H]1CCc1ccc(C(F)(F)F)cc1
Temperature: 80 °C

Procedure:
To the solution of the compound 7 in MIBK are added 1.2 equivalents of the compound 6, 1.1 equivalents caustic soda and 1.1 equivalents potassium carbonate and heated to 70-90° C. Water is added and the mixture is heated at the same temperature for 0.5 to 3 hours and then cooled to RT. Alternatively, after full conversion the solution is cooled to RT and water is added. Phase separation is followed by a second washing of the organic phase with water and again phase separation.
Reaction SMILES: Br[Si](C)(C)C.CC(O[O:10][P:11]([CH2:18][P:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])([O:21]C(C)C)=[O:20])(=[O:17])[O:12]OC(C)C)C.C(N(CCCC)CCCC)CCC.[Na+:55].[I-].CC(C)=O>CO>[Na+:55].[Na+:55].[Na+:55].[CH2:25]([P:19]([CH2:18][P:11](=[O:10])([O-:17])[O-:12])([OH:21])=[O:20])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCCCCCCCCCP(=O)(CP(=O)(OOC(C)C)OOC(C)C)OC(C)C
Agent: C[Si](C)(C)Br
Agent: [I-]
Agent: [Na+]
Solvent: CCCCN(CCCC)CCCC
Solvent: CO
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCP(=O)(O)CP(=O)([O-])[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 85 %

Procedure:
Bromotrimethylsilane (0.34 mL, 2.58 mmol) was added dropwise to ((n-heptadecyl)-2-propoxyphosphinyl)methylphosphonic acid di-2-propoxy ester (0.150 g, 0.286 mmol) in a 3 mL vial. The resulting solution was stirred for 14-16 hours at ambient temperature. Excess bromotrimethylsilane was then removed by passing a steady stream of dry nitrogen over the solution for 2 hours. The solution was then placed under high vacuum for 3 hours to remove any residual bromotrimethylsilane. Tributylamine (0.24 g, 1.29 mmol) and methanol (2 mL) were then added to the vial resulting in a clear solution. This solution was then added dropwise to a 0.5 M solution of NaI in acetone (5.0 mL, 2.5 mmol). A white precipitated immediately appeared. The solid was collected by centrifugation and the acetone solution was discarded. The solid was then washed by suspension in clean acetone (20 mL), centrifugation and removal of acetone supernatant. After this washing procedure was completed 3 times, the solid was placed under vacuum for a period of 12-16 hours providing the desired product (0.113 g, 85% yield). 1H NMR (400 MHz D2O): δ 1.7 (m, 2H), 1.3 (m, 4H), 1.1 (m, 28H), 0.7 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([CH2:4][CH2:3][CH2:2][CH2:7][CH2:6][CH:18]3[C:19](=[O:14])[NH:11][CH2:10][C:9]4[CH:8]=[CH:13][CH:12]=[CH:15][C:16]=4[O:17]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: C1COCCO1
Reactant: Clc1ccc(C2CCNCC2)cc1
Product: O=C1NCc2ccccc2OC1CCCCCN1CCC(c2ccc(Cl)cc2)CC1
Temperature: 110 °C
Reaction time: 6 h
Yield: 52.4 %

Procedure:
In 10 ml of dioxane was dissolved 65.2 mg of the compound prepared in Reference Example 2, then 123 mg (3 equivalents) of 4-(4-chlorophenyl)piperidine was added thereto, and the resulting mixture was stirred at 110° C. for 6 hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 46.7 mg (yield: 52.4%) of the title compound. The hydrochloride of this compound was obtained by converting the compound into hydrochloride in the usual manner, and then recrystallizing the salt from methylene chloride-ether.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[H-].[Al+3].[Li+].[H-].[H-].[H-].[F:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH2:18][C:19]#[N:20])[CH:17]=1.[OH-].[Na+]>C1COCC1>[F:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH2:18][CH2:19][NH2:20])[CH:17]=1
Reactant: COc1ccc(F)cc1CC#N
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(F)cc1CCN
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under argon, 17.6 g (132 mmol) of aluminium trichloride are dissolved in THF, and the mixture is cooled to 0° C. 87 ml of lithium aluminium hydride solution (1M in THF) are slowly added dropwise. A solution of 14.5 g (87.8 mmol) of (5-fluoro-2-methoxyphenyl)acetonitrile in 100 ml is added slowly. The reaction mixture is stirred at RT for 2 hours. At 0° C., ice/water is then added, the mixture is made alkaline using sodium hydroxide solution and extracted with ethyl acetate and the extract is dried and concentrated using a rotary evaporator.
Reaction SMILES: [OH:1][CH:2]([CH2:16][NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:3][O:4][C:5]1[C:13]2[NH:12][C:11](=[O:14])[NH:10][C:9]=2[C:8]([CH3:15])=[CH:7][CH:6]=1.C[O-].[Na+].[C:25](N=[N+]=[N-])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[ClH:36]>CN(C)C=O>[ClH:36].[C:25]([O:1][CH:2]([CH2:16][NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:3][O:4][C:5]1[C:13]2[NH:12][C:11](=[O:14])[NH:10][C:9]=2[C:8]([CH3:15])=[CH:7][CH:6]=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: [N-]=[N+]=NC(=O)c1ccccc1
Reactant: Cc1ccc(OCC(O)CNC(C)(C)C)c2[nH]c(=O)[nH]c12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCC(CNC(C)(C)C)OC(=O)c2ccccc2)c2[nH]c(=O)[nH]c12

Procedure:
4-(2-Hydroxy-3-tert.-butylaminopropoxy)-7-methyl-2-benzimidazolinone (prepared from the hydrochloride (see Example 3) and methanolic sodium methylate solution) is stirred for 5 days at ambient temperature with an equimolar amount of benzoic acid azide in dimethylformamide. The crystalline precipitate obtained is mixed with ethereal hydrochloric acid and, after evaporation, recrystallised from ethanol to give 4-[2-benzoyloxy-3-tert.-butylaminopropoxy]-7-methyl-2-benzimidazolinone hydrochloride; m.p. 216°-218° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](O)[CH:8]=[C:7]([CH:12]([F:14])[F:13])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:17])=O.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([C:5]1[N:10]=[C:9]([Cl:17])[CH:8]=[C:7]([CH:12]([F:14])[F:13])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1nc(O)cc(C(F)F)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)c1nc(Cl)cc(C(F)F)n1

Procedure:
2.8 g of 2-tert-butyl-4-hydroxy-6-difluoromethyl-pyrimidine (13.9 mmol) and 3 ml of thionylchloride were stirred 14 h at room temperature and an additional 3 h at 76° C. 20 ml of dichloromethane were added with cooling, followed by addition of 15 ml of a saturated aqueous solution of sodium bicarbonate. The organic layer was separated, dried over magnesium sulfate and the solvent was evaporated to yield the crude title compound which was purified by column chromatography on silica gel (dichloromethane/hexane 1:1) to yield 0.8 g of product.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:14][OH:15].[CH3:16][C:17]1([CH3:27])[CH:19]([CH:20]=[C:21]([CH3:23])[CH3:22])[CH:18]1[C:24](Cl)=[O:25].CCCCCC>N1C=CC=CC=1.C(OCC)C>[CH3:16][C:17]1([CH3:27])[CH:19]([CH:20]=[C:21]([CH3:22])[CH3:23])[CH:18]1[C:24]([O:15][CH2:14][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]=1[CH3:1])=[O:25]
Reactant: CC(C)=CC1C(C(=O)Cl)C1(C)C
Reactant: Cc1c(CO)cccc1-c1ccccc1
Solvent: CCCCCC
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)=CC1C(C(=O)OCc2cccc(-c3ccccc3)c2C)C1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
A solution of 2.97 g (15.0 mmol) of (2-methyl-3phenylphenyl)methanol in 1.5 ml of pyridine and 10 ml of diethyl ether, was dropwise added to a solution of 2.80 g (15.0 mmol) of 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarbonyl chloride in 10 ml of diethyl ether, and the mixture was stirred at room temperature for 3 hours. After an addition of 20 ml of hexane thereto, the inorganic salt was filtered off, and the filtrate was concentrated under reduced pressure. The product was purified by column chromatography (silica gel, dichloromethane/hexane=1/2) to obtain 4.23 g of (2-methyl-3-phenylphenyl)methyl 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:13].C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>>[CH3:17][N:18]([CH:20]=[C:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[C:8]1=[O:13])[CH3:19]
Reactant: COc1cccc2c1CCCC2=O
Reactant: CCOC(OCC)N(C)C
Product: COc1cccc2c1CCC(=CN(C)C)C2=O

Procedure:
The 3,4-dihydro-2-(dimethylaminomethylene)-5-methoxy-1(2H)-naphthalenone starting material was prepared from 5-methoxy-1-tetralone (5.0 g, 28.4 mmol) and N,N-dimethylformamide diethyl acetal (25 g, 170.2 mmol) to give the desired product as brown needles (5.27 g). m.p. 108-110°. MS (ES+) 232 (MH+, 100%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][CH:10]([NH:13]C(=O)OC(C)(C)C)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.Cl.CO>O1CCOCC1>[O:1]1[CH2:2][CH2:3][CH:4]([N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C2CCOCC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
9.2 g (0.0323 mol, 1 eq) of 1,1-dimethylethyl [1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]carbamate, 65 mL (0.258 mol, 8 eq) of 4 M HCl in dioxane, and enough methanol to achieve dissolution were combined and stirred at ambient temperature overnight. The reaction mixture was then evaporated. Dichloromethane and 1 M NaOH were added. Sodium chloride was then added to saturate the aqueous layer. The aqueous layer was extracted with dichloromethane twice. The organic layers were combined, dried with sodium sulfate, and evaporated to yield 5.5 g (92% yield) of 1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine as a low melting white solid. 1H-NMR (400 MHz, DMSO-d6): δ 3.86 (m, 2H), 3.24 (m, 2H), 2.77 (m, 2H), 2.46 (m, 1H), 2.35 (m, 1H), 2.25-1.05 (v br s, 2H, NH2), 2.07 (m, 2H), 1.64 (m, 4H), 1.39 (m, 2H), 1.16 (m, 2H); MS (ESI): 185 [M+H]+.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH3:10])=[N:6][CH:7]=1.N([O-])=[O:12].[Na+].C(=O)([O-])O.[Na+]>Cl.O>[OH:12][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH3:10])=[N:6][CH:7]=1
Reactant: CCCc1ccc(N)cn1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCc1ccc(O)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5-Amino-2-n-propylpyridine (70.3 g, 516 mmol) was dissolved in 1300 ml of 1M hydrochloric acid and sodium nitrite (35.6 g, 516 mmol) dissolved in 300 ml of water was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1/2 hour, heated to 70° C. for 2 hours, and then stirred at room temperature the overnight. The reaction mixture was neutralised to pH=8 by adding solid sodium hydrogen carbonate, and the product was extracted into ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and the solvent was evaporated. The crude product was purified by column chromatography over silica gel 60, using ethyl acetate:petroleum ether (1:1) as the eluent. This gave 65.7 g (92%) of 5-hydroxy-2-n-propylpyridine as an orange wax. 1H-NMR (CDCl3, 200 MHz) δ: 0.91 (t, 3H); 1.68 (sext, 2H); 2.71 (t, 2H); 7.09 (d, 1H); 7.25 (dd, 1H); 8.13 (d, 1H); 11.79 (s, 1H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:24]2([CH2:29][NH2:30])[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:24]2([CH2:29][NH:30][C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[O:13])[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(C2(CN)CCCC2)cc1OC
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(C2(CNC(=O)c3ccc4ccccc4n3)CCCC2)cc1OC
Reaction time: 16 h
Yield: 37.6 %

Procedure:
Quinoline-2-carboxylic acid (0.502 g, 2.90 mmol) and C-[1-(3,4-Dimethoxy-phenyl)-cyclopentyl]-methylamine (0.678 g, 2.90 mmol) were dissolved in acetonitrile (20 mL) containing triethylamine (894 μL, 6.38 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.54 g, 4.06 mmol) was added and the solution was allowed to stir for 16 hours. The reaction mixture was evaporated to dryness and purified by column chromatography on silica gel using a gradient of 0-40% ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to yield a white solid (0.426 g, 1.09 mmol, 37.7%). ESI-MS m/z calc. 390.2, found 391.2 (M+1)+. Retention time of 3.94 minutes. 1H NMR (400 MHz, CD3CN) δ 1.69-2.15 (m, 8H), 3.62 (d, J=30.1 Hz, 2H), 3.77 (s, 3H), 3.90 (s, 3H), 6.91-7.03 (m, 3H), 7.69 (t, J=8.1 Hz, 1H), 7.83 (t, J=7.7 Hz, 1H), 7.99 (t, J=8.8 Hz, 2H), 8.08 (s, 1H), 8.18 (d, J=8.5 Hz, 1H), 8.44 (d, J=8.5 Hz, 1H)
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O.C(OCC)(=O)C>[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc(Sc2ccc(C(=O)O)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 72.9 %

Procedure:
A solution of 4-chloro-3-nitrobenzoic acid (2.00 g, 10.0 mmol), 4-aminothiophenol (10.0 mmol), and cesium carbonate (6.52 g, 20.0 mmol) in anhydrous N,N-dimethylformamide (10 mL) was heated at 90° C. under a nitrogen atmosphere for 2 hours. The reaction was cooled to room temperature and poured into 50 mL of ice water and ethyl acetate (100 mL). The mixture was stirred while adjusting the pH to 2 with concentrated hydrochloric acid. The layers were separated and the organic phase washed with water (2×50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo. The residue was co-evaporated with methylene chloride/hexanes and the residue triturated with methylene chloride to provide the title compound as a dark yellow solid (2.115 g, 73%).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:36]1[CH:41]=[CH:40][C:39]([CH:42]([CH3:44])[CH3:43])=[CH:38][CH:37]=1)[CH2:22][C:23]1[CH:24]=[N:25][C:26]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:27][CH:28]=1)=[O:20])C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[C].[Pd]>[OH:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:36]1[CH:41]=[CH:40][C:39]([CH:42]([CH3:44])[CH3:43])=[CH:38][CH:37]=1)[CH2:22][C:23]1[CH:24]=[N:25][C:26]([O:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:27][CH:28]=1)=[O:20]
Reactant: CC(C)c1ccc(N(Cc2ccc(Oc3ccccc3)nc2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)c1ccc(N(Cc2ccc(Oc3ccccc3)nc2)C(=O)C2CCCc3c(O)cccc32)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-benzyloxy-N-(4-isopropylphenyl)-N-[(6-phenoxypyridin-3-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.42 g) in methanol (3 mL) were added 10% palladium carbon (0.05 g) and ammonium formate (0.23 g), and the mixture was stirred at room temperature for one day. The reaction mixture was filtrated, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give 5-hydroxy-N-(4-isopropylphenyl)-N-[(6-phenoxypyridin-3-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide. This compound was dissolved in ethyl acetate, and 4 mol/L-hydrochloric acid/dioxane (0.20 mL) was added. The precipitated solid was collected by filtration to give 5-hydroxy-N-(4-isopropylphenyl)-N-[(6-phenoxypyridin-3-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.11 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([CH3:24])([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH2:14][CH2:15][CH3:16])[CH:8]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:32]1([C:38]2[O:39][C:40]([CH3:56])=[C:41]([CH2:43][CH2:44]OS(C3C=CC(C)=CC=3)(=O)=O)[N:42]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:25])[C:5]([CH3:24])([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:44][CH2:43][C:41]2[N:42]=[C:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:39][C:40]=2[CH3:56])=[C:9]([CH2:14][CH2:15][CH3:16])[CH:8]=1)[CH3:2]
Reactant: CCCc1cc(CC(C)(Oc2ccccc2)C(=O)OCC)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(CC(C)(Oc2ccccc2)C(=O)OCC)ccc1OCCc1nc(-c2ccccc2)oc1C
Temperature: 55 °C
Yield: 60 %

Procedure:
A solution of 3-(4-hydroxy-3-propylphenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (266 mg, 1.0 mmol) in DMF (10 mL) was treated with cesium carbonate (407 mg, 1.25 mmol) and toluene-4-sulfonic acid 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester and then heated at 55° C. for 18 h. After cooling to ambient temperature, the mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc and then the organic phases were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (100 mL SiO2, hexanes to 30% EtOAc/hexanes) to provide the desired product (315 mg, 60%) as a clear, colorless oil: MS (EI) 528.3 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([NH:12][C:13]([O:15]CC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][CH2:37][CH2:38][CH2:39][NH:40][C:41](=[O:47])[NH:42][CH2:43]C(O)=O.Cl.Cl.N1C=CC=CC=1NCCCN.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.NCC(OC(C)(C)C)=O>>[C:1]1([CH:7]([NH:12][C:13](=[O:15])[CH2:43][NH:42][C:41]([NH:40][CH2:39][CH2:38][CH2:37][NH:36][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=2)=[O:47])[CH2:8][C:9]([OH:11])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CC(NC(=O)OCC1c2ccccc2-c2ccccc21)c1ccccc1
Reactant: O=C(O)CNC(=O)NCCCNc1ccccn1
Agent: CC(C)(C)OC(=O)CN
Agent: Cl
Agent: NCCCNc1ccccn1
Product: O=C(O)CC(NC(=O)CNC(=O)NCCCNc1ccccn1)c1ccccc1

Procedure:
prepared by reaction of 3-(phenyl)-3-(9H-fluoren-9-ylmethoxycarbonylamino)propionic acid with the solid phase polystyrene A OH (Rapp, Art. No. HA 1 400 00), is reacted with {3-[3-(pyridin-2-ylamino)propyl]ureido}acetic acid (prepared analogously to Example 1 by reaction of N1-pyridin-2-ylpropane-1,3-diamine dihydrochloride with 4-nitrophenyl chloroformate and tert-butyl aminoacetate and cleavage of the ester) and cleaved off from the support, giving 3-phenyl-3-(2-{3-[3-(pyridin-2-ylamino)propyl]ureido}ethanoylamino)propionic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[O:11][CH2:10][CH2:9][O:8]1.CCCCCC.C([Li])CCC.CN(C)[CH:25]=[O:26].[Cl-].[NH4+]>O1CCCC1>[O:8]1[CH2:9][CH2:10][O:11][CH:7]1[C:3]1[S:4][C:5]([CH:25]=[O:26])=[CH:6][C:2]=1[CH3:1]
Reactant: Cc1ccsc1C1OCCO1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(C=O)sc1C1OCCO1
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
To a solution of 2-(3-methylthiophen-2-yl)-1,3-dioxolane (3.198 g, 18.79 mmol) in anhydrous tetrahydrofuran (30 ml) was added dropwise 1.55M butyllithium hexane solution (12.1 ml, 18.8 mmol) at −78° C. After stirring for 30 min, anhydrous N,N-dimethylformamide (4.36 ml, 56.3 mmol) was added dropwise. After stirring at −78° C. for 1 hr, the reaction mixture was warmed, saturated aqueous ammonium chloride was added, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. BW-300SP 80 g, ethyl acetate:hexane=1:5) to give 5-(1,3-dioxolan-2-yl)-4-methylthiophene-2-carbaldehyde (3.309 g, 16.69 mmol, yield 88.8%) as a brown oil.
Reaction SMILES: [OH-].[NH4+:2].[F:3][C:4]([F:13])([F:12])[C:5]1([C:8]([F:11])([F:10])[F:9])[CH2:7][O:6]1>CCOCC.O>[NH2:2][CH2:7][C:5]([OH:6])([C:8]([F:11])([F:10])[F:9])[C:4]([F:13])([F:12])[F:3]
Reactant: FC(F)(F)C1(C(F)(F)F)CO1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: NCC(O)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 1:1 mixture of ether (1.85 mL) and 30% ammonium hydroxide (1.85 mL) was added drop-wise 2,2-bis(trifluoromethyl)oxirane (1.00 g, 5.5 mmol). The reaction mixture was stirred for 2 h at rt, then diluted with ether and H2O. The aqueous layer was extracted twice with ether and the combined ether layer was dried over MgSO4, filtered and concentrated to give 2-(aminomethyl)-1,1,1,3,3,3-hexafluoropropan-2-ol as a semi solid (0.87 g, 81% yield). 1H NMR (400 MHz, CDCl3) ppm 3.14 (s, 2H), 3.25 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[O:11][C:10]([CH3:18])([CH3:17])[C:9]2=[O:19])=[C:4]([CH2:20][CH3:21])[CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=1[F:30].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.ClCCl.Cl.FC(F)(F)S([O-])(=O)=O.[Cu+2].FC(F)(F)S([O-])(=O)=O>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[O:11][C:10]([CH3:18])([CH3:17])[C:9]3=[O:19])=[C:4]([CH2:20][CH3:21])[CH:3]=2)=[CH:25][C:24]=1[F:30]
Reactant: Oc1ccc(Cl)c(F)c1
Reactant: CCc1cc(Br)ccc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Agent: [Cu+2]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCc1cc(Oc2ccc(Cl)c(F)c2)ccc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 160 °C

Procedure:
A mixture of 4-(4-bromo-2-ethylphenyl)-2,2,6,6-tetramethylpyran-3,5-dione (0.20 g, 0.57 mmol), 4-chloro-3-fluorophenol (0.41 g, 2.83 mmol), cesium carbonate (0.40 g, 1.13 mmol), copper(II) trifluoromethanesulfonate (0.01 g, 0.03 mmol) and powdered molecular sieve, 4 Å (0.40 g) in dry toluene (3.5 ml) is heated to 160° C. under microwave irradiation for 1 hour. The mixture is cooled to room temperature diluted with dichloromethane and 2M aqueous hydrochloric acid (10 ml) and passed through a phase separation cartridge. The organic phase is dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. The residue is dissolved in N,N-dimethylformamide (1 ml) and purified by preparative reverse phase HPLC to give 4-[4-(4-chloro-3-fluorophenoxy)-2-ethylphenyl]-2,2,6,6-tetramethylpyran-3,5-dione.