Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH2:9])(=[O:8])=[O:7].[P:10]([O-:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13].[C:18]1([CH2:24][CH:25]=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(=O)C>[CH2:12]([O:11][P:10]([CH:25]([NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:8])=[O:7])[CH2:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])[O:14][CH2:15][CH3:16])[CH3:13]
Reactant: CCOP([O-])OCC
Reactant: O=CCc1ccccc1
Reactant: NS(=O)(=O)c1cccs1
Solvent: CC(=O)Cl
Product: CCOP(=O)(OCC)C(Cc1ccccc1)NS(=O)(=O)c1cccs1
Temperature: 0 °C
Yield: 349.4 %

Procedure:
To a suspension of sulfonamide (vi) (500 mg; 0.31 mmol) in acetyl chloride (5 mL) was slowly added diethyl phosphite (400 μL; 0.31 mmol). The reaction was cooled to 0° C. and then phenylacetaldehyde (450 μL; 0.39 mmol) was added dropwise. The reaction was gradually warmed to ambient temperature and after 6 hrs the homogeneous solution was concentrated. The residue was diluted with dichloromethane (25 mL) then washed successively with water (10 mL), saturated sodium bicarbonate (10 mL) and brine (10 mL). The combined organic extracts wre dried (MgSO4), evaporated and initially purified by flash chromatography (ethyl acetate-hexanes; 3:2). A second purification by flash chromatography (acetone-hexanes; 3:7) yielded diethyl phosphonate (xii) (437 mg, 35%) as a colorless solid; 1H NMR (400 MHz, CDCl3) δH 1.22 (t, J=7 Hz, 3 H, OCH2CH3), 1.26 (t, J=7 Hz, 3 H, OCH2CH3), 2.89 (dt, J=8, 14 Hz, 1 H, CHPh), 3.12 (dt, J=6, 14 Hz, 1 H, CHPh), 3.96-4.23 (m, 5 H, NCHP and OCH2CH3), 6.38 (dd, J=2, 9.5 Hz, 1 H, NH), 6.92-6.93 (m, 1 H, Ar—H), 7.12-7.20 (m, 5 H, Ar—H), 7.33-7.34 (m, 1 H, Ar—H), 7.43-7.45 (m, 1 H, Ar—H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[C:12]1([Mg]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(OCC)C>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[OH:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: Br[Mg]c1ccccc1
Reactant: O=Cc1ccc2occc2c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(c1ccccc1)c1ccc2occc2c1
Reaction time: 1 h

Procedure:
To a solution of 1-benzofuran-5-carbaldehyde (2.70 g, 18.5 mmol) in 50 mL THF under N2 was added phenylmagnesium bromide 3.0M solution in diethyl ether (7.39 mL, 22.2 mmol). The reaction was allowed to stir for 1 h, then was quenched with NH4Cl sat'd aq., extracted with diethyl ether, washed with brine, dried over anhyd. sodium sulfate, filtered, and concentrated in vacuo to a solid to give benzofuran-5-yl(phenyl)methanol which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.94 (d, J=2.0 Hz, 1H), δ 7.64 (s, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.36-7.42 (m, 2H), 7.26-7.33 (m, 3H), 7.19 (t, J=7.3 Hz, 1H), 6.92 (d, J=1.5 Hz, 1H), 5.88 (d, J=4.0 Hz, 1H), 5.77-5.83 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.[NH:22]1[CH2:25][CH:24]([C:26]#[N:27])[CH2:23]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([N:22]3[CH2:25][CH:24]([C:26]#[N:27])[CH2:23]3)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Reactant: N#CC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)[C@H](C(=O)N1CC(C#N)C1)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Yield: 31.1 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (10 mg, 0.032 mmol). THF (0.5 mL), azetidine-3-carbonitrile (2.7 mg, 0.032 mmol), 4-methylmorpholine (4.93 mg, 0.049 mmol) and HATU (14.83 mg, 0.039 mmol) were added and the solution was stirred at 25° C. for 1 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 5-50%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a semi-solid (3.7 mg, 30.6%). 1H NMR (400 MHz, CD3OD) δ 0.94 (t, J=6.32 Hz, 3 H) 1.07 (dd, J=18.19, 6.32 Hz, 3 H) 2.44-2.59 (m, 1 H) 3.47-3.79 (m, 1 H) 4.15-4.40 (m, 2 H) 4.57 (dt, J=9.73, 4.99 Hz, 1 H) 4.63-4.78 (m, 1 H) 4.84 (d, J=19.71 Hz, 1 H) 5.06-5.30 (m, 2 H) 7.82 (d, J=11.37 Hz, 1 H) 8.25 (d, J=5.56 Hz, 1 H). [M+H] calc'd for C18H18ClN5O2, 372; found, 372.4.
Reaction SMILES: [C:1]([NH:9][NH:10][C:11]([NH2:13])=[S:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[C:2]1([C:1]2[N:9]=[N:10][C:11](=[S:12])[N:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=S)NNC(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: S=C1N=NC(c2ccccc2)=N1

Procedure:
The key starting material 2-bromo-5-nitrothiazole was prepared by treating 2-amino-5-nitrothiazole (Aldrich) with sodium nitrite and hydrogen bromide (Fr. Demande 2,015,434, 1970). 3-Phenyl-1,2,4-triazole-5-thione (E. Hogarth, J. Chem. Soc. (1949) 1163) was prepared by first reacting benzoyl chloride with thiosemicarbazide in pyridine at 0° C. to give benzoyl thiosemicarbazide. Benzoyl thiosemicarbazide was treated with potassium hydroxide in ethanol to give 3-phenyl-1,2,4-triazole-5-thione. 3-Phenyl-1,2,4-triazole-5-thione (1.77 g) was then dissolved in 50 mL of methanol and treated with 0.57 g of 95% sodium methoxide, and then with 2-bromo-5-nitrothiazole (2.09 g). The mixture was stirred at room temperature for 2 hours and the precipitated sodium bromide was removed by filtration. The methanol was evaporated and the product crystallized from ethanol and water to give 1.5 g of 3-[(5-nitrothiazol-2-yl)mercapto]-5-phenyl-1,2,4-triazole, an orange solid.
Reaction SMILES: [CH2:1]([N:3]([CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[C:4]1[CH:5]=[C:6]([CH:15]2[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]2)[CH:7]=[C:8]([C:11]([O:13]C)=[O:12])[C:9]=1[CH3:10])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:22]([O:21][C:19]([N:17]1[CH2:18][CH:15]([C:6]2[CH:5]=[C:4]([N:3]([CH2:1][CH3:2])[CH:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[C:9]([CH3:10])=[C:8]([CH:7]=2)[C:11]([OH:13])=[O:12])[CH2:16]1)=[O:20])([CH3:24])([CH3:25])[CH3:23]
Reactant: CCN(c1cc(C2CN(C(=O)OC(C)(C)C)C2)cc(C(=O)OC)c1C)C1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(c1cc(C2CN(C(=O)OC(C)(C)C)C2)cc(C(=O)O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.7 %

Procedure:
To a stirred solution of tert-butyl 3-{3-[ethyl(oxan-4-yl)amino]-5-(methoxycarbonyl)-4-methylphenyl}azetidine-1-carboxylate (78 mg, 0.18 mmol) in THF (2 ml) and MeOH (0.1 ml) was added 2M NaOH solution (0.9 ml, 1.8 mmol) and the reaction was stirred at room temperature for 16 h followed by heating at 50° C. for 22 h. The reaction was cooled to room temperature and the solvent removed in vacuo after which the aqueous solution was adjusted to pH5 using 1M HCl. The product was extracted into DCM (2×50 ml), dried with Na2SO4 and filtered to afford the title compound as a colourless oil (54 mg, 72%). LC-MS 100%, 1.70 min (3.5 minute LC-MS method), m/z=419.2, 1H NMR (500 MHz, MeOD) δ 7.77 (s, 1H), 7.55 (s, 1H), 4.36 (t, J=8.2 Hz, 2H), 3.90 (d, J=27.0 Hz, 5H), 3.71 (t, J=6.5 Hz, 1H), 3.36 (t, J=11.3 Hz, 3H), 2.55 (s, 3H), 1.92-1.81 (m, 1H), 1.64 (d, J=55.8 Hz, 3H), 1.49-1.42 (m, 10H), 0.93 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1)[CH3:2].[BrH:11]>>[CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Br:11])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(CO)cc1
Reactant: Br
Product: CCc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2.72 g (20.0 mmol) of 4-ethylbenzyl alcohol (purchased from Aldrich) and 50 ml of 47% hydrobromic acid (purchased from Wako Junyaku Kogyo) was stirred at room temperature for 30 minutes vigorously and extracted with hexane to give 3.98 g of 4-ethylbenzyl bromide as a colorless oil. Subsequently, to 20 ml of 1.96 g (40.0 mmol) of sodium cyanide (purchased from Kokusan Kagaku) in dimethyl sulfoxide (purchased from Aldrich) solution heated at 50° C. was added 3.98 g of the above 4-ethylbenzyl bromide, the mixture was stirred at ambient temperature for 3 hours, the resultant reaction mass was dissolved in water and extracted with hexane, and hexane was removed to give 2.70 g (yield: 93.1%) of 4-ethylphenylacetonitrile as a light yellow oil.
Reaction SMILES: [CH3:1][Mg]Cl.[Br:4][C:5]1[CH:6]=[CH:7][C:8]([C:11](N(OC)C)=[O:12])=[N:9][CH:10]=1>C1COCC1>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([C:11](=[O:12])[CH3:1])=[N:9][CH:10]=1
Reactant: C[Mg]Cl
Reactant: CON(C)C(=O)c1ccc(Br)cn1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
Methylmagnesium chloride 3.0 M in THF (0.5 mL) was added dropwise to a mixture of 5-bromo-N-methoxy-N-methylpyridine-2-carboxamide (200 mg, 0.8 mmol) in tetrahydrofuran (10 mL) at 0° C. After stirring for 1 hr at room temperature, the reaction was quenched with 1 N NH4Cl and was extracted with EtOAc. The combined organic layer was washed with brine and dried over MgSO4, concentrated to give the crude product 1-(5-bromopyridin-2-yl)ethanone (0.15 g, 90%). LCMS calculated for C7H7BrNO (M+H)+: m/z=199.9, 201.9; found: 199.9, 201.9.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Sn](CCCC)(CCCC)CCCC)[N:19]=1>>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH3:16])[N:19]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(OC)n1
Product: COc1cccc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)n1

Procedure:
Prepared according to Procedure E using 2,4-dichloro-5,7-difluoro-3-methylquinoline (250 mg, 1.01 mmol) and 2-methoxy-6-(tributylstannyl)pyridine to give 4-chloro-5,7-difluoro-2-(6-methoxypyridin-2-yl)-3-methylquinoline. Mass Spectrum (ESI) m/e=321.1 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:9]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O)C.[H-].[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[CH3:19][S:16]([C:10]1[CH:11]=[N:12][C:13]2[C:8]([C:9]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:7][C:6]([CH2:4][OH:3])=[CH:15][CH:14]=2)(=[O:18])=[O:17]
Reactant: CCOC(=O)c1ccc2ncc(S(C)(=O)=O)c(-c3ccccc3)c2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cnc2ccc(CO)cc2c1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
3-Methanesulfonyl-4-phenyl-quinoline-6-carboxylic acid ethyl ester (example 61g, 100 mg, 0.28 mmol) in anhydrous tetrahydrofuran (8 mL) was cooled to 0° C. First portion of diisobutylaminum hydride in THF (1 M, 930 uL, 0.93 mmol) was added to the above mixture, and the reaction went for 1 hr at about room temperature. Then the reaction was cooled to 0° C., and second portion of diisobutylaluminum hydride in THF (1 M, 930 uL, 0.93 mmol) was added. The reaction continued for another 45 min at about room temperature. The completion of the reaction was monitored using LC-MS. Additional portion of diisobutylaluminum hydride in THF (1 M, 620 uL, 0.62 mmol) was added, and the reaction went for another 30 min. The reaction was quenched with saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic solution was filtered through a bed of celit with ethyl acetate. The filtrate was collected, washed with water, brain, dried over sodium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 60% ethyl acetate in hexane in 10 min, then 60%-100% ethyl acetate in hexane in 13 min) afforded (3-methanesulfonyl-4-phenyl-quinolin-6-yl)-methanol (70 mg, 79%). LC-MS m/e 314 (MH+).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:35][C:36]12[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:44][C:38]([CH2:46][OH:47])([CH2:39]3)[CH2:37]1)[CH2:43]2>CN(C)C=O>[C:1]([NH:8][C@H:9]([C:17]([CH:37]1[C:36]2([NH2:35])[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:44][C:38]1([CH2:46][OH:47])[CH2:39]3)[CH2:43]2)=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: NC12CC3CC(C1)CC(CO)(C3)C2
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)C1C2(N)CC3CC(C2)CC1(CO)C3
Temperature: -40 °C
Reaction time: 8 h

Procedure:
To a solution of 1.83 g of Boc-L-phenylalanine in 15 ml of dimethylformamide is added 0.76 of N-methylmorpholine. The reaction mixture is cooled to -40° C. and 0.90 ml of isobutylchloroformate is added with stirring. The reaction mixture is stirred for 15 minutes at a temperature below -10° C. then 1.04 g of 3-amino-1-adamantanemethanol is added. The reaction mixture is stirred for 15 minutes at -20° C. then stored overnight at 5° C. The dimethylformamide is removed under reduced pressure and the residue is dissolved in methylene chloride and water. The methylene chloride phase is separated and washed twice with 35 ml of water, 3 times with 35 ml of a 0.5 M potassium bisulfate solution, and twice with 35 ml of water and then dried over magnesium sulfate. The solvent is removed under reduced pressure, and the residue is purified by chromatography on Whatman 10 micron silica gel eluting with a gradient of 1:1 hexane-chloroform to chloroform to give Boc-L-phenylalanyl-3-amino-adamantanemethanol. 2.0 Grams of this product is dissolved in 5 ml of a 6 N solution of hydrogen chloride in dioxane. The reaction mixture is allowed to stand for 20 minutes at room temperature then the solvent is removed under reduced pressure at 30° C., and the residue is stirred with diethyl ether to give the product as a solid. The solid product is collected by filtration and dried under reduced pressure to give L-phenylalanyl-3-amino-1-adamantanemethanol hydrochloride which is represented by the following structure ##STR70## When an equivalent quantity of L-phenylalanyl-3-amino-1-adamantanemethanol hydrochloride is substituted for the methyl L-phenylalanyl-3-amino-1-adamantanecarboxylate hydrochloride of Example 4 and the procedures detailed in Examples 4 through 9 substantially repeated there is obtained L-tyrosyl-D-methionyl-glycyl-L-phenylalanyl-3-amino-1-adamantanemethanol hydrochloride which is represented by the following formula ##STR71##
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][O:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][C:16]3([N:21]([CH3:22])[CH2:20][CH2:19][CH2:18]3)[CH2:15]2)[C:11]([NH2:23])=[CH:10][C:9]=1[NH:24][C:25]1[N:30]=[C:29]([C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]([CH3:40])[CH:32]=2)[CH:28]=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:6][O:7][C:8]1[C:9]([NH:24][C:25]2[N:30]=[C:29]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]([CH3:40])[CH:32]=3)[CH:28]=[CH:27][N:26]=2)=[CH:10][C:11]([NH:23][C:1](=[O:4])[CH:2]=[CH2:3])=[C:12]([N:14]2[CH2:17][C:16]3([N:21]([CH3:22])[CH2:20][CH2:19][CH2:18]3)[CH2:15]2)[CH:13]=1
Reactant: COc1cc(N2CC3(CCCN3C)C2)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cn(C)c4ccccc34)n2)c(OC)cc1N1CC2(CCCN2C)C1
Reaction time: 1 h
Yield: 27.4 %

Procedure:
A solution of acryloyl chloride (24 μL, 0.30 mmol) in CH2Cl2 (1 mL) was added dropwise to 4-methoxy-6-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-N′-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 146, 140 mg, 0.30 mmol) and DIPEA (57 μL, 0.33 mmol) in CH2Cl2 (10 mL), which was cooled in an ice/water bath. The mixture was stirred for 1 h and was then washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 2% 7N methanolic ammonia in CH2Cl2 gave the title compound (43 mg, 28%) as a beige solid after trituration with CH3CN; 1H NMR: 1.63-1.76 (2H, m), 2.00-2.10 (2H, m), 2.38 (3H, s), 2.63 (2H, t), 3.64 (2H, d), 3.86 (3H, s), 3.89 (3H, s), 3.93 (2H, d), 5.70 (1H, dd), 6.21 (1H, dd), 6.26 (1H, s), 6.50 (1H, dd), 7.13 (1H, d), 7.16-7.29 (2H, m), 7.51 (1H, d), 7.73 (1H, s), 7.93 (1H, s), 8.26 (1H, d), 8.31-8.39 (2H, m), 9.24 (1H, s); m/z: ES+ MH+ 524.7.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:19][C:20]([O:22]C)=[O:21])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:10].[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:19][C:20]([OH:22])=[O:21])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:10]
Reactant: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(NC(=O)Nc2ccccc2Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 86.4 %

Procedure:
To a stirred solution of methyl 3-chloro-4-[N′-(2-chlorophenyl)ureido]phenylacetate (1.35 g, 3.82 mmol) in THF (30 ml) was added 0.25 N NaOH (30 ml). After stirring at room temperature for 14 h, the solvent was concentrated in vacuo. The residue was triturated by the addition of 1 N HCl and dried at 60° C. for 2 days under a reduced pressure to give 3-chloro-4-[N′-(2-chlorophenyl)ureido]phenylacetic acid (1.12 g, 86%) as colorless powder. 1H-NMR (DMSO-d6) δ3.52 (s, 2H), 7.05 (m, 1H), 7.17 (d, J=8.5 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.37 (s, 1H), 7.46 (dd, J=8.0, 1.5 Hz, 1H), 7.95 (dd, J=8.3, 1.2 Hz, 1H), 8.07 (d, J=8.3 Hz, 1H), 9.00 (d, J=8.0 Hz, 2H); MS (FAB) m/z 339 (M++1), 341 (M++3), 343 (M++5).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.O[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1ccccn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccn2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-hydroxypyridine (2.0 g), tert-butyl 4-hydroxy-1-piperidinecarboxylate (5.3 g) and triphenylphosphine (8.3 g) in tetrahydrofuran (63 ml) was slowly added diethyl azodicarboxylate (5.5 g) at 8° C., and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo to give the crude product of the title compound and the crude product was purified by chromatography on silica gel.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:13]([Br:14])=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)=[N+:2]=[N-:3].[CH3:18][NH2:19]>O1CCCC1.C(N(CC)CC)C.ClC(OCC)=O.C(OCC)(=O)C>[CH3:18][NH:19][C:9](=[O:10])[C:8]1[CH:12]=[C:13]([Br:14])[C:5]([CH2:4][N:1]=[N+:2]=[N-:3])=[CH:6][C:7]=1[O:15][CH2:16][CH3:17]
Reactant: CCOc1cc(CN=[N+]=[N-])c(Br)cc1C(=O)O
Reactant: CN
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1cc(CN=[N+]=[N-])c(Br)cc1C(=O)NC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After dissolving the 4-(azidomethyl)-5-bromo-2-ethoxybenzoic acid (7.67 g) in tetrahydrofuran (100 ml), triethylamine (3.2 ml) and ethyl chloroformate (2.11 ml) were added in that order and the mixture was stirred at room temperature for 30 minutes. Aqueous methylamine (3.2 ml) was added and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with ethyl acetate and washed with water and 1 N hydrochloric acid, and then the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to yield the title compound (5.328 g) as a white solid.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:14]1([CH2:20][CH2:21][C:22](O)=O)[CH2:19]CCCC1>>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([CH:19]2[CH2:14][CH2:20][CH2:21][CH2:22]2)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CCC1CCCCC1
Reactant: O=C(O)CCCCC1CCCCC1
Product: O=C(CCCCC1CCCCC1)C1CCCC1

Procedure:
The title compound was prepared analogously to Example A(44), where cyclohexanepentanoic acid was substituted in place of 3-cyclohexylpropionic acid in Step 1 of that example. 1H NMR (DMSO-d6): δ 0.79-0.91 (m, 2H), 1.11-1.85 (m, 23H), 2.40 (t, J=7, 2H), 2.8-2.90 (m, 1H).
Reaction SMILES: [CH2:1]=[CH:2][CH3:3].O=O.C([O:9][C:10](=[O:12])[CH3:11])(=O)C.[C:13]([OH:16])(=[O:15])[CH3:14]>>[C:13]([O:16][CH2:1][CH:2]([O:9][C:10](=[O:12])[CH3:11])[CH3:3])(=[O:15])[CH3:14]
Reactant: CC(=O)O
Reactant: C=CC
Reactant: CC(=O)OC(C)=O
Agent: O=O
Product: CC(=O)OCC(C)OC(C)=O
Temperature: 150 °C

Procedure:
Propylene and oxygen were introduced, in the manner described in Example 1, into a solution of 500 ml glacial acetic acid and 50 ml acetic anhydride containing 2 g aluminum acetate and 2 g cupric chloride. The contents were then heated to approximately 150°C. After cooling and release of pressure, the contents were subjected to distillation. 30.6 g propylene glycol diacetate were obtained.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][CH2:25][C:24]1=[O:43])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:44]([N-]C(C)C)(C)[CH3:45].[Li+].ICC>C1COCC1>[Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][CH:25]([CH2:44][CH3:45])[C:24]1=[O:43])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCC1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a −78° C. solution of (5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (764 mg, 1.211 mmol; Example 185, Step C) in THF (6 mL) under argon was added 1.0M lithium diisopropyl amide solution in THF (1.211 mL, 1.211 mmol). The mixture was warmed to 0° C. for 30 minutes. The mixture was cooled to −78° C. and iodoethane (0.117 mL, 1.454 mmol) was added. The resulting solution stirred at 0° C. for 1 hour. The mixture was quenched with sat. aq. NH4Cl solution. The mixture was extracted with ethyl acetate. The combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel (eluent: 5 to 25% ethyl acetate/hexanes) to afford the title compound as a mixture of diastereomers.