Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:17][CH2:18][C@H:19]([CH2:21][O:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[K+].O>C1C=CC=CC=1>[CH2:1]([O:17][CH2:18][C@H:19]([CH2:21][O:22][C:23]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[O:20][CH2:1][CH2:2][CH:3]=[CH:4][CH2:5][CH3:6])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOC[C@@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CCC=CCCO[C@H](COCCCCCCCCCCCCCCCC)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 195.4 %

Procedure:
10.60 grams of (R)-1-hexadecyl-3-trityl-sn-glycerol was dissolved in a mixture of 50 ml benzene and 50 ml petroleum ether. 16.65 grams of powdered KOH was added, and the reaction mixture was heated to reflux under nitrogen. A solution of 10 ml 3-hexenyl-1-methane sulfonate in 50 ml benzene and 200 ml petroleum ether was added dropwise to the refluxing reaction mixture over the course of over 10 hours while removing the water formed in the reaction by azeotropic distillation. After completion of the addition, stirring was continued for 2 hours. The reaction mixture was cooled to room temperature and 200 ml water was added. The mixture was extracted thrice with 200 ml diethyl ether, the combined organic phase was washed thrice with 200 ml water, and the solvent was removed under reduced pressure, yielding 11.88 grams of crude (R)-1-hexadecyl-2-(3 hexenyl)-3-trityl-sn-glycerol. The 1-hexadecyl-2-(3-hexenyl)-3-trityl-glycerol was dissolved in 100 ml methanol, 4 ml concentrated HCl was added, and the resulting solution was refluxed for 4 hours. 100 ml water was added and the mixture extracted four times with 100 ml diethyl ether. The combined organic phase was washed with 100 ml water and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The obtained residue was dissolved in hexane and stored at 4° C. overnight. Filtration of the precipitate and removal of the solvent under reduced pressure yielded 10.08 grams of crude product. This product was purified by chromatography on silica gel (95.91 grams). 3.71 grams of the product, (S)-1-hexadecyl-2-(3′-hexenyl)-sn-glycerol, was eluted with a 1:1 (v/v) mixture of hexane and chloroform, followed by chloroform and then chloroform with 2% acetone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(C(C)C)C(C)C)C.[C:18]1(=[CH:22][C:23](Cl)=[O:24])[CH2:21][CH2:20][CH2:19]1>ClCCl>[C:18]1(=[CH:22][C:23]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=2)=[O:24])[CH2:21][CH2:20][CH2:19]1
Reactant: O=C(Cl)C=C1CCC1
Reactant: Nc1cccc(F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C=C1CCC1)Nc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
1.5 g (13.50 mmol) of 3-fluoroaniline were dissolved in 20 ml of dichloromethane and treated with 5.19 g (29.7 mmol) of N-ethyl-N-isopropylpropan-2-amine. Within 10 min 12.82 g (16.20 mmol) of 2-cyclobutylideneacetyl chloride were added at 0° C. and the solution was stirred overnight at room temperature. The mixture was poured on ice water and extracted 2× with dichloromethane. The combined organic phases were washed once with saturated sodium chloride solution, dried with MgSO4 and evaporated in vacuo. The crude oil was treated with heptane and decanted twice, redissolved in ether-dichloromethane and treated with heptane till crystallization, yielding 2.2 g (77%) of a beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1.Cl.[NH2:13][CH2:14][C:15]([NH2:17])=[O:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([C:6]#[N:7])=[C:8]([NH:13][CH2:14][C:15]([NH2:17])=[O:16])[CH:9]=1
Reactant: NCC(N)=O
Reactant: N#Cc1c(F)cc(Br)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cc(Br)cc1NCC(N)=O
Temperature: 70 °C
Yield: 84 %

Procedure:
12.6 (58.3 mmol) 4-bromo-2,6-difluorobenzonitrile, 6.8 g (61.5 mmol) glycinamide hydrochloride and 16.1 g (116.5 mmol) K2CO3 were suspended in 50 ml DMF and heated at 70° C. for 18 h. Having cooled down to room temperature, the solvent was concentrated and water was added. The resulting precipitate was sucked off and washed with water. 13.3 g (84%) 2-(5-bromo-2-cyano-3-fluorophenylamino)acetamide was obtained. ESI-MS [m/z]: 272, 274 [M+H]+
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](O)=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:4]=1)#[N:2].P(Cl)(Cl)([Cl:21])=O.C(N(CC)CC)C>>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([Cl:21])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:4]=1)#[N:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1nc(O)c(-c2cccc(Cl)c2)nc1C#N
Solvent: CCN(CC)CC
Product: N#Cc1nc(Cl)c(-c2cccc(Cl)c2)nc1C#N
Yield: 84 %

Procedure:
2,3-Dicyano-5-hydroxy-6-(m-chlorophenyl)pyrazine (25.67 g; 0.10 mole) was put into 46.2 g (0.30 mole) of phosphorus oxychloride. The mixture was cooled to 0° to 5° C., and with stirring 10.1 g (0.1 mole) of triethylamine was added dropwise over the period of 30 minutes. After the addition, the mixture was refluxed for 3 hours. The reaction mixture was worked up in the same way as in Example 3. Petroleum ether (50 ml) was added to the resulting oily product, and the precipitate was collected by filtration. Recrystallization from carbon tetrachloride afforded 23.1 g (yield 83%) of 2,3-dicyano-5-chloro-6-(m-chlorophenyl)pyrazine.
Reaction SMILES: C[O-].[Na+].[C:4]([O:11][CH3:12])(=[O:10])[CH2:5][C:6]([O:8]C)=O.[CH3:13][C:14](=[O:22])[CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CO>[CH2:17]([CH:16]1[CH:5]([C:4]([O:11][CH3:12])=[O:10])[C:6]([OH:8])=[CH:13][C:14](=[O:22])[CH2:15]1)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: COC(=O)CC(=O)OC
Reactant: CCCCCC=CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCC1CC(=O)C=C(O)C1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a stirring solution of sodium methoxide (32.4 g, 0.60 mol) and dimethyl malonate (90 g, 0.68 mol) in 230 mL of anhydrous methanol was added portion wise 75 g (0.48 mol) of 90% 3-nonen-2-one. The reaction mixture was then refluxed for 3 h under N2 and allowed to cool to room temperature. The solvent was distilled under reduced pressure and the residue dissolved in 350 mL of water. The slurry of white crystals and the almost clear solution was extracted thrice with 80 mL of chloroform. The aqueous layer was acidified to pH 4 with concentrated HCl and the white precipitate that formed was allowed to stand overnight prior to filtration. The crystals were dried at 50° C. under high vacuum for 5 hours to yield 106.5 g (0.4416 mol) (92%) of methyl 6-n-Pentyl-2-hydroxy-4-oxo-cyclohex-2-ene-1-carboxylate (mp 96-98 C). The product was recrystallized using a mixture of petroleum ether:ethyl acetate (9:1), and gave 94 g of pure methyl 6-n-Pentyl-2-hydroxy-4-oxo-cyclohex-2-ene-1-carboxylate (melting point of 98-100 C).
Reaction SMILES: [F:1][C:2]([F:26])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:26][C:2]([F:1])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH:3]([F:4])[F:5]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(OC(F)(F)C(F)F)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)C(F)(F)Oc1ccc(N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
Crude t-butyl 4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine-1-carboxylate (15.30 g, 0.04M) was dissolved in DCM (150 ml) and TFA (30 ml) was added. The mixture was stirred at room temperature overnight, evaporated to dryness and azeotroped with toluene. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution and the organic phase was collected, dried over MgSO4, filtered and evaporated to dryness to yield 1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine as a solid (10.97 g, 98%)
Reaction SMILES: Br[C:2]1[O:11][CH2:10][C:9]2[CH:8]([N:12]([CH3:14])[CH3:13])[CH2:7][C:6]3=[CH:15][N:16]([Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[CH:17]=[C:4]([C:5]=23)[CH:3]=1.[Li]CCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:43])(=O)=O)=CC=1>O1CCCC1.[Cl-].[NH4+]>[F:43][C:2]1[O:11][CH2:10][C:9]2[CH:8]([N:12]([CH3:14])[CH3:13])[CH2:7][C:6]3=[CH:15][N:16]([Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[CH:17]=[C:4]([C:5]=23)[CH:3]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)N1C=C2C=C(Br)OCC3=C2C(=C1)CC3N(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)N1C=C2C=C(F)OCC3=C2C(=C1)CC3N(C)C
Reaction time: 1 h

Procedure:
A solution of compound (42) 451 mg in dry tetrahydrofuran 5 ml was cooled at −70° C. n-BuLi (1.56 mol/l hexane solution) 1.3 ml was added dropwise to the mixture, which was stirred for 1 h. Then, N-fluorobenzenesulfonimide 694 mg was added and the mixture was stirred for 3.5 h. The reaction mixtures was diluted with an aqueous ammonium chloride solution, extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in ethyl acetate:hexane (1:5) to give a yellow oil. This was chromatographed on thin aluminum oxide plates (Merck precoated TLC plate alumina 60F254 in ethyl acetate:hexane (1:5)) to give the titled compound as a pale yellow oil, 100 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:14]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)C=Cc1ccc(Cl)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc(Cl)c(Cl)c1
Reaction time: 0.25 h
Yield: 148.5 %

Procedure:
Cool a solution of 3-(3,4-dichlorophenyl)-2-propeneoic acid (100 g, 461 mmol) in dry DMF (500 mL) to 0° C. and treat with Cs2CO3 (100 g, 307 mmol, 0.66 eq). Stir the resulting off-white slurry for 15 min, then add CH3 l (33 mL, 530 mmol, 1.15 eq) via syringe. After 1 h, add additional DMF (250 mL), stir the slurry for 14 h and partition between EtOAc (1.5 L) and half saturated aqueous NaHCO3 (500 mL). Separate the organic layer and extract the aqueous layer twice with EtOAc (1 L, 500 mL). Wash the combined organic layers with half saturated aqueous NaHCO3 (500 mL) and water (5×500 mL), then dry (Na2SO4) and concentrate to obtain 105.4 g (456 mmol, 99%) of methyl 3-(3,4-dichlorophenyl)-2-propenoate as light brown needles.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:16]1(=O)[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH:16]1[CH:21]=[CH:20][C:19]([N:8]([C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:18][CH:17]=1
Reactant: Brc1ccc(Nc2ccc(Br)cc2)cc1
Reactant: O=C1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1ccc(N(c2ccccc2)c2ccc(Br)cc2)cc1
Yield: 91 %

Procedure:
The preparation was carried out analogously to K. Haga et al, Bull. Chem. Soc. Jpn., 1986, 59, 803-7: 3.10 g (10.4 mmol) of bis(4-bromophenyl)amine (J. Berthelot et al, Can. J. Chem., 1989, 67, 2061), 1.28 g of cyclohexane-1,4-dione (11.4 mmol) and 2.17g (11.4 mmol) of p-toluenesulfonic acid hydrate were heated in 50 ml of toluene on a water separator. After a reaction time of 12 hours, the solvent was removed and the product was purified by column chromatography (hexane/ethyl acetate 4:1). 3.82 g (9.46 mmol, 91%) of 4,4′-dibromotriphenylamine were obtained as a viscous oil.
Reaction SMILES: [O:1]1[CH:8]2[CH:2]1[CH2:3][O:4][CH2:5][O:6][CH2:7]2.[C:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1)(=[O:11])[CH3:10]>>[C:9]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([NH:22][C@@H:2]2[CH2:3][O:4][CH2:5][O:6][CH2:7][C@H:8]2[OH:1])(=[O:20])=[O:21])=[CH:17][CH:18]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)Nc1ccc(S(N)(=O)=O)cc1
Reactant: C1OCC2OC2CO1
Product: CC(=O)Nc1ccc(S(=O)(=O)N[C@@H]2COCOC[C@H]2O)cc1
Temperature: 25 °C

Procedure:
A mixture of 5,6-epoxy-1,3-dioxepane (0.5 g) and of 4-acetylaminobenzenesulfonamide (0.92 g) was heated in a sealed ampule at the temperature of 150° C. for 15 minutes. The mixture was cooled to room temperature, chromatographed on a silica gel column by elution with a mixture of ethyl acetate-methanol (9.5:0.5) and trans-6-(4-acetylaminobenzenesulfonamido)-1,3-dioxepane-5-ol was obtained. M.p. 208°-210° C./ethyl acetate-methanol (6:1).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([O:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])=[N:17][CH:18]=2)[CH2:4][CH2:3]1.ClC(Cl)(Cl)C[O:30][C:31](=O)[NH:32][C:33]1[N:34]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:35]=[C:36]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:37]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:38]([C:36]1[CH:37]=[C:33]([NH:32][C:31]([NH:1][C@@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C@H:5]([O:12][C:13]3[CH:18]=[N:17][C:16]([C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:20])=[CH:15][CH:14]=3)[CH2:4][CH2:3]2)=[O:30])[N:34]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:35]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: N[C@H]1CC[C@@H](Oc2ccc(C(=O)N3CCOCC3)nc2)c2ccccc21
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc(C(=O)N4CCOCC4)nc3)c3ccccc32)cc1
Temperature: 60 °C
Yield: 30 %

Procedure:
Intermediate 17b (234 mg, 0.66 mmol) was dissolved in 1,4-dioxane (7.0 mL) and [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 268 mg, 0.66 mmol) and diisopropylethylamine (229 μL, 1.32 mmol) were added. The reaction mixture was heated to 60° C. for 20 h, then cooled, partitioned between EtOAc (50 mL) and water (50 mL), and extracted into EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (120 mg, 0.20 mmol, 30%). LCMS (Method 5): Rt 4.76 min, m/z=609 [MH+]. 1H NMR (400 MHz, d4-MeOD): 1.30 (9H, s), 1.85-2.05 (2H, m), 2.05-2.18 (2H, m), 2.38 (3H, s), 3.57-3.76 (8H, br m), 4.86-4.92 (1H, dd, J 8.6, 5.5 Hz), 5.54-5.57 (1H, t, J 4.3 Hz), 6.33 (1H, s), 7.20-7.34 (9H, m), 7.58-7.65 (2H, m), 8.24-8.26 (1H, dd, J 2.4, 0.8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:41])[CH:5]=[C:6]([O:39][CH3:40])[C:7](=[O:38])[C:8]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[C:30](=[O:31])[C:29]([O:32][CH3:33])=[C:28]([CH3:34])[C:27](=[O:35])[C:26]=1[O:36][CH3:37].ClC1C=C(C=CC=1)C(O)=[O:47]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4](=[O:41])[CH:5]=[C:6]([O:39][CH3:40])[C:7](=[O:38])[C:8]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]1[O:47][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[C:30](=[O:31])[C:29]([O:32][CH3:33])=[C:28]([CH3:34])[C:27](=[O:35])[C:26]=1[O:36][CH3:37]
Reactant: COC1=CC(=O)C(OC)=C(CCCCCCC/C=C\CCCCCCCC2=C(OC)C(=O)C(C)=C(OC)C2=O)C1=O
Reactant: O=C(O)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC1=CC(=O)C(OC)=C(CCCCCCCC2OC2CCCCCCCC2=C(OC)C(=O)C(C)=C(OC)C2=O)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
25 Milligrams of 1-(2,5-dimethoxy-1,4-benzoquinon-3-yl)-16-(2,5-dimethoxy-6-methyl-1,4-benzoquinon-3-yl)-Z-8-hexadecene was dissolved in 2 ml of methylene chloride, then to this solution was added 30 mg of m-chlorobenzoic acid and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed the solvent was removed by evaporation under reduced pressure, then the residue obtained was purified by means of a preparative thin layer chromatography [adsorbent: "Silica gel F254 " manufactured by E. Merck A. G., developing solvent: benzene-ethyl acetate (5:1 mixture by volume/volume)] to obtain 9 mg of 1-(2,5-dimethoxy-1,4-benzoquinon-3-yl)-16-(2,5-dimethoxy-6-methyl-1,4-benzoquinon-3-yl)-8,9-epoxyhexadecane. Yellow oily substance.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8])(C)([CH3:3])[CH3:2].C(N)(C)C.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>>[CH:1]([NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)C(C)(C)C
Agent: CC(C)(C)C(=O)Cl
Solvent: CC(C)N
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)C(C)(C)C
Yield: 96 %

Procedure:
In a fashion similar to the preparation of LtBu,tBuH, treatment of isopropylamine (9.0 mL, 105 mmol) and triethylamine (14.9 mL, 105 mmol) with pivaloyl chloride (8.9 mL, 100 mmol) afforded LtBu,iPrH as white crystalline solid (13.75 g, 96%) upon sublimation at 55° C./0.05 Torr: mp 106-108° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][OH:9])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:18]([C:20]([CH2:27][CH3:28])([C:24](Cl)=[O:25])[C:21](Cl)=[O:22])[CH3:19]>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([N:8]2[C:21](=[O:22])[C:20]([CH2:27][CH3:28])([CH2:18][CH3:19])[C:24](=[O:25])[O:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCC(CC)(C(=O)Cl)C(=O)Cl
Reactant: O=C(NO)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC1(CC)C(=O)ON(C(=O)c2ccc(Cl)cc2)C1=O
Yield: 16.4 %

Procedure:
A mixture consisting of 2.70 g (0.0157 mol) of 4-chlorobenzohydroxamic acid, mp 170-171° C. (dec). (lit. mp 168° C. dec., Bielstein Handbook of Organic Chemistry, series H, vol 9. p. 341), 5 ml of pyridine, and 100 ml of methylene chloride was prepared in a 250 ml round bottom flask. The mixture was cooled in an ice bath, and 3.097 g (0.0157 mol) of diethylmalonyl chloride was added dropwise over a 15 minutes period with stirring. The reaction mixture was stirred for 4 hours at room temperature after which time all the hydroxamic acid had dissolved. The solution was extracted two times with 50 ml portions of water, three times with 50 ml portions of 5% hydrochloric acid, and two times with 50 ml portions for 5% sodium carbonate. The methylene chloride was dried (MgSO4) and evaporated to dryness under reduced pressure to give 0.76 g (16.4%) of crude 2-(4-chlorobenzoyl)-4,4-diethylisoxazolidine-3,5-dione as a solid residue. Recrystallization of the solid from methanol gave pure 2-(4-chlorobenzoyl)-4,4-diethylisoxazolidine-3,5-dione as a white solid: mp 98-100° C.; IR (Nujol) 1812 (s, C=0) 1745 (s C=0) 1700 cm-1 (s, C=0); 1H NMR (400 MHz, CDCl3) 7.77-7.80 (m, 2H), 7.49-7.52 (m, 2H), 1.99 (q/ 4H), 1.04 (t, 6H); High resolution MS, calc'd for: C14H14NO4 -Cl: 295.0612. Found: 295.0615. Anal. Calc'd for: C14H14NO4Cl: C, 56.86; H, 4.77; N, 4.74; Cl, 11.99. Found: C, 57.04; H, 4.63; N, 4.58; Cl, 11.88.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[OH:32][C@@H:33]([CH3:37])[C:34](O)=[O:35]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)[C@@H:19]([NH:21][C:34](=[O:35])[C@@H:33]([OH:32])[CH3:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc(C(F)(F)F)cc1
Reactant: C[C@H](O)C(=O)O
Product: C[C@H](O)C(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc(C(F)(F)F)cc1

Procedure:
Prepared as described in Example 105 using (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(trifluoromethyl)phenyl]propan-2-amine (59a, 21 mg, 50 μmol) and (S)-2-hydroxypropanoic acid (12 mg, 150 μmol). Yield 13 mg (56%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](Br)=[C:4]([CH3:10])[N:3]=1.C([Mg]Cl)(C)C.CN(C)[CH:18]=[O:19].O>O1CCCC1>[Br:1][C:2]1[N:3]=[C:4]([CH3:10])[C:5]([CH:18]=[O:19])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(Br)c(C)nc1Br
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C=O)c(C)nc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47.5 %

Procedure:
To a solution of 2,5-dibromo-3,6-dimethylpyridine (989 mg, 3.75 mmol) in tetrahydrofuran (6 mL) was added isopropylmagnesium chloride (2 mol/L in tetrahydrofuran; 2.0 mL, 4.0 mmol) under nitrogen atmosphere, and the mixture was stirred at room temperature for 1.5 h. Dimethylformamide (0.58 mL, 7.5 mmol) was added, and the mixture was stirred for additional 10 min. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (7:1 hexane/ethyl acetate) to afford 6-bromo-2,5-dimethyl-3-pyridinecarboxaldehyde (381 mg, 47%).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH2:8]1[C@H:13]2[O:14][C@H:10]([C@H:11]([C:18]([OH:20])=[O:19])[C@@H:12]2[C:15]([OH:17])=O)[CH2:9]1>C1C=CC=CC=1>[CH2:9]1[CH:10]2[O:14][CH:13]([CH:12]3[C:15](=[O:17])[O:20][C:18](=[O:19])[CH:11]32)[CH2:8]1
Reactant: O=C(O)[C@@H]1[C@H](C(=O)O)[C@H]2CC[C@@H]1O2
Solvent: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: O=C1OC(=O)C2C3CCC(O3)C12
Temperature: 80 °C
Yield: 50.6 %

Procedure:
As shown in scheme 1, we prepared endothal anhydride by adding acetic anhydride (0.5 mL) (4) to a suspension of Endothall (186 mg) (3) in benzene (3 mL) and the mixture was then stirred until the solid had gone into solution (2 hours). The solution was heated under vacuum to remove the benzene and the residue was then heated at 80° C. for 30 min. Petroleum ether (5 mL) was then added and the desired anhydride spontaneously crystallized. The product was removed by filtration washed with a little petroleum ether to give the pure product (85 mg) which was used immediately in the following two preparations.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]([N-]C(C)C)(C)C.[Li+].CI>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)([CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1c1cccc(Cl)c1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1(c2cccc(Cl)c2)CN(Cc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 1-benzyl-3-(3-chlorophenyl)-4-piperidone (75 mmol) in anhydrous THF (250 mL) is cooled to −30° C., then treated with a solution of freshly prepared lithium diisopropylamide (2.0 M in THF/heptane, 45 mL). After stirring for 15 minutes, a solution of methyl iodide (80 mmol) in THF (40 mL) is rapidly added. The mixture is stirred for 1 hour at −30° C., warmed quickly to room temperature, and quenched with a saturated aqueous solution of ammonium chloride. The organic layer is collected, washed with water, brine, and dried (MgSO4). After filtering, the filtrate is concentrated in vacuo to afford the desired intermediate.