Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][C:4](=O)[N:3]=[C-:2]1.[H-].[Na+].[CH2:9]([O:11][C:12](=[O:30])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[CH2:28]Br)[CH:15]=1)[CH3:10].[O:31]1CCOCC1>>[CH2:9]([O:11][C:12](=[O:30])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[CH2:28][N:3]2[CH2:4][CH2:5][O:1][C:2]2=[O:31])[CH:15]=1)[CH3:10]
Reactant: C1COCCO1
Reactant: O=C1CO[C-]=N1
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(F)cc2CBr)c1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)Cc1cccc(Oc2ccc(F)cc2CN2CCOC2=O)c1
Reaction time: 0.17 h

Procedure:
To 2-oxazolidone (0.12 g, 1.4 mmol) in 1,4-dioxane (10 mL) was added sodium hydride (60% in mineral oil; 0.06 g, 1.5 mmol), and the mixture was stirred for 10 minutes. [3-(2-Bromomethyl-4-fluoro-phenoxy)-phenyl]-acetic acid ethyl ester (0.35 g, 0.95 mmol) was added in 1,4-dioxane, and the reaction was stirred for 1 hour at room temperature. After work-up, the crude material was purified by preparative HPLC to give the desired product (0.16 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[C:18]([CH:25]=[CH:26][CH:27]=1)[O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[CH:12]([CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[C:18]([CH:25]=[CH:26][CH:27]=1)[O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:11]
Reactant: COC(=O)COc1cccc(CCCCO)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC(=O)COc1cccc(CCCC=O)c1
Temperature: -70 °C
Yield: 73.3 %

Procedure:
To a solution of oxalyl chloride (1.26 ml) in methylene chloride (30 ml) at -70° C., a solution of dimethylsulfoxide (2.11 ml) in methylene chloride (3.0 ml) was added dropwise. To the obtained solution, a solution of methyl 3-(4-hydroxybutyl)phenoxyacetate (1.94 g) in methylene chloride (8.0 ml) was added dropwise. Triethylamine (6.9 ml) was added dropwise thereto while the reaction temperature was maintained at -70° C. The reaction mixture was warmed slowly to -40° C. over a 30 min period and then quenched by addition of a saturated aqueous solution of ammonium chloride. The reaction mixture was extracted with ether. The extract was washed with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:2) to give the title compound (1.41 g) having the following physical data.
Reaction SMILES: C[O:2][C:3](=[O:11])[CH2:4][CH:5](O)[CH2:6][CH2:7][CH2:8]Cl.CO[C:14](=O)[CH:15]=[CH:16][CH2:17]CCCl>>[C:3]([OH:2])(=[O:11])[CH:4]=[CH:5][CH2:6][CH2:7][CH:8]=[CH:14][CH:15]=[CH:16][CH3:17]
Reactant: COC(=O)CC(O)CCCCl
Reactant: COC(=O)C=CCCCCl
Product: CC=CC=CCCC=CC(=O)O

Procedure:
GC/MS (m/e); 166 (M+, 8%), 148 (2), 121 (2), 105 (2), 91 (4), 81 (100), 65 (5), 53 (18), 41 (16)
Reaction SMILES: [CH:1]1([NH:5][C:6]2[C:15]3[C:10](=[CH:11][C:12]([O:18][CH2:19][C:20]4[CH:21]=[C:22]([S:26]([CH2:34][CH3:35])(=[N:28]C(OCC)=O)=[O:27])[CH:23]=[CH:24][CH:25]=4)=[C:13]([O:16][CH3:17])[CH:14]=3)[N:9]=[CH:8][N:7]=2)[CH2:4][CH2:3][CH2:2]1.ClCCl.CO>CO>[CH:1]1([NH:5][C:6]2[C:15]3[C:10](=[CH:11][C:12]([O:18][CH2:19][C:20]4[CH:21]=[C:22]([S:26]([CH2:34][CH3:35])(=[NH:28])=[O:27])[CH:23]=[CH:24][CH:25]=4)=[C:13]([O:16][CH3:17])[CH:14]=3)[N:9]=[CH:8][N:7]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(=O)N=S(=O)(CC)c1cccc(COc2cc3ncnc(NC4CCC4)c3cc2OC)c1
Solvent: ClCCl
Solvent: CO
Product: CCS(=N)(=O)c1cccc(COc2cc3ncnc(NC4CCC4)c3cc2OC)c1
Yield: 94 %

Procedure:
According to GWP 6, the conversion of (RS)-S-[3-({[4-(cyclobutylamino)-6-methoxy-quinazolin-7-yl]oxy}methyl)phenyl]-N-(ethoxycarbonyl)-S-ethylsulphoximide (48 mg, 0.096 mmol) and chromatographic purification (silica gel, dichloromethane/methanol: 0→30% methanol) gives the desired product in 94% yield (39 mg).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:6]([NH:8][C@H:9]([C:14]([NH2:16])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])[CH2:3][CH2:4][CH3:5].[ClH:24]>C(OCC)(=O)C.CCOCC>[NH2:1][C@H:2]([C:6]([NH:8][C@H:9]([C:14]([NH2:16])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])[CH2:3][CH2:4][CH3:5].[ClH:24]
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(N)=O
Reaction time: 1 h
Yield: 83 %

Procedure:
4.12 g (12.5 mmoles) of BOC-Nva-Leu-NH2 are suspended in 15 ml of ethyl acetate, and 20 ml of a 6 n hydrochloric acid solution in ethyl acetate are added to the suspension. After one hour of standing the reaction mixture is diluted with ether, the separated precipitate is filtered off, and the resulting 3.64 g of crude product is recrystallized from 25 ml of methanol. 2.75 g (83%) of H-Nva-Leu-NH2.HCl are obtained; m.p.: 215°-216° C., Rf5 =0.45, [α]D25 =-3.47° (c=1%, in methanol).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:14]([O-:16])=[O:15])[C:7](=[CH:12][CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])([O-])=O.[O-:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Na+].[CH3:25]N(C=O)C>>[O:17]([C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:25])=[O:15])[C:7](=[CH:12][CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C(=O)[O-]
Reactant: CN(C)C=O
Reactant: [O-]c1ccccc1
Agent: [Na+]
Product: COC(=O)c1ccc(Oc2ccccc2)cc1C(=O)OC

Procedure:
Methyl 4-nitrophthalate was reacted in DMF with sodium phenoxide to give dimethyl 4-phenoxyphthalate in analogy to a process known from the literature (J. Org. Chem. Vol. 42, No. 21, 1977, 3419-3425). After standard working up and chromatography using hexane/EA, the diester was isolated as a yellowish oil.
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[Al+3].[Cl-].[Cl-].[Cl-].Cl[CH:17](Cl)[O:18]C>C(Cl)Cl.[N+](C)([O-])=O>[Cl:11][C:2]([Cl:1])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[C:8]([CH:17]=[O:18])[CH:9]=1)=[O:4]
Reactant: COC(Cl)Cl
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Product: O=Cc1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of the compound obtained in Step A (87 mmoles) and AlCl3 in a DCM/nitromethane mixture (80 ml/80 ml) there is added, dropwise, at −30° C., dichloro-methoxy-methane (130.5 mmoles). After stiffing for two hours, the reaction mixture is poured into 800 ml of ice-cold water. The aqueous phase is extracted with AcOEt, and then the organic phases are combined. The organic phase is washed with saturated aqueous NaCl solution, dried over sodium sulphate, filtered and evaporated to dryness to yield the title product (brown crystals), which is used directly in the next Step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1COCC1.C(=O)([O-])O.[Na+]>[CH3:8][C:6]1[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=[C:2]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:7]=1
Reactant: C1CCNCC1
Reactant: COC(=O)Cc1c(C)nc(Cl)nc1-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Cc1c(C)nc(N2CCCCC2)nc1-c1ccccc1
Temperature: 110 °C
Yield: 67.2 %

Procedure:
A mixture of methyl 2-(2-chloro-4-methyl-6-phenylpyrimidin-5-yl)acetate (200 mg; 0.723 mmol) and piperidine (0.286 mL; 2.89 mmol) in THF (2 mL) was placed in a sealed tube and heated via microwave irradiation at 110° C. for 1 h. The reaction mixture was diluted with a saturated sodium hydrogen carbonate solution and extracted twice with ethyl acetate. The organic layers were combined, washed with brine, dried over magnesium sulphate and concentrated under vacuum. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (2-20%) in heptane to give 158 mg (63%) of methyl 2-(4-methyl-6-phenyl-2-(piperidin-1-yl)pyrimidin-5-yl)acetate. ESI/APCI(+): 326 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:13]1(=[O:20])[NH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C1CCCCC1.N1C=CC=CC=1>[C:1]([N:19]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:20])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:19]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13]2=[O:20])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: O=C1CCCCCN1
Solvent: C1CCCCC1
Solvent: c1ccncc1
Product: O=C1CCCCCN1C(=O)c1ccc(C(=O)N2CCCCCC2=O)cc1

Procedure:
Terephthaloyl chloride (51 g, 0.25 mol) is added in the course of 30 minutes to a solution of ε-caprolactam (56.6 g, 0.5 mol) in 400 ml of cyclohexane and 117 ml of pyridine at room temperature. The mixture is then refluxed for 4 h. After cooling, the resulting light yellow precipitate is filtered off by suction, washed with water and dried. Yield 81 g (91%).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8]N(C)[CH2:6][CH2:5]1.[CH2:11]([N:15]1[CH2:19][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:17]([OH:26])[C:16]1=[O:27])[CH2:12][CH2:13][CH3:14].[H-].[Na+].[H][H]>CN(C)C=O>[CH2:11]([N:15]1[CH2:19][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:17]([O:26][CH2:8][CH2:9][N:4]([CH2:3][CH3:2])[CH2:5][CH3:6])[C:16]1=[O:27])[CH2:12][CH2:13][CH3:14]
Reactant: [H][H]
Reactant: CN1CCN(CCCl)CC1
Reactant: CCCCN1CC(c2ccccc2)=C(O)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN1CC(c2ccccc2)=C(OCCN(CC)CC)C1=O
Temperature: 40 °C

Procedure:
N1 -β-chloroethyl-N4 -methylpiperazine, 1-n-butyl-3-[N1 -β-(N4 -methyl)-piperazinoethoxy]-4-phenyl-3-pyrrolin-2-one; dioxalate m.p. 199° C. 32.5 g. (0.14 mol) 1-n-butyl-3-hydroxy-4-phenyl-3-pyrrolin-2-one is added, with stirring, at 40° C. to a suspension of 4.2 g. sodium hydride (80%) in 200 ml. dimethyl formamide. When the evolution of hydrogen ceases, 30.0 g. N1 -β-chloroethyl-N4 -methylpiperazine is added and the mixture allowed to react for 30 minutes at 70° C. The mixture is immediately poured into 1.5 liters of ice water. This is then extracted twice with dichloromethane and the organic phase is washed with water. After drying over anhydrous magnesium sulphate, the solvent is distilled off. The residue (base) is taken up in diethyl ether and oxalic acid is added to precipitate out the di-oxalate. After recrystallization of this dioxalate from aqueous methanol, there is obtained 33.0 g. (44% of theory) of the desired end product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:15][CH2:16][CH2:17][OH:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Yield: 91.5 %

Procedure:
A mixture of 1-tert-butoxycarbonylpiperazine (1.0 g, 5.37 mmol), 3-bromo-1-propanol (0.49 ml, 5.37 mmol) and potassium carbonate (1.86 g, 13.4 mmol) was heated at reflux in acetonitrile (10 ml) for 1.5 hours. The mixture was concentrated under reduced pressure and column chromatography of the residue, eluting with 2% methanol/methylene chloride, gave 1-tert-butoxycarbonyl-4-(3-hydroxypropyl)piperazine (1.2 g, 91%).
Reaction SMILES: [SH:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.C(N(CC)CC)C.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19]Cl>C1(C)C=CC=CC=1>[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][S:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1
Reactant: SC1=NCCS1
Reactant: ClCc1cccs1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: c1csc(CSC2=NCCS2)c1
Temperature: 25 °C
Yield: 101.3 %

Procedure:
To a stirred solution of 1.3 grams (0.011 mole) of 2-mercaptothiazoline in 20 ml of toluene was added 1.1 grams (0.011 mole) of triethylamine, followed by 1.5 grams (0.011 mole) of 2-thienylmethyl chloride. Upon completion of addition the reaction mixture was heated under reflux for five hours. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure to give 2.4 grams of 2-(2-thienylmethylthio)-4,5-dihydrothiazole as an oil, Compound No. 22 of Table I.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13](OCC)=[O:14])[CH:10]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13][OH:14])[CH:10]([CH2:18][N:20]2[CH2:21][CH2:22][CH:23]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH2:24][CH2:25]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC1C(=O)N1CCC(c2ccc(F)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCC1CN(Cc2ccccc2)CC1CN1CCC(c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
To a solution of 6.4 g (14.6 mmol) of 1-benzyl-3-(RS)-(4-(4-fluorophenyl)piperidinylcarbonyl)-4-(RS)-(ethoxycarbonyl)pyrrolidine in 60 mL of THF at 0° C. was added 17.5 mL (17.5 mmol) of a 1M solution of lithium aluminum hydride (LAH) in ether and the reaction was stirred at 0° C. for 30 min. The reaction mixture was quenched with SN NaOH. The reaction mixture was extracted with ether and the combined organic fractions were washed with 5N NaOH solution. The organic fractions were dried over Na2SO4, filtered and the filtrate was purified by chromatography [silica, hexanes:ethyl acetate:(2N NH3 in MeOH), 10:10:1] to give 4.7 g of the title compound. Spectrum (ESI) m/e=383 (M+1). 1H NMR (CDCl3) δc7.31-7.33 (m, 4 H), 7.26-7.28 (m, 1H), 7.16-7.19 (m, 2H), 6.97 (t, 2H, J=8.5 Hz), 3.63-3.66 (m, 2H), 3.57 (d, 1H, J=13Hz), 3.43 (t, 1H, J=10 Hz), 3.22 (d, 1H, J=11 Hz),2.97 (d, 1H, J=11 Hz), 2.80 (d of d, 1H, J=8.5, 7.5 Hz), 2.76 (t, 1H, J=9 Hz), 2.12-2.54 (m, 8 H), 2.02 (t of d, 1H, J=2.5, 12 Hz), 1.75-1.85 (m, 5H).
Reaction SMILES: [PH:1](=[O:4])([OH:3])[OH:2].[NH2:5][C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10]N.CO.[CH2:17](OCC)C>O.N1C=CC=CC=1>[NH2:5][CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:17][P:1]([OH:3])([OH:2])=[O:4])[C:12]([OH:14])=[O:13]
Reactant: CCOCC
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: O=[PH](O)O
Solvent: c1ccncc1
Solvent: CO
Solvent: O
Product: NC(CCCCCP(=O)(O)O)C(=O)O
Temperature: 60 °C

Procedure:
Equimolar quantities of the phosphonic acid, and L-lysine, were dissolved in water and warmed for 1/2 hr at 60° C. Two volumes of hot methanol were then added and the mixture brought to room temperature. Diethyl ether was added carefully, until a slight cloudiness appeared in the solution, which was left to stand. The phosphonic acid/lysine salt was filtered off and dissolved in water. A "Dowex" 50×8 column was prepared by passed 2M pyridine down it, and washing with water, the lysine salt solution was passed down the column and washed through with water, the phosphonic acid passing straight through. The amine acid containing fractions were collected and evaporated to dryness; a solution of known concentration was then made up, and the rotation of plane polarised light recorded on a "TBL" Automatic Polarimeter 143D using a mercury lamp. The first isomer to be precipitated was found to be (-), and circular dichroism studies indicated it to have the D configuration.
Reaction SMILES: Br[CH:2]([S:4]([O-:7])(=[O:6])=[O:5])[CH3:3].[Na+].[CH2:9]([CH2:11][NH2:12])[OH:10]>O.C(O)C>[OH:10][CH2:9][CH2:11][NH:12][CH2:3][CH2:2][S:4]([OH:7])(=[O:6])=[O:5]
Reactant: CC(Br)S(=O)(=O)[O-]
Reactant: NCCO
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)(O)CCNCCO
Reaction time: 17.5 h

Procedure:
A solution in 2 liters of water of 315 g of sodium bromoethanesulphonate (Organic Synthesis, Coll. Vol. II, p. 558) and 450 g of ethanolamine was heated to 60°-70° C. for 30 minutes. Excess ethanolamine and water were then distilled off under vacuum, and the residue dissolved in 250-270 ml of water. 2.2 Liters of concentrated hydrochloric acid was added and the solution kept in a refrigerator for 15-20 hours. The precipitated sodium chloride was filtered off using a filter pump, and the solution concentrated until a viscous oil was obtained. The oil was diluted with 60 ml of water and ethanol (about 500 ml) then added to precipitate the reaction product. After the mixture has been left one night in a refrigerator, precipitation was almost complete. The product obtained was filtered off with a filter pump. About 130-140 g of crystalline product was obtained, having a melting point of 180°-183° C.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=4)[CH:14]=[CH:15][C:16]=3[O:17]COC)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl>C1COCC1.C(O)(C)C.O>[C:1]12([C:11]3[CH:12]=[C:13]([C:21]4[CH:22]=[CH:23][C:24]([CH:25]=[O:26])=[CH:27][CH:28]=4)[CH:14]=[CH:15][C:16]=3[OH:17])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COCOc1ccc(-c2ccc(C=O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(-c2ccc(O)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Reaction time: 57 h
Yield: 98.6 %

Procedure:
To a solution of 4-[3-(1-adamantyl)-4-methoxymethoxyphenyl]benzaldehyde (6.88 g, 18.30 mmol) in 200 mL of THF:isopropanol (1:1) was a added 30 mL of6 N HCl at room temperature. After 20 hours 30 mL of 12 N HCl was added. After 57 hours starting material was still present, 60 mL of additional 12 N HCl was added and stirred for 16 hours. The resulting mixture was diluted with water and extracted with ether (2×200 mL). The combined organics were washed with water (150 mL), brine (100 mL), dried over anhydrous magnesium sulfate, filtered and evaporated to give 6.00 g (99%) of 4-[3-(1-adamantyl)-4-hydroxyphenyl]benzaldehyde as a solid. 1H NMR (300 MHz; DMSO-d6): δ 1.72 (brs, 6H), 2.00–2.20 (m, 9H), 6.88 (d, J=8.7 Hz, 1H), 7.36–7.48 (m, 2H), 7.78 (d, J=8.1 Hz, 2H), 7.90 (d, J=8.1 Hz, 2H), 9.67 (s, 1H), 9.98 (s, 1H).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[S:16])=[C:13]([CH2:20][CH3:21])[N:12]=[C:11]([CH3:22])[N:10]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:28][CH2:29][NH2:30].O>C1(C)C=CC=CC=1>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:28][CH2:29][NH:30][C:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[S:16])=[C:13]([CH2:20][CH3:21])[N:12]=[C:11]([CH3:22])[N:10]=2)[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]
Reactant: COc1ccc(CCN)cc1OC
Reactant: CCOC(=S)c1c(Cl)nc(C)nc1CC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=S)c1c(CC)nc(C)nc1NCCc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 50.7 %

Procedure:
Triethylamine (0.17 g, 1.68 mmol) was added to a solution of ethyl 4-chloro-6-ethyl-2-methylthiopyrimidine-5-carboxylate (0.21 g, 0.81 mmol) in toluene (4 ml), followed by addition of 3,4-dimethoxyphenethylamine (0.18 g, 0.99 mmol). The mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into water, extracted with ethyl acetate and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=8/2) to give the desired ethyl 4-(2-(3,4-dimethoxyphenyl)ethylamino)-6-ethyl-2-methylthiopyrimidine-5-carboxylate (0.16 g, 49%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:8]=2)[NH:3]1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.[C:35]1([CH2:41][CH2:42][SH:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH3:21][C:2]1([CH3:1])[CH:11]=[C:10]([CH2:12][S:43][CH2:42][CH2:41][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:23]([F:34])([F:33])[F:22])[CH:8]=2)[NH:3]1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: CC1=CC(C)(C)Nc2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: SCCc1ccccc1
Product: CC1(C)C=C(CSCCc2ccccc2)c2cc(-c3ccccc3C(F)(F)F)ccc2N1

Procedure:
Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-yl ester was coupled with 2-trifluoromethylphenylboronic acid. Bromination and coupling reaction with 2-phenylethanethiol gave 49 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39][CH:40]([C:44](O)=[O:45])[C:41](O)=[O:42])([CH3:32])[CH3:31]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:10][C:41](=[O:42])[C:40]([S:39][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH:30]([CH3:31])[CH3:32])=[C:44]([OH:45])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Reactant: CC(=O)c1cccc(Cl)c1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2cccc(Cl)c2)oc1=O
Yield: 70 %

Procedure:
The title compound was prepared by Method A using 3'-chloroacetophenone (3 g, 19.41 mmol), trimethylsilyl triflate (4.31 g, 19.41 mmol), triethylamine (3.92 g, 38.82 mmol), methylene chloride (20 mL), and diethyl ester of [(2-isopropylphenyl)thio]-propanedioic acid (3.0 g, 9.71 mmol). Isolated yield: 70% m.p. 177-178° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.28 (d, 6H), 3.42 (m, 1H), 6.92 (d, 1H), 6.94 (s, 1H), 7.06 (t, 1H), 7.13 (t, 1H), 7.28 (d, 1H), 7.58 (t, 1H), 7.63 (t, 1H), 7.83 (d, 1H), 7.89 (s, 1H).
Reaction SMILES: [C:1]([N+:5]([O-:13])=CC1C=CC=CC=1)([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O.[C:19]([OH:22])(=[O:21])[CH3:20].[OH-].[Na+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[C:19]([O-:22])(=[O:21])[CH3:20].[C:1]([NH2+:5][OH:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(C)(C)[N+]([O-])=Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)[O-]
Product: CC(C)(C)[NH2+]O
Reaction time: 2 h
Yield: 94.4 %

Procedure:
N-tert-butylphenylnitrone (44.8 g, 0.25 mol) was dissolved in toluene (134 g) in a 500 ml bottle. Sulphuric acid (27.5 g, 95 to 97%, 0.27 mol, 1.1 equiv.) was diluted in water (134 g) and added to the reaction bottle. The two-phase mixture was then heated to +50° C. and stirred vigorously for approximately 2 h. At that time, GC indicated that only 0.2 area % of N-tert-butylphenylnitrone remained. After cooling to +20° C., the dark red organic phase was discarded and the clear, yellow water phase was extracted once with toluene (46 g). To the remaining water phase was then added acetic acid (14.8 g, 0.25 mol, 1.0 equiv.) followed by sodium hydroxide (45% aqueous solution) until the pH of the water phase was approximately 5.5. Ethyl acetate (224 g) was then added and the mixture was stirred vigorously. The organic phase was then separated and the aqueous phase was extracted once more with ethyl acetate. The combined organic fractions were then evaporated to leave an oil (35.2 g). This material was purified by distillation under reduced pressure. A stable distillation point was achieved at 19 mbar/ +78° C. Fraction 1, retrieved below +70° C., contained 2.7 g and fraction 2, collected between +70° C. and +80° C., con a highly viscous oil (28.7 g, 76%) that crystallized as a white solid upon standing. pKa 6.4 Chromatographic purity (GC): 99.4 area %