Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:9]=2[CH3:17])=[CH:4][C:3]=1[NH:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20].C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>C1COCC1>[C:14]([NH:13][C:11]1[S:12][C:8]([C:5]2[CH:4]=[C:3]([N:18]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:20])=[O:21])[C:35](=[O:37])[CH3:36])[C:2]([Cl:1])=[N:7][CH:6]=2)=[C:9]([CH3:17])[N:10]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(NS(=O)(=O)c3ccccc3)c2)s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(N(C(C)=O)S(=O)(=O)c3ccccc3)c2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
N-{5-[6-Chloro-5-(phenylsulfonylamino)pyridin-3-yl]-4-methyl-1,3-thiazol-2-yl)acetamide was dissolved in THF. Triethylamine (0.113 mL, 0.811 mmol) was added. The solution was placed in an ice-bath and acetyl chloride (0.058 mL, 0.81 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours and then evaporated. Water and ethyl acetate were added. The organic phase was dried with magnesium sulfate, filtered and evaporated. The reaction product was purified by preparative HPLC (Method A) to give the title product (retention time 9.2 minutes) in 91% yield; 1H NMR Spectrum: (DMSOd6) 12.33 (1H, s); 8.69 (1H, d); 8.24 (1H, d); 8.06-8.00 (2H, m); 7.82 (1H, t); 7.72-7.67 (2H); 2.42 (3H, s); 2.17 (3H, s); 1.96 (3H, s); Mass Spectrum: M+H+ 465 and 467.
Reaction SMILES: [CH2:1]1[CH2:9][O:8][C:7]2[C:3](=[C:4]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=3)[S:5][CH:6]=2)[O:2]1.O.NN.CCCCCC>C(O)C.[Pt]>[CH2:1]1[CH2:9][O:8][C:7]2[C:3](=[C:4]([C:10]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=3)[S:5][CH:6]=2)[O:2]1
Reactant: O=[N+]([O-])c1ccc(-c2scc3c2OCCO3)cc1
Agent: [Pt]
Agent: NN
Solvent: CCCCCC
Solvent: O
Solvent: CCO
Product: Nc1ccc(-c2scc3c2OCCO3)cc1
Yield: 66 %

Procedure:
A solution of 1-(3,4-ethylenedioxythien-2-yl)-4-nitrobenzene (0.663 g, 2.52 mmol) in 95% ethanol (60 mL) containing platinum on sulfide carbon (50 mg) was added hydrazine hydrate (1.0 mL). The mixture was refluxed for 10 hours. After cooling, the mixture was filtered and the solvent was evaporated to give a solid. Addition of hexane followed by filtration gave 1-(3,4-ethylenedioxythien-2-yl)-4-aminobenzene. It was recrystallized from ethanol, 0.39 g, yield=66%, mp=98.5-99° C. IR (KBr; cm-1) 3433, 3352, 3032, 2924, 1624, 1520, 1428, 1365, 1288, 1170, 1071, 920 and 833. 1H NMR(CDCl3 ; δ in ppm): 3.604 (br, s, 2H), 4.208 (m, 4H), 6.176 (s, 1H), 6.651 (d, J=9.6 Hz, 2H) and 7.492 (d, J=9.6 Hz, 2H). 13C NMR(CDCl3 ; δ in ppm): 64.45, 64.59, 95.61, 115.10, 117.98, 123.60, 127.25, 136.61, 142.09 and 145.20. MS(EI) m/z (rel int): 233 [(M)+, 55%], 177 [(M+ --C3H4O), 6.6%], 149 [(M+ --C4H4O2, 11%] and 136 [(M+ --C5H5O2) 100%]. Anal. Calcd for C12H11NO2S: C, 61.78; H, 4.75; N, 6.00; S, 13.74. Found: C, 60.82; H. 4.87; N, 5.64; S, 12.86.
Reaction SMILES: C([N:8]1[CH2:16][C@@H:15]2[C@:10]([CH3:24])([CH2:11][CH2:12][C:13]3[C:20]([C:21]([CH3:23])=[CH2:22])=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)C1C=CC=CC=1.CC(Cl)OC([Cl:30])=O.CO>C1(C)C=CC=CC=1>[ClH:30].[CH3:24][C@@:10]12[CH2:9][NH:8][CH2:16][C@H:15]1[C:14]1[CH:17]=[CH:18][CH:19]=[C:20]([C:21]([CH3:23])=[CH2:22])[C:13]=1[CH2:12][CH2:11]2
Reactant: C=C(C)c1cccc2c1CC[C@]1(C)CN(Cc3ccccc3)C[C@@H]21
Reactant: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: C=C(C)c1cccc2c1CC[C@]1(C)CNC[C@@H]21
Product: Cl
Temperature: 160 °C
Yield: 43.3 %

Procedure:
trans-2-Benzyl-3a-methyl-6-(prop-1-en-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (0.359 mmol, 134 mg) was dissolved in toluene (1 ml). ACE-Cl (2.95 mmol, 325 μl) was added and the reaction mixture was heated in a microwave reactor at 160° C. for 15 minutes. MeOH (1 ml) was added and the mixture was again heated in a microwave reactor at 160° C. for 5 minutes. The resulting mixture was passed through an SCX cartridge and the resulting filtrate was concentrated in vacuo to give a crude residue that was purified by preparative-HPLC. To the pure fractions was added HCl in ether (1 ml) and the resulting solution was concentrated in vacuo to afford trans-3a-methyl-6-(prop-1-en-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole hydrochloride (41 mg), MS m/z: 228.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[OH2:16].Cl>C1(C)C=CC=CC=1>[Cl:9][C:4]1[N:3]=[C:2]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:7]=[C:6]([N:10]2[CH2:15][CH2:14][O:16][CH2:12][CH2:11]2)[CH:5]=1
Reactant: O
Reactant: C1COCCN1
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: Cl
Solvent: Cc1ccccc1
Product: Clc1cc(N2CCOCC2)nc(N2CCOCC2)n1
Temperature: 83 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
Prepare a solution of 22 g (0.12 mol) of 2,4,6-trichloropyrimidine 1, in 95.2 g (110 mL) of toluene and charge it to the 125 mL addition funnel. Charge a nitrogen-flushed 500 mL round bottom 4-neck flask that equipped with a condenser, heating mantle, thermocouple, 125 mL addition funnel, mechanical stirrer and nitrogen inlet/outlet with 62.7 g (63 mL, 0.72 mol) of morpholine 2, 95.2 g (110 mL) of toluene and 44 g (44 mL) of water. Add the toluene solution of 1 over 10 minutes. Heat the reaction mixture to 83±3° C. Stir at 83±3° C. for 2 h. Check the progress of the reaction. Cool to 30±3° C. Transfer the 2-phase mixture to a 1 L separatory funnel. Separate the phases. Wash the organic phase (top) twice with 200 mL (2×100 mL) of warm (30° C.) water. Separate the phases after each wash. Transfer the organic (top) phase back to the 500 mL reaction flask that equipped with a condenser, heating mantle, thermocouple, 125 mL addition funnel, mechanical stirrer and nitrogen inlet/outlet. Stir and add 50.0 mL of 10.0 N aqueous hydrochloric acid solution. Heat the solution to 53±3° C. and stir for 12-18 h. Check the progress of the reaction. Cool to 22±3° C. Transfer the 2-phase mixture to a 1 L separatory funnel. Separate the phases. Transfer the aqueous (bottom) phase to a 500 mL round bottom 4-neck flask equipped with a cooling bath, thermocouple, addition funnel, pH probe, mechanical stirrer and nitrogen inlet/outlet. Stir and cool to 0±3° C. Add 85.0 g of 25% aqueous sodium hydroxide solution by drops over 30 minutes, maintaining a batch temperature of 10±10° C. throughout the addition. Warm to 20±3° C. and stir for 30 minutes. Isolate the solids by vacuum filtration. Wash the cake with 3×100 mL of water. Dry the solids (55° C., 30 mbar) for 24 hours to afford 30.9 g (91.9% yield) of 3 as a white crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.[CH3:24][N:25]1[CH:29]=[CH:28][N:27]=[C:26]1[C:30](O)=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O.CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[S:12][C:10]3[C:9]([N:14]=2)=[CH:8][CH:7]=[C:6]([O:5][C:4]2[CH:3]=[C:2]([NH:1][C:30]([C:26]4[N:25]([CH3:24])[CH:29]=[CH:28][N:27]=4)=[O:31])[CH:23]=[CH:22][CH:21]=2)[N:11]=3)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c1
Reactant: Cn1ccnc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccnc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.3 %

Procedure:
A mixture of N-[5-(3-aminophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (175 mg, 0.536 mmol), 1-methyl-1H-imidazole-2-carboxylic acid (101 mg, 0.804 mmol), HATU (367 mg, 0.965 mmol), N,N-diisopropylethylamine (420 μL, 2.41 mmol) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=50/50→0/100) and recrystallized from ethyl acetate-tetrahydrofuran to give the title compound (152 mg, 65%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[O:14]=[C:15]1[C:20]2[S:21][CH:22]=[C:23]([S:24](Cl)(=[O:26])=[O:25])[C:19]=2[CH2:18][CH2:17][CH2:16]1>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([OH:13])[CH2:2][NH:1][S:24]([C:23]2[C:19]3[CH2:18][CH2:17][CH2:16][C:15](=[O:14])[C:20]=3[S:21][CH:22]=2)(=[O:25])=[O:26])=[CH:7][CH:8]=1
Reactant: NCC(O)COc1ccc(Cl)cc1
Reactant: O=C1CCCc2c(S(=O)(=O)Cl)csc21
Product: O=C1CCCc2c(S(=O)(=O)NCC(O)COc3ccc(Cl)cc3)csc21

Procedure:
From 1-amino-3-(4-chloro-phenoxy)-propane-2-ol (58 mg) and 7-oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-sulfonyl chloride (the compound of Preparation Example 7) (70 mg), a yield (45 mg) was obtained as a colorless amorphous substance, in the same way as Preparation Example 41
Reaction SMILES: C1(S([C:10](=[CH:15][C:16]2[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]([OH:26])=[C:18]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:17]=2)[C:11]([NH:13][CH3:14])=[O:12])(=O)=O)C=CC=CC=1.COCCO.[N-:36]=[N+:37]=[N-:38].[Na+]>O>[CH3:30][C:27]([C:18]1[CH:17]=[C:16]([C:15]2[NH:36][N:37]=[N:38][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[CH:21]=[C:20]([C:22]([CH3:23])([CH3:24])[CH3:25])[C:19]=1[OH:26])([CH3:28])[CH3:29]
Reactant: CNC(=O)C(=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)S(=O)(=O)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: COCCO
Solvent: O
Product: CNC(=O)c1nn[nH]c1-c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 105 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
A 250 mL 3-neck round-bottom flask immersed in an oil bath, equipped with a mechanical stirrer, thermometer, reflux condenser and nitrogen bubbler, was charged with 42.96 g (0.100 mol) of 2-(benzenesulfonyl)-3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methylacrylamide (II), 100 mL of 2-methoxyethanol and 6.83 g (0.105 mol) of sodium azide. The yellow mixture was heated at 105° C. for 30 h. The cooled orange solution was poured onto a mixture of 150 g of ice and 150 mL of deionized water. The yellow suspension was agitated for 1 h at 5° C. The resulting solid precipitate was filtered off and washed with 5×50 mL of cold deionized water. The recovered solids were dried in vacuo over potassium hydroxide flakes to afford yellow solids, 30.2 g of crude product (I), 98.7% purity by HPLC.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>O1CCCC1.O>[CH2:16]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[O:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)CCON(Cc1ccccc1)Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCON(Cc1ccccc1)Cc1ccccc1

Procedure:
A solution of 22.4 g of methyl 3-[N,N-dibenzylaminoxy]propanoate and 4.50 g of potassium hydroxide in 200 ml of tetrahydrofuran and 200 ml of water is heated under reflux for 12 hours under N2. The mixture is concentrated under reduced pressure and the residue is partitioned between water and ether. The combined aqueous extracts are acidified with hydrochloric acid and then extracted with methylene chloride. The combined organic extracts are dried (MgSO4) and evaporated under reduced pressure to afford the title compound as a pale yellow oil.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH3:27][CH:28]([CH3:33])[CH2:29][C:30](O)=[O:31]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[CH2:29][CH:28]([CH3:33])[CH3:27])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: CC(C)CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: CC(C)CC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, off-white solid (74 mg, 72%), MS (ISP) m/z=411.5 [(M+H)+], mp 182° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 3-methyl-butyric acid.
Reaction SMILES: Br[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])[CH:4]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CCOCC.CC(C)=O.CCOCC>[N:17]1([CH2:2][C:3]2[O:7][N:6]=[C:5]([C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[O:9])[CH:4]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: O=C(c1ccc(F)cc1)c1cc(CBr)on1
Reactant: C1COCCN1
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=C(c1ccc(F)cc1)c1cc(CN2CCOCC2)on1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 4.5 g of (5-bromomethylisoxazol-3-yl-4-fluorophenylmethanone in 100 ml of Et2O was added dropwise to a solution of 7 ml of morpholine in 300 ml of 50% acetone/Et2O. The resulting mixture was stirred at room temperature for 20 hours. This mixture was filtered and the volatiles evaporated to give a residue which was dissolved in 600 ml of Et2O. The organic solution was washed with water until it became neutral and then with saturated NaCl, and dried over Na2SO4 and concentrated in vacuo to give 4.3 g of a crystalline solid. A 3.6 g sample of the amine was recrystallized from 65 ml of 8% toluene/hexane to yield 2.4 g (64%) of crystals, m.p. 72°-74°.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:16][C:17]([OH:19])=O)[CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.Cl.[CH3:25][O:26][CH2:27][NH2:28].CCN(C(C)C)C(C)C.Cl>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH3:25][O:26][CH2:27][NH:28][C:17](=[O:19])[CH2:16][N:11]([CH2:12][C:13]([OH:15])=[O:14])[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: COCN
Reactant: O=C(O)CN(CC(=O)O)C(=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COCNC(=O)CN(CC(=O)O)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of N-[(benzyloxy)carbonyl]-N-(carboxymethyl)glycine (28.45 g, 106.46 mmol) in DMF (163 mL) was added EDC (24.08 g, 125.62 mmol). The solution was cooled to 0° C. and treated with a mixture of N-methoxymethylamine hydrochloride (12.25 g, 125.62 mmol) and Hunig's base (21.88 mL, 125.62 mmol) in DMF (55 mL). The reaction was stirred at room temperature overnight and poured over a mixture of ice and aqueous 10% HCl solution. The mixture was extracted twice with EtOAc. The combined organics were washed twice with aqueous 10% HCl solution and once with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford a crude oil which was suspended in saturated aqueous NaHCO3 solution. The mixture was washed with EtOAc, adjusted to pH 2 with aqueous 1N HCl, and extracted three times with EtOAc. The final three organic extracts were combined, dried over MgSO4, filtered, and concentrated in vacuo to afford the product as a golden oil.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(OCC)(=O)C.O1C=CCCC1.N1CCCCC1>C(N(CC)CC)C>[N:3]1[CH:4]=[C:5]2[C:9]([N:8]=[CH:7][NH:6]2)=[N:10][CH:2]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: C1=COCCC1
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Solvent: CCN(CC)CC
Product: c1ncc2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 201.4 %

Procedure:
In a 100 ml three-mouth bottle, 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt of paratoluenesulfonic acid (0.2 g) are mixed. The above mixture is stirred and heated to a temperature of 35° C., 2,3-dihydropyrane (12 ml) is added thereto within 5 min. The above mixture is reacted at 50˜60° C. for 3 h. The completion of reaction is checked with TCL analysis. Triethylamine (8 ml) is added to the bottle, and piperidine (9.2 ml) is added thereto at the temperature within 20 min. The above mixture is reacted at the temperature for 0.5 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethyl acetate, and a filtrate is washed with water for 3 times and delaminated. Organic layer is concentrated till large amount of solid is separated out. After filtration, a filter cake is washed with ethyl acetate for 3 times and then dried in vacuum at 50° C. for 5 h to obtain solid purin (12.8 g). The yield is about 75.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[NH:4][C:5](=[O:10])[CH2:6][C:7]([CH3:9])=[O:8].Cl[C:16]1[CH:22]=CC=[CH:19][C:17]=1N.C1(C)C=CC=CC=1.[OH2:30]>Cl>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[NH:4][C:5]([C:6]1[C:19](=[O:30])[CH:17]=[C:16]([CH3:22])[O:8][C:7]=1[CH3:9])=[O:10]
Reactant: O
Reactant: Nc1ccccc1Cl
Reactant: CC(=O)CC(=O)Nc1ccccc1Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1cc(=O)c(C(=O)Nc2ccccc2Cl)c(C)o1

Procedure:
A mixture of 4.23 g (20 m mol) of o-chloroacetoacetanilide, 2.55 g (20 m mol) of o-chloroaniline and 20 ml of toluene, after adding one drop of hydrochloric acid was refluxed for 2 hours while the resulted water was distilled off from the reaction system together with about 10 ml of toluene. After 9.30 g (80 m mol) of N,N,N',N'-tetramethylethylenediamine was added to the remaining solution, a solution of 9.94 g (70 m mol) of 2,2,6-trimethyl-4H-1,3-dioxin-4-one in 25 ml of toluene was dropwise added over a period of 15 minutes.
Reaction SMILES: CN(C)CCCNC(C1C=C(C2C=CC(CSCCOC3C=CC=CC=3)=CC=2)C=CC=1)=O.[O:33]([CH2:40][CH2:41][S:42][CH2:43][C:44]1[CH:45]=[C:46]([C:50]2[CH:55]=[CH:54][C:53]([C:56]([OH:58])=O)=[CH:52][CH:51]=2)[CH:47]=[CH:48][CH:49]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[CH3:59][N:60]([CH3:66])[CH2:61][CH2:62][CH2:63][CH2:64][NH2:65]>C1COCC1>[CH3:59][N:60]([CH3:66])[CH2:61][CH2:62][CH2:63][CH2:64][NH:65][C:56]([C:53]1[CH:54]=[CH:55][C:50]([C:46]2[CH:47]=[CH:48][CH:49]=[C:44]([CH2:43][S:42][CH2:41][CH2:40][O:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:45]=2)=[CH:51][CH:52]=1)=[O:58]
Reactant: CN(C)CCCCN
Reactant: O=C(O)c1ccc(-c2cccc(CSCCOc3ccccc3)c2)cc1
Agent: CN(C)CCCNC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Solvent: C1CCOC1
Product: CN(C)CCCCNC(=O)c1ccc(-c2cccc(CSCCOc3ccccc3)c2)cc1

Procedure:
3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (4-dimethylamino-butyl)-amide was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide. 3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (1.50 g, 4.12 mmol, 1 eq.) in anhydrous THF was treated with 1,1-carbonyldiimidazole (0.68 g, 4.20 mmol, 1.02 eq.) and 4-dimethylaminobutylamine (0.57 g, 4.94 mmol, 1.2 eq.). When complete, the reaction was worked up as described leaving a yellow oil.
Reaction SMILES: OO.[OH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][S:9][CH2:8][C:7]1=[O:12].C(OC(=O)C)(=[O:15])C.C(OC(C)C)(C)C.C(O)(C)C>>[OH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][S:9](=[O:15])[CH2:8][C:7]1=[O:12]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CSCCN1CCO
Agent: OO
Solvent: CC(C)OC(C)C
Solvent: CC(C)O
Product: O=C1CS(=O)CCN1CCO

Procedure:
This sulfoxide is prepared by reacting, for a week, one equivalent of H2O2 with 4-(2-hydroxyethyl) 3-thiamorpholinone (obtained in Example 9) solubilized at 0° C. in an acetic acid-acetic anhydride mixture. After concentration of the mixture the resulting liquid is solubilized in a minimum of an isopropyl ether-isopropyl alcohol mixture. Starting with this solution, placed at -25° C., white crystals whose melting point is 45° C. are isolated.
Reaction SMILES: [CH2:1]([O:17][C:18]1[CH:35]=[CH:34][C:21]([O:22][CH2:23][C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[O:25])=[CH:20][CH:19]=1)[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].[CH2:36]([I:38])[CH3:37]>>[I-:38].[CH2:36]([N+:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][NH:26][C:24](=[O:25])[CH2:23][O:22][C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:1][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])=[CH:35][CH:34]=1)[CH3:37]
Reactant: CCI
Reactant: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)NCc2ccccn2)cc1
Product: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)NCc2cccc[n+]2CC)cc1
Product: [I-]
Temperature: 115 °C
Yield: 80.1 %

Procedure:
The title compound is prepared by the procedure of Example 8, using 0.50 g of product from Example 88, 8.1 g of ethyl iodide and heating the mixture at 115° C. for 22 hours. The residue is recrystallized from methyl alcohol to give 0.53 g of the desired product as light yellow prisms.
Reaction SMILES: [OH:1][CH:2]([C:9]([OH:11])=[O:10])[C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[OH:1][CH:2]1[C:9](=[O:10])[O:11][C:4](=[O:6])[C:3]1([CH3:7])[CH3:8]
Reactant: CC(C)(C(=O)O)C(O)C(=O)O
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC1(C)C(=O)OC(=O)C1O
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
(3RS)-3-Hydroxy-2,2-dimethyl-succinic acid [Tetrahedron Letters (2002), 43(52), 9513-9515] (120 mg, 0.74 mmol) was suspended in CH2Cl2 (2 ml) and cooled to 0-5° C. Trifluoroacetic anhydride (260 μl, 1.85 mmol) was added and the reaction mixture stirred for 2 hours at room temperature. The reaction mixture was evaporated to dryness and used without any further purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[NH:6][C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:30]2)=CC=1.O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][C:7](=[S:30])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(=O)Nc1cc(OC)c(OC)c(OC)c1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C(=S)Nc1cc(OC)c(OC)c(OC)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Ethyl 3,4,5-trimethoxyoxanilate (3.0 g) was dissolved in benzene (20 mL), and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (2.14 g) was added to the solution. The reaction mixture was stirred at 80° C. for 1 hour, and water was added thereto. After conducting extraction with ethyl acetate, the resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:4) to obtain the title compound.