Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([N:20]([CH3:22])[CH3:21])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=O)C.[C:23]1(C)[CH:28]=[CH:27]C(S(O)(=O)=O)=[CH:25][CH:24]=1>C(O)C1C=CC=CC=1.C1C=CC=CC=1>[OH:4][C@H:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([N:20]([CH3:21])[CH3:22])[CH:13]=1)[C:6]([O:8][CH2:9][C:10]1[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=1)=[O:7]
Reactant: CCOC(=O)[C@@H](Cc1ccc(OC)c(N(C)C)c1)OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: OCc1ccccc1
Product: COc1ccc(C[C@@H](O)C(=O)OCc2ccccc2)cc1N(C)C
Yield: 59.3 %

Procedure:
To a solution of ethyl (R)-2-acetoxy-3-(4-methoxy-3-dimethylaminophenyl)propionate(1.56 g) in benzyl alcohol (3.7 ml)and benzene (7.4 ml) was added p-toluenesulfonic acid (0.82 g)and heated under reflux for 6 hours. After cooling, the solvent wasevaporated in vacuo, and the gained crude product was purified bysilica gel column chromatography. The residue was eluted withmixed solvent of hexane, ethyl acetate, and ethanol (60:35:5, v/v).The fractions containing the desired product were combined andevaporated in vacuo to obtain benzyl (R)-2-hydroxy-3-(4-methoxy-3-dimethylaminophenyl)propionate(0.93 g).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][N:4]=[N+]=[N-].CO.[H][H]>[Pd].O1CCCC1>[C:8]1([CH2:7][C:2]([CH3:14])([CH3:1])[CH2:3][NH2:4])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(CN=[N+]=[N-])Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(CN)Cc1ccccc1

Procedure:
A mixture of 2,2-dimethyl-3-phenyl-1-azidopropane (3 gm), 10% Pd-C, methanol (60 mL) and tetrahydrofuran (15 mL) was stirred under 1 atmosphere of hydrogen at rt for 18 h. The mixture was filtered and concentrated to give the title compound as an oil, MS (m/z): 164.1 (M+H)+; C11H17N requir. 163.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][OH:19])[CH2:13][CH:12]=1.I.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](SC)=[NH:27].C([O-])(O)=O.[Na+]>C(O)C>[OH:19][CH2:18][CH2:17][N:14]1[CH2:15][CH:16]=[C:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:26]([C:22]4[S:21][CH:25]=[CH:24][CH:23]=4)=[NH:27])[CH:3]=3)[NH:7][CH:6]=2)[CH2:12][CH2:13]1
Reactant: CSC(=N)c1cccs1
Reactant: Nc1ccc2[nH]cc(C3=CCN(CCO)CC3)c2c1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N=C(Nc1ccc2[nH]cc(C3=CCN(CCO)CC3)c2c1)c1cccs1
Reaction time: 18 h
Yield: 61.4 %

Procedure:
A solution of 2-(4-(5-amino-1H-indol-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanol (0.16 g, 0.622 mmol) in dry ethanol (5 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.355 g, 1.244 mmol) at room temperature and stirred overnight (18 h). The reaction was basified with sat. NaHCO3 solution (50 mL) and product was extracted into CH2Cl2 (3×20 mL). The combined CH2Cl2 layer was washed with brine (20 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 1:9) to obtain N-(3-(1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)thiophene-2-carboximidamide (0.14 g, 61.4%) as a solid. 1H NMR (DMSO-d6) δ 10.92 (s, 1H), 7.71 (d, 1H, J=3.6 Hz), 7.58 (d, 1H, J=5.1 Hz), 7.33-7.30 (m, 2H), 7.21 (s, 1H), 7.09 (t, 1H, J=3.9 Hz), 6.66 (d, 1H, J=8.4 Hz), 6.23 (brs, 2H), 6.03 (s, 1H), 4.40 (t, 1H, J=5.1 Hz), 3.54 (q, 2H), 3.16-3.10 (m, 2H), 2.66 (t, 2H, J=5.4 Hz), 2.50-2.44 (m, 4H, merged with DMSO-peak); ESI-MS (m/z, %): 367 (MH+, 33), 294 (100).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[C:13]([O:17][C:18]([N:20]1[CH2:28][CH:27]([OH:29])[CH2:26][C@H:21]1[C:22]([O:24][CH3:25])=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl-].[Na+]>O1CCCC1>[C:13]([O:17][C:18]([N:20]1[CH2:28][C@H:27]([O:29][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:26][C@H:21]1[C:22]([O:24][CH3:25])=[O:23])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)[C@@H]1CC(O)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
2.02 ml of methanesulfonyl chloride, followed by 3.65 ml of triethylamine were added, whilst ice-cooling, to a solution of 6.1 g of methyl 1-(t-butoxycarbonyl)-4-hydroxyprolinate [prepared as described in step (6) above] dissolved in 120 ml of dry tetrahydrofuran. The mixture was stirred first at 0° to 5° C. for 1 hour and then at room temperature for 1 hour, after which it was poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to afford 8.13 g of the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[Cl:11])[NH:4][N:3]=1.[O:12]1[C:16]2([CH2:21][CH2:20][CH:19](O)[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[Cl:11])[N:4]([CH:19]2[CH2:20][CH2:21][C:16]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:17][CH2:18]2)[N:3]=1
Reactant: Clc1ncnc2[nH]nc(Br)c12
Reactant: OC1CCC2(CC1)OCCO2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ncnc2c1c(Br)nn2C1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
To a solution of 3-bromo-4-chloropyrazolo[3,4-d]pyrimidine (Intermediate B) (7.5 g, 32 mmol), 1,4-dioxaspiro[4.5]decan-8-ol (Intermediate M) (15.17 g, 96 mmol), triphenylphosphine (16.86 g, 64 mmol) in THF (275 mL) was added diethylazodicarboxylate (11.14 g, 64 mmol) in THF (50 mL) at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 1 hour, warmed to room temperature and then stirred at room temperature for 3 hrs. The reaction mixtures was concentrated in vacuo and dissolved in hot heptane/EtOAc/DCM (5:1:5). Flash silica gel column chromatography using heptane, heptane/EtOAc (5/1) then heptane/EtOAc (4/1) gave a solid which was triturated with heptane and the solids removed by filtration to furnish 8.2 g of 3-bromo-4-chloro-1-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazolo[3,4-d]pyrimidine as a white solid (69%) [Rf in 1:1 heptane:EtOAc=0.5]1H NMR (400 MHz, d6-DMSO): 8.89 (1H, s), 4.92 (1H, m), 3.90 (4H, m), 2.16 (2H, m), 1.96 (2H, m), 1.81 (6H, m) HPLC: Tr=17.11 mins, 96.6%.
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[C:20]1(B(O)O)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[CH3:17][C:4]1([CH3:18])[C:3](=[O:19])[C:2]([C:28]2[C:29]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:25]=[CH:26][CH:27]=2)=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[O:5]1
Reactant: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
Reactant: OB(O)c1cccc2ccccc12
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2cccc3ccccc23)C1=O

Procedure:
200 mg of 4bromo-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone was coupled with 114 mg of naphthalene-1-boronic acid by a procedure similar to the procedure employed for Example 2 to afford 2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-4-(1-naphthyl)-3(2H)-furanone as a solid. mp: 194-195° C. NMR: δ1.67 (s, 3H), 1.71 (s, 3H), 2.97 (s, 3H), 7.33-7.43 (m, 2H), 7.48-7.60 (m, 2H), 7.51-7.52 (m, 1H), 7.66-7.69 (m, 2H), 7.76-7.78 (m, 2H), 7.90-7.94 (m, 2H), IR (cm−1): 1698, 1404, 1318, 1149, 1092, 772.
Reaction SMILES: [C:1]([S:9]CC(O)=O)(=S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:15]([NH:19][NH2:20])([CH3:18])([CH3:17])[CH3:16].O>N1C=CC=CC=1>[C:15]([NH:19][NH:20][C:1](=[S:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)NN
Reactant: O=C(O)CSC(=S)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)NNC(=S)c1ccccc1
Temperature: 120 °C

Procedure:
S-(thiobenzoyl)thioglycolic acid (3.0 g) was dissolved in 20 ml pyridine, treated with t-butyl hydrazine hydrochloride (excess, ca. 4 g) and then was heated at ca. 120° C. for 14 hours. Water (120 ml) was added and the mixture was extracted with ether. The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated to give crude N'-t-butyl-N-(thiobenzoyl)hydrazine as a viscous yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(Cl)Cl>[C:17]([O:16][C:14]([N:13]1[CH2:12][C:7]2[C:6](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:5]1[CH2:4][C:3]([O:2][CH3:1])=[O:21])=[O:15])([CH3:18])([CH3:20])[CH3:19]
Reactant: COC(=O)C=Cc1ccccc1CNC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CC1c2ccccc2CN1C(=O)OC(C)(C)C
Reaction time: 2.5 h
Yield: 45 %

Procedure:
To a 0° C. solution of (116.9 g, 401.2 mmol) material from Step B in DCM (800 mL) was added 200 mL of TFA dropwise over 15 minutes. After removing the cooling bath, the mixture was stirred for about 2.5 hours and then concentrated to dryness. The residue was dissolved in 500 mL of DCM and saturated aqueous sodium bicarbonate is slowly added until the mixture was slightly basic. The organic portion was separated and the aqueous portion is extracted two times with DCM. The combined organic portions were dried (Na2SO4) and concentrated to dryness. The residue was dissolved in 800 mL of DCM and DIPEA (57.0 g, 441.4 mmol) was added. To the mixture was added di-tert-butyl dicarbonate (96.3 g, 441.4 mmol) in five portions over 45 minutes and then stirred at r.t. for 16 hours. The mixture was washed with 10% aqueous sodium bisulfate, and the organic portion was separated and the aqueous portion is extracted two times with DCM. The combined organic extracts were dried ((Na2SO4) and concentrated to dryness. The resulting residue was dissolved in a small amount of DCM and filtered through 7 inch silica gel in a 2L sintered glass funnel eluting with 25% EtOAc/hexanes. The eluent was concentrated to dryness and the enantiomers were separated by chiral chromatography. The first eluting isomer was labeled as isomer #1 and the second eluting is labeled as isomer #2, which afforded about 52.6 g (45%) of the final compound (isomer 2). EIS-MS 292 [M+1].
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:11])([CH2:9][CH3:10])[S:4]1)[OH:2].[CH3:12][N:13]=[C:14]=[O:15]>>[CH3:12][NH:13][C:14]([O:2][N:1]=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:11])([CH2:9][CH3:10])[S:4]1)=[O:15]
Reactant: CCC1(C)SC(=NO)N=C1C
Reactant: CN=C=O
Product: CCC1(C)SC(=NOC(=O)NC)N=C1C

Procedure:
2-oxo-4,5-dimethyl-5-ethyl-3-thiazoline-oxime was reacted with methyl isocyanate as described in Example 4 to yield 2-oxo-4,5-dimethyl-5-ethyl-3-thiazoline-O-(methylcarbamoyl)-oxime, m.p. 115°-117° C. The 2-oxo-4,5-dimethyl-5-ethyl-3-thiazoline-oxime starting material melts at 143.5°-144.5° C.
Reaction SMILES: C(OC[C@@H](OC(C)(C)C)C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(N1CCOCC1)C=C2)(=[O:6])C(C)(C)C.[CH2:39]([O:46][C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][C:51]([CH3:72])=[C:52]([C@H:64]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])[CH2:65][OH:66])[C:53]=2[C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=2)[N:48]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(N1CCOCC1)C=C2)CO)(C)(C)C>>[CH2:39]([O:46][C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][C:51]([CH3:72])=[C:52]([C@H:64]([O:67][C:68]([CH3:69])([CH3:71])[CH3:70])[C:65]([OH:6])=[O:66])[C:53]=2[C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=2)[N:48]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: Cc1cc2nc(N3CCOCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: Cc1cc2nc(OCc3ccccc3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Agent: Cc1cc2nc(N3CCOCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Product: Cc1cc2nc(OCc3ccccc3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-(2-(Benzyloxy)-5-(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-butoxyacetic acid (65A) (3.3 mg) was prepared in a similar manner as compound ((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)acetic acid of Example 29 except using (S)-2-(2-(benzyloxy)-5-(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-butoxyethanol instead of ((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethanol. 1H-NMR 400 MHz (CD3OD) δ 7.82 (d, J=9.6 Hz, 1 H), 7.71 (s, 1 H), 7.80 (m, 3 H), 7.51 (m, 2 H), 7.41-7.10 (m, 4 H), 7.12 (d, J=9.6 Hz, 1 H), 5.58 (s, 2 H), 5.18 (s, 1 H), 2.66 (s, 3 H), 0.97 (s, 9 H); LCMS-ESI+ (m/z): [M+H]+ calcd for C29H29ClNO4: 490.2. Found: 490.2.
Reaction SMILES: [OH-].[Na+].O.Cl.[F:5][C:6]([F:20])([F:19])[C:7]1[CH:8]=[C:9]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1.Br[CH2:22][CH2:23][CH2:24][Cl:25]>CC(C)=O>[F:20][C:6]([F:5])([F:19])[C:7]1[CH:8]=[C:9]([N:13]2[CH2:18][CH2:17][N:16]([CH2:22][CH2:23][CH2:24][Cl:25])[CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: ClCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: FC(F)(F)c1cccc(N2CCN(CCCCl)CC2)c1
Reaction time: 18 h

Procedure:
To a solution of 7.36 g. (0.184 mole) of sodium hydroxide in 75 ml. of water and 75 ml. of acetone there is added 19.02 g. (0.074 mole) of 1-[3-(trifluoromethyl)phenyl]piperazine hydrochloride and 11.59 g. (0.074 mole) of 1-bromo-3-chloropropane, and the resulting mixture is stirred at 27° for 18 hrs. The organic layer is then separated and concentrated to an oil under reduced pressure. The oil is treated with hot (85°) 6 N HCl until solution is complete, and the resulting solution is filtered and stored at 5° for 18 hrs. The precipitate which forms is collected on a filter to afford 14.73 g. (66%) of the hydrochloride salt of the product, m.p. 190°-192°.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([CH2:27][NH2:28])[C:23]([CH3:29])=[N:22]1.CCN(C(C)C)C(C)C>>[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([CH2:27][NH:28][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)[C:23]([CH3:29])=[N:22]1
Reactant: Cc1nn(C)c(C)c1CN
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(C)c(C)c1CNC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, (1,3,5-trimethyl-1H-pyrazol-4-ylmethyl)-amine and DIEA to give 2-[(1,3,5-trimethyl-1H-pyrazol-4-ylmethyl)-amino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 378 (MH+).
Reaction SMILES: [Br:1][CH:2]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=1)[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[S:21]1[CH2:25][C:24](=[O:26])[NH:23][C:22]1=[O:27].C(O)(=O)C.N1CCCCC1>C1(C)C=CC=CC=1>[Br:1][CH:2]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=1)[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[C:25]2[S:21][C:22](=[O:27])[NH:23][C:24]2=[O:26])=[CH:7][CH:6]=1
Reactant: CCc1ccc(C(Br)COc2ccc(C=O)cc2)nc1
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCc1ccc(C(Br)COc2ccc(C=C3SC(=O)NC3=O)cc2)nc1

Procedure:
To stirred solution of 5 g (0.015 mol) 4-[2-bromo-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzaldehyde dissolved in 50 mL toluene was added 1.85 g (0.015 mol) thiazolidin-2,4-dione followed by addition of 2 g (0.03 mol) acetic acid and 3 g (0.03 mol) piperidine. Reaction mixture was heated and water was removed azeotropically. After completion of the reaction on TLC, toluene was distilled out completely under reduced pressure. Product was poured into excess of water and extracted with ethyl acetate. On concentrating ethyl acetate in vacuo, 0.65 g (10%) desired product obtained with satisfactory mass. The 1H NMR was similar to the 1H NMR of example 79.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].Br[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:19](=[O:20])[O:18]1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:15])[C:12]([O:14][CH:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:19](=[O:20])[O:18]2)=[O:13])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Reactant: O=C1OC(Br)c2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)Cc1ccc(C(C)C(=O)OC2OC(=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.2 %

Procedure:
To a solution of 6.2 g of 2-(4-isobutylphenyl)propionic acid in 30 ml of chloroform and 3.4 g of triethylamine, a solution of 6.2 g of 3-bromophthalide in 20 ml of chloroform is added. The solution thus obtained is stirred 24 hours at room temperature (about +22° C.), the organic phase is washed with an aqueous solution of sodium bicarbonate, then with water and finally it is dried on anhydrous sodium sulfate and evaporated to dryness. The residue, crystallized from petroleum ether, yields 8.1 g of phthalidyl 2-(4-isobutylphenyl)propionate; m.p. 62°-65° C. IR: 1795 and 1780 cm1
Reaction SMILES: [CH3:1][CH:2]1[C:6](=O)[CH2:5][C:4]2([CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)[O:3]1.[CH2:14]([SH:17])[CH2:15][SH:16].[OH-].[Na+]>ClCCl>[NH3:10].[CH3:13][N:10]1[CH2:11][CH2:12][C:4]2([O:3][CH:2]([CH3:1])[C:6]3([S:17][CH2:14][CH2:15][S:16]3)[CH2:5]2)[CH2:8][CH2:9]1
Reactant: CC1OC2(CCN(C)CC2)CC1=O
Reactant: SCCS
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC1OC2(CCN(C)CC2)CC12SCCS2
Product: N
Reaction time: 1 h

Procedure:
A solution of 0.5 g 2,8-dimethyl-1-oxa-8-azaspiro[4,5]-decan-3-one in 10 ml dichloromethane was cooled in ice, 0.45 ml 1,2-ethanedithiol was added, and 2 ml boron trifluoride/ether complex was then added dropwise while maintaining the temperature below 10° C. After stirring at that temperature for one hour, the reaction mixture was poured into 30 ml of 20% aqueous caustic soda solution. The insoluble matters were filtered off, the filtrate was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The dried solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography using, as eluent, a mixed solvent of chloroform/methanol/conc. ammonia (20:1:0.1 by volume), giving 0.46 g of 10,14-dimethyl-13-oxa-1,4-dithia-10-azadispiro[4,1,5,2]tetradecane. It was dissolved in methanol and converted to maleate by addition of an equimolar amount of maleic acid dissolved in the same solvent.
Reaction SMILES: Br.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:3]1.[C:16]1([CH2:22][CH2:23][CH:24]=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([CH2:22][CH2:23][CH2:24][N:2]2[CH2:7][CH2:6][CH2:5][CH:4]([S:8][C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=3)[CH2:3]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccc(SC2CCCNC2)cc1
Reactant: O=CCCc1ccccc1
Agent: Br
Product: Oc1ccc(SC2CCCN(CCCc3ccccc3)C2)cc1

Procedure:
The title compound, MS: m/e=328.3 (M+H+) was prepared from (RS)-4-(piperidin-3-yl-sulfanyl)-phenol hydrobromide and 3-phenylpropionaldehyde.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:7](=[O:19])[C:6]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[NH:37][C:36](=[O:38])[O:35][N:34]=2)=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH3:4].[Si]([O:46][CH:47]1[CH2:52][CH2:51][CH:50](O)[CH2:49][CH2:48]1)(C(C)(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C@H:50]3[CH2:51][CH2:52][C@@H:47]([OH:46])[CH2:48][CH2:49]3)=[CH:14][CH:13]=2)[C:7](=[O:19])[C:6]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[NH:37][C:36](=[O:38])[O:35][N:34]=2)=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(O)CC1
Reactant: CCCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nc(C)n(-c2ccc(O[C@H]3CC[C@@H](O)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 2 h

Procedure:
To a solution of 6-butyl-3-(4-hydroxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one (1.2 g), 4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanol (1.2 g) and triphenylphosphine (1.4 g) in tetrahydrofuran (12 mL) was added dropwise diisopropyl azodicarboxylate (1.9 M toluene solution, 2.8 mL). After stirring for 2 hr, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and a mixture of the residue, hydroxylammonium chloride (0.87 g), sodium hydrogen carbonate (1.3 g) and dimethyl sulfoxide (9 mL) was stirred overnight at 90° C. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (9 mL). N,N′-carbonyldiimidazole (0.3 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, and the mixture was stirred at room temperature for 30 min. Tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 2.5 mL) was added, and the mixture was stirred overnight at 50° C. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.37 g, 28%) as an amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11]Br.[F:18][C:19]([F:34])([F:33])[C:20]1[C:24]2[CH:25]=[CH:26][C:27]([OH:32])=[C:28]([CH2:29][CH2:30][CH3:31])[C:23]=2[O:22][N:21]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:32][C:27]1[CH:26]=[CH:25][C:24]2[C:20]([C:19]([F:34])([F:33])[F:18])=[N:21][O:22][C:23]=2[C:28]=1[CH2:29][CH2:30][CH3:31]
Reactant: COC(=O)Cc1ccc(OCCCBr)c(F)c1
Reactant: CCCc1c(O)ccc2c(C(F)(F)F)noc12
Product: CCCc1c(OCCCOc2ccc(CC(=O)OC)cc2F)ccc2c(C(F)(F)F)noc12

Procedure:
Using the method in example 17 step D substituting methyl 3-fluoro-4-(3-bromopropyloxy)phenylacetate and 3-trifluoromethyl-7-propyl-6-hydroxybez-[4,5]-isoxazole as the starting materials, the titled compound was obtained.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.CO.[NH4+:12]>>[NH2:12][CH2:3][C@H:2]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)[OH:1]
Reactant: c1cncc([C@H]2CO2)c1
Reactant: [NH4+]
Solvent: CO
Product: NC[C@@H](O)c1cccnc1

Procedure:
The title compound was prepared from 3-[(2S)-oxiranyl]pyridine (which was obtained in Example 129) and saturated ammonium methanol in substantially the same manner, as described in Example 124. The product was obtained as a brown oil; 1H NMR (400 MHz, DMSO-d6) δ 1.60 (brs, 2H), 2.59-2.71 (m, 2H), 4.47-4.50 (m, 1H), 5.20 (brs, 1H), 7.31-7.34 (m, 1H), 7.68-7.71 (m, 1H), 8.42-8.43 (m, 1H), 8.50-8.51 (m, 1H); MS (ES) m/z: 139 (MH+).