Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([CH:23]=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:30][CH2:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl([O-])=[O:35].[Na+].P([O-])(O)(O)=O.[Na+].CC(=CC)C>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([C:23]([OH:35])=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:30][CH2:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: [O-][Cl+][O-]
Reactant: CCCO[C@@H]1CN(c2nc(C=O)c(C(=O)OCC)s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Product: CCCO[C@@H]1CN(c2nc(C(=O)O)c(C(=O)OCC)s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 97.4 %

Procedure:
The same operation as in Example (33c) was performed using ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl)-4-formyl-1,3-thiazole-5-carboxylate obtained in Example (74b) (445 mg, 0.89 mmol), sodium chlorite (180 mg, 1.99 mmol), sodium dihydrogenphosphate (557.6 mg, 3.57 mmol) and 2-methyl-2-butene (0.57 mL, 5.36 mmol), to obtain 445.4 mg of the title compound as a white solid (97%).
Reaction SMILES: [C:1]([CH2:3][C@@H:4]([O:16][Si](C(C)(C)C)(C)C)[CH2:5][C:6](=[O:15])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])#[N:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)C>O1CCCC1>[C:1]([CH2:3][C@@H:4]([OH:16])[CH2:5][C:6](=[O:15])[CH2:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])#[N:2]
Reactant: CC(C)(C)OC(=O)CC(=O)C[C@@H](CC#N)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CC(=O)C[C@H](O)CC#N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of crude (R)-1,1-dimethylethyl 6-cyano-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-oxohexanoate, 43 g (0.126 mol) in 350 mL of tetrahydrofuran is treated with 213 mL of tetrabutylammonium fluoride solution (1.0M in hexane). The resulting mixture is stirred for five hours, at 25° C. The mixture is treated with 500 mL of water, 300 mL of diethyl ether is added, and the layers separated. The organic layer is dried (magnesium sulfate) and then filtered through a plug of silica gel with the aid of anhydrous diethyl ether. The solvent is removed under a vacuum to obtain 21 g of crude (R)-1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate with acceptable NMR, MS and IR spectra.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:28])[C:5]2[CH:11]=[C:10]([CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([O:23]C(C)(C)C)=[O:22])=[CH:17][CH:16]=3)[CH3:14])[CH:9]=[N:8][C:6]=2[N:7]=1.Cl>[N+](C)([O-])=O>[NH2:1][C:2]1[N:3]=[C:4]([NH2:28])[C:5]2[CH:11]=[C:10]([CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][CH:16]=3)[CH3:14])[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: CC(=Cc1cnc2nc(N)nc(N)c2c1)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C[N+](=O)[O-]
Product: CC(=Cc1cnc2nc(N)nc(N)c2c1)c1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A suspension containing 4.58 g of 2,4-diamino-6-[2-(4-tert-butoxycarbonylphenyl)prop-1-enyl]pyrido[2,3-d]pyrimidine in 200 mL of a saturated solution of hydrogen chloride gas in nitromethane was stirred at 0° C. for 1 hour, and then at room temperature for 3 hours. After dilution with ether, the reaction mixture was filtered and the collected solid was washed successively with water, methanol, and acetone and then dried under reduced pressure to give 3.90 g (100%) of 2,4-diamino-6-[2-(4-carboxyphenyl)prop-1-enyl]pyrido[2,3-d]pyrimidine. NMR (DMSO-d6, 80 MHz) d 2.31 (brs, 3H), 6.77 and 7.07 (brs, 1H), 7.74 (d, 2H, J=8.5 Hz), 7.98 (d, 2H, J=8.5 Hz), 8.26, (d, 1H, J=2.0 Hz), 8.74 d, 1H, J=2.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14]CC)=O.[NH:17]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[NH2:18]>CO>[ClH:1].[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([N:17]2[C:12](=[O:14])[C:3]3=[CH:4][NH:5][C:6]4[CH:7]=[CH:8][N:9]=[CH:10][C:11]=4[C:2]3=[N:18]2)[CH:20]=1
Reactant: CCOC(=O)c1cnc2ccncc2c1Cl
Reactant: NNc1cccnc1
Solvent: CO
Product: Cl
Product: O=c1c2c[nH]c3ccncc3c-2nn1-c1cccnc1

Procedure:
A solution of 2.84 g of ethyl 4-chloro-1,6-naphthyridine-3-carboxylate and 1.35 g of 3-hydrazinopyridine in 36 ml of methanol is stirred at room temperature for 2.5 hours, then refluxed for 4.5 hours, then cooled in an ice bath and filtered. Collected solid is washed with methanol, then with ether to yield 2-(3-pyridyl)pyrazolo[4,3-c][1,6]naphthyridin-3-(5H)-one hydrochloride, m.p. 302°-305°.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21](Br)=[C:20]([CH3:25])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][C:34]1([CH3:41])[C:38]([CH3:40])([CH3:39])[O:37][BH:36][O:35]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([B:36]2[O:37][C:38]([CH3:40])([CH3:39])[C:34]([CH3:41])([CH3:33])[O:35]2)=[C:20]([CH3:25])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OBOC1(C)C
Reactant: COC(=O)[C@H](Cc1ccc(Br)c(C)c1)NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1)NC(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a mixture of methyl (2S)-2-[(benzyloxy)carbonyl]amino-3-(4-bromo-3-methylphenyl)propanoate (1.23 g, 3.03 mmol), 1,4-dioxane (8 mL), triethylamine (1.69 mL, 12.1 mmol), palladium acetate (17 mg, 76 μmol), O-(dicyclohexylphosphino)biphenyl (106 mg, 0.303 mmol) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.10 mL, 7.57 mmol) dropwise. The greenish reaction mixture was stirred at 80° C. for 30 min. The reaction was quenched with saturated NH4Cl solution. The aqueous solution was extracted with ethyl acetate twice. The organic solutions were washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (1.25 g, 91%). 1H NMR (400 MHz, CDCl3): δ 7.67 (d, 1H), 7.3 (m, 5H), 6.9 (m, 2H), 5.22 (d, 1H), 5.10 (m, 2H), 4.64 (m, 1H), 3.70 (s, 3H), 3.06 (m, 2H), 2.48 (s, 3H), 1.33 (s, 12H); MF=C25H32BNO6; LCMS found for C25H33BNO6 (M+H)+: m/z=454.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=2)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].C(N(C(C)C)CC)(C)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37].C(C1C=C(C2C=CC=C(CS(C)(=O)=O)C=2)C2N(C3C=CC=CC=3)C=NC=2C=1)#N>ClCCl>[C:1]([C:3]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:20][CH:19]=2)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1cc(-c2ccc(CO)cc2)c2c(c1)ncn2-c1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: CS(=O)(=O)Cc1cccc(-c2cc(C#N)cc3ncn(-c4ccccc4)c23)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)Cc1ccc(-c2cc(C#N)cc3ncn(-c4ccccc4)c23)cc1

Procedure:
5-Cyano-7-(4-methanesulphonylmethylphenyl)-1-phenylbenzimidazole was prepared from 5-cyano-7-(4-hydroxymethylphenyl)-1-phenylbenzimidazole (500 mg, 1.54 mmol), diisopropylethylamine (0.82 ml, 4.62 mmol) and methanesulphonyl chloride (0.13 ml, 1.69 mmol) in dichloromethane (10 ml) using the method described for 5-cyano-7-(3-methanesulphonylmethylphenyl)-1-phenylbenzimidazole. The crude solution (approximately 0.14 M of product) was used directly in the next stage.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])[N:5]=[N:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:23][CH3:24]>CC(C)=O>[CH2:23]([O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=1[N:6]1[C:2]([CH3:1])=[N:3][N:4]=[N:5]1)[CH3:24]
Reactant: Cc1nnnn1-c1ccccc1C(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccccc1-n1nnnc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
Acetone (3.2 L) and 2-(5-methyl-1H-tetrazol-1-yl)benzoic acid (228 g) were combined then stirred at ambient temperature for 15 minutes. Potassium carbonate (228 g) was added to the reaction mixture in a single portion. Iodoethane (366.8 g) was added dropwise to the reaction mixture producing a slight exotherm. The reaction mixture was heated at reflux for about 4 hours then stirred overnight while cooling to ambient temperature. The precipitated salts were removed by filtration then rinsed with acetone. The combined filtrates were evaporated under vacuum. The residue was dissolved in dichloromethane (1.5 L). The dichloromethane solution was washed with water (1.5 L), dried over magnesium sulfate then concentrated under vacuum to provide 227 g of ethyl-2-(5-methyl-1H-tetrazol-1-yl)benzoate as a white solid m.p. 98–100° C.
Reaction SMILES: C(O[C:4]([C:6]1[O:10][N:9]=[C:8]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:7]=1)=[O:5])C.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>CO>[CH2:21]([N:23]([CH2:24][CH3:25])[C:4]([C:6]1[O:10][N:9]=[C:8]([CH:11]=[CH:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[N:7]=1)=[O:5])[CH3:22]
Reactant: CCOC(=O)c1nc(C=Cc2ccc(OC)cc2)no1
Reactant: CCNCC
Solvent: CO
Product: CCN(CC)C(=O)c1nc(C=Cc2ccc(OC)cc2)no1
Yield: 87.4 %

Procedure:
5-Ethoxycarbonyl-3-p-methoxystyryl-1,2,4-oxadiazole (1.25 g.) was suspended in dry methanol (5 ml.) and diethylamine (7.25 ml.) was added. The mixture was heated under reflux for 1 hour, when a solution was obtained. The solvent was removed under reduced pressure and the residual oil was dissolved in methanol and treated with charcoal. Evaporation of the filtrate left an oil, which was recrystallised from aqueous methanol to give the amide (1.199 g., 87.4%), m.p. 69°-70°, λmax. (EtOH) 225.5 300 (infl.) and 308 nm. (ε15400, 24400 and 25000), εmax. (CHBr3) 820 (C6H4), 970 (trans-CH=CH), 1650 (CO.N<),
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]([N+:14]([O-])=O)[C:8]=1[OH:17])(=[O:6])=[O:5])[CH3:2].[H][H]>[Pd]>[CH2:1]([NH:3][S:4]([C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]([NH2:14])[C:8]=1[OH:17])(=[O:5])=[O:6])[CH3:2]
Reactant: [H][H]
Reactant: CCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Agent: [Pd]
Product: CCNS(=O)(=O)c1c(Cl)ccc(N)c1O
Yield: 66.8 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, crude N-ethyl-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (1.34 g) was reduced with hydrogen and 10% Pd/C (400 mg) to form the desired product (800 mg, 82% for two steps). 1H NMR (MeOD-d4): δ 6.85 (d, 1H), 6.78 (d, 1H), 2.85 (q, 2H), 0.95 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10]([O:12][CH:13]1[CH2:19][CH:18]2[N:20]([CH3:21])[CH:15]([CH2:16][CH2:17]2)[CH2:14]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:28][CH3:29]>CN(C=O)C>[I-:28].[C:1]([O:5][C:6]([NH:8][CH:9]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:10]([O:12][CH:13]1[CH2:14][CH:15]2[N+:20]([CH3:29])([CH3:21])[CH:18]([CH2:17][CH2:16]2)[CH2:19]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1C2CCC1CC(OC(=O)C(NC(=O)OC(C)(C)C)c1ccccc1)C2
Reactant: CI
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(C(=O)OC1CC2CCC(C1)[N+]2(C)C)c1ccccc1
Product: [I-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 28 %

Procedure:
To a solution of 8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(tert-butoxycarbonyl-amino)-2-phenylacetate (C58) (230 mg, 0.61 mmol) in DMF (15 ml), was added iodomethane (42.1 μl, 0.68 mmol). The reaction was stirred at RT for 15 hours, and then the solvent was evaporated. The crude was triturated with i-Pr2O and then purified by flash chromatography (DCM/MeOH=95/5 to 9/1) to obtain 3-(2-(tert-butoxycarbonylamino)-2-phenylacetoxy)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane iodide (88.2 mg: 28% yield).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[N-:10]=[N+:11]=[N-:12].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]=[N+:11]=[N-:12])=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A mixture of 4-bromobenzyl bromide (54) and sodium azide (2.0 equiv.) in DMF was stirred at 50° C. for 3 h. The reaction mixture was diluted with water and extracted with CH2Cl2. The combined organic extract was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography to yield 55 as colorless oil in 92% yield.
Reaction SMILES: CN(C)C1C=CC([C:7]([C:9]2[C:17]([Cl:18])=[C:16]([Cl:19])[C:15]([Cl:20])=[C:14]([Cl:21])[C:10]=2[C:11]([OH:13])=[O:12])=O)=CC=1.C(N(CC)C1C=CC=C(N(CC)CC)C=1)C.C(OC(=O)C)(=O)C>CO>[Cl:18][C:17]1[C:16]([Cl:19])=[C:15]([Cl:20])[C:14]([Cl:21])=[C:10]2[C:9]=1[CH2:7][O:12][C:11]2=[O:13]
Reactant: CN(C)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)cc1
Agent: CCN(CC)c1cccc(N(CC)CC)c1
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: O=C1OCc2c(Cl)c(Cl)c(Cl)c(Cl)c21
Temperature: 91 °C

Procedure:
A mixture of 2-(4-(dimethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid (16.28 g.), N,N,N',N'-tetraethyl-m-phenylenediamine (9.68 g.) and acetic anhydride (10 ml.) was heated (at 91° C.) during two hours. Addition of methanol (20 ml., then 12 ml., then 10 ml.) afforded 3-(2,4-bis(diethylamino)phenyl)-3-(4-dimethylamino)phenyl)-4,5,6,7-tetrachlorophthalide (I: X=(CH3CH2)2N, Y2 =H, Y4 =(CH3)2N, Z4 =Z5 =Z6 =Z7 =Cl) in three fractions (m.p. 174°-176° C., m.p. 180°-181° C. and m.p. 180°-181° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[N:13]([O-])=O.[Na+].[C:17]1([CH:24]=[CH:23][CH:22]=[C:20]([OH:21])[CH:19]=1)[OH:18]>Cl.O.C(O)C>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([N:7]=[N:13][C:22]2[CH:23]=[CH:24][C:17]([OH:18])=[CH:19][C:20]=2[OH:21])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: O=N[O-]
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: Oc1cccc(O)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(N=Nc2ccc(O)cc2O)c([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 74 %

Procedure:
A solution of diazonium salt, obtained beforehand by diazotization of 67.2 g (equivalent to 0.4 mol) of 4-methoxy-2-nitroaniline contained in 150 ml of concentrated HCl with a sodium nitrite solution containing 28 g (equivalent to 0.4 mol) in 100 ml of water at 0°-5° C., was added at a temperature of between 5° and 10° C. and over one hour into a reactor containing 44 g (equivalent to 0.4 mol) of resorcinol dissolved in a mixture of 400 ml of ethanol and 400 ml of water. The mixture was maintained under stirring for 2 hours. The red precipitate was filtered off and then rinsed copiously with water. 86 g (yield: 74%) of the desired compound was thereby obtained.
Reaction SMILES: [OH-:1].[Li+].COC(=O)/C(/NC(=O)C1C=CC(C(NCC2C=CC=C(O)C=2)=O)=CC=1Br)=[CH:7]/[C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[O:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.CO>>[CH3:7][C:8]1[S:9][C:36]([CH:37]=[CH:38][C:39]([OH:35])=[O:1])=[C:11]([CH3:10])[N:12]=1
Reactant: C1CCOC1
Reactant: [OH-]
Reactant: COC(=O)/C(=C/c1nccs1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Br
Agent: [Li+]
Solvent: CO
Product: Cc1nc(C)c(C=CC(=O)O)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1N lithium hydroxide (0.3 mL, 0.3 mmol) is added to a solution of (Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(thiazol-2-yl)propenoic acid methyl ester (Example 332; 55.6 mg, 0.1 mmol) in tetrahydrofuran/methanol (2:1; 1 mL). After the solution is allowed to stir at room temperature for 16 h, the volatiles are evaporated in vacuo and the residue is purified by reverse phase HPLC (increasing percentages of acetonitrile in water containing 0.1% trifluoroacetic acid). The appropriate fractions are combined and evaporated to yield to give (Z)-2-[2,6-dimethyl-4-[5-[(1H-indol-4-yl)methylamino]tetrazol-1-yl]benzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid.
Reaction SMILES: [NH2:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]2[C:12]=1[CH2:13][CH2:14][C:15](=[O:23])[NH:16]2.O.[OH-].[Na+].[CH:27](O)=[O:28]>>[CH:27]([NH:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]2[C:12]=1[CH2:13][CH2:14][C:15](=[O:23])[NH:16]2)=[O:28]
Reactant: O=CO
Reactant: COc1ccc(-c2nc3ccccn3c2N)c2c1NC(=O)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(-c2nc3ccccn3c2NC=O)c2c1NC(=O)CC2

Procedure:
A solution of 5-(3-aminoimidazo[1,2-a]pyridine-2-yl)-8-methoxy-3,4-dihydrocarbostyril (5 g) in 90% formic acid (10 ml) was heated at 100° C. for 2 hours. After completion of reaction, water was added to the reaction mixture followed by neutralizing with 1 N sodium hydroxide. Crystals which precipitated were collected by filtration, washed with methanol and recrystallized from chloroform-methanol to give 3.05 g of 5-(3-formylaminoimidazo[1,2-a]pyridine-2-yl)-8-methoxy-3,4-dihydrocarbostyril.
Reaction SMILES: [CH2:1]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].O.[ClH:18].[CH3:19][N:20](C)[CH:21]=[O:22]>C(O)C>[ClH:18].[CH2:1]([N:11]1[CH2:12][CH2:13][N:14]([C:3]2[CH:5]=[C:6]3[C:19](=[CH:1][CH:2]=2)[NH:20][C:21](=[O:22])[CH2:8][CH2:7]3)[CH2:15][CH2:16]1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: CN(C)C=O
Reactant: CC(C)=CCC/C(C)=C/CN1CCNCC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)=CCC/C(C)=C/CN1CCN(c2ccc3c(c2)CCC(=O)N3)CC1
Reaction time: 24 h

Procedure:
127 Milligrams of succinimide 3,4-dihydrocarbostyril-6-carbostyril-6-carboxylate and 117 mg of geranylpiperazine were dissolved in 2 ml of dimethylformamide, and the solution was stirred for 24 hours. To the reaction mixture was added a certain amount of water and then extracted with chloroform, the chloroform layer was washed with water and an aqueous solution saturated with sodium chloride. Then the chloroform extract was dried with anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The residue thus obtained was crystallized by adding diethyl dether, and the crystals formed were dispersed in 20 ml of ethanol, then converted into hydrochloride by adding 1.3 ml of concentrated hydrochloric acid. Recrystallized from ethanol-water to obtain 132 mg of 6-(4-geranyl-1-Piperazinyl)-3,4-dihydrocarbostyril.hydrochloride.mono-hydrate. Colorless needle-like crystals. Melting point: 265°-266° C. (dec.)
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[O-:27][Mn](=O)(=O)=O.[K+].CCOC(C)=O.[OH2:39]>CC(C)=O>[O:39]=[C:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:18]([C:15]1[CH:14]=[CH:13][C:12]([C:8]2([NH:7][C:6](=[O:26])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:9][CH2:10][CH2:11]2)=[CH:17][CH:16]=1)=[O:27]
Reactant: O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C#Cc3ccccc3)cc2)CCC1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(=O)c3ccccc3)cc2)CCC1
Temperature: 35 °C

Procedure:
To a solution of tert-butyl{1-[4-(phenylethynyl)phenyl]cyclobutyl}carbamate (7-3, 6.65 g, 19.14 mmol) in anhydrous acetone (38.3 ml) was added KMnO4 (12.10 g, 77 mmol). The reaction mixture was heated to 35° C. for 2 hours. The reaction mixture was cooled to room temperature and EtOAc and water were added to the mixture. The suspension was filtered through a glass frit and the filtrate was extracted into EtOAc, washing with water and brine. The organic layer was dried over Na2SO4, filtered and reduced in vacuo to give 7-4 as a brown oil.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[CH3:13][CH:14]([CH2:16][CH2:17][CH2:18][C@H:19]([C@@H:21]1[C@:39]2([CH3:40])[C@H:24]([C@H:25]3[C@H:36]([CH2:37][CH2:38]2)[C@:34]2([CH3:35])[C:28]([CH2:29][C@H:30]([CH2:32][CH2:33]2)[OH:31])=[CH:27][CH2:26]3)[CH2:23][CH2:22]1)[CH3:20])[CH3:15].[OH:41][C:42]([CH2:45][CH2:46][CH2:47][C@H:48]([C@@H:50]1[C@]2(C)[C@H:53]([C@H:54]3[C@H](CC2)[C@:63]2(C)[C:57]([CH2:58][C@H:59]([CH2:61][CH2:62]2)O)=[CH:56][CH2:55]3)[CH2:52][CH2:51]1)C)(C)C.S([O-])(OCCCCCCCCCCCC)(=O)=O.[Na+]>>[CH3:63][CH2:62][CH2:61][CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]/[CH:54]=[CH:53]\[CH2:52][CH2:51][CH2:50][CH2:48][CH2:47][CH2:46][CH2:45][C:42]([O:31][C@@H:30]1[CH2:29][C:28]2[C@@:34]([CH3:35])([C@@H:36]3[C@@H:25]([CH2:26][CH:27]=2)[C@@H:24]2[CH2:23][CH2:22][C@H:21]([C@@H:19]([CH2:18][CH2:17][CH2:16][CH:14]([CH3:13])[CH3:15])[CH3:20])[C@@:39]2([CH3:40])[CH2:38][CH2:37]3)[CH2:33][CH2:32]1)=[O:41]
Reactant: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1

Procedure:
More specifically, cultured J774 cells were plated on a 24F culture plate containing a serum-free RPMI 1640 medium so as to account for 1×106 cells/well. Added to the cells were [14C]oleic acid, delipidized BAS (bovine serum albumin), reconstituted ribosome (0.3M glucose solution containing cholesterol and phosphatidylcholine at a weight ratio of 2:1) and 25-hydroxycholesterol to culture the cells for 4 hours at 37° C. under 5% CO2. After the culturing, the cultured cells were disrupted with a 1% SDS (sodium lauryl sulfate) solution, and the lipid in the disrupted solution was extracted with hexane. The extract was dried to solid under reduced pressure. After the resultant residue was then developed (developing solvent: diethyl ether/hexane/acetic acid=80/20/1) by TLC (thin-layer chromatography), the amount of cholesteryl oleate formed was determined by an imaging plate.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([CH:16]=[O:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:18]Cl.[Na+].[CH3:21][OH:22]>C(O)(=O)C>[CH3:1][O:8][C:9]([CH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]1)=[O:18].[CH3:21][O:22][C:16]([CH:13]1[CH2:12][CH2:11][CH:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:15][CH2:14]1)=[O:17]
Reactant: O=CC1CCC(COCc2ccccc2)CC1
Reactant: [O-]Cl
Reactant: CO
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)C1CCC(CO)CC1
Product: COC(=O)C1CCC(COCc2ccccc2)CC1
Temperature: 2.5 °C

Procedure:
4-Benzyloxymethyl-cyclohexanecarbaldehyde (1.70 g, 2.0 mmol) is dissolved in acetic acid (0.24 mL) and 2 mL of MeOH. The reaction mixture is cooled to 0-5° C. and stirred while 10% NaOCl solution (2.5 mL, 4 mmol) is added dropwise over 20 minutes. The cooling bath is removed and the mixture is allowed to come to room temperature. After addition of saturated aqueous NaHCO3, the aqueous layer is extracted with EtOAc. The combined organic layer (dried with MgSO4) is concentrated. The desired product, 4-benzyloxymethyl-cyclohexanecarboxylic acid methyl ester, is obtained (343 mg, 65%) after purification using silica gel column chromatography (eluent: EtOAc/hexane).