Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:32][C:10]3([CH2:15][CH2:14][N:13]([C:16]4[S:17][C:18]([C:21]5[N:22]=[N:23][N:24]([CH2:26][C:27]([O:29]CC)=[O:28])[N:25]=5)=[CH:19][N:20]=4)[CH2:12][CH2:11]3)[CH:9]=2)=[CH:4][CH:3]=1.FC1C=CC(C2C3C(=CC=CC=3)OC3(CCNCC3)C=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C(Cl)Cl.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:32][C:10]3([CH2:11][CH2:12][N:13]([C:16]4[S:17][C:18]([C:21]5[N:22]=[N:23][N:24]([CH2:26][C:27]([OH:29])=[O:28])[N:25]=5)=[CH:19][N:20]=4)[CH2:14][CH2:15]3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cn1nnc(-c2cnc(N3CCC4(C=C(c5ccc(F)cc5)c5ccccc5O4)CC3)s2)n1
Agent: Fc1ccc(C2=CC3(CCNCC3)Oc3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: CO
Product: O=C(O)Cn1nnc(-c2cnc(N3CCC4(C=C(c5ccc(F)cc5)c5ccccc5O4)CC3)s2)n1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Step 3 Ethyl 2-(5-(2-(4-(4-fluorophenyl)spiro[chromene-2,4′-piperidine]-1′-yl)thiazol-5-yl)-2H-tetrazol-2-yl)acetate In a pressure vial, a mixture of 4-(4-fluorophenyl)spiro[chromene-2,4′-piperidine] (128 mg, 0.433 mmol), Intermediate 4 (175 mg, 0.550 mmol) and K2CO3 (127 mg, 0.919 mmol) were suspended in dry DME (2 mL). The vial was sealed and the mixture was stirred under N2 at an external temperature of 110° C. for 2 h. The reaction mixture was then cooled to room temperature, and diluted with DCM/methanol and concentrated under reduced pressure in the presence of silica gel. The resulting solid residue was purified by Combiflash™ chromatography (SiO2 (12 g), eluting with 3-10% EtOAc/hexanes) to afford the title compound as a solid.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])/[C:2](=[CH:4]\[CH3:5])/[CH3:3].[CH3:9][CH:10]([CH:14]=C)[CH2:11][CH2:12]O.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCCCCCC)CCCCCCC.C([O-])(=O)CCCCCCCCCCC>C1(C)C=CC=CC=1>[C:1]([O:7][CH2:8][CH2:9][CH:10]([CH3:14])[CH:11]=[CH2:12])(=[O:6])/[C:2](=[CH:4]\[CH3:5])/[CH3:3]
Reactant: C/C=C(/C)C(=O)OC
Reactant: C=CC(C)CCO
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCCCCCC[Sn+2]CCCCCCCC
Solvent: Cc1ccccc1
Product: C=CC(C)CCOC(=O)/C(C)=C\C

Procedure:
A mixture of 22.8 g. of methyl angelate, 10.0 g. of 3-methyl-4-pentenol, 100 ml. of toluene and 0.9 g. of dioctyltin laurate was reacted under the same conditions as in Example 1. The resulting mixture was subjected to single distillation to give 16.91 g. of a distillate boiling at 109° C. (21 mmHg). The distillate was further subjected to rectification to give 12.54 g. of a distillate boiling at 109° C. (21 mmHg). Analysis of the compound by gaschromatography done under the same conditions as in Example 12 indicated a purity of 99.653% in terms of the area ratio. Refractive index was 1.443.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13](=N)OC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31][NH2:32])=[O:30])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]2[O:30][C:13]([CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:32][N:31]=2)=[CH:33][CH:34]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NNC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: COC(=N)CNC(=O)OCc1ccccc1
Solvent: CO
Product: O=C(NCc1nnc(-c2ccc(OCc3ccccc3)cc2)o1)OCc1ccccc1

Procedure:
A solution of methyl 2-(((benzyloxy)carbonyl)amino)acetimidate (600 mg, 2.7 mmol) and 4-(benzyloxy)benzohydrazide (654 mg, 2.7 mmol) in methanol (45 mL) was heated at 80° C. in a sealed tube for 3 h. The solvent was removed under reduced pressure and the resulting residue was purified by chromatography (silica gel, heptane-ethyl acetate) to yield benzyl ((5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)methyl)carbamate. A solution of benzyl ((5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)methyl)carbamate (480 mg, 1.12 mmol) in 33% HBr in acetic acid (5 mL) was stirred for 1 h. Diethyl ether was added, and the supernatant was decanted. The process was repeated, and the resulting solid was collected by filtration to yield (5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)methanamine. A solution of (5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)methanamine (155 mg, 0.43 mmol), 7-(3-fluorophenoxy)-2-hydroxyheptanoic acid (110 mg, 0.43 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (99 mg, 0.52 mmol), DIPEA (0.224 mL, 1.3 mmol) and HOBt (70 mg, 0.52 mmol) in DMF (20 mL) was stirred overnight. The resulting mixture was diluted with NaHCO3 (saturated, aqueous) and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4) and concentrated to yield N-((5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)methyl)-7-(3-fluorophenoxy)-2-hydroxyheptanamide, which was in the next step used without further purification. To a solution of N-((5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)methyl)-7-(3-fluorophenoxy)-2-hydroxyheptanamide (190 mg, 0.37 mmol) in methylene chloride (5 mL) was added 1,1,1-tris(acetyloxy)1,1-dihydro-1,2-benziodoxol-3-(1H)-one (233 mg, 0.55 mmol) and the resulting mixture was stirred overnight, then quenched with excess sodium thiosulfate in saturated aqueous sodium bicarbonate. The mixture was then extracted twice with ethyl acetate and the combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by chromatography (silica gel, heptane-ethyl acetate) to yield the title compound. 1H NMR (400 MHz, CDCl3) δ 6.60-8.10 (overlapping m, 14H), 5.15 (s, 2H), 4.75-4.85 (m, 2H), 3.85-4.00 (m, 2H), 2.90-3.10 (m, 2H), 1.50-1.90 (m, 6H).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[CH2:11](O)[CH3:12]>S(=O)(=O)(O)O>[CH2:11]([O:9][C:8](=[O:10])[C@H:2]([CH2:3][CH2:4][CH2:5][CH2:6][NH2:7])[NH2:1])[CH3:12]
Reactant: CCO
Reactant: NCCCC[C@H](N)C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@@H](N)CCCCN
Temperature: 90 °C
Yield: 76.5 %

Procedure:
A solution of 2.2 g of L-lysine in 13.0 ml of ethyl alcohol and 1.6 ml of conc. sulfuric acid was heated under reflux at 90° C. for 5 hours, obtaining L-lysine ethyl ester in a yield of 76.5%. Separately, L-methionine ethyl ester was prepared from 0.8 g of L-methionine in the same manner as in Example 1. After 66 mg of papain and 6.6 mg of L-cysteine were dissolved in a solution of 1.8 g of sodium carbonate and 0.52 g of sodium hydrogen carbonate in 20 ml of water, 20 g of wheat gluten in limited amounts was added to the solution and mixed therewith. The previously prepared reaction solutions of L-lysine and L-methionine ethyl esters were all added to the protein system of wheat gluten, and the system was kept at 37° C. for 24 hours to effect plastein reaction. The rates of incorporation of L-lysine and L-methionine were 62.7% and 81.6%, respectively. At the end of the reaction, the reaction solution was diluted with water to a volume of 300 ml and adjusted to pH 7 with hydrochloric acid before it was subjected to repeated concentration operations for desalting and purification using a reverse osmosis membrane equipped small experimental apparatus (equipped with a DRS-10 flat membrane, manufactured by Daicell Chemical K.K.) under an operating pressure of 15 kg/cm2. The concentrate resulting from the reverse osmosis treatment was again diluted with water to a volume of 400 ml and adjusted to pH 2.0 with phosphoric acid. After 0.4 g of pepsin was added to the solution, the hydrolytic reaction was carried out for 3 hours. Thereafter, 0.4 g of orientase was added and the hydrolytic reaction was continued for an additional 30 hours. The reaction solution was heated to 90° C. for 10 minutes and then centrifuged under 2000G to remove the solids. The supernatant was freeze dried to yield 18.3 g of a low-molecular weight peptide mixture. This product had an average molecular weight of 350 and contained 8.9% of free amino acids, and the gel filtration showed that it contained 86.2% of compounds with a molecular weight of 700 or lower. Table 2 shows the amino acid composition of the starting protein, wheat gluten and the low-molecular weight peptide mixture produced therefrom. As seen from Table 2, the low-molecular weight peptide mixture had the increased contents of L-lysine and L-methionine as compared with the starting protein.
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:7][C:6](=O)[CH2:5][C:4]([CH3:10])([CH3:9])[P:3]1[C:11]1[N:15]([C:16]2[C:17]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:18][N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:14]=[CH:13][CH:12]=1.C(O)COCCO.O.NN.[OH-].[K+]>CCCCCCC.C(OCC)(=O)C>[C:27]1([N:19]2[C:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[C:16]([N:15]3[C:11]([P:3]4[C:2]([CH3:39])([CH3:1])[CH2:7][CH2:6][CH2:5][C:4]4([CH3:10])[CH3:9])=[CH:12][CH:13]=[N:14]3)[C:17]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[N:18]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC1(C)CC(=O)CC(C)(C)P1c1ccnn1-c1c(-c2ccccc2)nn(-c2ccccc2)c1-c1ccccc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC1(C)CCCC(C)(C)P1c1ccnn1-c1c(-c2ccccc2)nn(-c2ccccc2)c1-c1ccccc1
Temperature: 210 °C
Reaction time: 7 h
Yield: 68 %

Procedure:
A round bottom flask was charged with 2,2,6,6-tetramethyl-1-(1′,3′,5′-triphenyl-1′H-1,4′-bipyrazol-5-yl)phosphinan-4-one (1.25 g, 2.35 mmol, 1.0 equiv) and purged with nitrogen for 15 minutes. Then nitrogen-sparged diethylene glycol (12.3 mL, 129 mmol, 55 equiv) was added and the flask was equipped with a Claisen adapter and a Dean-Stark trap. The mixture was charged with hydrazine hydrate (1.07 mL, 11.7 mmol, 5 equiv, 55 wt % hydrazine) and potassium hydroxide (658 mg, 11.7 mmol, 5 equiv). The mixture was immersed in an oil bath at 125° C. under a nitrogen atmosphere. The temperature of the bath was increased to 210° C. over 1 hour and kept at that temperature for 7 hours. The reaction mixture was cooled to room temperature under a positive pressure of nitrogen, and then diluted with heptane (10 mL) and ethyl acetate (10 mL). The phases were partitioned, and the aqueous layer was collected. The aqueous layer was then washed with ethyl acetate (2×20 mL), and the combined organic fractions were washed once with aqueous saturated sodium chloride (50 mL), dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The crude concentrate was dissolved in a minimal amount of hot ethanol, and the solution was allowed to cool, effecting the crystallization of the product as a white solid. (826 mg, 95 area % by HPLC, 68% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.91 (d, J=1.9 Hz, 1H), 7.52-7.42 (m, 4H), 7.38-7.26 (m, 3H), 7.25-7.19 (m, 5H), 7.19-7.11 (m, 3H), 6.61 (d, J=1.8 Hz, 1H), 1.53 (dd, J=14.1, 12.0 Hz, 5H), 1.21 (ddd, J=24.9, 11.7, 5.7 Hz, 2H), 0.85 (dd, J=24.4, 18.8 Hz, 6H), 0.01 (d, J=11.6 Hz, 3H), −0.27 (d, J=11.5 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ ppm 149.3 (d, J=2 Hz), 145.0, 143.2 (d, J=27 Hz), 141.0 (d, J=2 Hz), 139.8, 139.6 (d, J=2 Hz), 131.5, 129.5, 128.5, 128.3, 128.0, 127.9, 127.8, 127.3, 127.2, 125.1, 120.9, 113.0 (d, J=5 Hz), 37.1 (dd, J=8, 2 Hz), 29.9, 29.8, 29.3 (d, J=2 Hz), 29.2 (d, J=2 Hz), 29.1 (d, J=2 Hz), 28.8 (d, J=2 Hz), 28.8 (d, J=8 Hz), 20.2. 31P NMR (CDCl3, 202 MHz) δ ppm −17.0 (s). LRMS (ESI+) found for [M+H, C33H36N4P]+ 519.2.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]3)[CH:3]=1.[Br:19]Br.C(O)(=O)C.C(N(CC)CC)C>CCOCC>[Br:19][C:12]1[C:13](=[O:18])[NH:14][C:15]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1)=[CH:17][CH:16]=2
Reactant: O=c1ccc2cc(-c3cccnc3)ccc2[nH]1
Reactant: BrBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=c1[nH]c2ccc(-c3cccnc3)cc2cc1Br

Procedure:
A mixture of 6-(3-pyridyl)-2-(1H)-quinolone monohydrochloride (0.50 g), bromine (3.2 g), acetic acid (10 cm3) and triethylamine (0.195 g) was heated under reflux for 24 hours and then cooled. Ether (20 cm3) was then added to the cooled reaction mixture and the resulting yellow solid was filtered off. This material was purified by preparative layer chromatography eluting with chloroform:methanol, 15:1 (4 elutions), to afford 3-bromo-6-(3-pyridyl)-2-(1H)-quinolone, m.p. 297°-300°, (0.11 g).
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:16]1[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:23]1([SH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC(C)=O>CCOCC>[C:8]([C:16]1[N:20]=[C:19]([CH2:21][S:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:18][N:17]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Sc1ccccc1
Reactant: O=C(c1ccccc1)c1noc(CCl)n1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C(c1ccccc1)c1noc(CSc2ccccc2)n1
Reaction time: 1 h

Procedure:
A solution of 11.4 ml of triethylamine in 30 ml Et2O was added dropwise to a solution consisting of 9.0 g of 3-benzoyl-5-chloromethyl-1,2,4-oxadiazole, 4.2 ml of thiophenol, 20 ml of acetone and 80 ml of Et2O at room temperature. The resulting mixture was stirred for one hour. The reaction mixture was diluted with Et2O, washed with 5% HCl (2×), water (2×) and brine, and dried over MgSO4. Concentration gave 11.5 g of an oil. Purification by high pressure liquid chromatography with 70% CH2Cl2 /hexane as an eluent yielded 10.3 g (84%) of an oil.
Reaction SMILES: Br[C:2]1[C:3](=[O:8])[CH2:4][CH2:5][C:6]=1[CH3:7].C([O-])([O-])=O.[K+].[K+].[C:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)#[N:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:7][C:6]1[CH2:5][CH2:4][C:3](=[O:8])[C:2]=1[C:20]1[CH:21]=[CH:22][C:17]([C:15]#[N:16])=[CH:18][CH:19]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC1=C(Br)C(=O)CC1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1=C(c2ccc(C#N)cc2)C(=O)CC1
Temperature: 80 °C

Procedure:
2-Bromo-3-methyl-cyclopent-2-enone (Intermediate TEN1) (commercially available from Aldrich) (2.04 g, 11.4 mmol) and K2CO3 (3.16 g in 11 mL H2O) in toluene (45 mL) was treated with a solution 4-cyanophenylboronic acid (commercially available from Aldrich) (2.2 g, 15 mmol) in EtOH (27 mL). Tetrakis(triphenylphosphine)palladium(0) Pd(PPh3)4 (0.4 g), bis(dibenzylideneacetone)palladium(0), Pd2(dba)3 (0.055 g, ˜5 mol %) and triphenylphosphine (0.4 g) were added and the mixture was purged with N2 for 15 m. The mixture was heated to 80° C. for 15 h. The mixture was diluted with water and EtOAc:hexane. After extracting with EtOAc:hexane, the combined organic layers were dried over MgSO4, filtered and evaporated to dryness. The crude oil was purified by column chromatography on silica gel with CH2Cl2 to give 4-(2-methyl-5-oxo-cyclopent-1-enyl)-benzonitrile (Intermediate TEN2) 1.74 g.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([C:10](O)=[O:11])[CH:7]=[CH:6][N:5]=1.[H][H].B(F)(F)F.CCOCC.Cl>O1CCCC1>[Br:3][C:4]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][N:5]=1
Reactant: [H][H]
Reactant: O=C(O)c1ccnc(Br)c1
Agent: Cl
Agent: FB(F)F
Agent: [BH4-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1ccnc(Br)c1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
17.4 g of sodium borohydride was suspended in 1.6 liters of tetrahydrofuran, and the suspension was stirred by a mechanical stirrer. The suspension was cooled with ice-water, and 62.2 g of 2-bromo-4-pyridinecarboxylic acid was added little by little. The mixture was heated to room temperature, and stirred until evolution of hydrogen ceased. A solution of 75.8 ml of boron trifluoride etherate in 500 ml of tetrahydrofuran was added dropwise at room temperature for 3 hours. After the addition, the mixture was stirred for 20 hours. The reaction solution was cooled with ice-water, and acidified to a pH of 1 to 2 by adding 1.5N hydrochloric acid. Tetrahydrofuran was evaporated under reduced pressure. A 4N aqueous solution of sodium hydroxide was added to adjust the pH of the mixture to 10 to 11. It was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium chloride. The aqueous layer was further extracted with ethyl acetate twice. The organic layers were combined, and dried over anhydrous sodium sulfate. The dried product was concentrated under reduced pressure to give 51.3 g of 2-bromo-4-pyridinemethanol in a yield of 88%.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH:15]=[CH2:16])=[O:14])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH:17]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)=[O:18].C(N(CC)CC)C>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[CH3:26][O:25][C:23]([C:22]1[CH:27]=[CH:28][C:19]([C:17](=[O:18])[CH2:16][CH2:15][C:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:12][CH:11]=2)=[O:14])=[CH:20][CH:21]=1)=[O:24]
Reactant: C=CC(=O)c1ccc(OCCCCC)cc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCCOc1ccc(C(=O)CCC(=O)c2ccc(C(=O)OC)cc2)cc1
Yield: 81.8 %

Procedure:
A suspension of 1-(4-n-pentyloxyphenyl)acrolein (2.38 g), methyl 4-formylbenzoate (1.97 g), 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride and triethylamine (0.91 ml) in ethanol (10 ml) was refluxed for 18 hours. After cooling, the solvents were removed under reduced pressure. The solids were taken up in 1N HCl and extracted with dichloromethane. The organic layer was washed successively with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with diisopropyl ether, collected by filtration and dried under reduced pressure to give 1-(4-methoxycarbonylphenyl)-4-(4-n-pentyloxyphenyl)butane-1,4-dione (3.41 g).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([CH3:11])=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:4].C([Li])CCC.[CH3:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28]>O1CCCC1.CCCCCC>[OH:23][C:22]1([CH2:11][C:6]2[C:5]([C:3]([NH:2][CH3:1])=[O:4])=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:21]2[C:20](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19](=[O:28])[N:18]1[CH3:17]
Reactant: CNC(=O)c1ccccc1C
Reactant: CN1C(=O)c2ccccc2C1=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CNC(=O)c1ccccc1CC1(O)c2ccccc2C(=O)N1C
Reaction time: 2 h

Procedure:
A solution of 29.8 grams (0.2 mole) of N-methyl-o-toluamide in 600 milliliters of dry tetrahydrofuran is treated dropwise with 275 milliliters (0.44 mole) of n-butyl lithium in hexane, while maintaining the temperature at 0° C. to 10° C. After the addition is complete, the mixture is stirred at 0° C. to 10° C. for 2 hours. The cooling bath is removed and a solution of 32.2 grams (0.2 mole) of N-methyl phthalimide in 330 milliliters of tetrahydrofuran is added dropwise. The temperature is maintained at 20° - 25° C. during the addition, afterwhich it is stirred for 11/2 hours at room temperature. The resulting mixture is cooled in ice and quenched by the addition of saturated ammonium chloride. The layers are separated and the organic layer is washed with ammonium chloride solution, dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting oil is crystallized from ethyl acetate to give α-(1-hydroxy-2-methyl-3-oxoisoindolin-1-yl)-N-methyl-o-toluamide, m.p. 175.5 - 177.5.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=1
Reactant: COC(=O)COc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)COc1ccc(N)cc1
Yield: 97.6 %

Procedure:
A procedure similar to that described in Example 6 was repeated, except that 30.8 g of methyl 4-nitrophenoxyacetate (prepared as described in Preparation 36), 5.0 g of 10% w/w palladium-on-charcoal and 500 ml of methanol were used, to give 25.8 g of the title compound having Rf=0.79 (on silica gel thin layer chromatography using ethyl acetate as the developing solvent).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>S(=O)(=O)(O)O>[Br:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]([I:1])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ccc(C(=O)O)c(Br)c1
Agent: O=S(=O)(O)O
Product: Cc1cc(Br)c(C(=O)O)cc1I
Temperature: 7.5 °C
Reaction time: 3 h

Procedure:
N-Iodosuccinimide (19.1 g) is added in portions to an ice-cold solution of 2-bromo-4-methyl-benzoic acid (18.4 g) dissolved in sulphuric acid (20 mL). The resulting mixture is stirred at 5-10° C. for 3 h before warming to room temperature overnight. Then, the mixture is poured on crushed ice and the resultant solution is extracted with ethyl acetate. The combined extracts are washed in succession with aqueous 10% Na2S2O3 solution (2×), water (3×), and brine (1×). After drying (MgSO4), the organic solvent is evaporated under reduced. The remaining solid is taken up in water and the resulting slurry is stirred at 70° C. for 5 min. The non-dissolving part is separated by filtration and dried to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[C:3]=1[OH:10].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](O)=[O:21])=[CH:15][CH:14]=1.B(F)(F)F.CCOCC>>[Cl:1][C:2]1[C:3]([OH:10])=[C:4]([CH3:9])[C:5]([OH:8])=[C:6]([C:20](=[O:21])[CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[CH:7]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: Cc1c(O)ccc(Cl)c1O
Agent: FB(F)F
Solvent: CCOCC
Product: COc1ccc(CC(=O)c2cc(Cl)c(O)c(C)c2O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-chloro-2-methyl-benzene-1,3-diol (1 eq) and p-methoxy phenyl acetic acid (1 eq) in boron trifluoride diethyl etherate (8 eq) was refluxed for 5 h, whilst stirring, under nitrogen. The solution was allowed to cool to room temperature, quenched with 10% NaOAc (aq) and left to stand overnight. The resultant precipitate was filtered, washed with water and dried to give 1-(5-chloro-2,4-dihydroxy-3-methyl-phenyl)-2-(4-methoxy-phenyl)-ethanone as a solid.
Reaction SMILES: [ClH:1].C[O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19]([C:21]3[S:29][C:24]4=[N:25][CH2:26][CH2:27][CH2:28][N:23]4[C:22]=3[CH:30]3[CH2:33][CH2:32][CH2:31]3)=[O:20])[CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)=[O:5]>Cl>[ClH:1].[C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19]([C:21]3[S:29][C:24]4=[N:25][CH2:26][CH2:27][CH2:28][N:23]4[C:22]=3[CH:30]3[CH2:33][CH2:32][CH2:31]3)=[O:20])[CH:15]=[CH:16][CH:17]=2)=[CH:10][CH:11]=1)([OH:5])=[O:3]
Reactant: COC(=O)c1ccc(-c2cccc(NC(=O)C3=C(C4CCC4)N4CCCN=C4S3)c2)cc1
Agent: Cl
Product: O=C(Nc1cccc(-c2ccc(C(=O)O)cc2)c1)C1=C(C2CCC2)N2CCCN=C2S1
Yield: 64.4 %

Procedure:
In 50 ml of 20% hydrogenchloride aqueous solution was dissolved 360 mg of N-[3-(4-methoxycarbonylphenyl)-phenyl]-3-cyclobutyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carboxamide hydrochloride obtained in Example 105, followed by stirring under heating 9 hours. Insoluble materials were collected by filtration. The mixture was washed with water and recrystallized from methanol-ethanol to obtain 225 mg of the titled compound.