Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:8][CH2:7][C:6]2[CH:9]=[C:10]([CH2:13][OH:14])[CH:11]=[CH:12][C:5]=2[CH2:4][O:3]1.N1C=CN=C1.[C:21]([Si:25](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:24])([CH3:23])[CH3:22]>CN(C)C=O.O>[C:21]([Si:25]([O:14][CH2:13][C:10]1[CH:11]=[CH:12][C:5]2[CH2:4][O:3][C:2]([CH3:15])([CH3:1])[O:8][CH2:7][C:6]=2[CH:9]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC1(C)OCc2ccc(CO)cc2CO1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCc2ccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2CO1
Reaction time: 2 h

Procedure:
To a solution of 3.227 g (15.495 mM) of (7,7-dimethyl-5,9-dihydro-6,8-dioxabenzocyclohepten-2-yl)-methanol and 1.27 g (18.6 mM) of imidazole in 20 ml of N,N-dimethylformamide was added 4.69 g (17.0 mM) of tert-butylchlorodiphenylsilane at room temperature and the mixture was stirred for 2 hours. This reaction mixture was poured in water and extracted with 3 portions of diethyl ether. The pooled organic layer was dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=30/1) to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1.F[C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1>>[CH3:1][C:2]1[N:3]([C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=2)[CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1
Reactant: Cc1ccnc(F)c1
Reactant: Cc1nc(C#Cc2cccc(C#N)c2)c[nH]1
Product: Cc1ccnc(-n2cc(C#Cc3cccc(C#N)c3)nc2C)c1

Procedure:
The title compound, MS: m/e=299.2 (M+H+), was prepared in accordance with the general method of example 1 from 3-(2-methyl-1H-imidazol-4-ylethynyl)-benzonitrile and 2-fluoro-4-methylpyridine.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:14](I)=[CH:13][C:3]=1[CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C([Mg]Cl)(C)C.[Cl-].[Li+].[Cl:25][CH2:26][C:27](N(OC)C)=[O:28]>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:16]=[CH:15][C:14]([C:27](=[O:28])[CH2:26][Cl:25])=[CH:13][C:3]=1[CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(I)ccc1Br
Reactant: CON(C)C(=O)CCl
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cc(C(=O)CCl)ccc1Br
Temperature: 25 °C
Yield: 66.5 %

Procedure:
To a solution of (2-bromo-5-iodobenzyloxy)-(tert-butyl)dimethylsilane (8.7 g, 20.3 mmol) in tetrahydrofuran (135 mL) under argon at −20° C. was added i-propylmagnesium chloride-lithium chloride solution (1.3M in THF, 16.4 mL, 21.3 mmol). After stirring at this temperature for thirty minutes, a solution of 2-chloro-N-methoxy-N-methyl acetamide (3.4 g, 24.3 mmol) in tetrahydrofuran (5 mL) was added to the reaction via cannula. The reaction was stirred at −20° C. for one hour and then warmed to room temperature. After one hour at room temperature the reaction was diluted with ethyl acetate and the organics were washed with saturated aqueous NH4Cl solution, water and brine. The organic layer was dried (MgSO4) and concentrated, and the resulting residue was purified by flash chromatography to yield 1-(4-bromo-3-((tert-butyldimethylsilyloxy)methyl)phenyl)-2-chloroethanone (5.1 g, 67%).
Reaction SMILES: Cl/[C:2](/[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3]/[O-].[K+].S(=O)(=O)(O)O.O.[CH:17]([N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][N:32]=[C:31]([NH2:35])[CH:30]=2)[CH2:22][CH2:21]1)([CH3:19])[CH3:18]>CCOCC>[CH:17]([N:20]1[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][N:32]3[C:2]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][N:35]=[C:31]3[CH:30]=2)[CH2:24][CH2:25]1)([CH3:19])[CH3:18]
Reactant: CC(C)N1CCN(CCOc2ccnc(N)c2)CC1
Reactant: CCOC(=O)/C(Cl)=C\[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1cnc2cc(OCCN3CCN(C(C)C)CC3)ccn12
Temperature: 65 °C
Yield: 59.4 %

Procedure:
Potassium (E)-2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate (Preparation E; 41.32 g, 219.0 mmol) was suspended (through vigorous magnetic stirring) in anhydrous ether (365 mL) and 6N sulfuric acid (18.25 mL, 109.5 mmol) was added. Water (100 mL) was added to aid in phase separation. When the pH of the bottom (aqueous) phase, dropped below 3, the ether layer was separated. The aqueous phase was further extracted with ether (400 mL). The combined ether phases were dried over sodium sulfate and magnesium sulfate for 10 minutes. The solution was filtered and concentrated under reduced pressure, with the temperature of the water bath not exceeding 20° C. A residual oil was obtained, which crystallized upon drying under high vacuum overnight. This residue was dissolved in absolute EtOH (360 mL). 4-(2-(4-Isopropylpiperazin-1-yl)ethoxy)pyridin-2-amine (Preparation G; 28.95 g, 109.5 mmol) was added, and the mixture was heated under nitrogen at 65° C. for 18 hours. After allowing the mixture to cool, the resulting suspension was evaporated to dryness. The resulting solids were shaken with THF and collected by filtration, then dried under vacuum. This material (HCl salt) was mixed with water (400 mL) and ethanol (200 mL). Sodium bicarbonate (20 g) was added and the mixture was stirred for 16 hours (some effervescence occurred). The suspension was evaporated to dryness under vacuum. The solids were shaken in EtOAc/THF and filtered. These solids were washed with a large volume of ethyl acetate and THF. The organic solution was further dried with sodium sulfate and magnesium sulfate, filtered and evaporated under vacuum to give an amber gum. This material was triturated with 2:1 ether-hexanes, and the resulting solids were collected by filtration to afford ethyl 7-(2-(4-isopropylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (23.46 g, 59% yield) as beige solids.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[O:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][N:31]=1>>[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[O:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:32][N:31]=1
Reactant: COc1ncc(B(O)O)cn1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3o2)CC1
Product: COc1ncc(-c2nc(N3CCOCC3)c3oc(CN4CCN(S(C)(=O)=O)CC4)cc3n2)cn1

Procedure:
2-Chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinofuro[3,2-d]pyrimidine (Example 153) was reacted with 2-methoxypyrimidine-5-boronic acid via General Procedure E to give, after purification by reverse HPLC, 4 mg of 237. MS (Q1) 490 (M+).
Reaction SMILES: Cl.[NH:2]=[C:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH3:8].[Cl:9][C:10]1[CH:11]=[C:12]([N:17]=[C:18]=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16]>C1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]([NH:17][C:18]([N:2]=[C:3]2[CH2:7][CH2:6][CH2:5][N:4]2[CH3:8])=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: CN1CCCC1=N
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: c1ccccc1
Product: CN1CCCC1=NC(=O)Nc1ccc(Cl)c(Cl)c1

Procedure:
A 6.73 g. (0.05 mole) sample of 2-imino-1-methylpyrrolidine HCl is converted to free base in the usual way. To the K 2 CO 3 -dried, benzene extracts are added a pre-filtered solution of 3,4 -dichlorophenylisocyanate (9.4 g.; 0.05 mole). Almost immediately there is a separation of product. After stirring for a short time, the product is collected and recrystallized from acetone-methanol-water and finally from acetone-water to give the pure product, 1(3,4-dichlorophenyl)-3-(1-methyl-2-pyrrolidylidene)urea. m.p. = 160°-⪆°C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[N:11]([CH2:21][C:22]([O:24]CC2C=CC=CC=2)=[O:23])[CH2:10][C@H:9]1[CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[N:11]([CH2:21][C:22]([OH:24])=[O:23])[CH2:10][C@H:9]1[CH3:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(CC(=O)OCc2ccccc2)[C@@H](CN2CCCC2=O)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(CC(=O)O)[C@@H](CN2CCCC2=O)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
(2R,5S)-4-Benzyloxycarbonylmethyl-2-methyl-5-(2-oxo-pyrrolidin-1-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (4.29 g, 9.64 mmol) and 10% Pd/C (1.35 g, 1 mmol) in EtOAc (45.9 mL) were hydrogenated at room temperature and 1 bar. After stirring for 30 minutes, the reaction was filtered and solids washed with EtOAc. The filtrate was evaporated in vacuo and the residue azeotroped with toluene to give the title compound (2.9 g,). MS: [M+H]+=356.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8]Br.[CH:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[C:16]([SH:21])[CH:17]=[CH:18]2)=[CH:13][CH:12]=1.C(N(CC)CC)C>C(OCC)C>[CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:21][C:16]1[CH:17]=[CH:18][C:19]2[C:14](=[CH:13][CH:12]=[CH:11][CH:20]=2)[CH:15]=1
Reactant: COC(=O)C=CC=CCBr
Reactant: Sc1ccc2ccccc2c1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)C=CC=CCSc1ccc2ccccc2c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a solution of 6-bromo-hexa-2,4-dienoic acid methyl ester (1.57 g, 7.66 mmol) and 2-thionaphthol (1.35 g, 8.42 mmol) in diethyl ether (40 mL) was added dropwise triethylamine (1.40 mL, 10.0 mmol) under an atmosphere of argon. The mixture was stirred for one hour 20° C. and filtered. The filtrate was washed saturated aqueous sodium hydrogen carbonate (25 mL), demineralised water (25 mL) and brine (25 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give a yellow oil that was purified by column chromatography (9:1 to 8:2 40-60° C. petroleum ether:diethyl ether). Recrystallisation from diethyl ether/petroleum ether afforded the title compound (1.9 g, 88%) as a white solid, mp 73-75° C.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][N:9]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:22]=[CH:21][C:7]([CH2:8][N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CN2CCNCCNCCNCC2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(CN2CCNCCNCCNCC2)cc1
Reaction time: 0.75 h

Procedure:
In 10 ml of methanol was dissolved 690 mg (2.25 mmole) of 1-(4-nitrobenzyl)-1,4,7,10-tetraazacyclododecane (prepared by the procedure of Example H). To the solution was added 350 mg of 10 percent palladium on carbon catalyst. Excess hydrogen was purged through the solution at 25° C. Within 45 minutes TLC indicated that the title product was prepared (Rf =0.33, Solvent System 3). Chromatographic purification of the formed titled product was conducted on 1 in.×16 in. flash silica column (Solvent System 3) and provided 480 mg (77 percent) of the title product as a pale yellow, clear oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[CH3:16][O:17][CH2:18][CH2:19][NH:20][CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:16][O:17][CH2:18][CH2:19][N:20]([CH3:21])[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1
Reactant: COC(=O)c1oc2ccc(Br)cc2c1C
Reactant: CNCCOC
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COCCN(C)c1ccc2oc(C(=O)OC)c(C)c2c1
Temperature: 25 °C

Procedure:
To a solution (50 mL) of methyl 5-bromo-3-methyl-1-benzofuran-2-carboxylate (2.7 g) synthesized in Example A186(1) in toluene were added 2-methoxy-N-methylethanamine (2.7 g), cesium carbonate (9.8 g), tris(dibenzylideneacetone)dipalladium (0) (0.69 g) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.87 g), and the mixture was heated under reflux under argon atmosphere for 6 hr. The reaction mixture was cooled to room temperature, and filtered through celite, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (2.7 g, quantitative) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1.C(OC(=O)C)(=O)C.C(N(CC)CC)C>C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[CH:18][C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: O=Cc1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)C(=Cc1ccncc1)c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
To mixture of (4-Chloro-phenyl)-acetic acid 9.78 g and pyridine-4-carbaldehyde 6.14 g was added acetic anhydride 20 mL and triethyl amine 20 mL. The reaction mixture was heated to 120° C. for 24 hours and cooled down to room temperature. Water and ethyl acetate were added. The solids formed was filtered, washed with water and ethyl acetate and dried to afford the title compound as a light yellow solid. MS (ES+): 260 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[CH:6]2.[CH2:13](B(CC)CC)[CH3:14].[K].ICC.[OH-].[Na+].[O-][O-].[Na+].[Na+]>C1COCC1.ClCCl.O>[CH2:13]([C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=[N:8][CH:7]=1)[CH3:14]
Reactant: CCB(CC)CC
Reactant: COc1ccc2cnccc2c1
Agent: [K]
Agent: [Na+]
Agent: [O-][O-]
Solvent: O
Solvent: ClCCl
Solvent: CCI
Product: CCc1cncc2ccc(OC)cc12
Temperature: 0 °C
Reaction time: 5 h

Procedure:
6 g of 6-Methoxy-isoquinoline (152) were dissolved in dry THF. Under argon a 1M solution of potassium triethylborane (37.7 mL) was added dropwise. The solution was stirred for five hours, then iodoethane (3.3 mL) was added dropwise. The solution was stirred overnight, cooled to 0° C. and 96 mL of 1N NaOH and 36 mL of 35% sodium peroxide were added. After gas evolution stopped, water and dichloromethane were added, the aqueous layer was extracted three times with dichloromethane the organic layer was dried over sodium sulfate and the solvent was removed in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[N:21][CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=1[OH:18])=O.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Cl:13][C:11]1[C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]2[O:18][C:4]([C:3]3[CH:19]=[CH:20][N:21]=[CH:22][C:2]=3[Cl:1])=[N:6][C:7]=2[CH:12]=1
Reactant: O=C(Nc1cc(Cl)c(C(F)(F)F)cc1O)c1ccncc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cc2oc(-c3ccncc3Cl)nc2cc1Cl
Reaction time: 1.5 h
Yield: 58.2 %

Procedure:
To a mixture of 0.67 g of 3-chloro-N-[5-chloro-2-hydroxy-4-(trifluoromethyl)phenyl]isonicotinamide, 7 ml of tetrahydrofuran and 0.55 g of triphenylphosphine, 0.91 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature. The reaction mixture was stirred for 1.5 hours. To the mixture, 0.14 g of triphenylphosphine and 0.23 g of 40% toluene solution of diethyl azodicarboxylate were added and stirred for further one hour. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the resultant crystals were washed with isopropanol and hexane to give 0.37 g of 5-chloro-2-(3-chloropyridin-4-yl)-6-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 79”).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.O1CCCC1.[CH2:29]([O:36][C:37]1[CH:61]=[CH:60][C:59]([CH:62]2[CH2:67][CH2:66][N:65]([CH2:68][CH2:69][O:70][Si](C(C)(C)C)(C)C)[CH2:64][CH2:63]2)=[CH:58][C:38]=1[C:39]([NH:41][C:42]1[CH:51]=[C:50]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:49]=[CH:48][C:43]=1[C:44]([O:46][CH3:47])=[O:45])=[O:40])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>C(OCC)(=O)C>[CH2:29]([O:36][C:37]1[CH:61]=[CH:60][C:59]([CH:62]2[CH2:63][CH2:64][N:65]([CH2:68][CH2:69][OH:70])[CH2:66][CH2:67]2)=[CH:58][C:38]=1[C:39]([NH:41][C:42]1[CH:51]=[C:50]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:49]=[CH:48][C:43]=1[C:44]([O:46][CH3:47])=[O:45])=[O:40])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCN(CCO[Si](C)(C)C(C)(C)C)CC2)ccc1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCN(CCO)CC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.6 %

Procedure:
A 1.0 mol/L tetrabutylammonium fluoride-tetrahydrofuran solution (0.38 mL) was added to a tetrahydrofuran (1.3 mL) solution of the obtained methyl 2-(2-(benzyloxy)-5-(1-(2-(tert-butyldimethylsilyloxy)ethyl)piperidin-4-yl)benzamido)-4-phenylbenzoate (0.13 g), followed by stirring at room temperature for 4 hours. Under ice-cooling, water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-92% chloroform/methanol] to obtain 0.085 g of methyl 2-(2-(benzyloxy)-5-(1-(2-hydroxyethyl)piperidin-4-yl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: C([NH:8][C:9]1[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[C:12]2[O:13][CH2:14][CH:15]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=3)[C:11]=2[C:10]=1[CH3:31])C1C=CC=CC=1>CCCCCC.C(OCC)(=O)C>[CH:22]([C:19]1[CH:18]=[CH:17][C:16]([CH:15]2[CH2:14][O:13][C:12]3[C:25]4[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=4[C:9]([NH2:8])=[C:10]([CH3:31])[C:11]2=3)=[CH:21][CH:20]=1)([CH3:24])[CH3:23]
Reactant: Cc1c(NCc2ccccc2)c2c(c3c1C(c1ccc(C(C)C)cc1)CO3)CCCC2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(N)c2c(c3c1C(c1ccc(C(C)C)cc1)CO3)CCCC2
Yield: 76 %

Procedure:
Using N-benzyl-3-(4-isopropylphenyl)-4-methyl-2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan-5-amine synthesized in Reference Example 289, the title compound was synthesized in the same manner as in Reference Example 30. Yield 76%. Melting point: 106-107° C. (hexane-ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([NH:15]C(=O)OC(C)(C)C)=[CH:11][CH:10]=2)[S:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:5]2[S:4][N:3]=[C:2]([Cl:1])[C:6]=2[C:7]#[N:8])=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2snc(Cl)c2C#N)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c(Cl)nsc1-c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-Butyl 4-(3-chloro-4-cyanoisothiazol-5-yl)phenylcarbamate (4.76 g, 13.38 mmol) in DCM (100 ml) was treated with 10 mL of TFA. The reaction mixture was stirred at RT overnight. Solvent was removed in vacuo. The residue was diluted with water and DCM (100 ml). Layers were separated and the aqueous layer was extracted with DCM×2. The combined organics was washed with brine and dried with MgSO4, filtered, and concentrated. Product was rinsed with Et2O/hexanes and collected by filtration as a bright yellow solid (3.15 g, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].N1C=CC=CC=1.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[C:31]([O:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:5]1[C:4](=[O:24])[C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[C:7](=[O:11])[C:6]=1[CH3:12])(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: COC1=C(OC)C(=O)C(CCCCCCCCCCO)=C(C)C1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCOC(C)=O)=C(C)C1=O

Procedure:
2,3-Dimethoxy-6-(10-hydroxydecyl)-5-methyl-1,4-benzoquinone (3.38 g) was dissolved in dichloromethane (50 ml). Pyridine (1 ml) was added, and acetyl chloride (0.8 ml) was added with stirring under ice-cooling. After stirring for 1 hour at the same temperature, the mixture was washed with 0.1N hydrochloric acid (50 ml) followed by water (50 ml). The dichloromethane layer was concentrated under reduced pressure to obtain 6-(10-acetoxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone as a red oil. This oil was dissolved in ether (50 ml), and a solution of sodium hydrosulfite (4 g) in water (50 ml) was added. Stirring was continued at room temperature until the red color of the ether layer disappeared. The ether layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired compound (3.8 g) as a pale yellow oil.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][C@@H:12]([CH2:15][CH2:16][C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][C:20]=2[F:31])=[O:18])[C@@H:11]([C:32]([O:34][CH3:35])=[O:33])[CH2:10]1)=O)(C)(C)C.[OH-].[Na+]>C(OCC)(=O)C.CO>[F:31][C:20]1[CH:21]=[N:22][C:23]2[C:28]([C:19]=1[C:17](=[O:18])[CH2:16][CH2:15][C@@H:12]1[CH2:13][CH2:14][NH:9][CH2:10][C@@H:11]1[C:32]([O:34][CH3:35])=[O:33])=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2
Reactant: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1CCC(=O)c1c(F)cnc2ccc(OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@H]1CNCC[C@H]1CCC(=O)c1c(F)cnc2ccc(OC)cc12
Temperature: 20 °C
Reaction time: 4 h
Yield: 86.1 %

Procedure:
9 cm3 of a 4N solution of hydrochloric acid in ethyl acetate and 10 cm3 of MeOH are added, at a temperature in the region of 20° C., to 4 g (7.23 mmol) of methyl (3R,4R)-1-tert-butyloxycarbonyl-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-oxopropyl]piperidine-3-carboxylate in solution in 20 cm3 of ethyl acetate. After stirring for 4 hours at a temperature in the region of 20° C., the reaction mixture is diluted with 25 cm3 of ethyl acetate and a 5N aqueous sodium hydroxide solution is then added in order to adjust the pH of the aqueous phase to a value of between 8 and 8.5. The organic phase is separated after settling out and the aqueous phase is then extracted with 3 times 40 cm3 of ethyl acetate. The organic phases are pooled, washed with 2 times 50 cm3 of a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (2.7 kPa) to give 2.33 g of methyl (3R,4R)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-oxopropyl]-piperidine-3-carboxylate in the form of an orange oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:12]2[CH:18]=C(C#N)[S:16][C:13]=2[NH:14][N:15]=1.S(=O)(=O)(O)O.[C:26]([OH:29])(=[O:28])[CH3:27]>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:12]2[CH:18]=[C:27]([C:26]([OH:29])=[O:28])[S:16][C:13]=2[NH:14][N:15]=1
Reactant: CC(=O)O
Reactant: N#Cc1cc2c(-c3ccc4ccccc4c3)n[nH]c2s1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cc2c(-c3ccc4ccccc4c3)n[nH]c2s1
Temperature: 110 °C

Procedure:
To a solution of 33 mg of 3-(naphthalen-2-yl)-1H-thieno[2,3-c]pyrazole-5-carbonitrile in 1.0 mL of acetic acid and 0.3 mL of water was added 0.3 mL of concentrated sulfuric acid at room temperature and stirred at 110° C. for a day. After cooling the solution to room temperature, 10 mL of ice water was added, and the precipitated crystals were collected by filtration and washed with water, to afford 33 mg of the title compound as pale brown crystals.