Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[C@H:15]([CH:16]([CH3:18])[CH3:17])[CH2:14][O:13][C:12]2=[O:19])=[O:10])=[CH:4][CH:3]=1.[CH3:20][Si]([N-][Si](C)(C)C)(C)C.[Na+].CC(O)=O>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:20])[C:9]([N:11]2[C@H:15]([CH:16]([CH3:17])[CH3:18])[CH2:14][O:13][C:12]2=[O:19])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H]1COC(=O)N1C(=O)Cc1ccc(Cl)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)[C@@H]1COC(=O)N1C(=O)[C@H](C)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of (4R)-3-[(4-chlorophenyl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one (2.80 g, 9.96 mmol) in dry THF (80 mL) at −78° C. under argon, was added dropwise 1.0M solution of NaHMDS in THF (11.0 mL, 11.0 mmol) over a period of 10 min. After stirring at −78° C. for 1 h, Mel (1.9 mL, 30.0 mmol) was added. The resulting reaction mixture was stirred at −78° C. for 1 h and −40° C. for 2 h, quenched with HOAc (30.0 mmol) in ether (20 mL), filtered over celite. The filtrate was concentrated in vacuo and the residue was dissolved in CH2Cl2 (100 mL) and washed with H2O following by brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (5%–10% EtOAc in hexane) to give 1.58 g (5.35 mmol, 54%) of (4R)-3-[(2R)-2-(4-chlorophenyl)propanoyl]-4-isopropyl-1,3-oxazolidin-2-one: 1H NMR (400 MHz, CDCl3) δ 7.30–7.23 (m, 4H), 5.11 (q, 1H, J=7.9 Hz), 4.35 (quintet, 1H, J=3.7 Hz), 4.16–4.09 (m, 2H), 2.46–2.36 (m, 1H), 1.49 (d, 3H, J=7.3 Hz), 0.91 (apparent t, 6H, J=6.9 Hz); ESMS m/e: 296.1 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:8]1[C@@H:13]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:31]([N:33]([CH2:39][CH3:40])[CH2:34][CH2:35][C:36](O)=[O:37])[CH3:32].CCN(CC)CC.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[CH2:1]([C@H:8]1[C@@H:13]([O:14][CH2:15][C:16]2[CH:17]=[C:18]([C:26]([F:29])([F:27])[F:28])[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=2)[CH2:12][CH2:11][N:10]([C:36](=[O:37])[CH2:35][CH2:34][N:33]([CH2:39][CH3:40])[CH2:31][CH3:32])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2Cc2ccccc2)cc(C(F)(F)F)c1
Reactant: CCN(CC)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCC(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 42767.1 %

Procedure:
To a solution of the compound (0.15 g) obtained in Example 404, 3-diethylaminopropionic acid hydrochloride (0.078 mg), Et3N (0.150 ml) and HoBt.H2O (0.083 mg) in DMF (2 ml), WSC.HCl (0.138 mg) was added, and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and then the residue was dissolved in ethyl acetate. The organic layer was washed with an aqueous saturated sodium bicarbonate solution and brine, dried, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by preparative thin layer chromatography to obtain the title compound as pale yellow oil (0.100 g, 51%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[O:1][CH2:17][C:18]2[N:19]=[C:20]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[S:21][CH:22]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Oc1cccc(CCCn2ccnc2)c1
Reactant: ClCc1csc(-c2ccccc2)n1
Product: c1ccc(-c2nc(COc3cccc(CCCn4ccnc4)c3)cs2)cc1
Yield: 81 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(3-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-phenylthiazole to give 4-[3-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-phenylthiazole. The yield was 81%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 63-64° C.
Reaction SMILES: [F:1][C:2]1[C:3]([CH:21]=[O:22])=[C:4]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[C:5](N(C(C)C)C(C)C)=[O:6].[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:4]2[C:3]=1[CH2:21][O:22][C:5]2=[O:6]
Reactant: CC(C)N(C(=O)c1cc(C(F)(F)F)cc(F)c1C=O)C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C1OCc2c(F)cc(C(F)(F)F)cc21
Temperature: 30 °C
Reaction time: 0.83 h
Yield: 71 %

Procedure:
To a solution of 5.39 mmol 3-fluoro-2-formyl-N,N-diisopropyl-5-trifluoromethyl-benzamide in 17 ml ethanol was added portionwise 5.39 mmol sodium borohydride. The temperature was maintained at 30° C. with a water bath. The mixture was then stirred at room temperature for 50 minutes then cooled in an ice-water bath. Excess sodium borohydride was destroyed by adding HCl 2N. Ethanol was removed in vacuo. The residue was taken in 25 ml HCl 6N and refluxed at 120° C. for 2 hours. The mixture was cooled to room temperature and extracted 3 times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a white solid (71% yield). MS (m/e): 220.2 (M+, 100%)
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[C:27](O)(=[O:30])[CH2:28][CH3:29]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: CCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (71 mg, 74%), MS (ISP) m/z=385.4 [(M+H)+], mp 192° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydro chloride (intermediate B) (100 mg, 0.25 mmol) and propionic acid.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][CH2:10]1)=[O:8])C>C1COCC1.O>[CH3:18][C:17]([CH3:20])([CH3:19])[CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([C:7]([OH:8])=[O:6])[CH2:10][CH2:11]1
Reactant: CCOC(=O)C1CCN(CCC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)CCN1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
Lithium hydroxide monohydrate (1.37 g, 32.6 mmol) was added to a solution of 1-(3,3-dimethyl-butyl)-piperidine-4-carboxylic acid ethyl ester from Example E15.1 (7.16 g, 29.7 mmol) in THF (50 ml) and water (5 ml). The mixture was stirred at room temperature for 18 h then concentrated in vacuo. The residue was purified by flash chromatography on silica gel through an isolute (eluant; 90% dichloromethane:9% methanol:1% acetic acid) to yield the title compound (5.51 g, 87%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.[C:7](Cl)([Cl:9])=[O:8].C1(C)C=CC=CC=1>C(Cl)Cl>[Cl:9][C:7]([O:6][C@@H:3]1[CH2:4][CH2:5][O:1][CH2:2]1)=[O:8]
Reactant: O[C@@H]1CCOC1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(Cl)O[C@@H]1CCOC1
Temperature: 25 °C
Yield: 85 %

Procedure:
A stirred solution of (R)-tetrahydrofuran-3-ol (7.9 g, 90 mmol) in anhydrous CH2Cl2 (50 mL) under an N2 atmosphere was cooled in an ice bath, and a 20% solution of phosgene in toluene (134 mL, 270 mmol) was slowly added. The reaction was allowed to warm to room temperature overnight, and the solvent was removed under vacuum to afford (R)-tetrahydrofuran-3-yl chloroformate (12.1 g, 85%) as a clear liquid.
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5](=[CH:17]OCC)[C:6](=[O:16])[C:7]1[CH:12]=[C:11]([F:13])[C:10]([Cl:14])=[CH:9][C:8]=1Cl)C.[CH:22]1([NH2:25])[CH2:24][CH2:23]1>C(Cl)Cl>[Cl:14][C:10]1[CH:9]=[C:8]2[C:7]([C:6](=[O:16])[C:5]([C:4]([OH:3])=[O:21])=[CH:17][N:25]2[CH:22]2[CH2:24][CH2:23]2)=[CH:12][C:11]=1[F:13]
Reactant: NC1CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(Cl)cc1Cl
Solvent: ClCCl
Product: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4 (80 g) in methylene chloride (800 mL), cyclopropylamine (44.0 g) was added with cooling below 10° C. The mixture was stirred at room temperature for 1 h and evaporated to a dry mixture. To the dry mixture in dimethoxyethane (800 mL), a 60% sodium hydride-in-oil suspension (12.0 g) was added slowly with cooling and stirring. The mixture was heated at 80-85° C. for 3 h under nitrogen atmosphere. It was cooled and water (5 L) was added and the precipitate was filtered and washed with water and dried. The ester was suspended in tetrahydrofuran (800 mL). A solution of sodium hydroxide (20.0 g) in water (500 mL) was added and the mixture was refluxed for 2 h. It was cooled and acidified with acetic acid and the precipitate was filtered. The solid was washed with water and acetone. wt=19.0 g of (7). m.p.=235-240° C.
Reaction SMILES: [ClH:1].[C:2]1([CH3:14])[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)=[CH:4][CH:3]=1.O.[OH-].[Na+].[CH2:18]=O>C(O)=O>[ClH:1].[CH3:18][N:10]1[CH2:11][CH:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:14])=[CH:7][CH:6]=3)([CH2:13]2)[CH2:9]1
Reactant: C=O
Reactant: Cc1ccc(C23CNCC2C3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Product: Cc1ccc(C23CC2CN(C)C3)cc1

Procedure:
A mixture of 4.19 g. of 1-(p-tolyl)-3-azabicyclo[3.1.0]hexane hydrochloride and 20 ml. of water is made basic with sodium hydroxide. This mixture is extracted with ether and the ether is evaporated to give an oil. This oil is combined with 40 ml. of 97% formic acid and 35 ml. of 37% formaldehyde and the solution is heated on a steam bath for 2 hours. The solution is cooled, made basic with sodium hydroxide and extracted with ether. The extract is dried over magnesium sulfate, filtered, and the filtrate is saturated with hydrogen chloride. The precipitated crystals are collected and recrystallized from isopropyl alcohol to give 3-methyl-1-(p-tolyl)-3-azabicyclo[3.1.0]hexane hydrochloride as colorless crystals, m.p. 197°-198° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[C:38]([C:41]([O:43][CH3:44])=[O:42])[S:39][CH:40]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.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>[F:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:25])[C:18]=1[N:9]1[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=2[C:7]([C:36]2[CH:37]=[C:38]([C:41]([O:43][CH3:44])=[O:42])[S:39][CH:40]=2)=[N:8]1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cs1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2-c1c(F)cccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2nn(-c3c(F)cccc3F)c3ccnc(OC)c23)cs1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
To a solution of 1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (100 mg) obtained in Step C of Example 35 in DMF (4 mL)/water (0.40 mL) were added methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (98.3 mg), tetrakis(triphenylphosphine)palladium(0) (28.2 mg) and potassium carbonate (67.5 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 30 min. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (44.9 mg).
Reaction SMILES: C1COCC1.[Al+3].[Cl-].[Cl-].[Cl-].[N-:10]=[N+:11]=[N-:12].[Na+].[CH2:14]([N:21]1[CH2:26][CH2:25][C:24]([C:35]#[N:36])([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[CH2:14]([N:21]1[CH2:22][CH2:23][C:24]([C:35]2[NH:36][N:12]=[N:11][N:10]=2)([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[CH2:25][CH2:26]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CC1(Nc2ccccc2F)CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccccc1NC1(c2nnn[nH]2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 70 %

Procedure:
To 250 ml of stirring dry THF in a 500 ml r.b. flask at 0° C. under N2, AlCl3 (23.0 g, 172 mmol) was added in small portions. Subsequently, NaN3 (47.4 g, 729 mmol) and 1-benzyl-4-cyano-4-(2-fluoroanilino)piperidine (21.8 g, 70 mmol) were added. The resulting mixture was refluxed for 20 hours. It was cooled to room temperature and poured onto stirring water (300 ml). The THF layer was separated and the aqueous layer was extracted with additional THF (3×500 ml). The combined THF layers were dried over MgSO4 and filtered. The filtrate was kept at 0° C. for 15 hours. After a filtration, the desired compound (17.1 g, 49 mmol) as white powder was obtained: m.p. 195°-198° C.; IR (nujol) 3360 cm-1 ; NMR (270 MHz, DMSO-d6) δ 2.29, 2.46 and 2.67 (3m, 8H, piperidine CH2 's), 3.53 (s, 2H, benzyl CH2), 6.12, 6.61, 6.72 and 6.98 (4m, 4H, anilinophenyl) H's), 7.2-7.4 (m, 5H, benzylphenyl H's). Anal. Calcd. for C19H21FN6 : C, 64.75; H, 6.01; N, 23.85. Found: C, 64.52; H, 5.94; N, 23.56. ##STR23##
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N:11]2[C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH2:19][F:20])[N:13]=[N:12]2)=[C:4]([F:21])[CH:3]=1.[H][H]>[Pt]=O.CO>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:21])=[C:5]([N:11]2[C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH2:19][F:20])[N:13]=[N:12]2)[CH:6]=1
Reactant: O=c1n(CCCF)nnn1-c1cc([N+](=O)[O-])c(Cl)cc1F
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: Nc1cc(-n2nnn(CCCF)c2=O)c(F)cc1Cl
Yield: 246.6 %

Procedure:
To a 500 ml Parr hydrogenation bottle was added 0.2 gram of platinum oxide, 200 ml of methanol, then 14.0 grams (0.014 mole) of 1-(4-chloro-2-fluoro-5-nitrophenyl)-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one. The bottle was placed in a Parr hydrogenator and the reaction mixture hydrogenated until the theoretical amount of hydrogen was taken up. The bottle was removed from the hydrogenator and the reaction mixture filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was dissolved in methylene chloride and subjected to column chromatography on silica gel. The appropriate fractions were combined and concentrated under reduced pressure to yield 10.0 grams of 1-(5-amino-4-chloro-2-fluorophenyl)-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one; m.p. 84°-86° C. The reaction was repeated several times.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:7])=[CH:5][N:6]=1.C(O[CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])C>>[C:18]([C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][NH:1][C:2]1[S:3][C:4]([CH3:7])=[CH:5][N:6]=1)([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Cc1cnc(N)s1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1ncc(C)s1)C(=O)OCC
Yield: 82.7 %

Procedure:
2-Amino-5-methylthiazole (6.85 g., 60 mmoles) and diethyl ethoxymethylenemalonate (14.3 g., 66 mmoles) were heated on a steam bath for 1 hour. The reaction mixture was cooled and the product precipitated by the addition of approximately 75 ml. of hexane. Purified 2-(2,2-dicarbethoxyethenylamino)-5-methylthiazole (14.1 g. in two crops, Rf 0.55-0.65 on silica gel thin layer chromatography with chloroform/1% ethanol as eluant) was obtained by recrystallization from hexane.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].I[CH2:24][CH:25]1[CH2:30][O:29][CH2:28][CH2:27][O:26]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(=O)CC.C(OCC)(=O)C>[O:26]1[CH2:27][CH2:28][O:29][CH2:30][CH:25]1[CH2:24][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: ICC1COCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: O=C1N(CC2COCCO2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
A mixture of 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.30 g, 1.03 mmol), 2-(iodomethyl)-1,4-dioxane (0.31 g, 1.35 mmol) and cesium carbonate (0.52 g, 1.58 mmol) in 2-butanone (7 mL) was stirred at reflux under nitrogen for 4 h. Once cooled, the reaction was diluted with ethyl acetate and the suspension was filtered through Celite. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography with dichloromethane/diethyl ether (14:1) to afford 1′-(1,4-dioxan-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one as an inseparable mixture with unreacted lactam (0.36 g). A mixture of this material, benzyl bromide (0.12 mL, 1.00 mmol) and cesium carbonate (0.50 g, 1.55 mmol) in 2-butanone (7 mL) was then stirred at reflux under nitrogen for 15 h. Work-up as described above and purified by flash column chromatography with (hexanes/ethyl acetate) (2:1, increased to 1:1) afforded 1-(1,4-dioxan-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.24 g, 58%) as a colorless solid, along with 1′-benzyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.09 g, 24%) as a colorless solid. Characterization for 1′-(1,4-dioxan-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one: mp 160-165° C. (hexanes); 1H NMR (300 MHz, CDCl3) (diastereomers) δ7.26-7.34 (m, 1H), 7.16 (d, J=7.5 Hz, 1H), 7.01-7.09 (m, 2H), 6.49 (s, 1H), 6.24 (s, 0.5H), 6.21 (s, 0.5H), 4.88 (d, J=8.9 Hz, 0.5 Hz), 4.87 (d, J=8.9 Hz, 0.5H), 4.64 (d, J=8.9 Hz, 0.5H), 4.63 (d, J=8.9 Hz, 0.5H), 4.22-4.16 (m, 2H), 4.15-4.09 (m, 2H), 3.99-3.78 (m, 4H), 3.76-3.55 (m, 4H), 3.47-3.37 (m, 1H); 13C NMR (75 MHz, CDCl3) (diastereomers) δ177.9, 177.8, 156.3, 155.3, 144.71, 144.69, 142.72, 142.66, 138.42, 138.39, 132.4, 132.3, 128.91, 128.85, 123.9, 123.8, 123.5, 121.3, 121.1, 111.7, 111.6, 109.6, 109.4, 99.49, 99.46, 80.2, 80.0, 73.32, 73.29, 69.4, 69.2, 66.8, 66.7, 66.52, 66.48, 64.6, 64.0, 58.1, 58.0, 41.85, 41.76; MS (ES+) m/z 396.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.C(OO)(=[O:17])C.C(O)(C)C>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][C:6]1[CH:7]=[N+:8]([O-:17])[CH:9]=[CH:10][CH:11]=1
Reactant: Clc1cccc(Oc2cccnc2)c1
Reactant: CC(=O)OO
Solvent: CC(C)O
Solvent: CC(=O)O
Product: [O-][n+]1cccc(Oc2cccc(Cl)c2)c1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A solution of 110 g of 3-(m-chlorophenoxy)pyridine [Agr. Biol. Chem., 34, 68 (1970)] at 35° C. in 125 ml of glacial acetic acid is treated with 112 g of 40% peracetic acid in acetic acid in four equal portions. The mixture is held at 27° C. for 16 hours and heated at reflux for 1 hour. The mixture is cooled to 70° C., 100 ml of isopropanol is added and the mixture is heated at 95° C. for 1 hour. The warm mixture is concentrated at reduced pressure, dissolved in 500 ml of dichloromethane and extracted with excess 25% sodium hydroxide solution. The dichloromethane is removed at reduced pressure and the 3-(m-chlorophenoxy)pyridine N-oxide is isolated by distillation; 150°-152° C. at 0.15 mm, mp 72°-75° C.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[NH:25]1[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:25]3[CH2:30][CH2:29][S:28][CH2:27][CH2:26]3)=[N:3][C:4]=2[CH3:24])=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: C1CSCCN1
Solvent: CCCCO
Product: Cc1nc(N2CCSCC2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure F was performed using 90 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 78 μL of thiomorpholine in 1 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-thiomorpholinonicotinamide. MS (Q1) 425.3 (M)+.
Reaction SMILES: O.CC1C=CC(S(O)(=O)=O)=CC=1.O[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:36])[CH2:22][C:23]1[NH:24][C:25](=[O:35])[CH:26]=[C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[N:28]=1>C1(C)C=CC=CC=1>[O:36]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]=[C:21]1[CH2:22][C:23]1[NH:24][C:25](=[O:35])[CH:26]=[C:27]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)[N:28]=1
Reactant: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1cc(N2CCOCC2)nc(Cc2nc3ccccc3o2)[nH]1
Temperature: 0 °C
Yield: 8.5 %

Procedure:
20 mg of 4-methylbenzenesulphonic acid hydrate are added to a solution of 200 mg of N-(2-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide in 40 ml of toluene. The reaction mixture is brought to reflux overnight. After cooling to 0° C., the insoluble material formed is filtered off. The filtrate is concentrated to dryness under reduced pressure and the residue is then chromatographed on a silica gel column, eluent: CH2Cl2/MeOH: 98/02 then 90/10. 16 mg of 2-(1,3-benzoxazol-2-ylmethyl)-6-(morpholin-4-yl)pyrimidin-4(3H)-one are thus obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [F:1][C:2]1[C:15]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[NH:18][C:17]2=[O:27])=[CH:14][C:5]2[N:6]([CH:10]([CH2:12][CH3:13])[CH3:11])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[H-].[Na+].[N+:30](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O.O>CN(C)C=O>[F:1][C:2]1[C:15]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[N:18]([NH2:30])[C:17]2=[O:27])=[CH:14][C:5]2[N:6]([CH:10]([CH2:12][CH3:13])[CH3:11])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: CCC(C)n1c(=O)sc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)n1c(=O)sc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(N)c3=O)cc21
Yield: 19.3 %

Procedure:
To a solution of 1-[6-fluoro-3-sec-butyl-2(3H)-benzothiazolon-5-yl]-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione (2.0 g) in dimethylformamide (10 g), sodium hydride (0.3 g) and 2,4-dinitrophenoxyamine (1.8 g) were added, and the resultant mixture was heated at 40 to 60° C. for 3 hours. After completion of the reaction, the reaction mixture was poured into water, extracted with ethyl acetate and concentrated. The residue was purified by silica gel column chromatography to give 1-[6-fluoro-3-sec-butyl-2(3H)-benzothiazolon-5-yl]-3-amino-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione (0.4 g).