Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:10]([F:13])([F:12])[F:11])=[C:5]([C:7]([OH:9])=O)[N:6]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:27]=[C:28]([CH:45]=[CH:46][CH:47]=1)[O:29][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([N:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[N:38]=2)[CH:35]=1>CN(C)C=O.CN(C)C(=O)C>[CH:42]1([C:40]([NH:39][C:37]2[N:38]=[C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:27]=[C:26]([NH:25][C:7]([C:5]5[N:6]=[C:2]([CH3:1])[O:3][C:4]=5[C:10]([F:13])([F:12])[F:11])=[O:9])[CH:47]=[CH:46][CH:45]=4)=[CH:35][N:34]3[N:36]=2)=[O:41])[CH2:43][CH2:44]1
Reactant: Cc1nc(C(=O)O)c(C(F)(F)F)o1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)c(C(F)(F)F)o1
Yield: 67.3 %

Procedure:
In the same manner as in Example 18-4 and using 2-methyl-5-(trifluoromethyl)-1,3-oxazole-4-carboxylic acid (110 mg, 0.564 mmol), tetrahydrofuran (8 mL), oxalyl chloride (98.0 μL, 1.13 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (70.0 mg, 0.226 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (74.0 mg, 67%) was obtained as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:14]3=[C:15]([CH2:17][CH2:18][CH2:19][N:13]3[C:12]3[CH2:11][CH2:10][CH2:9][CH2:8][C:7]2=3)[CH:16]=1)([O-])=O>[Pd].C(O)C>[CH:5]1[C:4]([NH2:1])=[CH:16][C:15]2[CH2:17][CH2:18][CH2:19][N:13]3[C:14]=2[C:6]=1[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=13
Reactant: O=[N+]([O-])c1cc2c3c(c1)c1c(n3CCC2)CCCC1
Agent: [Pd]
Solvent: CCO
Product: Nc1cc2c3c(c1)c1c(n3CCC2)CCCC1

Procedure:
Following the procedure of Example 1, Step 3, 2-nitro-5,6,8,9,10,11-hexahydro-4H-pyrido[3,2,1-jk]carbazole (1.1 g, 4.3 mmol) and 5% palladium on carbon (0.10 g) in ethanol (70 mL) was hydrogenated to provide 5,6,8,9,10,11-hexahydro-4H-pyrido[3,2,1-jk]carbazol-2-amine.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:27]=[C:26]4[C:22]([C:23]([CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:24][NH:25]4)=[CH:21][CH:20]=3)[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].I[CH3:38]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:27]=[C:26]4[C:22]([C:23]([CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])=[CH:24][N:25]4[CH3:38])=[CH:21][CH:20]=3)[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(CCC(=O)OC(C)(C)C)c[nH]c4c3)no2)cc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(CCC(=O)OC(C)(C)C)cn(C)c4c3)no2)cc1Cl
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% in mineral oil, 7.47 mg) was added to a solution of 1,1-dimethylethyl 3-[6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D17) (150 mg) in dry DMF (4 mL) at RT. After stirring for 5 min, iodomethane (0.029 mL) was added. The resulting solution was stirred at RT for 1.2 hours. Another portion of sodium hydride (4 mg) was added. After stirring for 5 min, methyliodide (0.015 mL) was added, and the resulting solution was stirred for 1 hour. DMF was evaporated. EtOAc (50 mL) was added and the resulting solution was washed with aqueous HCl (40 mL), followed by water (100 mL). The organic fraction was dried over anhydrous magnesium sulfate. The dried solution was concentrated. The residue was purified by Biotage (25% EtOAc in hexane) to afford 1,1-dimethylethyl 3-[6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]propanoate (D18) (113 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.38 (15H, m), 2.58 (2H, t), 2.93 (2H, t), 3.85 (3H, s), 4.89 (1H, m), 7.32 (1H, br s), 7.45 (1H, d), 7.75 (2H, m), 8.15 (2H, m), 8.22 (1H, d). MS (ES): C27H30ClN3O4 requires 495; found 496.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([OH:9])[N:3]=1.[H-].[Na+].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: Cc1cc(O)nc(N)n1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)nc(N)n1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
2-Amino-4-methyl-6-hydroxypyrimidine (62.5 g., 0.50 mole) is dissolved in 500 ml of dimethylformamide and sodium hydride (0.5 mole) is added over a 1 hour period under a nitrogen atmosphere. The mixture is heated at 75° C. for 11/2 hours. Benzyl chloride (69.3 g., 0.55 moles) is then added over 15 minutes and the mixture is heated at 90° C. and stirred for 11/2 hours. After cooling, the reaction mixture is filtered and concentrated under vacuum to an oil from which 2-amino-4-methyl-6-benzyloxypyrimidine melting at 108°-109.5° C. is obtained by crystallization from n-butyl chloride.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:22]=[O:23])[C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[N:10][C:9]=2[CH:21]=1>CO>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:22][OH:23])[C:8]2[O:12][C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[N:10][C:9]=2[CH:21]=1
Reactant: COc1ccc(-c2nc3cc(OC)cc(C=O)c3o2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2nc3cc(OC)cc(CO)c3o2)cc1
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
Sodium borohydride (66.8 mg, 1.76 mmol) was added into a solution of 5-methoxy-2-(4-methoxyphenyl)-1,3-benzoxazole-7-carbaldehyde (250 mg, 0.88 mmol) in anhydrous MeOH (8 mL) at 0° C. The reaction mixture was stirred for 30 min and then evaporated in vacuum. The residue was dissolved in diethyl ether and washed with water and brine, dried over MgSO4 and filtered. Evaporation and flash chromatography (50% EtOAc/petroleum ether) gave (210 mg, 83%) of the product, which was used directly in the next reaction.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].[NH2:7][C:8]1[N:16]=[C:15](Cl)[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].N>[Cu]I.C(OCC)C.O>[NH2:7][C:8]1[N:16]=[C:15]([O:3][CH2:2][CH2:1][OH:4])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: OCCO
Reactant: Nc1nc(Cl)ccc1C(=O)O
Agent: [Cu]I
Agent: N
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: Nc1nc(OCCO)ccc1C(=O)O
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To ethyleneglycol (0.50 mL) was added sodium hydride (70 mg, 1.7 mmol, 60% in oil), catalytic amount of copper(I) iodide and 2-amino-6-chloronicotinic acid (30 mg, 0.17 mmol), which was stirred for 3 hours at 110° C., then, further stirred overnight at 80° C. After cooling, water, diethyl ether and aqueous ammonia was added to the reaction solution, which was then partitioned, the aqueous layer was neutralized with citric acid, then, extracted with dichloromethane. The organic layer was washed with brine, then dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo to obtain the title compound (14 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:13]([O:15][CH3:16])=[O:14].CCN(CC)CC>C(Cl)Cl>[CH3:16][O:15][C:13](=[O:14])[NH2:10].[Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cl
Agent: NCCc1cccc(Cl)c1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(3-chloro-2-fluoro-phenyl)-ethylamine (1.30 g, 7.9 mmol) in CH2Cl2 (25 mL) was added dropwise methyl chloroformate (1.04 g, 11 mmol) and Et3N at 5° C. with vigorous stirring. The solution was then stirred at room temperature for 1 h. The reaction was poured into ice-water (50 mL) and extracted with CH2Cl2 (2×25 mL). The organic phase was washed with H2O (2×25 mL), dried over Na2SO4, filtered and evaporated to afford the final product without purification (1.78 g, 98%). MS: 232.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].Cl.CN(C)[CH2:15][CH2:16]CN=C=N.O.ON1C2C=CC=CC=2N=N1.C(O)C>CN(C)C=O.O>[CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([O:8][CH2:15][CH3:16])=[O:7]
Reactant: Cc1ccc(C(=O)O)c(O)c1
Reactant: CN(C)CCCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(C)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
4-Methylsalicylic acid (304 mg), 1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (420 mg), 1-hydroxybenzotriazole hydrate (337 mg), and ethanol (2 ml) were dissolved in N,N-dimethylformamide to prepare a solution which was then stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give ethyl 4-methylsalicylate (175 mg, yield 49%).
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=1)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:62]=[N+:63]=[N-:64])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.O>[N:62]([CH:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=1)[C:2]([CH3:16])([CH3:15])[CH3:1])=[N+:63]=[N-:64]
Reactant: CCCSc1ccc(C(O)C(C)(C)C)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCSc1ccc(C(N=[N+]=[N-])C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.3 %

Procedure:
To a stirred solution of 2,2-dimethyl-1-[4-(propylthio)phenyl)propan-1-ol (466 mg, 1.95 mmol) in THF (10 ml) were added triphenylphosphine (666 mg, 2.54 mmol), diethyl azodicarboxylate (0.40 ml, 2.54 mmol), and finally diphenylphosphoryl azide (0.55 ml, 2.54 mmol). The mixture was stirred at room temperature over for 3 days. Water (1 ml) was added and the mixture was evaporated. The residue was partitioned between ethyl acetate (50 ml) and water (30 ml). The organic phase was separated, washed with brine (30 ml), dried over MgSO4, filtered and evaporated to give an oil. The crude product was chromatographed on silica eluting with 4% EtOAc in hexanes to give the title product as a pale yellow oil (284 mg). 1H NMR δ (CDCl3) 7.29-7.27 (2H, m), 7.17-7.15 (2H, m), 4.23 (1H, s), 2.92 (2H, t, J=7.3 Hz), 1.73-1.67 (2H, m), 1.04 (3H, t, J=7.4 Hz), 0.90 (9H, s).
Reaction SMILES: [F:1][C:2]1[C:22](F)=[CH:21][C:5]2[C:6]3[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:10]([CH3:14])[C:11]=3[CH:12]=[N:13][C:4]=2[CH:3]=1.[CH3:24][C:25]12[CH2:32][CH:29]([NH:30][CH2:31]1)[CH2:28][C:27]([CH3:34])([CH3:33])[CH2:26]2>CS(C)=O>[F:1][C:2]1[C:22]([N:30]2[CH2:31][C:25]3([CH3:24])[CH2:32][CH:29]2[CH2:28][C:27]([CH3:34])([CH3:33])[CH2:26]3)=[CH:21][C:5]2[C:6]3[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:10]([CH3:14])[C:11]=3[CH:12]=[N:13][C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1cn(C)c2cnc3cc(F)c(F)cc3c2c1=O
Reactant: CC1(C)CC2CC(C)(CN2)C1
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(C)c2cnc3cc(F)c(N4CC5(C)CC4CC(C)(C)C5)cc3c2c1=O
Temperature: 90 °C
Reaction time: 288 h
Yield: 31.7 %

Procedure:
A suspension of 2 g of ethyl 8,9-difluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate and 2.6 g of 1,3,3-trimethyl-6-azabicyclo[3.2.1]octane in 50 cm3 of dimethyl sulphoxide was heated, with stirring, at a temperature of 90° C. for 12 days. After cooling to 20° C., the mixture was poured into 200 cm3 of ice-cold water. The medium was extracted 3 times with 200 cm3 of dichloromethane, and the organic extracts were washed 3 times with 100 cm3 of water, and dried over sodium sulphate. After filtration and concentration under reduced pressure (5.2 kPa), the compound obtained was purified by chromatography on 160 g of silica gel (0.06-0.20 mm). Elution was carried out with 3 liters of a dichloromethane-ethanol mixture (97-3 by volume), collecting 200 cm3 fractions. The fractions between 1.65 and 3 liters were concentrated to dryness under reduced pressure (5.2 kPa). 0.9 g of ethyl 8-fluoro-4-methyl-1-oxo-9-(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate was obtained in the form of yellow crystals, which melted at 187° C.
Reaction SMILES: [ClH:1].[CH2:2]([NH:6][CH2:7][C:8]1([CH3:22])[S:12](=[O:14])(=[O:13])[C:11]2[S:15][C:16]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:17][C:10]=2[CH2:9]1)[CH:3](C)C.[C:23](O)(C(F)(F)F)=O.Cl>>[ClH:1].[CH3:22][C:8]1([CH2:7][NH:6][CH:2]([CH3:3])[CH3:23])[S:12](=[O:14])(=[O:13])[C:11]2[S:15][C:16]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:17][C:10]=2[CH2:9]1
Reactant: CC(C)CNCC1(C)Cc2cc(S(N)(=O)=O)sc2S1(=O)=O
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Product: CC(C)NCC1(C)Cc2cc(S(N)(=O)=O)sc2S1(=O)=O
Yield: 48 %

Procedure:
The title compound was prepared in the same way as 5-(N-isobutylaminomethyl)4,5-dihydro-5-methylthieno[2,3-b]thiophene-2-sulfonamide-6,6-dioxide hydrochloride. Thus 5-(N-isopropylcarbamoyl)-4,5-dihydro-5-methylthieno[2,3-b]thiophene-2-N-t-butylsulfonamide-6,6-dioxide (3.0 g, 7.3 mmol) was reduced with borane-dimethylsulfide complex (5.0 mL, 50 mmol), deprotected with TFA, and converted to the HCl salt to give the title compound as a white solid (1.32 g, 48% over two steps), mp=132°-135° C. Anal. Calc. for C11H18N2O4S3.HCl.1/2H2O: C, 34.41; H, 5.25; N, 7.29. Found: C, 34.42; H, 5.19; N, 7.11.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][N:3]1[P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[C:13]1([Mg]Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Cu]I.C1COCC1>[C:13]1([CH2:4][CH:2]([NH:3][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])[CH3:1])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: CCOP(=O)(OCC)N1CC1C
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCOP(=O)(NC(C)Cc1ccccc1)OCC
Temperature: 30 °C
Reaction time: 0.08 h
Yield: 65 %

Procedure:
A 250 mL, jacketed, three necked flask equipped with an overhead stirrer, 50 mL pressure equalizing addition funnel and a temperature probe was charged with 2a (10 g, 51.7 mmol), THF (50 mL) and CuI (98 mg, 1.0 mol %) and the stirred mixture was heated to 30° C. The pressure equalizing addition funnel was charged with PhMgCl (2M in THF, 32.36 mL) and the solution was added over 20 minutes while maintaining an internal temperature of 30-32° C. After the addition was complete, the reaction mixture was heated to 45-50° C. for an additional 30 minutes and then cooled to ambient temperature. The reaction was quenched by slow addition to a cooled mixture of saturated aqueous ammonium chloride solution and water (50/50 v/v, 100 mL) while maintaining an internal temperature below 20° C. The flask was rinsed with methyl t-butyl ether (100 mL) and the rinse was transferred to the quenched reaction mixture. The biphasic mixture was stirred for 5 minutes, allowed to separate for 20 minutes and then the aqueous phase was removed. The organic phase washed with saturated sodium chloride solution (50 mL) and the organic phase was dried over sodium sulfate. The solution (a 97:7 mixture of 6a: 8a by GC analysis) was filtered and concentrated under reduced pressure until the product began to crystallize. Heptane (40 mL) was added to the slurry and the mixture was heated until a solution was obtained. The stirred solution allowed to cool to room temperature and stirred for 18 hours. The solid was collected by filtration and dried under reduced pressure at 30° C. for 18 hours affording diethyl (1-phenylpropan-2-yl)phosphoramidate (6a) as a white crystalline solid (9.12 g, 65% yield; 99.72% GC purity with 0.04% 8a present). Mp 66-67° C. (lit1 57-58° C.). 1H NMR (300 MHz, CDCl3) δ 7.36-7.08 (m, 5H), 4.14-3.85 (m, 3H), 3.85-3.66 (m, 1H), 3.58-3.32 (m, 1H), 2.81-2.61 (m, 2H), 2.38 (t, J=9.8 Hz, 1H), 1.38-1.18 (m, 6H), 1.15 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].F[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].CS(C)=O>[OH:5][CH2:4][CH2:3][N:2]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1)[CH3:1]
Reactant: O=Cc1ccc(F)cc1
Reactant: CNCCO
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CS(C)=O
Product: CN(CCO)c1ccc(C=O)cc1
Temperature: 95 °C

Procedure:
A 2 liter three-necked flask fitted with a mechanical stirrer, therometer and condenser is charged with 134 g of 2-(methylamino)ethanol, 74.4 g of 4-fluorobenzaldehyde, 1 ml of Aliquat 336, 750 ml of dimethylsulfoxide and 82.8 g of anhydrous potassium carbonate. The mixture is heated at 95° C. for three days. The product mixture is cooled and poured into 3 liters of ice water. The resultant solid precipitate is filtered, washed with water, and vacuum dried. The crude product is recrystallized from toluene, m.p. 72° C.
Reaction SMILES: N1C=CN=C1.[OH:6][C:7]1[C:12](=[O:13])[CH:11]=[CH:10][O:9][C:8]=1[CH3:14].[C:15]([Si:19]([CH3:22])([CH3:21])Cl)([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])O>CN(C)C=O>[Si:19]([O:6][C:7]1[C:12](=[O:13])[CH:11]=[CH:10][O:9][C:8]=1[CH3:14])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:22])[CH3:21]
Reactant: Cc1occc(=O)c1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1occc(=O)c1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.9 %

Procedure:
A solution of imidazole (Im, 5.45 g, 0.08 mol) in N,N-dimethylformamide (20 ml) is added in an inert atmosphere and dropwise to a solution containing 3-hydroxy-2-methyl-4-pyrone (5.00 g, 0.04 mol) and tert-butyl-dimethylchlorosilane (TBDMSCl, 7.00 g, 0.044 mol) in N,N-dimethylformamide (100 ml). The mixture obtained thereby is maintained stirring at a room temperature for 6 h and then diluted by adding a 5% hydrogen carbonate aqueous solution (150 ml). The mixture obtained thereby is extracted with hexane (6×50 ml); the extracted organic phases are combined, anhydrified on sodium sulphate, and evaporated under vacuum obtaining the desired 3-(tert-butyl-dimethylsilyl)oxy-2-methyl-4-pyrone compound as a colourless crystalline solid (9.61 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][C@@H:10]2[C@@:4]([C:24]([O-:26])=[O:25])([N:5]3[C@H:8]([S:9]2)[C@H:7]([NH:12][C:13](=[O:22])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]3=[O:23])[O:3]1.[Na+].[C:28](OCC)(=O)C.[N+](=C)=[N-].Cl>O.CCOCC>[O:1]=[C:2]1[CH2:11][C@@H:10]2[C@@:4]([C:24]([O:26][CH3:28])=[O:25])([N:5]3[C@H:8]([S:9]2)[C@H:7]([NH:12][C:13](=[O:22])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]3=[O:23])[O:3]1
Reactant: CCOC(C)=O
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2[C@@H]1S[C@@H]1CC(=O)O[C@@]12C(=O)[O-]
Agent: C=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COC(=O)[C@]12OC(=O)C[C@H]1S[C@@H]1[C@H](NC(=O)COc3ccccc3)C(=O)N12
Reaction time: 0.5 h

Procedure:
30 mg of the compound obtained in Example 4 was dissolved in 3 ml water. To this solution 3 ml ethyl acetate and 5 ml of diazomethane in ether were added, while cooling the solution with ice. After adding 83 μl of 1N hydrochloric acid, the resulting mixed solutio was stirred for 30 minutes, while cooling with ice. After 30 minutes of stirring, 8 ml of a solution of diazomethane in ether was added; the resulting mixed solution was stirred for 20 minutes, while cooling with ice. The reaction mixture, after dilution with water, was extracted with ethyl acetate. The organic layer was dried (MgSO4), then the solvent was evaporated under reduced pressure. The resulting residue was passed through a silica gel column and eluted with n-hexane-ethyl acetate (2:1), then the eluted fraction containing the desired product was collected and concentrated under reduced pressure to yield 13.5 mg of the subject compound in the form of a white crystal. Melting point: 182° to 184° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7](Br)[S:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[Na].[CH3:13][OH:14]>>[C:1]([NH:4][C:5]1[N:6]=[C:7]([O:14][CH3:13])[S:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(Br)sc1C
Reactant: CO
Agent: [Na]
Product: COc1nc(NC(C)=O)c(C)s1

Procedure:
4-Acetamido-2-bromo-5-methylthiazole (prepared by acylating 4-amino-2-bromo-5-methylthiazole with acetic anhydride) is treated with sodium in absolute methanol as described in Example 1 to give the title compound.
Reaction SMILES: C(O)C.[Cl:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH:19]=3)=[CH:10][NH:11]2)=[CH:7][CH:6]=1.[O:20]1[CH2:22][C@H:21]1[CH2:23][O:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[CH:28][NH:29]2>CS(C)=O>[Cl:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:14]3[CH2:15][CH2:16][N:17]([CH2:22][C@H:21]([OH:20])[CH2:23][O:24][C:25]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)[CH2:18][CH:19]=3)=[CH:10][NH:11]2)=[CH:7][CH:6]=1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Clc1ccc2c(C3=CCNCC3)c[nH]c2c1
Solvent: CS(C)=O
Solvent: CCO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CC=C(c2c[nH]c3cc(Cl)ccc23)CC1

Procedure:
To 5 mL of dry ethanol were added 6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (1.54 g, 6.61 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (1.25 g, 6.61 mmol). The mixture was heated at the reflux temperature for about 6 hours, and was then cooled and concentrated. The residue was purified by silica gel chromatography with 95/5 chloroform/methanol. The product was isolated as a yellow foam. Yield 1.52 g (55%). mp 200°-202° C. FDMS m/e=421 (M+ of free base). α[D]589 =+4.39 (c=1.00, dimethylsulfoxide)
Reaction SMILES: BrC1C=CC=C2C=1C(O)(C1C(O)=CC3OCOC=3C=1)C(=O)N2CCCCC.[CH2:28]([O:35][CH2:36][CH2:37][CH2:38][N:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41](O)([C:48]2[C:56]([OH:57])=[CH:55][C:51]3[O:52][CH2:53][O:54][C:50]=3[CH:49]=2)[C:40]1=[O:59])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][CH2:36][CH2:37][CH2:38][N:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]([C:48]2[C:56]([OH:57])=[CH:55][C:51]3[O:52][CH2:53][O:54][C:50]=3[CH:49]=2)[C:40]1=[O:59])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1N(CCCOCc2ccccc2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Agent: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: O=C1C(c2cc3c(cc2O)OCO3)c2ccccc2N1CCCOCc1ccccc1

Procedure:
Following the procedure as described in PREPARATION 1D, and making non-critical variations to replace 4-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 1-[3-(benzyloxy)propyl]-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (92%): 1H NMR (300 MHz, CDCl3) δ7.42-6.95 (m, 9H), 6.56 (s, 1H), 6.24 (s, 1H), 5.86 (ABq, 1H), 5.81(ABq, 1H), 4.99 (s, 1H), 4.42 (s, 2H), 3.91-3.76 (m, 2H), 3.46 (t, 2H), 2.03-1.93 (m, 2H); MS (ES+) m/z 418.3 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[NH:18][C:19](=O)[C:20]2[CH:25]=[CH:24][C:23]([S:26](=[O:29])(=[O:28])[NH2:27])=[CH:22][CH:21]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].P(Cl)(Cl)(Cl)=O.C(OCC)(=O)C>C(#N)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:7]([C:19]([C:20]3[CH:25]=[CH:24][C:23]([S:26](=[O:29])(=[O:28])[NH2:27])=[CH:22][CH:21]=3)=[N:18][C@@H:13]3[C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc([C@H]2CCCC[C@H]2NC(=O)c2ccc(S(N)(=O)=O)cc2)ccc1OC
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOc1cc2c(cc1OC)C(c1ccc(S(N)(=O)=O)cc1)=N[C@H]1CCCC[C@@H]21
Yield: 62.6 %

Procedure:
700 mg of (+/-)-cis-N-[2-(3-ethoxy-4-methoxyphenyl)cyclohexyl]-4-sulfamoylbenzamide (compound A1) are dissolved in 100 ml of acetonitrile and 2.0 ml of phosphorus oxychloride and the solution is stirred at 80° C. overnight. The reaction mixture is treated with 60 ml of ethyl acetate and extracted with sodium hydrogencarbonate solution. The organic phase is dried using sodium sulfate and concentrated. The residue is recrystallized from ethanol. 420 mg of the title compound are obtained.