Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:14]=[C:15]([NH2:24])[S:16][C:17]=1[CH2:18][CH2:19][O:20][N+:21]([O-:23])=[O:22]>>[F:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[C:3]=1[C:4]([NH:24][C:15]1[S:16][C:17]([CH2:18][CH2:19][O:20][N+:21]([O-:23])=[O:22])=[C:13]([CH3:12])[N:14]=1)=[O:6]
Reactant: Cc1nc(N)sc1CCO[N+](=O)[O-]
Reactant: O=C(O)c1c(F)cccc1F
Product: Cc1nc(NC(=O)c2c(F)cccc2F)sc1CCO[N+](=O)[O-]
Yield: 72 %

Procedure:
Pet-161 was prepared according to the general procedure described hereinabove and the procedure described above for the preparation of Pet-154, using 2,6-difluoro-benzoic acid and 4-methyl-5-(2-nitrooxy-ethyl)-thiazol-2-ylamine (Pet-10) as the starting materials, in an overall yield of 72%.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[CH:28][C:27]3[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=3[CH:21]=2)=[CH:12][CH:11]=1)[C:6](O)=[O:7])=[O:4].S(Cl)(Cl)=O.[NH3:38]>C1C=CC=CC=1.C(OCC)(=O)C>[C:6]([CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[CH:28][C:27]3[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=3[CH:21]=2)=[CH:12][CH:11]=1)[C:3]([O:2][CH3:1])=[O:4])(=[O:7])[NH2:38]
Reactant: N
Reactant: COC(=O)C(Cc1ccc(OCCOc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COC(=O)C(Cc1ccc(OCCOc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1)C(N)=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
To a solution of 2-(methoxycarbonyl)-3-[4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthoxy)ethoxy]phenyl]propionic acid (2.40 g, 5.29 mmol) in benzene (20 ml) at room temperature is added thionyl chloride (0.76 g, 6.34 mmol). Then the mixture is heated at 80° C. for 90 min. After cooled to room temperature, the solvent is removed under a vacuum. To the residue is added 28% ammonia solution (5.49 ml, 79.30 mmol) at room temperature. The mixture is stirred for 30 min, dissolved in ethyl acetate (20 ml), washed with brine (3×15 ml), dried over sodium sulfate, and concentrated. The crude product is crystallized from ethanol to give title compound (1.35 g, 56%). HRMS calcd for C27H35NO5: 453.5786. Found: 453.5784. MA calcd for C27H35NO5: C, 71.50%; H, 7.78%; N, 3.09. Found: C, 71.52%; H, 7.76%; N, 3.12%.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH:12]([OH:17])[C:13]([CH3:16])=[CH:14][CH3:15])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1C=CC=CC=1.[O-2].[O-2].[Mn+4]>[C:1]1([C:7]2[CH:11]=[C:10]([C:12](=[O:17])[C:13]([CH3:16])=[CH:14][CH3:15])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC=C(C)C(O)c1cc(-c2ccccc2)no1
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Product: CC=C(C)C(=O)c1cc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dissolved in 100 ml of benzene were 5.4 g (23.6 mmol) of 3-phenyl-5-(1-hydroxy-2-methyl-2-butenyl)isoxazole, followed by the addition of 21.0 g (0.24 mol) of manganese dioxide. The mixture was stirred at room temperature for 24 hours. An insoluble material was filtered off and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: 30:1 n-hexane/ethyl acetate), whereby 3-phenyl-5-(2-methyl-2butenoyl)isoxazole was obtained as colorless oil. Analytical results of the crystals obtained: Yield: 3.6 g (67%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:22]=2[NH:21][CH:20]=[C:19]3[S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[Cl:39]CCl>>[ClH:39].[C:26]1([S:23]([C:19]2[C:18]3[C:22](=[C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:15]=[CH:16][CH:17]=3)[NH:21][CH:20]=2)(=[O:24])=[O:25])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c(S(=O)(=O)c4ccccc4)c[nH]c23)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=S(=O)(c1ccccc1)c1c[nH]c2c(N3CCNCC3)cccc12

Procedure:
4-(3-Benzenesulfonyl-1H-indol-7-yl)-piperazine-1-carboxylic acid tert-butyl ester (1 g, 2.2 mmol) was dissolved in 5 mL of dichloromethane and 6 mL of trifluoroacetic acid was added. After 10 min the mixture was concentrated in vacuo, taken into water, and washed with ether. The aqueous layer was basified with ammonium hydroxide, extracted with dichloromethane, and the extract was dried (sodium sulfate) and evaporated to afford the crude free base. The hydrochloride salt was crystallized from ethanol to afford 550 mg of 3-benzenesulfonyl-7-piperazin-1-yl-1H-indole hydrochloride (101), m.p. 278-280° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH2:17][CH3:18])[N:14]=[C:15]([CH3:16])[C:3]=12.C(N(CC)CC)C>[Pd].C(O)(=O)C>[CH2:17]([N:13]1[C:4]2=[N:5][CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]=[C:3]2[C:15]([CH3:16])=[N:14]1)[CH3:18]
Reactant: CCOC(=O)c1cnc2c(c(C)nn2CC)c1Cl
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc2c(c1)c(C)nn2CC

Procedure:
To 80.3 g. of 4-chloro-1-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester (0.3 mol.) [prepared according to Journal of Heterocyclic Chemistry 9, 235-253 (1972)] dissolved in 270 ml. glacial acetic acid, are added 33.4 g. of triethylamine (0.33 mol.) and 7.5 g. of palladium on charcoal (10%). The mixture is hydrogenated at room temperature and a pressure of 2.5 atm. After about 19 hours the theoretical amount of hydrogen is absorbed. Then the catalyst is filtered off and the filtrate evaporated. The residue is treated with 200 ml. of water and extracted with ether. The combined ether extracts are dried and the ether distilled off. The oily 1-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester is distilled in vacuo; b.p.0.3 144°-146°, which after a short time begins to crystallize, yield: 64.5 g. (92%).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([N:16]2[C:20]([NH2:21])=[CH:19][C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])=[N:17]2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.[Cl:29][C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=1[N:37]=[C:38]=[O:39]>>[Cl:29][C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=1[NH:37][C:38]([NH:21][C:20]1[N:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][OH:8])[CH:11]=2)[N:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[CH:19]=1)=[O:39]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(-n2nc(-c3ccccc3F)cc2N)c1
Reactant: O=C=Nc1cccc(Cl)c1Cl
Product: O=C(Nc1cccc(Cl)c1Cl)Nc1cc(-c2ccccc2F)nn1-c1cccc(CO)c1
Yield: 59.4 %

Procedure:
Using general method A, 1-(3-((t-butyldimethylsilyloxy)methyl)phenyl)-3-(2-fluorophenyl)-1H-pyrazol-5-amine (available from ethyl 3-(5-amino-3-(2-fluorophenyl)-1H-pyrazol-1-yl)benzoate using general method C, followed by protection with TBSCl) (0.4 g, 1.0 mmol) was combined with 2,3-dichlorophenyl isocyanate (0.32 g, 1.2 mmol) to yield 1-(2,3-dichlorophenyl)-3-(3-(2-fluorophenyl)-1-(3-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)urea (0.28 g, 59% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.05 (s, 1H), 8.87 (s, 1H), 8.08 (m, 1H), 7.99 (dt, J=2.0, and 8.0 Hz, 1H), 7.58 (m, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.50 (brd, J=7.6 Hz, 1H), 7.45 (brd, J=7.2 Hz, 1H), 7.41 (m, 1H), 7.32 (m, 3H), 6.91 (d, J=4.4 Hz, 1H), 5.39 (t, J=6.0 Hz, 1H), 4.62 (d, J=6.0 Hz, 2H); MS (EI) m/z: 471.0 (M+H+).
Reaction SMILES: [CH:1]1[N:9]2[C:4]([CH2:5][O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[N:3][C:2]=1[C:14]([O:16][CH3:17])=[O:15].S(=O)(=O)(O)O.[N+:23]([O-])([OH:25])=[O:24]>O>[N+:23]([C:11]1[CH:12]=[CH:13][C:7]2[O:6][CH2:5][C:4]3=[N:3][C:2]([C:14]([O:16][CH3:17])=[O:15])=[CH:1][N:9]3[C:8]=2[CH:10]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1cn2c(n1)COc1ccccc1-2
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cn2c(n1)COc1ccc([N+](=O)[O-])cc1-2
Reaction time: 3 h
Yield: 79 %

Procedure:
8.0 g of methyl 4H-imidazo-[2,1-c][1,4]-benzoxazine-2-carboxylate were added to a stirred mixture of 25 ml of concentrated sulfuric acid and 25 ml of concentrated nitric acid at 10° C. The ester slowly went into solution with the solution turning yellow and after three hours at room temperature, thin layer chromatography indicated no starting material remained. 500 ml of water were then added and the yellow product thus formed was filtered off, washed well with water and then dried over P2O5 to obtain 7.5 g (79% yield) of methyl 8-nitro-4H-imidazo-[2,1-c][1,4]-benzoxazine-2-carboxylate with a melting point of 270°-2° C.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[CH3:6][CH2:7][CH2:8][CH2:9][CH:10]([C:24]#N)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.S(=O)(=O)(O)[OH:27]>O>[CH2:1]([O:5][C:24](=[O:27])[CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][CH2:8][CH2:7][CH3:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: O=S(=O)(O)O
Reactant: CCCCC(C#N)c1ccccc1Oc1ccccc1
Solvent: O
Product: CCCCOC(=O)C(CCCC)c1ccccc1Oc1ccccc1
Yield: 104.9 %

Procedure:
Into a 500-ml round bottom flask are placed 77.7 g (1 mole) of n-butanol, 36.5 g (0.14 mole) of δ-n-butyl o-phenoxybenzyl cyanide and 14.4 g (0.45 mole) of conc. sulfuric acid. The mixture is heated to reflux overnight. It is then cooled, poured into water and extracted with toluene. The combined extracts are washed with water and dried over MgSO4. Solvent is evaporated to give 50 g of product.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[S:15][C:14]([C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[O:17])=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[NH2:24][CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:18]1([C:16]([C:14]2[S:15][C:11]([C:9]3[CH:8]=[CH:7][N:6]=[C:5]([NH:24][CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][NH:29][C:28]4=[O:32])[N:10]=3)=[CH:12][CH:13]=2)=[O:17])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: CS(=O)(=O)c1nccc(-c2ccc(C(=O)N3CCOCC3)s2)n1
Reactant: NCCN1CCNC1=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1NCCN1CCNc1nccc(-c2ccc(C(=O)N3CCOCC3)s2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of (5-(2-(methylsulfonyl)pyrimidin-4-yl)thiophen-2-yl)(morpholino)methanone (100 mg, 0.26 mmol), 1-(2-aminoethyl)imidazolidin-2-one (36 mg, 0.28 mmol) and triethylamine (56 mg, 0.52 mmol) in toluene (3 mL) was refluxed for 6 h. After cooling to rt, the solvent was evaporated in vacuo and then methanol (5 mL) was added. After stirring for 15 min the solid was filtered and dried to give title compound as a light yellow solid. MS (M+H)+ 403.
Reaction SMILES: [CH2:1]([C:3]1([CH3:15])[CH2:12][C:11](=O)[C:10]2[C:5](=[CH:6][C:7]([OH:14])=[CH:8][CH:9]=2)[O:4]1)[CH3:2].C1(C=CC=C(O)C=1)O.B(F)(F)F.CCOCC.C1C=CC2OCCC(=O)C=2C=1.[F:44][C:45]([F:55])([F:54])[C:46]1[CH:47]=[C:48]([Mg]Br)[CH:49]=[CH:50][CH:51]=1>>[CH2:1]([C:3]1([CH3:15])[CH:12]=[C:11]([C:50]2[CH:49]=[CH:48][CH:47]=[C:46]([C:45]([F:55])([F:54])[F:44])[CH:51]=2)[C:10]2[C:5](=[CH:6][C:7]([OH:14])=[CH:8][CH:9]=2)[O:4]1)[CH3:2]
Reactant: FC(F)(F)c1cccc([Mg]Br)c1
Reactant: CCC1(C)CC(=O)c2ccc(O)cc2O1
Agent: FB(F)F
Agent: O=C1CCOc2ccccc21
Agent: Oc1cccc(O)c1
Solvent: CCOCC
Product: CCC1(C)C=C(c2cccc(C(F)(F)F)c2)c2ccc(O)cc2O1

Procedure:
2-Ethyl-7-hydroxy-2-methyl-4-chromanone, m.p. 109°-110.5° C., was prepared by condensing resorcinol with 3-methyl-2-pentanoic acid in the presence of boron trifluoride diethyl etherate. Reaction of the chromanone with 3-trifluoromethylphenyl magnesium bromide as described in Preparation 5 gave the title chromene as a golden yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.COC(=O)C=CC1C=CC(O)=CC=1.[CH2:27](Cl)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38].C(Cl)CCCCCC(C)C>>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]([CH3:38])[CH3:39])=[CH:8][CH:7]=1
Reactant: CC(C)CCCCCCCCCCCl
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: CC(C)CCCCCCCl
Agent: COC(=O)C=Cc1ccc(O)cc1
Product: COC(=O)CCc1ccc(OCCCCCCCCCCC(C)C)cc1

Procedure:
1.5 3-(4-isotridecyloxyphenyl)-propionic acid methyl ester (refractive index at 20° C. : 1.4902) was prepared from 3-(4-hydroxyphenyl)-propionic acid methyl ester, substituted on an equimolar basis for 4-hydroxycinnamic acid methyl ester, and isotridecyl chloride, substituted on an equimolar basis for isononyl chloride, by the method described in 1.1.
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:18])[NH:4][NH:5][C:6]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)=O.C([O-])(O)=O.[Na+].Cl>>[CH3:1][N:2]1[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)=[N:5][NH:4][C:3]1=[S:18]
Reactant: CNC(=S)NNC(=O)c1ccc2ccccc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1c(-c2ccc3ccccc3c2)n[nH]c1=S

Procedure:
4-Methy-1-(2-naphthoyl)thiosemicarbazide (12.9 g, 4.97×10-2 mole) and 1 molar aqueous NaHCO3 (480 ml, 4.80×10-1 mole) were stirred and warmed to reflux. After refluxing overnight, the reaction was cooled in an ice bath before being acidified by the dropwise addition of concentrated hydrochloric acid (40 ml, 4.8×10-1 mole). The resulting product was collected by filtration and dried by suction. Crystallization from ethanol afforded beige needles, Mp 223°-225° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[C:10]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[Pd+2].[OH-]>[CH2:17]([C:10]1([CH2:15][CH3:16])[CH:11]([OH:14])[CH2:12][CH2:13][NH:8][CH2:9]1)[CH3:18]
Reactant: [H][H]
Reactant: CCC1(CC)CN(Cc2ccccc2)CCC1O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC1(CC)CNCCC1O

Procedure:
A mixture of 1-benzyl-3,3-diethyl-4-hydroxypiperidine (3.9 g, 15.85 mmole) and 20% palladium hydroxide (1.0 g) in methanol (100 ml) was stirred at 40° C. in hydrogen atmosphere (3.5 atm.) for 6 hr. Catalyst was filtered off, washed with methanol, filtrate was concentrated to dryness to give 3,3-diethyl-4-hydroxypiperidine as oil. Yield 1.8 g (73%), C9H19NO, m/z 158 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([CH2:13][CH:14]([C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[C:15](O)=[O:16])[N:10]=[C:9]1[CH2:27][CH2:28][CH2:29][CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:32]([O:39][C:40](=[O:53])[C@H:41]([CH2:43][C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[NH:46][CH:45]=1)[NH2:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C>[CH2:32]([O:39][C:40](=[O:53])[C@H:41]([CH2:43][C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[NH:46][CH:45]=1)[NH:42][C:15](=[O:16])[CH:14]([C:18]1[CH:23]=[CH:22][C:21]2[O:24][CH2:25][O:26][C:20]=2[CH:19]=1)[CH2:13][C:11]1[N:10]=[C:9]([CH2:27][CH2:28][CH2:29][CH3:30])[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:12]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCCCc1nc(CC(C(=O)O)c2ccc3c(c2)OCO3)cn1C(=O)OC(C)(C)C
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCc1nc(CC(C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)OCc2ccccc2)c2ccc3c(c2)OCO3)cn1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 30.1 %

Procedure:
To a solution of 3-(1-tert-butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionic acid (250 mg), L-tryptophan benzyl ester hydrochloride (209 mg) and triethylamine (128 mg) in N,N-dimethylformamide (5 ml) was added diphenylphosphoryl azide (198 mg) and the mixture was stirred at ambient temperature for 5.5 hours. The resulting mixture was diluted with ethyl acetate and the organic layer was washed successively with 0.5N hydrogen chloride aqueous solution, saturated sodium bicarbonate aqueous solution and brine. Drying, filtering and removal of the solvents afforded a crude product. The crude product was chromatographed on silica gel (eluent; n-hexane:ethyl acetate=1:2) to give [3-(1-tert-butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-tryptophan benzyl ester (125 mg) as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1>>[Br:7][C:8]1[CH:9]=[C:10]([S:14]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: C1CNCCN1
Product: O=S(=O)(c1cccc(Br)c1)N1CCNCC1

Procedure:
Using analogous procedures to those described in the portion of Example 58 which is concerned with the preparation of starting materials, piperazine was reacted with 3-bromophenylsulphonyl chloride to give 1-(3-bromophenylsulphonyl)piperazine which, in turn, was reacted with 3,5-dichlorophenylboronic acid to give 1-(3′,5′-dichlorobiphenyl-3-ylsulphonyl)piperazine in 29% yield;
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([S:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH3:6])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:22][C:23](C)=O>>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([S:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:22][CH3:23])=[CH:12][CH:13]=1)[CH3:6])[CH3:2]
Reactant: CC(C)=O
Reactant: CCOC(=O)C(C)Sc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(C)Sc1ccc(OCC)cc1

Procedure:
To stirred solution of 2-(4-hydroxy-phenylsulfanyl)-propionic acid ethyl ester (11.3 g, 50 mmol), and K2CO3 (50 g, excess) in acetone (300 ml) ethyl iodide (20 ml, excess) was added and refluxed for 8 hrs. At the end, reaction mixture was filtered and concentrated. The residue obtained was extracted with chloroform and washed well with water. It was dried and concentrared. The product, 2-(4-ethoxy-phenylsulfanyl)-propionic acid ethyl ester was isolated as colorless oil. Yield: 12.0 g, 98%; MS: 255 (M+H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14]C(=O)OC(C)(C)C)=[N:12][CH:13]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClCCl>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN2CCOCC2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(CN2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.2 %

Procedure:
To a solution of tert-butyl 5-(morpholinomethyl)pyridin-2-ylcarbamate (107; 1.40 g, 4.77 mmol) in dichloromethane (10 mL) was added TFA (10.0 mL). The mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure. Enough saturated aqueous Na2CO3 was added to the resulting residue to adjust the pH=9. The mixture was extracted with dichloromethane (3×25 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to afford 5-(morpholinomethyl)pyridin-2-amine 108 (0.85 g, 92%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:18][CH3:19])[C:10]=2[C:14]([F:17])([F:16])[F:15])[C:5]=1[C:20]([NH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:21].Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>O1CCCC1>[Br:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:18][CH3:19])[C:10]=2[C:14]([F:17])([F:16])[F:15])[C:5]=1[C:20]([N:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:21]
Reactant: CCOC(=O)NC(=O)c1c(Br)ccc2c(C(F)(F)F)c(OC)ccc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N(CC(=O)OC(C)(C)C)C(=O)c1c(Br)ccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 55 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Sodium hydride (80% by weight dispersion in mineral oil, 0.347 g, 1.1 eq) was added to a stirred solution of 2-bromo-N-(ethoxycarbonyl)-6-methoxy-5-(trifluoromethyl)-1-naphthalenecarboxamide (4.41 g, 10.5 mmol) in anhydrous tetrahydrofuran (150 mL) at room temperture under a dry nitrogen atmosphere. After 1 hour, the t-butyl bromoacetate (2.54 mL, 1.5 eq) was added and the reaction was heated to 55° C. After 11/2 hours of heating, the reaction was cooled to room temperature and the THF was removed. The residue was suspended in ether (250 mL), washed with water (2×100 mL) and saturated aqueous NaCl (1×50 mL), dried with magnesium sulfate, and the ether was removed. The resultant oil was triturated with petroleum ether (1×50 mL) to provide the title compound as a white powder (4.78 g, 85%). A small samle was recrystallized in ether-petroleum ether to provide white crystals for analysis, m.p. 109.5°-112° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[S:18](Cl)(=[O:20])=[O:19]>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[S:18]([NH:1][CH2:2][CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1)(=[O:20])=[O:19]
Reactant: Cn1cccc1CCN
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Product: Cn1cccc1CCNS(=O)(=O)c1cc(Cl)ccc1Cl

Procedure:
Prepared from 2-(2-aminoethyl)-1-methylpyrrole and 2,5-dichlorobenzenesulphonylchloride analogously to Example A.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]4[CH2:25][CH2:26][CH2:27][CH:18]34)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[C:28]1([NH:34][C:35](=[O:36])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[CH:10][C:11]([S:14]([N:17]4[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]5[CH2:25][CH2:26][CH2:27][CH:18]45)(=[O:16])=[O:15])=[CH:12][CH:13]=3)=[CH:4][CH:3]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
500 mg (1.30 mmol) of 1-(4′-aminobiphenyl-4-sulfonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid were dissolved in 3 ml of DMF, after which the solution was cooled down to 0° C. in an ice bath and 1.4 mmol of phenylisocyanate were added. The reaction solution was then stirred at RT for a further 4 h. The crude product was purified using chromatographic methods.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2[CH:26]=[O:27])=[CH:20]1.[F:32][C:33]([Si](C)(C)C)([F:35])[F:34].Cl>C1COCC1>[F:32][C:33]([F:35])([F:34])[CH:26]([C:25]1[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=1[C:21]1[CH:22]=[CH:23][O:19][CH:20]=1)[OH:27]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccccc1-c1ccoc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccccc1-c1ccoc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
Tetrabutylammonium fluoride (0.1 ml of 1M in THF) was added to a solution of 2-furan-3-yl-benzaldehyde (110 mg, 0.64 mmol) and trifluoromethyl trimethylsilane (109 mg, 0.78 mmol) in 10 ml THF at 0° C. The mixture was warmed up to room temperature and stirred for 4 hours. The mixture was then treated with 3 ml of 1M HCl and stirred overnight. The product was extracted with ethyl acetate (3×20 ml). The organic layer was separated and dried over sodium sulfate. The organic solvent was evaporated to give 0.130 g of 2,2,2-trifluoro-1-(2-furan-3-yl-phenyl)-ethanol, which was directly used in next step without purification (yield: 90%).