Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][CH2:5][CH2:6][OH:7]>ClCCl>[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][CH2:5][CH:6]=[O:7]
Reactant: OCCCCC(F)(F)F
Solvent: ClCCl
Product: O=CCCCC(F)(F)F
Reaction time: 4 h
Yield: 43.2 %

Procedure:
Combine 3,3,3-triacetoxy-3-iodophthalide (17.91 g, 1.2 eq) and dichloromethane (95 mL). Add 5,5,5-trifluoro-1-pentanol (5.00 g, 35.18 mmol) in dichloromethane (238 mL) dropwise under nitrogen. After 4 hours, filter the reaction mixture through Celite®. Concentrate the filtrate in vacuo; combine with 50 mL of dichloromethane and wash with 1:1 10% sodium thiosulphate:aqueous sodium hydroxide (1N). Dry the organics with anhydrous sodium sulfate, filter, and concentrate in vacuo to give 5,5,5-trifluoropentanal as a colorless oil (2.13 g, 43%). 1H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 2.50 (m, 2H), 2.21 (m, 2H), 1.66 (m, 2H).
Reaction SMILES: ClC1C=CC(SCC2[C:19]3[C:14](=[CH:15][CH:16]=[C:17](C4C=CC=CC=4OC)[CH:18]=3)[NH:13]C(C)(C)C=2)=CC=1.Br[CH2:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[O:48][CH3:49])[CH:40]=2)[NH:35][C:34]([CH3:51])([CH3:50])[CH:33]=1.C(=O)([O-])[O-].[K+].[K+].ClC1C=CC(S)=CC=1>>[CH3:49][O:48][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=1[C:39]1[CH:40]=[C:41]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([CH3:51])([CH3:50])[CH:33]=[C:32]2[CH2:31][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Reactant: COc1ccccc1-c1ccc2c(c1)C(CSc1ccc(Cl)cc1)=CC(C)(C)N2
Agent: O=C([O-])[O-]
Agent: Sc1ccc(Cl)cc1
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
4-(4-Chlorophenylsulfanylmethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline 100 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 80 mg of potassium carbonate, and 84 mg of 4-chloro benzenethiol reacted to give 10 mg of the title compound as a foam.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[O:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[CH2:14][OH:15]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:15][CH2:14][CH:10]2[CH2:11][CH2:12][CH2:13][O:9]2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OCC1CCCO1
Product: Brc1ccc(OCC2CCCO2)nc1

Procedure:
Prepared from 2,5-dibromopyridine and tetrahydrofuran-2-methanol by the method of Example 10 (b).
Reaction SMILES: Br[C:2]([F:6])=[C:3]([F:5])[F:4].C(=O)=O.[CH3:10][O:11][CH2:12][CH2:13][CH:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)Br>CN(C)C=O.CC1CC[C@@H](C(C)=C)CC=1.[Zn]>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH:14]([CH2:13][CH2:12][O:11][CH3:10])[C:2]([F:6])=[C:3]([F:5])[F:4])=[CH:21][CH:20]=1
Reactant: FC(F)=C(F)Br
Reactant: COCCC(Br)c1ccc(Cl)cc1
Agent: C=C(C)[C@H]1CC=C(C)CC1
Agent: O=C=O
Agent: [Zn]
Solvent: CN(C)C=O
Product: COCCC(C(F)=C(F)F)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 13.1 %

Procedure:
Bromotrifluoroethylene (41.5 g, 257 mmol) was distilled (dry ice condenser) into a flask containing zinc (13.6 g, 208 mmol) and N,N-dimethylformamide (153 ml), and the resulting mixture was heated at approximately 60° C. for two hours. The reaction mixture was purged with nitrogen for one hour, cooled to −8° C., treated with cuprous bromide (29.83 g, 208 mmol), and stirred for 30 minutes without external cooling. 3-(4-chlorophenyl)-3-bromopropyl methyl ether (17.06 g, 64.7 mmol) in N,N-dimethylformamide (10 ml) was added followed by limonene (5 drops), and the resulting mixture was heated at 50° C. for 8 hours. The cooled reaction mixture was quenched with aqueous ammonium chloride and thoroughly extracted with hexane. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to a brown oil (10.76 g). Chromatography on silica gel eluting with methylene chloride:hexane (1:9) afforded the title compound as a yellow oil (2.25 g), which was characterized by IR, 1HNMR and mass spectral analysis.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH:9]([CH3:11])[CH3:10].[OH:12]OS([O-])=O.[K+].[OH2:18]>CO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH:9]([CH3:11])[CH3:10])(=[O:12])=[O:18]
Reactant: CC(C)Sc1ccccc1Br
Reactant: O=S([O-])OO
Reactant: O
Agent: [K+]
Solvent: CO
Product: CC(C)S(=O)(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
To 21A (0.7 g, 3.0 mmol) in methanol (5 mL) was added oxone®8 (5.6 g, 9.0 mmol) in water (5 mL). The reaction was stirred at rt for 4 h. The reaction was quenched with 5% NaHSO3 and then neutralized with 1 M NaOH. The organic solvent was evaporated and the aqueous layer was extracted with dichloromethane (3×). The combined extracts were washed with brine and dried over sodium sulfate. The solvent was removed to give 0.53 g of product 21B (67% yield). 1H NMR (400 MHz, Methanol-d4) δ ppm 1.26 (d, J=6.85 Hz, 6H) 3.80-4.00 (m, 1H) 7.45-7.68 (m, 2H) 7.87 (dd, J=7.46, 1.59 Hz, 1H) 8.10 (dd, J=7.34, 2.20 Hz, 1H).
Reaction SMILES: [Br:1]Br.[OH:3][C@@H:4]1[C@@H:23]([O:24][CH2:25][CH3:26])[CH2:22][C@@:21]2([CH3:27])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:20]2[C:19](=[O:28])[CH2:18][C@@:17]2([CH3:29])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C:14](=[O:16])[CH3:15])[CH2:5]1.C(Cl)(=O)C.O>CO>[Br:1][CH2:15][C:14](=[O:16])[C@@H:13]1[C@:17]2([CH3:29])[C@H:10]([C@H:9]3[C@H:20]([C:19](=[O:28])[CH2:18]2)[C@:21]2([CH3:27])[C@H:6]([CH2:5][C@H:4]([OH:3])[C@@H:23]([O:24][CH2:25][CH3:26])[CH2:22]2)[CH2:7][CH2:8]3)[CH2:11][CH2:12]1
Reactant: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O
Reactant: BrBr
Solvent: CO
Solvent: O
Solvent: CC(=O)Cl
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(=O)CBr)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O
Reaction time: 2 h

Procedure:
Bromine (0.53 g.) in methanol (1.45 ml.) was added dropwise to a stirred solution of 3α-hydroxy-2β-ethoxy-5α-pregnane-11,20-dione (2.0 g) in methanol (15 ml) containing a trace of acetyl chloride at 0°. The addition took 2 hr. and the clear solution was then poured into water and collected by filtration, washed with water and dried in vacuo to give title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[CH2:6][CH2:5]1.[CH2:17]([C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[N:20]=1)[CH3:18].C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[CH2:17]([C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:2][CH2:3][CH:4]3[CH2:9][CH2:8][N:7]([C:10]4[N:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=4)[CH2:6][CH2:5]3)=[CH:26][CH:25]=2)[N:20]=1)[CH3:18]
Reactant: Cc1ccc(N2CCC(CCCl)CC2)nn1
Reactant: CCc1nc(-c2ccc(O)cc2)no1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCc1nc(-c2ccc(OCCC3CCN(c4ccc(C)nn4)CC3)cc2)no1
Temperature: 110 °C
Reaction time: 8 h
Yield: 33.2 %

Procedure:
A mixture of 3.12 parts of 3-[4-(2-chloroethyl)-1-piperidinyl]-6-methylpyridazine, 2.47 parts of 4-(5-ethyl-1,2,4-oxadiazol-3-yl)phenol, 1.38 parts of sodium carbonate and 94 parts of N,N-dimethylacetamide was stirred overnight at 110° C. After cooling, the reaction mixture was poured into water. The precipitate was filtered off, washed with water and dissolved in trichloromethane. This solution was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CHCl3 /CH3OH 97:3). The eluent of the desired fraction was evaporated and the residue was crystallized from 2-propanone. The product was filtered off and dried, yielding 1.7 parts (33.2%) of 3-[4-[2-[4-(5-ethyl-1,2,4-oxadiazol-3-yl)phenoxy]ethyl]-1-piperidinyl]-6-methylpyridazine; mp. 125.3° C. (comp. 6).
Reaction SMILES: [O:1]([C:8]1[CH:12]=[CH:11][S:10][C:9]=1[CH:13]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([S:21]([CH2:24][C:25]#[N:26])(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[O:1]([C:8]1[CH:12]=[CH:11][S:10][C:9]=1/[CH:13]=[C:24](/[S:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:22])=[O:23])\[C:25]#[N:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1sccc1Oc1ccccc1
Reactant: N#CCS(=O)(=O)c1ccccc1
Product: N#C/C(=C\c1sccc1Oc1ccccc1)S(=O)(=O)c1ccccc1

Procedure:
Reaction of 3-phenoxythiophen-2-carboxaldehyde and phenylsulfonylacetonitrile as in Example 1 gave (E)-3-(3-phenoxythien-2-yl)-2-(phenylsulfonyl)acrylonitrile.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][C@H:3]2[CH2:7][CH2:8][CH2:9][C@@H:2]12.F[C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][N:12]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[I:17][C:14]1[CH:15]=[CH:16][C:11]([N:1]2[C:5](=[O:6])[CH2:4][C@H:3]3[CH2:7][CH2:8][CH2:9][C@@H:2]23)=[N:12][CH:13]=1
Reactant: O=C1C[C@H]2CCC[C@H]2N1
Reactant: Fc1ccc(I)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1C[C@H]2CCC[C@H]2N1c1ccc(I)cn1
Temperature: 105 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
To a solution of (3aR,6aR)-hexahydrocyclopenta[b]pyrrol-2(1H)-one (210 mg, 1.68 mmol) and 2-fluoro-5-iodopyridine (412 mg, 1.85 mmol, 1.1 equiv.) in toluene (1.1 ml) were added Cs2CO3 (656 mg, 2.01 mmol, 1.2 equiv.) The reaction was stirred for 16 h at 105° C. The residue was taken up in ethyl acetate, the solids were filtered off and washed with ethyl acetate. The filtrate was concentrated in vaccuo and the residue was purified by flash chromatography (SiO2, 20 g) using a 0% to 60% ethyl acetate in heptane gradient. One obtains the title compound, (300 mg 55%), as a colorless oil, MS: m/e=329.4 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH:10]([CH3:15])[CH2:11][C:12]([OH:14])=O)=[C:6]([CH2:18][CH2:19][CH3:20])[C:5]=1[OH:21])(=[O:3])[CH3:2].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])[CH:23]=1>>[C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH:10]([CH3:15])[CH2:11][C:12]([NH:32][CH2:31][CH2:30][CH2:29][CH2:28][C:24]2[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=2)=[O:14])=[C:6]([CH2:18][CH2:19][CH3:20])[C:5]=1[OH:21])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCC(C)CC(=O)O)ccc(C(C)=O)c1O
Reactant: NCCCCc1cccnc1
Product: CCCc1c(OCC(C)CC(=O)NCCCCc2cccnc2)ccc(C(C)=O)c1O

Procedure:
4-(4-Acetyl-3-hydroxy-2-propylphenoxy)-3-methyl butanoic acid was allowed to react with 3-pyridinebutanamine according to procedure A and the product was purified by HPLC to give 4-(4-acetyl-3-hydroxy-2-propylphenoxy)-3-methyl-N-[4-(3-pyridinyl)butyl]-butanamide, the title compound, mp 58°-60° (from ethyl acetate-hexane) in 84% yield.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1([CH3:25])[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:11]2[CH:22]=[N:23][NH:24][C:10]1=2.C(O)C.[Cl:29]CCl>>[ClH:29].[ClH:29].[CH3:8][C:9]1([CH3:25])[CH2:14][NH:13][CH2:12][C:11]2[CH:22]=[N:23][NH:24][C:10]1=2
Reactant: CC(C)(C)OC(=O)N1Cc2cn[nH]c2C(C)(C)C1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CC1(C)CNCc2cn[nH]c21
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 0° C. 5 mL trifluoroacetic acid was added to 1.60 g (6.05 mmol) tert-butyl 7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylate (synthesised analogously to WO2005/065779) in 15 mL dichloromethane and the reaction mixture was stirred for 2 h at RT. Then the solvent was eliminated i. vac. The residue was combined with ethanol and evaporated down again i. vac. The residue was dissolved in ethanol and 12 mL of a 1.25 M ethanolic HCl solution were added. The mixture was again evaporated down i. vac. The residue was triturated with ethanol. The solid was suction filtered and dried.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH2:16][OH:17])SC=2C)[CH:5]=1.[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.O.[C:26]1(C)C=C[C:29]([S:32](O)(=O)=O)=[CH:28][CH:27]=1>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[S:32][C:29]([CH2:28][CH2:27][CH3:26])=[C:12]([CH2:16][O:17][CH:24]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[N:11]=2)[CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C1=COCCC1
Reactant: COC(=O)c1cccc(-c2nc(CO)sc2C)c1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1sc(-c2cccc(C(=O)OC)c2)nc1COC1CCCCO1

Procedure:
3-(2-hydroxymethyl-5-methyl-thiazol-4-yl)-benzoic acid methyl ester (0.38 g), dihydropyrane (0.73 mL) and p-toluenesulfonic acid hydrate (0.07 g) in AcOEt (10 mL) was stirred at 20° C. for 1 h. The solution was diluted with AcOEt, washed with 5% NaHCO3 solution and brine, dried and evaporated. The residual oil was purified by chromatography on silica gel using AcOEt/hexane (1:3) as eluent to give 3-[5-propyl-4-(tetrahydro-pyran-2-yloxymethyl)-thiazol-2-yl]-benzoic acid methyl ester (0.36 g) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.[I:11]N1C(=O)CCC1=O.CN(C=O)C.CC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([I:11])[C:3]=12
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1ncnc2[nH]ncc12
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: Clc1ncnc2[nH]nc(I)c12
Temperature: 50 °C
Reaction time: 16 h
Yield: 61.4 %

Procedure:
Charge 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (6.1 g, 1.0 eq), N-iodosuccinimide (NIS) (21.55 g, 2.0 eq) and DMF (213.5 mL) in a round bottom flask. Stir the reaction mass at 50° C. for 16 h. Monitor the reaction by TLC (10% acetone in DCM). Concentrate the reaction mass under reduced pressure. Charge ethyl acetate and wash with water and saturated aq. sodium chloride. Dry the organic layer over anhydrous sodium sulfate and concentrate the organic layer under reduced pressure to give 4-chloro-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (6.8 g, 61.43%).
Reaction SMILES: Br[CH:2](C)[C:3](OC)(OC)[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[CH:5]=1.[C:21](=O)([O-:23])[O-:22].[Ca+2].CN(C)C=O.O>C(OCC)C>[CH3:15][O:14][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[CH:5]=[C:4]([CH:3]([CH3:2])[C:21]([OH:23])=[O:22])[CH:13]=[CH:12]2
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2cc(C(OC)(OC)C(C)Br)ccc2c1
Agent: [Ca+2]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 95 %

Procedure:
A mixture of 2-bromo-1,1-dimethoxy-1-(6-methoxy-2-naphthyl)-propane (3.39 g; 10 mmol), calcium carbonate (1 g; 10 mmol), N,N-dimethylformamide (12 g) and of water (8 g) is heated at reflux under stirring for 7 h. The mixture is cooled to 25° C., added with diethyl ether (100 ml) and the insoluble is filtered. The resulting solution is washed with water and the solvent is removed in vacuo. The residue is added with 30% sodium hydroxide aqueous solution (10 ml) and with methanol (30 ml). The reaction mixture is refluxed for 2 h and then cooled to room temperature, the mixture is diluted with water (100 ml) and extracted with diethyl ether (2×30 ml). The aqueous phase is acidified with concentrated hydrochloric acid, the insoluble is filtered, washed with water and dried at 80° C. under vacuum to give 2-(6-methoxy-2-naphthyl)-propionic acid (2.18 g; 9.5 mmol; yield 95 %), m.p. 154°-155° C.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=[O:22])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=4)[NH:12][CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:25][N:26]1[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]1.[ClH:39]>C(Cl)Cl.O1CCOCC1>[ClH:39].[ClH:39].[OH:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=[O:22])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=4)[NH:12][CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ccc([N+](=O)[O-])cc24)C3=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1/C(=C/c2c[nH]c3ccc([N+](=O)[O-])cc23)Oc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
A solution of tert-butyl (Z)-4-({6-hydroxy-2-[(5-nitro-1H-indol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.020 g, 0.038 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The mixture was azeotroped twice with toluene under reduced pressure, and then the residual solid was suspended in methylene chloride and thereby washed to obtain (Z)-6-hydroxy-2-[(5-nitro-1H-indol-3-yl)methylene]-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one dihydrochloride (0.013 g, 69%).
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:27])[CH:15]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[CH2:16][CH:17]=[CH2:18])C1C=CC=CC=1.[O:28]1CCCC1.O.[OH-].[Li+].OO>O>[Cl:26][C:21]1[CH:20]=[C:19]([C@H:15]([CH2:16][CH:17]=[CH2:18])[C:14]([OH:27])=[O:28])[CH:24]=[CH:23][C:22]=1[Cl:25]
Reactant: C1CCOC1
Reactant: C=CCC(C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccc(Cl)c(Cl)c1
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: C=CC[C@H](C(=O)O)c1ccc(Cl)c(Cl)c1
Reaction time: 2 h

Procedure:
Combine (S)-4-benzyl-3-(2-(3,4-dichlorophenyl)pent-4-enoyl)-2-oxazolidinone (13.7 g, 34.0 mol), tetrahydrofuran (300 mL), and water (60 mL). Cool in an ice bath. Add lithium hydroxide hydrate (1.7 g, 71.0 mmol) and an aqueous solution of hydrogen peroxide (12 mL, 30% 140 mmol). After 2 hours, quench by the addition of an aqueous 10% sodium thiosulfate solution (100 mL). Add an aqueous 1 M sodium hydroxide solution and extract twice with diethyl ether. Cool the aqueous layer in an ice bath, acidify with an aqueous concentrated hydrochloric acid solution (about 20 mL), and extract twice with dichloromethane. Combine the organic layers, dry over MgSO4, filter, and evaporate in vacuo to give (S)-2-(3,4-dichlorophenyl)pent-4-enoic acid.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:41][C:42]([N:44]([CH3:51])[CH2:45][C@@H:46]1[CH2:50][CH2:49][CH2:48][O:47]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:41][CH2:42][N:44]([CH3:51])[CH2:45][C@@H:46]2[CH2:50][CH2:49][CH2:48][O:47]2)=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CN(C[C@@H]1CCCO1)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN(C)C[C@@H]2CCCO2)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 27.7 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and 2-chloro-N-methyl-N-[(S)-tetrahydrofuran-2-ylmethyl]acetamide (10 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (4.8 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:18](=[O:19])[CH:17]=[C:16]([CH3:20])[NH:15][C:14]=3[CH3:21])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Cl:24]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:24][C:17]1[C:18](=[O:19])[C:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:22]=[CH:23][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:12][CH:11]=2)=[C:14]([CH3:21])[NH:15][C:16]=1[CH3:20]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(=O)c(-c2ccc(Oc3ccc(Cl)cc3)cc2)c(C)[nH]1
Solvent: CC(=O)O
Product: Cc1[nH]c(C)c(-c2ccc(Oc3ccc(Cl)cc3)cc2)c(=O)c1Cl
Temperature: 25 °C
Yield: 37.3 %

Procedure:
To a stirred solution of 3-(4-(4-chlorophenoxy)phenyl)-2,6-dimethylpyridin-4(1H)-one (0.8 g) in acetic acid (10 ml) was added N-chlorosuccinimide (0.39 g). The mixture was heated at 100° for 30 min, cooled to room temperature and the precipitate filtered and dried in vacuo to afford the title compound (0.33 g), m.p. 340°-343°, NMR δH (d6 -DMSO) 11.3 (1H, br.s), 7.42 (2H, m), 7.2 (2H, m), 6.95-7.12 (4H, m), 2.4 (3H, s), 2.1 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.Br.[Br:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[Na+].[Na+]>CO>[BrH:14].[N:1]1([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[NH:10][C:9](=[O:12])[CH2:8][CH2:7]3)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: Nc1cccc2c1NC(=O)CC2
Reactant: BrCCNCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CCc2cccc(N3CCNCC3)c2N1
Reaction time: 9 h
Yield: 16.6 %

Procedure:
8-Amino-3,4-dihydrocarbostyril (7.5 g, 46.2 mmols) and bis(β-bromoethyl)amine hydrobromide (15.9 g, 50.8 mmols) were suspended in methanol and the suspension was heated under reflux while stirring for 9 hours. After adding 2.5 g of sodium carbonate, the reaction mixture was further heated under reflux for 8 hours while stirring, and stirred on an ice bath for 1 hours. Crystals which precipitated were collected by filtration. The crude crystals thus obtained were recrystallized from methanol-ether to give 2.4 g of 8-(1-piperazinyl)-3,4-dihydrocarbostyril hydrobromide, m.p. above 300° C., colorless needles.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[P:11]([Cl:16])(Cl)(Cl)(Cl)[Cl:12].Cl.C(O)=[O:19]>C(Cl)(Cl)(Cl)Cl>[Cl:12][P:11]([Cl:16])([NH:8][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:19]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=CO
Reactant: Cc1ccc(C(N)=O)cc1
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(C(=O)NP(=O)(Cl)Cl)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 53 g (0.39 mole) of 4-methylbenzamide, 81.7 g (0.39 mole) of phosphorus pentachloride and 500 ml of AR carbon tetrachloride was heated at 60°-70° until the HCl gas evolution had ceased. Solution was cooled to 30° where 18.6 g (0.39 mole) of 97% formic acid was added. Continued to stir for 30 min. following the addition, then filtered, washed with AR carbon tetrachloride and air-dried to give 74.5 g, m.p. 96.5°-98°.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][CH2:6][C:7]1[N:8]([C:20]2[S:21][CH:22]=[C:23]([C:25](=[O:27])[NH2:26])[N:24]=2)[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)C.[Li+].[OH-]>CO.C1COCC1>[C:25]([C:23]1[N:24]=[C:20]([N:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:10][CH:11]=[C:7]2[CH2:6][CH2:5][C:4]([OH:28])=[O:3])[S:21][CH:22]=1)(=[O:27])[NH2:26]
Reactant: CCOC(=O)CCc1ccc(-c2ccc(OC)cc2)n1-c1nc(C(N)=O)cs1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2ccc(CCC(=O)O)n2-c2nc(C(N)=O)cs2)cc1
Reaction time: 24 h

Procedure:
To 3-[1-(4-Carbamoyl-thiazol-2-yl)-5-(4-methoxy-phenyl)-1H-pyrrol-2-yl]-propionic acid ethyl ester (0.15 mmol) in a 2:1 mixture of methanol/THF was added 2M LiOH (0.30 mmol). The reaction mixture was stirred for 24 hours. The solvent was removed in vacuo. The residue was diluted with water (2 mL) and extracted with ethyl ether. The pH of the aqueous layer was adjusted to 2 with 1N HCl. The resulting suspension was filtered; the solid was washed with water and dried to give the final compound. Yield: 36 mg, 69%.
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)=[O:7])=[CH:4][C:3]=1[S:20](=[O:28])(=[O:27])[NH:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25].[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[CH2:29]([NH:36][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)=[O:7])=[CH:4][C:3]=1[S:20](=[O:28])(=[O:27])[NH:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCc1ccccc1
Reactant: CC(C)CCNS(=O)(=O)c1cc(C(=O)NC2CCc3ccccc32)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)CCNS(=O)(=O)c1cc(C(=O)NC2CCc3ccccc32)ccc1NCc1ccccc1
Yield: 27.2 %

Procedure:
A solution of 100 mg of 4-fluoro-N-indan-1-yl-3-(3-methylbutylsulfamoyl)benzamide (Example 41), 29 mg of benzylamine, and 100 mg of potassium carbonate in 4 ml of N,N-dimethylacetamide was heated to 100° C. for 6 h. After the addition of water, extraction with EA, and chromatographic separation, 33 mg of 4-benzylamino-N-indan-1-yl-3-(3-methylbutylsulfamoyl)benzamide were obtained.