Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:17]([CH:21]=2)[C:18](O)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[F:30][C:31]([F:40])([F:39])[C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[C:17]([CH:21]=2)[C:18]([NH:36][C:35]2[CH:37]=[CH:38][C:32]([C:31]([F:39])([F:40])[F:30])=[CH:33][CH:34]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccccc3)c(C(=O)O)c2)=C(C)C1=O
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccccc3)c(C(=O)Nc3ccc(C(F)(F)F)cc3)c2)=C(C)C1=O
Reaction time: 16 h
Yield: 9.1 %

Procedure:
5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-phenylbenzoic acid (40 mg, 0.1020 mmol) was dissolved in methylene chloride (5 ml), then 4-trifluoromethylaniline (25 mg, 0.1552 mmol), triethylamine (21 mg, 0.2079 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (52 mg, 0.3076 mmol) were added thereto and the mixture was stirred for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (hexane:ethyl acetate=3:1) to give the title compound (5 mg, 0.0093 mmol, 9%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[ClH:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([NH:16][C:17]([C:19]1[S:20][C:21]3[C:27](Br)=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2.[CH3:29][O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([NH:16][C:17]([C:19]1[S:20][C:21]3[C:27]([C:35]4[CH:34]=[CH:33][CH:32]=[C:31]([O:30][CH3:29])[CH:36]=4)=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2s1
Reactant: COc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Temperature: 80 °C

Procedure:
0.16 ml of 2 M aqueous sodium carbonate solution and 4.2 mg (0.005 mmol) of PdCl2(dppf) are added to a mixture of 49 mg (0.10 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 15.8 mg (0.10 mmol) of 3-methoxyphenylboronic acid in 1 ml of DMF. The reaction mixture is heated at 80° C. for 14 h, then filtered through kieselguhr and evaporated to dryness. Purification of the crude product by preparative HPLC, subsequent addition of 1N hydrochloric acid and drying under high vacuum result in 8.0 mg (18% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH2:34][CH:35]=[CH2:36])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[N:12]=2)[N:7](COCC[Si](C)(C)C)[CH:6]=1)=[O:4].O.O.O.C([O-])(=O)C.[Na+]>ClCCl.FC(F)(F)C(O)=O>[CH3:1][C:2]([CH3:37])([CH2:34][CH:35]=[CH2:36])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[N:12]=2)[NH:7][CH:6]=1)=[O:4]
Reactant: C=CCC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cc(OC)c(OC)c(OC)c3)nc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: C=CCC(C)(C)C(=O)c1c[nH]c2ncc(-c3cc(OC)c(OC)c(OC)c3)nc12
Reaction time: 96 h
Yield: 50.2 %

Procedure:
A solution of 2,2-dimethyl-1-[2-(3,4,5-trimethoxy-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-pent-4-en-1-one (0.127 g, 0.242 mmol) in 4 mL of dichloromethane and 1 mL of trifluoroacetic acid was stirred for 3 h, then concentrated. The residue was taken up in 2 mL of ethanol (not all dissolves) and treated with sodium acetate trihydrate (0.329 g, 2.42 mmol). The mixture was stirred for 4 d, then concentrated to a residue. Column chromatography (0→5% MeOH/CH2Cl2) afforded 0.048 g (50%) of 2,2-dimethyl-1-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-pent-4-en-1-one as a white solid.
Reaction SMILES: Br.Br.[NH2:3][C:4]1[C:8]([NH2:9])=[CH:7][S:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[Cl:19][C:20]1[S:21][CH:22]=[C:23]([CH3:28])[C:24]=1[N:25]=[C:26]=[S:27]>C1COCC1>[NH2:9][C:8]1[C:4]([NH:3][C:26]([NH:25][C:24]2[C:23]([CH3:28])=[CH:22][S:21][C:20]=2[Cl:19])=[S:27])=[CH:5][S:6][CH:7]=1
Reactant: Cc1csc(Cl)c1N=C=S
Reactant: Nc1cscc1N
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc(Cl)c1NC(=S)Nc1cscc1N
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
0.55 g of 3,4-diaminothiophene dihydrobromide was added to a solution of 0.51 g of N-ethyl-N,N-diisopropylamine in 30 ml of anhydrous THF, the mixture was stirred at room temperature for approx. 5 minutes and the solution was then admixed with a mixture of 0.4 g of 2-chloro-4-methyl-3-thienyl isothiocyanate in 5 ml of THF. The mixture was stirred at room temperature for 3 hours and at 40° C. for 10 minutes. After it had been left to stand overnight, the solvent was distilled off, and the residue was treated with water and extracted with ethyl acetate. The insoluble fraction was filtered off, and the organic phase was washed with water and dried over sodium sulfate. After the solvent had been distilled off, the product was purified by column chromatography on silica gel using a mixture of 1 part by volume of toluene and 1 part by volume of ethyl acetate and, after the solvent had been distilled off, the N-(4-amino-3-thienyl)-N′-(2-chloro-4-methylthienyl)thiourea was obtained as a crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:18][CH3:19].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:18][CH3:19])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(Br)cc1C=O
Temperature: 90 °C
Reaction time: 3 h

Procedure:
In DMF (150 ml) was dissolved 5-bromosalicylaldehyde (18.6 g). To the mixture was added at room temperature potassium carbonate (16.6 g) and then was added iodoethane (17.3 ml), and the mixture was stirred at 90° C. for 3 hours and cooled to room temperature. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=8/1) to give 5-bromo-2-ethoxybenzaldehyde (17.2 g).
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9]([C:18]2[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH:21]=[CH:20][CH:19]=2)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[CH3:28][C:29]1([CH3:63])[C:53]2[C:33]([CH:34]=[C:35]3[CH:52]=[C:51]4[C:38]([C:39]5[C:44]([C:45]6[C:50]4=[CH:49][CH:48]=[CH:47][CH:46]=6)=[CH:43][CH:42]=[CH:41][CH:40]=5)=[CH:37][C:36]3=2)=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30]1.C([O-])([O-])=O.[Na+].[Na+].CCO>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.C1(C)C=CC=CC=1>[CH3:63][C:29]1([CH3:28])[C:53]2[C:33]([CH:34]=[C:35]3[CH:52]=[C:51]4[C:38]([C:39]5[C:44]([C:45]6[C:50]4=[CH:49][CH:48]=[CH:47][CH:46]=6)=[CH:43][CH:42]=[CH:41][CH:40]=5)=[CH:37][C:36]3=2)=[CH:32][C:31]([C:2]2[C:15]3[C:16]4=[C:17]5[C:12](=[CH:13][CH:14]=3)[CH:11]=[CH:10][C:9]([C:18]3[C:27]6[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=6)[CH:21]=[CH:20][CH:19]=3)=[C:8]5[CH:7]=[CH:6][C:5]4=[CH:4][CH:3]=2)=[CH:30]1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Reactant: Brc1ccc2ccc3c(-c4cccc5ccccc45)ccc4ccc1c2c43
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)C=C(c2ccc3ccc4c(-c5cccc6ccccc56)ccc5ccc2c3c54)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Temperature: 90 °C
Yield: 46.8 %

Procedure:
A mixture of 7 g (17.2 mmol) of 1-bromo-6-(naphthalen-1-yl)pyrene, 8.1 g (17.2 mmol) of 2-(10,10-dimethyl-10H-indeno[1,2-b]triphenylen-12-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 0.2 g (0.172 mmol) of Tetrakis(triphenylphosphine)Palladium, 13 ml of 2M Na2CO3, 30 ml of EtOH and 100 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 24 h. After the reaction finish, the mixture was allowed to cool to room temperature. Than 500 ml MeOH was added, while stirring and the precipitated product was filtered off with suction. To give 5.4 g (yield 47%) of yellow product which was recrystallized from toluene. MS(m/z,FAB+): 670.1; 1H NMR (CDCl3, 400 MHz): chemical shift(ppm) 9.11 (s, 1H), 8.89 (d, J=8.00 Hz, 1H), 8.82 (d, J=8.00 Hz, 1H), 8.78 (s, 1H), 8.72 (d, J=8.00 Hz, 2H), 8.38 (d, J=9.20 Hz, 1H), 8.30˜8.26 (m, 3H), 8.19˜8.05 (m, 7H), 8.02˜7.98 (m, 2H), 7.83˜7.82 (m, 2H), 7.78˜7.68 (m, 5H), 7.61˜7.59 (m, 2H), 1.79 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1.[H-].[Na+].Cl[CH2:21][C:22]1[N:23]=[C:24]([CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=2)[O:25][CH:26]=1.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([O:17][CH2:21][C:22]2[N:23]=[C:24](/[CH:27]=[CH:28]/[C:29]3[CH:30]=[CH:31][C:32]([O:35][C:36]([F:39])([F:37])[F:38])=[CH:33][CH:34]=3)[O:25][CH:26]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1
Reactant: FC(F)(F)Oc1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: Oc1ccc(COCCn2ccnn2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cc(OCc2coc(/C=C/c3ccc(OC(F)(F)F)cc3)n2)ccc1COCCn1ccnn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 201 mg (0.847 mmol) 3-Fluoro-4-(2-[1,2,3]triazol-1-yl-ethoxylmethyl)-phenol in 5 ml dimethylformamide was treated with 22.5 mg ( 0.890 mmol) 95% sodium hydride and stirred at room temperature for 20 min, then 257 mg (0.847 mmol) 4-chloromethyl-2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazole were added and stirring continued for 14 h. After addition of water, the precipitate was isolated, washed thoroughly with water, twice with ether and dried to give 1-[2-(2-fluoro-4-{2-[2-(E)-(4-trifluoromethoxy-phenyl)-vinyl]-oxazol-4-ylmethoxy}-benzyloxy)-ethyl]-1H-[1,2,3]triazole.
Reaction SMILES: [Br:1][C:2]1[O:3][C:4]2[C:16]([Br:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:18][C:14]1[CH:15]=[C:16]([Br:17])[C:4]2[O:3][C:2]([Br:1])=[C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:5]=2[CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Br)c2oc(Br)c(-c3ccccc3)c2c1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cc(Br)c2oc(Br)c(-c3ccccc3)c2c1
Reaction time: 1 h

Procedure:
A mixture containing 68.7 g. (0.19 mole) of 2,7-dibromo-5-methyl-3-phenylbenzofuran and 35.5 g. (0.19 mole) of N-bromosuccinimide in one liter of carbon tetrachloride is irradiated with a bulb simulating sunlight for two hours. An additional 10 g. of N-bromosuccinimide is added, and irradiation is continued for one hour. The mixture is cooled and filtered. The filtrate is evaporated to a brown oil which crystallizes when triturated with hexane to provide solid 5-bromomethyl-2,7-dibromo-3-phenylbenzofuran.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=3[O:19][CH3:20])[CH:14]=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH3:21][C@@H:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([C@H:22]([NH:29][CH2:14][C:13]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:2]([CH3:1])[CH:3]=[CH:4]4)[CH:12]=2)[CH3:21])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: COc1ccc(C=O)cc1-c1ccc2c(ccn2C)c1
Product: COc1ccc(CN[C@H](C)c2ccccc2)cc1-c1ccc2c(ccn2C)c1

Procedure:
The title compound was prepared from 3-(1-methylindol-5-yl)-4-methoxybenzaldehyde and (R)-α-methylbenzylamine according to general procedure C.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([CH2:14][OH:15])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:16]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([CH:14]=[O:15])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:16]
Reactant: Cc1nc2ccc(CO)cc2n1Cc1ccccc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: Cc1nc2ccc(C=O)cc2n1Cc1ccccc1Cl
Yield: 97.5 %

Procedure:
Manganese dioxide (3.46 g) was added to a solution of 3.46 g of 1-(2-chlorobenzyl)-6-hydroxymethyl-2-methylbenzimidazole in 100 ml of toluene, and toluene was heat-refluxed for 3.5 hours while the mixture was dehydrated using a molecular sieve 4A. The solid material was separated through filtration, and was washed with chloroform. The filtrate was concentrated to give 3.35 g of 1-(2-chlorobenzyl)-6-formyl-2-methylbenzimidazole.
Reaction SMILES: [CH2:1]([NH:5][NH2:6])[CH2:2][CH:3]=[CH2:4].[Cl:7][C:8]1[N:13]=[C:12](Cl)[C:11]([C:15]([NH:17][C:18]2[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:25])=[O:16])=[CH:10][N:9]=1.C(N(CC)CC)C>C1COCC1>[CH2:1]([N:5]([C:12]1[C:11]([C:15]([NH:17][C:18]2[C:19]([Cl:25])=[CH:20][CH:21]=[CH:22][C:23]=2[Cl:24])=[O:16])=[CH:10][N:9]=[C:8]([Cl:7])[N:13]=1)[NH2:6])[CH2:2][CH:3]=[CH2:4]
Reactant: O=C(Nc1c(Cl)cccc1Cl)c1cnc(Cl)nc1Cl
Reactant: C=CCCNN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCCN(N)c1nc(Cl)ncc1C(=O)Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 25 h

Procedure:
A solution of 230 mg (2.7 mmol) of 3-butenylhydrazine in 10.5 mL of THF was cooled to 0° C. and treated sequentially with 800 mg (2.4 mmol) of 2,4-dichloro-N-(2,6-dichlorophenyl)pyrimidine-5-carboxamide and 370 μl (2.6 mmol) of triethylamine. The resulting yellow slurry was warmed to room temperature and stirred for 25 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (15 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was purified by chromatography on silica gel (eluens CH2Cl2:MeOH, 99.5:0.5) to give the title compound 85. 1H-NMR (DMSO-d6) δ 3.17 (d, J=5.2 Hz, 2H), 3.31 (s, 2H), 3.80 (t, J=7.3 Hz, 2H), 5.04 (d, J=10.3 Hz, 1H), 5.13 (d, J=17.1 Hz, 1H), 5.77-5.88 (m, 1H), 7.35 (t, J=8.3 Hz, 1H), 7.55 (d, J=8.2 Hz, 2H), 8.15 (s, 1H), 10.19 (s, 1H). Mass Spectrum (ESI) m/e=385.9 (M+1).
Reaction SMILES: C(Cl)Cl.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[N+:12]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)([O-:14])=[O:13].[CH3:24][O:25][C:26]([C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[C:30](Cl)[CH:29]=1)=[O:27]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C.O1CCOCC1>[CH3:24][O:25][C:26]([C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[C:30]([C:18]2[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=2)[CH:29]=1)=[O:27]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(Cl)nc2ccccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)nc2ccccc12
Temperature: 85 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
PdCl2(dppf).CH2Cl2 (184 mg, 0.23 mmol), tripotassium phosphate (624 mg, 4.51 mmol), and 4-nitrophenylboronic acid (958 mg, 4.51 mmol) were added to a 1,4-dioxane (5 mL)/DMF (1 mL) mixed solution of 2-chloro-4-quinolinecarboxylic acid methyl ester (500 mg, 2.26 mmol) obtained in Reference Example 3, and the mixture was heated with stirring overnight at 85° C. in an argon atmosphere. After the reaction solution was concentrated, to the residue, a saturated aqueous solution of sodium chloride and methylene chloride were added, and insoluble matter was filtered off through celite. After that, the residue was subjected to extraction with methylene chloride and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography to obtain 2-(4-nitrophenyl)-4-quinolinecarboxylic acid methyl ester (549 mg, 1.78 mmol).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+]>>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1
Reactant: CCOC(=O)CCCOc1ccc(CCCO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(O)CCCOc1ccc(CCCO)cc1

Procedure:
After the method of Preparation 3, 4.13 g (15.51 mmol) of 4-[4-(3-hydroxypropyl)phenoxy]butanoic acid, ethyl ester is saponified with potassium carbonate to produce a solid. This is recrystallized from an ethyl acetate-hexane mixture giving 2.45 (66%) of 4-[4-(3-hydroxypropyl)phenoxy]butanoic acid as white crystals: m.p. 92°-94° C.; IR (KBr) 3420 (br.), 1710 cm-1 ; 1 H-NMR (CDCl3) is consistent with the desired product; MS (CI) m/e 239 (M+ +H). Analysis calculated. for C13H18O4 : C, 65.53; H, 7.61; O, 26.86. Found: C, 65.75; H, 7.87; O, 26.38.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:22]=[C:21]([C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:30])[CH:20]=[CH:19][C:11]=1[C:12]([O:14]C(C)(C)C)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[C:1]([NH:9][C:10]1[CH:22]=[C:21]([C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:30])[CH:20]=[CH:19][C:11]=1[C:12]([OH:14])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2c(F)cccc2Cl)cc1NC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2c(F)cccc2Cl)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 mL of trifluoroacetic acid was added to the obtained tert-butyl 2-(benzamido)-4-(2-chloro-6-fluorophenyl)benzoate and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and toluene was added. The solvent was evaporated under reduced pressure and the obtained residue was purified with reversed-phase silica gel column chromatography [eluent; 70-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to obtain 5.8 mg of 2-(benzamido)-4-(2-chloro-6-fluorophenyl)benzoic acid as white solid.
Reaction SMILES: BrC[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[OH:23]>>[Cl:14][C:11]1[CH:12]=[CH:13][C:4]([CH2:3][O:23][C:17]2[C:16]([F:15])=[CH:21][CH:20]=[CH:19][C:18]=2[F:22])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(Cl)ccc1CCBr
Reactant: Oc1c(F)cccc1F
Product: COC(=O)c1cc(Cl)ccc1COc1c(F)cccc1F

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from methyl 2-(bromoethyl)-5-chlorobenzoate and 2,6-difluorophenol:
Reaction SMILES: [NH2:1][C@H:2]([CH2:22][CH3:23])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[CH:14]=2)=[CH:10][CH:11]=1)=[O:4].C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH2:22]([C@H:2]1[NH:1][C:32](=[O:34])[N:5]([C:6]2[CH:7]=[N:8][C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:20])[CH3:21])[CH:14]=3)=[CH:10][CH:11]=2)[C:3]1=[O:4])[CH3:23]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC[C@@H](N)C(=O)Nc1ccc(Oc2cccc(C(C)C)c2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H]1NC(=O)N(c2ccc(Oc3cccc(C(C)C)c3)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(2R)-2-amino-N-(6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)butanamide (Intermediate 70, 930 mg) was dissolved in dry dichloromethane (100 mL). The reaction mixture, under argon, was cooled down in an ice bath. Triethylamine (2.482 mL, 17.81 mmol) was added. Then a solution of triphosgene in dry dichloromethane (352 mg, 1.187 mmol dissolved in 40 mL of dichloromethane) was added dropwise. The reaction mixture was stirred at 0° C., under argon, during 10 min. A saturated aqueous solution of NaHCO3 was added (100 mL) and the aqueous layer was extracted with dichloromethane 4 times (4×80 mL). After drying over sodium sulphate, the solvent was removed under vacuum. The residue obtained was purified by silica gel chromatography (Companion system, 120 g silica cartridge,) with a gradient cyclohexane/ethyl acetate 100/0 to 55/45. The title compound (5R)-5-ethyl-3-(6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione was obtained as a beige powder (768 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1Br)([CH3:4])([CH3:3])[CH3:2].[CH2:15]([OH:19])[CH2:16][CH:17]=[CH2:18]>CC([O-])=O.CC([O-])=O.[Pd+2].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.C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[CH:18]=[CH:17][CH2:16][CH2:15][OH:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1Br
Reactant: C=CCCO
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1C=CCCO
Temperature: 120 °C

Procedure:
A mix of 1-(tert-butyl)-2-bromo-4-nitrobenzene (3.652 g), TEA (5.92 ml), 3-buten-1-ol (5.48 ml), Pd(OAc)2 (32 mg), Pd(PPh3)4 (327 mg) and toluene (40 ml) was degassed with nitrogen and heated in a sealed vessel for 16 h at 120° C. The next day, the reaction mixture was cooled to RT, filtered, and concentrated in vacuo. The crude was eluted on a silica gel column with 15% to 22% EtOAc/hexanes gradient system to yield a yellow-brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:28][C:18]4[CH:19]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[NH:20][CH2:21][CH2:22][C:17]=4[C:15]=3[CH:16]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.F[C:30]1C=C(S(C2C=CC3OC=C(CCNC(=O)OC(C)(C)C)C=3C=2)(=O)=O)C=CC=1.C(N)(=O)C.O1CCOC1CNC.C(OC(=O)C)(=O)C>>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:28][C:18]4[CH:19]([CH2:23][N:24]([CH3:30])[C:25](=[O:27])[CH3:26])[NH:20][CH2:21][CH2:22][C:17]=4[C:15]=3[CH:16]=2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCc1coc2ccc(S(=O)(=O)c3cccc(F)c3)cc12
Reactant: CC(=O)NCC1NCCc2c1oc1ccc(S(=O)(=O)c3cccc(F)c3)cc21
Agent: CC(N)=O
Agent: CNCC1OCCO1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N(C)CC1NCCc2c1oc1ccc(S(=O)(=O)c3cccc(F)c3)cc21

Procedure:
Prepared as described for N-({6-[(3-fluorophenyl)sulfonyl]-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridin-1-yl}methyl)acetamide using tert-butyl (2-{5-[(3-fluorophenyl)sulfonyl]-1-benzofuran-3-yl}ethyl)carbamate and N-[1,3]dioxolan-2-ylmethyl-methyl)-acetamide, which was prepared from [1,3]dioxolan-2-ylmethyl-methyl-amine and acetic anhydride. MS m/z 417 [M+H]+.