Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:9](=[O:16])[C@@H:10]1[CH2:14][C@H:13]([Cl:15])[CH2:12][NH:11]1)=O)(C)(C)C.Cl.[CH2:22]([N:29]([C@@H:37]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C@H:38]([OH:42])[C:39](O)=[O:40])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.P(C#N)(OCC)(OCC)=O>O1CCOCC1.CN(C)C=O.C(N(CC)CC)C>[CH2:22]([N:29]([C@@H:37]([CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[C@H:38]([OH:42])[C:39]([N:11]1[CH2:12][C@@H:13]([Cl:15])[CH2:14][C@H:10]1[C:9]([NH:8][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:16])=[O:40])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)[C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N(C(=O)[C@@H]1C[C@H](Cl)CN1)C(C)(C)C
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 24 h
Yield: 88.9 %

Procedure:
12.2 g (0.04 mol) of (4S)-N-t-butoxycarbonyl-4-chloro-N-t-butyl-L-prolinamide were treated with 50 ml of a 4N solution of hydrogen chloride in dioxane, in order to remove the t-butoxycarbonyl group. The product thus obtained and 15.0 g (0.04 mol) of (2S,3S)-3-(N,N-dibenzylamino)-2-hydroxy-4-phenylbutyric acid were dissolved in 50 ml of dimethylformamide, and the solution was cooled with ice. 8.48 ml (52.0 mmol) of diethyl cyanophosphate, and then 11.2 ml (0.08 mmol) of triethylamine, were then added dropwise to the resulting mixture, which was then stirred for 1 day. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the concentrate was diluted with ethyl acetate. The diluted solution was washed with a 5% w/v aqueous solution of citric acid and with a 5% w/v aqueous solution of sodium hydrogencarbonate, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography, using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent, to give 20.0 g of the title compound as a colorless powder, melting at 64°-67° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[C:5]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])=[CH:4][CH:3]=1.FC(F)(F)S(O)(=O)=O.[I:41]N1C(=O)CCC1=O>CC#N.C(Cl)Cl>[I:41][C:3]1[CH:4]=[C:5]([C:19]([NH:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=2)=[O:20])[C:6](=[O:18])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)[C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ccc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC#N
Product: Cc1c(I)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 0.75 h

Procedure:
To a solution of 6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (200 mg, 0.43 mmol) in MeCN (1.5 ml) at RT and under argon, was added trifluoromethanesulfonic acid (1 ml) followed by N-iodosuccinimide (97 mg, 0.43 mmol). After 45 min, the reaction mixture was diluted with DCM, washed with aqueous NaHCO3, with aqueous NaS2O4 and water, dried (Na2SO4), and evaporated to give the title compound SM1 (200 mg).
Reaction SMILES: [I-].C[N+]1C=CN([C:8](=[O:30])/[N:9]=[C:10]2\[S:11][C:12]([CH3:29])=[CH:13][N:14]\2[C:15]2[CH:28]=[CH:27][C:18]3[O:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[O:22][C:17]=3[CH:16]=2)C=1.[NH:31]1[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32]1.CCN(C(C)C)C(C)C>C(#N)C.C(Cl)Cl>[OH:36][C@H:33]1[CH2:34][CH2:35][N:31]([C:8](/[N:9]=[C:10]2\[S:11][C:12]([CH3:29])=[CH:13][N:14]\2[C:15]2[CH:28]=[CH:27][C:18]3[O:19][C:20]([F:26])([F:25])[C:21]([F:23])([F:24])[O:22][C:17]=3[CH:16]=2)=[O:30])[CH2:32]1
Reactant: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)n2cc[n+](C)c2)s1
Reactant: O[C@H]1CCNC1
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)N2CC[C@H](O)C2)s1

Procedure:
A solution of (Z)-3-methyl-1-(5-methyl-3-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thiazol-2(3H)-ylidenecarbamoyl)-1H-imidazol-3-ium iodide (Example 81A, 0.1 g, 0.18 mmol), (S)-pyrrolidin-3-ol (0.016 g, 0.18 mmol) and Hunig's base (0.023 g, 018 mmol) in dry acetonitrile (5 mL) was heated to 60° C. for three hours. After cooling, the mixture was diluted with CH2Cl2 (50 mL) and washed with water and brine. The organic phase was dried over sodium sulfate, filtered and dried. After evaporation under reduced pressure, the residue was chromatographed over silica using CH2Cl2 and then 2% MeOH/CH2Cl2 to give the titled compound. 1H NMR (CDCl3) δ ppm 1.99 (2H), 2.20 (3H), 3.40-3.70 (4H), 4.42 (1H), 6.60 (1H), 7.20-7.50 (3H); MS (ESI) m/z 434(M+H).
Reaction SMILES: [F:1][C:2]([Cl:6])([Cl:5])[S:3]Cl.[Cl:7][C:8]1[CH:9]=[C:10]([N:15]2[C:19](=[O:20])[CH2:18][NH:17][C:16]2=[O:21])[CH:11]=[CH:12][C:13]=1[CH3:14].C(N(CC)CC)C>C(OC(=O)C)C>[Cl:5][C:2]([Cl:6])([F:1])[S:3][N:17]1[CH2:18][C:19](=[O:20])[N:15]([C:10]2[CH:11]=[CH:12][C:13]([CH3:14])=[C:8]([Cl:7])[CH:9]=2)[C:16]1=[O:21]
Reactant: Cc1ccc(N2C(=O)CNC2=O)cc1Cl
Reactant: FC(Cl)(Cl)SCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(N2C(=O)CN(SC(F)(Cl)Cl)C2=O)cc1Cl
Reaction time: 3 h

Procedure:
23.8 g of fluorodichloromethanesulphenyl chloride in 100 ml of acetic acid ethyl ester is added dropwise within 20 minutes at -10°C, with vigorous stirring, to a suspension of 22.5 g of 3-(3'-chloro-4'-methylphenyl)imidazolidine-2,4-dione in 400 ml of acetic acid ethyl ester, and after one hour there is also added dropwise, at 0°C in the course of 10 minutes, 14.2 g of triethylamine in 100 ml of acetic acid ethyl ester; the cooling bath is subsequently removed and stirring is continued for 3 hours at room temperature. The triethylamine hydrochloride that has precipitated is filtered off and then washed with 100 ml of acetic acid ethyl ester; the solvent is evaporated off in vacuo to obtain, after recrystallisation in methanol, Compound No. 1 which melts at 166° - 167°C.
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[NH:15][CH:16]=1.O>C(O)(=O)C.CCOC(C)=O>[Br:1][C:16]1[NH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][C:12]=1[CH2:11][CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[Br:3]
Reactant: O=C(O)c1cc(CCc2ccccc2Br)c[nH]1
Reactant: BrBr
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc(CCc2ccccc2Br)c(Br)[nH]1
Yield: 44.6 %

Procedure:
Bromine (0.021 mL, 0.414 mmol) was added dropwise over 5 minutes to a stirring solution of 65 (0.1014 g, 0.345 mmol) in acetic acid (1.1 mL). When the reaction was judged complete by HPLC (20 min), H2O was added, and the solid that precipitated was filtered off and washed with H2O. The light purple solid that was obtained was dissolved in EtOAc, washed with Na2SO3 and H2O, then dried with Na2SO4, filtered, and concentrated. The product was purified by preparative reverse phase HPLC with 40:60 H2O:CH3CN (w/0.05% TFA); 20 mL/min.; λ=214 nM. 0.0574 g (44.6%) of 173 was obtained as a fluffy pale pink solid. 1H (CD3OD, 400 MHz): δ 7.50 (1H, d, J=7.8 Hz), 7.24-7.00 (3H, m), 6.68 (1H, s), 2.92 (2H, t, J=7.8 Hz), 2.67 (2H, t, J=−7.8 Hz) ppm. Partial 13C (CD3OD, 100 MHz): δ 163.25, 141.86, 133.73, 131.85, 128.89, 128.54, 125.26, 124.68, 117.16, 105.89, 37.91, 27.62 ppm. DEPT (CD3OD, 100 MHz): CH2 carbons: 37.91, 27.62; CH carbons: 133.73, 131.85, 128.89, 128.54, 117.16 ppm. HPLC: 10.473 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]2[C:8](=[O:10])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=3)[NH:11][C:6]=2[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Nc2c([N+](=O)[O-])ccc(Cl)c2C(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Cc1ccc2[nH]c3c([N+](=O)[O-])ccc(Cl)c3c(=O)c2c1

Procedure:
A solution of 10.2 g of the above carboxylic acid in 135 ml of chloroform containing 0.4 ml of N,N-dimethylaniline and 20.0 ml of phosphorus oxychloride was heated at reflux for three hours, cooled, and reddish-orange crystals of the title compound, mp 239-241° C., were collected.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[CH2:8][N:7]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:6]1)=[O:4].O[Li].O>O.CO>[CH2:18]([N:7]1[CH2:8][C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[C@H:5]([C:3]([OH:4])=[O:2])[CH2:6]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)c(F)c1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: O=C(O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)c(F)c1
Temperature: 80 °C
Yield: 80.8 %

Procedure:
A mixture of 19.5 g (56 mmol) (3S,4R)-1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidine-3-carboxylic acid methyl ester and 14.1 g (337 mmol) LiOH.H2O in water (100 mL) and methanol (10 mL) was heated to 80° C. for 45 min. The organic solvents were removed under vacuum and the aqueous phase acidified with 2N HCl tp pH=1-2. The precipitate was filtered off, washed with acetonitrile and dried to yield 15.1 g (73%) of the title compound as off-white solid. MS m/e: 334.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[NH2:10].C([O:13][C:14](=O)[C:15](=O)[CH2:16][CH2:17][CH2:18][Cl:19])C.C(O)(=O)C.C(OCC)(=O)C>CN(C=O)C>[Cl:8][C:6]1[CH:7]=[C:2]2[C:3](=[CH:4][C:5]=1[Cl:9])[NH:10][C:14](=[O:13])[C:15]([CH2:16][CH2:17][CH2:18][Cl:19])=[N:1]2
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: CCOC(=O)C(=O)CCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2nc1CCCCl
Temperature: 25 °C
Reaction time: 72 h
Yield: 25 %

Procedure:
1,2-Diamino-4,5-dichlorobenzene (1.63 g, 9.22 mmol), dissolved in a small amount of DMF, as added dropwise to a stirred solution of 5-chloro-2-oxo-pentanoic acid ethyl ester (1.50 g, 9.22 mmol) [J. H. Hoare, P. Yates J. Org. Chem. 1983, 4, 3333] in a mixture of DMF:glacial acetic acid 7:3 (5 ml). After stirring for 3 days at room temperature, the solvent was removed in vacuo leaving a dark coloured solid. Ethyl acetate was added and the insoluble material was removed by filtration over a short pad of silica. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (ethyl acetate:heptane 25:75), to yield 25% of 6,7-dichloro-3-(3-chloropropyl)-1H-quinoxalin-2-one as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH:33]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:8][C:5]2[N:4]=[N:3][C:2]([C:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH:29]=3)=[CH:7][CH:6]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CS(=O)(=O)c1ccc(OCc2ccc(Cl)nn2)cc1
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: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(COc3ccc(S(C)(=O)=O)cc3)nn2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 13.8 %

Procedure:
To a solution of 3-chloro-6-(4-methanesulfonylphenoxymethyl)pyridazine (79 mg, 0.26 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (82 mg, 0.26 mmol) in dry N,N-dimethylformamide (3 mL) was added tetrakis(triphenylphosphine)palladium (9.0 mg, 7.9 μmol) and cesium carbonate (129 mg, 0.397 mmol). The mixture was stirred at 80° C. for 2 hours, allowed to cool to room temperature, poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/ethyl acetate=10/1 and hexane/ethyl acetate=1/2) to give the title compound as a white crystal (16 mg, yield 14%).
Reaction SMILES: [CH2:1]([C:13]1[CH:14]=[C:15]([C:18]([NH:20][NH2:21])=[O:19])[NH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N1C=CC=CC=1.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.Cl>O>[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34]([N:20]([C:18]([C:15]2[NH:16][CH:17]=[C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:14]=2)=[O:19])[NH2:21])(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: CCCCCCCCCCCCc1c[nH]c(C(=O)NN)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCc1c[nH]c(C(=O)N(N)S(=O)(=O)c2ccc(C)cc2)c1
Reaction time: 1.5 h
Yield: 92.4 %

Procedure:
Into a mixture of 3.29 g (11 mmol) of 4-dodecylpyrrole-2-carboxylic acid hydrazide obtained in Synthesis Example 9 and 35 ml of pyridine, was added little by little 2.23 g (12 mmol) of p-toluenesulfonyl chloride under stirring and cooling with ice. The reaction was carried out for 1.5 hours at room temperature, and the reaction mixture was added to an iced water containing 70 ml of 6N hydrochloric acid. The crystals precipitated by stirring were collected by filtration, washed with water and recrystallized from a mixed solvent of ethanol/water (10/1) to obtain 4.55 g of 4-dodecylpyrrole-2-carboxylic acid p-toluenesulfonylhydrazide as white crystals. The yield was 91% and the melting point was 134.5° to 135.5° C.
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([NH:9][CH:10]=[N:11][O:12][CH3:13])=[O:8])=[C:5]([CH3:16])[CH:4]=1)=O.Cl.[OH:18][NH2:19]>CO.O>[OH:18][N:19]=[CH:1][C:3]1[CH:15]=[CH:14][C:6]([C:7]([NH:9][CH:10]=[N:11][O:12][CH3:13])=[O:8])=[C:5]([CH3:16])[CH:4]=1
Reactant: CON=CNC(=O)c1ccc(C=O)cc1C
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: O
Product: CON=CNC(=O)c1ccc(C=NO)cc1C
Yield: 102.4 %

Procedure:
In a solution of 64 mg of 4-formyl-N-(methoxyiminomethyl)-2-methyl benzoic acid amide in 4 mL of methanol and 1 mL of water, 30 mg of hydroxyamine hydrochloride was added at room temperature with stirring, and continued to stir at the same temperature for 1.5 hour. After the completion of the reaction, 10 mL of water was added in the reaction mixture, and extracted with ethyl acetate (10 mL×2). The combined organic phases were dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that were eluated with ethyl acetate-hexane (1:1) to obtain 70 mg of the aimed product as white crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].[Br:12]N1C(=O)CCC1=O>[H-].[Na+].C(Cl)(Cl)Cl>[Br:12][C:7]1[CH:6]=[C:5]([O:9][CH3:10])[C:4]([OH:11])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(OC)c1O
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1cc(Br)cc(OC)c1O
Temperature: -40 °C
Reaction time: 1 h
Yield: 21.3 %

Procedure:
To a 500 mL flask fitted with a condenser, 2,6-dimethoxyphenol (10 g, 64.86 mmol) and 80 mL of anhydrous CHCl3 was added. The solution was cooled to −40° C. and NaH (60% dispersion in mineral oil, 26 mg, 0.65 mmol) was added. Another 20 mL of anhydrous CHCl3 was added followed by rapid addition of N-bromo-succinimide (12.77 g, 71.35 mmol). The reaction mixture was stirred for 1 hour at −35° C., heated to room temperature over the next 30 minutes and heated to reflux for another 30 minutes. The solvent was evaporated under vacuum overnight. The tan solid was stirred with 100 mL ether, the mixture was filtered, and the residue was washed with ether. The solvent was evaporated under vacuum to yield a tan solid, which was then dissolved in boiling hexanes. The solution was decanted from the brown oil and filtered through a pre-heated celite pad into a heated flask. The light yellow solution was allowed to cool at room temperature for 3 hours. White wooly needles were filtered off and dried to yield 217 (3.22 g, 22%). 1H NMR (CDCl3) δ 6.72 (s, 2H), 5.44 (s, 1H), 3.88 (s, 6H); 13C NMR (CDCl3) 147.47, 133.93, 110.88, 108.38, 56.33.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[CH3:28][O:27][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[C:17]([CH2:16][N:7]1[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[C:6]1[C:4]([OH:3])=[O:5])=[CH:18][CH:19]=[CH:20]2
Reactant: COc1ccc2c(CBr)cccc2c1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Product: COc1ccc2c(Cn3c(C(=O)O)cc4ccccc43)cccc2c1

Procedure:
Using general procedure B, 1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-6-methoxy-naphthalene (Lit. 15) and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 330.1 ([M−H]−).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:27](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:27])[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(CC(c1ccc(Br)cc1)C1CCCCC1)c1ccc(=O)[nH]c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: Cn1cc(C(=O)CC(c2ccc(Br)cc2)C2CCCCC2)ccc1=O

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-phenyl)-3-cyclohexyl-propionyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a light pink solid, MS (ESI+): m/z=402.2 [M+H]+.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7]1([C:13](Cl)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[C:1]([O:6][C:13]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: C=C(C)C(=O)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 96.8 %

Procedure:
The anion exchange resin used in Example 7 was regenerated by washing with 500 ml of a 4% aqueous caustic soda solution and then with methanol and acetonitrile to remove water. 0.43 g (0.005 mol) of methacrylic acid and 1.39 g (0.005 mol) of triphenylmethyl chloride were dissolved in methylene chloride and reacted together batchwise in the presence of the above regenerated resin to give 1.59 g (yield: 96.0%) of triphenylmethyl methacrylate.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.N1C2C(=CC=CC=2)C[C:13]1=O.[N:22]1([CH2:28][CH2:29][CH2:30][NH:31][C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.NC1C=CC=CC=1>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[CH:13][NH:38][C:35]1[CH:36]=[CH:37][C:32]([NH:31][CH2:30][CH2:29][CH2:28][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:33][CH:34]=1)[C:5](=[O:11])[NH:6]2
Reactant: Cc1cccc2c1CC(=O)N2
Reactant: Nc1ccc(NCCCN2CCOCC2)cc1
Reactant: O=C1Cc2ccccc2N1
Solvent: Nc1ccccc1
Product: Cc1cccc2c1C(=CNc1ccc(NCCCN3CCOCC3)cc1)C(=O)N2

Procedure:
The named compound is prepared by substituting 4-methyl-1,3-dihydro-indol-2-one for the 1,3-dihydro-indol-2-one and N-(3-morpholin-4-yl-propyl)-benzene-1,4-diamine (used for the preparation of Example 290) for aniline in the reaction of Example 1.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12](Br)[C:11]2[CH:15]=[CH:16][S:17][C:10]=2[C:9]=1[OH:18])=[O:7])[CH2:2][CH2:3][CH3:4].[C:19]([Si](C)(C)C)#[CH:20].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O>[CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12]([C:19]#[CH:20])[C:11]2[CH:15]=[CH:16][S:17][C:10]=2[C:9]=1[OH:18])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2ccsc2c1O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: C#Cc1nc(C(=O)OCCCC)c(O)c2sccc12
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 21.8 %

Procedure:
A mixture of 4-bromo-7-hydroxy-thieno[3,2-c]pyridine-6-carboxylic acid butyl ester (example 44a, 165 mg, 0.5 mmol), ethynyl-trimethyl-silane (87 μl, 0.6 mmol), dichlorobis(triphenylphosphine)palladium(II) (11 mg, 0.015 mmol), CuI (5 mg, 0.025 mmol), and triethylamine (1.5 ml) was heated in a microwave oven at 100° C. with stirring for 15 min. After cooling to ambient temperature water (20 ml) was added and the mixture was extracted with diethylether (1×30 ml). The organic phase was dried over MgSO4. Then silica gel was added and the mixture concentrated in vacuo. The residue was added on top of a short column filled with silica gel. Elution with ethyl acetate:hexanes=9:1 and in vacuo concentration gave the title compound as a dark oil (30 mg); MS-(+)-ion: MS-(+)-ion: M+1=275.9.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]=1[O:21][C:22]1[CH:37]=[CH:36][C:25]([O:26][CH2:27][CH2:28][N:29]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(OCC)(=O)C.CO.[Pd]>[N:29]1([CH2:28][CH2:27][O:26][C:25]2[CH:24]=[CH:23][C:22]([O:21][C:10]3[C:11]4[C:16](=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=4)[CH:17]=[CH:18][C:9]=3[OH:8])=[CH:37][CH:36]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCCC4)cc3)c(OCc3ccccc3)ccc2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCCC4)cc3)c(O)ccc2c1
Temperature: 25 °C
Yield: 97.5 %

Procedure:
Combine 2-benzyloxy-1-bromo-6-methoxy-naphthalene (31 g, 90 mmol), 4-(2-azepan-1-yl-ethoxy)-phenol (31 g, 132 mmol), copper bronze (12 g, 189 mmol), potassium carbonate (25 g, 181 mmol) and pyridine (400 mL). Heat the reaction mixture to reflux for 85 hours. Cool and filter the residue with celite and elute with methanol and methylene chloride (500 mL, V/V=1:5). Evaporate solvent under reduced pressure and chromatograph the residue on a silica gel column eluting the material with a step gradient of methanol/dichloromethane (0 to 10%) to get 19 g (43%) of 1-{2-[4-(2-benzyloxy-6-methoxy-naphthalen-1-yloxy)-phenoxy]-ethyl}-azepane. Dissolve 1-{2-[4-(2-benzyloxy-6-methoxy-naphthalen-1-yloxy)-phenoxy]-ethyl}-azepane (19 g, 38 mmol) in ethyl acetate (500 mL) and methanol (600 mL). Heat the mixture to obtain a clear solution. Cool to room temperature. Add ammonium formate (30 g, 476 mmol) and palladium on carbon (2 g, 1.9 mmol). Heat to reflux for 30 minutes. Add ammonium formate (7 g, 111 mmol) and palladium on carbon (0.7 g, 0.7 mmol). Heat to reflux for 30 minutes. Filter the suspension through a pad of celite and elute with ethyl acetate (500 mL). Evaporate solvent under reduced pressure and add water (100 mL). Dilute the mixture with ethyl acetate (500 mL) and separate layers. Wash the organic layer with saturated sodium bicarbonate solution (2×200 mL), dry with magnesium sulfate, filter and evaporate solvent under reduced pressure to give 15.1 g (97%) of 1-[4-(2-azepan-1-yl-ethoxy)-phenoxy]-6-methoxy-naphthalen-2-ol.