Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]2[S:6][C:7]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([OH:17])=[O:16])[C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl.[CH2:21](O)[CH3:22]>C(OCC)(=O)C.C1C=CC=CC=1>[OH:1][C:2]1[CH:19]=[CH:18][C:5]2[S:6][C:7]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([O:17][CH2:21][CH3:22])=[O:16])[C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: CCO
Reactant: O=C(O)c1cccc2c1CCc1cc(O)ccc1S2
Agent: Cl
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc2c1CCc1cc(O)ccc1S2
Yield: 85 %

Procedure:
An amount of 1.7 g of 2-hydroxy-9-carboxy-10,11-dihydrodibenzo[b,f]thiepin was dissolved in 50ml of anhydrous ethanol and the mixture was refluxed for 3 hours, while hydrogen chloride gas was bubbled into the mixture. The solvent was distilled off to obtain the residue which was dissolved in the mixed solvent of ethyl acetate-benzene. The solution was washed with saturated sodium chloride solution and freed of solvent by distillation to obtain 1.6 g (85%) of 2-hydroxy-9-ethoxycarbonyl-10,11-dihydrodibenzo[b,f]thiepin as brown crystals having a melting point of 125°-129° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:21]([O-])=O)[C:5]([NH:8][C:9]2[CH:10]=[C:11]([N:15]3[CH2:19][CH2:18][CH2:17][C:16]3=[O:20])[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.[CH2:24](O)C>>[Br:1][C:2]1[CH:3]=[C:4]2[N:21]=[CH:24][N:8]([C:9]3[CH:10]=[C:11]([N:15]4[CH2:19][CH2:18][CH2:17][C:16]4=[O:20])[CH:12]=[CH:13][CH:14]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CCO
Reactant: O=C1CCCN1c1cccc(Nc2ncc(Br)cc2[N+](=O)[O-])c1
Product: O=C1CCCN1c1cccc(-n2cnc3cc(Br)cnc32)c1

Procedure:
1-[3-(6-Bromo-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]pyrrolidin-2-one was prepared from 1-[3-(5-bromo-3-nitropyridin-2-ylamino)phenyl]pyrrolidin-2-one as described in Example 1. Oxalate salt, white crystals, m.p. 194-195° C. (from ethanol); δH (360 MHz, d6-DMSO) 2.10 (2H, quin, J 7), 2.56 (2H, t, J 8), 3.92 (2H, t, J 7), 7.58-7.65 (2H, m), 7.78-7.81 (1H, m), 8.19 (1H, s), 8.52-8.54 (2H, m), 8.93 (1H, s); m/z (ES+) 357 and 359 (M++H).
Reaction SMILES: [C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=3)[CH:22]=2)=[C:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>C(Cl)Cl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[C:1]1([C:7](=[C:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:21]2[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=2)[O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][N:29]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=C(c2ccccc2)c2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(Oc2cccc(C(=C3CCNCC3)c3ccccc3)c2)nc1
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of tert-butyl 4-(phenyl(3-(5-(trifluoromethyl)pyridin-2-yloxy)phenyl)methylene)piperidine-1-carboxylate in CH2Cl2 (3 mL) was added trifluoroacetic acid (0.5 mL). The reaction was stirred overnight. The reaction was concentrated, redissolved in CH2Cl2 and concentrated again to give the title compound as an oil (33.7 mg, 70% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([OH:13])[CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:21][CH:22]([F:24])I>CN(C=O)C>[F:21][CH:22]([F:24])[O:13][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[N+:10]([O-:12])=[O:11])[C:3]([O:2][CH3:1])=[O:14]
Reactant: FC(F)I
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc([N+](=O)[O-])c(OC(F)F)c1
Temperature: 25 °C

Procedure:
To a cooled solution of 1 g of methyl-3-hydroxy-4-nitrobenzoate, 3.31 g of cesium carbonate in 20 mL of DMF, was carefully added 1.5 equivalents of difluoroiodomethane. The reaction was allowed to warm to room temperature and followed by TLC. Upon completion of the reaction, the mixture was concentrated and purified by silica get chromatography to give 1.2 g of methyl 3-(difluoromethoxy)-4-nitrobenzoate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[C:21]1([S:27][CH2:28][CH2:29]O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:29][CH2:28][S:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: OCCSc1ccccc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCSc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 39.3 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with the mesylate of 2-phenylthioethanol (1.16 g). The mixture was heated at 60° C. for five hours and worked up as in Example 20. The material was purified by HPLC (dichloromethane-hexane; 4:1) and crystallized from diethyl etherhexane to provide 0.5 g of alpha-oxo-4-[[2-(phenylthio)ethyl]oxy]benzeneacetic acid methyl ester, mp 49°-51° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[N:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)[C:5]2=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1)CCC>C1(C)C(C)=CC=CC=1.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>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:9]2[N:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)[C:5]3[C:6]([N:8]=2)=[N:7][C:2]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)=[CH:3][CH:4]=3)=[CH:24][CH:25]=1
Reactant: Fc1ccc(-c2nc3nc(Cl)ccc3n2-c2ccnc(NC3CCCC3)n2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1C
Product: Fc1ccc(-c2nc3nc(-c4cccnc4)ccc3n2-c2ccnc(NC3CCCC3)n2)cc1
Yield: 58.8 %

Procedure:
5-Chloro-2-(4-fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)imidazo[4,5-b]pyridine (2 g 4.9 mmol), 3-tributylstannylpyridine (3.6 g 9.8 mmol) and PdCl2(PPh3)2 (340 mg 0.48 mmol) are heated in xylene (50 ml) for 3 h at 150° C. under argon. The reaction mixture is filtered at 60° C. and chromatographed over SiO2 (acetone/hexanes 3/7 to 6/4) to yield pale yellow crystals (1.3 g). Recrystallisation from THF/hexanes renders the title compound as colorless crystals (985 mg 45%).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[OH:20])=[CH:17][CH:16]=[C:15]([F:21])[CH:14]=2.[C:22](Cl)(=[O:26])[CH2:23][CH2:24][CH3:25].C(=O)(O)[O-].[Na+]>O1CCCC1>[F:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19]([OH:20])=[C:10]([NH:9][C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[CH:11]=[N:12]2)=[CH:17][CH:16]=1
Reactant: Nc1cnc2cc(F)ccc2c1O
Reactant: CCCC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1cnc2cc(F)ccc2c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.3 %

Procedure:
Under a nitrogen atmosphere, triethylamine (6.4 mL, 46.2 mmol) was added to a suspension of 3-amino-7-fluoro-4-quinolinol hydrochloride (3 g, 14.0 mmol) in tetrahydrofuran (50 mL). Butyryl chloride (1.6 mL, 15.4 mmol) was added dropwise at ambient temperature. The reaction mixture was stirred at ambient temperature for 4 hours. Aqueous sodium bicarbonate was added and the reaction mixture was allowed to stir at ambient temperature for about 1 hour. The resulting biphasic mixture was filtered to remove solids. The solids were rinsed with diethyl ether to provide a slightly pink powder. The tetrahydrofuran layer was concentrated under vacuum to provide a dark pink solid. This solid was triturated with ether and then oven dried. The solids were combined to provide 3.0 g of N-(7-fluoro4-hydroxyquinolin-3-yl)butanamide. A 300 mg portion was recrystallized from ethyl acetate/ethanol to provide a light gray fluffy solid, m.p. 306-308° C. Analysis: Calculated for C13H13FN2O2: %C, 62.90; %H, 5.28; %N, 11.28; Found: %C, 62.95; %H, 5.34; %N, 11.14.
Reaction SMILES: [OH:1][CH:2]1[CH:6]=[CH:5][C:4](=O)[CH:3]1[CH2:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][C:14]([O:16]CC)=[O:15].S(=O)(=O)(O)[OH:20].[Cl-].[Na+]>>[C:14]([CH2:13][S:12][CH2:11][CH2:10][CH2:9][CH2:8][C:3]1[C:2](=[O:1])[CH2:6][CH:5]([OH:20])[CH:4]=1)([OH:16])=[O:15]
Reactant: CCOC(=O)CSCCCCC1C(=O)C=CC1O
Reactant: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Product: O=C(O)CSCCCCC1=CC(O)CC1=O

Procedure:
The solution, containing crude 3-hydroxy-2-[4-(carbethoxymethylthio)butyl]cyclopent-4-en-1-one, is cooled and treated during 10 minutes with 75 ml of sulfuric acid (d=1.84) with stirring. The stirred solution is refluxed for 16 hours, cooled, saturated with sodium chloride, and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate, and concentrated. The residue is subjected to chromatography on silica gel with chloroform progressively enriched in ether, ether, and ether progressively enriched in acetone to afford the subject compound as an oil, pmr spectrum (CDCl3): δ3.24 (singlet, --S--CH2 --CO2C2H5), 5.0 (broad singlet --CHOH--).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]#[N:22])=[CH:11][CH:10]=2)[C:6]2[CH:23]=[C:24]([N:27]([CH3:37])[S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH:25]=[CH:26][C:5]=2[N:4]=1)[CH3:2].[N-:38]=[N+:39]=[N-:40].[Na+]>CN(C)C=O>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:40][N:39]=[N:38][N:22]=3)=[CH:13][CH:14]=2)[C:6]2[CH:23]=[C:24]([N:27]([CH3:37])[S:28]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)(=[O:29])=[O:30])[CH:25]=[CH:26][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccc(N(C)S(=O)(=O)c3ccccc3)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2ccc(N(C)S(=O)(=O)c3ccccc3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 41 from 4'-[[2-ethyl-6-(N-benzenesulphonyl-methylamino)-benzimidazol-1-yl]methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: C(=O)([O:10][C:11]1[C:16]2[NH:17][C:18](=[O:20])[S:19][C:15]=2[C:14]([C:21](=[O:24])[CH2:22]Br)=[CH:13][CH:12]=1)OCC1C=CC=CC=1.[CH2:26]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)C(C)C)(C)C.Cl>CN(C=O)C>[CH2:26]([N:33]([CH2:22][C:21]([C:14]1[C:15]2[S:19][C:18](=[O:20])[NH:17][C:16]=2[C:11]([OH:10])=[CH:12][CH:13]=1)=[O:24])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: c1ccc(CCCCOCCCCCCNCc2ccccc2)cc1
Reactant: O=C(OCc1ccccc1)Oc1ccc(C(=O)CBr)c2sc(=O)[nH]c12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CN(CCCCCCOCCCCc1ccccc1)Cc1ccccc1)c1ccc(O)c2[nH]c(=O)sc12
Temperature: 40 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
To a solution of benzyl 7-(bromoacetyl)-2-oxo-2,3-dihydro-1,3-benzothiazol-4-yl carbonate (50 mg) in dry DMF (1 ml) stirring under nitrogen was added N-benzyl-6-(4-phenylbutoxy)hexan-1-amine (Tetrahedron Letters. 1994, 35, 9375) (60 mg) and N,N-diisopropylethylamine (32 μl). After stirring at 40° C. for 2 h, 2N HCl was added and the mixture extracted with ethyl acetate. The solution was dried (MgSO4), filtered and evaporated in vacuo. The residue was purified on a 5 g silica SPE cartridge, eluting with a stepped gradient of 2% to 10% methanol-dichloromethane mixtures to give the title compound (50 mg). LCMS RT=3.14 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8]Br.C(N(CC)CC)C.[I-].C([NH3+])(C)(C)C.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1>C1COCC1>[CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:31][C:28]1[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: COC(=O)C=CC=CCBr
Agent: CC(C)(C)[NH3+]
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C=CC=CCSc1ccc(Cl)cc1
Yield: 63 %

Procedure:
To a solution of 6-bromohexa-2,4-dienoic acid methyl ester (1.03 g, 5 mmol), triethylamine (1.4 mL, 10 mmol) and tert-butylammonium iodide (92 mg, 0.25 mmol) in freshly distilled THF (25 mL) was added 4-chlorothiophenol under an atmosphere of nitrogen. The mixture was stirred at reflux for 2 hours after which it was concentrated under reduced pressure. The oil was dissolved in, ethyl acetate (100 mL) and then washed successively with saturated aqueous sodium hydrogen carbonate (50 mL), distilled water (50 mL) and brine (50 mL). The organic layer was then dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give an oil that was purified by flash chromatography (1:9 diethyl ether:40-60° C. petroleum ether). The resulting yellow solid was recrystallised from diethyl ether/40-60° C. petroleum ether to give the title compound (0.85 g, 63%) as a white solid, mp 75-77° C.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11]C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:18][CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.CC(C)([O-])C.[K+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[N:21]1([CH2:20][CH2:19][O:18][C:2]2[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Clc1ncccc1OCCOC1CCCCO1
Reactant: OCCN1CCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: OCCOc1cccnc1OCCN1CCCC1
Temperature: 50 °C
Reaction time: 48 h
Yield: 71.8 %

Procedure:
A solution of 2-chloro-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine (from Example 4; 100 mg, 0.39 mmol), 1-(2-hydroxyethyl)pyrrolidine (68 μl, 0.58 mmol) and 1.0 M potassium tert-butoxide in tert-butanol (0.8 mL, 0.80 mmol) in 4 mL of toluene was heated at 100° C. for 1 day. The organic phase was washed with 3×2 mL of water and 2 mL of brine. The organic phase was shaken at 50° C. with 4 mL of 2.0 M acetic acid for 2 days. The aqueous phase was washed with 3×3 mL of ethyl acetate, made basic by addition of potassium hydroxide, saturated with sodium chloride and extracted with 3×2 mL of ethyl acetate. The organic phase was dried (MgSO4) and concentrated under reduced pressure to give 71 mg (0.28 mmol, 72%) of the title compound as a colorless oil. LC-UV purity 95%. MS m/z 253 (M+1)+, calc. 253 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][N:5]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:14]=[C:13]([OH:36])[CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8].Cl[CH2:39][CH2:40][CH2:41][CH2:42][C:43]1[CH:52]=[CH:51][C:50]2[C:45](=[CH:46][C:47]([O:61][CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[C:48]([O:53][CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[CH:49]=2)[CH:44]=1.C(=O)([O-])[O-].[I-].[Na+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:37])[CH2:4][N:5]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[C:11]1[CH:12]=[C:13]([O:36][CH2:39][CH2:40][CH2:41][CH2:42][C:43]2[CH:44]=[C:45]3[C:50](=[CH:51][CH:52]=2)[CH:49]=[C:48]([O:53][CH2:54][C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:47]([O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[CH:46]3)[CH:14]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:16]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(N(CC(=O)OC)CC(=O)OC)c1
Reactant: ClCCCCc1ccc2cc(OCc3ccccc3)c(OCc3ccccc3)cc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCc2ccc3cc(OCc4ccccc4)c(OCc4ccccc4)cc3c2)cc(N(CC(=O)OC)CC(=O)OC)c1
Yield: 49.3 %

Procedure:
A mixture of 1.5 g (2.88 mmol) of N-[3-hydroxy-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester, 1.24 g (2.88 mmol) of 2-(4-chlorobutyl)-6,7-bis(phenylmethoxy) naphthalene, 0.8 g (5.75 mmol) ofpotassium carbonate and 0.43 g (2.88 mmol) of sodium iodide in 50 ml of acetone and 10 ml of DMF was stirred at reflux under argon for 40 hours. The acetone was removed by distillation and 50 ml of DMF, 1.24 g of 2-(4-chlorobutyl)-6,7-bis(phenylmethoxy)naphthalene, 0.8 g of potassium carbonate and 0.43 g of sodium iodide were added and the mixture was stirred and heated at 85° for 4 days. The DMF was removed using an oil pump at 55°. The residue was extracted with methylene chloride,the extract was concentrated and the product was purified by HPLC using 20%ethyl acetate-hexane to give 1.3 g (49% yield) of N-(2 -methoxy-2oxoethyl)-N-[3-(octadecyloxy)-5-[4-[2,3-bis(phenylmethoxy)-6-naphthalenyl]butoxy]phenyl]glycine methyl ester as a semisolid. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[N+:10]([O-])([OH:12])=[O:11].O>C(OC(=O)C)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: COc1ccccc1F
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc([N+](=O)[O-])cc1F
Reaction time: 15 h

Procedure:
To a cold (-2°), stirred solution of 285 g. (2.26 mol) of 2-fluoroanisole in 1.1 L of acetic anhydride was added, dropwise, 114 mL of fuming nitric acid (sp. gr. 1.59) at such a rate that the reaction temperature remained between -2° and 0°. The reaction mixture was stirred for 5 hours at this temperature then poured into 4.0 L of water. The suspension was stirred for 1.5 hours, stored for 15 hours, then extracted with methylene chloride (2×1.0 L). The combined extracts were washed with water (2×500 mL), dried over anhydrous magnesium sulfate, then concentrated in vacuo (475 g.). Crystallization from ethanol gave 147.4 g. (38%) of material suitable for further transformation. Additional material (34.5 g.) was obtained from three scouting runs.
Reaction SMILES: [C:1](Cl)([CH3:3])=[O:2].[C:5]([SiH2:9][O:10][C:11]([CH3:22])([CH3:21])[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:15][NH2:16])([CH3:8])([CH3:7])[CH3:6].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:5]([SiH2:9][O:10][C:11]([CH3:22])([CH3:21])[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:15][NH:16][C:1](=[O:2])[CH3:3])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CN)ccc1Cl
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
AcCl (0.547 mL, 7.70 mmol) was added to a sol. of 3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzylamine (2.00 g, 7.00 mmol) and DIPEA (4.80 mL, 28.0 mmol) in CH2Cl2 (70 mL) at 0° C. The mixture was stirred for 1 h while warming up to rt. CH2Cl2 (30 mL) was added, and the mixture was washed with aq. sat. NH4Cl (2×), aq. 1M NaOH (1×) and brine (1×). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 60:40) yielded the title compound (2.10 g, 91%). LC-MS: tR=1.07 min; ES+: 369.19.
Reaction SMILES: [Br:1][C:2]#[C:3][CH2:4][C@@:5]12[C@@H:22]3[C@H:13]([C@H:14]4[C@@:18]([CH2:20][CH2:21]3)([CH3:19])[C:17](=[O:23])[CH2:16][CH2:15]4)[CH2:12][CH2:11][C:10]1=[CH:9][C:8](=[O:24])[CH2:7][CH2:6]2.C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C(O)(C)(C)C.C(OCC)(=O)C>[Br:1][C:2]#[C:3][CH2:4][C@@:5]12[C@@H:22]3[C@H:13]([C@H:14]4[C@@:18]([CH2:20][CH2:21]3)([CH3:19])[C:17](=[O:23])[CH2:16][CH2:15]4)[CH:12]=[CH:11][C:10]1=[CH:9][C:8](=[O:24])[CH2:7][CH2:6]2
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CC#CBr)[C@@H]1CCC2=O
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: C[C@]12CC[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@]43CC#CBr)[C@@H]1CCC2=O
Yield: 45 %

Procedure:
A mixture of 313 mg of 10β-(3-bromo-2-propynyl)estr-4-ene-3,17-dione and 575 mg of chloranil in 21 ml of tert-butyl alcohol is heated at reflux for 2 hours. The mixture is diluted with ethyl acetate and filtered and the filtrate is washed with aqueous 1N sodium hydroxide, with brine and dried over sodium sulphate. The solvent is then evaporated and the residue chromatographed on silica gel using ethylacetate/n-hexane to give 140 mg of the title compound.
Reaction SMILES: [ClH:1].[CH2:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH2:5][CH2:4][NH:3]1.[C:21]1(NN)C=CC=CC=1>>[ClH:1].[CH3:21][C:9]1[C:8]2[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3[CH2:5][CH2:4][NH:3][CH2:2][C:14]=3[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CNCC2
Agent: Cl
Product: CCOC(=O)Cn1c2c(c3cccc(C)c31)CNCC2

Procedure:
The title compound is prepared using a procedure analogous to Intermediate 1, substituting 2-methylphenylhydrazine for phenylhydrazine in Step 1a).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16].CCN(CC)CC>C(Cl)Cl>[S:15]([O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
A mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (5.00 g, 24.80 mmol, 1 eq), TsCl (5.70 g, 29.80 mmol, 1.2 eq) and Et3N (10.7 mL, 74.40 mmol, 3 eq) in 100 mL of anhydrous CH2Cl2 was stirred for 8 h at room temperature. The resulted mixture was washed with brine (30 mL) and water (30 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (5:1 (v/v) PE/EtOAc) to afford the title compound as a white solid (5.50 g, 68.00%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 356.2 (M+1).
Reaction SMILES: [C:1]([OH:7])(=[O:6])/[C:2](=[CH:4]/[CH3:5])/[CH3:3].[CH3:8][S:9][CH2:10]Cl.C(N(CC)CC)C>>[C:1]([O:7][CH2:8][S:9][CH3:10])(=[O:6])/[C:2](=[CH:4]/[CH3:5])/[CH3:3]
Reactant: C/C=C(\C)C(=O)O
Reactant: CSCCl
Solvent: CCN(CC)CC
Product: C/C=C(\C)C(=O)OCSC

Procedure:
This product was prepared according to the procedure described in Example 1, by reacting tiglic acid with chloromethyl methyl sulfide in the presence of one equivalent of triethylamine; b.p. 95° C./12 mm Hg, nD20 1.4890.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[C@@H:13]([O:15][CH3:16])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20]1>CCCCO>[Br:1][C:2]1[C:3]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:20]2)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[C@@H:13]([O:15][CH3:16])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CO[C@@H](C)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCCCO
Product: CO[C@@H](C)C(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Yield: 44.5 %

Procedure:
(S)—N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide (120 mg, 0.38 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (228 mg, 1.14 mmol) in n-BuOH (4 mL) were heated to 160° C. for 18 hours in a sealed tube. After concentration, the residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 10-90% CH3CN/water gradient; 30 CV) to yield tert-butyl (R)-1-(5-bromo-3-((S)-2-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (84 mg, 45% yield) as a solid.