Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[C@@H:3]([NH:7][S:8]([C:11]1[CH:21]=[CH:20][C:14]2[N:15]=[C:16]([S:18][CH3:19])[S:17][C:13]=2[CH:12]=1)(=[O:10])=[O:9])[C:4](O)=[O:5].C(Cl)(=O)C([Cl:26])=O.CN(C=O)C>ClCCl>[CH3:1][CH:2]([CH3:22])[C@@H:3]([NH:7][S:8]([C:11]1[CH:21]=[CH:20][C:14]2[N:15]=[C:16]([S:18][CH3:19])[S:17][C:13]=2[CH:12]=1)(=[O:10])=[O:9])[C:4]([Cl:26])=[O:5]
Reactant: CSc1nc2ccc(S(=O)(=O)N[C@@H](C(=O)O)C(C)C)cc2s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CSc1nc2ccc(S(=O)(=O)N[C@@H](C(=O)Cl)C(C)C)cc2s1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
(2R)-3-methyl-2-[(2-methylthiobenzthiazol-6-sulfonyl)amino]butanoic acid (54 mg, 0.15 mmol) prepared in Example 14 was dissolved in dichloromethane (2 mL) and cooled down to 0° C., and added oxalylchloride (0.04 mL, 3 equi.) and DMF of catalytic amount. The reaction solution was subjected at room temperature for 3 hours. Then, the reaction solution was distilled and dried under reduced pressure to remove the solvent. And then, (2R)-3-methyl-2-[(2-methylthiobenzthiazol-6-sulfonyl) amino]butanoic chloride thus obtained was dissolved in THF (1 mL). Hydroxylamine hydrochloride (0.11 g, 10 equi.) and NaHCO3 (0.15 g, 12 equi.) were dissolved in THF/H2O (1 mL/1 ml) and cooled down to 0° C. The above acid chloride THF solution was slowly added to hydroxylamine solution while maintaining the temperature of 0° C. The solvent was removed from the reaction solution after 1 hour. Then, the product was extracted with ethylacetate (5 mL) and washed with H2O and 0.1N HCl, dried over MgSO4, distilled under reduced pressure and dried under vacuum, to prepare the titled compound, (2R)-N-hydroxy-3-methyl-2-[(2-methylthiobenzthiazol-6-sulfonyl)amino]butyric amide(50 mg, 90%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[O:14]=[C:4]1[CH:3]([CH2:2][O:1][C:29](=[O:30])[NH:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]1=2
Reactant: O=C1c2ccccc2SCCC1CO
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)OCC1CCSc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxymethyl-3,4-dihydro-2H-benzo[b]thiepin-5-one (359 mg, 1.726 mmol) in 22 ml of tetrahydrofuran were added, at 0° C., triethylamine (0.26 ml, 1.9 mmol) and phenyl isocyanate (410 μl, 3.8 mmol). The mixture was stirred at room temperature for 2 hours, concentrated and purified by column chromatography on silica gel (eluent: 1:2 tert-butyl methyl ether/cyclohexane). The product was obtained in a yield of 350 mg (62%).
Reaction SMILES: [NH2:1][C:2]1=[N:3][C:4]2([CH2:21][O:22][CH2:23][CH2:24]1)[C:17]1[CH:16]=[C:15]([OH:18])[CH:14]=[C:13]([F:19])[C:12]=1[O:11][C:10]1[C:5]2=[CH:6][C:7]([Br:20])=[CH:8][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.[CH2:36](I)[C:37]([CH3:40])([CH3:39])[CH3:38]>O>[Br:20][C:7]1[CH:6]=[C:5]2[C:10]([O:11][C:12]3[C:13]([F:19])=[CH:14][C:15]([O:18][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:16][C:17]=3[C:4]32[CH2:21][O:22][CH2:23][CH2:24][C:2]([NH2:1])=[N:3]3)=[CH:9][CH:8]=1
Reactant: CC(C)(C)CI
Reactant: NC1=NC2(COCC1)c1cc(Br)ccc1Oc1c(F)cc(O)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)COc1cc(F)c2c(c1)C1(COCCC(N)=N1)c1cc(Br)ccc1O2
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A vial was charged with (E)-5-amino-7′-bromo-4′-fluoro-6,7-dihydro-2H-spiro[[1,4]oxazepine-3,9′-xanthen]-2′-ol (222.7 mg, 0.566 mmol), cesium carbonate (738 mg, 2.265 mmol), and DMF (2832 μL) to give a yellow suspension. The resulting mixture was stirred for 10 min, then neopentyl iodide (225 μL, 1.699 mmol) was added. The vial was capped and heated to 100° C. for 2 h. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (0-10% MeOH/DCM) to give (E)-7′-bromo-4′-fluoro-2′-(neopentyloxy)-6,7-dihydro-2H-spiro[[1,4]oxazepine-3,9′-xanthen]-5-amine as a yellow oil.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][C:11]2[N:21]3[C:22]4[C:17]([CH:18]([OH:23])[CH2:19][CH2:20]3)=[CH:16][CH:15]=[CH:14][C:13]=4[N:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:24]I.O>O1CCCC1>[CH3:24][O:23][CH:18]1[C:17]2[C:22]3=[C:13]([N:12]=[C:11]([CH2:10][CH2:9][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[N:21]3[CH2:20][CH2:19]1)[CH:14]=[CH:15][CH:16]=2
Reactant: OC1CCn2c(CCc3ccccc3)nc3cccc1c32
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC1CCn2c(CCc3ccccc3)nc3cccc1c32
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 49 %

Procedure:
A portion (115 mg) of 60% sodium hydride was added to anhydrous tetrahydrofuran (15 mL) under an argon atmosphere; 0.2 g of 5,6-dihydro-2-(2-phenylethyl)-4H-imidazo[4,5,1-ij]quinolin-6-ol obtained in Example 4 was dissolved in anhydrous tetrahydrofuran (4 mL) and the solution was added dropwise to the first mentioned solution at room temperature. After stirring for 35 min at room temperature, methyl iodide (1.02 g) was added dropwise and the mixture was stirred for 4 hrs. Water was added to the reaction solution and the mixture was stirred; thereafter, the reaction solution was extracted with dichloromethane, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to yield the titled compound as a yellow oil (103 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.Cl.Cl[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]Cl.C(=O)([O-])[O-].[K+].[K+].Cl>C(O)CCC>[N:1]1([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][NH:6]3)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: ClCCNCCCl
Reactant: Nc1cccc2[nH]ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: c1cc(N2CCNCC2)c2cc[nH]c2c1
Yield: 22.4 %

Procedure:
A suspension of 4-aminoindole (2.30 g, 0.017 moles), bischloroethylamine hydrochloride (3.49 g, 0.02 moles) and potassium carbonate (5.41 g, 0.02 moles) in butanol (50 ml) was heated at reflux under argon for 7 h. Further bischloroethylamine hydrochloride (0.70 g, 0.04 moles) and potassium carbonate (1.1 g 0.04 moles) was added, then the suspension was heated at reflux for 18 h. The solvent was evaporated in vacuo to give a brown gummy residue which was taken up into dilute hydrochloric acid (200 ml), washed with ethyl acetate (2×100 ml), made basic with potassium carbonate, extracted into dichloromethane (3×50 ml), dried (MgSO4) then evaporated in vacuo to give a white solid which was triturated with ethyl acetate and dried to give 4-(1-piperazinyl)indole (0.78 g, 0.0038 moles) as white crystals.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:11][CH:10]=2)[S:3]1.[Br:27]Br>C(O)(=O)C>[Br:27][C:11]1[CH:10]=[C:9]([CH:8]=[C:4]2[S:3][C:2](=[O:1])[NH:6][C:5]2=[O:7])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]
Reactant: BrBr
Reactant: O=C(O)CCCCOc1ccc(C=C2SC(=O)NC2=O)c2ccccc12
Solvent: CC(=O)O
Product: O=C(O)CCCCOc1c(Br)cc(C=C2SC(=O)NC2=O)c2ccccc12
Temperature: 25 °C
Reaction time: 336 h

Procedure:
5-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)-naphthalen-1-yloxy]pentanoic acid (example 292, 185 mg, 0.5 mmol) was treated with an equimolar amount of bromine in acetic acid (10 mL). Stirring at RT for 14 days followed by evaporation to dryness afforded a mixture of the brominated compound and unchanged starting material. Purification by preparative HPLC on a C18 column using acetonitrile and water as eluent afforded 8 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[CH:6]=1.[CH2:18]([S:20]([C:23]1[CH:28]=[CH:27][C:26](F)=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][C:26]2[CH:25]=[CH:24][C:23]([S:20]([CH2:18][CH3:19])(=[O:22])=[O:21])=[CH:28][CH:27]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[CH:6]=1
Reactant: CCS(=O)(=O)c1ccc(F)cc1
Reactant: COC(=O)Cc1cc(O)c2cc(F)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)OC)cc3ccc(F)cc23)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A sealed tube containing (6-fluoro-4-hydroxy-naphthalen-2-yl)-acetic acid methyl ester (49 mg, 0.21 mmol), 1-ethanesulfonyl-4-fluoro-benzene (87 mg, 0.427 mmol), and potassium carbonate (73 mg, 0.53 mmol) was evacuated and filled with nitrogen. Anhydrous N,N-dimethylformamide (2 mL) was added. After being stirred at 100° C. overnight, the mixture was cooled to room temperature, then diluted with water (10 mL), and extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with brine (10 mL×3), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (elution with 30% ethyl acetate in petroleum ether) to give [4-(4-ethanesulfonyl-phenoxy)-6-fluoro-naphthalen-2-yl]-acetic acid methyl ester (67.6 mg, 80%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([NH:25][O:26][CH2:27][C@@H:28]3[CH2:32][O:31]C(C)(C)[O:29]3)=[O:24])=[C:16]2[N:15]=1.Cl>C1COCC1.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([NH:25][O:26][CH2:27][C@@H:28]([OH:29])[CH2:32][OH:31])=[O:24])=[C:16]2[N:15]=1
Reactant: CC1(C)OC[C@@H](CONC(=O)c2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nc23)O1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(NOC[C@@H](O)CO)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyrazolo[1,5-a]pyrimidine-3-carboxamide (135 mg, 0.285 mmol) in THF (4.0 mL) was added 6M HCl (1.0 mL) dropwise and the mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was concentrated to approximately 1 mL and was diluted with H2O (5 mL). The resulting milky white mixture was extracted with EtOAc and the combined extracts were washed with 1M Na2CO3 and saturated NaCl. The EtOAc solution was dried over MgSO4 and filtered through a packed Celite pad capped with a layer of MgSO4. The solution was concentrated to give a colorless foam that was dissolved in minimal CH2Cl2 and treated with hexanes to give a white suspension. The suspension was concentrated to give the title compound as a white solid that was dried in vacuum (102 mg, 82%). MS (apci) m/z=434.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.[Cl:13]N1CCOCC1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[C:10]([Cl:13])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C(=O)O
Reactant: ClN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Cl)c(Cl)cc1C(=O)O
Temperature: 0 °C
Yield: 16.9 %

Procedure:
To an ice cold solution of 4-chloro-2-methoxybenzoic acid (1.0 g, 5.36 mmol) in trifluoroacetic acid (7 ml) was added N-chloromorpholine (0.67 g, 5.5 mmol) dropwise, maintaining the internal temperature below 10° C. After stirring overnight at room temperature the trifluoroacetic acid was removed in vacuo and the residue partitioned between ethyl acethate and water. The organic layer was dried over magnesium sulfate, concentrated in vacuo and the residue recrystallised from methanol to afford the title compound as a white solid (200 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH3:8][O:9][C:10](=O)[O:11]C.CC(C)([O-])C.[K+]>>[CH3:8][O:9][C:10]([CH:3]1[C:4](=[O:7])[CH2:5][CH2:6][O:1][CH2:2]1)=[O:11]
Reactant: COC(=O)OC
Reactant: O=C1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COC(=O)C1COCCC1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 26.5 %

Procedure:
To a solution of tetrahydro-pyran-4-one (1.3 kg, 12.98 mol) and carbonic acid dimethyl ester (11.69 kg, 129.8 mol) was added solid potassium tert-butoxide (1.89 kg, 16.08 mol) in portions at −10° C. over 2 h under nitrogen protection. The suspension was stirred at room temperature 10 h after the addition. LCMS (215 nm) indicated that tetrahydro-pyran-4-one had been completely consumed. The reaction was acidified by HCl (2 N) to pH 6˜7 and then the phases were separated. The organic phase was washed with water (3 L×2) and the combined aqueous phases were extracted with MTBE (2.5 L×2). The combined organic phase was concentrated under reduced pressure at 25° C. to remove most of MTBE. The residue was distilled out by oil pump (˜200 Pa) at 74° C. to give the title compound as colorless oil (545 g, 26.3%). CHN analysis: calculated (results). C, 53.16; (53.10), H, 6.37; (6.245), N, 0.00; (0.00).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[O:10][CH2:9][CH2:8][N:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][CH:5]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[O:10][CH2:9][CH2:8][N:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CN=[N+]=[N-])C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CN)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.5 %

Procedure:
To a solution of tert-butyl (6RS,7SR)-6-(azidomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (570 mg) in THF (5 mL) were added triphenylphosphine (447 mg) and water (1 mL), and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/methanol) to give the title compound (477 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][CH3:25])[C:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[NH2:17][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][N:24]([CH3:25])[C:33]([NH:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:34])[C:7]=2[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[N:10]=1
Reactant: O=C=Nc1ccccc1
Reactant: CNCCOCCn1c(CCOC)nc2c(N)nc3c(c21)CCCC3
Solvent: ClCCl
Product: COCCc1nc2c(N)nc3c(c2n1CCOCCN(C)C(=O)Nc1ccccc1)CCCC3
Reaction time: 8 h
Yield: 16.9 %

Procedure:
2-(2-Methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline-4-amine (750 mg, 2.16 mmol) was dissolved in 30 mL of anhydrous CH2Cl2 and treated with phenyl isocyanate (239 μL, 2.20 mmol). After stirring under N2 overnight, the reaction mixture was concentrated under reduced pressure. Crystallization from EtOAc and CH2Cl2 gave 170 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy} ethyl)-N-methyl-N′-phenylurea as fluffy white crystals. m.p. 167.7-170.0° C.;
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:13]([O:15][CH3:16])=[O:14])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:13]([O:15][CH3:16])=[O:14])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: COC(=O)C1(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Ni]
Solvent: CO
Product: COC(=O)C1(c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
To a solution of methyl 1-(4-nitrophenyl)cyclopropanecarboxylate (20 g, 0.09 mol) in MeOH (400 mL) was added Ni (2 g) under nitrogen atmosphere. The mixture was stirred under hydrogen atmosphere (1 atm) at room temperature overnight. The catalyst was filtered off through a pad of Celite and the filtrate was evaporated under vacuum to give crude product, which was purified by chromatography column on silica gel (petroleum ether/ethyl acetate=10:1) to give methyl 1-(4-aminophenyl)cyclopropanecarboxylate (11.38 g, 66%). 1H NMR (300 MHz, CDCl3) δ 7.16 (d, J=8.1 Hz, 2H), 6.86 (d, J=7.8 Hz, 2H), 4.31 (br, 2H), 3.61 (s, 3H), 1.55-1.50 (m, 2H), 1.30-1.12 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20](O)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>O1CCCC1>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=Cc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=O)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 150.6 %

Procedure:
A solution of 4.9 g (0.040 mol) 4-hydroxy-benzaldehyde, 10.0 g (0.050 mol) 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (analogously to K. L. Bhat, D. M. Flanagan, M. M. Jouille, Synth. Commun. 1985, 15, 587-598) and 13.1 g (0.050 mol) triphenylphosphine in 200 ml tetrahydrofuran is mixed at 5° C. with 7.9 ml (0.050 mol) azodicarboxylic acid diethyl ester and stirred for 24 hours at room temperature. After concentration the residue is purified by chromatography on a silica gel column (mobile solvent: isohexane/ethyl acetate 8:2, 7:3). After concentrating the appropriate column fractions one obtains 18.4 g (85%) of the title compound as a yellowish solid substance. Melting point. 63-64° C.; EI-MS: 305 (M+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]2[S:11][C:12]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]45OCC(C)(C[O:31]4)C[O:27]5)=[C:20]([CH3:35])[CH:19]=3)=[C:13]([CH3:15])[CH:14]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl>CC(O)C>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([C:10]2[S:11][C:12]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:31])=[O:27])=[C:20]([CH3:35])[CH:19]=3)=[C:13]([CH3:15])[CH:14]=2)=[CH:9][C:2]=1[F:1])#[N:5]
Reactant: Cc1cc(CCc2sc(-c3ccc(C#N)c(F)c3)cc2C)ccc1OCC12OCC(C)(CO1)CO2
Agent: Cl
Solvent: CC(C)O
Product: Cc1cc(CCc2sc(-c3ccc(C#N)c(F)c3)cc2C)ccc1OCC(=O)O

Procedure:
A mixture of 2-fluoro-4-[4-methyl-5-(2-{3-methyl-4-[(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)methoxy]phenyl}ethyl)thien-2-yl]benzonitrile (intermediate 101, 0.016 g) in 2-propanol (2 ml) was treated with 2M aqueous hydrochloric acid (1 ml) and the mixture stirred at reflux for 2 hours. The solvent was removed and the residue dissolved in 1,4-dioxane (2 ml) and water (1 ml). This mixture was treated with 2M aqueous sodium hydroxide (0.5 ml) and the mixture stirred for 16 hours). The solvent was removed and the residue purified by SPE (aminopropyl). The title compound, as the free acid, was recovered by treating a solution of this product with Dowex H+.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:14][CH:15]([CH3:18])[CH2:16]Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H-].[Na+]>O1CCCC1>[CH2:7]([O:14][CH:15]([CH3:18])[CH2:16][CH:2]1[CH2:3][CH2:4][CH2:5][C:1]1=[O:6])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(CCl)OCc1ccccc1
Reactant: O=C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(CC1CCCC1=O)OCc1ccccc1

Procedure:
5,7-dihydroxyoctanoic acid delta-lactone was prepared in several steps from cyclopentanone and 2-benzyloxy-1-chloropropane. Thus, alkylation of cyclopentanone was effected by treatment with sodium hydride in tetrahydrofuran (THF) solution to generate the alpha-anion, followed by the dropwise addition of a THF solution of 2-benzyloxy-1-chloropropane. Reaction workup yielded 2-(2-benzyloxy-1-propyl) cyclopentanone. This ketone was treated with peroxy trifluoroacetic acid under Baeyer-Villiger conditions to give the 7-benzyl ether of 5,7-dihydroxyoctanoic acid gamma-lactone. The benzyl group was removed by catalytic hydrogenation, yielding 5,7-dihydroxyoctanoic acid delta-lactone.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[Li]CCCC.[S:17](Cl)([Cl:20])(=[O:19])=[O:18].C(Cl)Cl>C1COCC1>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:2]2[S:1][C:5]([S:17]([Cl:20])(=[O:19])=[O:18])=[CH:4][CH:3]=2)[CH:7]=1
Reactant: c1cncc(-c2cccs2)c1
Reactant: O=S(=O)(Cl)Cl
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=S(=O)(Cl)c1ccc(-c2cccnc2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.1 %

Procedure:
To a solution of 3-thiophen-2-yl-pyridine (0.35 g, 2.20 mmol) in 15 mL of THF at -78° C. is added n-BuLi (1.44 mL of a 1.6M solution in hexanes, 2.31 mmol). After stirring for 15 minutes, SO2 gas is bubbled through the solution for 30 minutes. The solution is then allowed to warm to room temperature and stirred overnight. The solution is concentrated to dryness and the resulting solid is suspended in 20 mL of hexane. Sulfuryl chloride (0.185 mL, 2.31 mmol) is added and the reaction mixture is stirred for 30 minutes and then a small amount of methylene chloride is added and the mixture is stirred for another 30 minutes. The mixture is then concentrated to dryness and diluted with ethyl acetate and washed with saturated NaHCO3 (aq), water and brine. The organic layer is dried over MgSO4, filtered and concentrated to give a brown solid as the title product (0.452 g, 1.74 mmol) which is used in the subsequent step without further purification.
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18]([OH:20])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[C:28]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[CH2:11]([O:10][C:8]([NH:7][CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]([NH:1][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:18]([O:20][CH3:28])=[O:19])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To a solution of Boc-L-Lys(Z)OH (2.00 g, 5.2 mmol) in dry DMF (50 mL) was added Cs2CO3 (1.71 g, 5.2 mmol). The mixture was stirred at rt for 2 h. To the reaction mixture was then added dropwise methyl iodide (392 μL, 6.3 mmol) and the mixture was stirred at rt overnight. The solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL) and washed with saturated NaHCO3 solution water and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude compound was purified on column of silica gel (2% MeOH/DCM) to give the subject compound (2.00 g, yield 97%). Intermediate 31 was characterized by the following spectroscopic data: 1H NMR (DMSO-d6, 300 MHz) δ (ppm) 7.34 (m, 5H), 7.23 (t, 1H), 4.99 (s, 2H), 3.91 (m, 1H), 3.60 (s, 3H), 3.34 (s, 2H), 2.96 (m, 2H), 1.56 (m, 2H), 1.37 (m, 11H), 1.32 (m, 2H).