Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][C:13]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:15]=2[C:16]#[N:17])[C:7]([Cl:22])=[CH:6][C:5]=1[O:23][CH3:24].[OH-].C[Sn+](C)C>ClCCCl>[Cl:22][C:7]1[C:8]([C:10]2[CH:11]=[N:12][C:13]([C:18]([F:19])([F:21])[F:20])=[CH:14][C:15]=2[C:16]#[N:17])=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[C:5]([O:23][CH3:24])[CH:6]=1
Reactant: COC(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OC
Agent: C[Sn+](C)C
Agent: [OH-]
Solvent: ClCCCl
Product: COc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1C(=O)O
Temperature: 80 °C
Yield: 63.3 %

Procedure:
A mixture of 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzoic acid methyl ester (1.2 g, 3.2 mmol) and trimethyltin hydroxide (1.75 g, 9.7 mmol) in 1,2-dichloroethane (50 mL) was heated to 80° C. in a sealed tube for 4 hrs. Additional 5.0 eq. of trimethyltin hydroxide was added and the mixture was heated for total of 48 hrs. The mixture was then cooled to rt, quenched with HCl (2N, 40 mL) and diluted with 1,2-dichloroethane. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was purified via silica gel flash column chromatography eluting with dichloromethane:methanol (9:1) to afford 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzoic acid (723 mg). NMR (CDCl3), δ, 8.82 (1H, s), 7.94 (1H, s), 7.81 (1H, s), 7.20 (1H, s), 3.90 (3H, s).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:27]=[CH:26][C:12]([O:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=3[C:22]([F:25])([F:24])[F:23])=[C:11]([F:28])[CH:10]=2)[S:3]1.Cl[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[F:28][C:11]1[CH:10]=[C:9]([CH:8]=[C:4]2[S:3][C:2](=[O:1])[N:6]([CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:5]2=[O:7])[CH:27]=[CH:26][C:12]=1[O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=1[C:22]([F:25])([F:23])[F:24]
Reactant: N#Cc1ccc(Oc2ccc(C=C3SC(=O)NC3=O)cc2F)c(C(F)(F)F)c1
Reactant: ClCCN1CCOCC1
Product: N#Cc1ccc(Oc2ccc(C=C3SC(=O)N(CCN4CCOCC4)C3=O)cc2F)c(C(F)(F)F)c1

Procedure:
The title compound was prepared using 4-[4-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-2-fluoro-phenoxy]-3-trifluoromethyl-benzonitrile and 4-(2-Chloro-ethyl)-morpholine as described in Example 1. 1H NMR (400 Hz, CDCl3) δ 8.01 (s, 1H), 7.83 (s, 1H), 7.74 (dd, 1H), 7.34 (m, 3H), 6.91 (d, 1H), 3.92 (t, 2H), 3.69 (bt, 2H), 2.69 (bt, 2H), 2.57 (bs, 2H); LC/MS (m/z) [M+1]+ 522.2 (calculated for C24H20F4N3O4S, 522.49).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])[N:3]=1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[SH:30]>>[OH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([S:30][C:21]2[CH:22]=[CH:23][C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]=2)=[N:3][C:4]=1[C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14]
Reactant: Sc1ccc2ccccc2c1
Reactant: O=C(O)CNC(=O)c1nc(Cl)c2ccccc2c1O
Product: O=C(O)CNC(=O)c1nc(Sc2ccc3ccccc3c2)c2ccccc2c1O

Procedure:
The title compound was prepared from [(1-chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid (U.S. Pat. No. 6,093,730) and 2-napthalenethiol under conditions analogous to Example D-110. The final product was purified by triturating the crude product twice with methanol and twice with dichloromethane; MS (+) m/z 405.08 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[C:3]1=[O:13].C([N-:17]C(C)C)(C)C.[Li+].O>C1COCC1>[ClH:12].[NH2:17][C:2]1([CH3:1])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[C:3]1=[O:13]
Reactant: CC1CCc2cc(Cl)ccc2C1=O
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(N)CCc2cc(Cl)ccc2C1=O
Product: Cl
Temperature: -50 °C
Reaction time: 1 h
Yield: 167.8 %

Procedure:
Ice cold sodium hydroxide solution (75 mL, 2N) was added to hydroxylamine-O-sulfonic acid (17.1 g, 0.15 mol) in water (150 mL) at 0° C. When the solution had cooled to about 5° C. it was added in one portion to a mixture of sodium hydroxide solution (75 mL, 2N), cyclohexanone (15 g, 0.15 mol) and toluene (270 mL) at 0° C. The mixture was stirred for 10 min. The organic layer was separated, dried and decanted from the drying agent. This afforded a solution of the cyclohexane-spiro-3'-oxaziridine which was used directly. The oxyaziridine solution prepared as above (540 mL) was added in one portion to an enolate (previously prepared by addition of 2-methyl-6-chlorotetralone (18.07 g, 92.9 mmol) in THF (40 mL) to lithium diisopropylamide (10.4 g, 97.1 mmol) in THF/hexanes (60 mL/40 mL) at -50° C. When the addition was complete, the mixture was stirred for 1 h at -50° C.). The reaction was stirred for 1 h, and was allowed to warm to 0° C. The mixture was poured into water (500 mL), and the organic layer was separated. The aqueous layer was further extracted with dichloromethane (3×250 mL). The combined extracts were dried, hydrochloric acid (about 10 mL, conc.) was added, and the mixture was evaporated. Ether (250 mL) was added and hydrochloric acid (about 10 mL, conc.) was added. The mixture was stirred overnight and was filtered to give the product as a solid (19.18 g, 83%). 1H NMR (free base) (CDCl3) δ8.00 (d, 1H), 7.32-7.25 (m, 2H), 3.19-2.89 (m, 2H), 2.18-1.98 (m, 2H), 1.29 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][CH2:8][C:9](Cl)=[O:10]>ClCCl>[Cl:7][CH2:8][C:9]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:10]
Reactant: C1CCNCC1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Product: O=C(CCl)N1CCCCC1
Temperature: 0 °C

Procedure:
To a solution of piperidine (0.084 mL, 0.86 mmol, d=0.862) stirring in dichloromethane (4 mL) at 0° C., was added chloro acetylchloride (0.034 mL, 0.43 mmol, d=1.419). After stirring at 0° C. for a hour, the reaction mixture was diluted with dichloromethane (25 mL), washed with dilute citric acid, water and brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to obtain 2-chloro-1-(piperidin-1-yl)ethanone.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.Cl[CH:8]([CH2:12][CH3:13])[C:9](Cl)=[O:10].[Cl-:14].[Al+3].[Cl-].[Cl-].Cl>C(Cl)(Cl)(Cl)Cl>[Cl:14][CH2:13][CH2:12][CH2:8][C:9]([C:4]1[S:3][C:2]([Cl:1])=[CH:6][CH:5]=1)=[O:10]
Reactant: [Cl-]
Reactant: CCC(Cl)C(=O)Cl
Reactant: Clc1cccs1
Agent: Cl
Agent: [Al+3]
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(CCCCl)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 59 g. (0.50 mole) 2-chlorothiophene, α-chlorobutyroylchloride and 500 ml. carbon tetrachloride maintained at 15°-25° C. with the aid of an ice bath was added portionwise 70.5 g. (0.60 mole) of aluminum chloride. The mixture was stirred at room temperature overnight and then carefully poured into 500 ml. of 20% hydrochloric acid solution. The organic layer was separated and washed with sodium bicarbonate solution followed by water. The organic solution was dried over (MgSO4), filtered, and concentrated to an oil under vacuum. The oil was distilled to give 82 g. of material which boiled at 140° C./2 mm. This material solidified on cooling.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:10]2[C:22]2[C:23]([CH3:28])=[N:24][O:25][C:26]=2[CH3:27])=[CH:5][CH:4]=1.B(Br)(Br)Br.O.CCOC(C)=O>C(Cl)Cl>[CH3:28][C:23]1[C:22]([C:10]2[N:9]([C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=3)[C:17]3[C:12]([C:11]=2[S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][CH:14]=[CH:15][CH:16]=3)=[C:26]([CH3:27])[O:25][N:24]=1
Reactant: COc1ccc(-n2c(-c3c(C)noc3C)c(S(C)(=O)=O)c3ccccc32)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1noc(C)c1-c1c(S(C)(=O)=O)c2ccccc2n1-c1ccc(O)cc1
Temperature: -78 °C
Yield: 27 %

Procedure:
4-(1-(4-Methoxyphenyl)-3-(methylsulfonyl)-1H-indol-2-yl)-3,5-dimethylisoxazole was dissolved in 2 ml of dry DCM and cooled to −78° C. under nitrogen. BBr3 (31 μl, 0.33 mmol) was added and the temperature was allowed to warm to RT for 2 h. Water and EtOAc were added and the phases were separated. After evaporation of the solvents, the residue was purified by preparative HPLC to provide 4-[2-(3,5-dimethyl-isoxazol-4-yl)-3-methanesulfonyl-indol-1-yl]-phenol in 27% yield. ES/MS m/z: 383.11 (M+H), 381.13 (M−H); 1H NMR (acetone-d6, 500 MHz): 8.12 (m, 1H), 7.39-7.34 (m, 2H), 7.25-7.19 (m, 3H), 6.98 (m, 2H), 3.06 (s, 3H), 2.30 (s, 3H) and 2.09 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([NH:8][C:9]2[O:10][C:11]3[C:17]([F:18])=[C:16]([CH2:19][C:20]([O:22]C)=[O:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:7]=1.[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([NH:8][C:9]2[O:10][C:11]3[C:17]([F:18])=[C:16]([CH2:19][C:20]([OH:22])=[O:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:7]=1
Reactant: COC(=O)Cc1ccc2nc(Nc3cc(Cl)ccc3C)oc2c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(Cl)cc1Nc1nc2ccc(CC(=O)O)c(F)c2o1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.7 %

Procedure:
In THF/methanol (4:1, v/v, 100 ml) was dissolved methyl (2-(5-chloro-2-methylphenylamino)-7-fluoro-6-benzoxazolyl)acetate (1.67 g, 4.79 mmol). To the resulting solution was added 1N NaOH (40 ml). After stirring at room temperature for 12 hours, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was acidified with 1N HCl. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (2-(5-chloro-2-methylphenylamino)-7-fluoro-6-benzoxazolyl)acetic acid (1.39 g, 87%) as a colorless crystalline powder.
Reaction SMILES: O.[NH2:2][NH2:3].[O:4]=[C:5]([NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6](OC)=[O:7]>C(O)C>[NH:2]([C:6](=[O:7])[C:5]([NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:4])[NH2:3]
Reactant: NN
Reactant: COC(=O)C(=O)NCCCOc1ccccc1
Solvent: O
Solvent: CCO
Product: NNC(=O)C(=O)NCCCOc1ccccc1
Temperature: 85 °C

Procedure:
Hydrazine monohydrate (6.3 mL) was added to a stirred suspension of methyl oxo[(3-phenoxypropyl)amino]acetate (3080 mg) in ethanol (50 mL). The reaction mixture was heated to 85° C. for 3 hours then allowed to cool. The precipitate was filtered off, washed with Et2O and dried under vacuum, to give the title compound (Intermediate 46, 2.269 g) as a solid; 1H NMR δ 9.95 (1H, s), 8.77 (1H, s), 7.28 (2H, m), 6.92 (3H, m), 4.50 (2H, s), 3.99 (2H, t), 3.30 (2H+H2O, m), 1.94 (2H, t); MS m/e MNa+ 260.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:14])[CH:12]=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(O)(=[O:17])C.CC1C=CC=C(C)N=1.C(OO)(=O)C>C(OCC)(=O)C>[OH:13][C:12]([CH:11]([C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:10][CH:9]=1)[CH3:14])=[O:17]
Reactant: CC(C)Cc1ccc(C(C)C=O)cc1
Reactant: CC(=O)O
Agent: CC(=O)OO
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Yield: 92.2 %

Procedure:
To a stirred solution of 109 g (573 mmol) of 2-(4-isobutylphenyl)-propionaldehyde (ibuprofen aldehyde) in ethyl acetate (5 12 mL) cooled in a wet-ice bath (ca. 2° C.) was added concurrently 34.4 g (573 mmol) of glacial acetic acid and 61.4 g (573 mmol) of 2,6-dimethyl pyridine (2,6-lutidine). To this solution was then added slowly dropwise 276 mL (859 mmol) of a 23.7 weight percent solution of peracetic acid in ethyl acetate, at a rate slow enough such that the reaction temperature did not exceed 7° C. (ca. 1 h 40 min). After the initial exotherm, the temperature returned to 2° C,, and the reaction was maintained at this temperature for an additional 2 hours. Conversion of aldehyde at this time was ca. 99%, as monitored by GC (DB-1 column). The cold reaction solution was then transferred into a separatory funnel, was diluted with ethyl acetate (650 mL), and was washed with a 7% aqueous solution of sodium thiosulfate (Na2S2O3, 500 mL). The ethyl acetate layer was further washed with two portions of water (750 mL each), and the combined water washes were back-extracted with ethyl acetate (300 mL). The combined ethyl acetate layers were extracted with three portions of a 5% aqueous solution of sodium hydroxide (NaOH, 750 mL twice, then 500 mL). The combined NaOH solutions were acidified to pH=1 with a 10% aqueous solution of hydrochloric acid. The resulting solution was extracted with three portions of dichloromethane (500 mL twice, then 300 mL), and the extract was dried over anhydrous Na2SO4. The extract was filtered and concentrated in vacuo to give 109 g (92.2%) of ibuprofen as an off-white solid. HPLC analysis of this material indicated an `S` acid content of 83%, the same as the starting aldehyde as measured following KMnO4 oxidation.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:16]([C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: O=Cc1cccc(F)c1
Solvent: O
Solvent: CCO
Product: O=C1CC(c2cccc(F)c2)Oc2ccc(Br)cc21
Yield: 36.9 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (15 g, 0.07 mol), 3-fluorobenzaldehyde (8.7 g, 0.07 mol) and borax (26.7 g, 0.07 mol) in ethanol (90 mL) and H2O (150 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O, and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2-(3-fluorophenyl)chroman-4-one (8.3 g, 37%). 1H-NMR (CDCl3): 2.93 (d, 1H), 3.03 (m, 1H), 5.47 (d, 1H), 7.06 (d, 1H), 7.11 (m, 1H), 7.22 (m, 2H), 7.40 (m, 1H), 7.57 (d, 1H), 8.04 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]1[S:47][C:46]([S:48](Cl)(=[O:50])=[O:49])=[CH:45][CH:44]=1>ClC(Cl)C>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:48]([C:46]2[S:47][C:43]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][N:37]=3)=[CH:44][CH:45]=2)(=[O:49])=[O:50])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3nccs3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccc(-c3ccccn3)s2)c1
Reaction time: 72 h
Yield: 33.9 %

Procedure:
To a solution of {3-[(4-thiazol-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester (111 mg, 0.270 mmol), prepared in Step A of Example 13i, triethylamine (120 mg, 1.19 mmol) and dichloroethane (10 mL) was added 5-pyridin-2-yl-thiophene-2-sulfonyl chloride (77.2 mg, 0.297 mmol). The reaction was stirred for 72 h and additional 5-pyridin-2-yl-thiophene-2-sulfonyl chloride (38.5 mg) was added. The reaction was stirred for an additional 48 h. The organic solution was washed sequentially with 5.5% HCl, water, saturated sodium bicarbonate solution, and brine. The organic solution was dried (MgSO4), filtered, and concentrated. Flash chromatography (CHCl3:MeOH 99:1) provided the title compound of Step A (58 mg). MS 633 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.[C:27]([CH2:29][CH2:30][CH:31](O)[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])#[N:28].N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl.CCOCC>[C:27]([CH2:29][CH2:30][CH:31]([O:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])#[N:28]
Reactant: CCOC(=O)CCCC(O)CCC#N
Reactant: Oc1cccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)CCCC(CCC#N)Oc1cccnc1
Reaction time: 0.08 h

Procedure:
To a mixture of triphenylphosphine (2.42 g, 9.2 mmol) and 3-hydroxypyridine (0.7 g, 7.3 mmol) in methylene chloride (20 ml) is added the ethyl 7-cyano-5-hydroxyheptanoate obtained above. The reaction mixture is stirred for 5 min and then diethyl azodicarboxylate (1.0 ml, 6.3 mmol) is added dropwise. The reaction mixture is stirred overnight and the solvent is evaporated. The residue is chromatographed on silica gel using ether as eluent to obtain an amber oil. The oil is dissolved in 10 ml ether, cooled to 0° and the precipitated triphenylphosphine oxide is filtered off. The filtrate is evaporated to give crude ethyl 7-cyano-5-(3-pyridyloxy)-heptanoate, IR (CH2Cl2): 2239, 1729, 1576, 1229, 1167, 1120 cm-1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]1[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1.[O:13]=[C:14]([NH:29][CH2:30][C:31](=O)[NH:32][C@@H:33]1[CH2:37]CNC1)[CH2:15][NH:16][C:17](=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O.C(Cl)Cl.CCOC(C)=O>[O:13]=[C:14]([NH:29][C@@H:30]1[CH2:37][CH2:33][N:32]([CH:9]2[CH2:10][CH2:11][CH:6]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[CH2:7][CH2:8]2)[CH2:31]1)[CH2:15][NH:16][C:17](=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1
Reactant: O=C1CCC(c2nccs2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC(=O)N[C@@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCC(c3nccs3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
To a mixture of 4-(1,3-thiazol-2-yl)cyclohexanone (0.069 g, 0.38 mmol) and N-[2-oxo-2-({2-oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}amino)ethyl]-3-(trifluoromethyl)benzamide (0.10 g, 0.32 mmol) in 2% AcOH/CH2Cl2 (10 mL) was added NaB(OAc)3H (0.134 g, 0.634 mmol). After being stirred overnight at room temperature under N2, the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), concentrated and flash chromatographed [EtOAc to MeOH/EtOAc (1:9) then to 5% MeOH/EtOAc/Et3N (1:9:0.5)] to give 0.129 g of the title compound in 85% yield. MS (EI) calcd: (M+H)+=480.2; found: 480.3.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=1[CH3:9].[C:10]1([S:16](Cl)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[C:10]1([S:16]([O:1][C:2]2[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=2[CH3:9])(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1occc(=O)c1O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Cc1occc(=O)c1OS(=O)(=O)c1ccccc1
Yield: 71 %

Procedure:
3-Hydroxy-2-methyl-4H-pyran-4-one (1.0 g, 7.9 mmol) was reacted with benzenesulfonyl chloride (3.0 mL, 23.7 mmol) in 75 mL of pyridine to afford PZBG-2a in 71% yield (1.50 g, 5.6 mmol). 1H NMR (500 MHz, CDCl3) δ=8.12 (d, J=8.6 Hz, 2H), 7.69 (t, J=7.5 Hz, 1H), 7.65 (d, J=5.8 Hz, 1H), 7.58 (t, J=8.0 Hz, 2H), 6.33 (d, J=5.2 Hz, 1H), 2.46 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ=172.1, 163.1, 154.3, 138.4, 136.6, 134.7, 129.2, 129.0, 117.7, 16.3. ESI-MS(+): m/z 267.06 [M+H]+, 289.03 [M+Na]+.
Reaction SMILES: C([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH3:52])[CH2:24][CH2:25][N:26]([C:28]3[CH:29]=[CH:30][C:31]([C:34]4[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42]CC5C=CC=CC=5)=[C:36]([O:50][CH3:51])[CH:35]=4)=[N:32][CH:33]=3)[CH3:27])=[CH:19][N:18]=2)=[CH:11][C:10]=1[O:53][CH3:54])C1C=CC=CC=1.[CH3:55][S:56]([OH:59])(=[O:58])=[O:57]>C(O)(=O)C.[Pd].CO>[CH3:55][S:56]([OH:59])(=[O:58])=[O:57].[CH3:55][S:56]([OH:59])(=[O:58])=[O:57].[OH:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH3:52])[CH2:24][CH2:25][N:26]([C:28]3[CH:29]=[CH:30][C:31]([C:34]4[CH:35]=[C:36]([O:50][CH3:51])[C:37]([OH:42])=[C:38]([O:40][CH3:41])[CH:39]=4)=[N:32][CH:33]=3)[CH3:27])=[CH:19][N:18]=2)=[CH:11][C:10]=1[O:53][CH3:54]
Reactant: COc1cc(-c2ccc(N(C)CCN(C)c3ccc(-c4cc(OC)c(OCc5ccccc5)c(OC)c4)nc3)cn2)cc(OC)c1OCc1ccccc1
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(-c2ccc(N(C)CCN(C)c3ccc(-c4cc(OC)c(O)c(OC)c4)nc3)cn2)cc(OC)c1O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 30.1 %

Procedure:
To a solution of N,N′-bis[2-(4-benzyloxy-3,5-dimethoxyphenyl)-5-pyridyl]-N,N′-dimethylethylenediamine (64.0 mg, 0.090 mmol) in acetic acid (1.0 mL) was added 10% palladium on charcoal (43.0 mg). Under hydrogen, the mixture was stirred at 50° C. for 1 hour and 30 minutes. Insoluble materials were removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. A solution of the residue in methanolchloroform (1:10) was washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a solution of the residue in methanol (2.0 mL) was added a 1.0 M aqueous methanesulfonic acid (0.20 mL, 0.20 mmol), and the reaction mixture was concentrated under reduced pressure. Ethanol (5.0 mL) was added to the residue, and the mixture was concentrated under reduced pressure. The residue was recrystallized from methanol-diethyl ether to afford the title compound as a yellow crystalline powder (melting point:≧300.0°) (20.0 mg, yield: 31% based on N,N′-bis[2-(4-benzyloxy-3,5-dimethoxyphenyl)-5-pyridyl]-N,N′-dimethylethylenediamine).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]([C:8]1[S:12][C:11]2[CH2:13][CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17](=[O:18])[C:10]=2[CH:9]=1)=[O:7].[OH-].[K+].Cl>O1CCOCC1.O>[O:18]=[C:17]1[C:10]2[CH:9]=[C:8]([C:6](=[O:7])[CH2:5][CH2:4][C:3]([OH:23])=[O:2])[S:12][C:11]=2[CH2:13][CH2:14][C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]1=2
Reactant: COC(=O)CCC(=O)c1cc2c(s1)CCc1ccccc1C2=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCC(=O)c1cc2c(s1)CCc1ccccc1C2=O

Procedure:
A solution of 3.0 g of 4-(9,10-dihydro-4-oxo-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-2-yl)-4-oxobutyric acid methyl ester and 1.5 g of potassium hydroxide in 60 cc of dioxane and 30 cc of water is stirred at room temperature for 3 hours, dilution is effected with 200 cc of water and the pH of the solution is adjusted to 1 with concentrated hydrochloric acid at 10°-15°. The resulting title compound is extracted with methylene chloride, the organic solution is washed with water, dried over magnesium sulphate, concentrated by evaporation, and the title compound is recrystallized from dimethyl formamide/acetone. M.P. 167°-168°.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]([N:17]=[CH:18]N(C)C)=[S:16])=[O:7])([CH3:4])[CH3:3].Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH3:33])=[O:25]>CN(C)C=O.ClCCl>[C:2]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[S:16][C:23]([C:24](=[O:25])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][CH3:33])=[CH:18][N:17]=1)=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: CN(C)C=NC(=S)NC[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: CCc1ccccc1C(=O)CBr
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1ccccc1C(=O)c1cnc(NC[C@@H]2CCCN2C(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 65 h
Yield: 65.1 %

Procedure:
To a solution of 2-(S)-(3-dimethylaminomethylene-thioureidomethyl)-pyrrolidine-1-carboxylic acid 1,1-dimethylethyl ester (150 mg) in N,N-dimethylformamide (2 ml) was added 2-bromo-1-(2-ethylphenyl)-ethanone (109 mg). The mixture was stirred 65 h at room temperature, diluted with dichloromethane, washed twice with water, once with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (2:1 ethyl acetate/hexane eluant) to afford the product as yellow oil (129 mg, 65%).