Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.[C:15]([O:19][CH3:20])(=[O:18])[CH:16]=[CH2:17]>C(Cl)Cl>[F:11][C:10]([F:13])([F:12])[C:6]1[CH:5]=[C:4]([C:3]2[CH2:17][CH:16]([C:15]([O:19][CH3:20])=[O:18])[O:1][N:2]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: ON=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: C=CC(=O)OC
Solvent: ClCCl
Product: COC(=O)C1CC(c2cccc(C(F)(F)F)c2)=NO1
Temperature: 25 °C
Reaction time: 20 h
Yield: 105.2 %

Procedure:
To a flask containing N-hydroxy-3-(trifluoromethyl)benzenecarboximidoyl chloride (2.0 g, 8.9 mmol) and methyl acrylate (0.7 g, 8 mmol) in methylene chloride (100 mL) at 0° C. under an inert atmosphere was added TEA (0.90 g, 8.8 mmol). The reaction mixture was slowly warmed to ambient temperature, stirred for 20 h, quenched with water (30 mL), and extracted with methylene chloride (2×50 mL). The organic extracts were combined, washed with saline solution (50 mL), dried over sodium sulfate, concentrated in vacuo, and chromatographed on silica gel, eluting with methylene chloride/methanol (100/1 to 95/5). The appropriate fractions were combined and concentrated in vacuo to give methyl 3-[3-(trifluoromethyl)phenyl]-4,5-dihydroisoxazole-5-carboxylate (2.3 g, 100%): LCMS: 274.2 (M+H+, 100%); 1H NMR: (CDCl3) δ 8.03 (s, 1H), 7.92 (d, 1H), 7.71 (d, 1H), 7.59 (dd, 1H), 5.28 (dd, 1H), 3.86 (s, 3H), 3.71 (dd, 2H).
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([S:14][CH2:15][CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)[CH:18]=2)=[CH:8][C:7]=1[CH3:37].COC(=O)COC1C=C(OC)C(SCCC2C3C(=CC=CC=3)NC=2)=CC=1C.[H-].[Na+].FC(F)(F)C1C=CC(CBr)=CC=1.Cl>CN(C=O)C>[CH3:13][O:12][C:10]1[C:9]([S:14][CH2:15][CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=3)[CH:18]=2)=[CH:8][C:7]([CH3:37])=[C:6]([CH:11]=1)[O:5][CH2:4][C:3]([OH:38])=[O:2]
Reactant: COC(=O)COc1cc(OC)c(SCCc2cn(Cc3ccc(C(F)(F)F)cc3)c3ccccc23)cc1C
Agent: COC(=O)COc1cc(OC)c(SCCc2c[nH]c3ccccc23)cc1C
Agent: Cl
Agent: FC(F)(F)c1ccc(CBr)cc1
Solvent: CN(C)C=O
Product: COc1cc(OCC(=O)O)c(C)cc1SCCc1cn(Cc2ccc(C(F)(F)F)cc2)c2ccccc12
Reaction time: 0.5 h

Procedure:
Preparation of {4-[2-(1H-Indol-3-yl)-ethylsulfanyl]-5-methoxy-2-methyl-phenoxy}-acetic acid methyl ester (compound 54A) The compound 1D (1.622 g, 6.7 mmol) and 3-(2-bromo-ethyl)-1H-indole (1.50 g, 6.69 mmol) was dissolved in 5 ml DMF. Potassium carbonate (1.11 g, 8.03 mmol) was added followed by stirring at room temperature for 3 h. The reaction was filtered, concentrated and purified by MPLC to give the title compound. MS m/z 225 (M+1). Step 2. Preparation of (5-Methoxy-2-methyl-4-{2-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-ethylsulfanyl}-phenoxy)-acetic acid methyl ester (compound 54B) The compound 54A (0.300 g, 0.778 mmol) was dissolved in 5 ml DMF. NaH was added and stirred for ½ h. 4-trifluoromethylbenzyl bromide (0.223 g, 0.934 mmol) was added and the reaction was stirred for 1.5 h. 10 ml 2N HCl was added to pH<4. The DMF solution was partitioned between 30 ml water and 30 ml ethyl acetate. The organic solution was washed 2×30 ml water 1×30 ml brine, dried over sodium sulfate, decanted, concentrated and purified by MPLC to give the title product. MS m/z 544 (m+1). Step 3. Preparation of (5-Methoxy-2-methyl-4-{2-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-ethylsulfanyl}-phenoxy)-acetic acid (compound 54) The title compound was prepared in the manner analogous to Example 1 using 54B. 400 MHz 1H NMR (DMSO-d6) δ 13.0 (br(s), 1H), 7.60 (d, 1H, J=8.1 Hz), 7.42 (d, 1H, J=7.96 Hz), 7.31 (m, 4H), 7.04 (m, 2H), 6.96 (m, 1H), 6.53 (s, 1H), 5.43 (s, 2H), 4.70 (s, 2H), 3.72 (s, 3H), 3.03 (t, 2H, J=8.8 Hz), 2.86 (t, 2H, J=7.6 Hz), 2.04 (s, 3H). MS m/z 530 (M+1).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:3]=1.[I-:17].[Na+].C1(C)C=CC=CC=1.CNCCNC>[Cu]I.O>[I:17][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:3]=1
Reactant: [I-]
Reactant: CCOC(=O)c1ccc(Br)cc1S(C)(=O)=O
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(I)cc1S(C)(=O)=O
Yield: 64.5 %

Procedure:
To a mixture of ethyl 4-bromo-2-methanesulfonylbenzoate (13.88 g), sodium iodide (13.54 g) and copper(I) iodide (4.30% g) were added toluene (46 mL) and N,N′-dimethylethylenediamine (4.86 mL), and the mixture was stirred with heating under reflux for 8 hr under a nitrogen stream. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer, the obtained residue was purified by column chromatography (hexane:ethyl acetate) to give ethyl 4-iodo-2-methanesulfonylbenzoate (10.32 g). To a mixture of the obtained ethyl 4-iodo-2-methanesulfonylbenzoate (3.22 g), (R)-3-methylisothiazolidine 1,1-dioxide (1.23 g) described in Preparation Example 2, copper(I) iodide (4.30 g), N,N′-dimethylethylenediamine (0.92 mL) and potassium carbonate (2.52 g) was added toluene (9.2 mL), and the mixture was stirred with heating under reflux for 8 hr under a nitrogen stream. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer, and the obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (1.7 g).
Reaction SMILES: N1C(C2C=CC([C:12]3[C:21](C)=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:23]C)[CH:18]=4)[N:13]=3)=CC=2)=NN=N1.B(Br)(Br)Br.C(Cl)[Cl:30]>>[Cl:30][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:23])[CH:18]=2)[N:13]=1
Reactant: COc1ccc2nc(-c3ccc(-c4nnn[nH]4)cc3)c(C)cc2c1
Reactant: ClCCl
Agent: BrB(Br)Br
Product: Oc1ccc2nc(Cl)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of 2-chloro-6-methoxyquinoline (Intermediate 1) (2.00 g, 10.4 mmol) in anhydrous DCM (100 mL) was added BBr3 (6 mL, 62.2 mmol) dropwise at 0° C. The reaction mixture was stirred at 25° C. for 2 hours, then quenched with aqueous saturated NH4Cl (50 mL) and filtered. The filtrate was extracted with CH2Cl2/MeOH (v/v=10/1, 30 mL×2) and the combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-chloroquinolin-6-ol (1.30 g, yield 70%) as yellow solid. 1H NMR (CDCl3 300 MHz): δ 7.95 (t, J=8.1 Hz, 2H), 7.35 (dd, J=6.0, 3.3 Hz, 2H), 7.13 (d, J=2.7 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH2:15])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[N:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:26](=[O:27])[C:25]3[CH:24]=[CH:23][C:22]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][N:16]=4)=[CH:30][CH:29]=3)=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(-c2cnccn2)cc1
Reactant: Cc1cc(-c2ccc(CN)cn2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(CNC(=O)c3ccc(-c4cnccn4)cc3)cn2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (2′-methyl-[2,4′-bipyridin]-5-yl)methanamine 18-2 (10.0 mg, 0.05 mmol), 4-(pyrazin-2-yl)benzoic acid 18-3 (10.0 mg, 0.05 mmol), and HATU (23 mg, 0.06 mmol) were added N,N-diisopropylethylamine (DIEA, 17 μL, 0.1 mmol) and DMF (0.5 mL). The solution was stirred overnight at room temperature and was subjected directly to reverse phase preparative HPLC to yield N-42′-methyl-[2,4′-bipyridin]-5-yl)methyl)-4-(pyrazin-2-yl)benzamide 18 as a white powder. MS m/z 382.2 (M+1). 1H NMR 400 MHz (CDCl3) δ 9.06 (d, 1H), 8.73 (d, 1H), 8.66 (dd, 1H), 8.59 (d, 1H), 8.56 (d, 1H), 8.15-8.08 (m, 2H), 8.00-7.91 (m, 2H), 7.86 (dd, 1H), 7.80-7.73 (m, 2H), 7.65 (dd, 1H), 6.90 (t, 1H), 4.76 (d, 2H), 2.64 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8]C)=[CH:6][CH:5]=[CH:4][C:3]=1[CH:10]([CH2:15][CH3:16])[CH2:11][C:12]([OH:14])=[O:13].CN1C(=O)CCC1.[OH-].[Na+].C(S)CCCCCCCCCCC>Cl.CCOC(C)=O>[F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:10]([CH2:15][CH3:16])[CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCC(CC(=O)O)c1cccc(OC)c1F
Agent: CCCCCCCCCCCCS
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCC(CC(=O)O)c1cccc(O)c1F
Temperature: 125 °C
Reaction time: 5 h
Yield: 100.1 %

Procedure:
A 500 mL round bottom flask was charged with 3-(2-fluoro-3-methoxyphenyl)pentanoic acid 77.D (3.44 g, 15.2 mmol), NMP (30 mL), NaOH (2.74 g, 68.4 mmol), and 1-dodecanethiol (available from Aldrich) (12.8 mL, 53.2 mmol). The mixture was stirred for 5 hours at 125° C. under N2, cooled to room temperature, and diluted with 1 N HCl and EtOAc. The combined organic layers were washed with water and brine, dried (MgSO4), and concentrated to afford 3-(2-fluoro-3-hydroxyphenyl)pentanoic acid 77.E as a yellow liquid (3.23 g). The product so obtained was used without further purification.
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=O.C(O)(=O)C.[CH3:14][C:15]1[CH:16]=[C:17]([NH2:20])[NH:18][N:19]=1>COC(C)(C)C>[CH3:14][C:15]1[CH:16]=[C:17]2[NH:20][C:3]([CH3:5])=[CH:2][C:1](=[O:7])[N:18]2[N:19]=1
Reactant: Cc1cc(N)[nH]n1
Reactant: CCOC(=O)CC(C)=O
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: Cc1cc2[nH]c(C)cc(=O)n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.9 %

Procedure:
Add ethyl acetoacetate (128 g, 0.98 mol) dropwise to an acetic acid solution (500 mL) of 5-methyl-2H-pyrazol-3-ylamine (100 g, 0.95 mol), keeping the temperature at 25-28° C. Heat the mixture at reflux for 10 h and then cool to room temperature. Add the reaction to tert-butyl methyl ether (5 L) cooled to 5° C., keeping the temperature below 10° C. Stir for 1 h at 5° C., and filter. Dry the resulting material in vacuo overnight to provide a white solid (158 g, 96%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=O)[CH2:6][CH2:5]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[S:23])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)c(F)cc2N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Fc1cc2c(cc1Br)CCC(=S)N2
Temperature: 100 °C

Procedure:
To a stirred solution of 6-bromo-7-fluoro-3,4-dihydroquinolin-2(1H)-one (122-3; 13 g, 0.02 mol) in toluene (50 mL) was added Lawesson's reagent (21.54 g, 0.0532 mol). Reaction mass was refluxed at 100° C. for 12 h. The reaction mixture was concentrated and directly purified by silica gel column chromatography to obtain title compound. MS (M+1): 261.88.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:6][CH:5]([CH:7]([CH2:20]O)[CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:4][O:3]1.C(N(C(C)C)CC)(C)C.[CH3:32][S:33](Cl)(=O)=O.C[S-].[Na+]>ClCCl.CN(C=O)C.CCOC(C)=O.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:22])[O:6][CH:5]([CH:7]([CH2:20][S:33][CH3:32])[CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:4][O:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OCC(C(CO)CNC(=O)OCc2ccccc2)O1
Agent: C[S-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSCC(CNC(=O)OCc1ccccc1)C1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
To a solution of benzyl (RS)-2-((RS)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-hydroxypropylcarbamate (0.843 g, 2.73 mmol) in dry dichloromethane (30 mL) was added diisopropylethylamine (1.351 ml, 8.18 mmol) and then methanesulfonyl chloride (0.274 ml, 3.54 mmol) and the resulting solution was stirred at RT. After 15 mins it was washed with water, dil HCl, and sat aq NaHCO3 and then processed normally. A solution of the crude product in DMF (15 mL) was treated with sodium thiomethoxide (0.573 g, 8.18 mmol) and the mixture was stirred at RT for 1 h. Then toluene was added and the mixture was washed with water (×2) and processed normally. Chromatography (EtOAc/Hex 1:2) gave benzyl (SR)-2-((RS)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-(methylthio)propylcarbamate (0.77 g, 2.268 mmol, 83% yield) as a syrup. 13C NMR (CDCl3) δ156.9, 136.9, 128.9, 128.5, 128.5, 109.3, 76.8, 67.7, 67.1, 41.9, 33.7, 26.9, 25.6, 16.6.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19]>C(Cl)Cl.[OH-].[Na+]>[C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][S:9]([C:2]1[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=1[CH3:13])(=[O:11])=[O:10])(=[O:11])=[O:10]
Reactant: NCCCCN
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)NCCCCNS(=O)(=O)c2c(C)cc(C)cc2C)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.5 %

Procedure:
2-Mesitylenesulfonyl chloride (54.40 g, 0.249 mol) in CH2Cl2 (300 ml) was added to 1,4-diaminobutane (11.34 g, 0.129 mol) in 1 N NaOH (300 ml) at 0° C., and the biphasic mixture was stirred for 24 hours at room temperature. Organic solvent was evaporated and 2.4 N HCl (250 ml) was added to the combined portions. Solid was filtered, washed with water (250 ml) and recrystallized from aqueous ethanol to give 50.46 g (90%) of (1) as needles: mp 156.5-157.5° C.; NMR (CDCl3/TMS) δ 1.36-1.60 (m, 4H), 2.27 (s, 6H), 2.57 (s, 12H), 2.69-2.96 (m, 4H), 4.65 (t, 2H, J=6), 6.89 (s, 4H). Anal. calcd. for C22H32N2O4S2: C—58.38, H—7.13, N—6.19. Found: C—58.31, H—7.19, N—6.14.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH3:16])[C:14]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)(O)[O:13]C1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@@H:15]([CH3:16])[C:14]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)=[O:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C2(O)OCN(C(=O)OCc3ccccc3)[C@H]2C)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)[C@H](C)NC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 0.1 %

Procedure:
In tetrahydrofuran (4 mL) was dissolved (4S)-N-benzyloxycarbonyl-5-(4-methoxyphenyl)-4-methyl-5-hydroxyoxazolidine (1.72 g) prepared in Example 10 and then water (5 mL) and conc. hydrochloric acid (2 mL) were added. The mixture was stirred at room temperature for 24 hours. The reaction was diluted with toluene, the aqueous layer was discarded, and then the organic layer was dried over anhydrous magnesium sulfate. After concentration under a reduced pressure, the residue was purified by silica column chromatography (eluent: hexane/ethyl acetate=3/1) to give the title compound (1.40 mg) as white crystals in a yield of 89%.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25](C(F)(F)F)[CH:26]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1I)[C:8](=[O:11])[O:9][CH3:10].[C:33]([Cu])#[N:34].[NH4+].[OH-]>CN(C=O)C>[CH3:10][O:9][C:8](=[O:11])[N:7]([CH2:6][C:5]1[CH:24]=[C:25]([C:2]([F:32])([F:31])[F:1])[CH:26]=[C:3]([C:2]([F:31])([F:1])[F:32])[CH:4]=1)[CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:33]#[N:34]
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1I
Reactant: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1C#N
Temperature: 25 °C

Procedure:
To a solution of Example 5 dissolved in DMF (1.5 mL) was added CuCN (20 mg, 0.22 mmol) and the resultant mixture was heated at 100° C. for 16 h. The reaction was cooled to room temperature, poured into NH4OH (10 mL) and extracted with EtOAC (4×30 mL). The combined organic extracts were washed with H2O and brine (10 mL each), dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography (0 to 25% EtOAc/hexanes) afforded the title compound as a colorless oil. LCMS=485 (M+1)+. H NMR (CDCl3, 500 MHz): δ 7.81 (s, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.67-7.31 (m, 4H), 4.82 (br s, 2H), 4.72 (s, 2H), 3.91 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH:7]([N:12]1[C:18](=[O:19])[CH:17]2[CH:13]1[S:14][C:15]([CH3:21])([CH3:20])[NH:16]2)[CH2:8][C:9]([OH:11])=[O:10])(C)(C)C.F[C:24](F)(F)C(O)=O>>[CH3:1][O:5][C:6](=[O:22])[CH:7]([N:12]1[C:18](=[O:19])[CH:17]2[CH:13]1[S:14][C:15]([CH3:21])([CH3:20])[NH:16]2)[CH2:8][C:9]([O:11][CH3:24])=[O:10]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)C(CC(=O)O)N1C(=O)C2NC(C)(C)SC21
Product: COC(=O)CC(C(=O)OC)N1C(=O)C2NC(C)(C)SC21
Reaction time: 18 h

Procedure:
A mixture of 0.025 g of the isomer B of α-(3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo[3,2,0]heptyl)-α-(carboxymethyl)-acetic acid tert.-butyl ester (Example 39) and 1 ml of trifluoroacetic acid is kept for 18 hours at 0°, is then evaporated under reduced pressure, and the residue containing the α-(3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3,2,0]heptyl)-α-(carboxymethyl-acetic acid, is taken up in 1 ml of dioxane and then mixed with an ether solution of diazomethane until saturated. After 3 minutes reaction time, the mixture is evaporated under reduced pressure and the residue is filtered through a silica gel column (diameter: 0.8 cm; hight: 10 cm), a 2:1-mixture of hexane and ethyl acetate being used for elution; the isomer B of α-(3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo[3,2,0]heptyl)-α-(carbomethoxymethyl)-acetic acid methyl ester of the formula ##STR56## which is obtained as a crude product, melts at 136°-137° after recrystallisation from a mixture of ether, methylene chloride and hexane.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([NH:12]N)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].O=[C:15]1[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][C:22](=[O:24])[CH3:23])[CH2:16]1.CC(O)=O>O>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:9]([C:20]3[CH2:19][CH2:18][CH:17]([NH:21][C:22](=[O:24])[CH3:23])[CH2:16][C:15]=3[NH:12]2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)NC1CCCC(=O)C1
Reactant: CCCCOc1cccc(NN)c1
Solvent: O
Solvent: CC(=O)O
Product: CCCCOc1ccc2c3c([nH]c2c1)CC(NC(C)=O)CC3
Temperature: 25 °C
Reaction time: 3 h
Yield: 17 %

Procedure:
A mixture of 0.2 mol of 3-n-butyloxyphenylhydrazine, 0.2 mol of N-(3-oxocyclohexyl)acetamide, and 350 ml of glacial HOAc was stirred at room temperature for 3 hr and then refluxed for 2 hr. After pouring into 2.5 l of H2O and stirring overnight, the insoluble material had partly crystallized. The crystalline material was filtered, washed with H2O, and dried (23 g, Fraction A). The remaining insoluble semi-solid was taken up in EtOAc, washed with H2O, dried, and evaporated. The dark residue was triturated with Et2O and filtered (6.7 g, mp 181°-183°, Fraction B). Additional product was extracted from Fraction A by stirring with two 4 l. portions of Et2O. The combined extracts were evaporated and the resulting residue combined with Fraction B and recrystallized twice from Me2CO to yield 10.2 g of the title compound, mp 182°-184°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[C:26]([CH:29]1[CH2:33][CH2:32][CH2:31][N:30]1[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])(=[O:28])[NH2:27].CC(C)([O-])C.[Na+]>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:27][C:26]([CH:29]3[CH2:33][CH2:32][CH2:31][N:30]3[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:28])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(N)=O
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)C3CCCN3C(=O)OC(C)(C)C)c2c1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 29 %

Procedure:
To a solution of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (0.60 g, 1.6 mmol, prepared in analogy to the one in Example 2-1), tert-butyl 2-carbamoylpyrrolidine-1-carboxylate (0.34 g, 1.6 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (0.13 g, 0.16 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.089 g, 0.16 mmol) and sodium tert-butoxide (0.307 g, 3.2 mmol) in 1,4-dioxane (25 mL) was heated with stirring for 1.5 hours at 120° C. under microwave irradiation. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by preparative TLC (eluting with 50% ethyl acetate in petroleum ether, V/V=1:1) to give 250 mg of the desired product (yield was 29%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[H-].[Na+].[N+]([C:15]1[CH:16]=[C:17]([CH3:22])[N+:18]([O-:21])=[CH:19][CH:20]=1)([O-])=O>CN1CCCC1=O.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:15]2[CH:20]=[CH:19][N+:18]([O-:21])=[C:17]([CH3:22])[CH:16]=2)=[C:4]([F:9])[CH:3]=1
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Reactant: Oc1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1cc(Oc2ccc(Br)cc2F)cc[n+]1[O-]
Temperature: 180 °C
Yield: 46.6 %

Procedure:
To a room temperature solution of 4-bromo-2-fluorophenol (3.44 ml, 31.41 mmol) in N-methylpyrrolidone (20 ml) was added sodium hydride (1.34 g, 56 mmol, 60% in mineral oil) portionwise. After stirring for 20 minutes 4-nitro-2-picoline N-oxide (5.6 g, 36.12 mmol) was added The reaction mixture was heated at 180° C. for 60 minutes under microwave irradiation. After cooling to room temperature the mixture was diluted with EtOAc (250 ml) and washed with water (250 ml). The solution was then extracted with additional EtOAc (2×150 ml). The combined organic extracts were dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM to DCM/MeOH(NH3) up to 2% as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate 15 (4.36 g, 47%).
Reaction SMILES: [Na].C(OP([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(OCC)=O)C.[CH3:16][CH:17]1[CH2:22][CH:21]([CH3:23])[CH2:20][C:19](=O)[CH2:18]1>C1(C)C=CC=CC=1>[CH3:16][CH:17]1[CH2:22][CH:21]([CH3:23])[CH2:20][C:19](=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:18]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC1CC(=O)CC(C)C1
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C1CC(C)CC(C)C1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
85 g of dry toluene are added to a round flask which is fitted with a stirrer, thermometer, dropping funnel and reflux condenser. Under a nitrogen atmosphere there are now introduced 17.2 g of sodium in small portions and the mixture is heated to boiling. After dissolution of the sodium (after about 3 hours), the mixture is cooled to 20° C. and there is slowly added dropwise thereto (during about 11/2 hours) a mixture of 219 g of ethyl diethylphosphonoacetate, 95 g of 3,5-dimethyl-cyclohexanone and 220 g of dry toluene. The temperature is held between 25° and 30° C. The mixture is stirred at this temperature for a further 2 days and thereupon poured on to 400 g of ice, extracted with toluene, washed neutral and concentrated. The residue is distilled over a Widmer column and thus yields 110 g of ethyl 3,5-dimethyl-cyclohexylideneacetate.