Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:7]([O:15][C:16]2[CH:23]=[CH:22][C:19](C=O)=[CH:18][CH:17]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4].[C:30](O)(=O)[CH2:31][C:32]([OH:34])=[O:33].CO>N1CCCCC1.N1C=CC=CC=1>[CH2:1]([C:5]1[C:6]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:7]([O:15][C:16]2[CH:23]=[CH:22][C:19](/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33])=[CH:18][CH:17]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2ccccc2c(Oc2ccc(C=O)cc2)c1-c1ccccc1
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: CO
Solvent: c1ccncc1
Product: CCCCc1cc2ccccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccccc1
Yield: 53.3 %

Procedure:
4-[(3-Butyl-2-phenyl-1-naphthalenyl)oxy]benzaldehyde (173) (0.14 g, 0.36 mmol) was heated with malonic acid (0.12 g, 1.09 mmol) and 1 drop of piperidine in pyridine at 85° C. overnight to give the crude product as a light yellow viscous oil, which upon trituration with 1% MeOH in hexanes, yielded 81 mg (53%) of the title compound (174) as a white solid. mp 160-161° C. 1H NMR (400 MHz, CH3OH-d4): δ 0.76 (t, J=7.3 Hz, 3H), 1.15-1.30 (m, 2H), 1.40-1.55 (m, 2H), 2.60 (t, J=7.9 Hz, 2H), 6.26 (d, J=16.0 Hz, 1H), 6.56 (d, J=8.6 Hz, 2H), 7.14-7.19 (m, 2H), 7.20-7.30 (m, 3H), 7.35 (d, J=8.6 Hz, 2H), 7.37-7.42 (m, 1H), 7.46-7.56 (m, 2H), 7.70-7.77 (m, 2H), 7.91 (d, J=8.2 Hz, 1H). LCMS (APCI): m/z 423 (M+H)+, m/z 421 (M−H)−. Anal. Calc for C29H26O3.⅙H2O: C, 81.86; H, 6.24. Found: C, 81.86; H, 6.25.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.I[C:10]1C=CC(NS(C)(=O)=O)=CC=1.[CH2:21]([S:23](Cl)(=[O:25])=[O:24])[CH3:22]>>[I:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]([CH3:10])[S:23]([CH2:21][CH3:22])(=[O:25])=[O:24])=[CH:4][CH:3]=1
Reactant: Nc1ccc(I)cc1
Reactant: CCS(=O)(=O)Cl
Reactant: CS(=O)(=O)Nc1ccc(I)cc1
Product: CCS(=O)(=O)N(C)c1ccc(I)cc1

Procedure:
The product so obtained was used in place of 4-iodoaniline in the procedure described in Example 3 for the preparation of N-(4-iodophenyl) methanesulphonamide and ethanesulphonyl chloride was used in place of methanesulphonyl chloride. Thus was obtained N-(4-iodophenyl)-N-methylethanesulphonamide as an oil. NMR Spectrum 1.45 (3H, t), 3.00 (2H, q), 3.35 (3H, s), 7.15 (2H, m), 7.70 (2H, m).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=O)=[CH:19][CH:18]=2)[NH:3]1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[O:1]=[C:2]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:26])=[CH:19][CH:18]=2)[NH:3]1
Reactant: O=C(O)Cc1ccc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Reactant: Nc1ccccc1
Product: O=C(Cc1ccc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)cc1)Nc1ccccc1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 300 using 302 (50 mg, 0.14 mmol), and aniline to provide 303. LC-MS (M+H=421, obsd.=421).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:4][CH2:3][CH2:2]1.[C:7]([C:9]1[S:10][C:11](SC)=[C:12]2[C:17](=[O:18])[CH2:16][C:15]([CH3:20])([CH3:19])[CH2:14][C:13]=12)#[N:8]>>[C:7]([C:9]1[S:10][C:11]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[C:12]2[C:17](=[O:18])[CH2:16][C:15]([CH3:20])([CH3:19])[CH2:14][C:13]=12)#[N:8]
Reactant: CSc1sc(C#N)c2c1C(=O)CC(C)(C)C2
Reactant: Br[Mg]C1CCC1
Product: CC1(C)CC(=O)c2c(C3CCC3)sc(C#N)c2C1
Yield: 18 %

Procedure:
In the same way as described in Example 6, Step 1, using cyclobutylmagnesium bromide and 1-cyano-6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the title compound (0.37 g, 18%) was isolated as a pale yellow solid. mp 65-68° C. 1HNMR (360 MHz, CDCl3) δ 1.06 (6H, s), 1.90-1.98 (1H, m), 2.00-2.12 (3H, m), 2.40 (2H, s), 2.50-2.62 (2H, m), 2.83 (2H, s), 4.45-4.56 (1H, m).
Reaction SMILES: [CH:1]1([CH2:5][CH2:6][CH2:7][C@@H:8]([C:17]2[O:18][CH:19]=[C:20]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[N:21]=2)[CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:5][CH2:6][CH2:7][C@@H:8]([C:17]2[O:18][CH:19]=[C:20]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[N:21]=2)[CH2:9][C:10]([OH:12])=[O:11])[CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(=O)c1coc([C@H](CCCC2CCC2)CC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)c1coc([C@H](CCCC2CCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.1 %

Procedure:
A solution of tert-butyl (3R)-6-cyclobutyl-3-{4-[(dimethylamino)carbonyl]-1,3-oxazol-2-yl}hexanoate (Preparation 120) (240 mg, 0.66 mmol) in dichloromethane (4 ml) was treated with trifluoroacetic acid (1.2 ml) and stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene and dichloromethane. The oil was purified by column chromatography on silica gel eluting with 97:3:0.3 (dichloromethane:methanol:acetic acid) to afford the title compound as a white solid (161 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][N:10]([C:19]([NH:30][CH3:31])=[N:20][S:21]([N:24]3[CH2:29][CH2:28]O[CH2:26][CH2:25]3)(=[O:23])=[O:22])[N:9]=2)=[CH:4][CH:3]=1.[CH2:32](O)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][N:10]([C:19]([NH:30][CH3:31])=[N:20][S:21]([N:24]3[CH2:29][CH2:28][CH2:32][CH2:26][CH2:25]3)(=[O:23])=[O:22])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCO
Reactant: CNC(=NS(=O)(=O)N1CCOCC1)N1C[C@H](c2ccccc2)C(c2ccc(Cl)cc2)=N1
Product: CNC(=NS(=O)(=O)N1CCCCC1)N1C[C@H](c2ccccc2)C(c2ccc(Cl)cc2)=N1

Procedure:
(−)-(4S)-3-(4-Chlorophenyl)-N-methyl-N′-((morpholin-4-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine ([α25D]=−144°, c=0.01, MeOH). (Chiral stationary phase: Chiralpak AD). The mobile phase consisted of ethanol. Amorphous.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:3].[Br:17][C:18]1[N:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([O:16][CH2:15][CH:12]2[CH2:13][CH2:14][N:9]([C:7]3[O:6][N:5]=[C:4]([CH:2]([CH3:1])[CH3:3])[N:8]=3)[CH2:10][CH2:11]2)=[CH:22][N:23]=1
Reactant: CC(C)c1noc(N2CCC(CO)CC2)n1
Reactant: Oc1ccc(Br)nc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC(COc3ccc(Br)nc3)CC2)n1
Yield: 87.4 %

Procedure:
2-Bromo-5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]pyridine (1 g, 60%) was prepared from {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol (prepared as in Example 20, Step 3, 1 g, 4.4 mmol), 6-bromo-3-pyridinol (522 mg, 3 mmol), Ph3P (1.15 g, 4.4 mmol), diisopropyl azodicarboxylate (0.866 mL, 4.4 mmol), diisopropyl azodicarboxylate (0.866 mL, 4.4 mmol), and THF (15 mL) in a manner similar to Example 1, Step 2, and purified by reverse-phase preparative HPLC using a CH3CN:H2O gradient (30:70 to 100:0) with 0.05% TFA as a modifier. 1H NMR (400 MHz, CDCl3): δ 8.04 (d, 1H, J=3.1 Hz), 7.37 (d, 1H, J=8.7 Hz), 7.08 (dd, 1H, Ja=8.7 Hz, Jb=3.2 Hz), 4.22 (d, 2H, J=13.1 Hz), 3.85 (d, 2H, J=6.3 Hz), 3.09 (m, 2H), 2.89 (m, 1H), 2.13-1.99 (m, 1 H), 1.93 (d, 2H, J=12.4 Hz), 1.54-1.35 (m, 2H), 1.28 (d, 6H, J=6.9 Hz); LRMS (ESI m/z 381/383 (M+H).
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([C:22](=[O:28])[C:23]([C:26]#[N:27])([CH3:25])[CH3:24])[CH:14]2[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]2)[CH2:10][C@H:9]1[C:29]([N:31]([CH3:33])[CH3:32])=[O:30])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H][H]>CO.[Pd]>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([C:22](=[O:28])[C:23]([CH3:24])([CH3:25])[CH2:26][NH2:27])[CH:14]2[CH2:19][CH2:18][C:17]([CH3:20])([CH3:21])[CH2:16][CH2:15]2)[CH2:10][C@H:9]1[C:29]([N:31]([CH3:32])[CH3:33])=[O:30])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CN(C)C(=O)[C@@H]1C[C@H](N(C(=O)C(C)(C)C#N)C2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)[C@@H]1C[C@H](N(C(=O)C(C)(C)CN)C2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C
Yield: 77.9 %

Procedure:
To a solution of 1-BOC-(2S,4S)-4-[(2-cyano-2-methylpropanoyl)(4,4-dimethylcyclohexyl)amino]-2-[(dimethylamino)carbonyl]pyrrolidine (1.07 g, 2.31 mmol) prepared in Step A in methanol was added Pd/C (9 mg), and carried out hydrogen reaction at rt for 10 h. After the reaction finished, the reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo, and purified by HPLC to give the title compound (0.84 g, 78%).
Reaction SMILES: C([C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:13])CC[O:10]2)=[CH:5][CH:4]=1)=C.C[N+]1([O-])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.[OH2:22]>C1COCC1.ClCCl.[Os](=O)(=O)(=O)=O.O>[OH:22][CH:12]([C:3]1[CH:20]=[C:19]2[C:6]([C:7](=[O:13])[CH2:16][CH2:17][O:18]2)=[CH:5][CH:4]=1)[CH2:11][OH:10]
Reactant: C=Cc1ccc2c(c1)OCCC2=O
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1CCOc2cc(C(O)CO)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a mixture of 7-vinylchroman-4-one (Preparation 2D, 0.801 g, 4.60 mmol) and a 50% solution of NMO in water (0.953 mL, 4.60 mmol) in THF (11 mL) at room temperature was added a 4% aqueous solution of osmium tetroxide in water (1.44 mL, 0.184 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane (200 mL) and washed with water (40 mL). The organic layer was collected and was washed with brine (40 mL). The combined aqueous layers were extracted with dichloromethane (200 mL), and the combined organic layers were dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 7-(1,2-dihydroxyethyl)chroman-4-one (0.950 g, 4.56 mmol, 99% yield) as a dark yellow oil. The product had an HPLC ret. time=0.587 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=209.0.
Reaction SMILES: Cl.[CH:2]([C:4]1[C:5]([O:18]COC)=[CH:6][C:7]2[C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)=[O:3].O>O1CCCC1>[CH:2]([C:4]1[C:5]([OH:18])=[CH:6][C:7]2[C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][C:11]([CH3:14])([CH3:15])[C:12]=2[CH:13]=1)=[O:3]
Reactant: COCOc1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(C=O)c(O)cc21
Temperature: 50 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
A 10% aqueous solution of hydrochloric acid was added to 30 ml of a solution of 2.4 g of 3-formyl-5,6,7,8-tetrahydro-2-methoxymethoxy-5,5,8,8-tetramethylnaphthalene in tetrahydrofuran at room temperature. The obtained mixture was stirred at 50° C. for 4 hours, followed by the addition thereto of 30 ml of water. The obtained mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and distilled to removd the solvent. The residue was purified by silica gel chromatography (developer: 10% diethyl ether/n-hexane) to give 1.8 g of the title compound as a colorless oil.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([N:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]2[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH:30]([OH:33])([CH3:32])[CH3:31]>>[O:33]1[CH2:32][CH:30]1[CH2:31][N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[N:8]=[CH:20][C:19]1[CH:18]=[CH:17][C:16]([N:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:23][CH:22]=1
Reactant: NNc1ccccc1
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)O
Product: C(=NN(CC1CO1)c1ccccc1)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
Phenylhydrazine (0.1 mole, from Aldrich, Milwaukee, Wis.) and 4-(diphenylamino)benzaldehyde (0.1 mole, from Fluka, Buchs SG, Switzerland) were dissolved in 100 ml of isopropanol in a 250 ml 3-neck round bottom flask equipped with a reflux condenser and a mechanical stirrer. The solution was refluxed for 2 hours. At the end of the reaction, as indicated by thin layer chromatography the disappearance of the starting materials, the mixture was cooled to room temperature. The 4-(diphenylamino)benzaldehyde phenylhydrazone crystals that formed upon standing were filtered off, washed with isopropanol, and dried in a vacuum oven at 50° C. for 6 hours.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14]Br)[CH:6]=1.[C:17]1([CH:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:24][NH2:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CS(C)=O.O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:25][CH2:24][CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=1
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: COC(=O)Cc1cccc(OCCCBr)c1
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)Cc1cccc(OCCCNCC(c2ccccc2)c2ccccc2)c1
Yield: 96.3 %

Procedure:
A solution of [3-(3-bromo-propoxy)-phenyl]-acetic acid methyl ester (2) (2.0 g, 0.007 mol) and 2,2-diphenylethylamine (2.5 g, 0.013 mol) in DMSO (5 mL) was stirred at room temperature for 18 hours. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, concentrated to an oil, which was purified by flash chromatography (9:1 CH2Cl2/MeOH) to give the desired product as oil 2.72 g in 96% yield. 1H NMR (CDCl3) δ 7.24 (m, 7H), 7.19 (t, 3H), 6.85 (d, 1H), 6.74 (s, 1H), 6.72 (d, 2H), 5.26 (s, 1H), 4.22 (t, 1H), 3.96 (t, 2H), 3.68 (s, 3H), 3.57 (d, 2H), 3.26 (d, 2H), 2.84 (t, 2H), 1.92 (m, 2H). 13C NMR (CDCl3) δ 173.3, 160.5, 144.4, 136.7, 130.9, 130.1, 129.5, 129.4, 127.9, 122.9, 116.9, 114.6, 67.6, 56.0, 53.5, 52.6, 48.3, 42.6, 31.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][CH:7]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]4[CH2:29][CH2:28][O:27][C:26]4=[O:30])[CH2:19][CH2:18]3)[C:6]=2[CH:31]=1.[C:32]([OH:41])(=[O:40])[C@@H:33]([C@H:35]([C:37]([OH:39])=[O:38])[OH:36])[OH:34]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][C@@H:7]([N:17]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][N:25]4[CH2:29][CH2:28][O:27][C:26]4=[O:30])[CH2:21][CH2:22]3)[C:6]=2[CH:31]=1.[C:37]([C@@H:35]([C@H:33]([C:32]([O-:41])=[O:40])[OH:34])[OH:36])([O-:39])=[O:38]
Reactant: Cc1ccc2c(c1)CC(N1CCN(CCN3CCOC3=O)CC1)c1cc(F)ccc1S2
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CC(C)=O
Product: Cc1ccc2c(c1)C[C@@H](N1CCN(CCN3CCOC3=O)CC1)c1cc(F)ccc1S2
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]

Procedure:
5.0 G. of the salt of racemic 3-{2-[4-(8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone with (+)-(R,R)-tartaric acid [α546 =+15.0° (water; c = 10%)] in the molar ratio of 1:1 are dissolved in 500 ml. of acetone and, after stirring for 24 hours at room temperature, the mixture is filtered. The filter cake is washed with acetone, dried under reduced pressure, and there is obtained 3-[2-{4-[(R)-8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl}-1-piperazinyl]-ethyl]-2-oxazolidinone-(R,R)-tartrate (1:1); α365 =+98.6° (dimethylformamide; c = 2.0%); decomposition point 172° C. After liberation of the base by treatment with aqueous sodium hydroxide, there is obtained crystalline (R)-3-{2-[4-(8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone; α365 =+183.85° (chloroform; c = 0.5%) in a purity above 99%. The yield amounts to 54.4% of theory.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:18])[CH:15]([CH3:17])[CH3:16])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[O:25]1[CH2:30][CH2:29][O:28][C:27]2[CH:31]=[C:32]([C:35](O)=[O:36])[CH:33]=[CH:34][C:26]1=2>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:18][C:35]([C:32]2[CH:33]=[CH:34][C:26]3[O:25][CH2:30][CH2:29][O:28][C:27]=3[CH:31]=2)=[O:36])[CH:15]([CH3:17])[CH3:16])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](N)C(C)C)c2c1N
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](NC(=O)c3ccc4c(c3)OCCO4)C(C)C)c2c1N

Procedure:
Prepared as in Example 24a from (5)-ethyl 4-amino-5-(2-amino-3-methylbutoxy)-2-methylquinoline-3-carboxylate (Example 95b) and 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid as brown solid (29%). MS 494 (MH+).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:15][CH:14]2[NH:16][CH:10]1[CH2:11][C:12](=[CH:17][C:18]([O:20][CH3:21])=[O:19])[CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:22](Cl)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(Cl)Cl>[Si:1]([O:8][CH:9]1[CH2:15][CH:14]2[N:16]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH:10]1[CH2:11][CH:12]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COC(=O)C=C1CC2CC(O[Si](C)(C)C(C)(C)C)C(C1)N2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: COC(=O)CC1CC2CC(O[Si](C)(C)C(C)(C)C)C(C1)N2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of compound 109d (40 g, 0.13 mol, 1.0 eq) and TEA (40 g, 0.39 mol, 3.0 eq) in DCM (800 mL) was added a solution of CbzCl (45 g, 0.26 mol, 2.0 eq) in DCM (150 mL) slowly. The resulting mixture was stirred at room temperature for 16 h. The mixture was quenched with water, washed with 1N HCl (500 mL), the organic layer was dried over Na2SO4 and concentrated to give benzyl 6-[tert-butyl(dimethyl)silyl]oxy-3-(2-methoxy-2-oxo-ethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate 109e as a crude product.
Reaction SMILES: Br[C:2]1(Br)[CH2:4][C:3]1(Br)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]CCC(O)=O.C[Li].[OH2:19].CC[O:22][CH2:23][CH3:24]>>[C:3]1([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:24][C:23]([OH:22])=[O:19])[CH2:4][CH:2]=1
Reactant: CCOCC
Reactant: O
Reactant: O=C(O)CCCCCCCC1(Br)CC1(Br)Br
Agent: [Li]C
Product: O=C(O)CCCCCCC1=CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
1,1,2-Tribromo-2-(7-carboxyheptyl)-cyclopropane (1.28 g, 3.1 mmol) was dissolved in 60 ml of ether and cooled to −78° C. Methyllithium (9.0 ml, 12.6 mmol) was added and the reaction was stirred at −78° C. for two hours. The reaction mixture was put in an ice bath for 5 minutes, then recooled to −78° C. until workup. Water was added to the reaction mixture, which was warmed to room temperature. The aqueous phase was separated, and the ether phase was extracted with three times with 1N NaOH solution. The combined aqueous extracts were acidified with aqueous HCl, and extracted with ether three times. The ether extracts were washed with brine, dried over magnesium sulfate and stripped to give 300 mg of 7-cycloprop-1-enyl-heptanoic acid.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([S:17]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[C:25]([Cl:30])[CH:26]=4)[CH:21]=3)(=[O:19])=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.O1CCCC1.[C:43]([O:47][C:48]([NH:50][C:51](=[N:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])SC)=[O:49])([CH3:46])([CH3:45])[CH3:44]>CO>[Cl:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:17]([N:14]1[CH2:13][CH2:12][N:11]([C:9]([CH:6]3[CH2:7][CH2:8][CH:3]([NH:2][C:51]([NH:50][C:48]([O:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:49])=[N:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:4][CH2:5]3)=[O:10])[CH2:16][CH2:15]1)(=[O:18])=[O:19])[CH:29]=[CH:28]2
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: NC1CCC(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)NC1CCC(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Temperature: 40 °C
Reaction time: 24 h
Yield: 53.9 %

Procedure:
To a solution of 1-(4-aminocyclohexane-1-ylcarbonyl)-4-(6-chloronaphthalene-2-sulfonyl)piperazine hydrochloride (220 mg) and triethylamine (232 mg) in methanol (10 ml)-tetrahydrofuran (10 ml) was added N,N′-di-tert-butoxycarbonyl-S-methylisothiourea (135 mg) and the solution was stirred at 40° C. for 24 hours. The reaction solution was concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:2) to give a colorless solid of the title compound (170 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[C:5]([C:10]#[N:11])=[C:6]([CH3:9])[C:7]=1I.[C:21]1(B2OCCCO2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[C:5]([C:10]#[N:11])=[C:6]([CH3:9])[C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1c(Br)c(I)c(C)c(C#N)c1NC(=O)C(F)(F)F
Reactant: c1ccc(B2OCCCO2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1c(Br)c(-c2ccccc2)c(C)c(C#N)c1NC(=O)C(F)(F)F
Temperature: 95 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
N-(3-Bromo-6-cyano-4-iodo-2-methoxy-5-methylphenyl)-2,2,2-trifluoroacetamide (I-36) (1.29 g, 2.79 mmol), 2-phenyl-1,3,2-dioxaborinane (474 mg, 2.93 mmol), tripotassium phosphate (74-85%, 1.48 g, 5.58 mmol) and tetrakis(triphenylphosphine)palladium(0) (406 mg, 0.352 mmol) were added to a 30-ml eggplant-type flask, followed by purging with nitrogen, N,N-dimethylformamide (50 ml) was injected into it with a syringe, followed by stirring overnight at 95° C. After cooling, the reaction liquid was diluted with ethyl acetate, successively washed with saturated brine (×3), 1 N hydrochloric acid, saturated brine, an aqueous saturated sodium hydrogencarbonate solution and saturated brine. The organic layer was dried on anhydrous magnesium sulfate, then the solvent was concentrated under reduced pressure to obtain a brown residue. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1) to obtain the entitled compound (968 mg, 84%) as a brown solid.