Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].[Cl:8][CH2:9][C:10]([OH:12])=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:8][CH2:9][C:10]([O:7][CH2:1][CH2:2][O:3][CH2:4][CH2:5][O:6][C:10](=[O:12])[CH2:9][Cl:8])=[O:12]
Reactant: O=C(O)CCl
Reactant: OCCOCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(CCl)OCCOCCOC(=O)CCl
Temperature: 25 °C
Yield: 90.1 %

Procedure:
In a 10-liter 4-neck round bottom flask equipped with a mechanical stirrer and Dean-Stark apparatus was added a solution of diethylene glycol (500 g), chloro acetic acid (980 g) and para-toluene sulphonic acid (25 g) in toluene (2.5 L). The solution was refluxed with stirring and azeotropic removal of water for 5 hours, and then cooled to room temperature. The toluene layer was washed with 5% sodium bicarbonate solution (3×1000 ml) and water (3 L). The toluene layer was dried over anhydrous sodium sulphate, filtered, and distilled to obtain chloro-acetic acid 2-[2-(2-chloro-acetoxy)-ethoxy]-ethyl ester (1.1 Kg) as light yellow oil. The product was characterized by 1H NMR (CDCl3) δ 3.75 (t, 2H, CH2), 4.12 (s, 2H, CH2), 4.36 (t, 2H, CH2)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:20][C:21]3([OH:34])[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([O:18][CH3:19])[CH:12]=3)[C:3]=12.[C:35]1([C@@H:41]2[CH2:43][C@H:42]2[C:44](Cl)=[O:45])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:20][C:21]3([OH:34])[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:25][CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:44]([C@@H:42]4[CH2:43][C@H:41]4[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:45])=[C:13]([O:18][CH3:19])[CH:12]=3)[C:3]=12
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: COc1cc(-c2nn(CC3(O)CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c23)ccc1N
Solvent: c1ccncc1
Product: COc1cc(-c2nn(CC3(O)CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c23)ccc1NC(=O)[C@@H]1C[C@H]1c1ccccc1
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 76.5 %

Procedure:
To a mixture of tert-butyl 4-{[4-amino-3-(4-amino-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl}-4-hydroxy-1-piperidinecarboxylate (0.08 g, 0.00017 mol) in pyridine (4 mL) was added trans-2-phenyl-cyclopropane carbonyl chloride (0.035 g, 0.00019 mol) at −5° C. The mixture was stirred at −5° C. for 10 minutes then warmed up to room temperature to stir for 1 hours. The mixture was quenched with an aqueous 1N solution of sodium hydroxide. Pyridine was removed under reduced pressure. The residue was partitioned between water and dichloromethane (50 mL). The organic layer was washed with water. The solvents were removed under reduced and the residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield trans tert-butyl 4-{[4-amino-3-(3-methoxy-4-{[(2-phenylcyclopropyl)carbonyl]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl}-4-hydroxy-1-piperidinecarboxylate (0.08 g, 0.00013 mol).
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH3:24][N:25]1[C:34](=[O:35])[C:33]([CH3:37])([CH3:36])[C:32]2[C:27](=[CH:28][C:29]([NH2:38])=[CH:30][CH:31]=2)[C:26]1=[O:39].O>CN(C=O)C>[CH3:24][N:25]1[C:34](=[O:35])[C:33]([CH3:37])([CH3:36])[C:32]2[C:27](=[CH:28][C:29]([NH:38]/[C:4](=[C:11]3\[C:12](=[O:23])[NH:13][C:14]4[C:19]\3=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=4)/[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:30][CH:31]=2)[C:26]1=[O:39]
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CN1C(=O)c2cc(N)ccc2C(C)(C)C1=O
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)c2cc(N/C(=C3\C(=O)Nc4ccc([N+](=O)[O-])cc43)c3ccccc3)ccc2C(C)(C)C1=O
Temperature: 120 °C

Procedure:
Prepared from 3-(1-ethoxy-1-phenylmethylidene)-5-nitro-2-indolinone and 1.5 equivalents of 2-methyl-7-amino-4,4-dimethyl-1,3-dioxo-1,2,3,4-tetrahydro-isoquinoline, melting point 169-171° C., in DMF by heating to 120° C. for 1 hour, pouring into water, filtering and washing the precipitate with MeOH and ether.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].I[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1>C(#N)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]([CH3:7])([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:31]=2)[CH:10]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(N)c1
Reactant: FC(F)(F)c1ccc(CCI)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1cccc(NCCc2ccc(C(F)(F)F)cc2)c1
Reaction time: 72 h
Yield: 43.3 %

Procedure:
To a solution of 2-(3-Amino-phenoxy)-2-methyl-propionic acid ethyl ester (0.25 g, 1.11 mmol) in acetonitrile (5 ml), Na2CO3 (0.131 g, 1.24 mmol) and 1-(2-Iodo-ethyl)-4-trifluoromethyl-Benzene (0.372 g, 1.24 mmol) were added. The reaction mixture was stirred at r. t for 3 days, solvent was removed under reduced pressure and extracted in Ethyl acetate (75 ml) and washed with brine (2×10 ml) dried over Na2SO4. After evaporation, the residue was purified by flash chromatography (1:5 ethyl acetate:hexanes) to give 2-Methyl-2-{3-[2-(4-trifluoromethyl-phenyl)-ethylamino]-phenoxy}-propionic acid ethyl ester (0.19 g, 43%).
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][Mg]Br)[CH3:2].[CH2:11]([CH:13]([CH2:17][CH2:18][CH2:19][CH3:20])CC#N)[CH3:12].C([O:23][CH2:24][CH3:25])C>>[CH2:1]([CH:3]([CH2:4][C:24](=[O:23])[CH2:25][CH:13]([CH2:11][CH3:12])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2]
Reactant: CCCCC(CC)CC#N
Reactant: CCOCC
Reactant: CCCCC(CC)C[Mg]Br
Product: CCCCC(CC)CC(=O)CC(CC)CCCC
Reaction time: 12 h

Procedure:
A Grignard solution of 2-ethylhexylmagnesiumbromide in diethylether (1.0 M, 47 mL, 47 mmol) was slowly added via syringe to a stirred mixture of 3-ethylheptanenitrile (VI) (3.3 g, 24 mmol) in diethyl ether (50 mL) at 0° C. under N2 atmosphere. After stirring for 12 h at reflux temperature, the reaction was quenched with an aqueous HCl-solution (2.0 M, 50 mL) at 0° C. and subsequently vigorously stirred for an additional 3 h at room temperature. The organic phase was separated and the aqueous phase was extracted with diethylether. The combined organic phases were washed with a saturated bicarbonate solution and brine, dried over MgSO4 and evaporated under reduced pressure to give a crude brown oil. The resulting brown oil was purified by vacuum distillation (95° C., 10−2 mbar) to afford a yellow oil (VII). (5.8 g, 35%). 1H-NMR (CDCl3): δ=2.66-2.63 (m, 2H), 2.24 (d, J=6.9 Hz, 4H), 1.36-1.04 (m, 16H), 0.91-0.63 (m, 12H). 13C-NMR (CDCl3): δ=211.59, 48.32, 39.74, 35.53, 33.57, 30.22, 26.65, 23.59, 14.61.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[C:8]([CH2:10][C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)#[N:9].C(Cl)(Cl)[Cl:17]>C(O)C>[ClH:17].[ClH:17].[NH:12]1[CH:13]=[CH:14][N:15]=[C:11]1[CH2:10][C:8](=[NH:9])[O:5][CH2:3][CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: N#CCc1ncc[nH]1
Reactant: ClC(Cl)Cl
Solvent: CCO
Product: CCOC(=N)Cc1ncc[nH]1
Product: Cl
Reaction time: 168 h

Procedure:
Into the suspension of 2-cyanomethylimidazole trifluoroacetate (7 g) in a mixture of chloroform (25 ml) and ethanol (2.42 ml) was absorbed hydrogen chloride gas (2.54 g) at 0° C. The resulting mixture was allowed to stand at 0° C. for 7 days. The residue was triturated with diisopropyl ether to give ethyl 2-(imidazol-2-yl)-acetimidate dihydrochloride (6.28 g).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18](=O)[CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13](=[O:28])[CH2:12]1)=[O:10])[CH3:7].O>O1CCOCC1>[CH2:6]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2[N:17]=[C:18]([CH2:19][O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:28][C:13]=2[CH2:12]1)=[O:10])[CH3:7]
Reactant: CCOC(=O)N1CCC(NC(=O)COc2ccccc2)C(=O)C1
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)N1CCc2nc(COc3ccccc3)oc2C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
Phosphorus oxychloride (9.3 mL, 99.9 mmol) was added to a stirred solution of 3-oxo-4-(2-phenoxy-acetylamino)-piperidine-1-carboxylic acid ethyl ester (30.3 g, 90.8 mmol) in 1,4-dioxane (454 mL). The mixture was stirred at 100° C. for 2 hours. The mixture was cooled at 0° C., treated with water and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The product was purified by flash column chromatography (AcOEt in DCM 0/100 to 30/70). The desired fractions were collected and evaporated in vacuo to yield 2-phenoxymethyl-6,7-dihydro-4H-oxazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (23.2 g, 84% yield) as a colourless oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:25]>O1CCCC1>[OH:25][CH:24]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7]
Reactant: CCCCCCCCCCCCCCCCCC(=O)CCCCCCCCCCCCCCCCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCC(O)CCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
18-Hydroxypentatriacontane was prepared as follows and used without further purification. In a dry flask charged with argon was prepared a solution of lithium aluminum hydride (0.75 g, (19.8 mmol)) in freshly distilled tetrahydrofuran (400 mL). To this solution was added stearone (5.0 g, (9.9 mmol)). The reaction mixture was slowly brought to reflux (and allowed to stir at reflux overnight). After cooling to room temperature, the remaining lithium aluminum hydride was quenched by the dropwise addition of water (0.76 mL), followed by 15% NaOH (0.76 mL), and water again (2.2 mL). The reaction mixture was allowed to stir for 1 hour. The solvent was evaporated, and the resulting solids were triturated with hot toluene (300 mL). The toluene was evaporated to yield the desired alcohol (4.9g. 97%). 1H NMR (300 MHz, CDCl3, TMS=0), δ 3.58 (m, !H), 1.38 (m, 4H), 1.25 (bs, 60H), 0.88 (t, 6H, J =6.5).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:13][CH2:14][C:15]([OH:17])=O)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([S:13][CH2:14][C:15]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: C1CCNC1
Reactant: O=C(O)CSc1nc(-c2ccc(F)cc2)cs1
Product: O=C(CSc1nc(-c2ccc(F)cc2)cs1)N1CCCC1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.37 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylsulfanyl]-acetic acid and 52.8 mg (0.74 mmol) of pyrrolidine. Yield: 17 mg.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[S:15]1[CH:19]=[C:18]([C:20]2[S:21][CH:22]=[CH:23][C:24]=2[NH2:25])[N:17]=[CH:16]1>>[CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([NH:25][C:24]3[CH:23]=[CH:22][S:21][C:20]=3[C:18]3[N:17]=[CH:16][S:15][CH:19]=3)=[O:14])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=C(O)Cc1cccc2cnccc12
Reactant: Nc1ccsc1-c1cscn1
Product: O=C(Cc1cccc2cnccc12)Nc1ccsc1-c1cscn1

Procedure:
2-(Isoquinolin-5-yl)-N-(2-(thiazol-4-yl)thiophen-3-yl)acetamide was prepared from 2-(isoquinolin-5-yl)acetic acid (120 mg, 0.641 mmol) and 2-(thiazol-4-yl)thiophen-3-amine (117 mg, 0.641 mmol) according to protocol A. Retention time (min)=2.147, method [7], MS(ESI) 352.0 (M+H); 1H NMR (300 MHz, CDCl3) δ 10.99 (s, 1H), 9.63 (s, 1H), 8.59 (d, J=5.9 Hz, 1H), 8.43 (d, J=1.6 Hz, 1H), 8.23-8.42 (m, 2H), 8.04-8.08 (m, 2H), 7.90 (dd, J=8.1, 7.2 Hz, 1H), 7.18-7.23 (m, 2H), 4.31 (s, 2H).
Reaction SMILES: Cl.O.[C:3]([O:11][C:12]1[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[CH:15]=[CH:14][C:13]=1[C:21]1([NH:35][C:36](=[O:43])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[N+:31]([O-])=O)[C:22]1=[O:34])(=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>C(O)C.[Fe]>[C:3]([O:11][C:12]1[CH:17]=[C:16]([CH:18]([CH3:19])[CH3:20])[CH:15]=[CH:14][C:13]=1[C:21]1([NH:35][C:36](=[O:43])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[NH2:31])[C:22]1=[O:34])(=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCC(=O)NC1(c2ccc(C(C)C)cc2OC(=O)CCCCCC)C(=O)c2cccc([N+](=O)[O-])c2C1=O
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCCCCC(=O)NC1(c2ccc(C(C)C)cc2OC(=O)CCCCCC)C(=O)c2cccc(N)c2C1=O
Yield: 37.4 %

Procedure:
Iron powder (0.03 g, 0.5 mmol), conc. HCl (0.05 ml), and water (0.5 ml) were added in that order to a solution of 2-(2-heptanamido-4nitro-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl heptanoate (60 mg, 0.10 mmol) in ethanol (5 ml). The reaction mixture was heated for 1 hrs under reflux. The reaction mixture was hot filtered off, the filtrate was concentrated in a vacuum and purified by column chromatography (ethylacetate:hexane=1:6 to 1:4) to afford the title compound (20 mg, 36%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]2([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17][CH2:16]2)[CH:5]=[C:6]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[C:7]=1I.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.[F-].[Cs+].CCOC(C)=O>COCCOC.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.O>[CH2:22]([O:21][C:19]([C:15]1([C:4]2[CH:5]=[C:6]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[C:7]([C:29]3[CH:30]=[CH:31][C:26]([C:25]([F:36])([F:35])[F:24])=[CH:27][CH:28]=3)=[C:2]([Cl:1])[CH:3]=2)[CH2:18][CH2:17][CH2:16]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)C1(c2cc(Cl)c(I)c(OCC(F)(F)F)c2)CCC1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)C1(c2cc(Cl)c(-c3ccc(C(F)(F)F)cc3)c(OCC(F)(F)F)c2)CCC1
Yield: 25.7 %

Procedure:
A mixture of ethyl 1-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (0.35, 7.35 mmol), 4-trifluoromethylphenylboronic acid (0.277 g, 1.47 mmol), CsF (0.277 g, 1.83 mmol) and Pd (PPh3)4 (0.084 g, 0.36 mmol) in 20 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 20 mL of EtOAc and 20 mL of water were added. The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to yellow oil. The oil was purified by column chromatography over silica gel (hexane/EtOAc, 95:5) to give ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclobutanecarboxylate (0.182 g) as a colorless oil.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:13]([CH2:34][O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:12][C@H:11]1SCCNC(=O)OCC1C=CC=CC=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:58][CH2:59][CH:60]([NH:65][C:66](=[O:84])[CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH3:83])[C:61]([O:63][CH3:64])=[O:62].IN1C(=O)CCC1=O.FC(F)(F)S(O)(=O)=O>C(Cl)(Cl)Cl>[C:66]([NH:65][CH:60]([CH2:59][O:58][C@@H:11]1[O:12][C@H:13]([CH2:34][O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:14]([O:25][C:26](=[O:33])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:10]1[O:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:61]([O:63][CH3:64])=[O:62])(=[O:84])[CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH3:83]
Reactant: CCCCCCCCCCCCCCCCCC(=O)NC(CO)C(=O)OC
Reactant: O=C(NCCS[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)OCc1ccccc1
Agent: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCC(=O)NC(CO[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)C(=O)OC
Temperature: 0 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
In 35 mL of chloroform were dissolved 2.4 g of benzyl 2-(2,3,4,6-tetra-O-benzoyl-β-D-galactopyranosylthio)ethylcarbamate and 1 g of methyl 3-hydroxy-2-(octadecanoylamino)propionate, and after cooling the solution to 0° C., 1.4 g of N-iodosuccinimide and 0.13 mL of trifluoromethanesulfonic acid were added to the solution and the resulting mixture was stirred at room temperature for 3 hours. Then, chloroform was added to the reaction mixture, and the resulting mixture was washed with a saturated aqueous sodium hydrogen carbonate solution and 10% aqueous sodium thiosulfate solution. The chloroform layer was dried over anhydrous magnesium sulfate, magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (Eluent; n-hexane:ethyl acetate=3:1) to obtain 1.4 g of methyl 2-(octadecanoylamino)-3-(2,3,4,6-tetra-O-benzoyl-β-D-galactopyranosyloxy)propionate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14][CH3:15])[C:9]=1[C:16](=[O:18])[NH2:17])=[O:6])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:25].C(Cl)Cl.C(=O)(O)[O-].[Na+]>O>[CH2:1]([O:3][C:4](=[O:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([CH3:15])=[O:25])[C:9]=1[C:16]([NH2:17])=[O:18])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)Nc1cccc(SC)c1C(N)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(=O)Nc1cccc(S(C)=O)c1C(N)=O

Procedure:
A mixture of 2.0 g. of [2-carbamyl-3-(methylthio)phenyl] oxamic acid ethyl ester and 1.44 g. of m-chloroperoxybenzoic acid in 200 ml. of methylene chloride is stirred for 2 hours. 0.6 g. of sodium bicarbonate in 20 ml. of water is added, the methylene chloride layer is separated, dried and evaporated. The residue is recrystallized from ethanol-diethyl ether, m.p. 164°-166° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-])=O)[CH:8]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.[CH:25]([N:28]=[C:29]=[O:30])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:29]([NH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:22][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)[CH:11]=[CH:10]2)=[O:30])([CH3:27])[CH3:26]
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Reactant: COc1ccc(CN)cc1
Reactant: CC(C)N=C=O
Product: COc1ccc(CNc2ccc3cc(NC(=O)NC(C)C)ccc3n2)cc1

Procedure:
The title compound, MS: m/e=365.1 (M+H+), was prepared in accordance with the general method of example 14 from 2-chloro-6-nitro-quinoline, 4-methoxy-benzylamine and isopropyl isocyanate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH3:27])[N:5]([C:13](=[O:26])[CH2:14]OS(C1C=CC(C)=CC=1)(=O)=O)[C:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[CH3:12].[CH3:29][N:30]([CH3:32])[NH2:31]>C(O)C>[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH3:27])[N:5]([C:13](=[O:26])[CH2:14][NH:31][N:30]([CH3:32])[CH3:29])[C:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[CH3:12]
Reactant: COC(=O)[C@H](C)N(C(=O)COS(=O)(=O)c1ccc(C)cc1)c1c(C)csc1C
Reactant: CN(C)N
Solvent: CCO
Product: COC(=O)[C@H](C)N(C(=O)CNN(C)C)c1c(C)csc1C

Procedure:
A mixture of 8.5 g (0.02 mol) N-[(4-methylphenyl)-sulphonyloxyacetyl]-N-(2,4-dimethylthien-3-yl)-alanine-methylester (=Ex. 3.9) and 2.4 g (0.04 mol) 1,1-dimethylhydrazine in 150 ml ethanol is refluxed for four hours, then evaporated in vacuo, the residue taken up in dichloromethane, washed subsequently with water, aqueous 1 N HCl and water, dried over MgSO4, and evaporated in vacuo to yield the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([CH2:15][C@@H:16]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17]2)[CH:12]=[CH:11][C:10]=1[N:22]1[S:26](=[O:28])(=[O:27])[NH:25][C:24](=[O:29])[CH2:23]1)C1C=CC=CC=1>CCO.O.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([CH2:15][C@@H:16]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17]2)[CH:12]=[CH:11][C:10]=1[N:22]1[S:26](=[O:28])(=[O:27])[NH:25][C:24](=[O:29])[CH2:23]1
Reactant: O=C1CC[C@@H](Cc2ccc(N3CC(=O)NS3(=O)=O)c(OCc3ccccc3)c2)N1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: O=C1CC[C@@H](Cc2ccc(N3CC(=O)NS3(=O)=O)c(O)c2)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-[2-benzyloxy-4-((S)-5-oxopyrrolidin-2-ylmethyl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (0.017 g, 0.041 mmol) in EtOH/H2O (1:1, 10 mL) is added 10% Pd/C (0.010 g). The mixture is stirred under an atmosphere of H2 for 2 h at RT. The catalyst is filtered through Celite and is washed with EtOH. The solvent is evaporated off to the title compound. 1H NMR (DMSO-d6) δ 7.16 (d, J=8 Hz, 1H), 6.53 is, 1H), 6.36 (d, J=5.81 Hz, 1H), 4.08 (s, 2H), 2.42 (m, 2H), 2.07 (t, J=6.57 Hz, 2H), 1.51 (m, 3H); HPLC retention time=0.55 min (method A). (M−H)−=326.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[NH:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.O>CN(C)C=O.C(OCC)(=O)C>[F:35][C:32]1[CH:31]=[CH:30][C:29]([N:26]2[CH2:25][CH2:24][N:23]([CH2:22][CH2:21][CH2:20][N:9]3[C:8]4[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=4[C:6]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[S:10]3(=[O:12])=[O:11])[CH2:28][CH2:27]2)=[CH:34][CH:33]=1
Reactant: O=S1(=O)Nc2ccccc2-c2ccccc21
Reactant: Fc1ccc(N2CCN(CCCCl)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S1(=O)c2ccccc2-c2ccccc2N1CCCN1CCN(c2ccc(F)cc2)CC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
A solution of 6H-dibenzo[c,e]-1,2-thiazine 5,5-dioxide (2 g) in dry N,N-dimethylformamide (15 cc) is added dropwise to a suspension of sodium hydride (0.27 g, 80% suspension in oil) in N,N-dimethylformamide (5 cc). After 30 minutes' stirring, a solution of 1-(3-chloropropyl)-4-(4-fluorophenyl)piperazine (2.2 g) in N,N-dimethylformamide (15 cc) is added. The reaction mixture is heated to 100° C. for 1 hour and 15 minutes and is then cooled and poured into a mixture of water (200 cc) and ethyl acetate (180 cc). The organic phase is washed with water (3×80 cc) is dried over magnesium sulphate and is concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from acetonitrile (60 cc); the crystals obtained are filtered off, washed with acetonitrile (5 cc) and dried. 6-[3-(4-(4-Fluorophenyl)-1-piperazinyl)propyl]-6H-dibenzo[c,e]-1,2-thiazine 5,5-dioxide (2.8 g) is obtained, melting at 163° C.