Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@H:5]1[C:32](=[O:33])[N:31]2[CH2:34][C@@H:28]([CH2:29][C@H:30]2[C:35]([NH:37][C@:38]2([C:43](=[O:51])[NH:44][S:45]([CH:48]3[CH2:50][CH2:49]3)(=[O:47])=[O:46])[CH2:40][C@H:39]2[CH:41]=[CH2:42])=[O:36])[O:27][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([OH:26])=[C:16]2[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11][C@@H:10]2[CH2:52][CH2:53][CH2:54][C@H:9]2[O:8][C:7](=[O:55])[NH:6]1)([CH3:4])([CH3:3])[CH3:2].[N:56]1([CH2:62][CH2:63]O)[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1.CP(C)C.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C.O>[C:1]([C@H:5]1[C:32](=[O:33])[N:31]2[CH2:34][C@@H:28]([CH2:29][C@H:30]2[C:35]([NH:37][C@:38]2([C:43](=[O:51])[NH:44][S:45]([CH:48]3[CH2:50][CH2:49]3)(=[O:46])=[O:47])[CH2:40][C@H:39]2[CH:41]=[CH2:42])=[O:36])[O:27][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([O:26][CH2:63][CH2:62][N:56]3[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]3)=[C:16]2[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11][C@@H:10]2[CH2:52][CH2:53][CH2:54][C@H:9]2[O:8][C:7](=[O:55])[NH:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: OCCN1CCCCC1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1CCC[C@H]1CCC=CCc1c(nc3ccccc3c1O)O2)C(=O)NS(=O)(=O)C1CC1
Agent: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1CCC[C@H]1CC/C=C/Cc1c(nc3ccccc3c1O)O2)C(=O)NS(=O)(=O)C1CC1
Agent: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1CCC[C@H]1CC/C=C/Cc1c(nc3ccccc3c1OCCN1CCCCC1)O2)C(=O)NS(=O)(=O)C1CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1CCC[C@H]1CCC=CCc1c(nc3ccccc3c1OCCN1CCCCC1)O2)C(=O)NS(=O)(=O)C1CC1
Reaction time: 18 h

Procedure:
To a solution of (3aR,7S,10S,12R,21E,24aS)-7-tert-butyl-N-{(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-19-hydroxy-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,23,24,24a-tetradecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-10-carboxamide (synthesized by the method described in Example 17 with intermediates A1, B6, C3) (40 mg) in THF (0.8 mL) under nitrogen was added 2-(piperidin-1-yl)ethanol (0.137 mL), trimethylphosphine (1.028 mL) and diisopropylazodicarboxylate (0.200 mL). After stirring for 18 hours, the mixture was diluted with ethyl acetate and water was added. The mixture was extracted with ethyl acetate (3×). The combined organics were dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase HPLC (30%-100% ACN/0.015% TFA-water) yielded 13.2 mg of the desired product. HRMS (ES+) m/z 889.4523 (M+H)+.
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[CH3:11][C:12]1[C:17](=[O:18])[C:16]([CH3:19])=[C:15]([CH3:20])[C:14](=[O:21])[C:13]=1[CH:22]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:23][CH2:24][CH2:25][C:26]#[C:27][CH2:28][OH:29]>C(OCC)(=O)C>[CH3:11][C:12]1[C:17](=[O:18])[C:16]([CH3:19])=[C:15]([CH3:20])[C:14](=[O:21])[C:13]=1[CH:22]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][OH:29]
Reactant: CC1=C(C)C(=O)C(C(CCCC#CCO)c2ccccc2)=C(C)C1=O
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: CC1=C(C)C(=O)C(C(CCC/C=C\CO)c2ccccc2)=C(C)C1=O
Yield: 93.6 %

Procedure:
Rindler catalyst (90 mg) and quinoline (15 μl) were added to a solution of 7-(3,5,6-trimethyl-1,4-benzoquinon 2-yl)-7-phenyl-2-heptyn -1-ol (1.01 g, 3.0 mmole) in ethyl acetate (20 ml), and catalytic reduction was carried out at room temperature. 3 Hours later, when absorption (73 ml) of hydrogen was almost stopped, the reaction was suspended and the catalyst was filtered out. The ethyl acetate was distilled off under reduced pressure, and the residue was chromatographed on a silica gel column to elute with isopropayl ether to give (Z)-7-(3,5,6-trimethyl-1,4-benzoquinon -2-yl)-7-phenyl-2-hepten -1-ol (0.95 g, 94%). Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 1.
Reaction SMILES: Cl[C:2]1[S:6](=[O:7])[N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:15])[CH:3]=1.[CH2:16]([O:18][C:19]1[O:20][CH:21]=[CH:22][CH:23]=1)[CH3:17]>>[CH2:8]([N:5]1[C:4](=[O:15])[C:3]2[C:19]([O:18][CH2:16][CH3:17])=[CH:23][CH:22]=[C:21]([OH:20])[C:2]=2[S:6]1=[O:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOc1ccco1
Reactant: O=C1C=C(Cl)S(=O)N1Cc1ccccc1
Product: CCOc1ccc(O)c2c1C(=O)N(Cc1ccccc1)S2=O
Yield: 40 %

Procedure:
Reaction of 5.8 g (0.024 mol) of 5-chloro-2-benzyl-2H-isothiazol-3-one-1-oxide with 3.76 g (0.0335 mol) of 2-ethoxyfuran afforded 3.05 g (40%) of 2-benzyl-4-ethoxy-7-hydroxybenzisothiazol-3-one-1-oxide, 5.7 g of which was reacted with 3.6 g (0.0197 mol) of 2-[2-methoxyethoxy]ethyl bromide in the presence of 4.95 g (0.0358 mol) of potassium carbonate in 125 ml of methyl ethyl ketone and 25 ml of DMF to give 7.0 g (93%) of 2-benzyl-4-ethoxy-7-[2-(2-methoxy-ethoxy)ethoxy]benzisothiazol-3-one-1-oxide, which was oxidized as before with 3-chloroperbenzoic acid in MDC to give 2-benzyl-4-ethoxy-7-[2-(2-methoxyethoxy)ethoxy]-saccharin. Debenzylation of 6.6 g (0.015 mol) of the latter with 3.34 g (0.053 mol) of ammonium formate in the presence of 6.4 g of 10% palladium-on-charcoal catalyst in methanol afforded the ammonium salt of 4-ethoxy-7-[2-(2-methoxyethoxy)ethoxy]saccharin, which was reacted with 2.38 g (0.015 mol) of chloromethyl phenyl sulfide in 100 mL of DMF to give 1.46 g (21%) of 2-phenylthiomethyl-4-ethoxy-7-[2-(2-methoxyethoxy)-ethoxy]saccharin, mp 73°-75° C. (from isopropanol). Treatment of 1.4 g (0.0029 mol) of the product with 0.4 g (0.0029 mol) of sulfuryl chloride in MDC afforded 1.16 g (100%) of 2-chloromethyl-4-ethoxy-7-[2-(2-methoxyethoxy)ethoxy]-saccharin.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH2:19][C:20](Cl)=[O:21])=[N:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([OH:25])[CH3:24].N1C=CC=CC=1>C1C=CC=CC=1>[CH2:23]([O:25][C:20](=[O:21])[CH2:19][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:11][N:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:9]=1)[CH3:24]
Reactant: CCO
Reactant: Cc1ccc(-n2cc(-c3ccccc3)c(CC(=O)Cl)n2)cc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCOC(=O)Cc1nn(-c2ccc(C)cc2)cc1-c1ccccc1
Reaction time: 16 h

Procedure:
2.2 g. of [4-phenyl-1-(4-tolyl)-3-pyrazolyl]-acetyl chloride crude product are reacted with 5 ml. of absolute benzene and 5 ml. of absolute ethanol. 0.2 ml. of pyridine are added dropwise to this mixture, which is allowed to stand at room temperature for 16 hours, and then diluted with 20 ml. of benzene. The reaction mixture then is washed in turn with water, diluted hydrochloric acid and water; dried and concentrated in vacuum. The residue is recrystallized from acetone/hexane. 1.7 g. of [4-phenyl-1-(4-tolyl)-3-pyrazolyl]-acetic acid ethyl ester with a melting point of 76°-79° C., is obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([NH2:12])=[S:11].Br[CH2:14][C:15](=O)[C:16]([OH:18])=[O:17]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]1[S:11][CH:14]=[C:15]([C:16]([OH:18])=[O:17])[N:12]=1
Reactant: NC(=S)NCCc1ccccn1
Reactant: O=C(O)C(=O)CBr
Solvent: CO
Product: O=C(O)c1csc(NCCc2ccccn2)n1
Yield: 90.9 %

Procedure:
2-(2-Pyridin-2-yl-ethylamino)-thiazole-4-carboxylic acid (375 mg) was prepared according to General Procedure B using (2-pyridin-2-yl-ethyl)-thiourea (300 mg) and 3-bromo-2-oxo-propionic acid (295 mg) in methanol (3 mL). The crude product was used in a subsequent step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=1)[CH2:7][OH:8])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([NH2:12])[CH:11]=1)[CH2:7][OH:8]
Reactant: O=[N+]([O-])c1cc(CO)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(N)cc(CO)c1

Procedure:
A solution of 3,5-dinitrobenzylalcohol (2.20 g, 11.1 mmol) in methanol (90 ml) and a Pd/C catalyst (10%, 100 mg) was hydrogenated in a Parr apparatus at 60 psi. The solution was filtered and the solvent was removed by evaporation. The crude product was used without purification in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH:26]=O)=[C:20]([N+:23]([O-])=O)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]([CH3:26])=[C:20]([NH2:23])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])c(C=O)c3O2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc(N)c(C)c3O2)cc1

Procedure:
[(2R)-8-Formyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methyl-benzenesulfonate (1.4 g, 2.74 mmole) in methanol (40 mL) was was treated with 60 psi of hydrogen on a Parr shaker in the presence of 0.10 g 20% palladium hydroxide on carbon (Pearlman's catalyst) for 24 hours. The catalyst was removed by filtration and washed with methanol. The filtrate was evaporated in vacuum to give 0.94 g (93%) of the (R)-enantiomer of the title compound as a beige solid. 1H (DMSO) broad singlet 10.0 δ (2 H); doublet 7.8 δ (2 H); doublet 7.5 δ (2 H); doublet 6.9 δ (1H); doublet 6.8 δ (2 H); multiplet 4.0-4.6 δ (5 H); singlet 2.4 δ (3 H); singlet 2.1 δ (3 H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[O:21][C:8]2([CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH2:7][N:6]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:5]1.[ClH:28]>ClCCl>[ClH:28].[CH3:1][O:2][CH2:3][CH:4]1[CH2:5][N:6]([C:22]2[N:23]=[CH:24][CH:25]=[CH:26][N:27]=2)[CH2:7][C:8]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[O:21]1
Reactant: COCC1CN(c2ncccn2)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Agent: Cl
Solvent: ClCCl
Product: COCC1CN(c2ncccn2)CC2(CCNCC2)O1
Reaction time: 2 h

Procedure:
Tert-butyl 10-(methoxymethyl)-8-pyrimidin-2-yl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (1.18 g, 3.12 mmol) was dissolved in dichloromethane (2 mL) and treated with a solution of HCl (1.6 mL of 4 M in dioxane, 6.2 mmol). The mixture was allowed to stir for 2 h. The reaction mixture was evaporated to dryness to provide 2-(methoxymethyl)-4-(pyrimidin-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecane hydrochloride. ESI-MS m/z calc. 278.2. Found 279.2 M+1)+; Retention time: 0.68 min (3 min run). 1H NMR (400 MHz, MeOD) δ 8.59 (d, J=5.2 Hz, 2H), 6.99 (t, J=5.2 Hz, 1H), 4.52 (ddd, J=44.3, 13.4, 1.7 Hz, 2H), 4.12-3.97 (m, 1H), 3.56 (ddd, J=26.1, 10.3, 4.9 Hz, 2H), 3.42 (s, 3H), 3.34 (dd, J=10.9, 5.0 Hz, 2H), 3.27-3.19 (m, 2H), 3.13 (dd, J=13.2, 11.1 Hz, 2H), 2.42 (d, J=15.2 Hz, 1H), 1.94 (dd, J=10.7, 4.3 Hz, 2H), 1.74 (ddd, J=15.3, 12.8, 4.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[C:4](C1C=CC(C)=CC=1)=[O:5].O.C1(C)C=CC(S(O)(=O)=[O:26])=CC=1.OO>O1CCCC1.O>[Cl:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[C:4]([OH:5])=[O:26]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccc(C(=O)c2ccc(F)cc2Cl)cc1
Agent: OO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(F)cc1Cl
Temperature: 20 °C
Reaction time: 12 h
Yield: 87 %

Procedure:
12.4 g (0.05 mol) of 2-chloro-4-fluoro-4'-methylbenzophenone in 30 ml of tetrahydrofuran were added dropwise to a solution of 19.0 g (0.1 mol) of toluene-4-sulfonic acid hydrate and 3.8 g (0.1 mol) of 90% hydrogen peroxide in 100 ml of tetrahydrofuran. The mixture was subsequently stirred for 12 h at 20° C. and then diluted with 100 g of water. Further processing as described in Example 22 gave 7.6 g (43.5 mmol, 87%) of 2-chloro-4-fluorobenzoic acid (m.p. 181°-186° C.).
Reaction SMILES: [C:1]1([C:13]2[C:14](=[O:29])[NH:15][C:16](=[O:28])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([Br:27])[CH:25]=3)[NH:20][CH:19]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1>CO>[C:1]1([C@H:13]2[C@H:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([Br:27])[CH:25]=4)[NH:20][CH:19]=3)[C:16](=[O:28])[NH:15][C:14]2=[O:29])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2ccc(Br)cc12
Solvent: CO
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1c[nH]c2ccc(Br)cc12

Procedure:
3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(5-bromo-1H-indol-3-yl)pyrrole-2,5-dione, prepared as in Example 24, was reduced with Mg in methanol as described in Example 2, Procedure C, to yield (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(5-bromo-1H-indol-3-yl)pyrrolidine-2,5-dione. 1H NMR (CD3OD) δ: 2.18-2.26 (m, 2H), 2.96 (t, J=6.0 Hz, 2H), 4.12 (t, J=6.4 Hz, 2H), 4.40 (d, J=6.8 Hz, 1H), 4.52 (d, J=6.8 Hz, 1H), 6.86-6.96 (m, 2H), 7.08 (s, 1H), 7.13-7.30 (m, 5H)
Reaction SMILES: [Li]C(C)(C)C.I[C:7]1[C:8]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:9]=2[S:10][C:11]=1[CH3:12]>C1COCC1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:8]2[CH:7]=[C:11]([CH3:12])[S:10][C:9]=2[CH:13]=1
Reactant: COc1ccc2c(I)c(C)sc2c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc2cc(C)sc2c1
Temperature: 0 °C
Yield: 49.9 %

Procedure:
t-BuLi (1.7 M in pentane; 0.32 ml; 0.54 mmol) was added to a solution of the 3-iodo-6-methoxy-2-methylbenzo[b]thiophene (0.0863 g; 0.27 mmol) in anhydrous THF (2.5 ml) at −78° C. under N2. The mixture was allowed to warm up to 0° C. and quenched by the addition of saturated NH4Cl (1 ml). This was diluted to 15 ml with diethyl ether and washed with 5% NaHCO3 (10 ml), dried over anhydrous MgSO4, filtered off and filtrate evaporated to dryness. The residue was purified by flash column chromatography (SiO2, hexane, hexane/ethyl acetate 9.5:0.5) to give the title compound (0.024 g; 50% yield) as colourless solid. 1H-NMR (CDCl3) 2.53 (s, 3H); 3.84 (s, 3H); 6.86 (s, 1H); 6.92 (dd, 1H, J 2.24, 8.87 Hz); 7.222 (d, 1H, J=2.24 Hz); 7.51 (d, 1H, J=8.67 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][OH:20])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1>CCO.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][OH:20])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: OCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1
Solvent: CCO
Solvent: C1COCCO1
Product: OCCCc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
In analogy to example 20.1, 3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-yn-1-ol in EtOH/dioxane was converted to yield 3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-propan-1-ol as a brown oil, MS: 303 (M, 1Cl).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[CH2:29]1[O:38][C:37]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][C:31]=2[O:30]1>>[O:38]1[C:37]2[CH:36]=[CH:35][C:33]([NH:34][CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C:9]4[C:10]([NH:15][S:16]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=5[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=4)=[CH:5][CH:4]=3)=[CH:32][C:31]=2[O:30][CH2:29]1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Reactant: Nc1ccc2c(c1)OCO2
Product: O=S(=O)(Nc1nccnc1-c1ccc(CNc2ccc3c(c2)OCO3)cc1)c1ccccc1C(F)(F)F
Yield: 69 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 3,4-(methylenedioxy)aniline, the title compound was isolated as a yellow solid in 69% yield (96% purity by HPLC).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[C:9](=[O:10])[C:8]([C:11]2[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=2)=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH2:6]1)[CH3:3].[BH4-].[Na+]>>[CH3:1][N:2]([CH2:4][CH:5]1[CH:9]([OH:10])[C:8]([C:11]2[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=2)=[C:7]([C:18]2[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=2)[CH2:6]1)[CH3:3]
Reactant: Cc1cccc(C2=C(c3ccc(S(C)(=O)=O)cc3)CC(CN(C)C)C2=O)c1
Agent: [BH4-]
Agent: [Na+]
Product: Cc1cccc(C2=C(c3ccc(S(C)(=O)=O)cc3)CC(CN(C)C)C2O)c1

Procedure:
2.28 g of 5-dimethylaminomethyl-3-(4-methanesulfonylphenyl)-2m-tolyl-cyclopent-2-enone were reacted in a manner similar to the method described in Example 21 with 0.62 g of sodium borohydride to yield 5-dimethylaminomethyl-3-(4-methanesulfonylphenyl)-2m-tolyl-cyclopent-2-enol. After purification by column chromatography and precipitation of the hydrochloride with a hydrogen chloride/diethyl ether mixture, 0.95 g (corresponding to 41.4% of theoretical) were obtained in the form of colourless crystals with a melting point of 165–167° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[CH:8]1[O:10][CH2:9]1>>[C:12]1([O:11][CH2:7][CH:8]([OH:10])[CH2:9][N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc2c(OCC3CO3)cccc2c1
Reactant: C1CNCCN1
Product: OC(COc1cccc2ccccc12)CN1CCNCC1
Yield: 64.7 %

Procedure:
In the same manner as described in Example 1A, 9.1 g of piperazine is allowed to react with 10.8 g of α-naphthyl glycidyl ether to yield 10.0 g of N-[3-(naphth-1-yloxy)-2-hydroxypropyl]-piperazine. Five grams of this compound and 2.3 g of triethylamine are dissolved in 20 ml of benzene and, with stirring and at room temperature, 3.16 g of N,N-diethylcarbamyl chloride are added dropwise over a period of 30 minutes. When the addition is complete, the mixture is heated at reflux for 2 hours and, after cooling, washed with water and dried. The solvent is removed by distillation, the residue dissolved in ethanol and hydrogen chloride bubbled through the solution. The title compound is thus obtained as the hydrochloride which is recrystallized from isopropyl alcohol. Yield: 2.44 g; m.p. 152°-156° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][NH2:21])=O)[N:9]=2)=[CH:4][CH:3]=1.Cl.[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][C:33](=N)[NH2:34])[CH3:24]>CN(C=O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]3[NH:34][C:33]([CH2:32][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[O:25][CH2:23][CH3:24])=[N:21][N:20]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOc1ccccc1CC(=N)N
Reactant: NNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: CCOc1ccccc1Cc1nnc(Cn2nc(-c3ccc(Cl)cc3)n(C3CC3)c2=O)[nH]1
Temperature: 200 °C
Reaction time: 1 h

Procedure:
50 mg (0.16 mmol) of the compound from Example 21A were taken up in 1 ml of DMF, 52 mg (0.24 mmol) of 2-(2-ethoxyphenyl)ethaneimidamide hydrochloride were added and the mixture was stirred in a microwave oven at 200° C. for 1 h. After cooling, the reaction was diluted with about 1 ml of methanol and the solution was directly separated by preparative HPLC [Method 19]. This gave 21 mg (28% of theory) of the title compound.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](Cl)(=[O:12])[C:9](Cl)=[O:10].[Cl-].[Al+3].[Cl-].[Cl-]>CCOCC>[S:7]1[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[C:9](=[O:10])[C:8]1=[O:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Sc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: O=C1Sc2ccccc2C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
To a solution of thiophenol (100 g, 0.907 mol) in ether is added dropwise a solution of oxalyl chloride (175 g, 1.38 mol) in ether. The mixture is stirred two hours at reflux and concentrated in vacuo. The residue is taken up in methylene chloride and cooled to 0° C. Aluminum chloride (145 g, 1.09 mol) is added in portions such that the temperature does not exceed 25° C. The resultant mixture is stirred 30 minutes at reflux, cooled to room temperature and poured into ice water with stirring. The organic layer is washed with saturated sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to an orange solid which is recrystallized from methylene chloride:hexanes to afford the title compound (102 g, 69.0%) which is identified by NMR spectral analysis.
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:13])([CH2:9][CH:10]([CH3:12])[CH3:11])[S:4]1)[OH:2].[CH3:14][N:15]=[C:16]=[O:17]>>[CH3:14][NH:15][C:16]([O:2][N:1]=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:13])([CH2:9][CH:10]([CH3:11])[CH3:12])[S:4]1)=[O:17]
Reactant: CC1=NC(=NO)SC1(C)CC(C)C
Reactant: CN=C=O
Product: CNC(=O)ON=C1N=C(C)C(C)(CC(C)C)S1

Procedure:
2-oxo-4,5-dimethyl-5-isobutyl-3-thiazoline-oxime was reacted with methyl isocyanate as described in Example 4 to yield 2-oxo-4,5-dimethyl-5-isobutyl-3-thiazoline-O-(methylcarbamoyl)-oxime, m.p. 99°-101° C. The 2-oxo-4,5-dimethyl-5-isobuty-3-thiazoline-oxime starting material melts at 105°-107° C.
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[Na+]>CS(C)=O.O>[O:11]1[CH2:12][CH2:13][CH:8]([C:7]2[C:2]([O:21][C:18]3[CH:19]=[CH:20][C:15]([NH2:14])=[CH:16][CH:17]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1
Reactant: Nc1ccc(O)cc1
Reactant: Fc1ncccc1C1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ncccc2C2CCOCC2)cc1
Reaction time: 8 h

Procedure:
To a rbf was added 2-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridine (2.156 g, 11.90 mmol), 4-aminophenol (1.948 g, 17.85 mmol), and cesium carbonate (11.63 g, 35.7 mmol) in DMSO (39.7 mL) at 110° C. to stir overnight. Upon completion, the reaction mixture was diluted with water and sat sodium chloride solution and extracted with dichloromethane. The organic extract was washed with water and sat sodium chloride solution, dried with magnesium sulfate, filtered, and concentrated. MS (ESI, pos. ion) m/z: 271.1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][C@@H:15]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[C@@H:16]([OH:20])[C:17]([NH2:19])=[O:18].[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32]Cl>CS(C)=O>[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][C@@H:15]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[C@@H:16]([OH:20])[C:17]([NH2:19])=[O:18]
Reactant: COc1ccc([C@H](Sc2ccccc2N)[C@@H](O)C(N)=O)cc1
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc([C@H](Sc2ccccc2NCCN(C)C)[C@@H](O)C(N)=O)cc1
Temperature: 70 °C

Procedure:
Potassium carbonate is added to dimethyl sulfoxide, and the mixture is stirred at 70° C. The mixture is cooled to room temperature, and thereto is added (2S,3S)-3-(2-aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl)propionamide, and stirred. To the reaction mixture is added dropwise 2-dimethylaminoethyl chloride, and the mixture is stirred at room temperature. The reaction mixture is poured into ice-water, and extracted with ethyl acetate. The extract is dried, and concentrated under reduced pressure to remove the solvent to give (2S,3S)-3-[2-(2-dimethylaminoethylamino)phenylthio]-2-hydroxy-3-(4-methoxyphenyl)-propionamide.