Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8][CH2:9][C:10]1([CH3:25])[CH2:14][N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:12]([C:21](Cl)=[O:22])[C:11]1=[O:24])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:26][NH:27][C:28]1[CH:70]=[CH:69][CH:68]=[CH:67][C:29]=1[C:30]([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]([OH:43])=[C:35]([C:44](=[O:66])[NH:45][C:46]2[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=2[O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH:34]=1)=[O:31].CN(C)C1C=CC=CC=1.[O:80]1CCCC1>>[C:1]([O:8][CH2:9][C:10]1([CH3:25])[C:11](=[O:24])[N:12]([C:21]([N:27]([CH3:26])[C:28]2[CH:70]=[CH:69][CH:68]=[CH:67][C:29]=2[C:30]([O:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]([OH:43])=[C:35]([C:44](=[O:66])[NH:45][C:46]3[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=3[O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH:34]=2)=[O:31])=[O:22])[N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:14]1=[O:80])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)OCC1(C)CN(c2ccccc2)N(C(=O)Cl)C1=O
Reactant: CCCCCCCCCCCCOc1ccc(C)cc1NC(=O)c1cc(OC(=O)c2ccccc2NC)c2ccccc2c1O
Reactant: C1CCOC1
Solvent: CN(C)c1ccccc1
Product: CCCCCCCCCCCCOc1ccc(C)cc1NC(=O)c1cc(OC(=O)c2ccccc2N(C)C(=O)N2C(=O)C(C)(COC(=O)CCCCC)C(=O)N2c2ccccc2)c2ccccc2c1O
Reaction time: 72 h

Procedure:
Hexanoic acid, 2-chlorocarbonyl-4-methyl-3-oxo-1-phenyl-pyrazolidin-4-ylmethyl ester (0.80 g, 0.0022 mol) was dissolved in tetrahydrofuran (10 ml) and added to a stirred solution of 2-methylamino-benzoic acid, 3-(2-dodecyloxy-5-methyl-phenylcarbamoyl)-4-hydroxy-naphthalen-1-yl ester [A] (1.28 g, 0.0021 mol) and N,N-dimethylaniline (0.28 g, 0.0023 mol) in dry tetrahydrofuran (5 ml) and the solution stirred for 72 hr under argon atmosphere in a flask equipped with a reflux condenser to limit evaporation. The reaction mixture was evaporated, re-dissolved in ethyl acetate (300 ml) and washed with 2 M aqueous hydrochloric acid (150 ml) followed by water (20 ml). The organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated to give a yellow-brown oil which contained product and starting amine. The oil was chromatographed on a Flashpak Si 50 g column eluting with hexane/ethyl acetate (4:1->2:1). The higher running components were discarded. The more polar component was evaporated to give pale yellow viscous oil. Analysis was consistent with the desired product. The total yield of product was 1.3 g (62%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][NH2:9])[N:5]=[C:4]([O:10][CH2:11][CH3:12])[N:3]=1.C(#N)C.[C:16](=S)=[S:17].OO>O>[Cl:1][C:2]1[N:3]=[C:4]([O:10][CH2:11][CH3:12])[N:5]2[C:16](=[S:17])[NH:9][N:8]=[C:6]2[CH:7]=1
Reactant: CCOc1nc(Cl)cc(NN)n1
Reactant: S=C=S
Agent: OO
Solvent: O
Solvent: CC#N
Product: CCOc1nc(Cl)cc2n[nH]c(=S)n12
Temperature: 0 °C

Procedure:
A mixture containing 20 g of 93 percent purity (99 mmol) 4-chloro-2-ethoxy-6-hydrazinopyrimidine in a solvent composed of 90 mL of acetonitrile and 26 mL of water was prepared under nitrogen in a 500 mL flask equipped with a condensor and an opening covered by a septum through which the syringe of a syringe pump was inserted. To this was added 11.3 g (148 mmol) of carbon disulfide and, after a 15-min reaction period, 16.7 g of 30 percent aqueous hydrogen peroxide (147 mmol) was added over a 15-min period by means of the syringe with stirring and cooling to hold the temperature at about 25° C. The mixture was allowed to react for another 4 hours and then was cooled to about 0° C. The precipitated product and sulfur by-product were recovered by vacuum filtration and washed with water, a 1:1 mixture of water and acetonitrile, and finally acetonitrile. The wet cake was slurried in 1 L of water at 70° C. and about 600 mL of acetonitrile was added to dissolve the solid. The resulting mixture was gravity filtered and the filtrate was allowed to cool over the weekend. The mixture was further cooled in a refrigerator and the crystals that formed were recovered by vacuum filtration, washed with acetonitrile, and dried to constant weight to obtain 14.1 g (62 percent of theory) of the title compound as an amber solid which decomposed on heating above 187° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]([CH3:37])([CH3:36])[C:21]([NH:23][CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[CH:28]=1)=O)=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:47])=CC=1>C1(C)C=CC=CC=1>[Si:1]([O:18][CH2:19][C:20]([C:21]1[S:47][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[CH:28]=2)=[CH:24][N:23]=1)([CH3:37])[CH3:36])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)NCC(=O)c1cccc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ncc(-c2cccc([N+](=O)[O-])c2)s1
Temperature: 100 °C
Yield: 68.1 %

Procedure:
To a solution of the product of Step 1 (680 mg, 1.31 mmol) in toluene (6.5 mL) was added Lawesson's reagent (530 mg, 1.31 mmol) and the mixture was heated to 100° C. for 20 hours and then cooled to it then the mixture was concentrated in vacuo. Purification by chromatography on silica gel (100:0 to 50:50, hexanes:ethyl acetate) provided 461 mg (0.892 mmol, 68%) of 2-(1-{[tert-butyl(diphenyl)silyl]oxy}-2-methylpropan-2-yl)-5-(3-nitrophenyl)-1,3-thiazole as a colorless viscous oil.
Reaction SMILES: [N+](=[CH2:3])=[N-].[O:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[N:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([C:21]([F:24])([F:23])[F:22])=[CH2:20])=[CH:16][CH:17]=2)[C:12]([C:25]2[N:30]=[C:29]([O:31][C@H:32]3[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37][CH2:36][C:33]43[CH2:35][CH2:34]4)[CH:28]=[N:27][CH:26]=2)=[N:11]1.CC(O)=O>C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[N:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]3([C:21]([F:24])([F:22])[F:23])[CH2:3][CH2:20]3)=[CH:16][CH:17]=2)[C:12]([C:25]2[N:30]=[C:29]([O:31][C@H:32]3[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37][CH2:36][C:33]43[CH2:35][CH2:34]4)[CH:28]=[N:27][CH:26]=2)=[N:11]1
Reactant: C=C(c1ccc2c(c1)c(-c1cncc(O[C@H]3CN(C(=O)OC(C)(C)C)CCC34CC4)n1)nn2C1CCCCO1)C(F)(F)F
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(C5(C(F)(F)F)CC5)cc34)n2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
Diazomethane (˜0.25M in Et2O (prepared according to Aldrich Technical Bulletin AL-180, Aldrich, St. Louis, Mo.); 1.0 mL, 0.250 mmol) was added (dropwise) to a solution of (4R)-tert-butyl 4-(6-(1-(tetrahydro-2H-pyran-2-yl)-5-(3,3,3-trifluoroprop-1-en-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (41.8 mg, 0.070 mmol) and palladium(II) acetate (1.565 mg, 6.97 μmol) in DCM (1.0 mL) at 0° C., and the resulting solution was stirred at 0° C. for 30 min. Additional diazomethane (˜0.25M in Et2O; 2.0 mL, 0.500 mmol) was added, and the resulting solution was stirred at 0° C. for 30 min. Additional palladium(II) acetate (4.54 mg, 0.020 mmol) and diazomethane (˜0.25M in Et2O; 2×2.0 mL, 2×0.500 mmol) were sequentially added, and the reaction was stirred at 0° C. for 5 min. Additional diazomethane (˜0.25M in Et2O; 2.0 mL, 0.500 mmol) was added, the reaction was stirred at 0° C. for 5 min. HOAc (0.160 mL, 2.79 mmol) was added to quench excess diazomethane, and the resulting mixture was stirred at 25° C. for 12 h. The mixture was concentrated onto silica gel and chromatographically purified (ISCO, 12 g silica gel column, 0-60% EtOAc/hexanes, 15 min, 254 nm) to provide (4R)-tert-butyl 4-(6-(1-(tetrahydro-2H-pyran-2-yl)-5-(1-(trifluoromethyl)cyclopropyl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (25.2 mg, 0.041 mmol, 59% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ ppm 9.03 (1 H, s), 8.52 (1 H, s), 8.21 (1 H, br. s.), 7.63 (1 H, s), 7.53 (1 H, d, J=8.8 Hz), 5.80 (1 H, d, J=9.0 Hz), 4.69 (1 H, d, J=11.5 Hz), 4.44 (1 H, br. s.), 4.24-4.36 (1 H, m), 4.03 (1 H, d, J=11.5 Hz), 3.71-3.84 (1 H, m), 3.24 (1 H, d, J=14.7 Hz), 2.88-3.03 (1 H, m), 2.56-2.71 (1 H, m), 2.42-2.55 (1 H, m), 2.17-2.29 (1 H, m), 2.12 (1 H, d, J=7.8 Hz), 1.65-1.88 (5 H, m), 1.37-1.55 (9 H, m), 0.81-0.92 (2 H, m), 0.72 (1 H, br. s.), 0.48-0.63 (4 H, m). 19F NMR (377 MHz, CDCl3) δ ppm −70.26 (3 F, br. s.). MS (ESI, pos. ion) m/z: 614.3 (M+1).
Reaction SMILES: CS(O)(=O)=[O:3].[OH-].[NH4+].O[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([C:15]2[S:19][C:18]([NH:20][C:21](=[O:32])[C:22]3[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=3[O:30][CH3:31])=[N:17][N:16]=2)[CH:14]=1>>[OH:3][C:10]1[CH:11]=[CH:12][C:13]([C:15]2[S:19][C:18]([NH:20][C:21](=[O:32])[C:22]3[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=3[O:30][CH3:31])=[N:17][N:16]=2)=[CH:14][CH:9]=1
Reactant: COc1cccc(OC)c1C(=O)Nc1nnc(-c2cccc(O)c2)s1
Reactant: CS(=O)(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: COc1cccc(OC)c1C(=O)Nc1nnc(-c2ccc(O)cc2)s1
Temperature: 0 °C

Procedure:
The residue produced above was stirred, and 20 g. of methanesulfonic acid was added dropwise to it. After 4 hours of stirring, at room temperature, the solution was poured into 300 ml. of ice water, and the pH was adjusted with ammonium hydroxide to 7.5. A precipitate separated, which was collected and recrystallized from acetone to produce 2.5 g. of N-[5-(5-hydroxyphenyl)-1,3,4-thiadiazol-2-yl]-2,6-dimethoxybenzamide, m.p. above 260°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:19])[C:7]([S:10]([N:13]2[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14]2)(=[O:12])=[O:11])=[CH:8][CH:9]=1)=[O:4].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:19])[C:7]([S:10]([N:13]2[CH2:17][CH2:16][C@H:15]([O:18][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:14]2)(=[O:11])=[O:12])=[CH:8][CH:9]=1)=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(S(=O)(=O)N2CC[C@H](O)C2)n1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(S(=O)(=O)N2CC[C@H](OS(C)(=O)=O)C2)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
To a solution of (S)-5-(3-hydroxy-pyrrolidine-1-sulfonyl)-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (Ex. 13a, 6.1 g, 21.2 mmol) and triethylamine (8.9 mL, 63.5 mmol) in methylene chloride (75 mL) at 0° C. was added methanesulfonyl chloride (2.4 mL, 31.8 mmol). The resulting solution was warmed to room temperature and stirred at room temperature for 2 h. Upon completion, as determined by HPLC, the reaction was quenched with 1N HCl (150 mL) and diluted with water (100 mL). The layers were cut and the organic layer was washed with 1N HCl (2×100 mL), a 50% aqueous brine solution (1×100 mL) and brine (1×100 mL), dried over Na2SO4, and concentrated under reduced pressure to afford 7.8 g (99%) of (S)-5-(3-methanesulfonyloxy-pyrrolidine-1-sulfonyl)-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester as an orange foam. This material was used without further purification. 1H-NMR (400 MHz, CDCl3): δ 7.27 (d, 1H, J=2.0 Hz), 7.17 (d, 1H, J=2.0 Hz), 5.15-5.17 (m, 1H), 3.97 (s, 3H), 3.84 (s, 3H), 3.43-3.60 (m, 3H), 3.30-3.37 (m, 1H), 2.94 (s, 3H), 2.17-2.23 (m, 1H), 2.09-2.16 (m, 1H). mp 79-81° C. Anal. Calcd. for C12H18N2O7S2: C, 39.34; H, 4.95; N, 7.65; S, 17.50. Found: C, 39.20; H, 5.00; N, 7.56; S, 17.66.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH2:14][CH2:13][CH:12]([N:15]([C:17]4[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:19][CH:18]=4)[CH3:16])[C:9]=3[CH:10]=2)[N:5]=[C:4]([CH2:30][N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[NH:3]1.[H-].[Na+].[CH3:39]N(C=O)C>>[CH3:39][N:3]1[C:2](=[O:1])[C:11]2[C:6](=[CH:7][C:8]3[CH2:14][CH2:13][CH:12]([N:15]([C:17]4[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:19][CH:18]=4)[CH3:16])[C:9]=3[CH:10]=2)[N:5]=[C:4]1[CH2:30][N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CN(C)C=O
Reactant: CN(c1ccc(C(=O)OC(C)(C)C)cc1)C1CCc2cc3nc(CN4CCCCC4)[nH]c(=O)c3cc21
Agent: [H-]
Agent: [Na+]
Product: CN(c1ccc(C(=O)OC(C)(C)C)cc1)C1CCc2cc3nc(CN4CCCCC4)n(C)c(=O)c3cc21
Reaction time: 0.02 h
Yield: 91 %

Procedure:
To a solution of tert-butyl 4-[N-[4-oxo-2-(piperidin-1-yl)methyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]-N-methylamino]benzoate (0.060 g, 0.123 mmol) in anhydrous DMF (3 ml) under argon was added a dispersion of NaH in mineral oil (60% w/w) (0.0060 g, 0.147 mmol) and the reaction mixture was stirred for 1 min. Mel (15 μL, 0.246 mmol) was then added via syringe and the reaction mixture was stirred for a further 2 hours. The reaction mixture was then partitioned between a saturated aqueous solution of sodium bicarbonate (40 ml) and ethyl acetate (75 ml) and the organic phase was then successively washed with a saturated aqueous solution of sodium bicarbonate (30 ml), brine (30 ml), then dried (Na2SO4) and concentrated under reduced pressure to afford the title compound (0.056 g, 91%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](OS(C(F)(F)F)(=O)=O)=[C:7]([Cl:19])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:22]=[C:23]([CH2:28][CH2:29][NH2:30])[CH:24]=[CH:25][C:26]=1[Cl:27].CN([CH:34]=[O:35])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:34]([NH:30][CH2:29][CH2:28][C:23]2[CH:24]=[CH:25][C:26]([Cl:27])=[C:21]([Cl:20])[CH:22]=2)=[O:35])=[C:7]([Cl:19])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1
Reactant: CN(C)C=O
Reactant: NCCc1ccc(Cl)c(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)c1ccc(C(=O)NCCc2ccc(Cl)c(Cl)c2)c(Cl)c1
Temperature: 70 °C
Yield: 58 %

Procedure:
363 mg (1.15 mmol) of trifluoro-methanesulfonic acid 4-tert-butyl-2-chloro-phenyl ester (prepared as described in example S80) and 440 mg (2.29 mmol) of 2-(3,4-dichloro-phenyl) ethyl amine were dissolved in 5.8 ml DMF. Under argon at rt 7.7 mg (0.035 mmol) of palladium acetate and 14.1 mg (0.035 mmol) of dppp were added. The reaction mixture was evacuated and charged with carbon monoxide gas three times. The reaction mixture was heated to 70° C. under a carbon monoxide atmosphere for 1 h. Water was added and the reaction mixture was extracted twice with EtOAc. The combined organic layers were washed with 1N aqueous HCl solution, once with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (45 g silica gel; heptane/EtOAc 7:3) to yield 255 mg (58%) of 4-tert-butyl-2-chloro-N-[2-(3,4-dichloro-phenyl)-ethyl]-benzamide as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 8.41 (t, 1H), 7.55 (d, 1H), 7.54 (s, 1H), 7.42 (s, 1H), 7.38 (d, 1H), 7.28-7.23 (m, 2H), 3.46 (q, 2H), 2.83 (t, 2H), 1.27 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:24][C:25]([F:42])([F:41])[C:26]1[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][C:33]2[CH2:32][CH2:31][NH:30][CH2:29][C:28]=2[N:27]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>C(Cl)CCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[CH2:10][C:11]([N:30]1[CH2:29][C:28]2[N:27]=[C:26]([C:25]([F:42])([F:41])[F:24])[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][C:33]=2[CH2:32][CH2:31]1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cc2c(nc1C(F)(F)F)CNCC2
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)ccc1F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCOC(=O)c1cc2c(nc1C(F)(F)F)CN(C(=O)C[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C)CC2

Procedure:
(3R)-3-[(tert-Butoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoic acid (intermediate 1) and ethyl 2-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxylate hydrochloride (intermediate 27) were treated with EDC, HOBt and N,N-diisopropylethylamine according to the procedure described for Example 1, Step A to afford the title compound as a white foam.
Reaction SMILES: Cl[CH:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH:7]3[CH2:13][CH2:14][CH2:15][CH2:16][CH:6]3[CH2:5][C:4]=2[NH:3]1.[C:17]1([CH:23]([NH2:25])[CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:17]1([CH:23]([NH:25][C:2]2[CH:11]=[CH:10][C:9]3[C:8](=[O:12])[CH:7]4[CH2:13][CH2:14][CH2:15][CH2:16][CH:6]4[CH2:5][C:4]=3[N:3]=2)[CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1C2=C(CC3CCCCC13)NC(Cl)C=C2
Reactant: CC(N)c1ccccc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CCC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(Nc1ccc2c(n1)CC1CCCCC1C2=O)c1ccccc1
Yield: 23.9 %

Procedure:
To a solution of 2-chloro-2,5a,6,7,8,9,9a,10-octahydro-1H-benzo[g]quinolin-5-one (0.4 g, 1.7 mmol) and 1-phenyl-ethylamine (0.266 g, 2.2 mmol) in toluene (2 ml) under an argon atmosphere was added sodium tert-amylate (0.223 g, 2.03 mmol) and bis(tri-tert-butylphosphine)palladium (0.043 g, 0.084 mmol). The mixture was heated at reflux for 8 h. Then it was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel to give the title compound (0.13 g, 24%) as a colorless solid.
Reaction SMILES: [S:1]1(=[O:11])(=[O:10])[CH2:8][CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3][CH2:2]1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20]N)=[CH:16][CH:15]=1>C(O)(=O)C>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]2[NH:20][C:5]3[CH2:4][CH2:3][CH2:2][S:1](=[O:11])(=[O:10])[CH2:8][CH2:7][C:6]=3[C:16]=2[CH:15]=1
Reactant: COc1ccc(NN)cc1
Reactant: O=C1CCCS(=O)(=O)CCC1
Solvent: CC(=O)O
Product: COc1ccc2[nH]c3c(c2c1)CCS(=O)(=O)CCC3
Yield: 87.6 %

Procedure:
A mixture of 26.54g (0.15 mole) of 1-thiacyclooctane-5-one 1,1-dioxide and 22.0g (0.16 mole) of p-methoxyphenylhydrazine in 150 ml of glacial acetic acid is treated according to the procedure in Example 2. There is obtained 36.7g (88%) of a crystalline solid, m.p. 231°-233° C. Recrystallization from acetone-ethyl acetate gives 30g (72%) of an analytical sample, m.p. 233°-235° C.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](Cl)=[O:18])=[CH:12][CH:11]=1.[Cl-].[Al+3].[Cl-].[Cl-].O>C(=S)=S>[CH3:8][S:7][C:1]1[CH:6]=[CH:5][C:4]([C:17](=[O:18])[CH2:16][C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CSc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: O
Product: CSc1ccc(C(=O)Cc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.9 %

Procedure:
To a stirred solution of thioanisole (380 mL, 3.2 mol) and 4-fluorophenylacetyl chloride (300 g, 1.6 mol) in carbon disulfide (1.2 L), cooled to 5° C., was added anhydrous aluminum chloride portionwise at such a rate that the internal temperature did not rise above 15° C. The reaction was stirred at room temperature for 16 hours. The solution was cautiously poured into 2 L of ice and water. The aqueous solution was extracted with methylene chloride (6×150 mL), the combined extracts were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was dissolved in 800 mL of ether and cooled to 0° C. whereupon crystals of pure product formed which were isolated by filtration on a Buchner funnel and air dried to provide the ketone (199.6 g, 48%): mp 135°-138° C. 1H NMR (CDCl3 /TMS) 300 MHz 8.00 (d, J=8.7 Hz, 2H), 7.40-7.30 (m, 4H), 7.13-7.03 (m, 2H), 4.34 (s, 2H), 2.56 (s, 3H). Mass spectrum M+ =260.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>O1CCCC1>[S:25]([O:12][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:27])(=[O:26])[CH3:24]
Reactant: OCc1ccccc1OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 117.6 %

Procedure:
To a solution of 2-benzyloxybenzyl alcohol (2.1 g, 9.42 mmol) in tetrahydrofuran (10 mL), triethylamine (1.38 mL, 9.89 mmol) and methanesulfonyl chloride (0.766 mL, 9.89 mmol) were added under ice cooling and stirred at room temperature for 30 minutes. After filtration to remove the insoluble materials, the filtrate was concentrated to give (2-benzyloxyphenyl)methyl mesylate (3.24 g). To a suspension of methyl isobutyrylacetate (1.43 g, 9.89 mmol), sodium hydride (60% in oil; 396 mg, 9.89 mmol) and dimethoxyethane (10 mL), a solution of (2-benzyloxyphenyl)methyl mesylate (3.24 g) in dimethoxyethane (10 mL) was added and stirred at 70° C. overnight. After addition of 0.5 M HCl, the reaction mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give an oil. To this oil, toluene (20 mL) and hydrazine monohydrate (317 mg, 9.89 mmol) were added and the resulting mixture was heated under reflux for 3 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. The reaction mixture was concentrated and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=50:1 to 8:1) to give the titled compound (750 mg, 25%) as a light-yellow amorphous substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C(N(CC)CC)C.[C:32](Cl)(Cl)=[S:33].[NH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:32]([NH:36][N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[S:33])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: S=C(Cl)Cl
Reactant: NN1CCCCC1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=S)NN4CCCCC4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 27.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was dissolved in N,N-dimethylformamide (2 ml) and triethylamine (1 ml) to prepare a solution. Thiophosgene (51 mg) was then added to the solution, and the mixture was stirred at room temperature for 6 hr. Next, 1-aminopiperidine (50 mg) was added thereto, and the mixture was further stirred at room temperature for 14 hr. Ethyl acetate was added to the reaction solution, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (20 mg, yield 27%).