Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([Cl:10])[CH:3]=1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][S:19]([CH3:18])(=[O:21])=[O:20])=[C:4]([Cl:10])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(Br)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(Br)cc1Cl
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-2-chlorobenzyl alcohol (3.56 g) and anhydrous triethylamine (3 ml) in anhydrous dichloromethane (36 ml) was added dropwise methanesulfonyl chloride (1.4 ml) under ice-cooling in a nitrogen atmosphere. The mixture was stirred for 1 hr, and the reaction mixture was washed with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The filtrate was concentrated to give 4-bromo-2-chloro-1-((methanesulfonyloxy)-methyl)benzene as a pale-brown solid (4.77 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10](O)[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[SH:15][CH2:16][C:17]([OH:19])=[O:18].C1C=CC=CC=1>CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.CCOCC>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([S:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCCC(O)c1ccc2c(c1)OCO2
Reactant: O=C(O)CS
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCCC(SCC(=O)O)c1ccc2c(c1)OCO2
Yield: 89.3 %

Procedure:
A mixture comprising 103 g of 1-(1,3-benzodioxol-5-yl)-1butanol, 73.3 g of mercaptoacetic acid, 0.1 g of D-10-camphorsulfonic acid and 500 ml of benzene was heated under reflux for 2 hours, followed by the addition of 2000 ml of ether. The obtained mixture was washed with water and extracted with 750 ml and then 100 ml of 1 N sodium hydroxide successively. The extracts were combined, washed with ether and chloroform successively, acidified with concentrated hydrochloric acid and extracted with ethyl acetate (800 ml and 400 ml). The extracts were combined, washed with water, dried over magnesium sulfate and concentrated in a vacuum to obtain 132 g of a crude product. This crude product was purified by silica gel chromatography (ethyl acetate/hexane/formic acid =100:900:1) to obtain 127 g of a colorless oil. This oil was crystallized from n-hexane to obtain 115 g of the title compound as a white crystalline powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[CH:11][C:10]([C:20]([OH:22])=O)=[N:9]2)=[CH:4][CH:3]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:46]3[CH2:50][C:49](=[O:51])[NH:48][CH2:47]3)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[CH:11][C:10]([C:20]([N:46]3[CH2:50][C:49](=[O:51])[NH:48][CH2:47]3)=[O:22])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2cccc(F)c2)n(-c2ccc(Cl)cc2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Product: O=C1CN(C(=O)c2cc(-c3cccc(F)c3)n(-c3ccc(Cl)cc3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 105A in analogy to the synthesis of the compound of Example 1. 15 mg (39% of theory) of the title compound are obtained.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1COCC1.Cl[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][N:16]=1.[CH3:23][N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:23][N:24]1[CH:28]=[C:27]([C:15]2[N:16]=[CH:17][C:18]([CH2:21][OH:22])=[CH:19][CH:20]=2)[CH:26]=[N:25]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: OCc1ccc(Cl)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1cc(-c2ccc(CO)cn2)cn1
Temperature: 80 °C

Procedure:
To a pressure vessel was charged Pd(dppf)Cl2 (CH2Cl2 adduct, 341 mg, 0.418 mmol) and potassium phosphate (1.48 g, 6.97 mmol). Nitrogen was blown over the solids and THF (8 mL) and H2O (1.6 mL) were added. A solution of 2-chloro-5-hydroxymethylpyridine (500 mg, 3.48 mmol) and 1-methylpyrazole-4-boronic acid pinacol ester (797 mg, 3.83 mmol) was added; the resulting solution was capped and heated at 80° C. overnight, then cooled to rt and diluted with ethyl acetate. The organic solution was washed 1× with saturated aqueous sodium bicarbonate and 1× with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 30-100% ethyl acetate in hexanes to provide [6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl]methanol that gave a mass ion (ES+) of 190.1 for [M+H]+.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:10][CH2:9][C@H:8]([OH:11])[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[H-].[Na+].Cl[C:15]1[CH:24]=[N:23][C:22]2[C:17](=[CH:18][C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[CH:21]=2)[N:16]=1>C1COCC1>[CH3:26][O:25][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:27][CH3:28])[N:16]=[C:15]([O:11][C@@H:8]1[CH2:9][CH2:10][C@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][CH2:7]1)[CH:24]=[N:23]2
Reactant: COc1cc2ncc(Cl)nc2cc1OC
Reactant: CC(=O)O[C@H]1CC[C@@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2ncc(O[C@H]3CC[C@@H](OC(C)=O)CC3)nc2cc1OC

Procedure:
A mixture of cis 4-acetoxy-cyclohexanol (632 mg, 4 mmole) and NaH (60%, 220 mg, 5.5 mmole) in 15 mL of anhydrous THF is refluxed for 0.5 hour before addition of 2-chloro-6,7-dimethoxyquinoxaline (674 mg, 3 mmole). The resulting mixture is continued to be refluxed for two hours. The residue after filtration and concentration is chromatographed on silica gel (ether) to provide acetic acid cis-4-(6,7-dimethoxyquinoxalin-2-yloxy)-cyclohexyl ester (m.p. 150-152° C.). Anal. Calcd. for C18H22N2O5: C, 62.42: H, 6.40; N, 8.09. Found: C, 62.39; H. 6.55; N, 7.82 and cis-4-(6,7-dimethoxyquinoxalin-2-yloxy)-cyclohexanol (m.p. 148-150° C.). Anal. Calcd. for C16H20N2O4: C. 63.14; H, 6.62; N, 9.20; Found: C, 62.80; H, 6.76; N, 8.67.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:35]2([CH3:36])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:34]2[CH2:33][CH2:32][C@@:31]2([CH3:37])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:24][CH2:25][C:26]([N:28]([CH3:30])[CH3:29])=[O:27])[CH3:22])[CH2:12][C@@H:11]([O:38][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@@H:9]1[C@@:35]2([CH3:36])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:34]2[CH2:33][CH2:32][C@@:31]2([CH3:37])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:24][CH2:25][C:26]([N:28]([CH3:29])[CH3:30])=[O:27])[CH3:22])[CH2:12][C@@H:11]([OH:38])[CH2:10]1
Reactant: C[C@@H](OCCC(=O)N(C)C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H](OCCC(=O)N(C)C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1.5 h
Yield: 80.7 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-20(R)-(N,N-dimethylaminocarbonylethoxy)pregna-5,7,16-triene (100 mg, 0.15 mmol) was treated with a 1M tetrahydrofuran solution of tetra-n-butylammonium fluoride (1.5 ml) in tetrahydrofuran (6.0 ml) in the same manner as shown in Example 4(2) (at room temperature for 30 minutes and then at 50° C. for 1.5 hours), followed by work up and purification using preparative thin layer chromatography (0.5 mm×2 plates, chloroform:methanol=10:1) to give the titled compound (52 mg, 83.0%) as a colorless foam.
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:11]([CH3:26])[C:12]([CH:23]([CH3:25])[CH3:24])=[C:13]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[N:14]=1)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>Cl>[Cl:22][C:18]1[CH:17]=[C:16]([S:15][C:13]2[N:14]=[C:10]([CH2:9][OH:8])[N:11]([CH3:26])[C:12]=2[CH:23]([CH3:25])[CH3:24])[CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)c1c(Sc2cccc(Cl)c2)nc(COCc2ccccc2)n1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)c1c(Sc2cccc(Cl)c2)nc(CO)n1C
Temperature: 110 °C
Yield: 64.9 %

Procedure:
In 5.8 ml of concented hydrochloric acid was dissolved 580 mg (1.5 mmol)of 2-benzyloxymethyl-4-(3-chlorophenylthio)-5-isopropyl-1-methyl-1H-imidazole (17ab'), and the mixture was refluxed under heating at 110° C. for 6 hours. The reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with methylene chloride. The organic layer was washed with water and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The crude product was recrystallized from ethyl acetate-isopropyl ether to give 289 mg of the objective Compound I-38 (yield 65%). mp 105-106° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:14]([NH:16][C@@H:17]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:18]([OH:47])[CH2:19][C@@H:20]([NH:36]C(=O)OCC2C=CC=CC=2)[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[N:29]=3)=[CH:24][CH:23]=2)=[O:15])[C:9]1=[O:59])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO.[Pd]>[NH2:36][C@@H:20]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[N:29]=2)=[CH:26][CH:27]=1)[CH2:19][C@H:18]([OH:47])[C@@H:17]([NH:16][C:14](=[O:15])[C@@H:13]([N:10]1[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: COc1cccc(-c2ccc(C[C@@H](C[C@H](O)[C@H](Cc3ccccc3)NC(=O)[C@@H](N3CCN(Cc4ccccc4)C3=O)C(C)(C)C)NC(=O)OCc3ccccc3)cc2)n1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1cccc(-c2ccc(C[C@H](N)C[C@H](O)[C@H](Cc3ccccc3)NC(=O)[C@@H](N3CCN(Cc4ccccc4)C3=O)C(C)(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution containing the product from Example 114A (0.049 mmol) in methanol (1 mL) was treated with Pd on carbon (0.005 g, 10% Pd by wt.) and HCl solution (0.050 mL, 4N in dioxane), stirred under a hydrogen atmosphere (balloon pressure) at 25° C. for 3 hours, filtered through a bed of celite®, rinsed with methanol, and concentrated to give the title compound as the hydrochloride salt.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=2)=[O:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]([F:41])([F:40])[C:30]1[CH:35]=[CH:34][C:33](OB(O)O)=[CH:32][CH:31]=1.O>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].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>[C:1]([O:5][C:6](=[O:27])[C:7]([CH3:9])([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17](=[O:18])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:33]3[CH:34]=[CH:35][C:30]([C:29]([F:41])([F:40])[F:28])=[CH:31][CH:32]=3)=[CH:22][CH:21]=2)[N:15]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)Nc2ccc(Br)cc2)cs1
Reactant: OB(O)Oc1ccc(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: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)Nc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cs1
Yield: 80.5 %

Procedure:
Under nitrogen atmosphere, 2-[(4-{2-[(4-bromophenyl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (600 mg) synthesized in Example 458-1 and 4-trifluoromethylphenylboric acid (363 mg) were dissolved in dioxane (8 mL) and 2M aqueous sodium carbonate solution (4 mL), tetrakis(triphenylphosphine)palladium (73 mg) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1) to give the title compound (550 mg) as a colorless oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([CH2:16][OH:17])[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([CH:16]=[O:17])[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: OCc1cn2nccc(N3CCOCC3)c2n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cn2nccc(N3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of compound 5d (1.7 g, 7.3 mmol) in DCM (244 mL) was added manganese (IV) oxide (10 g, 116 mmol). The mixture was stirred at rt for 18 h, and filtered through a pad of diatomaceous earth. The filtrate was concentrated to give compound 5e as an off-white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 10.08 (s, 1H), 8.37 (s, 1H), 8.06 (d, J=5.6 Hz, 1H), 6.09 (d, J=5.6 Hz, 1H), 3.99-4.18 (m, 4H), 3.78-3.99 (m, 4H).
Reaction SMILES: [NH2:1][CH2:2][C@:3]([OH:21])([CH2:8][C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])([CH3:11])[CH3:10])[C:4]([F:7])([F:6])[F:5].Br[C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:33]1[CH:34]=[C:35]([CH:46]=[CH:47][CH:48]=1)[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:18][C:16]1[CH:15]=[CH:14][C:13]([O:19][CH3:20])=[C:12]([C:9]([CH3:11])([CH3:10])[CH2:8][C@:3]([OH:21])([C:4]([F:7])([F:6])[F:5])[CH2:2][NH:1][C:23]2[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]3[C:24]=2[CH:25]=[N:26][N:27]3[C:33]2[CH:34]=[C:35]([CH:46]=[CH:47][CH:48]=2)[C:36]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37])[CH:17]=1
Reactant: COc1ccc(F)cc1C(C)(C)C[C@@](O)(CN)C(F)(F)F
Reactant: Cc1cc(Br)c2cnn(-c3cccc(C(=O)OCc4ccccc4)c3)c2c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(F)cc1C(C)(C)C[C@@](O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)OCc2ccccc2)c1)C(F)(F)F
Reaction time: 0.25 h
Yield: 18.7 %

Procedure:
A mixture of (2R)-2-(aminomethyl)-1,1,1-trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-pentanol (54.7 mg, 0.177 mmol), phenylmethyl 3-(4-bromo-6-methyl-1H-indazol-1-yl)benzoate (65.3 mg, 0.155 mmol), tris(dibenzylideneacetone)dipalladium(0) (14.2 mg, 0.0155 mmol), racemic-BINAP (9.7 mg, 0.0155 mmol) and sodium tert-butoxide (20.9 mg, 0.217 mmol) in anhydrous toluene (0.9 mL) was heated in a microwave reactor at 120° C. (power set at 400 Watts, 30 seconds pre-stirring) for 15 min. The reaction mixture was filtered and the filtrate was partitioned between water and ethyl acetate (40 mL of each). The organic phase was separated, washed with brine, dried through a hydrophobic frit and evaporated and purified by mass directed autopreparation (System B). Product containing fractions were partitioned between dichloromethane and aqueous sodium bicarbonate. The aqueous layer was re-extracted with dichloromethane and the combined organic extracts were washed successively with water and brine, dried through a hydrophobic frit and evaporated in vacuo to give the title compound (18.8 mg).
Reaction SMILES: Cl.[NH2:2][C:3]1([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8][CH2:7][C:6](=[O:9])[NH:5][C:4]1=[O:10].[C:26]1(=O)[O:31][C:29](=[O:30])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.C([O-])(=O)C.[Na+]>C(O)(=O)C>[O:30]=[C:29]1[C:28]2[C:27](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:26](=[O:31])[N:2]1[C:3]1([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8][CH2:7][C:6](=[O:9])[NH:5][C:4]1=[O:10]
Reactant: NC1(CCCCNC(=O)OCc2ccccc2)CCC(=O)NC1=O
Reactant: O=C1OC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CCC(CCCCNC(=O)OCc2ccccc2)(N2C(=O)c3ccccc3C2=O)C(=O)N1
Temperature: 130 °C
Reaction time: 7 h

Procedure:
To a suspension of 4 (0.12 g, 0.324 mmol), phthalic anhydride (0.060 g, 0.401 mmol), and sodium acetate (0.037 g, 0.434 mmol) was added acetic acid (1.5 mL) and the resulting mixture was stirred at 130° C. After 7 h, the mixture was quenched with sodium bicarbonate and extracted with DCM. The organic layer was dried over MgSO4 and concentrated. Purification by preparative HPLC afforded 12. Rf=0.32 (95:5 DCM:MeOH). 1H NMR (400 MHz, CDCl3) δ 8.05-7.64 (m, 5H), 7.44-7.27 (m, 4H), 5.16-5.00 (m, 2H), 4.90 (m, 1H), 3.34-3.09 (m, 3H), 2.92-2.77 (m, 1H), 2.77-2.45 (m, 3H), 2.36-2.18 (m, 1H), 2.17-1.99 (m, 1H), 1.38 (d, J=6.8 Hz, 2H). MS (ESI) m/z calcd for C25H26N3O6 [M+H]+ 464.5, found 464.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[F:12])[NH:8][CH:7]=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]2=[O:19].C(=O)([O-])[O-].[K+].[K+].[CH2:26](I)[CH3:27]>CN(C)C=O>[CH2:26]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([F:12])[C:10]=2[F:13])[C:5](=[O:19])[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7]1)[CH3:27]
Reactant: CCI
Reactant: CCOC(=O)c1c[nH]c2c(F)c(F)c(F)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2c(F)c(F)c(F)cc2c1=O

Procedure:
A 49.1 g portion of 6,7,8-trifluoro-1,4-dihydro-oxo-3-quinolinecarboxylic acid, ethyl ester was reacted with 85 g of potassium carbonate, 266 g of ethyl iodide and 600 ml of dimethylformamide, giving 1-ethyl-1,4-dihydro-6,7,8-trifluoro-4-oxo-3-quinolinecarboxylic acid, ethyl ester.
Reaction SMILES: [CH:1]([C:4]1[S:8][C:7]([N:9](COCC[Si](C)(C)C)[S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[S:25][C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)=[N:23][C:22]=3[CH3:36])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[N:6][N:5]=1)([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[CH:1]([C:4]1[S:8][C:7]([NH:9][S:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]3[S:25][C:24]([C:26]4[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:31]=4)=[N:23][C:22]=3[CH3:36])=[CH:17][CH:18]=2)(=[O:12])=[O:11])=[N:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(S(=O)(=O)N(COCC[Si](C)(C)C)c2nnc(C(C)C)s2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(S(=O)(=O)Nc2nnc(C(C)C)s2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 24.7 %

Procedure:
160 mg of N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-4-[4-methyl-2-(4-trifluoromethylphenyl)-thiazol-5-ylmethoxy]-N-(2-trimethylsilanyl-ethoxymethyl)-benzenesulfonamide were dissolved in 3.8 ml tetrahydrofuran. 977 mg tetra-N-butylammoniumfluoride were added and the reaction mixture was stirred at room temperature for two hours and at 40° C. for twenty minutes. The solvent was removed in vacuo and the residue purified by RP-HPLC to obtain 32 mg N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzenesulfonamide as amorphous solid.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9](/[CH:40]=[CH:41]/[C:42]2C=C[C:45](OC)=[CH:44][CH:43]=2)=[N:8]1.O1[CH2:55][CH2:54][O:53][CH2:52]C1>Cl>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3/[CH:40]=[CH:41]/[C:42]2[CH:55]=[C:54]([O:53][CH3:52])[CH:45]=[CH:44][CH:43]=2)=[N:17]1
Reactant: COc1ccc(/C=C/c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)cc1
Reactant: C1COCCO1
Agent: Cl
Product: COc1cccc(/C=C/c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Yield: 17.4 %

Procedure:
Hydrolysis was performed by stirring 1-((1E)-2-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}vinyl-4-methoxybenzene in 4 mL of 4.0 N commercial solution of HCl in dioxane and 2 mL of 6.0 N aqueous HCl at room temperature for 6.5 hours. A mixture of 2 isomers was isolated after purification by preparative HPLC (3% of the minor isomer) (0.014 g, 17.4% yield) 1H NMR (DMSO-d6) δ 8.8 (s, 1H), 8.55 (s, 1H), 8.15 (d, 1H), 7.7 (t, 3H), 7.5 (d. 2H), 7.0 (d, 2H), 3.8 (s, 3H); ES-MS (m/z) 318 [M+1]+.
Reaction SMILES: [C:1]([NH:4][N:5]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].[CH3:24]I.[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([N:4]([CH3:24])[N:5]([C:13]1[CH:14]=[CH:15][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:18]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)c1ccc(N(NC(C)=O)C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N(C(=O)OC(C)(C)C)N(C)C(C)=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl 2-acetyl-1-[4-(ethoxycarbonyl)phenyl]hydrazinecarboxylate (606 mg) was dissolved in DMF (10 ml), and methyl iodide (0.14 ml) and then sodium hydride (60%, 83 mg) were added at 0° C. The mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, and washed with water and then saturated brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1 (volume ratio)→1:1 (volume ratio)), and further recrystallized from ethyl acetate-hexane to give the title compound (608 mg) as colorless crystals.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][S:7][C@H:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]1=[O:22].Br[CH:24]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:25]([O:27][CH2:28][CH3:29])=[O:26].C1C=CC=CC=1>C(OCC)(=O)C>[C:41]([O:40][C:38]([NH:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][C@@H:24]([NH:1][C@H:2]1[CH2:8][S:7][C@H:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:3]1=[O:22])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:39])([CH3:44])([CH3:43])[CH3:42]
Reactant: CCOC(=O)C(Br)CCCCCCCNC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CN1C[C@@H](c2cccs2)SC[C@H](N)C1=O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)[C@@H](CCCCCCCNC(=O)OC(C)(C)C)N[C@H]1CS[C@H](c2cccs2)CN(CC(=O)OC(C)(C)C)C1=O
Yield: 9.7 %

Procedure:
1.3 g of t-butyl α-[6(R)-amino-5-oxo-2(S)-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate was treated with 1.73 g of ethyl 2-bromo-9-t-butoxycarbonylaminononanoate prepared as described in Preparation 4) in a similar manner to that described in Example 4. The product was then subjected to column chromatography through silica gel using a mixture of benzene and ethyl acetate in the ratio 5:1 by volume as the eluent. 237 mg of t-butyl α-{6(R)-[8-t-butoxycarbonylamino-1(R)-ethoxycarbonyloctylamino]-5-oxo-2(S)-(2-thienyl)perhydro-1,4-thiazepin-4-yl}acetate was obtained as a syrup from the fractions eluted first.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([C:18](=[O:32])[NH:19][C:20]3([C:29]([OH:31])=[O:30])[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:33]>O1CCOCC1.O1CCOCC1.O>[ClH:33].[CH2:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][C:11]=2[C:18]([NH:19][C:20]2([C:29]([OH:31])=[O:30])[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)=[O:32])[CH2:16][CH2:17][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(C(=O)NC3(C(=O)O)Cc4ccccc4C3)c2C1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1cccc2c1CNCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of 8-(2-carboxy-indan-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (226) (128 mg, 0.29 mmol) in 6 ml dioxane is added dropwise 4N solution of HCl in dioxane/water (0.72 mL) and the resulting solution is stirred at RT for 4 h. The concentration gave an HCl salt of (219) as white solid (246 mg, 100%).