Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][C@@:3]12[CH2:11][NH:10][CH2:9][C@@H:8]1[C:7]1[CH:12]=[CH:13][CH:14]=[C:15](/[CH:16]=[CH:17]\[CH3:18])[C:6]=1[CH2:5][CH2:4]2.C(O)(=O)C>CCO.[Pd]>[ClH:1].[CH3:2][C@@:3]12[CH2:11][NH:10][CH2:9][C@@H:8]1[C:7]1[CH:12]=[CH:13][CH:14]=[C:15]([CH2:16][CH2:17][CH3:18])[C:6]=1[CH2:5][CH2:4]2
Reactant: C/C=C\c1cccc2c1CC[C@]1(C)CNC[C@H]21
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CCCc1cccc2c1CC[C@]1(C)CNC[C@H]21
Reaction time: 72 h
Yield: 28.9 %

Procedure:
cis-3a-Methyl-6-((Z)-prop-1-enyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole hydrochloride (0.352 mmol, 80 mg) was dissolved in EtOH (2 ml) and palladium (5% on carbon) (0.035 mmol, 3.74 mg) was added. The resulting suspension was stirred under an atmosphere of hydrogen (balloon) for 72 h. Acetic acid (1 ml) and further palladium (5% on carbon) (0.035 mmol, 3.74 mg) was added and the reaction mixture left to stir for further 2 hours and then filtered through dicalite. The filtrate was concentrated in vacuo and the resulting crude residue was passed through an SCX cartridge and then purified by silica column chromatography (eluting with DCM—16% (2 N NH3 in MeOH)/DCM)). The pure fractions were concentrated in vacuo and then dissolved in DCM (1 ml) and 2N HCl in ether added. The resulting solution was concentrated in vacuo to afford cis-3a-methyl-6-propyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole hydrochloride 27 mg. m/z: 230.1 [M+H]+.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.O>ClCCCl>[O:2]=[CH:3][CH2:4][N:5]1[C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1cccc2nc(-c3ccccc3)n(CC(OC)OC)c12
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)c1cccc2nc(-c3ccccc3)n(CC=O)c12
Yield: 85.1 %

Procedure:
Methyl 1-(2,2-dimethoxyethyl)-2-phenyl-1H-benzo[d]imidazole-7-carboxylate (719 mg, 2.1 mmol) from Step A above was heated to reflux in 1:1 trifluoroacetic acetic acid/water (6 mL) and 1,2-dichloroethane (2 mL) for 2 h. The reaction mixture was concentrated, diluted with ethyl acetate, and pH adjusted to 8 with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with additional ethyl acetate and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 1-(2-oxoethyl)-2-phenyl-1H-benzo[d]imidazole-7-carboxylate as a light pink solid (526 mg, 85%): 1H NMR (500 MHz, CDCl3) δ 9.80 (s, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.63 (d, J=8.0 Hz, 2H), 7.54-7.50 (m, 3H), 7.37 (d, J=7.5 Hz, 1H), 5.26 (s, 2H), 3.92 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH3:23])[CH2:3][N:4]1[C:16]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N+:9]([O-])=[CH:8][C:7]=2[N:6]=[C:5]1[NH:18][C:19](=[O:22])[O:20][CH3:21].[OH-].[NH4+:25].C1(S(Cl)(=O)=O)C=CC=CC=1>CO>[NH2:25][C:8]1[C:7]2[N:6]=[C:5]([NH:18][C:19](=[O:22])[O:20][CH3:21])[N:4]([CH2:3][CH:2]([CH3:23])[CH3:1])[C:16]=2[C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: COC(=O)Nc1nc2c[n+]([O-])c3cccnc3c2n1CC(C)C
Reactant: [NH4+]
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [OH-]
Solvent: CO
Product: COC(=O)Nc1nc2c(N)nc3cccnc3c2n1CC(C)C
Temperature: 50 °C
Yield: 29.7 %

Procedure:
A suspension of methyl [1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]carbamate (0.9 g, 3 mmol) in methanol (25 mL) was stirred vigorously and heated to 50° C. Concentrated ammonium hydroxide (0.95 mL, 14 mmol) was added followed by benzenesulfonyl chloride (1.06 g, 5.99 mmol), which was added dropwise. The mixture was stirred for two hours at 50° C. An analysis by LC/MS indicated the reaction was incomplete. Additional benzenesulfonyl chloride (1.06 g) and concentrated ammonium hydroxide (0.95 mL) were added, and the reaction mixture was stirred overnight at 45° C. The solvent was removed under reduced pressure, and the residue dissolved in chloroform (100 mL). The solution was washed sequentially with aqueous sodium carbonate (2×100 mL of 4% w/w) and water (100 mL) and then purified by automated flash chromatography (40+M silica cartridge, eluting with 5% to 25% CMA in chloroform) followed by recrystallization from ethyl acetate to provide 0.28 g of methyl [4-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]carbamate as a yellow solid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4]1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25](O)=[O:26])=[CH:19]2.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25]([NH:2][C@@H:3]1[C:9](=[O:10])[NH:8][C:7]3[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=3[O:5][CH2:4]1)=[O:26])=[CH:19]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: N[C@H]1COc2ccccc2NC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(N[C@H]1COc2ccccc2NC1=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
Alternatively, to a mixture of (S)-3-amino-2,3-dihydro-1,5-benzoxazepin-4(5H)-one hydrochloride salt (54 mg) (prepared in Itoh, et al., Chem. Pharm. Bull. 1986, 34, 1128–1147), tetrahydrofuran (10 mL), 5-chloroindole-2-carboxylic acid (39 mg), 1-hydroxy-7-azabenzotriazole (31 mg), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (57 mg) stirring at room temperature under argon was added diisopropylethylamine (65 mg). The resulting yellow suspension was stirred for 30 min, during which a solution formed. After evaporation under vacuum, the residue was redissolved in ethyl acetate (50 mL) and the resulting solution was washed sequentially with 1.0 M aqueous hydrochloric acid (25 mL), 1.0 M aqueous sodium hydroxide (25 mL), water (25 mL) and brine (25 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum. The resulting solid crude product was triturated with diethyl ether (20 mL three times), followed by drying under vacuum to provide the title compound (63 mg).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:30])[CH:20]=[C:21]([C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH:31]1([NH2:34])[CH2:33][CH2:32]1>>[Cl:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([Cl:28])[C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:34][CH:31]3[CH2:33][CH2:32]3)[CH2:17][C:16]=2[CH:18]=[C:19]([F:30])[CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4c(Cl)cccc4Cl)c3O2)cc1
Reactant: NC1CC1
Product: Fc1cc2c(c(-c3c(Cl)cccc3Cl)c1)OC(CNC1CC1)C2

Procedure:
The title compound was prepared (0.035 g, 30%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-fluoro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.14 g, 0.30 mmol) and cyclopropylamine (0.17 g, 3.0 mmol). mp 112-113° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][C:12]([CH3:17])([CH3:16])[C:13](=[O:15])[CH3:14].[N:18]([CH:21]1[CH:28]2[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:30][CH:22]1[CH2:23]3)[CH2:27]2)=[C:19]=[O:20].Cl.C12CC3CC(CC(C3)C1N)C2.[NH4+].[Cl-]>C1COCC1>[CH:28]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:30][CH:22]([CH2:23]3)[CH:21]1[NH:18][C:19](=[O:20])[CH2:14][C:13](=[O:15])[C:12]([CH3:17])([CH3:16])[CH3:11])[CH2:27]2
Reactant: CC(=O)C(C)(C)C
Reactant: O=C=NC1C2CC3CC(C2)CC1C3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: NC1C2CC3CC(C2)CC1C3
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)CC(=O)NC1C2CC3CC(C2)CC1C3
Temperature: -78 °C
Yield: 81 %

Procedure:
A 1M solution of solution of lithium bis(trimethylsilyl)amide in THF (22.84 ml, 22.84 mmol) was added to THF (25 mL) and cooled under nitrogen to −78° C. A solution of 3,3-dimethyl-2-butanone (2.287 g, 22.84 mmol) in THF (25 mL) was added drop wise over a period of 5 minutes. The resulting solution was stirred at −78° C. under nitrogen for minutes. A solution of 2-isocyanatoadamantane (prepared from 2-adamantylamine hydrochloride by the method of R. Reck & C. Jochims Chem. Ber. 115 (1982) p 864) (3.68 g, 20.76 mmol) in THF (20 mL) was added over a period of 5 minutes. The resulting solution was stirred at −78° C. for 1 hour and then allowed to warm to 20° C. over 1 h. The reaction mixture was poured into saturated NH4Cl (150 mL) and extracted with EtOAc (2×100 mL), the organic layer was washed with water (50 mL) and brine (50 mL) dried over MgSO4, filtered and evaporated to afford a yellow oil. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford N-(2-adamantyl)-4,4-dimethyl-3-oxo-pentanamide (4.64 g, 81%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:6]([N:12]=1)=[N:7][CH:8]=[CH:9][C:10]=2[CH3:11])[CH3:2].C(O)(=[O:16])CC.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[NH:4][C:5]2[C:6]([N:12]=1)=[N+:7]([O-:16])[CH:8]=[CH:9][C:10]=2[CH3:11])[CH3:2]
Reactant: CCC(=O)O
Reactant: CCc1nc2nccc(C)c2[nH]1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCc1nc2c([nH]1)c(C)cc[n+]2[O-]

Procedure:
A solution of 28 g (174 mmol) of 2-ethyl-7-methylimidazo[4,5-b]pyridine prepared according to Example 1, Steps A and B, but substituting propionic acid in place of butyric acid in Step B (described in European Patent Application No. 400,974, May 12, 1990) and m-chloroperbenzoic acid (80-90%, 44.6 g) in CHCl3 (300 mL) was heated at reflux for 0.5 hours. The mixture was concentrated and purified (SiO2, 100% CH2Cl2 gradient to 30% CH2Cl2 /MeOH) to give 29.8 g of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.C(N(CC)CC)C.[CH:19]1(B(O)O)[CH2:21][CH2:20]1>C(Cl)Cl.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][N:8]([CH:19]3[CH2:21][CH2:20]3)[C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: OB(O)C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Clc1nc(Cl)c2ccn(C3CC3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.4 %

Procedure:
A mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (210 mg, 1.12 mmol) in methylene chloride (4.86 mL) was treated with triethylamine (314 μL, 2.26 mmol), copper(II) acetate monohydrate (232 mg, 1.16 mmol) and cyclopropylboronic acid (95.9 mg, 1.12 mmol). The reaction was stirred at room temperature overnight. At this time, the reaction was warmed to 70° C. for 3 h. At this time, the reaction was treated with additional triethylamine (314 μL, 2.26 mmol), copper(II) acetate monohydrate (232 mg, 1.16 mmol) and cyclopropylboronic acid (95.9 mg, 1.12 mmol). The reaction was allowed to stir overnight at room temperature. At this time, the reaction was filtered through a plug of Celite®, washing with a 10% methanol/methylene chloride solution. The filtrate was concentrated in vacuo onto silica gel. Flash chromatography (24 g silica gel column, 2-20% ethyl acetate/hexanes) afforded 2,4-dichloro-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine as an off-white solid (70 mg, 27.5%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.82-1.28 (m, 4H) 3.62 (s, 1H) 6.66 (d, J=3.58 Hz, 1H) 7.73 (d, J=3.39 Hz, 1H). LC-MS calcd. for C9H8Cl2N3 [(M+H)+] 228, obsd. 227.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:32])[C:5]([CH3:31])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:27]C(=O)C)=[C:17]([CH:26]=2)[C:18]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:32])[C:5]([CH3:31])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:27])=[C:17]([CH:26]=2)[C:18]([N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)N3CCCCC3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)N3CCCCC3)c2)=C(C)C1=O
Yield: 69.1 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]piperidine (0.040 g, 0.0906 mmol) was dissolved in methanol (2 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.025 g, 0.0626 mmol, 69%).
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1)C.C(O)C.[OH-].[Na+]>O>[Br:21][C:17]1[CH:16]=[C:15]([C:7]2[N:6]([CH2:5][C:4]([OH:22])=[O:3])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)Cn1c(-c2cccc(Br)c2)nc2cccnc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cn1c(-c2cccc(Br)c2)nc2cccnc21
Yield: 88.3 %

Procedure:
A solution of 2-(3-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid ethyl ester (4.8 g, 0.0133 mole), 95% ethanol (50 ml), sodium hydroxide pellets (0.6 g, 0.014 mole), and water (5 ml) was refluxed for 2 hrs. The ethanol was evaporated and water (50 ml) added. Glacial acetic acid was added dropwise until precipitation began (pH neutral). The precipitated solid was collected by filtration and recrystallized from ethanol-tetrahydrofuran, giving 3.9 g (88% yield) of white needles, mp 247°-249° C.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[C:7]([O:17][CH3:18])[CH:8]=[C:9]([C:12]([O:14]CC)=[O:13])[CH:10]=2)[N:5]([CH3:19])[N:4]=1)[CH3:2].[Li+].[OH-]>C1COCC1>[CH2:1]([C:3]1[C:11]2[C:6](=[C:7]([O:17][CH3:18])[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[N:5]([CH3:19])[N:4]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(OC)c2c(c1)c(CC)nn2C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nn(C)c2c(OC)cc(C(=O)O)cc12
Temperature: 25 °C
Yield: 98.2 %

Procedure:
To a solution of ethyl 3-ethyl-7-methoxy-1-methyl-1H-indazole-5-carboxylate (52 mg, 0.20 mmol) in THF (1.5 mL) was added 1 M LiOH (0.36 mL, 0.36 mmol). The mixture was heated at reflux overnight. The reaction was cooled to room temperature, concentrated, triturated with 1 N HCl, the filtered solids were then washed with water and air dried to provide the title compound (46 mg, 94%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.Br[C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([C:34]3[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=3)[CH2:17][CH2:18]1)=[N:7]2
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Reactant: Brc1cccnc1
Solvent: Cc1ccccc1
Product: Cc1c(N2CCN(c3cccnc3)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Essentially prepared according to Procedure H using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (50.0 mg, 0.11 mmol) and 3-bromopyridine in toluene to give 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(4-(pyridin-3-yl)piperazin-1-yl)quinolin-4-amine. 1H NMR (CDCl3) δ ppm 8.53 (1H, d, J=2.9 Hz), 8.11 (1H, d, J=4.3 Hz), 7.89 (1H, d, J=2.2 Hz), 7.72-7.80 (2H, m), 7.63-7.71 (1H, m), 7.53 (1H, d, J=8.4 Hz), 7.41 (1H, dd, J=9.6, 1.4 Hz), 7.12 (1H, t, J=2.2 Hz), 6.86 (1H, ddd, J=13.3, 8.5, 2.4 Hz), 3.85-3.94 (4H, m), 3.70-3.80 (4H, m), 3.52-3.61 (4H, m), 3.24-3.36 (4H, m), 2.22 (3H, s). Mass Spectrum (ESI) m/e=518.2 (M+1).
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH2:22][OH:23].N1C=CC=CC=1.Cl>C(Cl)CCl>[CH2:26]([O:25][C:21](=[O:24])[CH2:22][O:23][C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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)[CH3:27]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CO
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CCOC(=O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 40 °C
Reaction time: 19 h

Procedure:
Trityl chloride (279 g, 1.0 mol) was dissolved in EDC (680 ml, 5 ml/g with respect to ethyl glycolate), and ethyl glycolate (135 g, 1.3 mol) was added to the mixture. Pyridine (99 g, 1.25 mol) was added thereto, and the mixture was stirred for 19 hours at 40° C. After completion of the reaction was confirmed by HPLC, 0.5 N aqueous hydrochloric acid solution (270 ml, 2 ml/g with respect to ethyl glycolate) was added to make the reaction solution a two-phase solution, which was then extracted. After the extraction was performed once again, EDC was distilled under reduced pressure. In order to obtain the compound of formula (8) as a solid form, hexane (680 ml) was added to the concentrated compound, the temperature was lowered to 0° C., and the mixture was stirred for about 3 hours and filtered.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30](O)=[O:31])=[CH:20][C:19]=3[CH:33]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.S(Cl)(Cl)=O.[CH3:43][C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][C:50]=1[S:51][CH2:52][C:53]1[N:57]([CH2:58][CH2:59][CH3:60])[CH:56]=[N:55][C:54]=1[CH3:61])[NH2:47]>O1CCCC1.N1C=CC=CC=1.O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:47][C:46]4[CH:48]=[CH:49][C:50]([S:51][CH2:52][C:53]5[N:57]([CH2:58][CH2:59][CH3:60])[CH:56]=[N:55][C:54]=5[CH3:61])=[C:44]([CH3:43])[CH:45]=4)=[O:31])=[CH:20][C:19]=3[CH:33]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCn1cnc(C)c1CSc1ccc(N)cc1C
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCCN3CC(C)C)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4c(C)ncn4CCC)c(C)c2)CCCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 63.9 %

Procedure:
To a solution of 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylic acid (350 mg) in tetrahydrofuran (10 ml) was added a drop of DMF. Then, after adding thionyl chloride (0.073 ml), the mixture was stirred under nitrogen atmosphere for 1 hour. The solution was slowly added dropwise to a solution of 3-methyl-4-[((4-methyl-1-propylimidazol-5-yl)methyl)sulfanyl]aniline (235 mg) in pyridine (10 ml) at 0° C. under nitrogen atmosphere. After stirring the mixture at room temperature under nitrogen atmosphere overnight, water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by basic silica gel column chromatography (hexane:ethyl acetate=1:1→ethyl acetate) to give 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[[[4-methyl-1-propylimidazol-5-yl]methyl]sulfanyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (351 mg) as a yellow amorphous material (Compound 40).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:9](O)=[O:10])=[CH:4][CH:3]=1.O=S(Cl)[Cl:25]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:9]([Cl:25])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(Oc1cccc(C(F)(F)F)c1)c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: O=C(Cl)C(Oc1cccc(C(F)(F)F)c1)c1ccc(Cl)cc1
Temperature: 68 °C

Procedure:
A 2-L evaporation flask with magnetic stirrer, Claissen adapter, pot thermometer and a reflux condenser routed to a gas scrubber was charged with (−)4-chlorophenyl-(3-trifluoromethylphenoxy)-acetic acid (143 g, 0.42 mole based on 97% purity) and CHCl3 (170 ml) and heated to boiling in order to dissolve. SOCl2 (38 ml, 62.1 gm, 0.52 mole) was added. The mixture was heated to reflux (68° C. final) for 4.5 hours and then stripped of volatiles to obtain 151 g yellow, turbid liquid (103% apparent yield). The material was used in the next step without further purification.
Reaction SMILES: [Na+].[F:2][C:3]([F:25])([F:24])[C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][C:15]3[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:17]([O-:19])=[O:18])=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1.Cl[CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][O:31][C:30]1=[O:34]>CN(C)C=O>[O:34]=[C:30]1[N:29]([CH2:28][CH2:27][O:18][C:17](=[O:19])[C:16]2[C:15](=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:14][C:8]2[C:7]3[C:12](=[CH:13][C:4]([C:3]([F:24])([F:2])[F:25])=[CH:5][CH:6]=3)[N:11]=[CH:10][CH:9]=2)[CH2:33][CH2:32][O:31]1
Reactant: O=C1OCCN1CCCl
Reactant: O=C([O-])c1ccccc1Nc1ccnc2cc(C(F)(F)F)ccc12
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCCN1CCOC1=O)c1ccccc1Nc1ccnc2cc(C(F)(F)F)ccc12
Temperature: 120 °C
Reaction time: 5 h
Yield: 65.2 %

Procedure:
A mixture comprising 10.62 g of N-(7-trifluoromethyl-4-quinolyl)-anthranilic acid sodium salt, 4.98 g of 90% 3-(β-chloroethyl)-oxazolidin-2-one and 60 ml of dimethylformamide was heated under stirring at 120° C. for five hours. Upon completion of the reaction, the mixture was cooled, insoluble sodium chloride was filtered off, and the solvent was evaporated off in vacuo. The residue was treated with 200 ml of water and the solid, collected by filtration, crystallized from methylene dichloride: petroleum ether. 8.7 g of N-(7-trifluoromethyl-4-quinolyl)-anthranilic acid β-(2-oxo-3-oxazolidinyl)-ethyl ester, melting at 124°-125° C., were obtained.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8](I)[CH:7]=[CH:6][C:5]=2[F:11])[CH2:3][CH2:2]1.[C:12]([C:16]1[CH:29]=[CH:28][C:19]([CH2:20][N:21]2[CH2:25][CH2:24]OS2(=O)=O)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([CH2:20][NH:21][CH2:25][CH2:24][C:8]2[CH:7]=[CH:6][C:5]([F:11])=[C:4]([CH:1]3[CH2:3][CH2:2]3)[CH:9]=2)=[CH:28][CH:29]=1)([CH3:14])([CH3:13])[CH3:15]
Reactant: CC(C)(C)c1ccc(CN2CCOS2(=O)=O)cc1
Reactant: Fc1ccc(I)cc1C1CC1
Product: CC(C)(C)c1ccc(CNCCc2ccc(F)c(C3CC3)c2)cc1
Yield: 28.3 %

Procedure:
The title compound was synthesized in analogy to example S6-C using 2-cyclopropyl-1-fluoro-4-iodobenzene (100 mg, 0.38 mmol) and 3-(4-tert-butylbenzyl)-[1,2,3]oxathiazolidine 2,2-dioxide (103 mg, 0.38 mmol). The residue was purified by flash column chromatography to give the desired product (35 mg, 28%) as a colorless oil. MS (ISP) 326.3 (M+H)+.